Clinical trial NCT04049617
Conditions: Advanced Solid Tumors
Sponsor: Gilead Sciences
Start date: 2019-08-26; Completion date: 2021-03-30
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objectives of this study are to characterize the safety and tolerability of evixapodlin (formerly GS-4224) and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of evixapodlin in participants with advanced solid tumors.

Detailed description:
This was a planned Phase 1/2 study. However, Phase 2 was not conducted because the study was closed due to sponsor decision prior to opening the dose expansion cohort and hence, RP2D analysis was not performed.

Arms: arm 1: Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle. arm 2: Participants will receive Evixapodlin 700 mg once daily for 21 days of each cycle. arm 3: Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle. arm 4: Participants will receive Evixapodlin 1500 mg once daily for 21 days of each cycle. arm 5: Participants are planned to receive Evixapodlin 1000 mg twice daily (BID) for 21 days of each cycle. arm 6: Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle. arm 7: Participants are planned to receive Evixapodlin 700 mg once daily for 21 days of each cycle. arm 8: Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle. arm 9: Dose expansion is planned to begin when the recommended Phase 2 dose (RP2D) will be determined.
Interventions: intervention 1: Evixapodlin
Intervention descriptions: intervention 1: Tablets administered orally.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
A Phase 1b/2 Dose Escalation/Expansion Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in 
Subjects with Advanced Solid Tumors 
Sponsor:
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
143047 
2019-004605-27
NCT04049617
Indication:
Advanced Solid Tumors 
Protocol ID:
GS-US-494-5484
Contact Information:
The medical monitor name and contact information will be 
provided on the Key Study Team Contact List.
Protocol 
Version/Date:
Original:
10 May 2019
Amendment 1: 
07 June 2019
Amendment 2:
12 August 2019
Amendment 3:
04 May 2020
Amendment 4:
07 August 2020
Amendment 5:
02 October 2020
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 and Switzerland are not included under the IND and are considered 
non-IND sites.
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.
(rJ GILEAiJ 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................................................. 2 
LIST OF IN-TEXTTABLES ........................................................................................................................................ 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................................... 5 
PROTOCOL SYNOPSIS .............................................................................................................................................. 6 
GLOSSARY OF ABBREVIATIONS AN D DEFINITION OF TERMS .................................................................... 24 
I. 
INTRODUCTION .............................................................................................................................................. 29 
1.1. 
Background ............................................................................................................................................ 29 
1.2. 
GS-4224 ................................................................................................................................................. 29 
1.2.1. 
General Information ............................................................................................................. 29 
1.2.2. 
Preclinical Pharmacology and Toxicology ........................................................................... 29 
1.2.3. 
Clinical Trials ofGS-4224 ................................................................................................... 3 1 
1.3. 
Rationale for this Study .......................................................................................................................... 3 1 
1.4. 
Rationale for the Dose Selection ............................................................................................................ 3 1 
1.5. 
Risk/Benefit Assessment for the Study .................................................................................................. 33 
1.6. 
Compliance ............................................................................................................................................ 33 
2. 
OBJECTIVES ..................................................................................................................................................... 34 
3. 
STUDY DESIGN ................................................................................................................................................ 35 
3.1. 
3.2. 
3.3. 
3.4. 
3.5. 
3.6. 
3.7. 
Endpoints ............................................................................................................................................... 35 
Study Design .......................................................................................................................................... 36 
3 .2.1. 
Dose Escalation (Phase I b) .................................................................................................. 36 
3 .2.2. 
Dose Expansion (Phase 2) .................................................................................................... 40 
3.2.3. 
Safety Review Team ............................................................................................................ 40 
Study Treatments ................................................................................................................................... 40 
Duration of Treatment ............................................................................................................................ 4 1 
Study Discontinuation Criteria ............................................................................................................... 4 1 
Poststudy Care ........................................................................................................................................ 4 1 
Source Data ............................................................................................................................................ 4 1 
4. 
SUBJECT POPULATION .................................................................................................................................. 44 
4.1. 
Number of Subjects and Subject Selection ............................................................................................ 44 
4.1.1. 
Target Population ................................................................................................................. 44 
4.1.2. 
Subject Replacement ............................................................................................................ 44 
4.2. 
Inclusion Criteria .................................................................................................................................... 45 
4.3. 
Exclusion Criteria ................................................................................................................................... 46 
5. 
INVESTIGATIONAL MEDICINAL PRODUCTS ........................................................................................... 49 
5.1. 
Randomization, Blinding and Treatment Codes .................................................................................... 49 
5.2. 
Description and Handt ing of GS-4224 ................................................................................................... 49 
5.2.1. 
Formulation .......................................................................................................................... 49 
5.2.2. 
Packaging and Labeling ....................................................................................................... 49 
5.2.3. 
Storage and Handling ........................................................................................................... 50 
CONFIDENTIAL 
Page 2 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 3
02 October 2020
5.3.
Dosage and Administration of GS-4224 ................................................................................................50
5.4.
Dose Modifications and Treatment Interruption of GS-4224.................................................................50
5.4.1.
Dose Modifications ..............................................................................................................50
5.4.2.
Treatment Interruption for GS-4224 ....................................................................................51
5.4.3.
Management of Immune-Related Adverse Events...............................................................51
5.4.4.
Dermatological irAEs...........................................................................................................52
5.4.5.
Gastrointestinal (GI) irAEs ..................................................................................................52
5.4.6.
Pulmonary irAEs..................................................................................................................53
5.4.7.
Hepatic irAEs .......................................................................................................................54
5.4.8.
Endocrine irAEs ...................................................................................................................55
5.4.9.
Renal irAEs ..........................................................................................................................56
5.4.10.
Neurological irAEs...............................................................................................................57
5.5.
Prior and Concomitant Medications.......................................................................................................58
5.5.1.
Concomitant Medications.....................................................................................................58
5.5.2.
Rescue Medications and Supportive Care............................................................................60
5.5.3.
Prohibited and/or Restricted Treatments ..............................................................................61
5.5.4.
Other Restrictions and Precautions ......................................................................................62
5.6.
Accountability........................................................................................................................................62
5.7.
Investigational Medicinal Product (IMP) Return or Disposal................................................................62
6.
STUDY PROCEDURES ....................................................................................................................................63
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................63
6.2.
Pretreatment Assessments......................................................................................................................63
6.2.1.
Screening Visit .....................................................................................................................63
6.2.2.
Re-screening Criteria............................................................................................................65
6.2.3.
Baseline Assessments and Medical History.........................................................................65
6.2.4.
Physical Examination Including Height and Weight............................................................66
6.2.5.
Vital Signs............................................................................................................................66
6.2.6.
Eastern Cooperative Oncology Group Performance (ECOG)..............................................66
6.2.7.
Electrocardiogram................................................................................................................66
6.2.8.
Prior and Concomitant Medications.....................................................................................67
6.2.9.
Clinical Laboratory Assessments .........................................................................................67
6.3.
Treatment Assessments..........................................................................................................................68
6.4.
Unscheduled Visits.................................................................................................................................68
6.5.
Pharmacokinetic, Pharmacodynamic, Genetic, and Other Assessments................................................69
6.5.1.
Pharmacokinetic Assessments..............................................................................................69
6.6.
Disease Assessments..............................................................................................................................71
6.6.1.
CT with Contrast or MRI Scan.............................................................................................71
6.6.2.
PET-CT ................................................................................................................................72
6.6.3.
Response Assessment...........................................................................................................72
6.7.
End of Study...........................................................................................................................................73
6.8.
Posttreatment Assessments ....................................................................................................................73
6.8.1.
End of Treatment Visits .......................................................................................................73
6.9.
Assessments for Premature Discontinuation from Study.......................................................................74
6.10.
Criteria for Discontinuation from Treatment or Study...........................................................................74
6.10.1.
Criteria for Discontinuation from Treatment........................................................................74
6.10.2.
Discontinuation from Disease Response Evaluation............................................................75
6.10.3.
Criteria for Discontinuation from Study...............................................................................75
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................76
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................76
7.1.1.
Adverse Events.....................................................................................................................76
7.1.2.
Serious Adverse Events........................................................................................................76
CCI-


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
7.1.3. 
Study Dtugs and Gilead Concomitant Therapy Special Situations Reports ......................... 77 
7.2. 
Assessment of Adverse Events and Serious Adverse Events ................................................................. 78 
7 .2.1. 
Assessment of Causality for Study Drugs and Procedures ................................................... 78 
7 .2.2. 
Assessment of Severity ........................................................................................................ 79 
7.3. 
Investigator Reporting Requirements and Instructions .......................................................................... 79 
7.3.1. 
Requirements for Collection Prior to Study Drug Initiation ................................................. 79 
7.3.2. 
Adverse Events ..................................................................................................................... 79 
7.3.3. 
Serious Adverse Events ........................................................................................................ 80 
7.3.4. 
Study Dtug Special Situations Reports ................................................................................ 80 
7.3.5. 
Concomitant Therapy Reports .............................................................................................. 80 
7.4. 
Reporting Process for Serious Adverse Events and Special Situation Reports ...................................... 8 I 
7.4.1. 
Serious Adverse Event Reporting Process ........................................................................... 81 
7.4.2. 
Special Situations Reporting Process ................................................................................... 82 
7.5. 
Gilead Reporting Requirements ............................................................................................................. 83 
7.5.1. 
Clinical Laboratory Abnormalities and Other Abnormal Assessmentsas 
Adverse Events or Serious Adverse Events ......................................................................... 84 
7 .6. 
Toxicity Management ............................................................................................................................ 84 
8. 
STA TIS TI CAL CONSIDERATIONS ................................................................................................................ 85 
9. 
8.1. 
8.2. 
8.3. 
8.4. 
8.5. 
8.6. 
8.7. 
I 
Analysis Objectives and Endpoints ........................................................................................................ 85 
8.1.1. 
Analysis Objectives .............................................................................................................. 85 
8.1.2. 
Primary Endpoint ................................................................................................................. 85 
8.1.3. 
Secondar End oint ............................................................................................................. 86 
P anned Ana yses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 
8.2.1. 
Interim Analysis ................................................................................................................... 87 
8.2.2. 
Final Analysis ....................................................................................................................... 87 
Analysis Conventions ............................................................................................................................. 87 
8.3. I. 
Analysis Sets ........................................................................................................................ 87 
Data Handling Conventions ................................................................................................................... 88 
Demographic Data and Baseline Characteristics ................................................................................... 89 
Efficacy Analysis ................................................................................................................................... 89 
Safety Analysis ....................................................................................................................................... 89 
8.7.1. 
Extent of Exposure ............................................................................................................... 90 
8.7.2. 
Adverse Events ..................................................................................................................... 90 
8.7.3. 
Laborator Evaluations ........................................................................................................ 9 1 
RESPONS lB lLITlES .......................................................................................................................................... 93 
9.1. 
Investigator Responsibilities .................................................................................................................. 93 
9.1.1. 
Good Clinical Practice .......................................................................................................... 93 
9 .1.2. 
Financial Disclosure ............................................................................................................. 93 
9.1.3. 
Institutional Review Board/Independent Ethics Committee Review and 
9.1.4. 
9.1.5. 
9.1.6. 
9.1.7. 
9.1.8. 
9.1.9. 
9.1. 10. 
A~row l ............................................................................................................................... 
Informed Consent ................................................................................................................. 93 
Confidentiality ...................................................................................................................... 94 
Study Files and Retention of Records .................................................................................. 94 
Case Report Forms ............................................................................................................... 95 
Investigational Medicinal Product Accountability and Return ............................................. 96 
Inspections ............................................................................................................................ 96 
Protocol Compliance ............................................................................................................ 96 
CONFIDENTIAL 
Page 4 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 5
02 October 2020
9.2.
Sponsor Responsibilities ........................................................................................................................96
9.2.1.
Protocol Modifications.........................................................................................................96
9.2.2.
Study Report and Publications .............................................................................................97
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................97
9.3.1.
Payment Reporting...............................................................................................................97
9.3.2.
Access to Information for Monitoring..................................................................................97
9.3.3.
Access to Information for Auditing or Inspections ..............................................................98
9.3.4.
Study Discontinuation..........................................................................................................98
10.
REFERENCES ...................................................................................................................................................99
11.
APPENDICES ..................................................................................................................................................100
Appendix 1.
Investigator Signature Page..................................................................................................101
Appendix 2.
Study Procedures Table........................................................................................................102
Appendix 3.
Tumor Specific Inclusion/Exclusion Criteria .......................................................................106
Appendix 4.
NCI-CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities .......................................................................................................................110
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements.................................................................................................111
Appendix 6.
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)................................114
Appendix 7.
Response Assessment for Classic Hodgkin Lymphoma (Lugano Classification)................118
Appendix 8.
Pandemic Risk Assessment and Mitigation Plan..................................................................122
LIST OF IN-TEXT TABLES
Table 1-1.
IND Nonclinical Safety Package............................................................................................30
Table 3-1.
Dose Escalation (Phase 1b) Dose Levels................................................................................37
Table 5-1.
Dermatological irAE Management Algorithm .......................................................................52
Table 5-2.
Gastrointestinal (GI) irAE Management Algorithm...............................................................53
Table 5-3.
Pulmonary irAE Management Algorithm ..............................................................................54
Table 5-4.
Hepatic irAE Management Algorithm....................................................................................55
Table 5-5.
Endocrine irAE Management Algorithm................................................................................56
Table 5-6.
Renal irAE Management Algorithm.......................................................................................57
Table 5-7.
Neurological irAE Management Algorithm ...........................................................................58
Table 5-8.
List of Agents Disallowed with GS-4224...............................................................................59
Table 6-1.
Analytes..................................................................................................................................68
LIST OF IN-TEXT FIGURES
Figure 3-1.
Phase 1b Study Design Schema..............................................................................................36


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 6
02 October 2020
PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
A Phase 1b/2 Dose Escalation/Expansion Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in 
Subjects with Advanced Solid Tumors
IND Number:
EudraCT Number:
Clinical Trials.gov 
Identifier:
143047 
2019-004605-27
NCT04049617
Study Centers 
Planned:
Approximately 35 centers in United States (US), Europe, and rest of 
world (ROW)
Objectives:
The primary objectives of this study are as follows:
Phase 1b Dose Escalation

Characterize the safety and tolerability of GS-4224 in subjects 
with advanced solid tumors

Determine the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) of GS-4224 in subjects with 
advanced solid tumors
The secondary objectives of this study are as follows: 
Phase 1b Dose Escalation

Evaluate the pharmacokinetics (PK) of GS-4224 in subjects with 
advanced solid tumors
Phase 2 Dose Expansion

Evaluate the safety and tolerability of GS-4224 in subjects with 
advanced solid tumors


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Study Design: 
CONFIDENTIAL 
Final 
Amendment 5 
This is an open-label, multicenter, sequential dose-escalation and 
dose expansion study to evaluate the safety, tolerability, PK, and 
efficacy of GS-4224 in subjects with advanced solid tumors. 
The study will consist of 2 parts: the dose escalation portion, 
followed by dose expansion in subjects with tumors for which 
programmed cell death protein 1 (PD-1 )/ligand 1 of progra1mned 
cell death protein 1 (PD-Ll) treatments are approved or are known 
to be active. 
Dose Escalation (Phase lb) 
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 oral GS-4224 as monotherapy once daily (400-1500 mg QD 
cohorts) and as monotherapy at 1000 mg twice daily (1000 mg BID 
cohort). 
Dose escalation will proceed using a standard 3+ 3 design. The 
starting dose is 400 mg QD, with subsequent doses of 700 mg QD, 
1000 mg QD, 1500 mg QD, and 1000 mg BID. Dose level increases 
will be 3-fold or less. 
Dose Level Schema 
GS-4224 (mg) 
Fold Increase 
400QD 
700QD 
1000 QD 
:S 3x 
1500 QD 
:S 3x 
1000 BID 
:S 3x 
Page 7 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 8
02 October 2020
In the 1000 mg BID dose cohort, at least 6 subjects (as part of the 
initial 3+3 design) and up to an additional 14 subjects (for a total of 
20 subjects) with locally advanced, inoperable or metastatic cancer 
expressing PD-L1 (tumor proportion score [TPS] ≥ 10% or
combined positive score [CPS] ≥ 10) and who have not previously 
been treated with anti-PD-1/L1 antibodies will be enrolled. The 
additional 14 subjects will not be enrolled at the 1000 mg BID dose 
level if the subject incidence of dose-limiting toxicity (DLTs) is > 1 
in the first 6 subjects. If the subject incidence of DLTs is > 1 in the 
first 6 subjects at 1000 mg BID, then 20 additional subjects with 
locally advanced, inoperable or metastatic cancer expressing PD-L1 
[TPS ≥ 10% or CPS ≥ 10] and who have not previously been treated 
with anti-PD-1/L1 antibodies will enroll at the MTD. Tumor types 
of interest include non-small cell lung cancer (NSCLC), melanoma, 
renal cell carcinoma (RCC), urothelial, esophageal, hepatocellular 
carcinoma (HCC), cutaneous squamous cell, Merkel cell, 
microsatellite instability-high (MSI-H) cancers, and classical 
Hodgkin lymphoma (cHL). See Appendix 3 for the PD-L1 
expression requirement for specific tumor types.
For the 1000 mg BID dose cohort, subjects must have available 
sufficient and adequate formalin-fixed tumor tissue sample 
preferably from a biopsy of a tumor lesion obtained either at the 
time of or after the diagnosis of advanced disease has been made 
and from a site not previously irradiated. Alternatively, subjects 
must agree to have a biopsy taken prior to entering the study to 
provide adequate tissue. Subjects with melanoma, Merkel cell, 
MSI-H cancers, and cHL are not required to have archival or fresh 
biopsy tissue.
The safety and tolerability of each dose level will be assessed by a 
safety review team (SRT) after up to 6 subjects enrolled in the dose 
level have been followed for at least 21 days after the first dose of 
GS-4224 or 2 DLTs have been observed, whichever is earlier. The 
SRT will consist of at least 1 investigator and the following Gilead 
study team members: the medical monitor, representatives from 
Global Patient Safety (GLPS), Clinical Operations, and 
Biostatistics. Others may be invited to participate as members of the 
SRT if additional expertise is desired. The SRT will review safety 
data and relevant clinical data and make the dose 
escalation/stay/de-escalation decision based on the 3+3 design dose 
escalation rules as follows.
The initial block of each dose consists of 3 subjects. Dose escalation 
may occur if no subjects experience DLT during the first 21 days of 
study drug dosing. If 1 subject within the initial cohort of 3 subjects 
experiences a DLT during the first 21 days of study drug dosing, an 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 9
02 October 2020
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 of the 6 subjects experience DLTs
within the first 21 days, dose de-escalation to an intermediate dose 
will occur. The MTD is the highest dose level with a subject 
incidence of DLTs during the first 21 days of study drug dosing of 
0 or 1 out of 6. 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 is withdrawn from the study before the completion of the first 
21 days for a reason other than a DLT will be replaced.
If 2 or more delayed DLT-type adverse events (AEs) are noted after 
the first 21-day observation period within a dose escalation cohort, 
further accrual at all sites will be held pending safety analysis of the 
event, and will be restarted only with investigator and sponsor 
approval.
DLT Definition
A DLT is any toxicity defined below excluding toxicities clearly 
related to disease progression or disease-related processes occurring 
during the DLT assessment window (Day 1 through Day 21):

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] 
< 500/mm3)

Grade ≥ 3 neutropenia (ANC < 1000/mm3) with fever (a single 
temperature of > 38.3°C or a sustained temperature of ≥38°C 
for more than 1 hour)

Grade ≥ 3 thrombocytopenia 

Grade ≥ 2 bleeding (eg, gastrointestinal [GI], respiratory, 
epistaxis, or purpura)

Grade ≥3 anemia

Grade ≥ 3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 
48 hours on adequate medical therapy
Grade 3 diarrhea which persists for < 72 hours in the 
absence of maximal medical therapy. 

Grade ≥ 2 non-hematologic 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


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 5 
• 
Continuous treatment interruption of~ 7 days due to m1resolved 
toxicity 
• 
Any toxicity event that precludes further administration of 
GS-4224 
• 
Any Grade 3 or Grade 4 elevation in aspartate aminotransferase 
(AST) or alanine transaminase (ALT) associated with a Grade 2 
elevation in bilirubin lasting~ 7 days 
• 
An immm1e-related adverse event (irAE, defined as AEs of 
unknown etiology that were consistent with an immune 
phenomenon primarily involving the GI tract and the skin, and 
were considered causally related to drug exposure by 
investigators) for which i1mnunotherapy should be pennanently 
discontinued ( eg, any grade encephalitis, Grade 3 myocarditis, 
reoccurrence of the same Grade 3 adverse reaction). 
For certain toxicities, such as laboratory assessments without a clear 
clinical correlate, a discussion between the investigator and medical 
monitor may take place to detennine if this AE should be assessed 
as aDLT. 
Excluded from this definition: 
• 
Grade 3 AEs of tumor flare ( defined as local pain, irritation, or 
rash localized at sites of known or suspected tumor) 
• 
Grade 3 rash without systemic signs or symptoms 
• 
Grade 3 irAE that resolves to a Grade 1 or less within 21 days 
except as described above. 
The RP2D will be detennined by Gileadin discussion with SRT 
based on all relevant clinical data from all subjects treated in the 
escalation phase. The RP2D will not exceed the MTD and will 
consider toxicities through 90 days of dosing. 
Page 10 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Dose Expansion (Phase 2) 
Final 
Amendment 5 
Dose expansion may begin when the RP2D has been detennined. 
The dose expansion part includes the following cohort: 
Cohort Bl (Basket Cohort expressing PD-LI [TPS 1% or CPS 
I or~ I OJ or MSI-H cancers, single arm, open label study of GS-
4224) 
To further characterize the safety and preliminary efficacy of 
GS-4224, a cohort of ~40 subjects with locally advanced, inoperable 
or metastatic cancer expressing PD-Ll [TPS 
1 % or CPS~ 1] will 
be enrolled at the RP2D level. Tumor types of interest include 
NSCLC, melanoma, RCC, urothelial, gastric, squamous cell head 
and neck, HCC, MSI-H cancers, Merkel cell, cutaneous squamous 
cell, esophageal cancers, and cHL. PD-Ll expression will not be 
required for Merkel cell, melanoma, MSI-H cancers, and cHL. See 
Appendix 3 for the PD-Ll expression requirement for specific 
tumor types. 
For this cohort, subjects must have available sufficient and adequate 
fonnalin-fixed tumor tissue sample preferably from a biopsy of a 
tumor lesion obtained either at the time of or after the diagnosis of 
advanced disease has been made and from a site not previously 
irradiated. Alternatively, subjects must agree to have a biopsy taken 
prior to entering the study to provide adequate tissue. Subjects with 
biopsy accessible tumors may also undergo optional posttreatment 
tumor biopsies at Cycle 3 and at end of treatment (EOT). Subjects 
Page 11 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 12
02 October 2020
must agree to and give a separate, specific written consent to 
provide baseline, on-treatment, and/or EOT biopsies. Biopsies at 
Cycle 3 should be collected after radiographic tumor scans 
scheduled for that cycle have been completed. 
Number of Subjects 
Planned:
Up to 120 subjects will be enrolled.

Phase 1b (Dose Escalation): Up to 44 subjects

Phase 2 (Dose Expansion): 
Cohort B1 (Basket): ~40 subjects 
Target Population:
Phase 1b: Adult subjects with a histologically or cytologically 
confirmed advanced malignant solid tumor that is refractory to or 
intolerant of standard therapy or for which no standard therapy is 
available. For the 1000 mg BID dose cohort, histologically or 
cytologically confirmed advanced tumor expressing PD-L1 (TPS ≥ 
10% or CPS ≥10) or MSI-H cancers. Tumor types of interest 
include NSCLC, melanoma, RCC, urothelial, esophageal, HCC, 
cutaneous squamous cell, Merkel cell, MSI-H cancers, and cHL. 
PD-L1 expression will not be required for Merkel cell, melanoma,
MSI-H cancers, and cHL. See Appendix 3 for the PD-L1 expression 
requirement for specific tumor types.
Phase 2: 

Cohort B1 (Basket): Histologically or cytologically confirmed 
advanced tumor expressing PD-L1 (TPS ≥ 1% or CPS ≥ 1 or 
≥10) or MSI-H cancers. Tumor types of interest include 
NSCLC, melanoma, RCC, urothelial, gastric, squamous cell 
head and neck, HCC, MSI-H cancers, Merkel cell, cutaneous 
squamous cell, esophageal cancers, and cHL. PD-L1 expression 
will not be required for Merkel cell, melanoma, MSI-H cancers, 
and cHL. See Appendix 3 for the PD-L1 expression requirement 
for specific tumor types.
Duration of 
Treatment:
GS-4224 will be administered until disease progression, 
unacceptable toxicity, substantial noncompliance with study 
procedures or study drug, study discontinuation, or withdrawal from 
study. 
CCII 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 13
02 October 2020
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria:
Subjects must meet all of the following inclusion criteria to be 
eligible for participation in this study. Additional indication-specific 
inclusion criteria for 1000 mg BID Dose Escalation Cohort and
Phase 2 are provided in Appendix 3.
1. Male or female ≥18 years of age. 
2. Dose Escalation Cohorts: Histologically or cytologically 
confirmed advanced malignant solid tumor that is refractory to 
or intolerant of all standard therapy or for which no standard 
therapy is available. 
3. Dose Expansion and 1000 mg BID Dose Escalation Cohorts: 
Subjects must have available sufficient and adequate formalin-
fixed tumor sample preferably from a biopsy of a tumor lesion 
obtained either at the time of or after the diagnosis of advanced 
disease has been made and from a site not previously irradiated. 
Alternatively, subjects must agree to have a biopsy taken prior
to entering the study to provide adequate tissue. For the 
1000 mg BID dose escalation cohort, subjects with melanoma, 
Merkel cell, MSI-H cancers, and cHL are not required to have 
archival or fresh biopsy tissue.
4. Dose Escalation Biopsy Substudy and 1000 mg BID Dose 
Escalation Cohorts: Documented PD-L1 expression in the tumor 
(TPS ≥10% or CPS ≥10). See Appendix 3 for the PD-L1 
expression requirement for specific tumor types.
a) In the 1000 mg BID Cohort, PD-L1 expression will not 
be required for Merkel cell, melanoma, MSI-H cancers, 
and cHL.
5. All persisting toxic effects of any prior antitumor therapy 
resolved to National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 5.0 
Grade ≤1 or baseline before the first dose of study drug (with 
the exception of alopecia [Grade 1 or 2 permitted] and 
neurotoxicity [Grade 1 or 2 permitted]).
6. Eastern Cooperative Oncology Group (ECOG) Performance 
Status of ≤ 2
7. Life expectancy of ≥ 3 months, in the opinion of the investigator


