Conditions: Neoplasms
Keywords: GSK3174998 Non-small Cell Lung Cancer (NSCLC) OX40 Pembrolizumab Monoclonal Antibody (mAb) Selected Advanced Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 141
Healthy volunteers: no

Brief summary:
This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of GSK3174998 administered intravenously to participants with selected advanced or recurrent solid tumors. This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy (Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with additional therapies.

The study will be conducted in 2 parts, each part consisting of starting with a dose-escalation phase followed by a cohort expansion phase. GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be evaluated with fixed doses of pembrolizumab.

The maximum duration of treatment with GSK3174998 and pembrolizumab will be approximately 2 years or 35 cycles, whichever comes first. The follow-up period for safety assessments will be a minimum of 3 months from the date of the last dose. The post-treatment follow-up period will include disease assessments every 12 weeks until documented progressive disease (PD). Approximately 141 participants with selected advanced or recurrent solid tumors will be enrolled.

Detailed description:

Arms:
arm 1: Participants will receive GSK3174998 intravenously (IV) (dose range 0.003 to 10.0 milligram per kilogram \[mg/kg\]) every 3 weeks (Q3W) for up to 2 years or 35 cycles, whichever comes first. arm 2: Participants will receive GSK3174998 IV (dose range 0.003 to 10.0 mg/kg) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 cycles, whichever comes first. arm 3: Participants will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation of part 2A) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for 2 years or 35 cycles, whichever comes first.

Interventions: intervention 1: GSK3174998 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to \<=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W intervention 2: Pembrolizumab as 100 mg/4 milliliter (mL) solution (dose: 200 mg) to be given as IV infusion for 30 min, Q3W

Protocol document:
Prot_000.pdf: 
2014N225045_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201212
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I, Open-Label Study of GSK3174998 Administered 
Alone and in Combination with Anticancer Agents including 
Pembrolizumab in Subjects with Selected Advanced Solid 
Tumors
Compound Number:
GSK3174998
Development Phase:
I
Effective Date
04-FEB-2020
Protocol Amendment Number:  04
Author (s):
 
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2014N225045_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201212
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N225045_00
2015-APR-29
Original
2014N225045_01
2015-AUG-17
Amendment No. 1
Amendment 1 incorporates changes to Section 4.1.4, Dose-Limiting Toxicities; 5.4 
Withdrawal/Stopping Criteria; and 6.3.1.12, Dose Delay as requested by the United 
States Food and Drug Administration (FDA).
2014N225045_02
2016-AUG-16
Amendment No. 2
Amendment 2 incorporates the following changes:

Addition of preliminary clinical data to support the initiation of Part 
2/combination with pembrolizumab.

Addition of a new “Pharmacodynamic Cohort” in the dose escalation phase.

Removal of Soft Tissue Sarcoma (STS) from the targeted tumor types.

Extension of GSK3174998 dosing up to 2 years/35 cycles.

Addition and clarification of procedures in the Time & Events Table.

Clarification on the use of Continual Reassessment Methodology (CRM) 
for dose escalation decisions.

Additional details on the definitions of analyses for anticancer activity.

Administrative corrections of minor typographical and/or inconsistent 
language throughout the protocol.
2014N225045_03
2018-MAR-16
Amendment No. 3
Amendment 3 incorporates the following changes:

Addition of preliminary clinical, safety, PK and PD data

Updated pembrolizumab background and dose rationale

Updated study design, with description of cohort expansion populations for 
Part 2B

Dose rationale for cohort expansion (Part 2B)

Updated risk assessment

Updates to Inclusion/Exclusion Criteria to define cohort expansion 
population

Consolidated Section 6.3 Dose and Safety Management Guidelines

Minor changes to Time & Events tables

Section 9 (Statistical Considerations and Data Analysis) – updates to 
hypothesis, sample size considerations, futility analysis and stopping rules


2014N225045_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201212
3
GlaxoSmithKline
Document Number
Date
Version
2014N225045_04
2020-FEB-04
Amendment No. 4
Amendment 4 documents the closure of Part 2B expansion cohorts, removes the 
requirement for future disease assessments and survival follow-up, and clarifies the 
impact of ending enrolment of expansion cohorts on the study objectives and efficacy 
analysis.
For expansion cohorts, enrolment of 10 subjects/cohort was initially planned, with a 
possibility of further enrolment if the cohorts passed planned futility analyses. 
However, in February 2019, a strategic decision was made not to initiate any new 
clinical investigations with the GSK3174998/pembrolizumab combination, including 
halting further expansion beyond 10 subjects/cohort. This decision was based upon the 
modest clinical activity observed within the study at that time, in addition to published 
data for other OX40 agonist antibodies combined with PD-1 or PD-L1 inhibitors
reporting low/modest clinical activity for these combinations. As a consequence, the 
futility analyses (described in Section 4.1.5) were deemed unnecessary. Ultimately, the 
three expansion cohorts in Melanoma, STS and NSCLC treated a total of 9, 9, and 5 
subjects, respectively. As of 5 November 2019, all subjects have completed treatment 
and are in post-treatment follow-up; no responses were observed in subjects enrolled in 
the expansion cohorts. Given the lack of responses in the expansion cohorts (Part 2B) 
and the modest clinical activity observed in dose escalation (Part 1A and 2A), no time-
to-event summaries and analyses (TTR, DOR, PFS, OS) will be performed for efficacy 
data; however, TTR and DOR will be calculated and listed and considered as 
exploratory endpoints.
Amendment 4 incorporates the following changes:

Removal of objectives to analyze/summarize efficacy time-to-event endpoints 
(PFS, OS)

Update to make durability of response endpoints (TTR, DOR) exploratory 

Halt to enrolment of new patients and halt the occurrence of any further futility 
analyses 

Removal of future disease assessments or follow-up for survival

Updated wording for treatment discontinuation

Updated the definition of subject and study completion to be 3 months post last 
dose 

Updated treatment after end of study

Updated footnotes in the T&E table to reflect the changes to further disease 
assessments and follow-up

Updated Evaluation of Anti-Cancer Activity 

Updated Interim Analysis Section 

Updated Secondary Analyses Section removing the objective to analyze/
summarize efficacy time-to-event endpoints

Updated PK analyses in section 9.4.2.2


PPD
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2014N225045_04
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5
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event (SAE) Contact Information:
Role
Name
Office Phone Email 
Address
Mobile
Fax 
Primary 
Medical Monitor 
, MD
Secondary 
Medical Monitors
, MD, PhD
 
SAE contact 
information 
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
GlaxoSmithKline
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline (GSK) 
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and 
contact person in the territory will be provided to the relevant regulatory authority as part 
of the clinical trial application.   
Regulatory Agency Identifying Numbers:  
Investigational New Drug (IND) number: IND124839
EudraCT number: 2015-000152-14
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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2014N225045_04
CONFIDENTIAL
201212
6
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 201212
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Signature
Date


2014N225045_04
CONFIDENTIAL
201212
7
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201212 (ENGAGE-1) ................................12
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
2.3.
GSK3174998..............................................................................................16
2.3.1.
Background .................................................................................16
2.3.2.
Nonclinical Pharmacokinetics of GSK3174998 ............................17
2.3.3.
Nonclinical Safety of GSK3174998 ..............................................17
2.3.4.
Nonclinical Activity and Pharmacodynamics of 
GSK3174998...............................................................................19
2.3.4.1.
In vitro Studies............................................................19
2.3.4.2.
In vivo Studies............................................................20
2.3.5.
Preliminary Clinical Data for GSK3174998...................................21
2.4.
Pembrolizumab...........................................................................................22
2.4.1.
Pembrolizumab Background and Clinical Trials ...........................22
2.4.2.
Rationale for Pembrolizumab Dose Selection..............................22
2.5.
Rationale for OX40 agonist and PD-1 inhibitor Combination.......................23
3.
OBJECTIVES AND ENDPOINTS...........................................................................25
4.
STUDY DESIGN ....................................................................................................29
4.1.
Overall Design ............................................................................................29
4.1.1.
Dose Escalation...........................................................................31
4.1.2.
Part 1A: Monotherapy Dose Escalation .......................................32
4.1.3.
Part 2A: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab)...........................................................................33
4.1.4.
Dose-Limiting Toxicity..................................................................34
4.1.5.
Cohort Expansion ........................................................................35
4.1.6.
Intra-Subject Dose Escalation......................................................36
4.2.
Treatment Arms and Duration.....................................................................37
4.3.
Type and Number of Subjects.....................................................................37
4.4.
Design Justification.....................................................................................38
4.5.
Dose Justification........................................................................................39
4.5.1.
Part 1: Starting Dose ...................................................................39
4.5.2.
Part 2: Starting Dose ...................................................................42
4.5.3.
Dose Rationale for Cohort Expansion (Part 2B)...........................43
4.6.
Benefit:Risk Assessment ............................................................................43
4.6.1.
Risk Assessment GSK3174998 Pembrolizumab.......................44
4.6.2.
Overall Benefit:Risk Conclusion...................................................45
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............45
5.1.
Inclusion Criteria.........................................................................................45
5.2.
Exclusion Criteria........................................................................................49
5.3.
Screening Failures......................................................................................52
5.4.
Withdrawal/Stopping Criteria.......................................................................52
5.4.1.
Treatment Discontinuation ...........................................................52


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8
5.4.2.
Liver Chemistry Stopping Criteria ................................................54
5.4.2.1.
Study Treatment Restart or Rechallenge....................54
5.4.3.
QTcF Stopping Criteria ................................................................55
5.4.4.
Stopping Rules for Clinical Deterioration......................................55
5.5.
Subject and Study Completion....................................................................56
6.
STUDY TREATMENT ............................................................................................57
6.1.
Investigational Product and Other Study Treatment....................................57
6.2.
Treatment Assignment................................................................................59
6.3.
Planned Dose Adjustments.........................................................................59
6.3.1.
Dose and Safety Management Guidelines...................................59
6.3.1.1.
Dose Modification and Toxicity Management 
for Immune-Related AEs Associated with 
GSK3174998 Pembrolizumab .................................59
6.3.1.2.
Liver Event Follow-up Assessments...........................63
6.3.1.3.
Dose Modification and Toxicity Management of 
Infusion-Reactions Related to GSK3174998 
Pembrolizumab ..........................................................65
6.3.1.4.
Dose Delay.................................................................67
6.4.
Blinding.......................................................................................................67
6.5.
Packaging and Labeling..............................................................................68
6.6.
Preparation/Handling/Storage/Accountability..............................................68
6.7.
Compliance with Study Treatment Administration.......................................68
6.8.
Treatment of Study Treatment Overdose....................................................68
6.8.1.
GSK3174998 Overdose...............................................................68
6.8.2.
Pembrolizumab Overdose ...........................................................69
6.9.
Treatment after the End of the Study ..........................................................69
6.10.
Concomitant Medications and Non-Drug Therapies....................................69
6.10.1.
Permitted Medications and Non-Drug Therapies..........................70
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................70
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................71
7.1.
Time and Events Table...............................................................................72
7.2.
Screening and Critical Baseline Assessments ............................................78
7.2.1.
Demographic and Baseline Assessments....................................78
7.2.1.1.
Critical Baseline Assessments....................................78
7.2.2.
Baseline Documentation of Target and Non-Target 
Lesions ........................................................................................78
7.3.
Efficacy.......................................................................................................79
7.3.1.
Evaluation of Anticancer Activity ..................................................79
7.4.
Safety .........................................................................................................80
7.4.1.
Adverse Events and Serious Adverse Events..............................80
7.4.1.1.
Time Period and Frequency for Collecting 
Adverse Events and Serious Adverse Events 
Information .................................................................80
7.4.1.2.
Method of Detecting Adverse Events and 
Serious Adverse Events .............................................81
7.4.1.3.
Follow-up of Adverse Events and Serious 
Adverse Events ..........................................................81
7.4.1.4.
Cardiovascular and Death Events ..............................81
7.4.1.4.1.
Definition of Cardiovascular 
Events ....................................................82


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9
7.4.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................82
7.4.1.6.
Regulatory Reporting Requirements for SAEs............82
7.4.2.
Pregnancy ...................................................................................83
7.4.3.
Physical Exams ...........................................................................83
7.4.4.
Vital Signs....................................................................................84
7.4.5.
Electrocardiogram (ECG).............................................................84
7.4.6.
Clinical Safety Laboratory Assessments ......................................84
7.5.
Pharmacokinetics .......................................................................................86
7.5.1.
Blood Sample Collection..............................................................86
7.5.2.
Blood Sample Analysis ................................................................86
7.6.
Biomarkers/Pharmacodynamic Markers .....................................................86
7.6.1.
Blood Biomarkers ........................................................................86
7.6.2.
Tumor Tissue...............................................................................87
7.7.
Anti-Drug Antibodies...................................................................................88
7.7.1.
Blood Sample Collection..............................................................88
7.8.
Genetics .....................................................................................................88
8.
DATA MANAGEMENT ...........................................................................................88
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................89
9.1.
Hypotheses.................................................................................................89
9.1.1.
Part 1: Monotherapy Dose Escalation (GSK3174998) .................89
9.1.2.
Part 2: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab)...........................................................................89
9.1.3.
Part 2: Combination Dose Expansion (GSK3174998 + 
Pembrolizumab)...........................................................................89
9.2.
Sample Size Considerations.......................................................................90
9.2.1.
Sample Size Re-estimation or Adjustment...................................91
9.3.
Data Analysis Considerations .....................................................................91
9.3.1.
Analysis Populations....................................................................92
9.3.2.
Interim Analysis ...........................................................................92
9.4.
Key Elements of Analysis Plan ...................................................................94
9.4.1.
Primary Analyses.........................................................................94
9.4.1.1.
Safety Analyses..........................................................94
9.4.1.2.
Extent of Exposure .....................................................95
9.4.1.3.
Adverse Events ..........................................................95
9.4.1.4.
Clinical Laboratory Evaluations ..................................95
9.4.1.5.
Other Safety Measures...............................................95
9.4.2.
Secondary Analyses ....................................................................95
9.4.2.1.
Anticancer Activity Analyses.......................................95
9.4.2.2.
Pharmacokinetic Analyses..........................................96
9.4.2.2.1.
Pharmacokinetic Parameters..................96
9.4.2.2.2.
Statistical Analysis of 
Pharmacokinetic Data.............................96
9.4.2.3.
Pharmacokinetic/Pharmacodynamic Analyses ...........96
9.4.2.4.
Immunogenicity Analyses...........................................97
9.4.3.
Other Analyses ............................................................................97
9.4.3.1.
Translational Research Analyses ...............................97
9.4.3.2.
Novel Biomarker(s) Analyses .....................................97
9.4.3.3.
Longitudinal tumor size modeling ...............................97
9.4.3.4.
Pharmacogenetic Analyses ........................................97


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10. STUDY GOVERNANCE CONSIDERATIONS........................................................98
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............98
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................98
10.3.
Quality Assurance.......................................................................................99
10.4.
Study and Site Closure ...............................................................................99
10.5.
Records Retention....................................................................................100
10.6.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ...............100
11. REFERENCES.....................................................................................................101
12. APPENDICES......................................................................................................106
12.1.
Appendix 1: Abbreviations and Trademarks..............................................106
12.2.
Appendix 2: Immune-related Diseases .....................................................110
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................112
12.4.
Appendix 4: NYHA Functional Classification System for Heart 
Failure ......................................................................................................115
12.5.
Appendix 5: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST version 
1.1 ............................................................................................................116
12.5.1.
Assessment Guidelines .............................................................116
12.5.2.
Guidelines for Evaluation of Disease .........................................117
12.5.2.1.
Measurable and Non-measurable Definitions ...........117
12.5.2.1.1.
Measurable lesion: ...............................117
12.5.2.1.2.
Non-measurable lesion:........................117
12.5.2.2.
Immune-Related RECIST Response Criteria............118
12.5.2.2.1.
Evaluation of target lesions...................118
12.5.2.2.2.
Antitumor response based on total 
measurable tumor burden.....................118
12.5.2.2.3.
Time-point response assessment 
using the Immune-Related 
RECIST criteria.....................................118
12.5.2.2.4.
Evaluation of non-target lesions............119
12.5.2.2.5.
New lesions ..........................................119
12.5.3.
Evaluation of overall response...................................................119
12.5.3.1.
Evaluation of best overall response..........................120
12.5.3.2.
Confirmation Criteria:................................................120
12.6.
Appendix 6: ECOG Performance Statusa..................................................121
12.7.
Appendix 7: Genetic Research .................................................................122
12.7.1.
Study Population........................................................................122
12.7.2.
Study Assessments and Procedures .........................................122
12.7.3.
Informed Consent ......................................................................123
12.7.4.
Subject Withdrawal from Study..................................................123
12.7.5.
Screen and Baseline Failures ....................................................123
12.7.6.
Provision of Study Results and Confidentiality of Subject’s 
Genetic Data..............................................................................124
12.8.
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................125
12.8.1.
Definition of Adverse Events......................................................125
12.8.2.
Definition of Serious Adverse Events.........................................126


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12.8.3.
Definition of Cardiovascular Events ...........................................127
12.8.4.
Recording of AEs and SAEs ......................................................128
12.8.5.
Evaluating AEs and SAEs..........................................................128
12.8.6.
Reporting of SAEs to GSK.........................................................130
12.9.
Appendix 9: Collection of Pregnancy Information......................................131
12.9.1.
Action to be taken if pregnancy occurs ......................................131
12.9.2.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ..............................................................131
12.10. Appendix 10: Country Specific Requirements...........................................132
12.11. Appendix 11: Adverse Events of Special Interest......................................133
12.12. Appendix 12:  CKD-EPI Formula ..............................................................135
12.13. Appendix 13: Protocol Amendment Changes............................................136


2014N225045_04
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12
1.
PROTOCOL SYNOPSIS FOR STUDY 201212
(ENGAGE-1)
Rationale
The stimulation of antitumor T-cell activity, through inhibition of negative T-cell 
regulatory pathways with immunotherapeutic checkpoint inhibitors, has been very 
successful in the treatment of melanoma and non-small cell lung cancer (NSCLC). 
Another approach that provides an attractive target for the development of 
immunotherapy anticancer agents is the modulation of costimulatory pathways to 
enhance T-cell function.  OX40 is a potent costimulatory receptor expressed primarily on 
activated CD4+ and CD8+ T cells. OX40 agonists have been shown to increase antitumor 
immunity and improve tumor-free survival in non-clinical models and OX40 agonist 
monoclonal antibodies (mAbs) are currently being evaluated in Phase I clinical trials.  
GSK3174998 is a humanized wild-type immunoglobulin G1 (IgG1) anti-OX40 agonistic 
mAb and will be evaluated as a single-agent treatment in Part 1 of the current study.  
The anticancer immune response is a multistep process and it is expected that tumors may 
utilize redundant mechanisms to block the antitumor response; in these instances, 
combination therapies will likely be required. Combining an OX40 agonist with a 
programmed death receptor-1 (PD-1) inhibitor targets two different steps in the cancer-
immunity cycle; OX40 agonism is expected to increase priming/activation of T cells, 
while inhibition of PD-1 blocks its interaction with programmed death ligand 1 (PD-L1) 
and programmed death ligand 2 (PD-L2), releasing the PD-1 pathway-mediated 
inhibition of the immune response.  Based on non-clinical data, combination treatment 
with an OX40 agonist and a PD-1 inhibitor is anticipated to have synergistic antitumor 
activity, compared with single-agent treatment.  The combination of GSK3174998 with 
the PD-1 inhibitor pembrolizumab will be evaluated in Part 2 of the current study.
Objectives/Endpoints
The primary objectives of the study are to evaluate the safety and tolerability and to 
identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of 
GSK3174998 when administered intravenously as monotherapy (Part 1) or in 
combination with pembrolizumab (Part 2) to subjects with selected advanced or recurrent 
solid tumors.  Secondary objectives include: the evaluation of antitumor activity;
characterization of pharmacokinetics (PK) for GSK3174998 when administered alone; 
characterization of PK for GSK3174998 and pembrolizumab when administered in 
combination; and determination of the immunogenicity of GSK3174998 when 
administered alone or for GSK3174998 and pembrolizumab when administered in 
combination. Exploratory objectives include evaluation of pharmacodynamic activity in 
the blood and tumor microenvironment.