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 14
02 October 2020
8. Adequate organ function defined as follows:
a) Hematologic: Platelets ≥ 100 109/L (≥ 60 109/L in 
subjects with HCC); Hemoglobin ≥9.0 g/dL; 
ANC ≥1.5 109/L (without blood transfusion, platelet 
transfusion, or growth factors within previous 7 days of the 
hematologic laboratory values obtained at screening visit) 
b) Hepatic: AST/ALT ≤ 2.5 upper limit of normal (ULN) 
(if liver metastases are present, ≤ 5 ULN); Total or
conjugated bilirubin ≤1.5 ULN
c) Renal: Creatinine clearance (CLcr) ≥ 45 mL/min as 
calculated by the Cockcroft-Gault method
9. Coagulation: Subjects on full-dose oral anticoagulation, except 
warfarin, which is an excluded medication, must be on a stable 
dose (minimum duration 14 days). Subjects on low molecular 
weight heparin will be allowed.
10. Negative serum pregnancy test for female subjects
11. Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use 
protocol-specified method(s) of contraception as described in 
Appendix 5. 
12. Females who are nursing must agree to discontinue nursing 
before the first dose of GS-4224. 
13. Able and willing to provide written informed consent to 
participate in the study 
14. Patients with history of human immunodeficiency virus (HIV) 
infection should have a CD4+ T-cell count ≥ 350 cells/µL at 
screening.
15. Patients with serological evidence of chronic hepatitis B virus 
infection (HBV) should have HBV viral load below the limit of 
quantification at screening.
16. Patients with serological evidence of hepatitis C virus infection 
(HCV) should have completed curative antiviral treatment and 
have HCV viral load below the limit of quantification at 
screening. 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 15
02 October 2020
Exclusion Criteria:
Subjects who meet any of the following exclusion criteria are not to 
be enrolled in this study. Additional indication-specific exclusion 
criteria for 1000 mg BID Dose Escalation Cohort and Phase 2 are 
provided in Appendix 3.
1) History or evidence of clinically significant disorder, condition, 
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.
2) Dose Escalation Cohorts: History of ≥Grade 3 AEs during prior 
treatment with an immune checkpoint inhibitor, or history of 
discontinuation of treatment with an immune checkpoint 
inhibitor due to AEs.
3) Dose Escalation 1000 mg BID and Dose Expansion Cohorts: 
Prior treatment with an immune checkpoint inhibitor (anti-PD-1, 
anti-PD-L1, or anti-ligand 2 of programmed cell death protein 1
[PD-L2] antibodies).
4) History of autoimmune disease (for example, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener's granulomatosis, Sjögren's syndrome, 
Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, 
autoimmune thyroid disease, vasculitis, or glomerulonephritis).
5) Positive serum pregnancy test (Appendix 5) 
6) Patient has known active central nervous system (CNS) 
metastases and/or carcinomatous meningitis. Patients with 
previously treated brain metastases may participate provided 
they are clinically stable for at least 4 weeks prior to study entry, 
have no evidence of new or enlarging brain metastases and if 
taking corticosteroids, are on stable or decreasing doses for at 
least 7 days from first dose of study drug.
7) Uncontrolled intercurrent illness including, but not limited to, 
active uncontrolled infection, active or chronic bleeding event 
within 28 days prior to first dose of study drug, or psychiatric 
illness/social situation that would limit compliance with study 
requirements as judged by treating physician.
8) Myocardial infarction, symptomatic congestive heart failure 
(New York Heart Association Classification > Class II), 
unstable angina, or serious uncontrolled cardiac arrhythmia 
within the last 6 months of first dose of study drug. 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 16
02 October 2020
9) Major surgery, defined as any surgical procedure that involves 
general anesthesia and a significant incision (ie, larger than what 
is required for placement of central venous access, percutaneous 
feeding tube, or biopsy) within 28 days of the first dose of study 
drug.
10) Impairment of GI function or GI disease that may significantly 
alter the absorption of GS-4224, including any unresolved 
nausea, vomiting, or diarrhea that is Common Terminology 
Criteria for Adverse Events (CTCAE) Grade > 1.
11) Symptomatic ascites or pleural effusion. A patient who is 
clinically stable following treatment for these conditions 
(including thora- or para-centesis) is eligible.
12) Minor surgical procedure(s) within 7 days of enrollment, or not 
yet recovered from prior surgery (placement of central venous 
access device, fine needle aspiration, or endoscopic biliary stent 
≥1 day before enrollment is acceptable).
13) Prior systemic radiation therapy completed within 4 weeks of 
the first dose of study drug, prior local radiation therapy 
completed within 2 weeks of Cycle 1 Day 1 (C1D1), or 
radiopharmaceuticals (strontium, samarium) within 8 weeks of 
C1D1.
14) Antitumor therapy (chemotherapy, antibody therapy, molecular 
targeted therapy) within 21 days or 5 half-lives, whichever is 
longer, of study drug dosing (6 weeks for nitrosoureas, 
mitomycin C, or molecular agents with t1/2 > 10 days); 
concurrent use of hormone therapy for prostate cancer is 
permitted.
15) History of long QT syndrome or additional risk factors for 
Torsades de Pointes or whose corrected QT interval (QTc) 
measured (Fridericia method) at screening is prolonged 
(> 480 ms). 
16) Use of concomitant medications that prolong QT/QTc interval at 
screening
17) Clinically significant bleeding within 28 days of the first dose of 
study drug
18) Known hypersensitivity to study drug, the metabolites, or 
formulation excipients
19) Use of any prohibited concomitant medications as described in 
Section 5.5 and any investigational agent within 2 weeks of 
study treatment initiation


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 17
02 October 2020
20) Breastfeeding female
21) Received live virus vaccination within 30 days of first dose of 
study treatment. Seasonal flu vaccines that do not contain live 
virus are permitted. 
22) History of hematologic stem cell transplant or solid organ 
transplant 
Study Procedures/
Frequency:
Screening:
Screening will commence with obtaining the subject’s signed
informed consent and will occur up to 28 days prior to the first
dosing of study drug. For Phase 1b, dose escalation, subjects in 
screening will be assigned to an applicable cohort. Screening 
procedures will include the following: medical history review;
physical exam; vital signs; 12-lead electrocardiogram (ECG); ECOG
Performance Status; prior/concomitant medication review; blood
collection for pregnancy test (females of child bearing potential);
chemistry, hematology, and coagulation; AE assessment; archival or 
recent biopsy formalin-fixed paraffin-embedded (FFPE) tissue 
block collection; and computed tomography (CT) or magnetic
resonance imaging (MRI) and positron emission tomography-
computed tomography (PET-CT) in subjects with cHL (scans that meet 
protocol requirements that are obtained as part of standard medical
practice up to 6 weeks prior to C1D1 are acceptable). For Phase 2, 
PD-L1 expression in the tumor will be determined by an 
immunohistochemistry (IHC) test. Baseline tumor lesions will be
measured and characterized prior to C1D1 to assess the subject
disease status prior to beginning treatment. 
Treatment:
Subjects who meet eligibility criteria will receive GS-4224 orally 
once daily in the 400 1500 mg QD cohorts and 1000 mg twice daily 
in the 1000 mg BID cohort (separated by approximately 12 hours). 
Each cycle will consist of 21 days. Safety and efficacy assessments
will occur on an outpatient basis including assessment of tumor
response, physical exam, vitals, ECG, collection of blood samples
(for routine safety labs, GS-4224 PK, pharmacodynamic markers,
and other biomarkers at applicable visits), urine pregnancy test 
(every 3 weeks while receiving GS-4224 in females of childbearing
potential), and assessment of AEs. In addition, subjects will undergo
postbaseline CT/MRI and PET-CT (for cHL) scans for tumor response 
assessment. A subject who does not show evidence of disease
progression by clinical assessment or by CT/MRI or applicable scan 
may continue receiving study treatment until disease progression
(clinical or radiographic), unacceptable toxicity, withdrawal of
consent, or other reasons specified in Section 3.5. 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Final 
Amendment 5 
After discontinuation of all study treatment, subjects will be 
followed for safety for 30 days. 
Pharmacokinetic Assessment: 
Intensive PK will be collected in all subjects in Phase 1 b dose 
cohorts between 400 mg and 1500 mg QD. In the 1000 mg BID 
dose escalation cohort, intensive PK will be collected at select sites 
and in at least 6 sub ·ects. 
Intensive PK samples will be collected predose on Cycle 1 Days 1 
and 15, followed by 0.5, 1, 1.5, 2.5, 4, 6, 12 (1000 mg BID dose 
cohort) and 0.5, 1, 1.5, 2.5, 4, 6, and 24 (400 1500 mg QD dose 
cohorts) hours postdose relative to the AM dose. For the 1000 mg 
BID cohort, the 12 hours postdose samples will be collected prior to 
the PM dose. Every effort should be made to collect Intensive PK 
samples at the indicated time; actual sample collection time should 
be recorded. 
Page 18 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
CONFIDENTIAL 
Page 19 
Final 
Amendment 5 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 20
02 October 2020
Tumor Assessment:
CT/MRI will be performed approximately every 6 weeks for the 
first 2 postbaseline scans and then every 9 weeks. The same method 
of assessment and the same technique (eg, scan type, scanner, 
subject position, dose of contrast, injection/scan interval) should be 
used to characterize each identified and reported lesion at baseline 
and during study treatment and follow up. 
For subjects with cHL, in addition to CT or MRI scan, a baseline 
PET-CT is required at screening (or within 6 weeks before C1D1 if 
the scan was performed as part of standard medical practice), at 
Cycle 3 Day 1, and Cycle 5 Day 1. Per Lugano 2014 criteria, 
PET-CT is required to confirm radiographic complete response 
(CR). If radiographic CR has not been confirmed by PET-CT at 
Cycle 3 or 5, additional PET-CT will be required within 4 weeks of 
the CT/MRI scan that assessed radiographic CR.
For solid tumors, responses will be evaluated using Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
with modifications. For subjects with cHL, Lugano 2014 response 
criteria will be used. Because of the potential for 
pseudo-progression, subjects whose scans show radiographic 
progression in the absence of clinical deterioration including 
worsening performance status as assessed by the investigator may 
remain on study treatments and an additional scan should be 
obtained no less than 4 weeks later as outlined in Section 6.6. If this 
subsequent scan shows disease progression, the subject will be 
discontinued from study treatments.
Response to disease (CR or partial response [PR]) will be confirmed 
by the same imaging technique no less than 4 weeks after the 
criteria for response are first met.
All relevant clinical and radiographic information required to make 
each assessment must be made available for source verification and 
submission to an independent review committee (IRC). Scans will 
be transferred to a central reader for collection and future analysis. 
Disease progression will be determined by the investigator or 
qualified designee for patient management in real time.


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Test Product, Dose, 
and Mode of 
Administration: 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Criteria for 
Evaluation: 
Safety: 
Efficacy: 
Pharmacokinetics: 
-
CONFIDENTIAL 
Final 
Amendment 5 
GS-4224 tablets will be self-administered orally once daily in the 
400 1500 mg QD cohorts and 1000 mg twice daily in the 1000 mg 
BID cohort, from their first dose and thereafter at approximately the 
same time each day until EOT. GS-4224 is supplied as 100 mg, 
200 mg, and 500 mg tablets. 
On the intensive PK sampling days for subjects in Phase 1 b, 
GS-4224 will be administered in the clinic under fasted conditions. 
Not Applicable 
Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination, 12-lead ECG, vital signs measurements, and 
the documentation of AEs. AEs will be graded using NCI-CTCAE 
version 5.0. 
Efficacy will be evaluated by overall response rate (ORR) 
(CR + PR), assessed as per RECIST v 1.1 with modifications, or per 
Lugano 2014 response criteria for cHL, and progression-free 
survival (PFS), defined as the interval from the first dosing date of 
study drug to the earlier of the first documentation of definitive 
disease progression or death from any cause. 
The following PK parameters for GS-4224 will be calculated as 
applicable: T1as1, T max, Cmax, C1rough, AUCiast, A UC1au, and h12. 
Dose proportionality and time-dependency in drug exposure may be 
evaluated as applicable. 
Page 21 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 22
02 October 2020
Statistical Methods:
The study primary analysis will be conducted when all enrolled 
subjects have discontinued the study or have been on treatment of 
GS-4224 for at least 48 weeks and completed response assessment 
of Week 48.
Analysis Data Set
The All Enrolled Analysis Set includes all subjects who received a 
study subject identification number in the study after screening.
The Full Analysis Set (FAS) includes all subjects who took at least 
1 dose of study treatment. It will be used in the analyses of efficacy 
endpoints.
The Safety Analysis Set will include data from all subjects who 
receive at least 1 dose of study treatment, with treatment 
assignments designated according to the actual treatment received. 
This analysis set will be used in the analyses of safety variables as 
well as study treatment administration. 
The DLT-Evaluable Analysis Set includes all subjects in the Safety 
Analysis Set who enroll to the dose escalation cohorts (up to the 
first 6 subjects in the 1000 mg BID dose escalation cohort; 
excluding the Dose Escalation Biopsy Substudy), complete ≥ 75% 
of the prescribed study treatment and have safety assessments 
through the protocol-specified DLT assessment window (first 21 
days of study dosing, inclusive) or have experienced a DLT prior to 
the completion of first 21 days of study dosing. Safety assessment 
relevant to the DLT-Evaluable Analysis Set definition will include 
laboratory serum chemistry tests and hematology tests as specified 
in the protocol. Determination of the MTD will be based on the 
DLT-Evaluable Analysis Set.
The PK Analysis Set will include data from subjects in the Safety 
Analysis Set who have received the study drug and have at least 
1 sample with detectable drug concentration. 
An IRC may review radiographic data in order to provide 
independent evaluation of tumor status. Tumor response status and 
progression will be assessed by the IRC using RECIST v1.1 with 
modifications or Lugano 2014 response criteria for cHL.
Efficacy Analysis
In efficacy analysis, ORR will be evaluated by tumor type and 
treatment in FAS. Tumor types with less than 5 subjects enrolled will 
be pooled for ORR summary. Subjects who do not have sufficient 
baseline or on-study tumor assessment to characterize response will 
be counted as nonresponders. Estimates and the corresponding 
95% CIs based on the Clopper-Pearson exact method will be 
provided. 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
Median, first quartile (Q 1 ), third quartile (Q3) of the PFS 
distribution, and the proportion of subjects who are progression-free 
at Week 12, 24, and 48 from the first dosing date will be estimated 
by tumor type using the Kaplan-Meier (KM) method along with the 
corresponding 95% Cls. KM curves will be provided. 
The ORR and PFS analyses will be conducted using the investigator 
assessments and IRC assessments if available. 
Safety Analysis 
Safety will be assessed via AEs, clinical laboratory tests, and 
concomitant medications in the Safety Analysis Set by cohort, 
indication and treatment. Infonnation regarding study drug 
administration, study drug compliance, and other safety variables 
will also be summarized. 
Phannacokinetic (PK) Analysis 
GS-4224 plasma concentrations and PK parameters will be 
described and summarized. Plasma concentrations of GS-4224 
metabolite(s) may also be detennined and explored. 
Sample Size 
The sample size of the study will be detennined based on the 
number of dose levels evaluated and the emerging GS-4224-related 
toxicities and efficacy. The study is planned to enroll approximately 
120 subjects. 
A 
. 
. 
. 
. 
. 
Approximately 
e Dose Expansion Cohort B 1. 
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents. 
CONFIDENTIAL 
Page 23 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 24
02 October 2020
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
β−hCG
beta-human chorionic gonadotropin
λz
terminal disposition rate constant, estimated by linear regression of the terminal 
elimination phase of the log concentration of drug versus time curve of the drug
3D
three-dimensional
ADA
anti-drug antibody
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
AJCC-8
American Joint Committee on Cancer staging manual
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AR
accumulation ratio
ARA
acid-reducing agent
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve 
AUClast
area under the drug concentration-time curve from time zero to last time point with 
measurable concentration
AUCtau
area under the concentration-time curve from time zero to the end of the dosing interval
aVR
augmented Vector Right
BCRP
breast cancer resistance protein
BOR
best overall response
BUN
blood urea nitrogen
C1D1
Cycle 1 Day 1
CD80
cluster determinant 80
CFR
Code of Federal Regulations
CHB
chronic hepatitis B
cHL
classical Hodgkin Lymphoma
CI
confidence interval
CL
systemic clearance
Cmax
maximum observed drug concentration
Ctrough
observed concentration at the end of the dosing interval
CNS
central nervous system
CPS
combined positive score
CR
complete response
CLcr
creatinine clearance


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 25
02 October 2020
CRF
case report form
CRO
Contract Research Organization
CRP
C-reactive protein
CRS
cytokine release syndrome
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP
cytochrome P450 enzyme
DCR
disease control rate
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
EC
effective concentration
EC50
Half-maximal effective concentration
EC90
90% effective concentration
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EF
ejection fraction
EOT
end of treatment
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose (18F)
FFPE
formalin-fixed paraffin-embedded
FIH
first-in-human
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
gamma-glutamyltransferase
GI
gastrointestinal
GLP
Good Laboratory Practices
GLPS
Global Patient Safety
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 26
02 October 2020
HCV
hepatitis C virus
HED
human equivalent dose
hERG
human ether-à-go-go-related gene
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methylglutaryl-coenzyme A
HNSCC
head and neck squamous cell cancer
HuMC38
Human PD-L1-expressing MC38
IB
investigator’s brochure
IC50
half-maximal inhibitory concentration
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
ICF
informed consent form
IEC
independent ethics committee
IgG1
immunoglobulin G1
IHC
immunohistochemistry
ILD
interstitial lung disease
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
irAE
immune-related adverse event
IRB
institutional review board
IRC
independent review committee
ITP
immune thrombocytopenia purpura
ITT
intent-to-treat 
IV
intravenous(ly)
IXRS
interactive voice/web response system
KM
Kaplan-Meier
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
MABEL
minimally anticipated biologic effect level
MRI
magnetic resonance imaging
MRSD
maximum recommended starting dose
MSI-H
microsatellite instability-high
NCA
noncompartmental analysis
NCI
National Cancer Institute


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 27
02 October 2020
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Events
NHP
non-human primate
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
NSCLC
non-small cell lung cancer
OATP
organic anion transporting polypeptide
ORR
overall response rate
OS
overall survival
OTC
over-the-counter (drug)
PBMC
peripheral blood mononuclear cell
PET-CT
positron emission tomography-computed tomography
PT
Preferred Term
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
ligand 1 of programmed cell death protein 1
PD-L1 high
tumor cells expressing high levels of PD-L1
PD-L1 low
peripheral immune cells expressing basal levels of PD-L1
PD-L2
ligand 2 of programmed cell death protein 1
PD PBMC
pharmacodynamic peripheral blood mononuclear cell
PFS
progression-free survival
P-gp
P-glycoprotein
PHI
protected health information
PI
Principal Investigator
PMBCL
primary mediastinal B-cell lymphoma
PK
pharmacokinetic(s)
PR
partial response
Q1, Q3
first quartile, third quartile
QT, QTc
QT interval corrected for heart rate
Q-TBNK
Quantitative T, B, and natural killer
RANKL
receptor activator of nuclear factor kappa-B ligand
RBC
red blood cell
RCC
renal cell carcinoma
RECIST v1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
ROW
rest of world
RP2D
recommended Phase 2 dose
TPS
tumor proportion score
SADR
serious adverse drug reaction
SAE
serious adverse event


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 28
02 October 2020
SAP
Statistical Analysis Plan
SD
stable disease
SDV
source data verification
SJS
Stevens-Johnson Syndrome
SOC
system organ class
SOP
standard operating procedure
SRT
safety review team
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal elimination half-life 
T4
thyroxine
TBL
total bilirubin
TCR
T-cell receptor
TEAE
treatment-emergent adverse event
TEN
toxic epidermal necrolysis
Tlast
time of last observable plasma concentration
Tmax
time to maximum observed concentration
TNM
tumor node metastasis
TSH
thyroid-stimulating hormone
UGT1A1
uridine diphosphate glucuronosyltransferase 1A1
ULN
upper limit of normal
US
United States
Vd
volume of distribution 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 29
02 October 2020
1.
INTRODUCTION
1.1.
Background
GS-4224 is a potent, selective, and orally bioavailable small molecule inhibitor that binds 
specifically to ligand 1 of programmed cell death protein 1 (PD-L1) and promotes dimerization, 
leading to inhibition of programmed cell death protein 1 (PD-1) receptor binding. 
The mechanism of action of GS-4224 translated to potent and rapid PD-L1 occupancy on tumor 
cells expressing high levels of PD-L1 (PD-L1 high), versus on peripheral immune cells 
expressing basal levels of PD-L1 (PD-L1 low). This unique feature may translate to an improved 
therapeutic index in patients with PD-L1 high tumors, as compared with existing antibodies that 
saturate PD-L1 (or PD-1) irrespective of cellular expression level. 
GS-4224 exhibits an on-target selectivity profile comparable with PD-L1 antibodies. GS-4224 
selectively blocks PD-1/PD-L1 and PD-L1/cluster determinant 80 (CD80) interactions and does 
not inhibit PD-1/programmed cell death protein 1 ligand 2 (PD-L2) or cytotoxic T lymphocyte 
associated-4 (CTLA-4)/CD80 receptor-ligand interactions. 
GS-4224 restored responses and effector functions of T cells inhibited by PD-L1 in a variety of 
T-cell activation assays and demonstrated potent antitumor activity in mouse tumor models. 
Furthermore, GS-4224 enhanced both cytolytic and noncytolytic functions of hepatitis B virus
(HBV)-specific T cells present in human peripheral blood mononuclear cells (PBMCs) isolated 
from chronic hepatitis B (CHB) patients.
Taken together, these data support the development of GS-4224 as a potent, selective, and orally 
bioavailable PD-L1 small molecule inhibitor for the treatment of solid tumors, as well as CHB. 
1.2.
GS-4224
1.2.1.
General Information
For further information on GS-4224, refer to the current investigator’s brochure (IB) for 
GS-4224.
1.2.2.
Preclinical Pharmacology and Toxicology
GS-4224 exhibits an on-target-selectivity profile comparable with PD-L1 antibodies, as it 
selectively blocks PD-1/PD-L1 and PD-L1/CD80 interactions (half-maximal inhibitory 
concentration [IC50] < 1 nM) and does not inhibit PD-1/ PD-L2 or CTLA-4/CD80 
receptor-ligand interactions (IC50 > 10,000 nM).
GS-4224 restored the responses and effector functions of T cells inhibited by PD-L1 in a variety 
of T-cell activation assays, including a three-dimensional (3D) spheroid co-culture assay that
measured T-cell mediated tumor lysis in response to GS-4224. Half-maximal effective 
concentration (EC50) values in these assays ranged between 12 nM and 94 nM. Furthermore, in a 
human whole blood stimulation assay, GS-4224 promoted interferon-gamma (IFN-γ) secretion 
with an average 90% effective concentration (EC90) of 338 nM.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 30
02 October 2020
GS-4224 demonstrated potent antitumor activity in mouse tumor models. The first model is a 
human PD-L1-expressing MC38 (HuMC38) colorectal tumor model where only tumor cells 
express human PD-L1 while mouse immune cells retain expression of mouse PD-1 and PD-L1. 
The second model is the implantation of HuMC38 tumor cells into a genetically engineered 
human PD-L1 knock-in (KI) mouse. In this model, both tumor and immune cells express human 
PD-L1. For both models, GS-4224 achieved > 90% target occupancy in tumor cells for at least 
24 hours at all doses administered: HuMC38 tumor model (10 mg/kg once daily, 25 mg/kg twice 
daily, and 50 mg/kg once daily) and HuMC38 tumor model in human PD-L1 KI mouse 
(30 mg/kg twice daily).
The nonclinical safety profile of GS-4224 has been well characterized through the conduct of 
safety pharmacology, repeat dose toxicity, genetic toxicology, and impurity qualification studies. 
Data from the investigational new drug (IND) nonclinical safety package (Table 1-1) and 
13-week interim analysis from the 26-week rat and 39-week monkey studies can be found in the 
GS-4224 IB. 
Table 1-1.
IND Nonclinical Safety Package
Study Type
Study Titlea
Safety Pharmacology
Effect of GS 4224 01b on Cloned hERG Potassium Channels Expressed in Human 
Embryonic Kidney Cells
Cardiovascular Assessment Following Single Oral Gavage Administration of 
GS 4224 01 to Conscious Radiotelemetry Instrumented Cynomolgus Monkeys
Central Nervous System (CNS) Assessment (Modified Irwin Test) of GS 4224 01 
Following Single Dose Oral Gavage Administration in Male Wistar Han Rats
Respiratory Assessment Following Single Dose Oral Gavage Administration of 
GS 4224 01 to Plethysmograph Restrained Male Wistar Han Rats
General Toxicology
A 4 Week Oral Gavage Toxicity and Toxicokinetics Study of GS 4224 01 in 
Wistar Han Rats with a Bone Marrow Micronucleus Assay
A 4 Week Oral Gavage Toxicity and Toxicokinetic Study of GS 4224 01 in 
Cynomolgus Monkeys
A 7 Day Oral Gavage Dose Range Finding Toxicity and Toxicokinetic Study of 
GS 954418 in Wistar Han Rats (Non GLP)
A 7 Day Oral Gavage Dose Range Finding Toxicity and Toxicokinetic Study of 
GS 954418 in Male Cynomolgus Monkeys (Non GLP)
Genetic Toxicology
GS 4224 01 Salmonella E. Coli/Mammalian Microsome Reverse Mutation Assay
GS 4224 01 In Vitro Chromosome Aberration Test in Cultured Human Peripheral 
Blood Lymphocytes
A 4 Week Oral Gavage Toxicity and Toxicokinetics Study of GS 4224 01 in 
Wistar Han Rats with a Bone Marrow Micronucleus Assay
Rat Alkaline Comet Assay Following Oral Gavage Administration of GS 4224 01
Other Studies
A 4 Week Oral (Gavage) Impurity Qualification Toxicity and Toxicokinetic Study 
of GS 4224 03 in Wistar Han Rats
CNS  central nervous system; GLP  Good Laboratory Practices; HCl
hydrochloride; hERG 
human ether à go go related 
gene; IND  investigational new drug
a
Studies are GLP except where indicated
b
GS 4224 01  bis HCl salt of GS 4224


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 31
02 October 2020
1.2.3.
Clinical Trials of GS-4224
Study GS-US-439-4660 is an ongoing Phase 1 study to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics of GS-4224 for the first time in humans. This 
study consists of 2 parts (A and B). Part A (Cohorts 1-5, 8-10) entails administration of GS-4224 
to healthy volunteers with the objective of better understanding the safety and clinical 
pharmacology profile of GS-4224. Part B (Cohorts 11-16) will be a multicenter, randomized, 
blinded, placebo-controlled study of GS-4224 in subjects with CHB. At this time, Cohorts 1-5 in 
Part A have been completed and used to support the study design outlined in this protocol. Full 
details on the study design and safety data from the completed portion can be found in the IB. 
1.3.
Rationale for this Study
Therapeutic antibodies that block the PD-1/PD-L1 interaction have emerged as a class of 
foundational cancer therapies. Six antibodies targeting the PD-1/PD-L1 pathway have been 
approved by the United States (US) Food and Drug Administration (FDA) in over 20 different 
tumor indications, with at least 50 additional antibodies targeting this axis in clinical 
development as monotherapy or in combination with other agents. By contrast, only one oral 
small molecule inhibitor of the PD-1/PD-L1 interaction has entered development (Phase 1 study, 
NCT03762447, initiated Dec 2018 for INCB086550). The current study will determine the safety 
and preliminary efficacy of GS-4224, an oral small molecule inhibitor of PD-1/PD-L1 
interaction, which may provide an alternative treatment option to patients with tumor types that 
have shown activity with antibodies that target the same pathway.
1.4.
Rationale for the Dose Selection
In Phase 1b of this study, starting dose of GS-4224 400 mg once daily will be administered to 
subjects with advanced solid tumors. This starting dose is supported by preclinical PK and 
toxicology studies as well as available safety, tolerability, and PK data in healthy volunteers 
(GS-US-439-4660).
The proposed starting dose of GS-4224 400 mg once daily is expected to be well tolerated for 
administration to subjects with advanced solid tumors. Based on available clinical PK data in 
healthy volunteers from Study GS-US-439-4660, the mean steady-state exposure (AUCtau) of 
once daily 400 mg GS-4224 is expected to be approximately 10,100 h*ng/mL, which is 5.1-fold 
lower exposure than that observed at the no observed adverse effect level (NOAEL) in the 
nonclinical multiple dose Good Laboratory Practices (GLP) 28-day toxicology study (the most 
sensitive species was rat; an AUCtau of 51,400 h*ng/mL was observed after 100 mg/kg/day 
GS-4224 administration, Section 1.2.2) and 1.6-fold that of the exposure observed at the NOAEL 
in the nonclinical multiple dose chronic toxicology study (the most sensitive species was rat; an 
AUCtau of 16,100 h*ng/mL was observed after 30 mg/kg/day GS-4224 administration, 
Section 1.2.2). These safety margins provide adequate coverage for the starting dose as well as 
the escalation strategy (escalation will proceed from the 400 mg QD starting dose to 700 mg QD,
1000 mg QD, 1500 mg QD, then to the maximum dose of 1000 mg BID). 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 32
02 October 2020
The proposed starting dose is also supported by the ongoing healthy volunteer study, 
GS-US-439-4660. This study is a Phase 1 study to evaluate the safety, tolerability, PK, and 
pharmacodynamics of GS-4224 (see GS-4224 IB). This study consists of 2 parts (A and B). 
Part A entails administration of GS-4224 to healthy volunteers for the first time with the 
objective of evaluating in a step-wise fashion the safety, tolerability, PK, and pharmacodynamics 
of single and multiple escalating doses of GS-4224. As of 8 July 2019, the 20, 60, 180, 540, and 
1000 mg single and multiple dosing cohorts have completed with no significant safety concerns. 
PK and preliminary pharmacodynamic data for single-/multiple-dose 20 to 1000 mg and 20 to
540 mg, respectively, are currently available (see GS-4224 IB).
Given this study includes subjects with advanced solid tumors, selection of a 
pharmacodynamically active dose is important. Daily administration of 400 mg GS-4224 is 
expected to provide pharmacodynamically active GS-4224 exposure. Average steady-state 
GS-4224 exposures at this dose approximate the protein adjusted EC90 for in vitro whole blood 
T-cell stimulation (see GS-4224 IB). Furthermore, available preliminary pharmacodynamic data 
in healthy volunteers (see GS-4224 IB) indicates that multiple daily doses of 400 mg GS-4224 is 
expected to provide similar or greater PD-L1 target occupancy in the PBMCs of subjects with 
solid tumors than that which was observed in healthy volunteers (17% and 36% PD-L1 target
occupancy after multiple dose administration of 180 mg and 540 mg GS-4224, respectively). 
Based on in vitro data, it is expected that target occupancy will be higher at the site-of-action if 
PD-L1 is over-expressed on the tumor (see GS-4224 IB).
Considering expected exposure to provide a pharmacological response, the supportive safety data 
from the ongoing clinical study and toxicology data, a starting dose of 400 mg once daily is 
considered appropriate for initial evaluation in this study.
A maximum GS-4224 dose of 2000 mg daily administered as 1000 mg twice daily will be 
evaluated in Phase 1b and dose escalation from the 400 mg once daily starting dose to the 
maximum dose will proceed via a standard 3+3 study design (as described in Section 3.2). The 
mean daily steady-state exposure (AUC0 24) of GS-4224 1000 mg twice daily is expected to be 
approximately 45,700 h*ng/mL, assuming dose proportionality. This is 1.1- and 0.4-fold relative 
to the exposures observed at the NOAELs of the most sensitive species tested (rat) in the 
nonclinical multiple dose GLP 28-day and chronic toxicology studies, respectively (see GS-4224 
IB). The NOAEL determining adverse effect observed in rats after chronic dosing (> 28 days) is 
readily monitorable in the clinic (see GS-4224 IB). In the dose escalation phase and healthy 
volunteer study (GS-US-439-4660), no clinically meaningful safety or tolerability findings have 
been observed at doses up to 1000 mg. Based on these data, a maximum daily dose of 2000 mg 
(1000 mg twice daily) is expected to maintain a favorable safety profile in subjects with solid 
tumors.
The recommended Phase 2 dose (RP2D) to be evaluated in Phase 2 will be selected based on all 
relevant clinical data from all subjects treated in Phase 1b dose escalation, will consider 
toxicities through 90 days of dosing, and will not exceed the maximum tolerated dose (MTD).


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 33
02 October 2020
1.5.
Risk/Benefit Assessment for the Study
Potential risks of a participant's study involvement include immune-related adverse events 
(irAEs) (defined as adverse events [AEs] of unknown etiology that were consistent with an 
immune phenomenon primarily involving the gastrointestinal [GI] tract and the skin, and were 
considered causally related to drug exposure by investigators) described with other 
anti-PD-1/PD-L1 agents, unknown AEs, general risks associated with frequent clinic visits and 
laboratory blood draws, and the associated pain and discomfort of phlebotomy. Strategies to 
mitigate these risks include close monitoring of lab values as well as AEs. Parameters for 
discontinuation of the study drug are defined in Section 6.10.1.
There may be no direct benefit to subjects participating in this study; however, data from this
study will support the development of GS-4224 for the treatment in subjects with advanced solid 
tumors. Potential benefits may include the participant's contribution to understanding the safety, 
tolerability, efficacy, pharmacodynamics, and PK of multiple and escalating doses of GS-4224.
Based on available information, the benefit/risk balance for this study is considered positive.
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 8 for further details on the risks and 
risk mitigation strategy.
1.6.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
2. 
OBJECTIVES 
The primary objectives of this study are as follows: 
Phase 1 b Dose Escalation 
Final 
Amendment 5 
• 
Characterize the safety and tolerability of GS-4224 in subjects with advanced solid tumors 
• 
Detennine the MTD and RP2D of GS-4224 in subjects with advanced solid tumors 
The secondary objectives of this study are as follows: 
Phase 1 b Dose Escalation 
• 
Evaluate the PK of GS-4224 in subjects with advanced solid tumors 
Phase 2 Dose Expansion 
• 
Evaluate the safety and tolerability of GS-4224 in subjects with advanced solid tumors 
I 
I 
I 
I 
CONFIDENTIAL 
Page 34 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
3. 
STUDY DESIGN 
3.1. 
Endpoints 
The primary endpoint of this study is as follows: 
Phase 1 b Dose Escalation 
• 
Incidence of dose-limiting toxicity (DLT) as defined in Section 3.2. 
The secondary endpoints are as follows: 
Phase 1 b Dose Escalation 
Final 
Amendment 5 
• 
PK parameters (T1as1, Tmax, Cmax, Ctrough, AUCiast, AUC1au and ti,2, as applicable) for GS-4224 
in subjects with advanced solid tumors. 
Phase 2 Dose Expansion 
• 
Incidence of Grade~ 3 treatment-emergent adverse events (TEAEs) in Cohort B 1 subjects 
with advanced solid tumors 
• 
Incidence of Grade~ 3 treatment-emergent laboratory abnonnalities in Cohort B 1 subjects 
with advanced solid tumors 
I 
I 
I 
I 
CONFIDENTIAL 
Page 35 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 36
02 October 2020
3.2.
Study Design
This is an open-label, multicenter, sequential dose escalation and dose expansion study to 
evaluate the safety, tolerability, PK, and efficacy of GS-4224 in subjects with advanced solid 
tumors. The study will consist of 2 parts: the dose escalation portion (Phase 1b), followed by 
dose expansion (Phase 2) in subjects with tumors for which PD-1/PD-L1 treatments are 
approved or are known to be active. 
3.2.1.
Dose Escalation (Phase 1b) 
The overall Phase 1b study design is presented graphically in Figure 3-1. 
Figure 3-1.
Phase 1b Study Design Schema
DL  dose level; HV  healthy volunteers; QD  once a day; BID  twice a day; RP2D  recommended Phase 2 dose
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 oral GS-4224 as monotherapy once daily (400 1500 mg QD cohorts) and as 
monotherapy at 1000 mg twice daily (1000 mg BID cohort).
Dose escalation will proceed using a standard 3+3 design. The starting dose is 400 mg QD, with
subsequent doses of 700 mg QD, 1000 mg QD, 1500 mg QD, and 1000 mg BID. Dose level 
increases will be 3-fold or less. 
..c 
.-I 
(I) 
VI 
C'Cl 
..c 
0... 
DL-1 
400 mgQD 
Study Schema 
3+3 Dose Escalat ion 
DL-2 
700mgQD 
DL-3 
1000 mgQD 
DL-4 
1500mg QD 
DL-5 
1000 mg BID 
( 
RP2D ) 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 37
02 October 2020
Table 3-1.
Dose Escalation (Phase 1b) Dose Levels
Dose Level Schema
GS-4224 (mg)
Fold Increase
400 QD
-
700 QD
≤3
1000 QD
≤3
1500 QD
≤ 3
1000 BID
≤ 3
In the 1000 mg BID dose cohort, at least 6 (as part of the initial 3+3 design) and up to an 
additional 14 subjects (for a total of 20 subjects) with locally advanced, inoperable or metastatic 
cancer expressing PD-L1 (tumor proportion score [TPS] ≥ 10% or combined positive score 
[CPS] ≥ 10) and who have not previously been treated with anti-PD-1/L1 antibodies will be 
enrolled. The additional 14 subjects will not be enrolled at the 1000 mg BID dose level if the 
subject incidence of DLTs is > 1 in the first 6 subjects. If the subject incidence of DLTs is > 1 in 
the first 6 subjects at 1000 mg BID, then 20 additional subjects with locally advanced, inoperable 
or metastatic cancer expressing PD-L1 [TPS ≥ 10% or CPS ≥ 10] and who have not previously 
been treated with anti-PD-1/L1 antibodies will enroll at the MTD. Tumor types of interest 
include non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), urothelial, 
esophageal, hepatocellular carcinoma (HCC), cutaneous squamous cell, Merkel cell, MSI-H 
cancers, and cHL. See Appendix 3 for the PD-L1 expression requirement for specific tumor 
types.
For the 1000 mg BID dose cohort, subjects must have available sufficient and adequate formalin-
fixed tumor tissue sample preferably from a biopsy of a tumor lesion obtained either at the time 
of or after the diagnosis of advanced disease has been made and from a site not previously 
irradiated. Alternatively, subjects must agree to have a biopsy taken prior to entering the study to 
provide adequate tissue. Subjects with melanoma, Merkel cell, MSI-H cancers, and cHL are not 
required to have archival or fresh biopsy tissue.
The safety and tolerability of each dose level will be assessed by a safety review team (SRT) after
up to 6 subjects enrolled in the dose level have been followed for at least 21 days after the first 
dose of GS-4224 or 2 DLTs have been observed, whichever is earlier. See Section 3.2.3 for more 
information about the SRT.
The initial block of each dose consists of 3 subjects. Dose escalation may occur if no subjects 
experience DLTs during the first 21 days of study drug dosing. If 1 subject within the initial 
cohort of 3 subjects experiences a DLT during the first 21 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 of the 6 subjects experience DLTs 
within the first 21 days, dose de-escalation to an intermediate dose will occur. The MTD is the 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 38
02 October 2020
highest dose level with a subject incidence of DLTs during the first 21 days of study drug dosing 
of 0 or 1 out of 6. 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 is withdrawn from the study before the 
completion of the first 21 days for a reason other than a DLT will be replaced.
If 2 or more delayed DLT-type AEs are noted after the first 21-day observation period within a 
dose escalation cohort, further accrual at all sites will be held pending safety analysis of the 
event, and will be restarted only with investigator and sponsor approval.
The SRT will review safety and relevant clinical data and make the dose 
escalation/stay/de-escalation decision. Source Data Verification (SDV) 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 SRT Charter.
3.2.1.1.
DLT Definition
A DLT is any toxicity defined below excluding toxicities clearly related to disease progression or 
disease-related processes occurring during the DLT assessment window (Day 1 through Day 21):

Grade ≥ 4 neutropenia (absolute neutrophil count [ANC] < 500/mm3)

Grade ≥ 3 neutropenia (ANC < 1000/mm3) with fever (a single temperature of > 38.3°C or a 
sustained temperature of ≥38°C for more than 1 hour)

Grade ≥ 3 thrombocytopenia 

Grade ≥ 2 bleeding (eg, GI, respiratory, epistaxis, or purpura)

Grade ≥ 3 anemia

Grade ≥ 3 or higher non-hematologic toxicity, except:
Grade 3 nausea or emesis with maximum duration of 48 hours on adequate medical 
therapy
Grade 3 diarrhea which persists for < 72 hours in the absence of maximal medical 
therapy. 

Grade ≥ 2 non-hematologic TEAE that in the opinion of the investigator is of potential 
clinical significance such that further dose escalation would expose subjects to unacceptable 
risk

Continuous treatment interruption of ≥ 7 days due to unresolved toxicity

Any toxicity event that precludes further administration of GS-4224


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
• 
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 
• 
An irAE for which immunotherapy should be penn anently discontinued ( eg, any grade 
encephalitis, Grade 3 myocarditis, reoccurrence of the same Grade 3 adverse reaction). 
For certain toxicities, such as laboratory assessments without a clear clinical correlate, a 
discussion between the investigator and medical monitor may take place to detennine if this AE 
should be assessed as a DLT. 
Excluded from this definition: 
• 
Grade 3 AEs of tumor flare ( defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor) 
• 
Grade 3 rash without systemic signs or symptoms 
• 
Grade 3 irAE that resolves to a Grade 1 or less within 21 days, except as described above. 
3.2.1.2. 
Recommended Phase 2 Dose Detennination 
The RP2D will be detenn ined by Gilead in discussion with the SRT based on all relevant clinical 
data from all subjects treated in the escalation phase. The RP2D will not exceed the MTD and 
will consider toxicities through 90 days of dosing. 
-
CONFIDENTIAL 
Page 39 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 40
02 October 2020
3.2.2.
Dose Expansion (Phase 2)
Dose expansion may begin when the RP2D has been determined. 
The dose expansion phase includes the following cohort:
Cohort B1 (Basket Cohort expressing PD-L1 [TPS ≥ 1% or CPS ≥ 1 or ≥ 10] or MSI-H cancers, 
single arm, open-label study of GS-4224)
To further characterize the safety and preliminary efficacy of GS-4224, a cohort of ~40 subjects 
with locally advanced, inoperable or metastatic cancer expressing PD-L1 [TPS ≥ 1% or CPS ≥1] 
will be enrolled at the RP2D level. Tumor types of interest include NSCLC, melanoma, RCC, 
urothelial, gastric, squamous cell head and neck, HCC, MSI-H cancers, Merkel cell, cutaneous 
squamous cell, esophageal cancers, and cHL. See Appendix 3 for the PD-L1 expression 
requirement for specific tumor types.
3.2.3.
Safety Review Team
An SRT will be established to assess safety, make decisions on dose escalation, define the MTD, 
and propose RP2D for dose expansion consideration. 
The SRT will consist of at least 1 investigator and the following Gilead study team members: the 
medical monitor, representatives from Global Patient Safety (GLPS) (formerly Gilead 
Pharmacovigilance and Epidemiology), Clinical Operations, and Biostatistics. Others may be 
invited to participate as members of the SRT if additional expertise is desired. The medical 
monitor serves as the chair of the SRT. 
An SRT Charter (or similar document) will be agreed by all SRT members prior to the first SRT 
meeting. The SRT Charter will describe the dose escalation process, including the following:

Data required for review before initiating the next specified dose

Data quality required

Stopping rules for individual and for the study

Minimum quorum of study and sponsor personnel required to make decisions

Who makes the final dose escalation decision and documentation of the decision
3.3.
Study Treatments
The study drug is GS-4224. Subjects will be given GS-4224 tablets once daily in the 
400-1500 mg QD cohorts and twice daily in the 1000 mg BID cohort. 
Formulation, packaging, and dosing regimens are further described in Section 5. 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
3.4. 
Duration of Treatment 
Final 
Amendment 5 
GS-4224 will be administered until disease progression, unacceptable toxicity, substantial 
noncompliance with study procedures or study drug, study discontinuation or withdrawal from 
study. 
3.5. 
Study Discontinuation Criteria 
The entire study may be discontinued in the event of any of the following: 
• 
New infonnation leading to unfavorable risk-benefit judgment of GS-4224 
• 
Sponsor's decision 
• 
Poor enrollment of subjects, making completion of the study within an acceptable timeframe 
unlikely 
• 
Discontinuation of development of GS-4224 
Health authorities and independent ethics c01mnittees (IECs)/institutional review boards (IRBs) 
will be infonned about study discontinuation in accordance with applicable regulations. 
The entire study may be tenninated or suspended upon request of health authorities. 
Recruitment at a center may be stopped for reason that may include low recruitment, protocol 
violation, or inadequate data recording quality control and quality assurance. 
3.6. 
Poststudy Care 
Upon withdrawal from study treatment, subjects may receive the care upon which they and their 
physicians agree. 
3.7. 
Source Data 
The subject identification nmnbers captured by the interactive voice/web response system 
(IXRS) are considered source data. 
-
CONFIDENTIAL 
Page 41 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
I 
I 
CONFIDENTIAL 
Page 42 
Final 
Amendment 5 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
-
CONFIDENTIAL 
Page 43 
Final 
Amendment 5 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 44
02 October 2020
4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Up to 120 subjects will be enrolled at approximately 35 centers in the US, Europe, and rest of 
world (ROW). 
Phase 1b (Dose Escalation): Up to 44 subjects
Phase 2 (Dose Expansion):

Cohort B1 (Basket): Approximately 40 subjects
4.1.1.
Target Population
Phase 1b: Adult subjects with a histologically or cytologically confirmed advanced malignant
solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy
is available. For the 1000 mg BID cohort, histologically or cytologically confirmed advanced 
tumor expressing PD-L1 (TPS ≥ 10% or CPS ≥ 10) or MSI-H cancers. Tumor types of interest 
include NSCLC, melanoma, RCC, urothelial, esophageal, HCC, cutaneous squamous cell, 
Merkel cell, MSI-H cancers, and cHL. PD-L1 expression will not be required for Merkel cell, 
melanoma, MSI-H cancers, and cHL. See Appendix 3 for the PD-L1 expression requirement for 
specific tumor types.
Phase 2 (See Appendix 3): 

Cohort B1 (Basket): Histologically or cytologically confirmed advanced tumor expressing 
PD-L1 (TPS ≥ 1% or CPS ≥ 1 or ≥ 10) or MSI-H cancers. Tumor types of interest include 
NSCLC, melanoma, RCC, urothelial, gastric, squamous cell head and neck, HCC, MSI-H 
cancers, Merkel cell, cutaneous squamous cell, esophageal cancers, and cHL. See 
Appendix 3 for the PD-L1 expression requirement for specific tumor types.
4.1.2.
Subject Replacement
A subject who is withdrawn from the study before the completion of the first 21 days for a 
reason other than a DLT or who receives less than 16 of 21 doses of GS-4224 in the first 21 days 
will be replaced.
CCI


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
4.2. 
Inclusion Criteria 
Final 
Amendment 5 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study. Additional indication-specific inclusion criteria for 1000 mg BID Dose Escalation Cohort 
and Phase 2 are provided in Appendix 3. 
1) Male or female 
18 years of age 
2) Dose Escalation Cohorts: Histologically or cytologically confinned advanced malignant solid 
tumor that is refractory to or intolerant of all standard therapy or for which no standard 
therapy is available. 
3) Dose Expansion and 1000 mg BID Dose Escalation Cohorts: Subjects must have available 
sufficient and adequate fonnalin-fixed tumor sample preferably from a biopsy of a tumor 
lesion obtained either at the time of or after the diagnosis of advanced disease has been made 
and from a site not previously irradiated. Alternatively, subjects must agree to have a biopsy 
taken prior to entering the study to provide adequate tissue. For the 1000 mg BID dose 
escalation cohort, subjects with melanoma, Merkel cell, MSI-H cancers, and cHL are not 
required to have archival or fresh biopsy tissue. 
5) All persisting toxic effects of any prior anti tumor therapy resolved to National Cancer 
Institute-Common Tenn inology Criteria for Adverse Events (NCI-CTCAE) version 5.0 
Grade :S 1 or baseline before the first dose of study drug (with the exception of alopecia 
[Grade 1 or 2 pennitted] and neurotoxicity [Grade 1 or 2 pennitted]). 
6) Eastern Cooperative Oncology Group (ECOG) Perfonnance Status of :S 2 
7) Life expectancy of~ 3 months, in the opinion of the investigator 
8) Adequate organ function defined as follows: 
a) Hematologic: Platelets~ 100 x 109/L (~ 60 x 109/L in subjects with HCC); Hemoglobin 
9.0 g/dL; ANC 
1.5 x 109/L (without blood transfusion, platelet transfusion, or growth 
factors within previous 7 days of the hematologic laboratory values obtained at screening 
visit) 
b) Hepatic: AST/ ALT :S 2.5 x upper limit of nonnal (ULN) (if liver metastases are present, 
:S 5 x ULN); total or conjugated bilirubin :S 1.5 x ULN 
c) Renal: Creatinine clearance (CLcr) 
45 mL/min as calculated by the Cockcroft-Gault 
method 
CONFIDENTIAL 
Page 45 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 46
02 October 2020
9) Coagulation: Subjects on full-dose oral anticoagulation, except warfarin, which is an 
excluded medication, must be on a stable dose (minimum duration 14 days). Subjects on low 
molecular weight heparin will be allowed.
10) Negative serum pregnancy test for female subjects
11) Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol-specified method(s) of contraception as described in 
Appendix 5.
12) Females who are nursing must agree to discontinue nursing before the first dose of GS-4224. 
13) Able and willing to provide written informed consent to participate in the study 
14) Patients with history of human immunodeficiency virus (HIV) infection should have a 
CD4+ T-cell count ≥ 350 cells/L at screening.
15) Patients with serological evidence of chronic HBV should have HBV viral load below the 
limit of quantification at screening.
16) Patients with serological evidence of hepatitis C virus infection (HCV) should have 
completed curative antiviral treatment and have HCV viral load below the limit of 
quantification at screening.
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
Additional indication-specific exclusion criteria for 1000 mg BID Dose Escalation Cohort and 
Phase 2 are provided in Appendix 3.
1) History or evidence of clinically significant disorder, condition, 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.
2) Dose Escalation Cohorts: History of ≥Grade 3 AEs during prior treatment with an immune 
checkpoint inhibitor, or history of discontinuation of treatment with an immune checkpoint 
inhibitor due to AEs.
3) Dose Escalation 1000 mg BID and Dose Expansion Cohorts: Prior treatment with an immune 
checkpoint inhibitor (anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies).
4) History of autoimmune disease (for example, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré 
syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis).
5) Positive serum pregnancy test (Appendix 5)


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 47
02 October 2020
6) Patient has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Patients with previously treated brain metastases may participate provided they 
are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or 
enlarging brain metastases and if taking corticosteroids, are on stable or decreasing doses for 
at least 7 days from first dose of study drug.
7) Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, 
active or chronic bleeding event within 28 days prior to first dose of study drug, or 
psychiatric illness/social situation that would limit compliance with study requirements as 
judged by treating physician.
8) Myocardial infarction, symptomatic congestive heart failure (New York Heart Association 
Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within 
the last 6 months of first dose of study drug.
9) Major surgery, defined as any surgical procedure that involves general anesthesia and a 
significant incision (ie, larger than what is required for placement of central venous access, 
percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug.
10) Impairment of GI function or GI disease that may significantly alter the absorption of 
GS-4224, including any unresolved nausea, vomiting, or diarrhea that is Common 
Terminology Criteria for Adverse Events (CTCAE) Grade > 1.
11) Symptomatic ascites or pleural effusion. A patient who is clinically stable following 
treatment for these conditions (including thora- or para-centesis) is eligible.
12) Minor surgical procedure(s) within 7 days of enrollment, or not yet recovered from prior 
surgery (placement of central venous access device, fine needle aspiration, or endoscopic 
biliary stent ≥ 1 day before enrollment is acceptable).
13) Prior systemic radiation therapy completed within 4 weeks of the first dose of study drug, 
prior local radiation therapy completed within 2 weeks of Cycle 1 Day 1 (C1D1), or 
radiopharmaceuticals (strontium, samarium) within 8 weeks of C1D1.
14) Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within 
21 days or 5 half-lives, whichever is longer, of study drug dosing (6 weeks for nitrosoureas, 
mitomycin C, or molecular agents with t1/2 > 10 days); concurrent use of hormone therapy for 
prostate cancer is permitted.
15) History of long QT syndrome or additional risk factors for Torsades de Pointes or whose 
corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged 
(> 480 ms). 
16) Use of concomitant medications that prolong QT/QTc interval at screening
17) Clinically significant bleeding within 28 days of the first dose of study drug


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 48
02 October 2020
18) Known hypersensitivity to study drug, the metabolites, or formulation excipients
19) Use of any prohibited concomitant medications as described in Section 5.5 and any 
investigational agent within 2 weeks of study treatment initiation
20) Breastfeeding female
21) Received live virus vaccination within 30 days of first dose of study treatment. Seasonal flu 
vaccines that do not contain live virus are permitted.
22) History of hematologic stem cell transplant or solid organ transplant


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 49
02 October 2020
5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Randomization, Blinding and Treatment Codes
An IXRS will be employed to manage the conduct of the study. In Phase 1b and/or Phase 2, the 
IXRS will be used to maintain a central log documenting enrollment, to manage dose 
modifications, to assess current inventories of study drug, to initiate any necessary resupply of 
study drug, and to document discontinuation of study drug and study participation.
This is an open-label study in both the dose escalation (Phase 1b) and the dose expansion 
(Phase 2) portions of the study. 
5.2.
Description and Handling of GS-4224
5.2.1.
Formulation
GS-4224 tablets are prepared using GS-4224-03 (bis-fumarate salt). Orange, film-coated tablets
are available at a strength of 100 mg (free base equivalent) and are supplied as orange,
capsule-shaped, plain-faced, film-coated tablets. In addition to the active ingredient, each orange,
film-coated tablet contains the following inactive ingredients: mannitol, microcrystalline 
cellulose, crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene 
glycol, talc, iron oxide yellow, iron oxide red, and ferrosoferric oxide.
Green, film-coated tablets are also prepared using GS-4224-03 (bis-fumarate salt) and are 
available in strengths of 100 mg, 200 mg, and 500 mg (free base equivalent). The 
100-mg-strength tablets are supplied as green, round, film-coated tablets that are debossed with 
“GSI” on one side of the tablet and “100” on the other side of the tablet. The 200-mg-strength 
tablets are supplied as green, round, film-coated tablets that are debossed with “GSI” on one side 
of the tablet and “200” on the other side of the tablet. The 500-mg-strength tablets are supplied 
as green, capsule-shaped, film-coated tablets that are debossed with “GSI” on one side of the 
tablet and “500” on the other side of the tablet. In addition to the active ingredient, each green,
film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, 
crospovidone, magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, 
talc, iron oxide yellow, and ferrosoferric oxide. 
5.2.2.
Packaging and Labeling
GS-4224 tablets are packaged in white, high density polyethylene bottles. Each bottle contains 
30 tablets, silica gel desiccant, and polyester packing material. Each bottle is capped with a 
child-resistant polypropylene screw cap fitted with an induction sealed, aluminum-faced liner.
Study drug(s) to be distributed to centers in participating countries shall be labeled to meet
applicable requirements of the FDA, European Union (EU) Guideline to Good Manufacturing 
Practice - Annex 13 (IMP), and/or other local regulations.