Safety endpoints: Adverse events (AEs), serious adverse events (SAEs), dose-
limiting toxicity (DLT), withdrawals due to AEs, dose reductions or delays, and 
changes in safety assessments (e.g., laboratory parameters, vital signs, and 
cardiac parameters).


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
Antitumor activity endpoints: Objective response rate (ORR) and Disease 
Control Rate (DCR) (complete response [CR]+partial response [PR]+stable 
disease [SD] ≥12 weeks).  Unless otherwise specified, all response endpoints 
will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 and by irRECIST (immune-related RECIST); the primary endpoint analysis 
will use irRECIST.

PK endpoints: Plasma GSK3174998 and serum pembrolizumab concentrations 
and PK parameters including maximum observed concentration (Cmax), area 
under the concentration-time curve over the dosing interval (AUC(0-τ)), and 
minimum observed concentration (Cmin).

Pharmacodynamic endpoints: Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by GSK3174998, along with the 
phenotype, quantity, and activation state of T cells in the periphery, T-cell 
receptor (TCR) diversity, expression of circulating soluble factors, and changes 
in genomic DNA and gene expression, and mutational load. Assessment of
tumor biopsies via immunohistochemistry (IHC) for the numbers of tumor-
infiltrating lymphocytes and other immune cells expressing key phenotypic 
markers. Changes in gene expression (RNA and protein), TCR diversity or 
mutational load (genomic DNA).

Immunogenicity endpoints: Number and percentage of subjects who develop 
detectable antidrug antibodies (ADA).
Overall Design
This is a first time in human (FTIH), open-label, non-randomized, multicenter study 
designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary 
clinical activity of GSK3174998 administered intravenously to subjects with selected 
advanced or recurrent solid tumors.  The study will be conducted in 2 parts, each part 
consisting of a dose-escalation phase followed by a cohort expansion phase.  Part 1 will 
evaluate GSK3174998 monotherapy, while Part 2 will evaluate GSK3174998 in 
combination with pembrolizumab. GSK3174998 will first be evaluated as monotherapy 
in escalating doses.  Once a dose of GSK3174998 has been identified that is both 
tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may begin.  
In Part 2, escalating doses of GSK3174998 will be evaluated with fixed doses of 
pembrolizumab. The transition of the study from dose-escalation to cohort expansion and 
from monotherapy (Part 1) to combination therapy with pembrolizumab (Part 2) will be 
performed under the guidance of a Protocol Steering Committee.  The remit, 
membership, roles, and responsibilities of the Steering Committee are described in a 
Steering Committee Charter. Pending a review of emerging data from this study and 
under the guidance of the Steering Committee, the protocol may be subsequently 
amended to include investigation of additional anticancer agent combinations with 
GSK3174998.  
Treatment Arms and Duration
The study includes a screening period, a treatment period, and a follow-up period.  
Subjects will be screened for eligibility beginning approximately 4 weeks before the start 


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of treatment. The maximum duration of treatment with GSK3174998 pembrolizumab
will be 2 years or 35 cycles, whichever comes first. The follow-up period for safety 
assessments will be a minimum of 3 months from the date of the last dose. The post-
treatment follow-up period includes disease assessments every 12 weeks until confirmed 
disease progression (PD). Following PD, subjects will be contacted every 3 months to 
assess survival status.  
With the implementation of Amendment 04, there will be no requirement to perform
future disease assessments or survival follow-up. In Part 1, dose escalation for 
GSK3174998 monotherapy will begin with a starting dose of 0.003 mg/kg GSK3174998
administered once every 3 weeks (Q3W).  In Part 2, dose escalation for GSK3174998 + 
pembrolizumab combination therapy will begin with a fixed dose of 200 mg 
pembrolizumab administered Q3W and a starting dose of 0.003 mg/kg GSK3174998.  
Dose adjustments are allowed to address tolerability and safety issues.  
Type and Number of Subjects
The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma 
(RCC), melanoma, bladder cancer, soft tissue sarcoma (STS), triple-negative breast 
cancer (TNBC), and colorectal carcinoma displaying high microsatellite instability (MSI 
CRC).  
Analysis
During the dose-escalation phases of the study, safety, PK, and pharmacodynamic marker 
data will be examined while the study is being conducted in order to determine 
subsequent dosing levels. After each dosing cohort, a continual reassessment method 
(CRM) analysis may be used to recommend the next dose level based on observed DLTs.
In each expansion cohort, clinical activity, safety, PK, and pharmacodynamic marker data
will be examined on an on-going basis and enrollment within each cohort may be 
curtailed or expanded in response to unfavorable or favorable outcomes.  Tumor response 
data will be monitored and a tumor cohort may be terminated if there is insufficient 
evidence of clinical activity.  The futility stopping rules are based on the methodology of 
Lee & Liu [Lee, 2008].  CRM-recommended dose-escalation levels, futility stopping 
rules, and posterior probabilities are only guidelines and the totality of the data will be 
considered by the team in decision making. 


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2.
INTRODUCTION
2.1.
Study Rationale
The stimulation of antitumor T-cell activity, through inhibition of negative T-cell 
regulatory pathways with immunotherapeutic checkpoint inhibitors, has been very 
successful in the treatment of melanoma and NSCLC. Another approach that provides an 
attractive target for the development of immunotherapy anticancer agents is the 
modulation of costimulatory pathways to enhance T-cell function.  OX40 is a potent 
costimulatory receptor expressed primarily on activated CD4+ and CD8+ T cells. OX40 
agonists have been shown to increase antitumor immunity and improve tumor-free 
survival in non-clinical models and OX40 agonist mAbs are currently being evaluated in 
Phase I clinical trials.  GSK3174998 is a humanized wild-type IgG1 anti-OX40 agonistic 
mAb and will be evaluated as a single-agent treatment in Part 1 of the current study.  
The anticancer immune response is a multistep process and it is expected that tumors may 
utilize redundant mechanisms to block the antitumor response; in these instances, 
combination therapies will likely be required. Combining an OX40 agonist with a PD-1 
inhibitor targets two different steps in the cancer-immunity cycle; OX40 agonism is 
expected to increase priming/activation of T cells, while inhibition of PD-1 blocks its 
interaction with PD-L1 and PD-L2, releasing the PD-1 pathway-mediated inhibition of 
the immune response.  Based on non-clinical data, combination treatment with an OX40 
agonist and a PD-1 inhibitor is anticipated to have synergistic antitumor activity, 
compared with single-agent treatment.  The combination of GSK3174998 with the PD-1 
inhibitor pembrolizumab will be evaluated in Part 2 of the current study.
This FTIH, open-label, dose-escalation study will assess the safety, PK, 
pharmacodynamics, and preliminary clinical activity of GSK3174998 in subjects with 
selected advanced or recurrent solid tumors as monotherapy (Part 1), in combination with 
pembrolizumab (Part 2), and potentially in combination with additional therapies.  
2.2.
Brief Background
Immunotherapy has emerged as a transformative anticancer therapeutic strategy over the 
past few years.  In particular, the inhibition of negative T-cell regulatory pathways with 
the checkpoint inhibitors has been very successful, first in the treatment of melanoma 
and, more recently, expanding to additional indications, including NSCLC.  Ipilimumab 
and pembrolizumab are examples of these initial checkpoint inhibitors, which are mAbs 
that block the activity of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and 
PD-1 pathways, respectively, thereby freeing the T-cell priming and T-cell effector 
functions from their negative regulatory effects.  
In addition to regulatory mechanisms that negatively regulate effector T-cell function, 
costimulatory pathways are also attractive targets to modulate for the development of 
anticancer agents.  OX40 (CD134) is a member of the tumor necrosis factor receptor 
(TNFR) family of transmembrane receptors, which is induced following antigen-
dependent stimulation of both CD4+ and CD8+ T cells and following interaction with its 
cognate ligand (OX40L, expressed on activated antigen presenting cells) generally 


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functions to transduce a costimulatory signal during the process of T-cell activation.  In 
blood and peripheral tissues, OX40 expression is limited to the small subset of recently 
activated CD4+ and CD8+ cells; however, in tumors, infiltrating T lymphocytes are 
enriched for OX40 positive cells, where it functions to augment T-cell activation, 
proliferation, and survival through direct and indirect (e.g., cytokine release) mechanisms 
[Betting, 2009; Croft, 2010].  In addition to its function on effector T cells, OX40 is also
expressed on tumor infiltrating regulatory T cells (Tregs), which tend to have an 
inhibitory effect on the immune response.  Indeed, the efficacy of anti-OX40 antibodies 
in animal tumor models relies to some extent also on the depletion of tumor-specific 
Tregs residing in the tumor microenvironment [Bulliard, 2014; Marabelle, 2013]. As has 
been shown for anti-CTLA4 and anti-GITR (Glucocorticoid-induced TNFR family 
related gene) antibodies, this intratumoral Treg depletion is critical for the in vivo
antitumor activity of immune checkpoint antibodies and is mediated by activatory FcR 
positive myeloid cells residing in the tumor microenvironment [Bulliard, 2013; Selby, 
2013; Simpson, 2013].  OX40 signaling has been shown to block the activity of induced 
Tregs, in part by blocking the release of the inhibitory cytokine interleukin-10 (IL-10),
thereby further promoting effector T-cell immune responses [Ito, 2006].  Finally, OX40 
can also be found on natural killer (NK) cells where it appears to stimulate NK-mediated 
antibody-dependent cellular cytotoxicity (ADCC) [Liu, 2008].  Together, these potential 
mechanisms of action make the stimulation of OX40 with agonistic agents an attractive 
target for a novel anti-cancer immunotherapy.
2.3.
GSK3174998
2.3.1.
Background
An overview of the nonclinical studies of GSK3174998 and preliminary clinical data 
from Protocol 201212 (ENGAGE-1) are provided below.  Detailed information 
concerning the biology, pharmacology, PK, and safety can be found in the Investigators’ 
Brochure (IB) [GlaxoSmithKline Document Number 2014N212091_06].
GSK3174998 is a humanized wild-type IgG1 anti-OX40 agonistic mAb.  GSK3174998
demonstrated several mechanisms of action in vitro including promoting effector CD4+ 
T-cell proliferation, inhibiting the induction of IL-10-producing CD4+ Type 1 regulatory 
(Tr1) cells and blocking the suppressive function of natural Tregs (nTregs), and binding 
to FcR, which is anticipated to augment OX40 signaling via cross-linking of the antibody 
via the Fc domain on FcR positive cells.  Importantly, it has been shown that OX40 
activation gives a costimulatory signal to T cells, dependent on a T-cell receptor (TCR) 
engagement, suggesting that GSK3174998 is not a super agonist in the models tested.
GSK3174998 is suitably cross-reactive to cynomolgus monkey OX40 to evaluate the 
pharmacology, pharmacodynamics, PK, and toxicology in this species. Single and repeat 
dose studies in cynomolgus monkeys demonstrated that GSK3174998 bound to OX40 
positive cells.  GSK3174998 is not cross-reactive with rodent OX40; however, a 
surrogate mAb to murine OX40 (OX86), was used to generate in vivo nonclinical 
evidence for both single agent efficacy and combination synergy with a variety of other 
immunotherapy agents in a range of syngeneic tumor models.  


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2.3.2.
Nonclinical Pharmacokinetics of GSK3174998
The nonclinical PK of GSK3174998 has been investigated in mice following a single 
intraperitoneal (IP) administration and in cynomolgus monkeys following single and 
repeated intravenous (IV) administration.  Details of the nonclinical PK are provided in 
Section 4.3 of the IB [2014N212091_06]. 
The PK of GSK3174998 in male mice following a single-dose IP administration had 
concentration profiles typical for mAbs (very slow plasma clearance and low volume of 
distribution at steady state) [Wang, 2008], suggesting that GSK3174998 was mainly 
confined to the systemic circulation. Due to lack of cross-reactivity with murine OX40 
the impact on PK expression of target is not evaluable in this species.
Similar PK profiles typical for mAbs were observed in monkeys. Following a single IV 
administration in male cynomolgus monkeys (n=3) at 2 mg/kg, all GSK3174998-treated 
animals showed similar Cmax values ranging from 31.8 to 39.9 g/mL and similar 
systemic exposures (AUC0-168h) through Day 5. There was a dramatic change in clearance 
observed from about 7 to 14 days in all treated animals, typical of an immunogenicity 
response; all animals were confirmed to be positive for ADA in an ADA bridging assay.
Following repeat dose IV administration in cynomolgus monkeys at 10 or 100 
mg/kg/week for 4 weeks, the mean AUC0-168h and Cmax values for GSK3174998 were 
similar between males and females at both doses during Weeks 1 and 4.  The systemic 
exposure to GSK3174998 (as defined by gender-averaged AUC0-168h and Cmax values) 
increased dose-proportionally (n=3/group). The increases in the gender-averaged AUC0-
168h and Cmax values of GSK3174998 from Week 1 to 4 ranged from 1.9- to 2.9 fold at 
both doses. Instances of decreased plasma concentrations were observed after the fourth 
dose in monkeys at 10 mg/kg/week due to primate ADA formation.   
2.3.3.
Nonclinical Safety of GSK3174998
The toxicology program was conducted in cynomolgus monkeys.  These monkeys were 
shown to be a suitable species based on OX40 receptor expression in tissues, orthologous 
protein sequence homology, and similar dose-dependent binding of GSK3174998 for 
both human and monkey OX40 receptor on CD4+ T cells.  IHC assessment of OX40 
distribution in normal human tissues showed positive staining in cells or lymphoid cell 
aggregates, considered likely to be a subset of T cells, in a number of the tissues.  These 
results are in general agreement with results from the evaluation of a microarray gene 
expression database (Gene Logic, Ocimum Biosolutions, LLC, Houston, TX, USA).    
GSK3174998 was well tolerated in monkeys following weekly IV dosing for 4 weeks at 
doses up to 100 mg/kg/week.  
ADA were observed in monkeys given ≤10 mg/kg/week; the incidence occurred 
inversely to dose. In a PK/pharmacodynamic study, all monkeys (n=3) or two of three 
monkeys given 2 or 10 mg/kg/week, respectively, demonstrated a dramatic increase in 
clearance as early as 7 days post-dose (2 mg/kg/week) and were confirmed to be positive 
for ADA. In monkeys given GSK3174998 weekly for 4 weeks followed by a 6 week off-
dose period, ADA were detected in two of ten monkeys given 10 mg/kg/week, in which 