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
5.2.3. 
Storage and Handling 
Final 
Amendment 5 
GS-4224 tablets should be stored refrigerated (2-8°C). Storage conditions are specified on the 
label. Keep bottles tightly closed to protect from moisture and allow them to warm to room 
temperature prior to opening. When a 100-mg bottle is removed from storage for dosing, keep 
tightly closed when not in use and store below 30°C for up to 4 weeks (28 days). The 200-mg 
and 500-mg tablets may be stored below 30°C for up to 12 weeks (84 days). Until dispensed to 
the subjects, all study drug bottles should be stored in a securely locked area, accessible only to 
authorized site personnel. To ensure the stability and proper identification, the drug products 
should be stored in the containers in which they were supplied. 
5.3. 
Dosage and Administration of GS-4224 
The GS-4224 study drug will be supplied as tablets in strengths of 100 mg, 200 mg, and/or 
500 mg. GS-4224 will be taken once daily in the morning (400 1500 mg QD cohorts) and 
1000 mg twice daily separated by approximately 12 hours (1000 mg BID cohort). 
On days with intensive PK (Cycle 1 Days 1 and 15), study drug will be administered at the same 
time every morning with approximately 240 mL of water and following an overnight fast 
(no food or drinks, except water, for at least 8 hours). For study treatments including those of 
more than 5 tablets, up to an additional 120 mL of water can be administered, if necessary. Water 
will be withheld starting 1 hour before and for 2 hours after dose administration, except for water 
given with the study drug. Water may be consumed by subjects following the 2-hour blood draw 
for the remainder of the collection period. A meal (standardized lunch) will be provided to 
subjects after the 4 hour postdose blood draw. All other fluids will be allowed after the 4 hour 
postdose blood draw. 
For all days that study drug is administered where no intensive PK assessments are required, 
GS-4224 should be administered without regard to food at approximately the same time every 
morning. Subjects should administer study drug with a full glass of water. 
If vomiting occurs after administration of study drug, the dose should not be repeated. 
5.4. 
Dose Modifications and Treatment Interruption of GS-4224 
5.4.1. 
Dose Modifications 
For Dose Escalation 400 1500 mg QD cohorts, after completing 4 cycles of treatment and C5D 1 
scans, subjects receiving GS-4224 at a dose level below that which has been deemed to be safe 
by the SRT may, at the investi ator's discretion receive GS-4224 at the hi hest dose deemed to 
be safe b the SRT. 
CONFIDENTIAL 
Page 50 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 51
02 October 2020
5.4.2.
Treatment Interruption for GS-4224
The following qualifying AEs must lead to interruption of GS-4224 administration, unless there 
is another obvious attribution (eg, trauma, PD):

Dose interruption should occur for Grade ≥ 3 serum creatinine (more than 3baseline) 
toxicity;

Dose interruption should occur in subjects with any Grade 3 or Grade 4 elevation in AST or 
ALT associated with a Grade 2 elevation in bilirubin;

Any Grade ≥ 3 non-skin, drug-related AE with the following exceptions:
Do not interrupt treatment for Grade ≥ 3 fatigue

Any Grade ≥ 3 drug-related laboratory abnormality with the following exceptions for 
lymphopenia:
Grade 3 lymphopenia does not require a dose interruption 

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants interrupting the dose of study drug
Subjects receiving GS-4224 who have drug-related toxicities that meet the criteria for dose 
interruption should have GS-4224 interrupted until criteria to resume treatment are met.
Note: GS-4224 should be discontinued in subjects who experience any Grade ≥ 3 skin 
drug-related AE with systemic signs or symptoms or suspected Stevens-Johnson syndrome (SJS) 
or toxic epidermal necrolysis (TEN).
5.4.3.
Management of Immune-Related Adverse Events
Immuno-oncology agents such as GS-4224 are associated with irAEs. Early recognition and 
management of irAEs may mitigate severe toxicity. Investigators should also monitor subjects 
closely for potential irAEs, which may manifest after weeks of treatment, at the earliest. 
Such events may consist of persistent rash, diarrhea, colitis, autoimmune hepatitis, pneumonitis, 
encephalitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other inflammatory 
eye conditions.
Management algorithms have been developed to assist investigators in assessing and managing 
the following groups of irAEs: GI, pulmonary, dermatological, renal, hepatic, neurological, and 
endocrine, among others. 
AEs (both non-serious and serious) associated with drug exposure and consistent with an 
immune phenomenon may represent an immunologic etiology. These irAEs may be predicted 
based on the nature of the study drugs, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action. An irAE can occur any time from 
shortly after the first dose to several months after the last dose of treatment. Particular attention 
should be paid to AEs that may be suggestive of potential irAEs, as outlined below.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 52
02 October 2020
5.4.4.
Dermatological irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol.
Table 5-1.
Dermatological irAE Management Algorithm
Dermatological irAEs
CTCAE Grade of Rash
Management
Follow Up
Grade 1-2
Covering ≤30% body surface 
area
Symptomatic therapy 
(eg, antihistamines, topical 
corticosteroids).
Continue GS-4224 therapy per 
protocol.
If persists > 1 to 2 weeks or recurs: 
Consider skin biopsy.
Delay GS-4224 therapy.
Consider 0.5-1 mg/kg/day 
methylprednisolone IV or oral equivalent. 
Once improving, taper corticosteroids over 
≥1 month; consider prophylactic 
antibiotics for opportunistic infections; and 
resume GS-4224 therapy per protocol.
If worsens: Treat as Grade 3-4.
Grade 3-4
Covering > 30% body surface 
area; life-threatening 
consequences
Interrupt or discontinue 
GS-4224 therapy per protocol.
Consider skin biopsy.
Dermatology consult
1-2 mg/kg/day 
methylprednisolone IV or IV 
equivalent.
If improves to Grade 1: Taper 
corticosteroids over ≥1 month; add 
prophylactic antibiotics for opportunistic 
infections.
Resume GS-4224 therapy per protocol.
CTCAE
Common Terminology Criteria for Adverse Events; irAE
immune related adverse event; IV
intravenous(ly)
5.4.5.
Gastrointestinal (GI) irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy. Opiates/narcotics may mask symptoms of perforation. Infliximab should not be 
used in cases of perforation or sepsis.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 53
02 October 2020
Table 5-2.
Gastrointestinal (GI) irAE Management Algorithm
Gastrointestinal (GI) irAEs
CTCAE Grade of Diarrhea/Colitis
Management
Follow Up
Grade 1
Diarrhea: < 4 stools/day over baseline.
Colitis: asymptomatic.
Continue GS-4224 
therapy per protocol.
Symptomatic treatment.
Close monitoring for worsening 
symptoms.
Educate subject to report worsening 
immediately.
Consider symptomatic treatment including 
hydration, electrolyte replacement, dietary 
changes (eg, American Dietetic 
Association colitis diet), and loperamide.
If worsens: Treat as Grade 2 or 3-4.
Grade 2
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated < 24 h; 
not interfering with activities of daily 
living (ADL).
Colitis: abdominal pain; blood in stool. 
Interrupt GS-4224 therapy 
per protocol.
Symptomatic treatment.
If improves to Grade 1: Resume 
GS-4224 therapy per protocol.
If persists > 5 to 7 days or recurs: 
0.5-1 mg/kg/day methylprednisolone or 
equivalent.
When symptoms improve to Grade 1, 
taper corticosteroids over ≥1 month; 
consider prophylactic antibiotics for 
opportunistic infections; resume GS-4224 
therapy per protocol.
If worsens or persists > 3 to 5 days with 
oral corticosteroids: Treat as Grade 3-4.
Grade 3-4
Diarrhea (Grade 3): ≥7 stools per day 
over baseline; incontinence; IV fluids 
≥24 h; interfering with ADL.
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs.
Grade 4: life-threatening, perforation
Discontinue GS-4224 
therapy per protocol.
1-2 mg/kg/day 
methylprednisolone IV or 
equivalent.
Add prophylactic 
antibiotics for 
opportunistic infections.
Consider lower 
endoscopy.
If improves: Continue corticosteroids 
until Grade 1, then taper over ≥1 month.
If persists > 3 to 5 days or recurs after 
improvement: Add infliximab 5 mg/kg 
(if no contraindication).
Note: Infliximab should not be used in 
cases of perforation or sepsis.
ADL
activities of daily living; CTCAE
Common Terminology Criteria for Adverse Events; irAE
immune related adverse 
event; IV
intravenous(ly)
5.4.6.
Pulmonary irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol. Evaluate with imaging and pulmonary consultation.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 54
02 October 2020
Table 5-3.
Pulmonary irAE Management Algorithm
Pulmonary irAEs
CTCAE Grade of Pneumonitis
Management
Follow Up
Grade 1
Radiographic changes only.
Consider interruption of 
GS-4224 therapy per protocol.
Monitor for symptoms every 2-3 
days.
Consider pulmonary and 
infectious disease consults.
Re-image every ≥3 weeks.
If worsens: Treat as Grade 2 or Grade 3-4.
Grade 2
Mild to moderate new symptoms
Interrupt GS-4224 therapy per 
protocol.
Pulmonary and infectious 
disease consults.
Monitor symptoms daily; 
consider hospitalization.
1 mg/kg/day 
methylprednisolone IV or oral 
equivalent.
Consider bronchoscopy, lung 
biopsy.
Re-image every 1-3 days.
If improves: When symptoms return to 
near baseline, taper corticosteroids over 
≥1 month, then resume GS-4224 therapy 
per protocol, and consider prophylactic 
antibiotics.
If not improving after 2 weeks or 
worsening: Treat as Grade 3-4.
Grade 3-4
Severe new symptoms; new/ 
worsening hypoxia; life-
threatening.
Discontinue GS-4224 therapy 
per protocol.
Hospitalize.
Pulmonary and infectious 
disease consults.
2-4 mg/kg/day 
methylprednisolone IV or IV 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider bronchoscopy, lung 
biopsy.
If improves to baseline: Taper 
corticosteroids over ≥6 weeks.
If not improving after 48 h or worsening: 
Add additional immunosuppression 
(eg, infliximab, cyclophosphamide, IV 
immunoglobulin, mycophenolate mofetil).
CTCAE
Common Terminology Criteria for Adverse Events; irAE
immune related adverse event; IV
intravenous(ly)
5.4.7.
Hepatic irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol. Consider imaging for obstruction.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 55
02 October 2020
Table 5-4.
Hepatic irAE Management Algorithm
Hepatic irAEs
CTCAE Grade of Liver Test Elevation
Management
Follow Up
Grade 1
AST or ALT > ULN to 3 ULN or total 
bilirubin > ULN to 1.5 ULN
Continue GS-4224 therapy per 
protocol
Continue liver function tests 
(LFT) monitoring per protocol.
If worsens: Treat as Grade 2 or 
Grade 3-4.
Grade 2
AST or ALT > 3 to ≤5 ULN or total 
bilirubin > 1.5 to ≤3 ULN
Interrupt GS-4224 therapy per 
protocol
Increase frequency of monitoring 
to every 3 days
If subject has concurrent AST or 
ALT > 3 ULN and total 
bilirubin > 2 ULN, discontinue 
GS-4224 therapy per protocol.
If returns to baseline: Resume 
routine monitoring; resume 
GS-4224 therapy per protocol.
If elevations persist > 5 to 7 days 
or worsen: 0.5-1 mg/kg/day 
methylprednisolone IV or oral 
equivalent. When LFT returns to 
Grade 1 or baseline, taper 
corticosteroids over ≥1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume GS-4224 therapy per 
protocol.
Grade 3-4
AST or ALT > 5 ULN and/or total 
bilirubin > 3 ULN.
Discontinue GS-4224 therapy per 
protocol
Increase frequency of monitoring 
to every 1-2 days
1-2 mg/kg/day 
methylprednisolone IV or oral
equivalent.*
Add prophylactic antibiotics for 
opportunistic infections
Consult gastroenterology
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted
If returns to Grade 2: Taper 
corticosteroids over ≥1 month.
If does not improve in > 3 to 
5 days, worsens or rebounds: 
Add mycophenolate mofetil 1 g 
twice daily. If no response within 
an additional 3-5 days, consider 
other immunosuppressants per 
local guidelines.
* 
The recommended starting dose for Grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV.
ALT
alanine aminotransferase; AST
aspartate aminotransferase; CT
computed tomography; CTCAE
Common 
Terminology Criteria for Adverse Events; irAE
immune related adverse event; IV
intravenous(ly); LFT
liver function test; 
MRI
magnetic resonance imaging; ULN
upper limit of normal
5.4.8.
Endocrine irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol. Consider visual field testing, endocrinology consultation, and 
imaging.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 56
02 October 2020
Table 5-5.
Endocrine irAE Management Algorithm
Endocrine irAEs
Endocrine Disorder
Management
Follow Up
Asymptomatic TSH abnormality
Continue GS-4224 therapy per protocol.
If TSH < 0.5 lower limit of normal (LLN) or TSH > 2 ULN, or 
consistently out of range in 2 subsequent measurements: Include free 
thyroxine at subsequent cycles as clinically indicated; consider 
endocrinology consult.
Symptomatic endocrinopathy
Evaluate endocrine function.
Consider pituitary scan.
Symptomatic with abnormal 
lab/pituitary scan: Interrupt
GS-4224 therapy per protocol; 
1-2 mg/kg/day 
methylprednisolone IV or oral 
equivalent; initiate appropriate 
hormone therapy
No abnormal lab/pituitary 
MRI scan but symptoms 
persist: Repeat labs in 
1-3 weeks, MRI in 1 month.
If improves (with or without hormone 
replacement): Taper corticosteroids over 
≥1 month and consider prophylactic 
antibiotics for opportunistic infections.
Resume GS-4224 therapy per protocol.
Subjects with adrenal insufficiency may 
need to continue corticosteroids with 
mineralocorticoid component.
Suspicion of adrenal crisis
(eg, severe dehydration, 
hypotension, shock out of 
proportion to current illness)
Interrupt or discontinue GS-4224 therapy per protocol
Rule out sepsis
Stress dose of IV corticosteroids with mineralocorticoid activity
IV fluids
Consult endocrinologist
If adrenal crisis ruled out, treat as above for symptomatic endocrinopathy
irAE
immune related adverse event; IV
intravenous(ly); LLN
lower limit of normal; MRI
magnetic resonance imaging; 
TSH
thyroid stimulating hormone; ULN
upper limit of normal
5.4.9.
Renal irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 57
02 October 2020
Table 5-6.
Renal irAE Management Algorithm
Renal irAEs
CTCAE Grade of Creatinine Elevation
Management
Follow Up
Grade 1
Creatinine > ULN and > baseline but ≤1.5 
baseline
Continue GS-4224 therapy per 
protocol.
Monitor creatinine weekly.
If returns to baseline: Resume 
routine creatinine monitoring per 
protocol.
If worsens: Treat as Grade 2 or 
Grade 3-4.
Grade 2-3
Creatinine > 1.5 baseline to 
≤6 ULN
Interrupt GS-4224 therapy per 
protocol
Monitor creatinine every 
2-3 days
0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent
Consider renal biopsy
If returns to Grade 1: Taper 
corticosteroids over ≥1 month, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume GS-4224 therapy and 
routine creatinine monitoring per 
protocol.
If elevations persist > 7 days or 
worsen: Treat as Grade 4.
Grade 4
Creatinine > 6 ULN
Discontinue GS-4224 therapy 
per protocol
Monitor creatinine daily
1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
Consult nephrologist
Consider renal biopsy
If returns to Grade 1: Taper 
corticosteroids over ≥1 month and 
add prophylactic antibiotics for 
opportunistic infections.
CTCAE
Common Terminology Criteria for Adverse Events; irAE
immune related adverse event; IV
intravenous(ly); 
ULN
upper limit of normal
5.4.10.
Neurological irAEs
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and 
continue therapy per protocol.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 58
02 October 2020
Table 5-7.
Neurological irAE Management Algorithm
Neurological irAEs
CTCAE Grade of Neurological Toxicity
Management
Follow Up
Grade 1
Asymptomatic or mild symptoms; 
intervention not indicated.
Continue GS-4224 therapy per 
protocol
Continue to monitor subject
If worsens: Treat as Grade 2 or 
Grade 3-4
Grade 2
Moderate symptoms; limiting instrumental 
ADL.
Interrupt GS-4224 therapy per 
protocol
Treat symptoms per local 
guidelines
Consider 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent
If returns to baseline: Resume 
GS-4224 therapy per protocol
If worsens: Treat as Grade 3-4
Grade 3-4
Severe symptoms; limiting self-care ADL; 
life-threatening
Discontinue GS-4224 therapy per 
protocol
Obtain neurology consult
Treat symptoms per local 
guidelines
1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade 2: Taper 
corticosteroids over ≥1 month
If worsens or atypical 
presentation: Consider IV 
immunoglobulin or other 
immunosuppressive therapies 
per local guidelines
ADL
activities of daily living; CTCAE
Common Terminology Criteria for Adverse Events; irAE
immune related adverse 
event; IV
intravenous(ly)
5.5.
Prior and Concomitant Medications
5.5.1.
Concomitant Medications
As of 30 March 2020, limited clinical drug-drug-interaction studies have been conducted with 
GS-4224.
In vitro data suggest that GS-4224 is a potential inhibitor of P-glycoprotein (P-gp), cytochrome 
P450 enzyme (CYP)2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, uridine diphosphate 
glucuronosyltransferase 1A1 (UGT1A1) and organic anion transporting polypeptide 
(OATP)1B1/3. In the absence of clinical data, administration of sensitive substrates of, or narrow 
therapeutic index drugs that are metabolized or transported by, these enzymes and transporters is 
not permitted from 14 days prior to the first dose of GS-4224, during the study period, and 
through the end of the follow-up visit, unless new data becomes available that would allow 
concomitant use of drugs described above during the study. Furthermore, in vitro data suggest 
that GS-4224 may be eliminated by metabolism with contribution by CYP3A and 
Sulfotransferase Family 2A Member 1 (SULT2A1), and may be a substrate of P-gp and breast 
cancer resistance protein (BCRP) transporters. In the absence of clinical data, administration of 
strong or moderate inhibitors or inducers of these enzymes and transporters is not permitted from 
14 days prior to the first dose of GS-4224, during the study period, and through the end of the 
follow-up visit.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 59
02 October 2020
Examples of medications which are prohibited 14 days prior to the first dose of study drug,
during the study period and through the end of the follow-up visit are listed in Table 5-8.
Administration of the listed medications may be permitted only if the study investigator deems it 
necessary for the treatment of a condition that emerges during the course of the study and with 
the approval of the medical monitor. 
Preliminary data from a study that evaluated the effect of famotidine on the plasma exposures of 
GS-4224 indicated no clinically meaningful effect of acid-reducing agents on the PK of 
GS-4224. Based on these results, subjects can be allowed to concomitantly administer acid-
reducing agents. It is recommended that subjects do not exceed the standard doses of the 
acid-reducing agents that are substrates for enzymes that are potentially inhibited by GS-4224 
(eg, rabeprazole 20 mg once daily, lansoprazole 30 mg once daily, omeprazole 40 mg once daily, 
etc.).
Any medications not on the list should be reviewed with the sponsor prior to and during the 
study treatment period with GS-4224.
Subjects who are currently taking other prescription or non-prescription medications may still be
entered into the study if, in the judgment of the sponsor and the investigator, the medication will
not interfere with the study procedures or compromise subject safety and/or PK assessments. In 
instances where an excluded medication is initiated prior to discussion with the sponsor, the 
investigator must notify Gilead as soon as he/she is aware of the use of the excluded medication. 
Vitamins, ibuprofen, acetaminophen (preferred over ibuprofen if both are applicable), and 
hormonal contraceptive medications are allowed during the study period.
Table 5-8.
List of Agents Disallowed with GS-4224
Drug Class
Agents Disallowed
Antibiotics
Ciprofloxacin, Clarithromycin, Erythromycin
Anticonvulsants
Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin
Antidiabetics
Glimepiride, Glyburide, Repaglinide
Antidepressants
Fluoxetine, Fluvoxamine, Nefazodone
Antifungals
Fluconazole, Itraconazole, Ketoconazole, Posaconazole, Voriconazole
Antimycobacterials
Rifamycins
Antipsychotic
Lurasidone, Pimozide, Quetiapine
Anxiolytics
Buspirone, Diazepam, Triazolam
Cardiac Medications
Amiodarone, Bosentan, Dabigatran Etexilate, Digoxin, Diltiazem, Dronedarone, 
Eplerenone, Felodipine, Nisoldipine, Propafenone, Quinidine, Ranolazine, 
Rivaroxaban, Telmisartan, Tolbutamide, Verapamil, Warfarin 
Diuretics
Conivaptan
GI Motility Agents
Cisapride
Herbal/Natural Supplements
Chinese herb sho saiko to (or Xiao Shai Hu Tang), Echinaccea. Milk thistle 
(ie, silymarin), St. John’s Wort
Other
Aprepitant, Celecoxib, Colchicine, Cyclosporine, Fexofenadine, HMG CoA
Reductase Inhibitors (“Statins”), Modafanil, Sildenafil, Tacrolimus, Tadalafil
GI  gastrointestinal; HMG CoA  3 hydroxy 3 methylglutaryl coenzyme A


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 60
02 October 2020
The potential for GS-4224 to prolong the QT interval has not been evaluated. In the absence of 
clinical data, administration of any drug that is known to demonstrate QT prolongation should 
not be permitted from 14 days prior to the first dose of GS-4224, during the study period and 
through the end of the follow-up visit. Administration of a drug that is known to demonstrate QT 
prolongation may be permitted only if the study investigator deems it necessary for the treatment 
of a condition that emerges during the course of the study and with the approval of the medical 
monitor. 
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 community standards of 
medical care. Concomitant medications include all prescription, over-the-counter (OTC), herbal
supplements, and IV medications and fluids. All concomitant medications received within 
30 days before the first dose of study treatment through the 30 day follow-up visit should be 
recorded on the electronic case report form (eCRF). Palliative and supportive care is permitted 
during the course of the study for underlying medical conditions and management of symptoms.
Surgery for tumor control or symptom management 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 and treatment is not
administered for tumor control. Study therapy should be held during the course of palliative 
radiotherapy and should be resumed no earlier than the next scheduled administration of study
therapy. The specifics of the radiation treatment, including the location, will be recorded.
5.5.2.
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 American Society of Clinical Oncology 
(ASCO) guidelines for use of erythropoietin or derivatives.

Neutropenia: Prophylactic use of colony-stimulating factors including Granulocyte 
Colony-Stimulating Factor (G-CSF), PEGylated (Polyethylene Glycol-Coated) G-CSF, or 
Granulocyte Macrophage Colony-Stimulating Factor (GM CSF) is not allowed in this study. 
Therapeutic use of G-CSF is allowed in subjects with Grade 3-4 febrile neutropenia. 
Consider a potential immunologic etiology.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 61
02 October 2020

Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. Immune 
thrombocytopenia purpura (ITP) 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 adverse 
experiences 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 (see Sections 5.4.3 to 5.4.10 for 
management algorithms guidance).
5.5.3.
Prohibited and/or Restricted Treatments
Pre-medications should not be administered routinely prior to dosing of study drugs.
Subjects are prohibited from receiving the following therapies and treatments during the study:

Immunotherapy not specified in this protocol

Chemotherapy

Investigational agents other than GS-4224

Corticosteroids for any purpose other than to modulate symptoms from an irAE, or for use as 
a premedication in subjects with a known history of hypersensitivity reactions (ie, IV contrast 
for imaging)
Note: Systemic corticosteroid dose of prednisone 10 mg daily or equivalent is permitted 
while on study
Note: Use of intraocular, intranasal, inhaled, or topical corticosteroid is permitted

Bisphosphonates and/or receptor activator of nuclear factor kappa-B ligand (RANKL)
inhibitor therapies should be initiated if indicated before informed consent has been signed. 
These therapies may be continued if treatment with an agent from one of these 2 classes was 
initiated prior to signing informed consent.

Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.

There are no prohibited therapies during the Posttreatment Follow-up Phase.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 62
02 October 2020
5.5.4.
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.
5.6.
Accountability
The investigator is responsible for ensuring adequate accountability of all used and unused study 
drug. This includes acknowledgment of receipt of each shipment of study drug (quantity and 
condition). All used and unused study drug dispensed to subjects must be returned to the site.
Each study site must keep accountability records for GS-4224 that capture:

The date received and quantity of study drug kits

The date, subject number, and the study drug kit number dispensed

The date, quantity of used and unused study drug kit returned, along with the initials of the 
person recording the information.
5.7.
Investigational Medicinal Product (IMP) Return or Disposal
Gilead recommends that used and unused study drug supplies be returned to the shipping facility 
from which it came for eventual destruction. The study monitor will provide instructions for 
return. If return is not possible, the study monitor will evaluate each study center’s study drug
disposal procedures and provide appropriate instruction for destruction of unused stud drug
supplies. If the investigator 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 the trial master file. 
If study drug is destroyed on site, the investigator must maintain accurate records for all study 
drug 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.
The study monitor will review study drug supplies and associated records at periodic intervals.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 63
02 October 2020
6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract 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. It is the responsibility of the investigator to ensure that subjects 
are eligible to participate in the study prior to enrollment and continue to remain eligible 
throughout the study.
6.2.
Pretreatment Assessments
6.2.1.
Screening Visit
Subjects will be screened within 28 days prior to the first dose of study drug to determine 
eligibility for participation in the study. The following will be performed and documented at 
screening: 
Within 28 days prior to the first dose of study drug:

Obtain written informed consent

Obtain medical and medication history

Complete physical examination including vital signs, body weight, and height

Obtain blood samples for serum pregnancy and biomarkers

Perform 12-lead electrocardiogram (ECG)

Perform computed tomography (CT) scan with contrast or magnetic resonance imaging 
(MRI). For subjects with cHL, positron emission tomography-computed tomography (PET-CT)
will also be performed. Baseline scans within 6 weeks of Cycle 1 Day 1 are acceptable.

Assess ECOG performance status

For the 1000 mg BID dose escalation cohort, 
 the 
Phase 2 Dose Expansion cohort, determine level of tumor PD-L1 

For the Phase 2 Dose Expansion cohort, collect archival tumor sample or, alternatively, 
consent for an additional pretreatment tumor biopsy.
CCI


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 64
02 October 2020
Within 10 days prior to the first dose of study drug:

Obtain blood sample for chemistry and hematology
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic within 28 days after screening into the study.
The investigator or qualified designee must obtain documented informed consent from each 
potential subject prior to participating in the clinical study.
After a subject signs an informed consent form (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.
All subjects will be given an Emergency Medical Support and Subject Card identifying them as 
participants in a research study. The card will contain study site contact information (including 
direct telephone numbers) to be utilized in the event of an emergency. The investigator or 
qualified designee will provide the subject with an Emergency Medical Support and Subject 
Card immediately after the subject provides written informed consent.
Subjects who fulfill all of the inclusion criteria and none of the exclusion criteria will be enrolled 
into the study. Subjects who do not meet any of the inclusion criteria or meet any of the
exclusion criteria will be considered screen fails, and their demographic information and reason 
for screen failure should be documented.
Screening procedures are to be completed within the windows detailed below and prior to the 
first dose of study treatment:
During the screening period, attention must be given to washout periods for prior treatments and 
prohibited medications.
Results from assessments performed during the initial screening period are acceptable in lieu of 
repeating a screening test if performed within the specified period and the results meet the 
inclusion/exclusion criteria.
From the time of obtaining informed consent through the first administration of study drug, 
record all serious AEs (SAEs), as well as any AEs related to protocol-mandated procedures on 
the AEs case report form (CRF/eCRF). All other untoward medical occurrences observed during 
the screening period, including exacerbation or changes in medical history are to be captured on 
the medical history CRF/eCRF. See Section 7 (Adverse Events and Toxicity Management) for 
additional details.
Subjects’ eligibility will be determined by results received from the central lab. If time 
constraints do not allow for timely processing of tests through central lab then eligibility may be 
determined using local lab results, with documentation of local lab results and sponsor approval.
PD-L1 expression may be performed using a central or local laboratory.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 65
02 October 2020
6.2.2.
Re-screening Criteria
Subjects who do not enroll within 28 days of screening will be screen failed. 
Re-screening may be allowed. Subjects who are re-screened after 28 days must be reconsented 
with a new screening number and the screening assessments must be repeated, as applicable. 
For subjects that are re-screened within 28 days, assessments with results that would exclude the 
subject will need to be repeated except for CT/MRI and/or PET-CT scans performed within 
6 weeks of C1D1 and screening biomarker samples.
6.2.3.
Baseline Assessments and Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history will 
include all active conditions; history of HBV, HCV, HIV, and/or human papilloma virus; and 
any condition diagnosed within the prior 10 years that is considered to be 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. Baseline symptoms will be 
graded and recorded according to NCI-CTCAE version 5.0. Baseline symptoms will be 
characterized in terms including seriousness, causality to previous treatment, toxicity grading, 
and action(s) taken if any.
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 staging 
manual (AJCC-8) Tumor Node Metastasis (TNM) classification at diagnosis

All therapy used for prior treatment of the tumor (including surgery, radiotherapy, 
chemotherapy, and immunotherapy)

Any other conditions treated with chemotherapy, radiation therapy, or immunotherapy

Current cancer disease status

Relevant somatic or germ line mutations detected

Chronic viral infection, status if available

Tumor markers if indicated


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 66
02 October 2020
6.2.4.
Physical Examination Including Height and Weight
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at the EOT visit as per Schedule of Assessments and Procedures 
(Appendix 2). Beginning on C1D1, a modified physical exam will be performed to monitor for 
any changes (eg, lymph nodes, lung, cardiac, abdomen, skin, neurologic, and any systems, as 
clinically indicated).
For cycles that do not require a full physical exam per the Schedule of Assessments and 
Procedures (Appendix 2), the investigator or qualified designee will perform a modified physical 
exam as clinically indicated prior to study treatment administration.
Weight without shoes should be measured at each exam. 
Height without shoes should be measured at screening only.
Clinically significant abnormal findings prior to the first dose of study drug should be recorded 
as medical history. After consent, new clinically significant abnormal findings should be 
recorded as AEs.
6.2.5.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study treatment, and at the EOT visit as specified in the table of 
assessments in Appendix 2. Vital signs will only be measured while subject is in seated or 
semi-recumbent position. Vital signs include temperature, pulse, respiratory rate, and blood 
pressure. 
6.2.6.
Eastern Cooperative Oncology Group Performance (ECOG)
ECOG performance status is an investigator assessment of the impact of the disease on the 
subject’s activities of daily living. ECOG assessments will be performed at the time points listed 
in the Study Procedures Table (Appendix 2). 
6.2.7.
Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures at screening and at 
subsequent visits as specified in Appendix 2. Clinically significant abnormal findings at 
screening should be recorded as medical history.
Subjects should rest quietly in the supine position for a minimum of 10 minutes prior to each 
scheduled ECG acquisition and should remain in that position until the recording is complete.
Where time points for ECG collection correspond to blood collection time points, ECGs should 
be acquired prior to blood collection.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 67
02 October 2020
There should be no environmental distractions (eg, TV, radio, conversation, etc.) while the 
subjects are resting prior to and during the recordings. Electrocardiograms will be recorded using 
the site's standard 12-lead ECG equipment. All ECGs will be obtained using instruments that 
analyze data using the same algorithms and produce the same data for interpretation. Electrode 
placement will be performed according to the method of Wilson, Goldberger, and Einthoven 
with a check to confirm that the augmented Vector Right (aVR) lead is not inverted.
The investigator or other qualified individuals at the study center will review ECGs to assess for 
changes in ECG intervals and morphology as compared to pretreatment ECGs.
6.2.8.
Prior and Concomitant Medications
Prior medication taken by the subject within 30 days before starting the study 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 Visit 1. Prior treatments for the current cancer will be recorded separately 
and not listed as a prior medication.
Concomitant medications, if any, taken by the subject during the study from the date of consent 
through the 30-day safety follow-up visit should be recorded. After the 30-day safety follow-up 
visit, all medications related to reportable SAEs will be recorded as defined in Section 7.
6.2.9.
Clinical Laboratory Assessments
The central laboratory will be responsible for chemistry, hematology, coagulation, urinalysis, 
and serum pregnancy testing (per Table 6-1) 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 lab results, will be reported on the eCRF. Gilead’s standard reference 
ranges will be used. 
Urine pregnancy test will be performed locally at the site.
Laboratory tests for screening (Table 6-1) should be performed within 28 days prior to the first 
dose of study treatment. After Cycle 1, predose laboratory procedures can be conducted up to 
72 h prior to dosing.
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each 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 2.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 68
02 October 2020
Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology 
Other 
Albumin
Alkaline phosphatase
ALT 
AST 
Bicarbonate
BUN/total urea
Calcium
Chloride
Serum Creatininea
GGT
Glucose
LDH
Lipase
Cholesterol
Triglycerides
Amylase
Magnesium
Phosphorus/phosphates
Potassium
Sodium
Total bilirubinb
Direct bilirubin
Total protein
Color and 
appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Nitrite
Urobilinogen
Ketones
Microscopicb
WBC and differential count
Hemoglobin
Hematocrit
Platelet count
ANC
MCH
MCHC
MCV
RBC
Differential
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Serum β−hCG or urine 
pregnancy testc
Endocrine Function Tests
TSH and freeT4d
Basal cortisol
HIV, HBsAg, and HCV
antibody viral testing in 
subjects with current or prior 
history of HIV, HBV, and 
HCV infection, respectively.b
CD4+ count will also be 
performed in subjects with 
current or prior history of 
HIV.
Coagulation
Prothrombin time (INR)
aPTT
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; CD4+  cluster 
determinant 4 positive; Free T4  free thyroxine; GGT
gamma glutamyltransferase; HBsAg  hepatitis B surface antigen; 
HBV
 hepatitis B virus; HCV  hepatitis C virus; HIV  human immunodeficiency virus; INR
international normalized ratio; 
LDH
lactate dehydrogenase; MCH
mean corpuscular hemoglobin; MCHC
mean corpuscular hemoglobin concentration; 
MCV
mean corpuscular volume; RBC
red blood cell; 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
Reflex testing based on other abnormalities
c
Females of childbearing potential only. Serum pregnancy will be conducted at screening within 72 h of first treatment dose 
(if performed earlier in screening period then a urine pregnancy test may be performed prior to first dose); urine pregnancy 
test performed at all other indicated visits. 
d
TSH and free T4 will be tested by the central laboratory. T4 will be tested reflexively based on abnormal TSH results.
6.3.
Treatment Assessments
Subject should continue to receive all assessments as defined in the Treatment Phase (C1D1 until 
EOT) of the Schedule of Assessments (Appendix 2) while they are actively receiving study
treatment.
6.4.
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 on the eCRFs.


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
6.5. 
6.5.1. 
Pharmacokinetic, Pharmacodynamic, Genetic, and Other Assessments 
Pharmacokinetic Assessments 
Intensive PK will be collected in all subjects in Phase 1 b dose cohorts between 400 mg and 
1500 mg QD. In the 1000 mg BID dose escalation cohort, intensive PK will be collected at select 
sites and in at least 6 subjects. Intensive PK samples will be collected predose on Cycle 1 Days 1 
and 15, followed by 0.5, 1, 1.5, 2.5, 4, 6, 12 (1000 mg BID dose cohort) and 0.5, 1, 1.5, 2.5, 4, 6 
and 24 (400-1500 mg QD dose cohorts) hours postdose relative to the AM dose. For the 1000 mg 
BID cohort, the 12 hours postdose samples will be collected prior to the PM dose. Every effort 
should be made to collect intensive PK samples at the indicated time; actual sample collection 
time should be recorded. 
Predose PK samples will be collected on the indicated days as described in the Study Procedures 
Table (Appendix 2) in all subjects in Phase 1 b who also have intensive PK collection (all 
subjects in dose cohorts between 400 mg and 1500 mg QD and at least 6 subjects in 1000 mg 
BID dose cohort). 
Postdose PK samples for the Sparse PK collection will be collected between 30 minutes and 
4 hours after the clinic dose on Day 1 and Day 8. 
6.5.1.1. 
Phannacokinetic Parameters 
GS-4224 plasma concentrations will be detennined by a validated method. The PK parameters to 
be estimated and reported may include, but may not be limited to, time of last observable plasma 
concentration (T1as1), maximum observed drug concentration at steady-state (Cmax), observed 
concentration at the end of the dosing interval at steady-state (C1rough), area m1der the 
concentration-time curve from time zero to last time point with measurable concentration 
(AUCias1), area under the concentration-time curve from time zero to the end of the dosing 
interval (AUCtau), time to maximum observed concentration (Tmax), tenninal disposition rate 
constant (AZ), tenn inal elimination half-life (t,12), systemic clearance after oral administration 
(CL/F), and volume of distribution after oral administration (V/F), etc. Noncompartmental 
(NCA) techniques will be used to analyze the PK. Compartmental modeling ( eg, population 
phann acokinetics [PopPK]) analysis may be conducted. 
CONFIDENTIAL 
Page 69 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
-
I 
I 
I 
I 
I 
I 
I 
I 
I 
I -
CONFIDENTIAL 
Page 70 
Final 
Amendment 5 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
6.5.2.2. 
Phase 2 Dose Expansion Biopsies: 
Final 
Amendment 5 
For the Dose Expansion Cohort B 1, subjects must have available sufficient and adequate 
fonnalin-fixed tumor tissue sample preferably from a biopsy of a tumor lesion obtained either at 
the time of or after the diagnosis of advanced disease has been made and from a site not 
previously irradiated. Alternatively, subjects must agree to have a biopsy taken prior to entering 
the study to provide adequate tissue. 
For additional details and instructions regarding tissue requirements, collection, storage and 
shipment, refer to the Study Laboratory Manual. 
6.6. 
6.6.1. 
Disease Assessments 
CT with Contrast or MRI Scan 
Subjects will be assessed by CT scan with contrast ( or MRI, if unable to tolerate CT contrast) of 
the chest, abdomen, and pelvis to document metastatic disease, identify target lesions, and to 
assess response as per RECIST vl .1 (refer to Appendix 6) for solid tumors and per Lugano 2014 
response criteria (refer to Appendix 7) for cHL. The same assessment methods should be used 
for the subject throughout all treatment cycles. CT or MRI scans will be obtained at the 
applicable study visits per the Study Procedures Table (Appendix 2) and transferred to a central 
vendor for storage. 
In subjects who caimot tolerate iodinated contrast, a CT of the lung without contrast and MRI of 
the abdomen, pelvis, and cervical region should be perfonned. Imaging by CT scan 
(with contrast) or MRI or applicable scan will be perfonned at screening ( or within 6 weeks 
before C 1 D 1 if the scan was perfonned as part of standard medical practice) and then every 
6 weeks after C 1 D 1 for the first 2 scans and then every 9 weeks during the treatment period 
regardless of cycle number or dose interruption. During the treatment, scans may be perfonned at 
time points other than specified in the protocol, as clinically indicated, to assess tumor 
progression. 
CONFIDENTIAL 
Page 71 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 72
02 October 2020
Note on PET-CT scans in subjects with cHL: Low dose or attenuation correction CT portions of 
a combined PET-CT are of limited use in anatomically based efficacy assessments and should 
not be substituted for dedicated diagnostic contrast enhanced CT scans for anatomically based 
measurements. However, if a site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with contrast) then the CT portion of the PET-CT 
can be used for measurements.
6.6.2.
PET-CT
As cHL is a fluorodeoxyglucose (18F) (FDG)-avid lymphoma, PET-CT is recommended to 
assess disease at baseline and postbaseline, using the Deauville 5-point scale (5-PS) with 
subassessments to describe the FDG-avidity of disease.
For subjects with cHL, in addition to CT or MRI scan, a baseline PET-CT is required at 
screening (or within 6 weeks before C1D1 if the scan was performed as part of standard medical 
practice), Cycle 3 Day 1, and Cycle 5 Day 1.
PET-CT will be used in lieu of a bone marrow biopsy/aspirate to assess bone marrow 
involvement. Per Lugano 2014 criteria, PET-CT is required to confirm radiographic CR in 
subjects with bone marrow involvement at screening. Thus, in subjects with bone marrow 
involvement at screening and at a time point where CR is suspected, PET-CT will be required to 
confirm CR if CR was not achieved at Cycle 3 and/or 5.
6.6.3.
Response Assessment
For subjects with solid tumors, RECIST v1.1 {Eisenhauer 2009} [Appendix 6] will be used for 
assessment of tumor responses for the purposes of study evaluation, managing subjects on 
protocol treatment, and decision making for discontinuation of study therapy due to disease 
progression, with some modifications to account for atypical responses which may occur with 
immune-based therapies {Swaika 2015}. Given that anti-PD-1 agents produce antitumor effects 
by potentiating endogenous cancer-specific immune responses, the response patterns seen with 
these agents may extend beyond the typical time course of responses seen with cytotoxic agents. 
In addition, anti-PD-1 therapies can occasionally manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions (“tumor flare” or 
“pseudoprogression”) {Topalian 2014}. In these cases, standard RECIST may not provide an 
accurate response assessment of anti-PD-1 agents. Therefore, RECIST v1.1 will be used
(see Appendix 6) with the following adaptations:

If imaging shows a CR or PR, tumor imaging should be repeated at least 4 weeks (≥4 weeks)
later to confirm response, per RECIST v1.1 guidelines. Subjects will then return to regular
scheduled imaging starting with the next protocol-specified imaging time point. Subjects who 
obtain a confirmatory scan do not need to undergo scheduled imaging assessment ≤2 weeks 
later (eg, if a subject obtains a scan at Week 22 to confirm a Week 16 response, they will not 
also be required to complete the scheduled Week 24 scan).


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 73
02 October 2020

If imaging shows PD, it is at the discretion of the investigator to keep the subject on study 
treatment or to stop study treatment until imaging is repeated ≥4 weeks later in order to 
confirm PD (adapted from the immune-related response criteria recommendations)
{Wolchok 2009}. Subjects that are deemed clinically unstable or who have biopsy-proven 
new metastatic lesions are not required to have repeat imaging for confirmation. The decision 
to continue a subject on study while awaiting PD confirmation will be based on clinical 
judgment of a patient’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data.

Subjects should not present clinical symptoms or signs indicating clinically significant 
disease progression; no decline in performance status; absence of rapid disease progression 
or threat to vital organs or critical anatomical sites (eg, CNS metastasis, respiratory failure 
due to tumor compression, spinal cord compression) requiring urgent alternative medical 
intervention; no significant, unacceptable or irreversible toxicities related to study treatment. 
For subjects with cHL, Lugano 2014 response criteria should be used {Cheson 2014}
[Appendix 7].
For additional details and instructions regarding imaging requirements, refer to the study 
imaging manual.
6.7.
End of Study
End of study will be defined when the last subject reaches the last scheduled follow-up time
point, is lost to follow up, withdraws from the study, dies, or the time at which the sponsor closes 
the study.
6.8.
Posttreatment Assessments
6.8.1.
End of Treatment Visits
The EOT visit requirements are outlined in Appendix 2. There is an EOT visit and a 30-day 
follow-up visit, which occurs 30 days (±7 days) after last dose of study treatment.
6.8.1.1.
End of Treatment Visit
The EOT visit should occur at the time the last dose of study drug is discontinued for any reason. 
If the EOT visit occurs 30 days (±7 days) from the last dose of study treatment, at the time of the 
mandatory 30-day safety follow-up visit, procedures do not need to be repeated. Procedures at 
the time of discontinuation are detailed in Appendix 2. Subjects that discontinue from the study 
treatment for reasons other than PD will continue to have imaging/CT scans at the predefined 
schedule until documented PD or initiation of a new treatment (refer to Section 6.6).


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 74
02 October 2020
6.8.1.2.
30-Day Safety Follow-up Visit
The mandatory 30-day follow-up visit should be conducted for all subjects approximately 
30 days after the last dose of study treatment or before the initiation of a new treatment, 
whichever comes first. Subjects who miss the 30-day safety follow-up visit will be contacted by 
phone 30 days (± 7 days) after the last dose of study treatment to assess AEs.
6.9.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (eg, as a result of an AE), every attempt should be made to 
keep the subject in the study and continue to perform the required study-related follow up and 
procedures (see Section 6.10, Criteria for Discontinuation of Study Treatment). If this is not 
possible or acceptable to the subject or investigator, the subject may be withdrawn from the 
study.
6.10.
Criteria for Discontinuation from Treatment or Study
6.10.1.
Criteria for Discontinuation from Treatment
Treatment with GS-4224 should be discontinued if any of the following occur:

Occurrence of an event that would have been considered an exclusion criterion prior to 
enrollment, that is clinically relevant and affects the subject’s safety, and if discontinuation is 
considered necessary by the investigator and/or sponsor.

Disease progression, defined by RECIST v1.1 or Lugano 2014 response criteria for cHL as 
defined in Section 6.6, unless the subject is considered to derive clinical benefit from the 
treatment by the investigator, is clinically stable, and there is agreement with the sponsor.

Occurrence of any condition that fulfills criteria for permanent treatment discontinuation, as 
defined in Section 3.5

Unacceptable toxicity, or toxicity that, in the judgment of the investigator, compromises the 
ability to continue study-specific procedures or is considered to not be in the subject’s best 
interest

Pregnancy during the study; refer to Appendix 5

Use of a non-permitted concomitant and/or prohibited medication, as defined in 
Sections 5.5.1 and 5.5.3, in which the predefined consequence is withdrawal from study drug
(sponsor may be contacted to discuss whether study drug must be discontinued).

Subject Noncompliance

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. 

Subject request to discontinue for any reason


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 75
02 October 2020
6.10.2.
Discontinuation from Disease Response Evaluation
Subjects should be discontinued from tumor evaluation in the event of progression of disease 
(compared to baseline assessment) or confirmed disease progression, defined as progression 
confirmed by a second, consecutive assessment ≥4 weeks apart, in a clinically stable subject as 
defined in Section 6.6 with the option for continuing treatment while awaiting radiographic 
confirmation of progression where feasible.
6.10.3.
Criteria for Discontinuation from Study
Subjects should be discontinued from the study for 1 or more of the following:

Withdrawal of consent

Lost to follow up

Death

Subject noncompliance

Study terminated by sponsor

Adverse event

PD

Investigator’s discretion


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 76
02 October 2020
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, 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 considered related to the study drug. AEs may also include pre-
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 adverse event and must be reported.

Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae (see 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 on the medical history CRF.
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 also 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 (Note: In the case of death, the primary cause of death or the event leading to death 
should be recorded and reported as an SAE. “Fatal” will be recorded as the outcome of this 
respective event; death will not be recorded as separate event. Only if no cause of death can 
be reported [eg, sudden death, unexplained death], the death can be reported as an SAE.)


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 77
02 October 2020

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.)

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
Protocol-specific SAE reporting exemptions: 
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 drugs caused or contributed to the disease.
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 health 
care professional, patient, 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 78
02 October 2020
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.
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. 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 79
02 October 2020
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 and recorded throughout the study and during the follow-up 
period according to NCI-CTCAE version 5.0. A general grading (severity/intensity) scale is 
provided at the beginning of the referenced document, and specific event Grades are also 
provided. If a particular AE severity/intensity is not specifically graded by the guidance 
document, the investigator is to revert to the general definitions of Grade 1 through Grade 5 and 
use his/her best medical judgment.
The 5 general Grades of AE severity are:

Grade 1:
Mild

Grade 2:
Moderate

Grade 3:
Severe

Grade 4:
Life-threatening or disabling

Grade 5:
Death related to AE
Refer to Appendix 4 for more information.
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 drug, 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 drug, collect all AEs, regardless of cause or relationship, until 
30 days after last administration of study drug and report them on the eCRFs as instructed.
All AEs 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 80
02 October 2020
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 30-day safety follow-up visit, must be reported on the applicable eCRFs and Gilead GLPS as 
instructed below in this section. This also includes any SAEs resulting from protocol-associated 
procedures performed after the ICF is signed.
Any SAEs and deaths that occur within 30 days of the last dose of study drug, regardless of 
causality, should also be reported (See Section 7.1.2.1. for protocol-specified exceptions).
Investigators are not obligated to actively seek SAEs after the protocol-defined follow-up period; 
however, if the investigator learns of any SAEs that occur after 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 30-day safety follow-up visit, must be reported to Gilead GLPS 
(Section 7.4.2.). Adverse events and SAEs resulting from SSRs must be reported in accordance 
to 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 ICF) and 
throughout the duration of the study, including the posttreatment follow-up visit, 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.
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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 81
02 October 2020
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
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 GLPS.
PPD
PPD


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 82
02 October 2020
7.4.2.
Special Situations Reporting Process 
7.4.2.1.
Paper Special Situations Reporting Process for Study Drug  

All SSRs will be recorded on the special situations report 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 drug initiation throughout the duration of the study, 
including the protocol-required posttreatment follow-up period.
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 
drug 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
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, including 
the after study drug follow-up period, 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
Email:
 
or
Fax: 
PPD
PPD
PPD
PPD
PPD
PPD


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 83
02 October 2020
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 the 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 (SADRs), or suspected unexpected serious adverse reactions (SUSARs). 
In accordance with the EU Clinical Trials Directive (2001/20/EC), Gilead or a specified designee 
will notify worldwide regulatory agencies and the relevant IEC in concerned Member States of 
applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the 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
PPD


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 84
02 October 2020
7.5.1.
Clinical Laboratory Abnormalities and Other Abnormal Assessmentsas 
Adverse Events or Serious Adverse Events
Laboratory abnormalities without clinical significance are not recorded as AEs or SAEs. 
However, laboratory abnormalities (eg, clinical chemistry, hematology, and urinalysis) that 
require medical or surgical intervention or lead to study drug interruption, modification, or 
discontinuation must be recorded as an AE, as well as an SAE, if applicable. In addition, 
laboratory or other abnormal assessments (eg, 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).
For specific information on handling of clinical laboratory abnormalities in this study, please 
refer to Section 7.6.
7.6.
Toxicity Management 
Severity should be recorded and graded according to NCI-CTCAE version 5.0 (Appendix 4).


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Analysis Objectives and Endpoints 
8.1.1. 
Analysis Objectives 
The primary objectives of this study are as follows: 
Phase 1 b Dose Escalation 
Final 
Amendment 5 
• 
Characterize the safety and tolerability of GS-4224 in subjects with advanced solid tumors 
• 
Detennine the MTD and RP2D of GS-4224 in subjects with advanced solid tumors 
The secondary objectives of this study are as follows: 
Phase 1 b Dose Escalation 
• 
Evaluate the PK of GS-4224 in subjects with advanced solid tumors 
Phase 2 Dose Expansion 
• 
Evaluate the safety and tolerability of GS-4224 in subjects with advanced solid tumors 
I 
I 
I 
I 
8.1.2. 
Primary Endpoint 
The primary endpoints of this study are as follows: 
Phase 1 b Dose Escalation 
• 
Incidence ofDLT as defined in Section 3.2. 
CONFIDENTIAL 
Page 85 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
8.1.3. 
Secondary Endpoint 
The secondary endpoints are as follows: 
Phase 1 b Dose Escalation 
Final 
Amendment 5 
• 
PK parameters (T1as1, Tmax, Cmax, Ctrough, AUCiast, AUC1au and t112, as applicable) for GS-4224 
in subjects with advanced solid tumors 
Phase 2 Dose Expansion 
• 
Incidence of Grade~ 3 TEAEs in Cohort B 1 subjects with advanced solid tumors 
• 
Incidence of Grade~ 3 treatment-emergent laboratory abnonnalities in Cohort B 1 subjects 
with advanced solid tumors 
-
I 
-
I 
I 
I 
I 
I 
CONFIDENTIAL 
Page 86 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 87
02 October 2020
8.2.
Planned Analyses
8.2.1.
Interim Analysis
8.2.1.1.
Analyses for Dose Escalation Decisions
To support dose escalation decision, safety data, including DLTs and other AEs may be listed 
and summarized, if appropriate. Supportive data including demographic, disease history, 
concomitant medication, and drug administration may be listed. The analysis will occur when all 
subjects enrolled in a dose level have been followed for at least 21 days after the first dose of 
GS-4224 or two DLTs have been observed, whichever is earlier.
8.2.1.2.
Analyses for Dose Expansion Decisions
To support dose expansion decision, available and relevant clinical data from all subjects treated 
in the escalation phase may be listed and summarized, if appropriate. The analysis will occur 
when all subjects enrolled in the last cohort of dose escalation phase have been followed for at 
least 21 days after the first dose of GS-4224 or two DLTs have been observed, whichever is 
earlier.
8.2.1.3.
Primary Analysis
The study primary analysis will be conducted when all enrolled subjects have discontinued the 
study or have been on treatment of GS-4224 for at least 48 weeks and completed response 
assessment of Week 48.
Prior to the final analysis, interim analyses may be conducted, and the analyses may be 
submitted to regulatory agencies to seek guidance for the overall clinical development program.
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 in the study after screening. This will be the primary analysis set for analyses of subject 
characteristics.