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one monkey (titer >10000) demonstrated a decrease in exposure following the fourth 
weekly dose, and the other monkey (titer = 1000), which did not have detectable ADA 
until the off-dose period, did not demonstrate a clear association to decreased exposure. 
As ADA were only noted in animals maintained throughout the off-dose period, the 
ability to determine toxicity in the terminal necropsy animals at this dose on this study 
was not compromised by ADA. The generation of ADA in animals administered 
humanized protein is generally not predictive of a potential for ADA formation in 
humans.
In an in vivo syngeneic efficacy study with BALB/c mice bearing 4T1 mammary 
carcinoma cells, mortality and clinical observations consistent with anaphylaxis were 
observed in the majority of mice given 20 g OX86 (rat wild-type IgG1 mAb against 
OX40 receptor) at 3 weeks of twice-weekly dosing (5th dose).  This effect appears to be 
unique to this specific model, as other efficacy studies using either BALB/c or C57BL/6 
mice with the same batch of OX86 given at comparable doses and duration with other 
syngeneic cell types demonstrated no tolerability issues.  Similar effects have been 
observed by others using 4T1 tumor-bearing mice given rat anti-PD-1 or hamster PD-L1 
[Mall, 2014] or with tumor administration only [duPre, 2007].  To date, anaphylaxis has 
not been reported in subjects receiving OX40 agonist mAbs or approved PD-1 therapies 
[Curti, 2013; KEYTRUDA Prescribing Information, 2019; OPDIVO Prescribing 
Information, 2014].  Therefore, based upon the data and literature findings described 
above, it suggests that the anaphylaxis seen in 4T1 tumor-bearing mice given OX86 is 
model specific and that the proposed safety monitoring strategy (real time monitoring of 
ADA and acute hypersensitivity reactions, see Section 6.3.1) adequately addresses the 
potential risk of this effect.  
The potential for GSK3174998 to induce cytokine release has been investigated.  In a 
human in vitro assay, using whole blood or isolated peripheral blood mononuclear cells 
(PBMCs) (with and without prior anti-CD3 and anti-CD28 stimulation), no release of 
cytokines in response to soluble or immobilized GSK3174998 was observed.  However, 
to further explore the potential for cytokine release, human PBMCs were incubated at 
higher (10X) cell density, incubated with immobilized GSK3174998 and stimulated 
instead with submaximal levels of immobilized anti-CD3 (10 and 100X lower), to 
provide more sensitive assay conditions.  In these assays increased cytokine production 
(IL-2, IFN, TNF) was observed compared to anti-CD3 alone.  Similar cytokine 
increases, along with proliferation, were also observed using isolated human CD4+ T 
cells with immobilized GSK3174998, prior anti-CD3 and anti-CD28 stimulation to 
upregulate OX40 expression and longer incubation periods (48-72 hours compared with 
24 hours).  In repeat dose monkey studies up to 4 weeks in duration of dosing over a dose 
range of 0.03 to 100 mg/kg/week, there were no GSK3174998-related changes in plasma 
cytokine levels at either 4 or 24 hours of the first dose or 4 hours after the second weekly 
dose.  While low levels of cytokine release in subjects given GSK3174998 is expected by 
activated T cells as part of the pharmacodynamics, the response may not be fully 
predicted by these in vitro assays, and close clinical monitoring is planned.  
Single-dose safety pharmacology studies have not been conducted with GSK3174998.  
Evaluations of cardiovascular function were performed on the 3rd week of the 4-week 
monkey toxicology study, which evaluated heart rate, electrocardiogram (ECG) 


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waveform evaluation, and corrected QT interval duration (QTc) evaluation.  There were 
no GSK3174998-related effects on these cardiovascular measurements nor were there 
any clinical observations of respiratory or general behavior effects of the antibody.  
The no observed adverse effect level (NOAEL) was determined to be 100 mg/kg/week,
the highest dose tested (Week 4 gender average mean AUC0-168h: 594 mg.h/mL, range 
548 to 634 mg.h/mL; Cmax: 4.88 mg/mL, range 4.27 to 5.46 mg/mL).
2.3.4.
Nonclinical Activity and Pharmacodynamics of GSK3174998
2.3.4.1.
In vitro Studies
GSK3174998 demonstrated several mechanisms of action in vitro, including promoting 
effector CD4+ T-cell proliferation, inhibiting the induction of IL-10 producing CD4+ Tr1 
cells and blocking the suppressive function of nTregs, and binding to FcR, which is 
anticipated to augment OX40 signaling via cross-linking of the antibody via the Fc 
domain on FcR positive cells. 
GSK3174998 bound specifically to the recombinant OX40 extracellular domain from 
cynomolgus monkeys (Kd 408 nM) and humans (Kd 4.9 nM), but not to the related 
human receptors DcR3 and CD40.  GSK3174998 bound to both activated cynomolgus
monkey and human CD4+ T cells with similar EC50 values (0.35 and 0.30 g/mL, 
respectively).  These data suggest that affinity differences observed for binding to 
recombinant OX40 are not truly reflective of the binding to cell-surface OX40.  
Many anti-TNFR family antibodies (including anti-OX40) appear to require the 
formation of high-density antibody complexes and costimulation which may occur in 
vivo during cell:cell interactions in tissues expressing various FcRs [White, 2013].  In 
the case of OX40 antibodies, this can be mimicked in vitro by immobilizing the antibody 
to the surface of plastic tissue-culture plates and incubating cells on this plate-bound 
antibody.  Importantly, it was shown that OX40 activation gives a costimulatory signal to 
T cells dependent on TCR engagement (e.g., CD3 ligation), suggesting that GSK3174998 
is not a super agonist in the in vitro systems tested in absence of TCR signal.  
GSK3174998 (immobilized) stimulated proliferation of immobilized anti-CD3 activated 
cynomolgus monkey CD4+ T cells with a mean EC50 value of 0.72 g/mL (4.8 nM) and 
anti-CD3 induced proliferation of activated human CD4+ T cells with a mean EC50 value 
of 0.19 g/mL (1.3 nM).  
OX40 agonist antibodies have been shown to reduce the suppressive function of human 
Tregs.  Human purified CD4+ T cells were differentiated into induced Tregs using 
vitamin D3 and dexamethasone and cultured with human CD32a (FcγRIIA)-expressing 
L-cells (which could facilitate antibody crosslinking via the FcγRIIA).  Addition of 
GSK3174998 in solution during the differentiation phase was able to prevent naïve 
T cells from differentiating into IL-10+ Tr1 cells.  
As expected for an IgG1 antibody, GSK3174998 bound to cynomolgus monkey and 
human FcRs (and to human complement C1q) and showed low but measurable levels of 
reporter FcRIIIA engagement in a reporter assay system.  In ADCC assays, some cell 


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lysis of an OX40+ target cell line was observed with GSK3174998 treatment.  However, 
in primary human PBMC assays, GSK3174998 generally did not impact  the viability of 
CD4+ and CD8+ T cells. Statistical analysis of the PBMC ADCC data did not support a 
robust effect on viability with GSK3174998. In all cases the reduction in viability with 
GSK3174998 was less than observed for anti-CD52 or anti-CD20 positive control 
antibodies.  Overall these in vitro findings suggest that GSK3174998 may have the 
potential to cause ADCC of OX40+ target cells in vivo, however effects were not 
consistent across donors and these in vitro assays may not fully reflect the immune 
microenvironments in vivo.  
2.3.4.2.
In vivo Studies
In cynomolgus monkeys given a single IV dose (2 mg/kg) of GSK3174998 there was a
transient decrease in the percentage of OX40+/CD4+ T cells on Day 2, recovering by 
Day 7, suggesting that GSK3174998 appears to bind to OX40+ cells in peripheral blood 
and that these cells and may reflect margination rather than depletion of these cells.  In a 
repeat-dose IV study, cynomolgus monkeys were given GSK3174998 (10 mg/kg/week) 
for 4 weeks.  As observed in the single-dose study, the percentage of free OX40 on 
peripheral blood T cells was reduced in groups treated with GSK3174998 compared with 
the vehicle group, which was sustained for the duration of the study.  This indirectly 
suggests that GSK3174998 was bound to OX40+ cells following dosing.  OX40-positive 
cells did not appear to be depleted as they could be detected using a non-competitive anti-
OX40 antibody.  No clear evidence of changes in T-cell activation markers were 
observed in peripheral blood, spleen, or lymph nodes in treated groups compared with 
non-treated groups in either study.  OX40 positive cells were also detected in these 
tissues in both treated and non-treated groups suggesting cells were not depleted in 
tissues by GSK3174998.  There were no clinical observations considered related to 
treatment in either study.  
A surrogate mAb to murine OX40 (OX86) was used to generate in vivo nonclinical
evidence for monotherapy activity in syngeneic tumor models.  In a series of 
experiments, female BALB/c mice bearing CT26 mouse colon carcinoma tumors 
(n=10/group), were given twice weekly IP doses of OX86 ranging from 1 to 
400 g/mouse in phosphate-buffered saline for 3 weeks.  All doses showed a significant 
increase in survival (Figure 1) compared to control groups.  Assuming similar potency
between anti-OX86 and GSK3174998, exposures that have demonstrated efficacy
preclinically are predicted to be achievable in human subjects.


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Figure 1
OX86 monotherapy results in a statistically significant increase in 
survival in nonclinical mouse model; (a) all dose levels tested and 
(b) the 5 µg dose
Additional in vivo experiments were performed with BALB/c mice bearing A20 mouse 
lymphoma cell line tumors and showed modest tumor reduction and with C57BL/6 mice 
bearing B16F10 mouse melanoma cell line tumors with no significant effect on tumor 
reduction or survival noted.  Additionally, the mouse adoptive cell transfer (ACT) model, 
MC38/gp100 was utilized to evaluate GSK3174998 in vivo since a humanized mouse 
model is unavailable.  Overall the ACT model was not robust and produced highly 
variable results.  Further details for all studies are available in Section 4.2.1.3 of the IB 
[2014N212091_06].
In vivo studies in syngeneic tumor models were also performed with GSK3174998 in 
combination with anti-PD-1 antibodies and anti-CTLA-4 antibodies; the anti-PD-1 
combination studies are briefly described in Section 2.5 of the protocol; further details for 
combination studies are available in Section 4.2.1.3 of the IB [2014N212091_06].
2.3.5.
Preliminary Clinical Data for GSK3174998
Data are summarized for the ongoing first time in human study with a clinical data cut-
off of 13 August 2019 in the Investigator’s Brochure [2014N212091_06]. Data are 
reported for 138 subjects; 45 subjects received doses up to 10 mg/kg of GSK3174998 
monotherapy and 96 subjects received doses up to 10 mg/kg of GSK3174998 + 200 mg 
of pembrolizumab.  Three subjects crossed over from monotherapy to combination 
therapy.


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2.4.
Pembrolizumab
Refer to the pembrolizumab IB/approved labeling for detailed background information on 
pembrolizumab [KEYTRUDA Prescribing Information, 2019; Merck Sharp & Dohme 
Corp 2019]
2.4.1.
Pembrolizumab Background and Clinical Trials
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 
thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
For more details on specific indications refer to the Investigator brochure. [Merck Sharp 
& Dohme Co, 2019].  
2.4.2.
Rationale for Pembrolizumab Dose Selection
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). 
Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically-based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different 
disease settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) 
and different treatment settings (monotherapy and in combination with chemotherapy). 
Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 
Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of 


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pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, 
PK data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 
mg Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over 
a wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-
dosing provides similar control of PK variability as weight based dosing, with 
considerable overlap in the distribution of exposures from the 200 mg Q3W fixed dose 
and 2 mg/kg Q3W dose. Supported by these PK characteristics, and given that fixed-dose 
has advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols.
2.5.
Rationale for OX40 agonist and PD-1 inhibitor Combination
The anticancer immune response is a multistep process that includes antigen processing 
and presentation, T-cell priming and activation, tumor infiltration, and subsequent 
destruction by activated effector T cells [Chen, 2013].  Each of these steps can be 
negatively regulated, which provides the malignant tumor with redundant mechanisms by 
which to block an anticancer immune response.  In some cases, tumors will be highly 
dependent on a single mechanism, and in these cases, there is the potential to achieve 
significant clinical activity with a single immunomodulatory therapy.  However, it is 
expected that tumors will often utilize redundant mechanisms to block the antitumor 
immune response.  In these instances, combination therapies will likely be required. One 
example of the benefit of combination immunotherapy is the very impressive clinical data 
generated by the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) 
in subjects with metastatic melanoma [Wolchok, 2013].  
The rationale for combining an OX40 agonist with an anti-PD-1 agent is based on the 
fact that these two agents target different steps in the cancer-immunity cycle.  Similar to 
the ipilimumab/nivolumab combination, GSK3174998 is expected to increase the 
priming/activation of antitumor T cells while the anti-PD-1 agent pembrolizumab 
prevents the inhibitory effect of the PD-1/PD-L1 pathway on effector T cells in the 
tumor. Guo et al reported synergistic antitumor activity for the combination of PD-1 
blockade and OX40 agonism in a murine ID8 ovarian cancer model.  The activity of the 
combination treatment was associated with increased CD4+ and CD8+ cells and 
decreased CD4+FoxP3+ Tregs and CD11b+Gr-1+ myeloid suppressor cells [Guo, 2014].  
A surrogate mAb to murine OX40 (OX86) was used to generate in vivo nonclinical 
evidence for combination synergy with a PD-1 inhibitor in syngeneic tumor models.  In a 
series of experiments, female BALB/c mice bearing CT26 mouse colon carcinoma cell 
line tumors (n=10/group) were given twice weekly IP dosing with OX86 at 1 to 
400 g/mouse and in combination with anti-PD-1 mAb at 20 or 200 g/mouse for 
4 weeks.  Both OX86 and anti-PD-1 mAb monotherapy decreased tumor volume and 
increased survival compared with saline and isotype controls; however, the combination 


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of OX86/anti-PD-1 significantly increased survival (Figure 2) compared with 
monotherapy and was well tolerated.  Similar combination efficacy and survival 
outcomes were reported for female BALB/c mice bearing A20 mouse lymphoma cell line 
tumors; however, no synergy or additive effects were reported in female C57BL/6 mice 
bearing B16F10 mouse melanoma cell line tumors. Further details for all studies are 
available in Section 4.2.1.3 of the IB [2014N212091_06].  
Figure 2
OX86 and anti-PD1 in CT26 Syngeneic Mouse Tumor Model: 
Combination Therapy vs. Monotherapy
The internal and published nonclinical data described, provide empirical support for the 
potential of the combination of PD-1 blockade and OX40 agonism.  This concept is 
currently being tested in the clinic with a murine OX40 antibody and a PD-L1 inhibitor 
(MEDI6469 and MEDI4736; Study NCT02205333).  In the current study, the attractive
safety profile of pembrolizumab is expected to make it a good combination partner with 
GSK3174998.  


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously to 
subjects with selected advanced or 
recurrent solid tumors.  

AEs, SAEs, DLT, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).  
Secondary

To evaluate the antitumor activity of 
GSK3174998 in subjects with selected 
advanced or recurrent solid tumors.

To characterize the PK of GSK3174998 
monotherapy.

ORR and DCR (CR+ PR+ SD ≥12 
weeks).b

GSK3174998 concentrations in plasma 
and PK parameters including Cmax, 
AUC(0-), and Cmin.

To determine the immunogenicity of 
GSK3174998. 

Number and percentage of subjects who 
develop detectable ADA.
Exploratory

To explore the relationship between 
antitumor activity, PK parameters,
pharmacodynamic activity and other 
patient characteristics.

To explore onset and durability of response

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, pharmacodynamic activity, 
and other patient characteristics.

TTR and DOR

To evaluate the pharmacodynamic activity 
of GSK3174998 in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, TCR diversity, expression of 
circulating soluble factors such as 
cytokines and stress-related proteins). 
Assessment of changes in genomic DNA, 
gene expression (RNA and protein), (e.g.
using cfDNA, exosomes or circulating 
tumor cells [CTCs]), and mutational load. 


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Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
Exploratory

To evaluate the pharmacodynamic activity 
of GSK3174998 in the tumor 
microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test. 

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity, or mutational load 
(genomic DNA).

Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host 
DNA and response to therapy or disease 
characterization.

Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 or any concomitant 
medicines.
Disease susceptibility, severity, and 
progression and related conditions.
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
a.
In the final determination of the MTD, all available safety and tolerability data will be considered
b.
Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and by irRECIST (immune-related RECIST); irRECIST will be used to determine treatment
decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid


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Objectives
Endpoints
PART 2: Combination GSK3174998 plus pembrolizumab
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously 
in combination with IV pembrolizumab to 
subjects with selected advanced or 
recurrent solid tumors. 

AEs, SAEs, DLTs, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate the antitumor activity of 
GSK3174998 in combination with 
pembrolizumab in subjects with selected 
advanced or recurrent solid tumors.

ORR and DCR (CR+PR+SD ≥12 weeks).b

To characterize the PK of GSK3174998
and pembrolizumab when administered in 
combination. 

Plasma GSK3174998 and serum
pembrolizumab concentrations and PK 
parameters including Cmax, AUC(0-τ), and 
Cmin.

To determine the immunogenicity of 
GSK3174998 and pembrolizumab when 
administered in combination.  

Number and percentage of subjects who 
develop detectable ADA. 
Exploratory

To explore the relationship between 
antitumor activity, PK parameters,
pharmacodynamic activity and other 
patient characteristics. 

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, pharmacodynamic activity, 
and other patient characteristics.

To explore onset and durability of response

TTR and DOR

To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, TCR diversity, expression of 
circulating soluble factors such as 
cytokines and stress related proteins). 
Assessment of changes in genomic DNA, 
gene expression (RNA and protein), (e.g.
using cfDNA, exosomes or CTCs), and 
mutational load. 


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Objectives
Endpoints
PART 2: Combination GSK3174998 plus pembrolizumab
Exploratory

To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the tumor 
microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test.

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity, or mutational load 
(genomic DNA).

PGx: To evaluate the association of genetic 
variations in the host DNA and response to 
therapy or disease characterization. 

Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 and pembrolizumab or 
any concomitant medicines. 