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
8.3.1.2. 
Full Analysis Set 
Final 
Amendment 5 
The Full Analysis Set (FAS) includes all subjects who took at least 1 dose of study treatment. 
It will be used in the analyses of efficacy endpoints. 
8.3.1.3. 
Safety Analysis Set 
The Safety Analysis Set includes all subjects who enrolled to the study and receive at least 
1 dose of study treatment, with treatment assigmnents designated according to the actual 
treatment received. This analysis set will be used in the analyses of safety variables as well as 
study treatment administration. 
8.3.1.4. 
DLT-Evaluable Analysis Set 
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who enroll to 
the dose escalation cohorts u to the first 6 sub ·ects in the 1000 mg BID dose escalation cohort; 
), complete~ 75% of the prescribed study 
treatment and have safety assessments through the protocol-specified DL T assessment window 
(first 21 days of study dosing, inclusive) or have experienced a DL T prior to the completion of 
first 21 days of study dosing. Safety assessment relevant to the D LT-Evaluable Analysis Set 
definition will include laboratory serum chemistry tests and hematology tests as specified in the 
protocol. Detennination of the MTD will be based on the DLT-Evaluable Analysis Set. 
8.3.1.5. 
Phannacokinetics (PK) Analysis Set 
The PK Analysis Set includes subjects in the Safety Analysis Set who have received the study 
drug and have at least 1 sample with detectable drug concentration. 
-
8.4. 
Data Handling Conventions 
By-subject listings will be created for important variables from each eCRF module. Smmnary 
tables for continuous variables will contain the following statistics: N (nmnber in analysis set), 
n (number with data), mean, standard deviation, 95% Cls on the mean, median, minimum, and 
maximum. Smmnary tables for categorical variables will include: N, n, percentage, and 95% Cls 
on the percentage. Unless otherwise indicated, 95% Cls for binary variables will be calculated 
using the binomial distribution ( exact method) and will be 2-sided. Data will be described and 
smmnarized by cohort, analysis set, and time point. 
CONFIDENTIAL 
Page 88 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 89
02 October 2020
The baseline value will be the last (most recent) pretreatment value before or on the first dosing 
date of study drug. As appropriate, changes from baseline to each subsequent time point will be 
described and summarized. Graphical techniques (eg, waterfall plots, Kaplan-Meier [KM]
curves, line plots) may be used when such methods are appropriate and informative. Data from 
all sites will be pooled for all analyses. Analyses will be based upon the observed data unless 
methods for handling missing data are specified. If there is a significant degree of non-normality, 
analyses may be performed on log-transformed data or nonparametric tests may be applied, as 
appropriate.
8.5.
Demographic Data and Baseline Characteristics
Demographic and baseline measurements will be summarized by cohort, indication, and 
treatment using standard descriptive methods.
Demographic summaries will include sex, race/ethnicity, and age.
Baseline data will include summaries of body weight, height, ECOG performance status score,
12-lead ECG, and PD-L1 expression (TPS or CPS).
8.6.
Efficacy Analysis
In efficacy analysis, ORR will be evaluated by tumor type and treatment in FAS. Tumor types 
with less than 5 subjects enrolled will be pooled for ORR summary. Subjects who do not have 
sufficient baseline or on-study tumor assessment to characterize response will be counted as 
nonresponders. Estimates and the corresponding 95% CIs based on the Clopper-Pearson exact 
method will be provided. The potential impact of subject baseline characteristics on treatment 
response may be explored with logistic regression modeling. 
Medians, first quartile (Q1), third quartile (Q3) of the PFS distribution, and the proportion of 
subjects who are progression-free at Weeks 12, 24, and 48 from the first dosing date will be 
estimated by tumor type using the KM method along with the corresponding 95% CIs. KM 
curves will be provided.
The similar ORR and PFS analyses will be conducted using the investigator assessments and 
independent review committee (IRC) assessments if available. 
8.7.
Safety Analysis
Safety will be assessed via AEs, clinical laboratory tests, and concomitant medications. 
All safety data collected on or after the date that study drug was first administered up to the date 
of last dose of study drug plus 30 days will be summarized by cohort, indication and treatment in 
the Safety Analysis Set. Information regarding study drug administration, 
study drug compliance, and other safety variables will be summarized. Data for the pretreatment 
will be included in data listings.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 90
02 October 2020
8.7.1.
Extent of Exposure
A subject’s extent of exposure to study drug data will be generated from the study drug
administration data. Descriptive information will be provided by cohort, indication and treatment
regarding the number of doses of study drug prescribed, the total number of doses taken, the 
duration of exposure to study drug, and the number and timing of prescribed dose interruptions.
GS-4224 compliance will be described in terms of the proportion of study drug actually taken 
based on returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed interruptions).
8.7.2.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). System 
Organ Class (SOC), High-Level Group Term, High-Level Term, Preferred Term (PT), and 
Lower-Level Term will be attached to the clinical database. The severity of AEs will be graded 
by the investigator according to the NCI-CTCAE, version 5.0, whenever possible. If a NCI-
CTCAE criterion does not exist for a specific type of AE, the grade corresponding to the 
appropriate adjective will be used by the investigator to describe the intensity of the AE: Grade 1 
(mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal). The 
relationship of the AE to the study drug will be categorized as related or unrelated.
All AEs will be listed. The focus of AE summarization will be on TEAEs. A TEAE is defined as 
any AE with onset date on or after the date of first dose of study drug up to 30 days after 
permanent study drug discontinuation or any AEs leading to premature study drug 
discontinuation. Summaries (number and percentage of subjects) of TEAEs by SOC and PT will 
be provided by cohort, indication, and treatment.
Summary tables will be presented to show the number and percentage of subjects reporting 
TEAEs by severity grade and corresponding percentages. A subject who reports multiple TEAEs 
within the same PT (or SOC) is counted only once for that PT (or SOC) using the worst severity 
grade. Separate listings and summaries will be prepared for the following types of TEAEs:

Study drug-related AEs

AEs that are Grade ≥3 in severity

AEs leading to study drug interruption and/or dose modification

AEs leading to study drug discontinuation

SAEs


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
8.7.3. 
Laboratory Evaluations 
Final 
Amendment 5 
Selected laboratory data will be smmnarized based on observed data. Data and change from 
baseline at all scheduled time points will be summarized. The focus of laboratory data 
smmnarization will be on treatment-emergent laboratory abnonnalities. A treatment-emergent 
laboratory abnonnality is defined as an abnonnality that, compared to baseline, worsens by 
1 grade in the period from the first dose of study drug to 30 days after the last dose of study 
treatment. If baseline data are missing, then any graded abnonnality (ie, an abnonnality that is 
Grade 
1 in severity) will be considered treatment emergent. 
Graded laboratory abnonnalities will be defined using the NCI-CTCAE version 5.0 when 
applicable. Smmnary tables will be presented for each relevant assay to show the number of 
subjects by CTCAE severity grade with corresponding percentages. For parameters for which a 
CTCAE scale does not exist, the frequency of subjects with values below, within, and above the 
nonnal ranges will be smmnarized. Subjects will be characterized only once for a given assay, 
based on their worst severity grade observed during a period of interest ( eg, during the study or 
from baseline to a particular visit). 
Shift tables for selected laboratory data may also be presented by showing change in CTCAE 
severity grade from baseline to the worst grade after baseline. For parameters for which a 
CTCAE scale does not exist, shift tables presented will show change in results from baseline to 
the worst grade after baseline. Separate listings and summaries will be prepared for laboratory 
abnonnalities that are Grade~ 3 in severity. 
CONFIDENTIAL 
Page 91 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
8.10. 
Sample Size 
Final 
Amendment 5 
The sample size of the study will be detenn ined based on the nmnber of dose levels evaluated 
and the emerging GS-4224-related toxicities and efficacy. The study is pla1med to enroll 
approximately 120 subjects. 
CONFIDENTIAL 
Page 92 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 93
02 October 2020
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) GCPs and applicable laws and regulations.
9.1.2.
Financial Disclosure
The investigator and subinvestigators will provide documentation of their financial interest or 
arrangements with Gilead, or proprietary interests in the investigational drug under study. 
This documentation must be provided prior to the investigator’s (and any subinvestigator’s) 
participation in the study. The investigator and subinvestigator agree to notify Gilead of any 
change in reportable interests during the study and for 1 year following completion of the study. 
Study completion is defined as the date when the last subject completes the protocol-defined 
activities.
9.1.3.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
The investigator (or sponsor 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 and before undertaking any study-related procedures. 
The investigator must use the most current IRB or IEC approved ICF 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 and the person conducting the 
consent discussion, and also by an impartial witness if required by local requirements. The ICF
will inform subjects about pharmacogenomic testing and sample retention, and their right to 
receive clinically relevant pharmacogenomic analysis results.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 94
02 October 2020
9.1.5.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as year of birth) will be recorded on any form 
or biological sample submitted to the sponsor, IRB/IEC, or laboratory. Laboratory specimens 
must be labeled in such a way as to protect subject identity while allowing the results to be 
recorded to the proper subject. Refer to specific laboratory instructions. NOTE: The investigator 
must keep a screening log showing codes, names, and addresses for all subjects screened and for 
all subjects enrolled in the study. Subject data will be processed in accordance with all applicable 
regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the 
IB, this protocol, CRF/eCRF, the study drug, and any other study information, remain the sole 
and exclusive property of Gilead during the conduct of the study and thereafter. This information 
is not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.6.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file, and (2) subject 
clinical source documents.
The investigator’s study file will contain the protocol/amendments; CRF and query forms;
IRB/IEC and governmental approval with correspondence; ICF; drug records; staff curriculum 
vitae and authorization forms; and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender)

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria)

Documentation of the reason(s) a consented subject is not enrolled

Participation in study (including study number)

Study discussed and date of informed consent

Dates of all visits


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 95
02 October 2020

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, and including causality 
and severity)

Concomitant medication (including start and end date, dose if relevant; dose changes)

Date of study completion and reason for early discontinuation, if it occurs
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, 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, until 2 years after the investigation is discontinued and regulatory authorities 
have been notified. Investigators may be required to retain documents longer if specified by 
regulatory requirements, by local regulations, or by an agreement with Gilead. The investigator 
must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.7.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. An eCRF should 
be completed on the day of the subject visit to enable the sponsor to perform central monitoring 
of safety data. The Eligibility Criteria eCRF should be completed only after all data related to 
eligibility have been received. Subsequent to data entry, a study monitor will perform SDV 
within the electronic data capture system. Original entries as well as any changes to data fields 
will be stored in the audit trail of the system. Prior to database lock (or any interim time points as 
described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately reflect 
the information in the source documents. The eCRF capture the data required per the protocol 
schedule of events and procedures. System-generated or manual queries will be issued to the 
investigative site staff as data discrepancies are identified by the monitor or internal Gilead staff, 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 96
02 October 2020
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the system, 
either by confirming the data as correct or updating the original entry, and providing the reason 
for the update (eg, data entry error). At the conclusion of the study, Gilead will provide the site 
with a read-only archive copy of the data entered by that site. This archive must be stored in 
accordance with the records retention requirements outlined in Section 9.1.6.
9.1.8.
Investigational Medicinal Product Accountability and Return
Where possible, study drug should be destroyed at the site. If the site has an appropriate SOP for 
drug destruction as determined by Gilead, the site may destroy used (empty or partially empty) 
and unused study drug supplies in accordance with that site’s approved SOP. A copy of the site’s 
approved SOP will be obtained for central files. If study drug is destroyed on site, the 
investigator must maintain accurate records for all study drug 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. 
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 eventual destruction. The study 
monitor will provide instructions for return.
The study monitor will review study drug supplies and associated records at periodic intervals.
9.1.9.
Inspections
The investigator will make available all source documents and other records for this study to 
Gilead’s appointed study monitors, IRB/IECs, or to regulatory authority or health authority 
inspectors.
9.1.10.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB/IEC in 
accordance with local requirements and receive documented IRB/IEC approval before 
modifications can be implemented.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 97
02 October 2020
9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). Gilead 
will ensure that the CSR meets the standards set out in the ICH Guideline for Structure and 
Content of CSRs (ICH E3). Note that an abbreviated report may be prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:
the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years
The investigator will submit to Gilead any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
No such communication, presentation, or publication will include Gilead’s confidential 
information.
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Payment Reporting
Investigators and their study staff may be asked to provide services performed under this 
protocol, eg, attendance at Investigator's Meetings. If required under the applicable statutory and 
regulatory requirements, Gilead will capture and disclose to Federal and State agencies any 
expenses paid or reimbursed for such services, including any clinical study payments, meal, 
travel expenses or reimbursements, consulting fees, and any other transfer of value.
9.3.2.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 98
02 October 2020
9.3.3.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.
9.3.4.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 99
02 October 2020
10.
REFERENCES
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations For Initial Evaluation, Staging, and Response Assessment Of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
2014;32 (27):3059-68.
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.
Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in 
cancer therapy. Mol Immunol 2015;67 (2 Pt A):4-17.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, 
durable tumor remission, and long-term safety in patients with advanced 
melanoma receiving nivolumab. J Clin Oncol 2014;32 (10):1020-30.
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related 
Response Criteria. Clin Cancer Res 2009;15 (23):7412-20.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5 
CONFIDENTIAL
Page 100
02 October 2020
11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
Tumor Specific Inclusion/Exclusion Criteria
Appendix 4.
NCI-CTCAE Grading Scale for Severity of Adverse Events and Laboratory 
Abnormalities
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Requirements
Appendix 6.
Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1)
Appendix 7.
Response Assessment for Classic Hodgkin Lymphoma (Lugano Classification)
Appendix 8.
Pandemic Risk Assessment and Mitigation Plan


GS-4224 
Protocol GS-US-494-5484 
Final 
Gilead Sciences, Inc. 
Amendment 5 
Appendix 1. 
Investigator Signature Page 
GILEAD SCIENCES, INC. 
333 LAKESIDE DRIVE 
FOSTER CITY, CA 94404 
A Phase l b/2 Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Efficacy of GS-4224 in Subjects with Advanced Solid Tumors 
Protocol Version 6.0 dated 02 October 2020 
STUDY ACKNOWLEDGEMENT 
This protocol has been approved by Gilead Sciences, Inc. The following signature documents 
fP
0D 
-
PD 
Name (Printed) 
'Signatut ... e __________ _ 
Author 
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 
CONFIDENTIAL 
Page IOI 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 102
02 October 2020
Appendix 2.
Study Procedures Table
Study Phase Cycle 
Day
Screening 
Day -28 to 
Day 1
Cycle 1 (First 21 Days)
C2D1
C3D1
C4D1
C5D1
Every 
3 weeks
Every 
6
weeks
Every 
9
weeks
EOT
f
30 day 
Safety 
Follow
-upf
Cycle
1 
Day 1
Day
2
Day
4
Day
8
Day
11
Day
15
Window (day)
-28
±0
±0
±0
±1
±1
±2
±2
±2
±2
±2
±7
±7
±7
±7
±7
Informed Consent
X
Medical and 
Medication Historya
X
Physical 
Examinationb
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signsc
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead ECGd
X
X
X
X
X
X
X
X
Xd
X
X
Adverse events/ 
Concomitant 
medicationse
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Dispensing 
X
X
X
X
X
X
Dosing Diary 
Accountability
X
X
X
X
X
X
X
X
X
X
X
IXRS Registration
X
X
X
X
X
X
X
X
CBC with 
differential
Xg
X
X
X
X
X
X
X
X
X
X
X
Coagulation
Xg
X
X
X
X
X
X
X
X
X
X
X
Chemistry
Xg
X
X
X
X
X
X
X
X
X
X
X
TSH
X
X
Basal Cortisol
X
X
Urinalysis
X
X
X
X
X
X
X
X
Pregnancy Testh
X
X
X
X
X
X
X
X


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 103
02 October 2020
Study Phase Cycle 
Day
Screening 
Day -28 to 
Day 1
Cycle 1 (First 21 Days)
C2D1
C3D1
C4D1
C5D1
Every 
3 weeks
Every 
6
weeks
Every 
9
weeks
EOT
f
30 day 
Safety 
Follow
-upf
Cycle
1 
Day 1
Day
2
Day
4
Day
8
Day
11
Day
15
Window (day)
-28
±0
±0
±0
±1
±1
±2
±2
±2
±2
±2
±7
±7
±7
±7
±7
HIV/CD4+/HBV/HC
V Testingi
X
Tumor PD L1 IHCp
X
Archival Tumor 
Tissue or pre
treatment biopsyq
X
CCI
CCICCI
CCI
CCI
CCI
CCI
CCI
I 
I I I I I I I 
I 
I 
I 
I 
I 
I 
I I 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 104
02 October 2020
Study Phase Cycle 
Day
Screening 
Day -28 to 
Day 1
Cycle 1 (First 21 Days)
C2D1
C3D1
C4D1
C5D1
Every 
3 weeks
Every 
6
weeks
Every 
9
weeks
EOT
f
30 day 
Safety 
Follow
-upf
Cycle
1 
Day 1
Day
2
Day
4
Day
8
Day
11
Day
15
Window (day)
-28
±0
±0
±0
±1
±1
±2
±2
±2
±2
±2
±7
±7
±7
±7
±7
CT Scan with 
Contrast or MRIt
X
X
X
X
Xs
PET CTu
X
X
X
ECOG Performance 
Status
X
X
X
X
X
a
Medical history includes significant past medical events (eg, prior hospitalizations or surgeries), a review of the disease under study, prior anti cancer therapies, and any 
concurrent medical illnesses.
b
Screening and end of treatment Physical Examinations will be a complete physical examination. Beginning on C1D1, a modified physical examination will be performed to 
monitor for any changes (eg, lymph nodes, lung, cardiac, abdomen, skin, neurologic, and any systems, as clinically indicated). Weight (without shoes) should be measured at 
each PE. Height (without shoes) should be measured at screening only.
c
Vital signs will be taken within 15 min pre GS 4224 dose. C1D1 vitals will also be collected at 2 and 4 hours postdose (± 15 min); vital signs will be taken predose only at all 
subsequent visits.
d
A triplicate 12 lead ECG will be collected at screening, at predose on Cycle 1 Day 1, Cycle 1 Day 8, 1.5 hours postdose (± 9 min) on Cycle 1 Days 1 and 15, at the EOT visit 
and at the 30 Day Safety Follow up visit. Triplicate ECGs should be taken 5 minutes apart. Single 12 lead ECGs will be collected predose on Day 1 of Cycles 2 6.
e
Adverse events will be assessed at pre and post GS 4224 dosing during applicable clinic visits. Subjects will also return to clinic at 30 day after last study drug dose, to 
assess AEs and SAEs. If the subject cannot return to the clinic, the site will contact the study subject by phone approximately 30 days after the last dose of study drug to 
assess AEs. 
f
End of treatment (EOT) and 30 day follow up visit are to be done 30 days after last dose of GS 4224. Subjects who miss the 30 day Safety follow up visit will be contacted 
by phone 30 days (± 7 days) after the last dose to assess AEs.
g
Screening chemistry, hematology, and coagulation to be collected within 10 days of Study Day 1/C1D1.
h
If applicable (females of child bearing potential). Serum pregnancy will be conducted at screening. Urine pregnancy will be conducted predose on Day 1 of each cycle and at 
EOT.
i
HIV, HBsAg, and HCV antibody viral testing in subjects with current or prior history of HIV, HBV, and HCV infection, respectively. CD4+ count will also be performed in 
subjects with current or prior history of HIV.
CCI
CCI


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
p 
Where re.quired for enrollment and if not already known, PD LI expression will be detem1ined. 
Final 
Amendment 5 
q 
Archival tumor tissue for biomarker analysis will be collected. The tissue should preferably be obtained either at the time of or after the diagnosis of advanced disease has 
been made and from a site not previously irradiated. Tissue must be collected between screening and Cycle 2. If archival tissue is not available, a pre treatment biopsy will be 
collected from enrolled subjects. For the I 000 mg BID dose escalation cohort, subjects with melanoma, Merkel cell, MS! 1-1 cancers, and classical Hodgkin lymphoma are not 
re. uired to have archival or fresh bio s tissue 
r 
r 
Tumor evalual!On by CT/MRI will be perfomied dunng screenmg (w1thm 28 days of Day I) and every 6 weeks for the first 2 scans and then every 9 weeks. A baseline scan 
within 6 weeks of Day I is acceptable. Cycle 3 Day I and Cyde 5 Day I scans can have a 7 day window. The same radiographic procedure used to define measurable lesions 
must be used throughout the study for each subject. 
u 
PET CT to be completed at screening ( within 28 days of Day I), Cycle 3 Day I, and Cycle 5 Day I only for subjects with cl-IL. Per Lugano 20 14 criteria, PET CT is re.quired 
to confim1 radiographic CR in subjects with bone marrow involvement at screening. In subjects with bone marrow involvement at screening and at a time point where CR is 
suspected, PET CT will be re.quired to confim1 CR if CR was not achieved at Cycle 3 and/or 5. 
CONFIDENTIAL 
Page 105 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 106
02 October 2020
Appendix 3.
Tumor Specific Inclusion/Exclusion Criteria
DOSE ESCALATION 1000 MG BID COHORT AND BASKET COHORT (COHORT B1)
Non-Small Cell Lung Cancer (NSCLC):
Inclusion Criteria:
1) Subjects must have histologically or cytologically confirmed NSCLC with disease 
progression on or after targeted therapy, platinum-containing chemotherapy, or a checkpoint 
inhibitor, unless they have no access to a checkpoint inhibitor or refused intravenous 
checkpoint inhibitor therapy.
2) Tumor PD-L1 expression with a TPS ≥ 1% (Basket Cohort) and TPS ≥ 10% (1000 mg BID 
Cohort)
Melanoma:
Inclusion Criteria:
1) Subjects must have a histologically or cytologically confirmed diagnosis of melanoma with 
advanced disease (previously treated, therapy-refractory or recurrent Stage III (unresectable) 
or Stage IV); disease no longer controlled by surgery, chemotherapy, or radiotherapy; and 
disease refractory to or relapsed after standard therapy (including, but not limited to, 
chemotherapy and/or interleukin-2). All melanomas regardless of primary site of disease will 
be allowed.
Renal:
Inclusion Criteria: 
1) Subjects must have histologically or cytologically confirmed renal cell carcinoma (RCC) 
(clear cell component) with advanced or recurrent and progressing disease that is not 
amenable to cure by surgery or other means, and must have failed at least 1 prior systemic 
therapy, including, but not limited to, treatment with Sunitinib, Temsirolimus, Sorafenib, 
IL-2, prior anti-angiogenic therapy, and/or chemotherapy.
2) Clinical evidence of or biopsy-proven metastatic disease to a site or sites distant from the 
primary tumor, that are not deemed to be surgically curative, or the subject is not a surgical 
candidate.
3) Tumor PD-L1 expression with a CPS ≥ 1 (Basket Cohort) and CPS ≥ 10 (1000 mg BID 
Cohort)


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 107
02 October 2020
Urothelial:
Inclusion Criteria:
1) Subjects must have histologically or cytologically confirmed locally advanced or metastatic 
urothelial carcinoma and are not eligible for cisplatin-containing therapy.
2) Tumor PD-L1 expression with a CPS ≥ 10
Gastric:
Inclusion Criteria:
1) Subjects must have histologically or cytologically confirmed recurrent locally advanced or 
metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors expression 
PD-L1 with disease progression on or after two or more prior lines of therapy including 
fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, 
HER2/neu-targeted therapy.
2) Tumor PD-L1 expression with a CPS ≥ 1
Head and Neck Squamous Cell Cancer (HNSCC):
Inclusion Criteria:
1) Subjects must have histologically or cytologically confirmed recurrent or metastatic HNSCC 
with disease progression on or after platinum-containing chemotherapy.
2) Tumor PD-L1 expression with a CPS ≥ 1
Hepatocellular Carcinoma:
Inclusion Criteria:
1) Subjects must have histologically or cytologically confirmed hepatocellular carcinoma 
(HCC) with disease progression after sorafenib or lenvatinib treatment unless the subject 
does not have access to either treatments. Subjects who do not have access to sorafenib or 
lenvatinib treatment may enroll to receive GS-4224 in the first-line setting.
2) Child-Pugh Class A liver score within 7 days of first dose of study drug
3) Tumor PD-L1 expression with a CPS ≥ 10 (1000 mg BID Cohort)


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 108
02 October 2020
Exclusion Criteria:
1) Esophageal or gastric variceal bleeding within the last 6 months 
2) Clinically apparent ascites on physical examination 
3) Portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac involvement of 
HCC based on imaging 
4) Encephalopathy in the last 6 months. Participants on rifaximin or lactulose to control their 
encephalopathy are not allowed 
MSI-H Cancer:
Inclusion Criteria:
1) Subjects with unresectable or metastatic, MSI-H or mismatch repair deficient solid tumors 
that have progressed following prior treatment and who have no satisfactory alternative 
treatment options
2) For subjects with colorectal cancer, progression following treatment with a fluoropyrimidine, 
oxaliplatin, and irinotecan.
Merkel Cell Carcinoma:
Inclusion Criteria:
1) Subject with biopsy-proven metastatic Merkel cell carcinoma (MCC) or locoregional MCC 
that has recurred following standard locoregional therapy with surgery and/or radiation 
therapy.
2) No prior systemic therapy for MCC
Classical Hodgkin Lymphoma (cHL):
Inclusion Criteria:
1) Subjects with refractory cHL or who have relapse after 3 or more prior lines of therapy.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 109
02 October 2020
Esophageal Squamous Cell Carcinoma:
Inclusion Criteria:
1) Subjects with recurrent locally advanced or metastatic squamous cell carcinoma of the 
esophagus with disease progression after one or more prior lines of systemic therapy.
2) Tumor PD-L1 expression with a CPS ≥ 1 (Basket Cohort) and CPS ≥ 10 (1000 mg BID 
Cohort)
Cutaneous Squamous Cell Carcinoma:
Inclusion Criteria:
1) Subjects with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable 
by surgery or radiation
2) Tumor PD-L1 expression with a CPS ≥ 1 (Basket Cohort) and CPS ≥ 10 (1000 mg BID 
Cohort)


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 110
02 October 2020
Appendix 4.
NCI-CTCAE Grading Scale for Severity of Adverse Events and 
Laboratory Abnormalities
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 111
02 October 2020
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 
permanently sterile or with medically documented ovarian failure. 
Women are considered to be in a postmenopausal state when they are ≥54 years of age with 
cessation of previously occurring menses for ≥12 months without an alternative cause. 
In addition, women < 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 permanently sterile by bilateral orchidectomy or medical documentation.
2. Contraception Requirements for Female Subjects
a. Study Drug Effects on Pregnancy and Hormonal Contraception
GS-4224 is contraindicated in pregnancy because a malformation effect has been 
demonstrated/suspected or is unknown, taking into consideration class effects or a strong 
suspicion of human teratogenicity/fetotoxicity in early pregnancy based on nonclinical data. 
GS-4224 has demonstrated/suspected or has insufficient data to exclude the possibility of a 
clinically relevant interaction with hormonal contraception that results in reduced contraception 
efficacy. Therefore, hormonal contraception is not recommended as a contraceptive method 
either solely or as a part of a contraceptive regimen. Refer to the latest version of the IB for 
additional information.
b.
Contraception Requirements for Female Subjects of Childbearing Potential 
The inclusion of female subjects of childbearing potential requires the use of highly effective 
contraceptive measures with a failure rate of < 1% per year. They must also not rely on 
hormone-containing contraceptives as a form of birth control during the study. They must have a 
negative serum pregnancy test at screening and a negative pregnancy test at the Admission 
(Day -1) visit prior to enrollment. Pregnancy tests will be performed at monthly intervals 
thereafter until the end of contraception requirement (30 days after last dose of study drug). 
Duration of required contraception for female subjects in this clinical study should start from 
Screening visit until 30 days after the last dose of study drug.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 112
02 October 2020
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
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)
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 contraception requirement (30 days after last dose of study drug).
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. Therefore, male subjects with female partners of childbearing potential must 
use condoms during treatment until 90 days after the last dose of study drug. 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 
contraception requirement (90 days after last dose of study drug).
4. Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). Female condom and male condom should not be used 
together.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 113
02 October 2020
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 30 days 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 within 90 days of last dose of study drug must also report the information to the investigator.
Instructions for reporting pregnancy, partner pregnancy, and pregnancy outcome are outlined in 
Section 7.4.2.3.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 114
02 October 2020
Appendix 6.
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 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 in 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 exam that is not 
measurable by reproducible imaging techniques.
Bone lesions:
Bone scan, 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 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 115
02 October 2020
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.
‘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 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 116
02 October 2020
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.
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 <10mm.
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
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).


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 117
02 October 2020
Table 1 -11me point response: patients with target (+/-
non-targe~ disease. 
Targ t les·on 
CR 
CR 
CR 
PR 
SD 
t all 
evaluated 
PD 
Any 
Any 
on-target lesions 
CR 
n-CR/non-PD 
t evaluated 
n-PD or 
not all evaluated 
n-PD or 
not all evaluated 
n-PD 
Any 
PD 
Any 
ew 
lesions 
0 
0 
0 
0 
0 
0 
Yi s or o 
Yes or o 
Yes 
0v rail 
res pons 
CR 
PR 
PR 
PR 
SD 
PD 
PD 
PD 
CR= complete response, PR= partial response, SD= stable disease, 
PD= progr sive disease, and 
= incvaluabl . 
Table 2 - Time point response: patients with non-target 
disease only. 
n-CR/non•PD 
t all evaluated 
Unequivocal PD 
Any 
Yi s 
esions 
0 
CR= comp! te 
response, 
PD= progtessiv 
NE= inevaluable. 
Overall respons 
CR 
n-CR/non•PD~ 
PD 
PD 
disease, 
and 
a ' 
n-CR/non-PD' is preferred over 'stable disease' for non-target 
disease since SD is increasingly used as endpoint for asse:ssment 
of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised. 


GS-4224 
Protocol GS-US-494-5484 
Final 
Gilead Sciences, Inc. 
Amendment 5 
Appendix 7. 
Response Assessment for Classic Hodgkin Lymphoma (Lugano Classification) 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Complete 
Complete metabolic response 
Complete radiologic response (all of the following) 
Lymph nodes and extralymphatic 
Score I, 2, or 3' with or without a residual mass on 
Target nodes/nodal masses must regress to < 1.5 cm in 
sites 
5PSt 
LDi 
It is recognized that in Waldeyer's ring or extranodal 
No extralymphatic sites of disease 
sites with high physiologic uptake or with activation 
within spleen or marrow (eg, with chemotherapy or 
myeloid colony-stimulating factors), uptake may be 
greater than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response may be 
inferred ifuptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the 
tissue has high physiologic uptake 
Nonmeasured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrow 
No evidence of FOG-avid disease in marrow 
Normal by morphology; if indeterminate, IHC negative 
Partial 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and extralymphatic 
Score 4 or St with reduced uptake compared with 
2: 50% decrease in SPD of up to 6 target measurable 
sites 
baseline and residual mass( es) of any size 
nodes and extranodal sites 
At interim, these findings suggest responding disease 
When a lesion is too small to measure on CT, assign 
5 mm x 5 mm as the default value 
At end of treatment (EOT), these findings indicate 
When no longer visible, 0 x O mm 
residual disease 
For a node > 5 mm x 5 mm, but smaller than normal, use 
actual measurement for calculation 
Nonmeasured lesions 
Not applicable 
Absent/normal, regressed, but no increase 
CONFIDENTIAL 
Page I 18 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Response and Site 
Organ enlargement 
New lesions 
Bone marrow 
No response or stable disease 
Target nodes/nodal masses, 
extranodal lesions 
Nonmeasured lesions 
Organ enlargement 
New lesions 
Bone marrow 
CONFIDENTIAL 
Final 
Amendment 5 
Revised Criteria for Response Assessment 
PET-CT-Based Response 
CT-Based Response 
Not applicable 
Spleen must have regressed by > 50% in length beyond 
normal 
None 
None 
Residual uptake higher than uptake in normal marrow 
Not applicable 
but reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, 
consideration should be given to further evaluation with 
MRI or biopsy or an interval scan 
No metabolic response 
Stable disease 
Score 4 or 5 with no significant change in FOG uptake 
< 50% decrease from baseline in SPD ofup to 6 
from baseline at interim or EOT 
dominant, measurable nodes and extranodal sites; no 
criteria for progressive disease are met 
Not applicable 
No increase consistent with progression 
Not applicable 
No increase consistent with progression 
None 
None 
No change from baseline 
Not applicable 
Page I 19 
02 October 2020 


GS-4224 
Protocol GS-US-494-5484 
Gilead Sciences, Inc. 
Final 
Amendment 5 
Revised Criteria for Response Assessment 
Response and Site 
PET-CT-Based Response 
CT-Based Response 
Progressive disease 
Progressive metabolic disease 
Progressive disease requires at least I of the following 
PPD progression: 
Individual target nodes/nodal 
Score 4 or 5 with an increase in intensity of uptake from 
An individual node/lesion must be abnormal with: 
masses 
baseline and/or 
LDi > 1.5 cm and 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at 
Increase by > 50% from PPD nadir and 
interim or EOT assessment 
An increase in LDi or SDi from nadir 
0.5 cm for lesions :S 2 cm 
1.0 cm for lesions > 2 cm 
In the setting of splenomegaly, the splenic length must 
increase by > 50% of the extent of its prior increase 
beyond baseline (eg, a 15-cm spleen must increase to 
> 16 cm). If no prior splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured lesions 
None 
New or clear progression of preexisting nonmeasured 
lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather 
Regrowth of previously resolved lesions 
than another etiology (eg, infection, inflammation). If 
A new node > 1.5 cm in any axis 
uncertain regarding etiology of new lesions, biopsy or 
A new extranodal site > 1.0 cm in any axis; if< 1.0 cm in 
interval scan may be considered 
any axis, its presence must be unequivocal and must be 
attributable to lymphoma 
Assessable disease of any size unequivocally attributable 
to Lymphoma 
Bone marrow 
New or recurrent FDG-avid foci 
New or recurrent involvement 
Abbreviations: 5PS, 5 point scale; CT, computed tomography; EOT, end of treatment; FOG, fluorodeoxyglucose; II-IC, immunohistochemistry; LDi, longest transverse diameter of 
a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to 
the LDi; SPD, sum of the product of the perpendicular diameters for multiple lesions. 
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in trials involving PET where 
de escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest 
dominant nodes, nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and 
CONFIDENTIAL 
Page 120 
02 October 2020 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 121
02 October 2020
should include, where applicable, mediastinal and retroperitoneal areas. Non nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease should be considered
not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or that do not meet the requirements for measurability but 
are still considered abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including 
pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer’s ring or in 
extranodal sites (eg, GI tract, liver, bone  marrow),  FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher than 
surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth factors).
†PET 5PS: 1, no uptake above background; 2, uptake ≤mediastinum; 3, uptake > mediastinum but ≤liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver 
and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.
Please reference {Cheson 2014} for further information on Lugano Classifications for cHL. 


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 122
02 October 2020
Appendix 8.
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 drugs, the subject 
would not be able to stay on the study drug as planned per protocol.
Mitigation plan: Study drug supplies may be provided to the subject from the site without 
a clinic visit, once it is confirmed that the subject may safely continue on study drug as 
determined by the principal investigator (PI). A virtual study visit, via phone or video 
conferencing, must be performed prior to remote study drug resupply. At the earliest 
opportunity, the site will schedule in-person subject visits and return to the protocol’s 
regular schedule of assessments. A qualified courier may be utilized to ship the study 
drug from sites to study subjects if permitted by local ethic committee (EC)/institutional 
review boards (IRB)/Regulatory Authority as applicable and with sponsor's approval.
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 PI 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 123
02 October 2020
ii) Review current list of concomitant medications and document any new concomitant 
medications.
iii) If applicable, confirm subjects study drug supply is sufficient to last until the next 
planned visit date. If study drug resupply is needed it will be provided as described 
above in (1).
iv) If applicable, remind subject to maintain current dosing and to keep all dispensed 
study drug kits for return at the next on-site visit.
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.
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 EC/IRB and national laws and regulations. Remote consent will be 
allowed if 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 eCRF and described in the 
clinical study report (CSR). 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.


GS-4224
Protocol GS-US-494-5484
Final
Gilead Sciences, Inc. 
Amendment 5
CONFIDENTIAL
Page 124
02 October 2020
b) Monitors may be unable to carry out source data review (SDR) or source data verification 
(SDV), or study drug accountability or assess protocol and 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. 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 trial data. 
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 CSR will describe the impact of the pandemic on the 
interpretability of study data.
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 GS-4224 in study subjects remains unchanged.  

SAP_001.pdf: 
  
STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 1b/2 Dose Escalation/Expansion Study to Evaluate the
Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 
in Subjects with Advanced Solid Tumors
Name of Test Drug:
GS-4224
Study Number:
GS-US-494-5484
Protocol Version (Date):
Original: 10 May 2019
Amendment 1: 07 June 2019
Amendment 2: 12 August 2019
Amendment 3: 04 May 2020
Amendment 4: 07 August 2020
Amendment 5: 02 October 2020
Analysis Type:
Final Analysis 
Analysis Plan Version:
Version 1.0
Analysis Plan Date:
29 JUNE 2021
Analysis Plan Author:
CONFIDENTIAL AND PROPRIETARY INFORMATION
PPD
(r) GILEAU 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 2
12 July 2021
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF ABBREVIATIONS.........................................................................................................................................4
PHARMACOKINETIC ABBREVIATIONS.................................................................................................................5
1.
INTRODUCTION..................................................................................................................................................6
1.1.
Study Objectives........................................................................................................................................6
1.1.1.
Primary Objectives ..................................................................................................................6
1.1.2.
Secondary Objectives ..............................................................................................................6
1.2.
Study Design .............................................................................................................................................7
1.2.1.
Dose Escalation (Phase 1b) .....................................................................................................7
1.3.
Sample Size and Power .............................................................................................................................8
2.
PLANNED ANALYSIS.........................................................................................................................................9
2.1.
Interim Analysis ........................................................................................................................................9
2.1.1.
Analyses for Dose Escalation Decisions .................................................................................9
2.1.2.
Analyses for Dose Expansion Decisions.................................................................................9
2.1.3.
Primary Analysis .....................................................................................................................9
2.2.
Final Analysis............................................................................................................................................9
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.............................................................................10
3.1.
Analysis Sets ...........................................................................................................................................10
3.1.1.
All Enrolled Analysis Set ......................................................................................................10
3.1.2.
Full Analysis Set....................................................................................................................10
3.1.3.
Safety Analysis Set................................................................................................................10
3.1.4.
DLT-Evaluable Analysis Set.................................................................................................10
3.1.5.
Pharmacokinetics (PK) Analysis Set.....................................................................................11
3.2.
Subject Grouping.....................................................................................................................................11
3.3.
Strata and Covariates...............................................................................................................................11
3.4.
Examination of Subject Subgroups .........................................................................................................11
3.5.
Multiple Comparison...............................................................................................................................11
3.6.
Missing Data and Outliers.......................................................................................................................11
3.6.1.
Missing Data..........................................................................................................................11
3.6.2.
Outliers ..................................................................................................................................12
3.7.
Data Handling Conventions and Transformations ..................................................................................12
3.8.
Analysis Visit Windows..........................................................................................................................13
3.8.1.
Definition of Study Day ........................................................................................................13
3.8.2.
Analysis Visit Windows........................................................................................................14
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window .................................................................................................................................14
4.
SUBJECT DISPOSITION ...................................................................................................................................15
4.1.
Subject Enrollment and Disposition........................................................................................................15
4.2.
Extent of Study Drug Exposure and Adherence......................................................................................16
4.2.1.
Extent of Exposure to Study Drug.........................................................................................16
4.2.2.
Adherence to Study Drug ......................................................................................................16
4.3.
Protocol Deviations .................................................................................................................................17
4.4.
Assessment of COVID-19 Impact...........................................................................................................17
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19.....................................................17
4.4.2.
Protocol Deviations Due to COVID-19 ................................................................................17
CCI-


GS-4224 
Study GS-US-494-5484 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
4.4.3. 
Missed and Virtual Visits Due to COVID-19 ....................................................................... 18 
5. 
BASELINE CHARACTERISTICS ..................................................................................................................... 19 
5 .1. 
De1nographics .......................................................................................................................................... 19 
5.2. 
Other Baseline Characteristics ................................................................................................................ 19 
5.3. 
Medical Histo1y ....................................................................................................................................... 19 
5.4. 
Prior Anti-Cancer Therapy ...................................................................................................................... 19 
5.5. 
Prior and On Study Radiotherapy ............................................................................................................ 20 
5.6. 
Sw·geries and Procedures ........................................................................................................................ 20 
I 
7. 
ANALYSIS OF ADVERSE EVENTS AND LABORATORY EVALUATIONS ............................................. 22 
7.1. 
Adverse Events and Deaths ..................................................................................................................... 22 
7.1.1. 
Adverse Event Dictiona1y ..................................................................................................... 22 
7.1.2. 
Adverse Event Severity ......................................................................................................... 22 
7.1.3. 
Relationship of Adverse Events to Study Dmg ..................................................................... 22 
7.1.4. 
Serious Adverse Events ......................................................................................................... 22 
7.1.5. 
Treatinent-Emergent Adverse Events .................................................................................... 22 
7.1.6. 
Summaries of Adverse Events and Dea.ths ............................................................................ 23 
7 .1. 7. 
Definition and Analysis of Dose Limiting Toxicity .............................................................. 25 
7.2. 
Laborato1y Evaluations ........................................................................................................................... 25 
7.2.1. 
Graded Laborato1y Values .................................................................................................... 26 
7.3. 
Body Weight and Vital Signs .................................................................................................................. 27 
7.4. 
Prior and Concolllitant Medications ........................................................................................................ 27 
7.4.1. 
Prior Medications .................................................................................................................. 27 
7.4.2. 
Conco1nitant Medications ...................................................................................................... 27 
7.5. 
Electrocardiogra1n Results ....................................................................................................................... 28 
7.6. 
Other Safety Measures ............................................................................................................................ 28 
7.7. 
Changes from Protocol-Specified Safety Analyses ................................................................................. 28 
8. 
PHARMA CO KINETIC ANALYSES .................................................................................................................. 29 
9. 
REFERENCES ..................................................................................................................................................... 30 
10. SOFTWARE ......................................................................................................................................................... 31 
11. SAP REVISION ................................................................................................................................................... 32 
12. APPENDICES ...................................................................................................................................................... 33 
Appendix 1. 
Appendix 2. 
CONFIDENTIAL 
COVID-19 SMQ with Broad Scope ........................................................................................ 34 
Dete1mining Missing and Viitual Visits Due to COVID-19 ................................................... 35 
Page3 
12 July 2021 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 4
12 July 2021
LIST OF ABBREVIATIONS
AE
adverse event
BID
twice daily
cHL
Classical Hodgkin lymphoma
CTCAE
Common Terminology Criteria for Adverse Events
CSR
Clinical Study Report
CPS
combined positive score
DLT
dose limiting toxicity
ECG
electrocardiogram 
ECOG
Eastern Cooperative Oncology Group
HCC
Hepatocellular carcinoma
HLGT
high-level group term
HLT
high-level term
irAE
immune-related adverse event 
LLT
lower-level term
LOQ
limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
MSI-H
microsatellite instability-high
MTD
maximum tolerated dose
NSCLC
non-small cell lung cancer
PD-1
programmed cell death protein 1
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
QD
once daily
RCC
renal cell carcinoma
RECIST v1.1
RECIST v1.1 Response Evaluation Criteria in Solid Tumors Version 1.1
RP2D
recommended Phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SE
standard error
SOC
system organ class
SRT
safety review team
StD
standard deviation
TPS
Tumor proportion score


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 5
12 July 2021
PHARMACOKINETIC ABBREVIATIONS
AUClast
area under the concentration versus time curve from time zero to the last quantifiable 
concentration
AUCtau
area under the concentration versus time curve over the dosing interval
Clast
last observed quantifiable concentration of the drug
Cmax
maximum observed concentration of drug
Ctau
observed drug concentration at the end of the dosing interval
CLss/F
apparent oral clearance after administration of the drug:
at steady state: CLss/F = Dose/AUCtau , where “Dose” is the dose of the drug
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)
Tlast
time (observed time point) of Clast
Tmax
time (observed time point) of Cmax
z
terminal elimination rate constant, estimated by linear regression of the terminal elimination 
phase of the concentration of drug versus time curve


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 6
12 July 2021
1.
INTRODUCTION
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report (CSR) 
for Study GS-US-494-5484. This SAP is based on the study protocol amendment 5.0 dated 
02 October 2020 and the electronic case report form (eCRF). The SAP will be finalized before 
database finalization. Any changes made after the finalization of the SAP will be documented in 
the CSR.
The study was originally designed to evaluate the safety, tolerability, Pharmacokinetics (PK), 
and efficacy of GS-4224 monotherapy in 2 stages: (1) Phase 1b dose-escalation in advanced 
solid tumors; and (2) Phase 2 dose expansion in select advanced solid tumors expressing ligand 1 
of programmed cell death protein 1 (PD-L1) [tumor proportion score (TPS) ≥ 1% or combined 
positive score (CPS) ≥ 1 or ≥ 10] or MSI-H cancers. The study was early terminated during 
Phase 1b dose escalation part due to lack of objective clinical efficacy in patients dosed in Phase 
1b dose-escalation. The Phase 2 part of the study was not be initiated. Subjects currently on 
study will continue to be treated and/or followed until the end of study criteria are met. The SAP 
describes the analyses based on the Phase 1b data collected in the study only for a synoptic CSR.
1.1.
Study Objectives
1.1.1.
Primary Objectives
Phase 1b Dose Escalation

To characterize the safety and tolerability of GS-4224 in subjects with advanced solid tumors

To determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of 
GS-4224 in subjects with advanced solid tumors
1.1.2.
Secondary Objectives
Phase 1b Dose Escalation

To evaluate the pharmacokinetics (PK) of GS-4224 in subjects with advanced solid tumors
Phase 2 Dose Expansion

To evaluate the safety and tolerability of GS-4224 in subjects with advanced solid tumors


GS-4224 
Study GS-US-494-5484 
Statistical Analysis Plan - Final Analysis 
-
I 
I 
I 
I 
1.2. 
Study Design 
Version 1.0 
GS-US-494-5484 is an open-label, multicenter, sequential dose-escalation and dose expansion 
study to evaluate the safety, tolerability, PK, and efficacy of GS-4224 in subjects with advanced 
solid tumors. The study will consist of2 pa1ts: the dose escalation po1tion, followed by dose 
expansion in subjects with tumors for which programmed cell death protein 1 (PD-1)/PD-Ll 
treatments are approved or are known to be active. 
1.2.1. 
Dose Escalation (Phase lb) 
Subjects with advanced solid tumors who have failed or are intolerant to standard therapy or for 
whom no standard therapy exists will be sequentially emolled at progressively higher dose levels 
of oral GS-4224 as monotherapy. 
Dose escalation will proceed using a standard 3+ 3 design. The staiting dose is 400 mg once daily 
(QD), with subsequent doses of700 mg QD, 1000 mg QD, 1500 mg QD, and 1000 mg twice 
daily (BID). Dose level increases ai·e 3-fold or less. 
Dose Level Schema 
GS-4224 (mg) 
Fold Increase 
400QD 
700QD 
1000 QD 
1500 QD 
1000 BID 
CONFIDENTIAL 
Page7 
12 July 2021 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 8
12 July 2021
In the 1000 mg BID dose cohort, at least 6 (as part of the initial 3+3 design) and up to an 
additional 14 subjects (for a total of 20 subjects) with locally advanced, inoperable or metastatic 
cancer expressing PD-L1 (tumor proportion score [TPS] ≥ 10% or combined positive score 
[CPS] ≥ 10) and who have not previously been treated with anti-PD-1/L1 antibodies will be 
enrolled. The additional 14 subjects will not be enrolled at the 1000 mg BID dose level if the 
subject incidence of DLTs is > 1 in the first 6 subjects. If the subject incidence of DLTs is > 1 in 
the first 6 subjects at 1000 mg BID, then 20 additional subjects with locally advanced, inoperable 
or metastatic cancer expressing PD-L1 [TPS ≥ 10% or CPS ≥ 10] and who have not previously 
been treated with anti-PD-1/L1 antibodies will enroll at the MTD.
The initial block of each dose consists of 3 subjects. Dose escalation may occur if no subjects 
experience DLTs during the first 21 days of study drug dosing. If 1 subject within the initial 
cohort of 3 subjects experiences a DLT during the first 21 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 of the 6 subjects experience DLTs 
within the first 21 days, dose de-escalation to an intermediate dose will occur. The MTD is the 
highest dose level with a subject incidence of DLTs during the first 21 days of study drug dosing 
of 0 or 1 out of 6. 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 is withdrawn from the study before the 
completion of the first 21 days for a reason other than a DLT will be replaced.
If 2 or more delayed DLT-type adverse events (AEs) are noted after the first 21 day observation 
period within a dose escalation cohort, further accrual at all sites will be held pending safety 
analysis of the event, and will be restarted only with Investigator and Sponsor approval.
The SRT will review safety and relevant clinical data and make the dose 
escalation/stay/de-escalation decision. Source Data Verification (SDV) 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 SRT Charter.
At dose levels equal to or below the MTD, up to 6 additional subjects per dose level with biopsy 
accessible, PD-L1-positive (TPS ≥ 10% or CPS ≥ 10) tumor lesions may be enrolled in the 
Dose Escalation Biopsy Substudy to evaluate the tumor target occupancy of GS-4224 in 
posttreatment tumor biopsy samples. Up to a total of 12 subjects may be enrolled at one of the 
dose levels in the biopsy substudy. The biopsy substudy cohort may be opened once the dose 
level has been cleared by the SRT for safety.
1.3.
Sample Size and Power
The sample size of the study will be determined based on the number of dose levels evaluated 
and the emerging GS-4224-related toxicities and efficacy. The study is planned to enroll 
approximately 120 subjects.
Approximately 44 subjects will be enrolled in the dose escalation phase (Phase 1b) and 
approximately 36 subjects will be enrolled in the Dose Escalation Biopsy Substudy (Phase 1b).
Approximately 40 subjects will be enrolled into the Dose Expansion Cohort B1.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 9
12 July 2021
2.
PLANNED ANALYSIS
2.1.
Interim Analysis
2.1.1.
Analyses for Dose Escalation Decisions
To support dose escalation decision, safety data, including DLTs and other AEs  will be listed 
and summarized, if appropriate. Supportive data including demographic, disease history, 
concomitant medication, and drug administration will be listed. The analysis will occur when all 
subjects enrolled in a dose level have been followed for at least 21 days after the first dose of 
GS-4224 or two DLTs have been observed, whichever is earlier.
2.1.2.
Analyses for Dose Expansion Decisions
To support dose expansion decision, available and relevant clinical data from all subjects treated 
in the escalation phase may be listed and summarized, if appropriate. This analysis was 
originally planned in the study protocol; however, it will not be done due to study early 
termination. 
2.1.3.
Primary Analysis
The study primary analysis will be conducted when all enrolled subjects have discontinued the 
study or have been on treatment of GS-4224 for at least 48 weeks and completed response 
assessment of Week 48.
This analysis was originally planned in the study protocol; however, it will not be done due to 
study early termination.
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.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 10
12 July 2021
3.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous variables, 
the number of subjects (n), mean, standard deviation (StD) or standard error (SE), median, first 
quartile (Q1), third quartile (Q3), minimum, and maximum will be presented.
By-subject listings will be presented for all subjects in the All Enrolled Analysis Set and sorted 
by dose cohort, subject ID number, visit date, and time (if applicable). Data collected on log 
forms, such as AEs, will be presented in chronological order within the subject. The cohort to 
which subjects were initially assigned will be used in the listings. Age, sex at birth, race, and 
ethnicity information for each subject will be presented in the listings, as space permits.
3.1.
Analysis Sets
Analysis sets define which subjects are included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing.
3.1.1.
All Enrolled Analysis Set
The All Enrolled Analysis Set includes all subjects who received a study subject identification 
number in the study after screening. 
The All Enrolled Analysis Set will be used for subject enrollment summary and for data listings, 
unless otherwise specified.
3.1.2.
Full Analysis Set
The Full Analysis Set includes all subjects who received at least 1 dose of study treatment. It will 
be used in the analyses of efficacy endpoints.
3.1.3.
Safety Analysis Set
The Safety Analysis Set includes all subjects who received at least 1 dose of study treatment, 
with treatment assignments designated according to the actual treatment received. This is the 
primary analysis set for the safety analyses as well as study treatment administration. 
3.1.4.
DLT-Evaluable Analysis Set
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who enroll to 
the dose escalation cohort (excluding the Dose Escalation Biopsy Substudy), complete ≥ 75% of 
the prescribed study treatment (ie., at least 16 of 21 doses) and have safety assessments through 
the protocol specified DLT assessment window (first 21 days of study dosing, inclusive) or have 
experienced a DLT prior to the completion of first 21 days of study dosing. Safety assessment 
relevant to the DLT-Evaluable Analysis Set definition will include laboratory serum chemistry 
tests and hematology tests as specified in the protocol. Determination of the MTD will be based 
on the DLT-Evaluable Analysis Set.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 11
12 July 2021
3.1.5.
Pharmacokinetics (PK) Analysis Set
The PK Analysis Set includes subjects in the Safety Analysis Set who have received the study 
drug and have at least 1 sample with detectable drug concentration.
3.2.
Subject Grouping
For analyses based on the Full Analysis Set[FAS], subjects will be grouped according to the 
treatment to which they were randomized. For analyses based on the Safety Analysis Set, 
subjects will be grouped according to the actual treatment received. The actual treatment 
received will differ from the randomized treatment only when their actual treatment differs from 
randomized treatment for the entire treatment duration.
For the PK Analysis Set, subjects will be grouped according to the actual treatment they 
received.
For a subject with intra-patient dose escalation per study protocol, the subject will be grouped 
under the original enrolled cohort in summary tables, unless otherwise specified. 
3.3.
Strata and Covariates
This study does not use a stratified randomization schedule when enrolling subjects. 
No covariates will be included in efficacy [and safety] analyses.
3.4.
Examination of Subject Subgroups
There are no prespecified participant subgroupings for efficacy and safety analyses.
3.5.
Multiple Comparison
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study.
3.6.
Missing Data and Outliers 
3.6.1.
Missing Data
In general, missing data will not be imputed unless methods for handling missing data are 
specified. 
For missing last dosing date of study drug, imputation rules are described in Section 4.2.1. The 
handling of missing or incomplete dates for AE onset is described in Section 7.1.5.2, and for 
prior and concomitant medications in Section 7.4.2.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 12
12 July 2021
3.6.2.
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis.
3.7.
Data Handling Conventions and Transformations
The following conventions will be used for the imputation of date of birth when it is partially 
missing or not collected:

If only month and year of birth is collected, then “15” will be imputed as the day of birth

If only year of birth is collected, then “01 July” will be imputed as the day and month of birth

If year of birth is missing, then date of birth will not be imputed
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 subject, then age derived based on date of birth and the Day 1 
visit date will be used instead.  If an enrolled subject was not dosed with any study drug, the 
enrollment date will be used instead of the Day 1 visit date.  For screen failures, the date the first 
informed consent was signed will be used for the age derivation.   Age required for longitudinal 
and temporal calculations and analyses (eg, estimates of creatinine clearance, age at date of AE) 
will be based on age derived from date of birth and the date of the measurement or event, unless 
otherwise specified
Non-PK data that are continuous in nature but are less than the lower limit of quantitation (LOQ) 
or above the upper LOQ will be imputed as follows:

A value that is 1 unit less than the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “ x” (where x is considered the LOQ). For example, if the 
values are reported as < 50 and < 5.0, values of 49 and 4.9, respectively, will be used to 
calculate summary statistics. An exception to this rule is any value reported as < 1 or < 0.1, 
etc. For values reported as < 1 or < 0.1, a value of 0.9 or 0.09, respectively, will be used to 
calculate summary statistics.