Disease susceptibility, severity, and 
progression and related conditions.
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
a.
In the final determination of the MTD, all available safety and tolerability data will be considered
b.
Unless otherwise specified, all response endpoints will be assessed by RECIST v1.1 and by irRECIST; irRECIST
will be used to determine treatment decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid


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4.
STUDY DESIGN
4.1.
Overall Design
This is a FTIH, open-label, non-randomized, multicenter study designed to evaluate the 
safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of
GSK3174998 administered intravenously to subjects with selected advanced or recurrent 
solid tumors. 
The study will be conducted in 2 parts, each part consisting of starting with a dose-
escalation phase followed by a cohort expansion phase (see Figure 3).  Part 1 will 
evaluate GSK3174998 monotherapy, while Part 2 will evaluate GSK3174998 in 
combination with pembrolizumab.  As shown in Figure 3, GSK3174998 will first be 
evaluated as monotherapy in escalating doses.  Once a dose of GSK3174998 has been 
identified that is both tolerable and demonstrates pharmacodynamic activity, enrollment 
of Part 2 may begin.  In Part 2, escalating doses of GSK3174998 will first be evaluated 
with fixed doses of pembrolizumab. Part 1A and 2A will also include a 
Pharmacodynamic Cohort, which requires mandatory fresh pre- and on-treatment 
biopsies and an additional disease assessment at week 6. Part 2 will also include 
expansion cohorts for specified tumor types.  
The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, SCCHN, RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.  In the 
dose-escalation phase of the study, subjects with any of the aforementioned tumor types 
may be included; whereas in the cohort expansion phase of the study, each expansion 
cohort will enroll subjects with one specific tumor type selected from the aforementioned 
list.    
A subject’s disease status and determination of disease progression at postbaseline visits 
will be evaluated by the local investigators’ assessments of radiology by RECIST v1.1 
and irRECIST; a decision to discontinue treatment due to disease progression will be 
based upon irRECIST and the primary endpoint analysis will use irRECIST. Scans will 
be collected centrally and stored to allow for the option of central radiologic audit or 
review.
A Steering Committee will be established to review safety, PK, and other clinical data 
during the course of the study, to provide objective interpretation of study results, and 
guidance for key decisions. The remit of the Steering Committee will include guidance 
for the transition of the study from dose-escalation to cohort expansion and from Part 1 to 
Part 2, the selection of specific tumor types to include in the expansion cohorts, and the 
selection of the recommended Phase 2 dose (RP2D); the study team will also seek 
endorsement from GSK Medical Governance for the transition of the study from one part 
to another. In the final determination of the MTD and RP2D, all available safety and 
tolerability data will be considered.  Pending a review of emerging data from this study 
and under the guidance of the Steering Committee, the protocol may be subsequently 
amended to include investigation of additional anticancer agent combinations with 
GSK3174998. The remit, membership, roles and responsibilities of the Steering 
Committee are described in a Steering Committee Charter. Key decisions of the Steering
Committee will be documented and reported to all participating principal investigators 
(PIs) and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs).  


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Figure 3
ENGAGE-1 Study Design
a)
Part 1 and Part 2 Design
b) Part 1A and Part 2A Dose Escalation
Figure 3a shows the overall study design: Part 1A GSK3174998 monotherapy dose escalation,  Part 2A GSK3174998 + pembrolizumab dose escalation, Part 2B 
GSK3174998 + pembrolizumab cohort expansion. Figure 3b shows dose escalation (Parts 1A and 2A) including the “pharmacodynamic cohort”.  Note: An example of 3 
dose levels being expanded in the pharmacodynamic cohort is provided to illustrate it is possible not all dose levels will be explored in the pharmacodynamic cohort, 
which mandates pre- and on-treatment tumor biopsies in order to further explore dose-response with biomarkers in the tumor microenvironment.  


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4.1.1.
Dose Escalation
For the first two dose levels (see Table 2), an accelerated titration design is planned with 
one subject enrolled at each of these dose levels. Each subject must complete the 4 week 
DLT evaluation period and the available safety data must be reviewed before a decision 
is made on whether to proceed to the next dose level.  If a subject experiences a DLT, 
then this will trigger the implementation of the modified 3+3 design as shown in Table 1.  
If a subject withdraws from the study before the completion of the 4 week DLT 
evaluation period for reasons other than DLT, the subject will be replaced.
For subsequent dose levels, a modified 3+3 design will be used for dose escalation as 
shown in Table 1.  The first three subjects treated at the third dose level will begin 
treatment 1 week apart to allow assessment of initial safety data in each subject before 
beginning the next subject’s treatment. Evaluation of the available safety data over the 
first 4 weeks of treatment is required from at least 3 subjects before a decision is made 
whether to enroll additional subjects at the same, or the next higher dose level.  Subjects 
who withdraw from the study before the completion of 4 weeks treatment and 2 doses for 
reasons other than DLT may be replaced. After the third dose level cohort is completed, 
subsequent dose levels may initially enroll up to 4 subjects and subjects will begin 
treatment at least one calendar day apart.
If 1 of 3 (or 1 of 4) subjects experiences a DLT at a particular dose level, additional 
subjects will be enrolled at that dose level so that a total of 6 subjects are treated at that 
dose level.  If at least 2 of 6 subjects experience a DLT at a particular dose level, a lower 
(or intermediate) dose level may be explored to better define the MTD.  The Steering 
Committee may propose that a given dose-escalation cohort be expanded up to a total of 
12 subjects if (i) further evaluation of the frequency of a given toxicity is warranted, 
based upon the observed safety profile in the 6 subjects already recruited in the cohort or 
(ii) further evaluation of pharmacodynamic markers to aid dose selection is warranted; in 
either case, the incidence of confirmed DLT must not exceed 33%.  Dose-escalation
decisions will be documented in writing with copies maintained at each site and the study
files.  
Table 1
3 + 3 Dose-Escalation Guidelines
Number of Subjects with DLT 
at a Given Dose Level
Actiona
0 out of 3 subjects
Escalate to next dose level and enter 3 subjects
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to next dose level
2 or more subjects in a dosing cohort 
(up to 6 subjects)
Dose escalation will be stopped.  At this dose level, the MTD has 
been exceeded (highest dose administered).
a.
The  Steering Committee may propose that a given dose-escalation cohort be expanded up to a total of 12 
subjects if (i) further evaluation of the frequency of a given toxicity is warranted, based upon the observed safety 
profile in the 6 subjects already recruited in the cohort or (ii) further evaluation of pharmacodynamic markers to aid 
dose selection is warranted; in either case, the incidence of confirmed DLT must not equal or exceed 33%.
DLT = Dose-limiting toxicity; MTD = Maximum tolerated dose


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In alignment with the guidance prospectively established in the Protocol (see above), the 
Steering Committee proposed that dose-escalation cohorts be expanded up to a total of 12 
subjects in order to further evaluate pharmacodynamic markers to aid dose selection. This 
proposal was agreed and implemented at the time of opening Cohort 4 (0.1 mg/kg) and 
documented in writing.  Since the incidence of confirmed DLT must not exceed 33% in 
this study, the recommended dose from a Continuous Reassessment Method (N-CRM) 
analysis [Neuenschwander, 2008] will be calculated (as prospectively described in 
Section 9.3). The N-CRM is a type of Bayesian adaptive dose-escalation scheme.  The 
method is fully adaptive and makes use of all the DLT information available at the time 
of each dose assignment.
From Part 1 Cohort 4 (0.1mg/kg) onwards and for all Part 2 dose levels, each dose level 
may initially enroll up to 4 subjects. Once at least 3 of these subjects have completed the 
DLT evaluation period (4 weeks), a decision may be made to initiate the next higher dose 
level, pending the evaluation of safety data using the N-CRM methodology.  Subjects 
identified as eligible for enrollment after the enrollment of 4 subjects in current dose level
and before next higher dose level is open may be assigned to a lower dose level.
A maximum of 12 subjects will be enrolled at any given dose level in Part 1A and Part 
2A; up to 6 of these subjects at any given dose level may be part of a “Pharmacodynamic 
Cohort” (Figure 3).  Subjects entering the “Pharmacodynamic Cohort” will have the 
following additional eligibility requirements (as described in Section 5.1):

Mandatory fresh biopsy collection at baseline, on treatment (at 6 weeks), and if 
feasible at the time of disease progression

Additional 6-week disease assessment and availability of a pre-baseline scan 
(within 24 weeks  before the baseline scan), if feasible, to support exploratory 
investigation of tumor growth kinetics
Exploration of lower dose levels than recommended by N-CRM (or expansion of a
previously-tested dose level) is allowed if agreed upon by the Medical Monitor and
treating investigators. The final dose escalation decision will be made by study team on 
all available data, including biomarker and PK data and the safety profile of prior cohorts.  
Dose-escalation decisions will be documented in writing with copies maintained at each 
site and the study files.
4.1.2.
Part 1A: Monotherapy Dose Escalation
Dose escalation for GSK3174998 monotherapy will begin with a starting dose of 
0.003 mg/kg GSK3174998 administered Q3W (see Section 4.5).  Table 2 illustrates the 
maximum dose that may be selected for each dose level increase.  The maximum increase 
in dose is 3.33-fold or less. Dose levels intermediate to those in Table 2, or schedules 
other than once every three weeks may be explored if exposure is significantly higher 
than predicted, if there is excessive toxicity, or if further evaluation of pharmacodynamic 
markers to aid dose selection is warranted.  


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Table 2
Part 1A Dose Levels
Dose 
Level
GSK3174998 (mg/kg)a
Dose Escalation
Cohort (n)
Pharmacodynamic 
Cohort (n)
1
0.003
1
6
2
0.01
1
6
3
0.03
3-6
6
4
0.1
3-6
6
5
0.3
3-6
6
6
1.0
3-6
6
7
3.0
3-6
6
8
10.0
3-6
6
a.
Lower dose intensities may be explored if exposure is significantly higher than predicted, if there is excessive 
toxicity, or if further evaluation of pharmacodynamic markers to aid dose selection is warranted. This may be 
achieved by reducing the dose or by alternate dosing schedules. 
4.1.3.
Part 2A: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab)
Dose escalation for GSK3174998 + pembrolizumab combination therapy will begin with 
a fixed dose of 200 mg pembrolizumab administered Q3W and a starting dose of 0.003 
mg/kg GSK3174998. 
GSK3174998 dose levels that may be administered in combination with pembrolizumab 
are described in Table 3.
Table 3
Part 2A Dose Levels
Dose 
Level
GSK3174998 
(mg/kg)
Pembrolizumab 
(mg)
Dose Escalation 
Cohort (n)
Pharmacodynamic 
Cohort (n)
1
0.003
200
3-6
6
2
0.01
200
3-6
6
3
0.03
200
3-6
6
4
0.1
200
3-6
6
5
0.3
200
3-6
6
6
1.0
200
3-6
6
7
3.0
200
3-6
6
8
10.0
200
3-6
6
If the combination doses in the starting dose cohort of Part 2A are not tolerable, lower 
dose intensities of GSK3174998 may be evaluated in combination with 200 mg 
pembrolizumab. This may be achieved by reducing the dose or alternate dosing 
schedules.  The dose of pembrolizumab will remain fixed at 200 mg throughout the 
study.
Dose escalation will proceed until the MTD or MAD of the combination regimen is 
identified, as described in Section 4.1.1.  Dose-escalation decisions will take into account 
all available data, including the safety profile of prior cohorts throughout the time 
subjects are on study, which will be reviewed by the investigator(s), GSK Medical 
Monitor, pharmacokineticist, and statistician.  The dose-escalation decision for the 


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subsequent cohort and rationale will be documented in writing with copies maintained at 
each site and the study files.
Any cohort may be expanded beyond the 3 to 6 subjects enrolled during dose escalation, 
to a maximum of 12 to facilitate collection of additional safety, PK, and 
pharmacodynamic data (Figure 3).  A total of up to 12 subjects may be treated at the dose 
of GSK3174998 selected for Parts 1B and 2B to better characterize the safety, PK, and 
pharmacodynamic data at that dose, before opening the Dose-Expansion phase. 
4.1.4.
Dose-Limiting Toxicity
All toxicities will be graded using National Cancer Institute - Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE) (version 4.0). 
An AE is considered to be a DLT if it is considered by the investigator to be clinically 
relevant and attributed (definitely, probably, or possibly) to the study treatment during the 
first 4 weeks (i.e., 28 days) of treatment and meets at least one of the criteria listed in 
Table 4.  If an AE is considered related to the underlying disease it is not a DLT.  For 
Part 2, Grade 3 toxicities that are known to occur with pembrolizumab and are 
controlled within 2 weeks using the recommended supportive measures (see Section 
6.3.1) may not be considered dose-limiting.  
Table 4
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Febrile neutropenia 

Grade 4 neutropenia of >7 days’ duration or requiring G-CSF

Grade 4 anemia of any duration

Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding
Non-
hematologic

Grade 4 toxicity

Grade 3 toxicity that does not downgrade to Grade 1 or baseline within 3 days 
despite optimal supportive care.a

Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 
ocular toxicity
Other

Toxicity that results in permanent discontinuation of GSK3174998 or 
GSK3174998 and pembrolizumab during the first 4 weeks of treatment

Any other toxicity considered to be dose-limiting that occurs beyond 4 weeks 
will be considered in the selection of the dose for expansion cohorts

Any other event which in the judgment of the investigator and GSK Medical 
Monitor is considered to be a DLT
a.
Suggested management guidelines described in Section 6.3.1 for toxicity and may include systemic 
corticosteroids for immune-related toxicities; if use of systemic corticosteroids delays administration of the second 
dose of study treatment but the event does not otherwise meet the DLT criteria for non-hematologic toxicity, the 
dose delay will not be considered a DLT. 
DLT = Dose-limiting toxicity; G-CSF = Granulocyte colony-stimulating factor; AST = Aspartate aminotransferase; ALT = 
Alanine aminotransferase; ULN = Upper limit of normal; GSK = GlaxoSmithKline


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If a subject experiences a DLT in the first 4 weeks of treatment, the subject will be 
discontinued from study therapy unless the investigator considers it in the best interest of 
the subject to continue on study (e.g., in case of tumor regression, symptomatic disease 
improvement, and/or if the type of DLT is viewed as preventable in subsequent cycles, 
e.g., by pre-medication).  Such cases will require approval by the Sponsor before
continuation on study treatment at the same or lower dose.  
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 6.3.1 and is based on the experience of management of immune-
related adverse events (irAEs) since the development of ipilimumab and PD-1 inhibitors 
such as pembrolizumab. 
4.1.5.
Cohort Expansion
In accordance with the Steering Committee Charter and based upon a review of pertinent 
data with input from the study team and investigators, the Steering Committee 
recommended initiation of Part 2B expansion cohorts, including the selection of tumor 
types and the dose of GSK3174998 to be administered to subjects who enter the 
expansion cohorts as described below. Criteria considered in the determination of which 
dose level(s) to expand and which tumor types to select for cohort expansion included:

Target engagement and PK:  Observed OX40 receptor occupancy and 
GSK3174998 exposure.

Safety and tolerability: The frequency of DLT, and frequency and severity of 
treatment-related AEs.  

Clinical activity: Evidence of clinical response, including SD of at least 12 weeks 
and/or minor responses.  
The preliminary clinical data supporting initiation of the expansion cohorts are 
summarized in Section 2.3.5.
The initial expansion cohorts in Part 2B will evaluate one dose level of 0.3 mg/kg 
GSK3174998 (see Section 4.5.3) in tumor types where confirmed response or prolonged 
SD (12 weeks) was observed in Part 1A or 2A of this study. Tumor types selected for 
initial evaluation in expansion cohorts are melanoma and dedifferentiated liposarcoma 
(see Table 5).  Additional tumor types may be included in Part 2B in accordance with 
existing inclusion/exclusion criteria. A maximum of approximately 120 subjects will be 
included in Part 2B. 


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Table 5
Part 2B Expansion Cohorts
Study Part 2B
Population
Prior PD-(L)1 
Treatment
GSK3174998
Dose
N
Melanoma
Yes
0.3 mg/kg
10-30
Dedifferentiated liposarcomaa
No
0.3 mg/kg
10-30
Additional tumor types b
TBD
TBD
10-60
a. Dedifferentiated liposarcoma will be the initial target; however, additional sarcoma sub-types may be included 
b. Any of the tumor types studied in Part A (may be enriched for selected biomarkers if validated biomarker selection 
assays are available)
Subsequent expansion cohorts are anticipated to receive 0.3 mg/kg GSK3174998, unless 
emerging data from Parts A or B of the study support further exploration of an alternative 
tested dose. These cohorts may include any of the tumor types studied in Part A, 
including additional subtypes of STS, and may be enriched for selected biomarkers if 
validated biomarker selection assays are available (e.g., PD-(L)1 expression, OX40 
expression on selected T cell populations, high mutational load, etc). The selection of any 
additional dose level(s) or dosing schedules and tumor types for cohort expansion will be 
communicated to the sites in writing.
A minimum of 10 subjects will be enrolled in each cohort. Until implementation of
Amendment 4, the first futility analysis of each expansion cohort was planned to occur
after approximately 10 subjects are enrolled for whom overall response data at 
approximately week 12 was available. After implementation of Amendment 4, no further 
subjects were enroled in the study, and no futility analyses were performed. 
Until implementation of Amendment 4, for any of the expansion cohorts tested, if the 
observed clinical benefit appeared to be associated with specific patient characteristics 
and/or biomarkers, a new cohort may have been opened for further investigation with 
subjects enriched with these specific patient characteristics and/or biomarkers. After 
implementation of Amendment 4, no further subjects were enroled in the study.
Expansion cohorts will require mandatory fresh pre- and on-treatment biopsies (see
Section 7.6.2) and an additional disease assessment at Week 6. This disease assessment is 
timed to coincide with the on-treatment (Week 6) tumor biopsy. If feasible, the disease 
assessment should be performed after the tumor biopsy. 
4.1.6.
Intra-Subject Dose Escalation
There will be no intra-subject dose escalation. 