A value that is 1 unit above the LOQ will be used to calculate descriptive statistics if the 
datum is reported in the form of “> x” (where x is considered the LOQ). Values with decimal 
points will follow the same logic as above.

The LOQ will be used to calculate descriptive statistics if the datum is reported in the form of 
“≤ x” or “≥ x” (where x is considered the LOQ).


GS-4224 
Study GS-US-494-5484 
Statistical Analysis Plan - Final Analysis 
Version 1.0 
If methods based on the assumption that the data are nonnally distributed are not adequate, 
analyses may be perfo1med on transfo1med data { or specify the transfo1mation method, 
e.g., log-transfo1med data} or nonparametric analysis methods may be used, as appropriate. 
I 
I 
I 
I 
3.8. 
3.8.1. 
Analysis Visit Windows 
Definition of Study Day 
Study day will be calculated from the first dosing date of study diu g and derived as follows: 
• 
For postdose study days: Assessment Date - First Dosing Date+ 1 
• 
For days prior to the first dose: Assessment Date - First Dosing Date 
Therefore, study day 1 is the day of first dose of study diug adininistration. 
For subjects with intra-patient dose escalation per study protocol, days relative to first dose date 
under each dose level will be calculated and presented respectively in a listing of AEs for such 
subjects. 
CONFIDENTIAL 
Page 13 
12 July 2021 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 14
12 July 2021
3.8.2.
Analysis Visit Windows
The nominal visit as recorded on the CRF will be used when data are summarized by visit. Any 
data relating to unscheduled visits will not be assigned to a particular visit or time point. 
However, the following exceptions will be made:

An unscheduled visit prior to the first dosing of study drug may be included in the calculation 
of the baseline value, if applicable.

Unscheduled visits after the first dosing of study drug will be included in determining the 
maximum postbaseline toxicity grade.

For subjects who prematurely discontinue from the study treatment, the EOT visit data will 
be assigned to what would have been the next scheduled visit where the respective data were 
scheduled to be collected.
3.8.3.
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window
Depending on the statistical analysis method, single values may be required for each analysis 
window.  For example, change from baseline by visit usually requires a single value, whereas a 
time-to-event analysis would not require 1 value per analysis window. 
If multiple valid, nonmissing measurements exist in an analysis window, records will be chosen 
based on the following rules if a single value is needed:

For baseline, the last nonmissing value on or prior to the first dosing date of study drug will 
be selected, unless specified differently. If there are multiple records with the same time or 
no time recorded on the same day, the baseline value will be the average of the 
measurements for continuous data, or the measurement with the lowest severity (eg, normal 
will be selected over abnormal for safety electrocardiogram [ECG] findings) for categorical 
data.

For postbaseline values:
The record closest to the nominal day for that visit will be selected.
If there are 2 records that are equidistant from the nominal day, the later record will be 
selected.
If there is more than 1 record on the selected day, the average will be taken for 
continuous data and the worse severity will be taken for categorical data, unless 
otherwise specified.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 15
12 July 2021
4.
SUBJECT DISPOSITION
4.1.
Subject Enrollment and Disposition
A summary of subject enrollment will be provided by cohort for each country and overall based 
on all enrolled subjects. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column.
A summary of subject disposition will be provided by cohort based on All Screened Subjects. 
This summary will present the number and percentage of subjects in the following categories:

Screened Subjects

All Enrolled Subjects

Safety Analysis Set

PK Analysis Set

DLT-Evaluable Analysis Set

Study Drug Completion Status 
Completed Study Drug
Discontinued Study Drug

Reasons for Discontinuation of Study Drug

Study Completion Status
Completed Duration of Study
Discontinued Study

Reasons for Discontinuation of Study 
For the status of study completion and reasons for discontinuation, the number and percentage of 
subjects in each category will be provided. The denominator for the percentage calculation will 
be the total number of subjects in the All Enrolled Analysis Set corresponding to that column.
The following by-subject listings will be provided by cohort and subject identification (ID) 
number in ascending order to support the above summary table:

Reasons for study drug or study discontinuation.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 16
12 July 2021
4.2.
Extent of Study Drug Exposure and Adherence
Extent of exposure to study drug (GS-4224) will be examined by assessing the total duration of 
exposure to study drug GS-4224, the actual duration of exposure to GS-4224, and prescribed 
adherence to study drug. The summaries will be based the Safety Analysis Set.
4.2.1.
Extent of Exposure to Study Drug
Total duration of exposure to study drug GS-4224 will be defined as last dosing date of study 
drug minus first dosing date plus 1, regardless of any temporary interruptions in study drug 
administration, and will be expressed in weeks using up to 1 decimal place (eg, 4.5 weeks). If the 
last study drug dosing date is missing,

If the study drug is permanently withdrawn, the latest date among the study drug end date, 
clinical visit date, laboratory sample collection date, and vital signs assessment date that 
occurred during the on-treatment period will be used for subjects included in the final 
analyses or the last available date in the database snapshot for subjects who were still on 
treatment at the time of an interim analysis.

If the study drug completion status is unknown, the earlier of the date of death or data cut-off 
date for analysis will be used.
The actual duration of exposure to GS-4224 during the DLT assessment window is defined as 
the last dosing date minus first dosing date plus 1 within the DLT assessment window (first 21 
days of study drug dosing), taking into account investigator-prescribed dose interruptions in 
study drug administration within the DLT assessment window. The level of prescribed adherence 
to the study drug GS-4224 during the DLT assessment window will be determined by the actual 
duration of exposure to GS-4224 relative to the total duration of exposure specified by study 
protocol during a subject’s DLT assessment window. 
4.2.2.
Adherence to Study Drug
The level of prescribed adherence during the DLT assessment window will be expressed as a 
percentage using the following formula:
Prescribed Adherence During DLT Assessment Window (%) =
=
 Actual Duration of Exposure to Study Drug During DLT Assessment Window
Total Duration of Exposure Specified by Protocol During DLT Assessment Window
 x 100  
Descriptive statistics for the level of prescribed adherence with the number and percentage of 
subjects belonging to adherence categories (eg, < 75%, ≥ 75%) will be provided by cohort for the 
Safety Analysis Set.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 17
12 July 2021
A by-subject listing of study drug (GS-4224) administration will be provided by cohort and 
subject ID number (in ascending order), including dosing date, total duration of exposure to 
GS-4224, actual duration of exposure, the prescribed adherence during the DLT assessment 
window, and reason for dose interruption.
The total duration of exposure to study drug will be summarized using descriptive statistics and 
using the number (ie, cumulative counts) and percentage of subjects exposed through the 
following time periods: 1 day, 3 weeks, 6 weeks, 9 weeks, 12 weeks, 18 weeks, and 24 weeks. 
Summaries will be provided by cohort for the Safety Analysis Set.
4.3.
Protocol Deviations
Subjects who did not meet the eligibility criteria for study entry, but enrolled in the study will be 
identified regardless of whether they were exempted by the sponsor or not. A by-subject listing 
will be provided for those subjects who did not meet at least 1 eligibility (inclusion or exclusion) 
criterion. The listing will present the eligibility criterion (or criteria if more than 1 deviation) that 
subjects did not meet and related comments, if collected.
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. A by-subject listing will be provided for those subjects with important protocol 
deviation.
4.4.
Assessment of COVID-19 Impact
This study was ongoing during the novel coronavirus (2019 nCOV [COVID-19]) pandemic, and 
the COVID-19 pandemic has caused a disruption in the regular visit schedules for this study. 
Some subjects were unable to attend onsite visits due to shelter in place guidelines, site closures, 
or other reasons. This section provides guidance on how to handle special situations due to 
COVID-19 in the analysis.
Adverse events (AEs) due to COVID-19 will be included in AE analyses if applicable. A 
by-subject listing of Adverse Events due to COVID-19 may be provided. The COVID-19
Standardized MedDRA Queries (SMQ) with Broad Scope in Appendix 1 will be implemented.
4.4.1.
Study Drug or Study Discontinuation Due to COVID-19
A by-subject listing of reasons for premature study drug or study discontinuation due to 
COVID-19 will be created.
4.4.2.
Protocol Deviations Due to COVID-19
A by-subject listing will be provided for subjects with important protocol deviation related to 
COVID-19. A separate listing will be provided for subjects with non-important protocol 
deviation related to COVID-19.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 18
12 July 2021
4.4.3.
Missed and Virtual Visits Due to COVID-19
A by-subject listing of subjects with missed or virtual visits due to COVID-19 will be provided 
by subject ID number in ascending order.
Information regarding virtual or missed visits due to COVID-19 was collected as free text in the 
CRF comment fields. The determination of missing or virtual visits due to COVID-19 was done 
using Natural Language Processing (NLP) to search the CRF comment fields. A detailed 
explanation of the algorithm is given in Appendix 2.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 19
12 July 2021
5.
BASELINE CHARACTERISTICS
5.1.
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized for Safety 
Analysis Set using descriptive statistics for age, and using number and percentage of subjects for 
sex, race, and ethnicity.
A by-subject demographic listing, including the informed consent date, will be provided by 
subject ID number in ascending order for All Enrolled Analysis Set.
5.2.
Other Baseline Characteristics
Other baseline characteristics include body weight (in kg), height (in cm), body mass index 
(BMI; in kg/m2), and ECOG status. BMI will be calculated by the formula:
BMI (kg/m2) = weight / (height2) (round to 1 decimal point).
Other baseline characteristics will be summarized by cohort and overall using descriptive 
statistics for continuous variables and using number and percentage of subjects for categorical 
variables. The summary of demographic and baseline characteristics data will be provided for the 
Safety Analysis Set.
A by-subject listing of other baseline characteristics will be provided by subject ID number in 
ascending order for All Enrolled Analysis Set.
5.3.
Medical History
Medical history will be collected at screening for disease-specific conditions including solid 
tumor malignancy status, and general conditions (i.e. conditions not specific to the disease being 
studied).
A by-subject listing of disease-specific medical history will be provided by cohort and subject ID 
number in ascending order. 
General medical history data will not be coded but will be listed only. A by-subject listing of 
general medical history will be provided by cohort and subject ID number in ascending order.
5.4.
Prior Anti-Cancer Therapy 
The details of prior anti-cancer therapy will be listed by cohort and subject ID number in 
ascending order. 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 20
12 July 2021
5.5.
Prior and On Study Radiotherapy
The details of all radiotherapy will also be listed by cohort and subject ID number in ascending 
order.
5.6.
Surgeries and Procedures
A by-subject listing of prior and on-study surgeries and procedures will be provided by cohort 
and subject ID number in ascending order.


GS-4224 
Study GS-US-494-5484 
Statistical Analysis Plan - Final Analysis 
I 
-
-
-
CONFIDENTIAL 
Version 1.0 
Page 21 
12 July 2021 


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 22
12 July 2021
7.
ANALYSIS OF ADVERSE EVENTS AND LABORATORY 
EVALUATIONS
All Adverse Events (AEs) will be listed.  The focus of AE summarization will be on 
treatment-emergent adverse events (TEAEs). Safety analyses will be conducted using Safety 
Analysis Set, unless otherwise specified.
7.1.
Adverse Events and Deaths
7.1.1.
Adverse Event Dictionary
Clinical and laboratory adverse events (AEs) will be coded using the current version of Medical 
Dictionary for Regulatory Activities (MedDRA). System organ class (SOC), high-level group 
term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will be 
provided in the AE dataset.
7.1.2.
Adverse Event Severity
Adverse events are graded by the investigator as Grade 1, 2, 3, 4, or 5 according to Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. The severity grade of events for 
which the investigator did not record severity will be categorized as “missing” for tabular 
summaries and data listings. The missing category will be listed last in summary presentation.
7.1.3.
Relationship of Adverse Events to Study Drug
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” 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. 
However, by-subject data listings will show the relationship as missing.
7.1.4.
Serious Adverse Events
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that are specified in the study protocol. SAEs captured and stored in the 
clinical database will be reconciled with the SAE database from then Gilead Global Safety 
Department before data finalization.
7.1.5.
Treatment-Emergent Adverse Events 
7.1.5.1.
Definition of Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following:

Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug

Any AEs leading to permanent discontinuation of study drug.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 23
12 July 2021
7.1.5.2.
Incomplete Dates
If the onset date of the AE is incomplete and the AE stop date is not prior to the first dosing date 
of study drug, then the month and year (or year alone if month is not recorded) of onset 
determine whether an AE is treatment emergent. The event is considered treatment emergent if 
both of the following 2 criteria are met:

The AE onset is the same as or after the month and year (or year) of the first dosing date of 
study drug, and

The AE onset date is the same as or before the month and year (or year) of the date 
corresponding to 30 days after the date of the last dose of study drug.
An AE with completely missing onset and stop dates, or with the onset date missing and a stop 
date later than the first dosing date of study drug, will be considered to be treatment emergent. In 
addition, an AE with the onset date missing and incomplete stop date with the same or later 
month and year (or year alone if month is not recorded) as the first dosing date of study drug will 
be considered treatment emergent.
In case when the AE onset date is incomplete and needs to be imputed, the following algorithm 
will be followed:

 If the day is missing but the month and year are available, then the imputed day will be the 
first day of the month or the first dosing date if they have the same month and year, 
whichever is later.

If the day and month are missing but year is available, then the imputed day and month will 
be 01Jan or the first dosing date if they have the same year, whichever is later.
7.1.6.
Summaries of Adverse Events and Deaths
TEAEs will be summarized by cohort/dose level based on the Safety Analysis Set.
7.1.6.1.
Summaries of Adverse Events Incidence by Severity
The number and percentage of subjects who experienced at least 1 TEAE will be provided and 
summarized by PT and severity in descending order of total frequency:

Treatment-Emergent Adverse Events by PT and Severity


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 24
12 July 2021
For the AE categorizes described below, summaries will be provided by PT in descending order 
of total frequency:

Grade 3 or Higher Treatment-Emergent Adverse Events 

Treatment-Emergent GS-4224 related Adverse Events 

Treatment-Emergent Serious Adverse Events 

Treatment-Emergent GS-4224 related Serious Adverse Events 

Treatment-Emergent Adverse Events leading to discontinuation of GS-4224

Treatment-Emergent Adverse Events leading to temporary interruption of GS-4224

Treatment-Emergent Adverse Events leading to Death

Treatment-Emergent Adverse Events leading to study discontinuation
A brief, high-level summary of AEs described above will be provided by cohort and by the 
number and percentage of subjects who experienced the above AEs.
For summaries of TEAEs by PT, multiple events will be counted only once per subject in each 
summary. Adverse events will be summarized and listed by PT in descending order of total 
frequency. For summaries by severity, the most severe severity will be used for those AEs that 
occurred more than once in a given subject during the study.
In addition, by-subject data listings will be provided by cohort and subject ID number in 
ascending order for the following:

All AEs, indicating whether the event is treatment emergent

All SAEs

All Deaths

All Adverse Events with Grade 3 or Higher

All Adverse Events leading to discontinuation of GS-4224

All Adverse Events leading to temporary interruption of GS-4224

Adverse Events for Subject(s) with Intra-Subject Dose Escalation

All Adverse Events leading to study discontinuation
A flag will be included in the listings to indicate whether the event is treatment emergent.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 25
12 July 2021
7.1.6.2.
Summary of Deaths
A summary (number and percentage of subjects) of deaths will be provided by cohort. The 
summary will include the following categories:

All deaths

Deaths within 30 days of the last dosing of study drug

Deaths beyond 30 days of the last dosing of study drug.
Every attempt will be made to ensure that complete death dates are recorded. In those rare 
instances where complete death dates are not recorded, the following algorithm will be used:

If day is missing but the month and year are available, then the imputed date will be the 1st 
day of the month or the last known alive date + 1, whichever is later.
A by-subject listing of all deaths occurred during this study will be provided by cohort and 
subject ID number in ascending order.
7.1.7.
Definition and Analysis of Dose Limiting Toxicity
Toxicity will be graded according CTCAE Version 5.0. A DLT is any toxicity specified in the 
study protocol occurring during the DLT assessment window (Day 1 through Day 21).
DLTs occurred within the 21-Day DLT observation period will be summarized by PT in 
descending order of total frequency for the DLT-Evaluable Analysis Set. Toxicities that meet the 
criteria of DLTs and occur beyond the first 21 days observation period (ie. DLT-type AEs) will 
also be summarized for the Safety Analysis Set by PT only in descending order of total 
frequency.
In addition, by-subject data listings will be provided by cohort and subject ID number in 
ascending order for the following:

Dose Limiting Toxicities

DLT-type AEs: toxicities that met the criteria of DLTs and occurred beyond the first 21 days 
observation period during study
7.2.
Laboratory Evaluations
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be provided for the 
Safety Analysis Set and will include data collected up to the last dose of study drug plus 30 days. 
The analysis will be based on values reported in conventional units. When values are below the 
LOQ, they will be listed as such, and the closest imputed value will be used for the purpose of 
calculating summary statistics as specified in Section 3.5.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 26
12 July 2021
A by-subject listing for all lab test results will be provided by cohort, subject ID number and 
time point in chronological order for hematology, serum chemistry, coagulation, endocrine 
function tests and urinalysis separately. Values falling outside of the relevant reference range 
and/or having a severity Grade of 1 or higher on the CTCAE severity grade will be flagged in the 
data listings, as appropriate. 
No formal statistical testing is planned.
7.2.1.
Graded Laboratory Values
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 (ie, increased, decreased) will be presented separately. 
Local labs will be graded based on central lab normal ranges with in-house macro. Baseline 
grade will be based on central laboratory results, unless only local labs are collected prior to the 
first dosing of study drug.  For post-baseline grade, the worst toxicity grade considering both 
central and local lab results will be used for the summary of lab toxicities. All central and local 
laboratory values will be listed for All Enrolled Subjects.
7.2.1.1.
Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last 
dose of study drug plus 30 days for subjects who permanently discontinued study drug, or the 
last available date in the database snapshot for subjects who were still on treatment at the time of 
an analysis. A baseline laboratory value will be defined as the last measurement obtained on or 
prior to the date/time of first dose of study drug. If the relevant baseline laboratory value is 
missing, any abnormality of at least Grade 1 observed within the time frame specified above will 
be considered treatment emergent.
7.2.1.2.
Summaries of Laboratory Abnormalities
The following summaries (number and percentage of subjects) for treatment-emergent laboratory 
abnormalities will be provided by lab test and cohort; subjects will be categorized according to 
the most severe postbaseline abnormality grade for a given lab test:

TE laboratory abnormalities
In the summary of laboratory abnormalities, the denominator is the number of subjects with 
nonmissing postbaseline values up to 30 days after last dosing date.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 27
12 July 2021
7.3.
Body Weight and Vital Signs
A by-subject listing of body weight and vital signs will be provided for All Enrolled Subjects by 
cohort subject ID number and visit in chronological order.
7.4.
Prior and Concomitant Medications
Medications collected at screening and during the study will be coded using the current version 
of the World Health Organization Drug dictionary.
7.4.1.
Prior Medications
Prior medications are defined as any medications begun before a subject took the first study 
drug.
For the purposes of analysis, any medication with a start date prior to the first dosing date of 
study drug will be considered as prior medication regardless of when the stop date is. If a partial 
start date is entered the medication will be considered prior unless the month and year (if day is 
missing) or year (if day and month are missing) of the start date are after the first dosing date. 
Medications with a completely missing start date will be considered as prior medication, unless 
otherwise specified.
All prior medications (other than per-protocol study drugs) will be provided in a by-subject 
listing sorted by cohort, subject ID number and administration date in chronological order based 
on All Enrolled Analysis Set.
7.4.2.
Concomitant Medications
For the purposes of analysis, concomitant medications are defined as any medications

started prior to or on the first dosing date of study drug and continued to be taken after the 
first dosing date, or 

started after the first dosing date but prior to or on the last dosing date of study drug.
Medications started and stopped on the same day as the first dosing date or the last dosing date of 
study drug will also be considered concomitant. Medications with a stop date that is prior to the 
date of first dosing date of study drug or a start date that is after the last dosing date of study drug 
will not be considered as concomitant medication. 
If a partial stop date is entered, any medication with the month and year (if day is missing) or 
year (if day and month are missing) prior to the date of first study drug administration will not be 
considered as concomitant medication. If a partial start date is entered, any medication with the 
month and year (if day is missing) or year (if day and month are missing) after the study drug 
stop date will not be considered as concomitant medication. Medications with completely 
missing start and stop dates will be considered as the concomitant medication, unless otherwise 
specified.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 28
12 July 2021
All concomitant medications (other than per-protocol study drugs) will be provided in a by-
subject listing sorted by cohort, subject ID number and administration date in chronological 
order based on All Enrolled Analysis Set.
7.5.
Electrocardiogram Results
A standard 12-lead electrocardiogram (ECG) will be performed using local standard procedures 
at screening and at subsequent visits as specified in Appendix 2 of the protocol.
For ECG data, corrected QT (QTc) intervals will be derived using Fridericia’s correction (QTcF) 
as follows: 
𝑄𝑇𝑐𝐹= 𝑄𝑇
3 𝑅𝑅
where QT is measured in msec; RR = 60/Heart Rate (beats per min [bpm]) and RR is measured 
in seconds. Per Gilead data collection standard, ventricular rate (VR) is taken as heart rate and 
will be used to derive RR. 
A by-subject listing of 12-lead ECG will be provided for All Enrolled Subjects by cohort, subject 
ID number and visit in chronological order.
7.6.
Other Safety Measures
Eastern Cooperative Oncology Group (ECOG) performance status is an investigator assessment 
of the impact of the disease on the subject’s activities of daily living. ECOG assessments will be 
performed at the time points listed in the Study Procedures Table (Appendix 2 of the protocol).
By-subject listings will be generated for the All Enrolled Analysis Set by cohort and subject ID 
number in ascending order for the following safety parameters and comments:

ECOG performance scores

General Comments
7.7.
Changes from Protocol-Specified Safety Analyses
There are no deviations from the protocol-specified safety analyses.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 29
12 July 2021
8.
PHARMACOKINETIC ANALYSES
GS-4224 plasma concentrations will be determined by a validated method. The PK parameters to 
be estimated and reported may include, but may not be limited to, maximum observed drug 
concentration at steady-state (Cmax), observed concentration at the end of the dosing interval at 
steady-state (Ctrough), area under the concentration-time curve from time zero to the end of the 
dosing interval (AUCtau), time to maximum observed concentration (Tmax), systemic clearance 
after oral administration (CL/F), and volume of distribution after oral administration (V/F), etc. 
Noncompartmental (NCA) techniques will be used to analyze the PK. Compartmental modeling 
(eg, population pharmacokinetics [PopPK]) analysis may be conducted.
GS-4224 plasma concentrations and PK parameters (Tmax, Cmax, Ctrough,  AUCtau, CL/F, V/F,  
Cmax/Dose Ctrough/Dose and AUCtau/Dose, if applicable) for GS-4224 will be listed and 
summarized using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, % 
coefficient of variation, standard deviation, median, minimum, and maximum). PK parameters 
will be generated based on the PK profiles observed at Cycle 1 day 1 and 15 and presented 
separately. 
 
CCI
-


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 30
12 July 2021
9.
REFERENCES
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol 
2014.
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.


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 31
12 July 2021
10.
SOFTWARE
SAS (SAS Institute Inc. Version 9.4, Cary, NC) is to be used for all programming of tables, 
figures, and listings (TFLs).


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 32
12 July 2021
11.
SAP REVISION
Revision Date
(DD MMM YYYY)
Section
Summary of Revision
Reason for Revision


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 33
12 July 2021
12.
APPENDICES
Appendix 1.
COVID-19 SMQ with Broad Scope
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 34
12 July 2021
Appendix 1.
COVID-19 SMQ with Broad Scope
Note: The list presented below is based on MedDRA Version 23.1. The actual list will be up-
versioned to the MedDRA version used at the time of database finalization.
MedDRA Preferred Term
PT Code
Asymptomatic COVID-19
10084459
Coronavirus infection
10051905
Coronavirus test positive
10070255
COVID-19
10084268
COVID-19 immunisation
10084457
COVID-19 pneumonia
10084380
COVID-19 prophylaxis
10084458
COVID-19 treatment
10084460
Exposure to SARS-CoV-2
10084456
Multisystem inflammatory syndrome in children
10084767
Occupational exposure to SARS-CoV-2
10084394
SARS-CoV-2 antibody test positive
10084491
SARS-CoV-2 carrier
10084461
SARS-CoV-2 sepsis
10084639
SARS-CoV-2 test false negative
10084480
SARS-CoV-2 test positive
10084271
SARS-CoV-2 viraemia
10084640
Suspected COVID-19
10084451
Antiviral prophylaxis
10049087
Antiviral treatment
10068724
Coronavirus test
10084353
Coronavirus test negative
10084269
Exposure to communicable disease
10049711
Pneumonia viral
10035737
SARS-CoV-2 antibody test
10084501
SARS-CoV-2 antibody test negative
10084509
SARS-CoV-2 test
10084354
SARS-CoV-2 test false positive
10084602
SARS-CoV-2 test negative
10084273


GS-4224
Study GS-US-494-5484
Statistical Analysis Plan – Final Analysis
Version 1.0
CONFIDENTIAL
Page 35
12 July 2021
Appendix 2.
Determining Missing and Virtual Visits Due to COVID-19
This appendix describes the clinical trial site collection of COVID-19 data pertaining to 
missed/virtual visits and the data processing algorithm used to determine which visits were 
missing and which visits were virtual.
Data collection
A COVID-19 supplement to the eCRF Completion Guidelines (CCG) was provided by data 
management to instruct clinical trial sites with respect to data entry expectations pertaining to 
scenarios related to the COVID-19 pandemic. If a visit was missed, sites should enter 
“Visit missed due to COVID-19.” If an in-person visit was conducted virtually, sites should enter
“Virtual visit due to COVID-19.”
Determination of Missed and Virtual visits
NLP was used to search the CRF comment fields to identify instances of “COVID-19” (or 
synonyms, see the table below) and “Virtual” (or synonyms, see the table below). The search 
terms are maintained in a global lookup table and can be modified to tune the NLP model. For 
any comments with COVID-19 search terms, assign “Missed visit” or “Virtual visit as follows:
i.
If COVID-19 terms are identified through NLP and the visit date is missing, then result is 
“Missed Visit”
ii. If COVID-19 and Virtual terms are identified through NLP for a visit, then result is “Virtual 
Visit”. When there are multiple records for the same subject and the same visit, NLP will be 
based on multiple records to ensure 1 unique category per subject per visit
iii. Otherwise result is missing
Examples of Search Terms for “COVID-19” and “Virtual” Used to Identify Missed and 
Virtual Visits
Search Terms for “COVID-19”
Search Terms for “Virtual”
COVID19
VIRTUAL
CORONA
TELEMED
CORONAVIRUS
TELEHEALTH
PANDEMIC
TELEPHONE
OUTBREAK
REMOTE
CRISIS
TELEMEDICINE
LOCKDOWN
TELECONSULTATION
QUARANTINE
TELEPHONICALLY
SHELTER
PHONE
HOME VISIT
ZOOM
SKYPE


GS-US-494-5484 SAP
ELECTRONIC SIGNATURES
Signed by
Meaning of Signature
Server Date
(dd-MMM-
yyyy hh:mm:ss)
Clinical Research eSigned
01-Jul-2021
03:18:41
Clinical Pharmacology
eSigned
02-Jul-2021
17:55:35
Biostatistics eSigned
12-Jul-2021
08:15:22
PPD
PPD
PPD