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4.2.
Treatment Arms and Duration
The study includes a screening period, a treatment period, and a follow-up period.  
Subjects will be screened for eligibility beginning approximately 4 weeks before the start 
of treatment.  The maximum duration of treatment with GSK3174998 and
pembrolizumab will be 2 years (Table 6) or 35 cycles whichever comes first. The follow-
up period for safety assessments will be a minimum of 3 months from the date of the last 
dose.  The post-treatment follow-up period includes disease assessments every 12 weeks 
until documented PD.  Following PD, subjects will be contacted every 3 months to assess 
survival status. 
With the implementation of Amendment 04, there will be no requirement to perform
future disease assessments or survival follow-up.
Table 6
Study Treatments
Study Part
Study Treatment
Part 1: GSK3174998 Monotherapy
1A – Dose escalation
GSK3174998 IVa Q3W for up to 2 years or 35 cycles, whichever comes 
first
Part 2: GSK3174998 in combination with pembrolizumab 
2A – Dose escalation
GSK3174998 IVb Q3W for up to 2 years or 35 cycles, whichever comes 
first
Pembrolizumab 200mg IV Q3W for up to 2 years or 35 cycles, 
whichever comes first
2B – Cohort expansion
GSK3174998 IVb Q3W for up to 2 years or 35 cycles, whichever comes 
first
Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 cycles, 
whichever comes first
a.
For dose levels see Table 2.
b.
For dose levels see Table 3.
Alternative dosing schedules may be explored if the data warrants. This will be communicated to the sites in writing 
prior to implementation.
IV = Intravenous; Q3W = Every 3 weeks
4.3.
Type and Number of Subjects
The number of dose levels and the level at which the MTD is reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish the recommended dose(s) for further study. It is estimated that a total of up to 
approximately 264 subjects will be enrolled in this two-part study (approximately 144 
subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects in Part 2B 
[cohort expansion]).  


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In Parts 1A and 2A, if a subject prematurely discontinues before the completion of 4
weeks treatment, for reasons other than DLT, a replacement subject may be enrolled at 
the discretion of the Sponsor in consultation with the investigator.  Subjects will not be 
replaced in Parts 1B and 2B of the study.  
4.4.
Design Justification
This study evaluates the safety, tolerability, pharmacodynamic effects, and preliminary 
clinical activity of GSK3174998 as a monotherapy (Part 1) and in combination with anti-
PD-1, pembrolizumab (Part 2).  The safety, tolerability, and pharmacodynamics of 
monotherapy GSK3174998 will be evaluated in a modified CRM dose escalation that 
includes an accelerated titration design for the first two dose levels. The dose escalation 
will be followed by expansion cohorts in defined subject populations. Dose escalation of 
GSK3174998 in combination with a 200 mg fixed dose of pembrolizumab will begin at a 
dose of 0.003 mg/kg GSK3174998 as described in Section 4.5.2.
In order to ensure sufficient safety and pharmacodynamic data were available before 
beginning enrollment to Part 2 of the study, available clinical data (clinical data cut-off: 
17 May 2016; (see Section 2.3.5) from Part 1 of the study, including safety, PK, 
pharmacodynamics and efficacy, were reviewed by the Steering Committee.  The 
Steering Committee also considered available data for other OX40 agonist antibodies as 
relevant background information [Hamid, 2016; Hansen, 2016; Infante, 2016].  GSK 
Medical Governance reviewed the same data as the Steering Committee and endorsed 
initiation of Part 2 of the study.  The decision to initiate Part 2 was documented and 
reported to all participating PIs and IRBs/ IECs.
In the dose escalation phase, subjects will be enrolled with selected solid tumors that are 
likely to respond to anti-OX40 therapy (e.g., indications previously reported to have a 
response to immunotherapies, predicted immunogenicity, and/or expression of OX40).  
The tumor types to be evaluated in dose escalation are as follows: NSCLC, SCCHN, 
RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.
Almost all of these histologies have demonstrated prior response to anti-CTLA-4 and/or 
anti-PD-1/PD-L1 therapies [Zamarin, 2015].  In addition, gene expression data [TCGA, 
2014] suggest that all of these tumor types have at least moderate expression of OX40.
The inclusion of the combination with pembrolizumab is based on the preference to 
identify potential transformational activity early in development.  Although GSK3174998 
is expected to have meaningful clinical activity as a monotherapy, the full potential of the 
molecule is likely to be discovered in combination with other agents, particularly 
immunotherapies.  Pembrolizumab is an ideal combination partner for GSK3174998 
because it targets a different aspect of the cancer-immunity cycle, has a toxicity profile of 
mainly Grade 1 or 2 events, and preclinical data strongly supports the potential for 
synergy.
Recently reported data with OX40 agonists and other TNFR agonists [Hamid, 2016; 
Hansen, 2016; Infante, 2016] has highlighted the importance of understanding the impact 
of treatment with these agents on the tumor microenvironment. To date TNFR agonist 
antibodies appear to saturate receptors in the periphery at low doses, be well-tolerated, 


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have demonstrated biological effects in the tumor microenvironment in some but not all 
tumors where serial fresh biopsies were available (e.g., increased CD8 infiltration, 
decreased Tregs), and have demonstrated modest clinical activity.  In order to better 
understand dose-response and variables that may influence clinical response to treatment 
with GSK3174998 alone or in combination with pembrolizumab, it is critical that 
immune biomarkers in the tumor microenvironment are assessed in this study across a 
range of doses and, if feasible, correlated with clinical response.  In alignment with the 
guidance prospectively established in the Protocol, the Steering Committee proposed that 
dose-escalation cohorts be expanded up to a total of 12 subjects in order to further 
evaluate pharmacodynamic markers to aid dose selection. In order to address the need to 
explore the potential relationships between dose, biological effects in the tumor 
microenvironment, and tumor response, a “pharmacodynamic cohort” is included in each 
of the dose-escalation parts of the study (Part 1A and Part 2A).  In order to be eligible to 
be enrolled in the pharmacodynamic cohorts, subjects must consent to mandatory fresh 
biopsy collection at baseline, on treatment (at 6 weeks), and if feasible at the time of 
disease progression. An additional disease assessment (at 6 weeks) and availability of a 
pre-baseline scan (within 24 weeks before the baseline scan), if feasible, will support 
exploratory investigation of tumor growth kinetics in this cohort.
4.5.
Dose Justification
4.5.1.
Part 1: Starting Dose
According to the International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH)S9 guidance, calculating a starting 
dose based on 1/6 of the highest non-severely toxic dose (HNSTD) in the most relevant 
species (cynomolgus monkey) yields a starting dose of ~16 mg/kg/week. By determining 
the minimum anticipated biological effect level (MABEL), a more conservative starting
dose of 0.003 mg/kg GSK3174998 Q3W was selected as a safe starting dose for this 
FTIH study.  The projected human GSK3174998 exposure predicted by cynomolgus 
monkey PK, GSK3174998 binding characteristics, and OX86 efficacy data in mouse, as 
well as consideration of prior clinical experience with agonizing the OX40 pathway also 
factored into the selection of the starting dose.  
Predicted exposure: The PK of GSK3174998 was assessed in several cynomolgus 
monkey studies, with single and repeat doses ranging from 0.03 mg/kg to 100 mg/kg; 
GSK3174998 exposure was approximately dose-proportional. Across the dose levels 
tested, PK profiles did not demonstrate any evidence of target-mediated disposition.  
These results suggest that allometric methods are appropriate to predict human PK; 
furthermore, human PK of GSK3174998 is expected to be similar to PK of mAbs of the 
same isotype. Assuming a plasma volume of 3L for a 70 kg subject, a Cmax of 
0.07 g/mL is predicted for a dose of 0.003 mg/kg.  
Nonclinical safety: In repeat-dose toxicology studies, GSK3174998 was well tolerated in 
cynomolgus monkeys following weekly IV dosing for up to 4 weeks at doses ranging 
from 0.03 to 100 mg/kg/week.  In these studies, there were no test article related changes, 
including those associated with T-cell modulation.  The NOAEL was determined to be 


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100 mg/kg/week, the highest dose tested, which is well above the proposed clinical 
starting dose regardless of the method for computing the human equivalent dose (HED).
Potential for severe cytokine release: Several lines of investigation were followed to 
assess the potential of GSK3174998 to induce an excessive cytokine response as 
observed for super agonist TGN1412. In vitro and ex vivo data show that OX40 is 
expressed on only a small proportion of T cells, i.e., recently activated effector and 
regulatory T cells in blood and tissues such as lymph node and spleen. Moreover, 
stimulation through the TCR and CD28 pathways is required for optimal T-cell activation 
with OX40 agonism.  A range of conditions were explored in vitro to assess the potential 
of GSK3174998 to induce cytokine release. In some assays, no evidence of cytokine 
release was observed; however, under the most sensitive assay conditions using 
immobilized GSK3174998 in pre-activated CD4+ T cells, increased cytokine production 
(IL-2, IFN, and tumor necrosis factor alpha [TNF-]) was observed. In vivo cytokine
monitoring in repeat dose monkey toxicology studies (doses of 0.03-100 mg/kg) and the 
CT26 mouse tumor model did not demonstrate excessive cytokine release. These data 
suggest that GSK3174998 is not a super agonist and has a low potential for severe 
cytokine release syndrome (sCRS).
MABEL determination: The MABEL assessment is based on receptor occupancy as 
characterized by in vitro binding experiments with primary human target cells. Using 
receptor occupancy as a surrogate for biological activity is appropriate as receptor 
occupancy provides a general characterization of GSK3174998 signaling in target cells 
and since individual biological effects of GSK3174998 are not yet prioritized in terms of 
their impact on subject safety. The binding of GSK3174998 to its ligand and target cells 
was characterized in several experiments yielding different binding coefficients 
depending on the degree of cellular activation and OX40 expression. 
OX40 expression in blood is limited to the small subset of recently activated CD4+ and 
CD8+ cells [Croft, 2010].  In ex vivo studies, the frequency of OX40+ T-cells in human 
blood or PBMC cultures from healthy volunteers ranged from <1% [GlaxoSmithKline
Document Number 2014N222697_00] to 25% [GlaxoSmithKline Document Number
2014N219733_00]. Also in cancer patients, lower OX40 expression was observed in 
peripheral blood compared to tumor sites and draining lymph nodes [Vetto, 1997]. Based 
on these findings, the unstimulated human whole-blood binding assay, which exhibited a 
low but quantifiable level of OX40 binding, was considered most representative for the 
OX40 response in peripheral blood and was selected to determine the MABEL. 
GSK3174998 was shown to bind to lymphocytes in whole blood in a concentration-
dependent manner with an EC50 value of 1.45 µg/mL (pooled data derived from 4 
donors) [2014N219733_00].   Using the Cmax of 0.07 µg/mL predicted for the first 0.003 
mg/kg dose, a receptor occupancy of 5% is predicted based on the binding to 
lymphocytes in human whole blood (the MABEL dose corresponding to 10% receptor 
occupancy in this experiment is 0.007 mg/kg).  Note, that the receptor occupancy 
calculations here and below assume that the difference between free and total 
GSK3174998 is negligible, i.e. receptor occupancy = Cmax/(EC50 + Cmax). This 
approach yields higher receptor occupancy and more conservative dose estimates 
compared to an approach which assumes a specific level of target expression. 


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OX40 expression in certain tissues may be higher than observed in peripheral blood; for 
example, in the spleen and additionally in the microenvironment of a tumor.  In normal 
cynomolgus monkeys, where GSK3174998 was well tolerated, a frequency of 2-30% of 
OX40+ lymphocytes was detected in lymphoid tissue (spleen) [2014N213593_00]. In the 
tumor and draining lymph nodes of cancer patients the frequency of activated 
CD4+/OX40+ T-cells was reported to be up to 30% in tumor and draining lymph node 
samples compared with 0% in peripheral blood [Vetto, 1997].  Data from stimulated 
OX40 binding experiments, in which cells are activated and OX40 expression is highly 
upregulated, are therefore expected to be more representative for the OX40 response to 
GSK3174998 in tumor and draining lymph node tissues.  For stimulated PBMC half-
maximal binding was typically achieved between 0.1 µg/mL to 0.3 µg/mL and similarly, 
GSK3174998 bound to activated human CD4+ T cells with a mean EC50 value of 
0.19 µg/mL [2014N219733_00].  Monoclonal antibody concentrations in peripheral 
tissues are expected to be substantially lower than time-matched concentrations in serum 
[Tabrizi, 2010; Shah, 2013]. Assuming an antibody biodistribution coefficient of 25% 
[Shah, 2013] for a given tumor tissue, the peak concentrations are expected be ≤0.018 
µg/mL resulting in ≤8% receptor occupancy when using a binding EC50 of 0.2 µg/mL 
for the stimulated PBMC or CD4+ T cell assays. Applying the stimulated binding EC50 
of 0.2 µg/mL to the Cmax of 0.07 µg/mL in peripheral blood yields predicted receptor 
occupancy of 26%. However, this prediction is not considered representative of the 
clinical OX40 response as the stimulated assays had much larger degrees of cellular 
activation than would be expected in patient blood.   
In summary, the starting dose of 0.003 mg/kg is expected to result in less than 10% 
occupancy of OX40 receptors in blood (based on unstimulated binding experiments) and 
tumor tissues and draining lymph nodes (based on stimulated binding experiments), 
which is generally assumed a safe level of receptor engagement for immune agonists.
Clinical experience with OX40 agonism: Clinical experience with MEDI6469 did not 
show cytokine release syndrome (CRS) or other severe toxicity in subjects dosed with
single cycles of 0.1 to 2 mg/kg of the antibody [Curti, 2013].  MEDI6469 did not show a 
significant dose-dependent difference in efficacy for single cycles of 0.1, 0.4, and 
2 mg/kg dose levels.  Maximal biological activity as defined by stimulation of T-cell 
proliferation measured by changes in Ki-67 expression in response to MEDI6469 dosing 
was achieved at the 0.4 mg/kg dose level.  With an EC50 of 0.048 g/mL for binding as 
measured by ELISA [Curti, 2013], the potency of MEDI6469 appears to be comparable 
to (or possibly higher than) that of GSK3174998. Using the same approach as specified 
above to predict Cmax and binding, the starting dose of 0.1 mg/kg MEDI6469 with a 
binding constant of 0.048 g/mL [Curti, 2013] leads to a predicted receptor occupancy of 
98% in the central circulation at Cmax, further supporting the starting dose of 
GSK3174998 of 0.003 mg/kg.
Potential for clinical benefit: Efficacy for agonizing the OX40 pathway has been 
assessed with an anti-OX86 antibody, a surrogate mAb to murine OX40.  In the CT26 
mouse colon cancer model, robust efficacy was observed at doses as low as 5 g per 
mouse in the most sensitive experiments (Figure 1b). Assuming similar potency between 
anti-OX86 and GSK3174998, the HED is estimated to be 0.015 or 0.027 mg/kg assuming 
that AUC drives efficacy and using a clearance based scaling approach with allometric 


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scaling exponents of 0.67 (body surface area normalization) or 0.75 (quarter power 
scaling) for systemic clearance and mouse and human weights of 0.025 kg and 70 kg, 
respectively. Assuming that Cmax drives efficacy and using a volume of distribution 
based scaling approach the HED is estimated to be 0.2 mg/kg assuming an allometric 
scaling exponent of 1 for volume of distribution. The starting dose is therefore predicted 
to lie at the lower end of the predicted therapeutic dose range in subjects.
Dosing frequency: In a clinical study with MEDI6469 a key biomarker, Ki-67 
expression on T cells exhibited maximal stimulation at about 14 days after the first dose 
[Curti, 2013]. The Ki-67 stimulation declined by about 28 days after the first dose (or 23 
days after the last dose in the cycle).  Guided by these biomarker dynamics and the 
expectation of standard IgG1 mAb PK (terminal elimination half-life longer than 2 
weeks), a dosing frequency of Q3W for GSK3174998 was chosen. This dosing frequency 
also increases subject convenience for administration with the planned combination 
partner pembrolizumab which is also dosed Q3W per label.  
In summary, the proposed 0.003 mg/kg starting dose of GSK3147998 Q3W in study 
201212 is anticipated to be safe and tolerable.  Subjects will undergo extended clinical 
observation following GSK3174998 dosing and other measures to monitor and treat all 
subjects for any possible excessive cytokine release.  
4.5.2.
Part 2: Starting Dose
No drug-drug interaction affecting the PK for the combination is expected for 
GSK3174998 and pembrolizumab. As a checkpoint inhibitor rather than a direct 
immune-stimulator pembrolizumab is not expected to substantially increase the potential 
for excessive cytokine release in response to GSK3174998, but specific synergies cannot
be excluded a priori.  In the CT26 mouse efficacy experiments, no differences with 
regard to indicators of excessive immune stimulation were noted in the anti-PD-1 
combination versus the OX86 monotherapy groups at all the dose levels tested.  Similar 
to monotherapy, robust efficacy was seen for OX86 doses as low as 5 g per mouse (in 
combination with 200 g anti-PD-1 mouse homolog) and combination dosing was well 
tolerated. 
The starting dose of GSK3174998 for the Part 2/Combination Dose-Escalation phase was 
planned to be at least 2 dose levels below a dose that has been shown to be tolerated
during the monotherapy dose escalation. This determination was based on an allowance 
that a 10-fold lower dose of GSK3174998 should provide a sufficient safety margin when 
pembrolizumab is added. Using these criteria, data from Part 1 Cohort 3 (0.03 mg/kg), 
with a clinical data cut-off of 17 May 2016, supported a Part 2 starting dose of 
0.003 mg/kg GSK3174998.  The 0.03 mg/kg dose level was tolerated and transient 
peripheral OX40 receptor saturation was observed in 3 of 4 subjects with the fourth 
subject having 100% OX40 receptor saturation throughout the first dosing period 
(21 days).  These data were reviewed by the Steering Committee and GSK Medical 
Governance (as described in Section 4.4) and are briefly summarized in Section 2.3.5 of 
the protocol.  The dose of pembrolizumab will be 200 mg IV Q3W (see Section 2.4.2).


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4.5.3.
Dose Rationale for Cohort Expansion (Part 2B)
GSK3174998 will be administered intravenously at a dose of 0.3 mg/kg once every 3 
weeks (Q3W) on Day 1 of each 21-day cycle in combination with 200 mg 
pembrolizumab Q3W.
For GSK3174998 doses of 0.3 mg/kg and higher peripheral receptor occupancy 
saturation over the whole dose interval was observed. Peripheral OX40 receptor 
occupancy on circulating CD3+ T cells, provides a measure of target engagement. While 
the relationship between the extent of peripheral receptor occupancy and clinical 
response has not been established, clinical activity was observed in Part 1A at this dose 
level for monotherapy. In Part 2A, clinical responses were reported at GSK3174998 dose 
levels 0.01 to 0.3 mg/kg in combination with pembrolizumab at the time of the clinical 
data cut off (13 August 2019). Please refer to the GSK3174998 Investigator’s Brochure 
for further details [2014N212091_06]. 
Safety data were reported for the full dose range of GSK3174998 monotherapy (0.003 to 
10 mg/kg) and for GSK3174998 (0.003 to 10 mg/kg) when administered in combination 
with pembrolizumab 200 mg at the time of the clinical data cut-off (13 August 2019). No 
DLTs were reported for monotherapy. Two DLTs (pleural effusion and myocarditis) 
were reported in the combination setting. Out of 9 subjects dosed at GSK31748998 0.03 
mg/kg + pembrolizumab, one DLT of pleural effusion was reported. Out of 4 subjects 
dosed at GSK3174998 10 mg/kg + pembrolizumab, one DLT of myocarditis was 
reported.  Overall, there did not appear to be a dose-relationship for AEs and the 0.3 
mg/kg dose level for the combination treatment was well tolerated. Safety data are 
described in more detail in the Investigator’s Brochure [2014N212091_06].
In summary, the 0.3 mg/kg GSK3174998 dose level was well tolerated during dose 
escalation, demonstrated target engagement on circulating T cells and clinical activity 
was observed at this dose level for both monotherapy and in combination with 
pembrolizumab.
4.6.
Benefit:Risk Assessment
Summaries of findings from nonclinical studies conducted with GSK3174998 can be 
found in the IB [2014N212091_06].  The following section outlines the risk assessment 
and mitigation strategy for this protocol.  
In toxicology studies performed in monkeys with GSK3174998, no adverse effects were 
observed.  Additionally, nonclinical data with GSK3174998 and a rat surrogate antibody 
in mouse models do not suggest CRS as a significant concern (limitations of nonclinical 
models are recognized). 
Another agonistic anti-OX40 antibody was previously administered in subjects without 
evidence of severe cytokine release [Curti, 2013]. MEDI6469 (mouse IgG1 mAb 
currently being developed by Medimmune/AZ) was very well tolerated for doses of 0.1 
to 2 mg/kg (single cycle of 3 doses per week), with transient lymphopenia and Grade 1/2 


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flu-like symptoms as primary toxicities. The proposed starting dose for GSK3174998 is 
well below those administered in the study using MEDI6469. 
In addition, OX40 is expressed on a small proportion of T cells, primarily recently 
activated effector T cells and Tregs. This significantly limits the potential for sCRS.
OX40 is not a super agonist and requires stimulation through TCR and CD28 for optimal 
T-cell activation.  
Due to the mechanism of action of GSK3174998, toxicities commonly associated with 
other immune-modulating agents such as checkpoint inhibitors may also occur after 
administration of GSK3174998. However, these toxicities were not seen in nonclinical 
models.  Table 7 outlines the risk assessment and mitigation strategy for this protocol.
4.6.1.
Risk Assessment GSK3174998 Pembrolizumab
Table 7
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hypersensitivity reaction

Risk for infusion reactions and 
hypersensitivity is inherent to many 
mAbs [Brennan, 2010]
Subjects Severe hypersensitivity to 
another mAb are not eligible for 
participation in this study
See Section 6.3.1.3
Severe cytokine release 
syndrome (sCRS)
OX40 is a costimulatory receptor that can 
stimulate proliferation and activation of T cells
GSK3174998 is an OX40 agonist that can 
costimulate T-cell activation in the context of 
TCR signal and CD28 cosignal.
An anti-CD28 super agonist (TGN1412) 
induced rapid-onset catastrophic CRS in 6 
healthy volunteers
See Section 6.3.1.3
Other immune-related 
AEs
Inflammatory AEs such as diarrhea/colitis, 
pneumonitis, and hepatotoxicity are well 
established after treatment with immune-
modulating agents, and are consistent with 
the immune-stimulatory mechanism of action 
of these agents. 
Subjects with the following medical 
history are not eligible for participation in 
this study
Toxicity (Grade 3) related to prior 
immunotherapy leading to study 
treatment discontinuation 
Severe hypersensitivity to another mAb
See Section 6.3.1.1


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Embryo-fetal toxicity
Currently there are a number of monoclonal 
antibodies targeting immune checkpoints 
approved for use in humans (e.g., ipilimumab, 
nivolumab, durvalumab and pembrolizumab).
These agents have embryo-fetal toxicity 
documented in the Warnings and Precautions 
section of the USPI and in Section 4.6 of the 
EU-SPC. This risk has been identified in a 
variety of animal species (generally 
cynomolgus monkeys or experiments in mice 
with PD-(L)1 antagonism), and link the PD-
1/PD-L1 signaling pathway with maintenance 
of pregnancy through
induction of maternal immune tolerance to 
fetal tissue. Human IgG4 (immunoglobulins) 
are known to cross the placenta; therefore, 
pembrolizumab has the potential to be 
transmitted from the mother to the developing 
fetus. There are no available human data 
informing the risk of embryo-fetal toxicity.
Advise females of reproductive potential 
of the potential risk to a fetus. Women of 
child-bearing potential and their male 
partners are required to use highly 
effective contraception as described in 
Section 5.1
TCR = T-cell receptor; mAb = Monoclonal antibody; AEs = Adverse Events
4.6.2.
Overall Benefit:Risk Conclusion
This is an open-label, dose escalation study and the FTIH study of this agent to be 
conducted in subjects with relapsed/refractory solid tumors for which no standard 
therapies are anticipated to result in a durable remission. GSK3174998 has nonclinical 
activity in vivo, however it is unknown whether GSK3174998 will have clinical activity, 
thus any potential beneficial effect for an individual subject attributable to GSK3174998
is unknown. Data obtained in this study may help identify individuals more likely to 
benefit or have side effects from GSK3174998. Study participants may benefit from the 
medical tests and screening performed during the study. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB/IB supplements.  Deviations from 
inclusion and exclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.  
5.1.
Inclusion Criteria
Subjects eligible for enrollment in the study must meet all of the following criteria: 


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1. Provide signed, written informed consent.  
2. Male and female subjects, age 18 years (at the time consent is obtained).  
3. Histological documentation of locally advanced, recurrent or metastatic solid 
malignancy that has progressed after standard therapy appropriate for the specific 
tumor type, or for which standard therapy has proven to be ineffective, 
intolerable, or is considered inappropriate (with the possible exception of the PD-
(L)1 naive populations described in inclusion criterion 4).  Subjects should not 
have received more than 5 prior lines of therapy for advanced disease including 
both standards of care and investigational therapies.  Subjects whose cancers 
harbor molecular alterations for which targeted therapy is standard of care should 
have received health authority-approved appropriate targeted therapy for their 
tumor types before enrollment. 
4. Subjects with the following solid tumors are eligible for screening: NSCLC, 
SCCHN, RCC, melanoma, bladder, STS, TNBC, and MSI CRC.
In Part 2B (Cohort Expansion), specific subgroups of the above solid tumors will 
be studied. These subgroups may be defined by specific lines of treatment, types 
of prior treatment, histological subtypes, and may be enriched for selected 
biomarkers or patient characteristics. Populations to be studied in Amendment 3 
include but are not limited to the following. Enrolment of additional populations 
will be communicated in writing.

Subjects with dedifferentiated liposarcoma who have not received prior 
treatment with a PD-(L)1 inhibitor

Subjects with melanoma who have received a prior PD-(L)1 inhibitor, had 
a CR, PR or SD and subsequently progressed while on PD-(L)1 therapy.
Subjects who have received prior treatment with a PD-(L)1 inhibitor must 
have documented disease progression as defined by meeting all of the 
following criteria:
Has received at least 2 doses of an approved PD-(L)1 inhibitor
Has demonstrated disease progression as defined by RECIST v1.1. 
The initial evidence of disease progression is to be confirmed by a 
second assessment no less than four weeks from the date of the 
first documented PD, in the absence of rapid clinical progression.
Progressive disease has been documented within 18 weeks from 
the last dose of the PD-(L)1 inhibitor.
5. In Parts 1A and 2A, a biopsy of the tumor tissue obtained at anytime from the 
initial diagnosis to study entry. Although a fresh biopsy obtained during screening 
is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a 
fresh biopsy.  
Subjects enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts or in 
Part 2B of the study must provide a fresh biopsy of a tumor lesion not 
previously irradiated during the screening period and must agree to 
provide at least one additional on-treatment biopsy. In addition, an 
archived tumor tissue should be submitted for subjects in Part 2B, if 


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available.The criterion for collection of fresh biopsies may be waived once 
GSK has determined an appropriate number of viable tissue samples have 
been analysed.
6. Measurable disease per RECIST version 1.1 - please refer to Appendix 5. 
Palpable lesions that are not measurable by radiologic or photographic evaluations 
may not be utilized as the only measurable lesion
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.  
8. Life expectancy of at least 12 weeks.  
9. Adequate organ function (see Table 8):
Table 8
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
ANC
≥1.5x109/L
Lymphocyte count
800/mm3
Hemoglobin
≥9 g/dL
Platelets
≥100x109/L
Hepatic
Total bilirubin
For subjects with Gilbert’s Syndrome (only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
Part 1A and 2A: ALT
≤1.5xULN
Part 2B: ALT
≤2.5xULN
Renal
Serum Creatinine
OR
Calculated CrCla
≤1.5xULN
> 50 mL/min
Endocrine
TSHb
WNL
ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal; WNL = within normal limits
a.
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula (see Appendix 12) or per institutional standard.
b.
If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 are 
within the normal limits.
10. QT duration corrected for heart rate by Fridericia’s formula (QTcF) <450 msec or 
QTcF <480 msec for subjects with bundle branch block.  
The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula, machine-read or manually over-read.
11. In France, a subject will be eligible for inclusion in this study only if either 
affiliated to or a beneficiary of a social security category. 
12. Female subject: is eligible to participate if she is not pregnant (as confirmed by a 
negative serum beta-human chorionic gonadotrophin (-hCG) test), not lactating, 
and at least one of the following conditions applies:


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a.
Non-reproductive potential defined as:

Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed below in 
the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP) requirements from 30 days prior to the 
first dose of study medication and until 120 days after the last dose of study 
medication and completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their 
preferred and usual lifestyle or for subjects who are and will continue to be 
abstinent from penile-vaginal intercourse on a long term and persistent basis.

Contraceptive subdermal implant with a <1% rate of failure per year, as 
stated in the product label

Intrauterine device or intrauterine system with a <1% rate of failure per 
year, as stated in the product label [Hatcher, 2007]

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007] 

Injectable progestogen [Hatcher, 2007]

Contraceptive vaginal ring [Hatcher, 2007]

Percutaneous contraceptive patches [Hatcher, 2007]

Male partner sterilization with documentation of azoospermia prior to the 
female subject's entry into the study, and this male is the sole partner for 
that subject [Hatcher, 2007].
These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label.  The 


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investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
13. Male subjects with female partners of child bearing potential must comply with 
the following contraception requirements from the time of first dose of study 
medication until 120 days after the last dose of study medication.

Vasectomy with documentation of azoospermia.  

Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant with a <1% rate of failure per year, as 
stated in the product label [Hatcher, 2007]

Intrauterine device or intrauterine system with a <1% rate of failure per 
year, as stated in the product label [Hatcher, 2007]

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007] 
Injectable progestogen [Hatcher, 2007]

Contraceptive vaginal ring [Hatcher, 2007]

Percutaneous contraceptive patches [Hatcher, 2007]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Prior treatment with the following agents (from last dose of prior treatment to first 
dose of GSK3174998): 

TNFR agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at 
any time. 
NOTE: Subjects treated in Part 1/monotherapy with GSK3174998 may be 
enrolled into Part 2/combination with pembrolizumab upon disease progression 
and upon discussion and approval from the GSK Medical Monitor.

Checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors: within 4
weeks. NOTE: Subjects entering the PD-(L)1 naive expansion cohort may not 
have received any prior PD-(L)1 anti-cancer treatment.

Other anticancer therapy, including chemotherapy, targeted therapy, and 
biological therapy: within 4 weeks or 5 half lives of the drug, whichever is 
shorter. Prior radiation therapy is permissible if at least one unirradiated 
measurable lesion is available for assessment via RECIST version 1.1. A wash 
out of at least two weeks before start of study drug for palliative radiation to the 


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extremities for osseous bone metastases and 4 weeks for radiation to the chest, 
brain, or visceral organs is required.

Investigational therapy: if the subject has participated in a clinical trial and has 
received an investigational product: within 30 days or 5 half-lives of the 
investigational product (whichever is shorter). At least 14 days must have passed 
between the last dose of prior investigational agent and the first dose of study 
drug. Note: if the agent is a TNFR agonist or a checkpoint inhibitor, the above 
exclusions take precedence.  
2. Prior allogeneic or autologous bone marrow transplantation or other solid organ 
transplantation.  
3. Toxicity from previous treatment:

Subjects with ≥Grade 3 toxicity related to prior immunotherapy leading to study 
treatment discontinuation are not eligible.  

Subjects whose toxicity related to prior treatment has not resolved to Grade 1 
(except alopecia, hearing loss, grade 2 neuropathy or endocrinopathy managed 
with replacement therapy) are not eligible.  
4. Malignancy other than disease under study, except as noted below:

Any other malignancy from which the subject has been disease-free for more 
than 2 years and, in the opinion of the principal investigators and GSK Medical 
Monitor, will not affect the evaluation of the effects of this clinical trial 
treatment on currently targeted malignancy, can be included in this clinical trial.  
5. Central nervous system (CNS) metastases, with the following exception:

Subjects who have previously-treated CNS metastases, are asymptomatic, and 
have had no requirement for steroids for 2 weeks prior to first dose of study 
drug.
Note: Subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
6. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including granulocyte colony-
stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-
CSF], recombinant erythropoietin) within 2 weeks before the first dose of study drug.  
7. Major surgery 4 weeks before the first dose of study treatment.  Subjects must have 
also fully recovered from any surgery (major or minor) and/or its complications 
before initiating study treatment.  
8. Active autoimmune disease (see Appendix 2) that has required systemic treatment 
within the last 2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  Replacement therapy (e.g., thyroxine or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.
9. Concurrent medical condition requiring the use of systemic immunosuppressive 
medications within 28 days before the first dose of study treatment.  Physiologic 


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doses of corticosteroids for treatment of endocrinopathies or steroids with minimal 
systemic absorption, including topical, inhaled, or intranasal corticosteroids may be 
continued if the subject is on a stable dose.  
10. Active infection, known human immunodeficiency virus infection, or positive test for 
hepatitis B surface antigen or hepatitis C.  
11. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease 
per investigator assessment).  
NOTE: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, persistent jaundice, or cirrhosis. 
12. Known, current drug or alcohol abuse.
13. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel 
disease, intra-abdominal abscess, or gastrointestinal obstruction
14. Receipt of any live vaccine within 4 weeks.  
15. Recent history of allergen desensitization therapy within 4 weeks of starting study 
treatment.  
16. History of severe hypersensitivity to other mAbs.  
17. History or evidence of cardiovascular risk including any of the following:

Recent (within the past 6 months) history of serious uncontrolled cardiac 
arrhythmia or clinically significant ECG abnormalities including second degree 
(Type II) or third degree atrioventricular block.  

Documented cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting, or bypass 
grafting within the past 6 months before enrollment.  

Documented congestive heart failure (Class II, III, or IV) as defined by the New 
York Heart Association functional classification system (NYHA, 1994).  

Recent (within the past 6 months) history of symptomatic pericarditis.  
18. Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or 
organizing pneumonia. Note: post-radiation changes in the lung related to prior 
radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring 
treatment may be permitted if agreed by the investigator and Medical Monitor.
19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
20. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural 
effusions.  
21. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other 
condition that could interfere with the subject’s safety, obtaining informed consent, or 
compliance to the study procedures.  


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22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
23. History of severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.
5.3.
Screening Failures
In order to ensure transparent reporting of screen failure subjects, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is 
required including Demography, Screen Failure details, Eligibility Criteria, and any SAE.  
5.4.
Withdrawal/Stopping Criteria
5.4.1.
Treatment Discontinuation
Subjects will receive study treatment for the scheduled time period, unless one of the 
following occurs earlier: disease progression (as determined by irRECIST), death, or 
unacceptable toxicity, including meeting stopping criteria for liver chemistry defined in 
Section 5.4.2. In addition, study treatment might be permanently discontinued for any of 
the following reasons:

Major deviation(s) from the protocol

Request of the subject or proxy (withdrawal of consent by subject or proxy)

Investigator’s discretion

Subject is lost to follow-up 

Study is closed or terminated

Subjects with infusion delays greater than 3 weeks due to toxicity should 
discontinue study drug(s) unless the treating investigator and Sponsor/Medical 
Monitor agree there is strong evidence supporting continued treatment. 
Note: Subjects who require permanent discontinuation of one of the study treatments due 
to toxicity in a given treatment combination must permanently discontinue both 
treatments (unless continued treatment with the remaining agent is agreed upon by the 
treating investigator and Sponsor/Medical Monitor) in that combination and the reason 
for discontinuation must be recorded. The treatment discontinuation visit (TDV) should 
be conducted within 30 days (+10 days) of the decision to discontinue study drug(s).

Intercurrent illness that prevents further administration of study treatment(s)

Criteria for discontinuation of study drug(s) as described in Section 6.3.1 (Safety 
Management Guidelines) have been met

Criteria described in Section 5.4.3 (QTcF Stopping Criteria) have been met


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
Criteria described in Section 5.4.4 (Stopping Rules for Clinical Deterioration)
have been met
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
All subjects who permanently discontinue study treatment without disease progression 
will be followed for disease progression according to the protocol schedule until:

New anticancer therapy is initiated

Disease progression

Death

Study closure/termination (with implementation of Protocol Amendment 4).
A subject with a CR requires confirmation of response via imaging at least 4 weeks after 
the first imaging showed a CR. Early discontinuation of GSK3174998 and/or 
pembrolizumab may be considered for subjects who have attained a confirmed complete 
response per RECIST 1.1 that have been treated for at least 6 months and had at least two 
treatments beyond the date when the initial CR was declared.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be re-treated.
The follow-up period for safety assessments will be a minimum of 3 months from the 
date of the last dose. The post treatment follow-up period includes disease assessments 
every 12 weeks until documented PD.  Following PD, subjects will be contacted every 3 
months to assess survival status. 
With the implementation of Amendment 04, there will be no requirement to perform 
future disease assessments or survival follow-up. If the subject voluntarily discontinues 
from treatment due to toxicity, ‘AE’ will be recorded as the primary reason for permanent 
discontinuation on the eCRF.  
All subjects who discontinue from study treatment will undergo safety assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in the 
Time and Events Table (see Section 7.1, Table 13 and Table 14).  


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5.4.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the Food and 
Drug Administration [FDA] pre-marketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
If any of the following criteria are met, study treatment must be discontinued:
Liver Chemistry Stopping Criteria –Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubina, b
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INRb
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomaticc
ALT  3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
a.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
c.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
For additional guidance on the management of hepatotoxicity, please see Section 6.3.1.1
5.4.2.1.
Study Treatment Restart or Rechallenge
If a subject meets liver chemistry stopping criteria do not restart/rechallenge the subject 
with study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 3 for full guidance.  


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5.4.3.
QTcF Stopping Criteria

The QTcF correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

The QTcF should be based on single or averaged QTcF values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minute) recording period. (i.e. single QTcF is 
used when a single ECG is performed, and averaged QTcF is used when triplicate 
ECGs are performed)
If a subject meets either of the following criteria, they must be discontinued.  

QTcF >500 msec
OR

Change from baseline of QTcF >60 msec
For subjects with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTcF with Bundle Branch Block
Discontinuation QTcF with Bundle Branch 
Block
<450 msec
500 msec
450 – 480 msec
530 msec
QTcF = QT duration corrected for heart rate by Fridericia’s formula
5.4.4.
Stopping Rules for Clinical Deterioration
Accumulating clinical evidence indicates that the emergence of objective responses to 
agents that activate antitumor immune responses may follow delayed kinetics of weeks or 
months, and can be preceded by initial apparent progression with appearance of new 
lesions or some enlarging lesions while certain index lesions are regressing (“mixed 
response”).  Therefore, it is reasonable to allow a subject experiencing apparent 
progression to continue to receive treatment until progression is confirmed at the next 
imaging assessment at least 4 weeks later.  These considerations should be balanced by 
clinical judgment as to whether the subject is clinically deteriorating and unlikely to 
receive any benefit from continued treatment.  
Such deterioration will be assessed to have occurred after a clinical event that, in the 
investigator’s opinion, is attributable to disease progression, is unlikely to reverse with 
continued study treatment and therefore indicates that the subject is not benefiting from 
study treatment and cannot be managed by the addition of supportive care (e.g., 
bisphosphonates and/or bone directed radiotherapy, thoracentesis, or paracentesis for 
accumulating effusions).  The decision to stop treatment should be discussed with the 
Sponsor’s Medical Monitor. Examples of events that may, in the investigator’s opinion, 
indicate a lack of clinical benefit include, but are not limited to, the following:

ECOG PS decrease of at least 2 points from baseline


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
Skeletal related events defined by the following:

pathologic bone fracture in the region of cancer involvement

cancer related surgery to bone, and/or

spinal cord or nerve root compression

Development of new CNS metastases

Any setting where the initiation of new antineoplastic therapy has been deemed 
beneficial to the subject even in the absence of any such documented clinical 
events
5.5.
Subject and Study Completion
Upon protocol Amendment 4 implementation, ongoing subjects will be considered 
withdrawn due to study closure and will be followed for up to 3 months after the last 
dose. Only when a subject dies is he/she considered to have completed the study; 
consequently “death” is not listed as a reason for withdrawal from the study. 
Furthermore, disease progression, discontinuation of study treatment, and AEs, are not by 
themselves reasons for withdrawal from the study. If a subject dies a copy of the death 
certificate should be available for review, if possible, and the cause of death should be 
evaluated and documented.
The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.  
GSK3174998 (Table 9) will be intravenously administered to subjects at each study site 
under medical supervision of an investigator or designee.  When administered in 
combination with pembrolizumab in Part 2 of the study, GSK3174998 will be 
administered first.  The date and time of administration will be documented in the source 
documents and reported in the eCRF.  
In Part 2 of the study, pembrolizumab (Table 9) will be intravenously administered to 
subjects starting at least 1 hour and no more than 2 hours following the end of the 
GSK3174998 infusion under medical supervision of an investigator or designee.  The 
date and time of administration will be documented in the source documents and reported 
in the eCRF.  
For drug administered by an investigator or designee, the dose of study treatment and 
study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study treatment.  The specific 
time of study treatment administration (e.g., time of the week for first administration; 
time of the day for each administration) should take into consideration PK sampling time 
points and study visit procedures. Infusions may be administered up to 72 hours before 
or after the planned date of treatment for administrative reasons only (e.g., scheduling an 
infusion around a holiday).  
The Study Reference Manual (SRM) contains specific instructions for the calculation of 
GSK3174998 doses, and for the preparation of both GSK3174998 and pembrolizumab 
infusions, and administration of these infusions.  


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Table 9
Investigational Product Dosage/Administration
Study Treatment
Product name:
GSK3174998
Pembrolizumab
Dosage form:
Lyophilized powder for 
reconstitution
Solution for infusion 
Unit dose strength(s)/ Dosage 
level(s):
40 mg lyophilized powder
Dose range: 0.003 to 
≤10 mg/kg
100 mg/ 4 mL solution 
Dose range: 200 mg
Route of Administration
IV infusion – 30 mina, b
IV infusion – 30 mina
Frequency of Administration
Q3Wb, c
Q3Wb
Dosing instructions:
Make every effort to target 
infusion timing to be as close 
to 30 min as possible. 
However, given the variability 
of infusion pumps from site to 
site, a window of -5 min and 
+10 min is permitted (i.e., 
infusion time is 30 min: -5 
min/+10 min or 25 to 40 min).
Make every effort to target 
infusion timing to be as close to 
30 min as possible. However, 
given the variability of infusion 
pumps from site to site, a 
window of -5 min and +10 min 
is permitted (i.e., infusion time 
is 30 min: -5 min/+10 min or 25 
to 40 min).
Manufacturer/ source of 
procurement
GSK
Merck
a.
Infusions may be prolonged in the event of an infusion reaction.  If multiple subjects experience clinically 
significant infusion reactions, the infusion rate may be slowed for all future administrations of study drug(s) for all 
subjects. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
b.
Dose levels 1 and 2 will be administered less than 30 min, please refer to the SRM for infusion directions
c.
Alternative dosing schedules may be explored if emerging data warrants. This will be communicated to the sites in 
writing prior to implementation.
Q3W = Every 3 weeks; GSK = GlaxoSmithKline


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6.2.
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.  
Upon completion of all the required screening assessments, eligible subjects will be 
registered into a GSK designated registration and medication ordering system, by the 
investigator or authorized site staff.  
Subjects will be assigned to study treatment in the order in which they complete 
screening assessments (i.e., the study is not randomized).  
6.3.
Planned Dose Adjustments
6.3.1.
Dose and Safety Management Guidelines
6.3.1.1.
Dose Modification and Toxicity Management for Immune-Related AEs 
Associated with GSK3174998 Pembrolizumab
AEs associated with treatment with GSK3174998 pembrolizumab exposure may be 
immune-mediated. These immune-related AEs (irAEs) may occur shortly after the first 
dose or several months after the last dose of GSK3174998 pembrolizumab treatment, or 
anywhere in between, and may affect more than on body system simultaneously. 
Therefore, early recognition of and initiation of treatment for these events is critical to 
reduce potential complications. Based on existing data from study 201212, most irAEs 
were reversible and could be managed with interruptions of GSK3174998 
pembrolizumab, administration of corticosteroids and/or other supportive care. For 
suspected irAEs, ensure adequate evaluation to confirm the etiology or exclude other 
causes. Additional procedures or tests such as, but not limited to bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue GSK3174998 pembrolizumab 
and administer corticosteroids. Dose modification and toxicity management guidelines 
for ir AEs associated with GSK3174998 pembrolizumab are provided in Table 10.


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Table 10
Dose modification and toxicity management guidelines for immune-
related AEs 
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
2.
For situations where GSK3174998 pembrolizumab has been withheld, GSK3174998 pembrolizumab can 
be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. GSK3174998 
pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
GSK3174998 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone or 
equivalent) followed by 
taper

Monitor subjects for 
signs and 
symptoms of 
pneumonitis

Evaluate subjects 
with suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic 
infections
Grade 3 or 4, or 
recurrent grade 
2
Permanently 
discontinue


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Immune-
related AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
GSK3174998 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone or 
equivalent) followed by 
taper

Monitor subjects for 
signs and 
symptoms of 
enterocolitis (i.e. 
diarrhea, abdominal 
pain, blood or 
mucus in stool with 
or without fever) 
and of bowel 
perforation (i.e. 
peritoneal signs and 
ileus).

Subjects with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis. 

Subjects with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
and electrolytes 
should be 
substituted via IV 
infusion.
Grade 4
Permanently 
discontinue


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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
GSK3174998 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
increased bilirubin
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
methylprednisolone or 
equivalent) followed by 
taper

Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is stable

See Section 6.3.1.2
for additional details 
on Liver Event 
Follow-Up 
Assessments
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone or 
equivalent) followed by 
taper
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -
cell failure
Withhold

Initiate insulin 
replacement therapy for 
subjects with T1DM 

Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia 

Monitor subjects for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.

Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective 
beta-blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs 
and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement hormones 
(e.g. levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs 
and symptoms of 
thyroid disorders. 


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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
GSK3174998 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Nephritis and 
renal dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(methylprednisolone 1-
2mg/kg or equivalent) 
followed by taper.

Monitor changes of 
renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes

Grade 3 or 4
Permanently 
discontinue
All other immune-
related AEs
Grade 3, or 
intolerable/ 
persistent 
Grade 2
Withhold

Based on severity of AE 
administer 
corticosteroids 

Ensure adequate 
evaluation to 
confirm etiology or 
exclude other 
causes
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue
NOTES: 
1.
The decision whether to withhold or permanently discontinue GSK3174998 pembrolizumab is at the discretion 
of the investigator or treating physician.
2.
For subjects with Grade 3 or 4 immune-related endocrinopathy where interruption of GSK3174998 
pembrolizumab is required, treatment with GSK3174998 pembrolizumab may be resumed when the event
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or, for T1DM, metabolic control has 
been achieved.
6.3.1.2.
Liver Event Follow-up Assessments

Viral hepatitis serology: Hepatitis A IgM antibody; Hepatitis B surface antigen 
and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM 
antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody

Quantitative hepatitis B DNA and hepatitis delta antibody: Only in those with 
underlying chronic hepatitis B at study entry (identified by positive hepatitis B 
surface antigen). If hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction of Hepatitis D RNA virus (where 
needed) [Le Gal, 2005].

Blood sample for PK analysis, obtained within 28 days after last dose of study 
drug: Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the eCRF. If the date or 
time of the last dose is unclear, provide the subject’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample


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
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH)

Fractionate bilirubin, if total bilirubin 2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on the concomitant medications report 
form including acetaminophen, herbal remedies, other over the counter 
medications

Record alcohol use on the liver event alcohol intake case report form

For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total IgG (or gamma globulins).

Serum acetaminophen adduct high-performance liquid chromatography 
(HPLC) assay (quantifies potential acetaminophen contribution to liver injury 
in subjects with definite or likely acetaminophen use in the preceding week 
[James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver 
Biopsy eCRF forms.


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6.3.1.3.
Dose Modification and Toxicity Management of Infusion-Reactions
Related to GSK3174998 Pembrolizumab
Infusion reactions are a well-documented AE associated with the administration of mAbs.  
Infusion reactions typically develop within 30 minutes to 2 hours after initiation of drug 
infusion, although symptoms may be delayed for up to 48 hours.  The incidence of 
infusion reactions varies by mAb agent, and there are multiple mechanisms known to 
lead to infusion-related reactions including both IgE-dependant anaphylactic and non-IgE 
dependent anaphylactoid hypersensitivities.  Cytokine release syndrome, and when 
severe, cytokine “storm”, has been identified as a sequelae of the immune system 
activation associated with infusion reactions.
Infusion reactions may affect any organ system in the body.  Most are mild in severity, 
although severe and even fatal reactions occur.  As a group, infusion reactions (including 
both cytokine mediated and allergic) usually occur during or within a few hours of drug 
infusion.  Occasionally, a reaction may occur one to two days after administration.  The 
NCI-CTCAE (version 4.0) for grading adverse reactions during chemotherapy 
administration has a scale for grading the severity of infusion reactions and separate 
grading scales for allergic reactions and anaphylaxis.  While use of these separate grading
scales may be useful for classifying the nature of an infusion reaction for research 
purposes, they are less useful for clinical care, since it may not be obvious if the subject 
is having an allergic infusion reaction or a non allergic infusion reaction. 
Clinically, infusion reaction may present with flushing, itching, urticaria, and/or 
angioedema, repetitive cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
pain.
In order to better understand the underlying etiology of these events, serum tryptase, C-
reactive protein (CRP), ferritin, and a cytokine panel should be drawn during the 
occurrence of an infusion reaction/CRS of any grade. The serum tryptase, CRP and 
ferritin panels should be performed at the PI’s designated local laboratory. The serum 
cytokine panel will be performed at a GSK designated laboratory. These results will help 
us better understand (albeit retrospectively) the etiology of the AE, as outlined in Table 
11.


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Table 11
Biomarker Panel
Biomarker
Relationship to Adverse Event
Serum tryptasea
IgE-related infusion reaction (Allergic/anaphylaxis) [Schwartz, 
2006]
Serum CRPa
Elevated in CRS [Lee, 2014]
Serum ferritina
Elevated in CRS [Lee, 2014]
Plasma cytokine panelb
(IFN-γ*^, TNF-α*^, IL-2*, IL-4, IL-
5*, IL-6*^, IL-8*, IL-10*, IL-12p70, 
IL-13, and IL-17)
* Reported to be elevated in CRS [Lee, 2014]
^consistently reported as elevated in CRS [Lee, 2014]
CRP=C-reactive protein; CRS= Cytokine release syndrome; IFN-= Interferon gamma; TNF-= Tumor necrosis factor 
alpha; IL = Interleukin. 
a.
Performed by PI designated local laboratory
b.
Performed by GSK designated laboratory
These guidelines are suggestions, and investigators and site staff may also follow their 
site’s standard operating procedures for the treatment of these events.
Table 12
GSK3174998 Pembrolizumab Infusion Reaction Dose Modification 
and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion interruption not 
indicated; intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study drugs with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of 
analgesic).


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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion 
of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Subject is permanently discontinued 
from further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
6.3.1.4.
Dose Delay
GSK3174998 pembrolizumab may be interrupted for situations other than treatment-
related AEs such as medical / surgical events or logistical reasons not related to study 
therapy. Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
If there is a dose delay between 1 and 49 days (2 dosing cycles + 7 days), the procedures 
at the original scheduled visit (including dosing) should be performed as soon as possible.   
All subsequent visits will follow a Q3W calendar schedule.  Subjects with infusion delays 
causing 2 consecutive missed doses due to toxicity should discontinue study drug(s) 
unless the treating investigator and Sponsor/Medical Monitor agree there is strong 
evidence supporting continued treatment.  While no washout from study treatments is 
required for subjects requiring elective surgery or palliative radiation therapy while on 
study, investigators and site staff are encouraged to schedule these procedures to fall in 
between dosing days (see Section 6.10.1. for details on permitted medications and non-
drug therapies).  
6.4.
Blinding
This will be an open-label study.  


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6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.  
6.6.
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments must be stored in a 
secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).  
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor, and/or GSK study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
6.7.
Compliance with Study Treatment Administration
GSK3174998 and pembrolizumab will be intravenously administered to subjects at the 
site.  Administration will be documented in the source documents and reported in the 
eCRF.  
6.8.
Treatment of Study Treatment Overdose
6.8.1.
GSK3174998 Overdose
An overdose is defined as administration of a dose that is at least 50% greater than the 
intended dose. In the event of an overdose the investigator should:

Contact the Medical Monitor immediately.  

Closely monitor the subject for AEs/SAEs and laboratory abnormalities for at least 90 
days. 

Obtain a plasma sample for PK analysis within 28 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).  


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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
There is no specific antidote for overdose with GSK3174998.  In the event of a suspected 
overdose, it is recommended that the appropriate supportive clinical care should be 
instituted, as dictated by the subject’s clinical status.
6.8.2.
Pembrolizumab Overdose
An overdose of pembrolizumab will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any overdose of pembrolizumab, or follow up to an 
overdose, whether or not related to the Sponsor’s product, must be reported within 5 days
to GSK as an AESI, either by electronic media or paper.
6.9.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition.
Refer to Section 5.4 and Section 7.1 for follow-up assessments.
6.10.
Concomitant Medications and Non-Drug Therapies
Subjects will be instructed to inform the investigator before starting any new medications 
from the time of first dose of study treatment until the end of the study (Final Study 
Visit).  Any concomitant medication(s), including non-prescription medication(s) and 
herbal product(s), taken during the study will be recorded in the eCRF. The minimum 
requirement is that drug name, dose, and the dates of administration are to be recorded.  
Additionally, a complete list of all prior anticancer therapies will be recorded in the 
eCRF.  
Medications or vaccinations specifically prohibited (see Section 6.10.2) are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  However, the decision 
to continue the subject on trial therapy or vaccination schedule requires the mutual 
agreement of the investigator, the Sponsor and the subject


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Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.  
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file.  Any such changes 
will be communicated to the investigative sites in the form of a letter.  
6.10.1.
Permitted Medications and Non-Drug Therapies
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusion of blood and blood products, palliative radiation to non-target 
lesions, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, as 
appropriate. Seasonal flu vaccine is permitted as an injection only. Intra-nasal flu vaccine 
is excluded. Elective surgery or non-palliative radiation may be permitted on a case-by-
case basis in agreement with the Medical Monitor.
Growth Factors and Bisphosphonates:  The use of growth factors, RANK-L inhibitors,
and bisphosphonates (if on a stable dose for at least 4 weeks) is permitted while 
participating in this study.  However, the initiation of growth factors and bisphosphonates 
is not allowed during the first 4 weeks of study treatment, unless used in the management 
of toxicity and agreed upon by the investigator and Medical Monitor.
Steroids:  Use of steroids is permitted for treatment of AEs (as per Table 10 and Table 
12, Dose Modification Guidelines for Immune-Related AEs or Infusion Reactions. 
All attempts should be made to rule out other causes such as metastatic disease, infection 
or other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported 
regardless of etiology.
Subjects with conditions pre-existing before study enrollment requiring steroids are 
permitted to continue taking up to a maximum of 10 mg of prednisone or equivalent 
provided that the subject has been on a stable dose for at least 4 weeks before enrollment.
6.10.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited before the first dose of study treatment (see 
Section 5.2 for specific time requirements) and while on treatment in this study:

Any investigational drug(s)

Other anticancer therapy (chemotherapy, radiation therapy [unless administered 
palliatively] – see Section 6.10.1), immunotherapy, biologic therapy, or hormone 
therapy other than for replacement).  The use of pembrolizumab during Part 2 is 
permitted.

Live vaccines such as intra-nasal flu vaccine.


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7.
STUDY ASSESSMENTS AND PROCEDURES
If assessments are scheduled for the same nominal time, it is recommended that the 
assessments should occur in the following order: 12-lead ECG, vital signs, and blood 
draws.  The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.  
The timing and number of planned study assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the following assessments: 
safety, PK, pharmacodynamic/biomarker, or other assessments.  
The change in timing or addition of time points for any planned study assessments must 
be approved by the relevant GSK study team member and then archived in the study 
Sponsor and site study files, but this will not constitute a protocol amendment.  
The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the informed consent form.  
No more than 500 mL of blood for the purposes of this study, will be collected over the 
first 6 doses of study treatment, plus the post-treatment follow-up period. No more than 
30 mL of blood will be collected at each dosing visit following dose number 6. The total 
volume will depend on how long the subject remains on treatment.  There may be 
additional blood collection performed for non-study reasons.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1, Table 13 and Table 14), are essential 
and required for study conduct.  
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1 (Table 
13 and Table 14). 


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7.1.
Time and Events Table
Table 13
Time and Events Table – Monotherapy and Combination Therapy
Scrna/b
Treatmenta
Follow-up
Weeka
≤4
0
1
2
3
4
5
6
9
12
> 12 - 48c
≥49 -105c
TDVd
DFS FUe
SFUf
Day
≤28
1
8
15
22
29
36
43
64
85
106-337
≥344-736
30d after 
last dose
Q12W
Q12W
Dose
1
2
3
4
5
6-17
18-36
Informed Consent
X
Inclusion/Exclusion
X
X
Demographics, Medical 
History, Prior Medications
X
Concomitant Medications
Assess at each visit from first dose until the TDV visit
Subject Registration
X
Anti-Cancer Treatmentf
X
X
X
Part I Study Treatment Monotherapy
Administer GSK3174998 
(± 3 days)g
X
X
X
X
X
X
X
Part 2 Study Treatment Combination Therapy (note: administer pembrolizumab 1 hour after the end of the GSK3174998 infusion)
Administer GSK3174998g
X
X
X
X
X
X
X
Administer 
Pembrolizumabg
X
X
X
X
X
X
X
Safety
AE/SAE Assessment
Assess at each visit from first dose until the TDV visit for AEs and until 90 days after last dose for AESI 
and SAEsd
ECOG PS
X
X
X
X
X
X
X
X
X
X
Q6w
Q6w
X
Physical Examination
X
X
X
X
X
X
Q6w
Q6w
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGl
X
X l
X l
X
X
Xl
Q12w
Q12w
X


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Scrna/b
Treatmenta
Follow-up
Weeka
≤4
0
1
2
3
4
5
6
9
12
> 12 - 48c
≥49 -105c
TDVd
DFS FUe
SFUf
Day
≤28
1
8
15
22
29
36
43
64
85
106-337
≥344-736
30d after 
last dose
Q12W
Q12W
Dose
1
2
3
4
5
6-17
18-36
Laboratory Assessments (Safety) – perform assessments pre-dose on each dosing day
Hepatitis B and C
X
Pregnancy Test: Serum
β-hCG
≤3d
Monthly (urine or serum)
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid function tests
X
X
X
Q6W
Q6W
X
Calculated CrCl
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessments
Tumor imaging h
X
Xj
X
Q12W
Telephone call for 
survival statusf
X
Tumor Biopsies
Archived tumor i
X
Fresh tissue samplei, m
X
X
PD tissue samplek
Xk


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Visit Abbreviations: Scrn = Screen; TDV = Treatment Discontinuation Visit; DFSFU = Disease-Free Survival Follow-up; SFU = Survival Follow-up; PD = Progressive Disease; AE = 
Adverse Event; SAE = Serious Adverse Event; AESI = Adverse Events of Special Interest; ECOG PS = Eastern Cooperative Oncology Group performance status; ECG = 
Electrocardiogram; -hCG = Beta-human chorionic gonadotropin; CrCl = Creatinine clearance
a.
Visit Windows: With the exception of Screening/baseline and Day 1 visits and unless otherwise specified, assessments performed at 3-week intervals will have a 3 day window 
and assessments performed at >3 week intervals will have a 1 week window. For Screening/Baseline and Day 1 visits, all procedures must be completed before first dose.
b.
Screening assessments or procedures to be performed within 4 weeks (28 days) of the first dose (unless otherwise specified, with the exception of the serum pregnancy test which
must be performed within 3 days of the first dose of study treatment).
c.
The frequency of safety assessments from week 12 onwards will be as follows (unless stated otherwise in the table):
Every GSK3174998 or pembrolizumab dosing day (pre-dose): Clinical chemistry, hematology, urinalysis, vital signs and weight
Every 6 weeks: Thyroid function tests, ECOG PS assessments, physical examination
Every 12 weeks: 12-lead ECG,
d.
The treatment discontinuation visit should be completed 30 days from the last dose of study treatment. The window for this visit is +10 days. All AEs and concurrent medications
will be collected until at least 30 days after the last dose of study treatment. All AESIs and SAEs and any concurrent medications relevant to the reported AESIs and SAEs will be 
collected until at least 90 days after the last dose of study treatment. If another anti-cancer agent is started during the 90 day reporting period, only AESI and SAEs that occur 
within 30 days from the last dose of study drug(s) should be recorded. (see Section 7.4.1.1)
e.
If study treatment has been permanently discontinued in the absence of PD, the subject will return for disease assessments every 12 weeks until PD is documented (by 
irRECIST), another anticancer treatment is initiated, or death, whichever occurs first. These visits are described as Disease Free Survival Follow-up (DFS FU) visits.  Upon 
implementation of Protocol Amendment 4, no future disease assessments are required. 
f.
The Survival FU visit should be completed every 12 weeks after documented disease progression (or after initiation of another anticancer treatment).  Subjects should be
contacted every 12 weeks (2 weeks) until death occurs. Upon implementation of Protocol Amendment 4, no future survival follow-up is required. 
g.
Dosing of GSK3174998 and pembrolizumab at every 3-week intervals is shown in the Time and Events Table; however, dosing of GSK3174998 may be delayed due to toxicity. 
During the combination phase, GSK3174998 should be administered first, and pembrolizumab should be administered at least 1 hour and no more than 2 hours following the end 
of the GSK3174998 infusion. GSK3174998 and pembrolizumab will be dosed for a maximum of 2 years or 35 cycles, whichever comes first. Alternative dosing schedules of 
GSK3174998 and pembrolizumab may be explored if the data warrants. This will be communicated in writing to sites prior to implementation.
h.
Screening tumor imaging must be obtained within 28 days of the first dose. Tumor imaging will be performed every 12 weeks (1 week) until disease progression has been 
confirmed by irRECIST; Subjects whose disease progresses must have a confirmatory scan performed at least 4 weeks after the date of assessment during which the first 
indication of PD was demonstrated. Immune-related RECIST will be used to determine treatment decisions for PD and the primary endpoint analysis will use irRECIST. If a 
subject has achieved a CR or PR in the previous radiologic assessment, a repeat scan should be performed as a part of the confirmation of response, within at least 4 weeks to 
confirm the response. At the TDV, tumor imaging is only required if the last disease assessment did not show PD and was performed 6 weeks before TDV. During the DFS FU 
visits (performed when a subject has permanently discontinued study treatment before disease progression has been documented), tumor imaging will be obtained every 12 
weeks (1 week) until PD, initiation of a new anticancer treatment, or death, whichever comes first. Pre-baseline scans (within 24 weeks before the baseline scan) may be 
collected to assess tumor growth rate in selected subjects to support exploratory investigation of tumor growth kinetics. Upon implementation of Protocol Amendment 4, no future 
disease assessments are required..
i.
A fresh tumor biopsy should be attempted at screening (before first dose) and at Week 6 (after the 3rd dose of study treatment +1 week). Fresh biopsies are mandatory for all patients in 
the Pharmacodynamic Cohort and the Dose Expansion phase.  Tumor lesions planned for biopsy must not be used as indicator lesions for assessment of disease, unless discussed 
and agreed with the GSK Medical Monitor. For subjects in the initial dose escalation cohorts, where biopsy is not mandatory, a recent archival tumor specimen is acceptable if it is 
not feasible to obtain a fresh biopsy.  


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j.
The 6-week disease assessment will be performed for subjects enrolled in Part A in the Pharmacodynamic Cohort and in all Part B expansion cohorts. This disease assessment is 
timed to coincide with the on-treatment (6 week) tumor biopsy. If feasible, the disease assessment should be performed after the tumor biopsy. 
k.
Progressive Disease Tissue Sample: An optional fresh tumor biopsy should be attempted at the time of disease progression.
l.
For Part 1A only: On Day 1 ECG measurements will be performed in triplicate predose and at the following times after the infusion: EOI+30m, EOI + 4h, EOI +24h, on Day 22 
ECG measurements will be performed in triplicate predose and on Day 85 ECG measurements will be performed in triplicate predose and at the following times after the infusion: 
EOI+30m.
m.
With subject consent and agreement by the PI and GSK Medical Monitor, additional, optional fresh biopsies may be obtained during the study. One example of when this may be 
considered is when a mixed response occurs and tumor biomarker data are anticipated to inform why some lesions are, and some are not, responding to the treatment. 


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Table 14
Time and Events Table – Pharmacokinetics, Antidrug Antibodies, and Pharmacodynamics (Parts 1 and 2)
Treatment
Day
1
2
8
15
22
23
29
36
43
64
85
106
≥148
30 D 
after 
Last 
Dose
12 Wks 
Post-
Treatment 
1 week
Dose
1
2
3
4
5
6
≥8
Pharmacogenetics 
(6 mL)a
X
Receptor 
occupancy and 
phenotyping 
panels(10 mL)i
Pre
EOI+4hg
EOI+24h
X
X
Pre
EOI+4hg
Pre
EOI + 4hg
X
X
Plasma + PBMC 
prep (20 mL)b
Pre
X
Pre
Pre
Pre
X
X
Cytokines (5 mL)
Pre
EOI+4h
EOI+24h
X
Pre
EOI+4h
Pre
EOI+4h
Pre
EOI+4h
Plasma for cfDNA + 
exosomes (20 mL)h
Pre
At time of 
biopsy if 
done
Serum (5 mL)
Pre
GSK3174998
Pharmacokinetics (1 
mL)
Pre
EOI+30m
EOI+4h
EOI+24hd
X
X
Pre
EOI+30m
EOI+4h
EOI+24d
X
X
Pre
EOI+30m
Pre
EOI+30m
Pre
EOI+30m
Pre
EOI+30m
Pree
X
X
Part 2 only: 
Pembrolizumab 
Pharmacokinetics (3  
mL)
Pre
EOPI+30m
EOI+24h
X
X
Pre
Pre
Pre
Pree
X
X
Anti- GSK3174998 
antibodiesc,f (4 mL)
Pre
Pre
Pre
Pre
Pre
Pre
Pree
X
Xf
Part 2 only: Anti-
Pembrolizumab 
antibodiesc,f (6 mL)
Pre
Pre
Pre
Pre
Pree
X
Xf


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Timepoint Definitions:
X = Anytime during visit
Pre = within 60 min before the start of the GSK3174998 infusion
EOI+30m = within 30 minutes of the end of the GSK 3174998 infusion
EOPI+30m = within 30 minutes of the end of the pembrolizumab infusion
EOI +4h = within 4 hours 10 minutes of the end of the GSK3174998 infusion
EOI+24h = 24 hours 4 hours after the end of the GSK3174998 infusion
a.
Informed consent for optional pharmacogenetics research must be obtained before collecting a sample. It is recommended that the blood sample be taken at the first opportunity 
after a subject has met all eligibility requirements, and can be done up to 28 days before Day 1.
b.
If the baseline/pre-dose sample is not viable, samples for PBMCs are not needed at subsequent visits.
c.
In addition to these scheduled immunogenicity assessments, “event-driven” testing will also be employed for those subjects that experience anaphylaxis, serious hypersensitivity, 
or AEs related to study drug administration that led to withdrawal from the study. See Section 9.4.2.4 for full details.
d.
Day 2 PK samples are only required during the dose-escalation phases of the study.
e.
Dose 8 and every 4 dosing cycles
f.
In the event of a hypersensitivity reaction that is either 1) clinically-significant in the opinion of the investigator, or 2) leads to the subject withdrawing from the study, blood samples 
should be taken from the subject for immunogenicity testing at the time of the event and again 30 days, 12 weeks, and 24 weeks after. 
g.
If the EOI+4h RO sample is scheduled to be collected after the last lab courier pick-up time of the day, the sample should be collected as late as possible to enable processing and 
shipping on the same day as collection.
h.
If a tumor biopsy is taken at the time of PD, then a plasma sample should also be collected for cfDNA + exosomes, 
i.
Receptor Occupancy and phenotyping panels will only be collected in Parts 1A and 2A of the study
D = Days; PBMC = Peripheral blood mononuclear cell; EOI = End of infusion
Procedures for blood sample collection, processing, storage, and shipping are described in the SRM.


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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Demographic and Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
counts, ECG, scans, etc) and obtained prior to signing of informed consent may be
utilized for screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.  
7.2.1.1.
Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.  
7.2.2.
Baseline Documentation of Target and Non-Target Lesions

All baseline lesion assessments must be performed within 28 days before the first 
dose.  

Lymph nodes that have a short axis of <10 mm are considered non-pathological
and should not be recorded or followed.  

Pathological lymph nodes with <15 mm, but 10 mm short axis are considered 
non-measurable.

Pathological lymph nodes with 15 mm short axis are considered measurable and 
can be selected as target lesions; however, lymph nodes should not be selected as 
target lesions when other suitable target lesions are available.  

Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
recorded and measured at baseline. These lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation should not be considered as target lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by computed tomography (CT) or magnetic 
resonance imaging (MRI) can be considered measurable.  Bone scans, 
fluorodeoxyglucose-positron-emission tomography (FDG-PET) scans or X-rays 
are not considered adequate imaging techniques to measure bone lesions.  


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
All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
The following are required at baseline: A CT scan with contrast of the chest, abdomen, 
and pelvis, other areas as indicated by the subject’s underlying disease, and clinical 
disease assessment for palpable lesions. For subjects with head and neck cancer, a CT or 
MRI of the head and neck area is required. At each post-baseline assessment, evaluations 
of the sites of disease identified by these scans are required.  
NOTE: Although CT scan is preferred, MRI may be used as an alternative method of 
baseline disease assessment, especially for those subjects where a CT scan is 
contraindicated due to allergy to contrast, provided that the method used to document 
baseline status is used consistently throughout study treatment to facilitate direct 
comparison.
Confirmation of CR and PR are required per protocol.  Confirmation assessments must be 
performed at least 4 weeks after the criteria for response have initially been met and may 
be performed at the next protocol scheduled assessment.  If a confirmation assessment is 
performed prior to the next protocol schedule assessment, the next protocol scheduled 
evaluation is still required (e.g., evaluations must occur at each protocol scheduled time
point regardless of unscheduled assessments).  
7.3.
Efficacy
7.3.1.
Evaluation of Anticancer Activity

Lesion assessment method and timing, evaluation of disease, disease progression 
and response criteria will be conducted according to RECIST (version 1.1) 
[Eisenhauer, 2009] and irRECIST as outlined below and in Appendix 5 of this 
protocol.  irRECIST will be used to determine treatment decisions and will be 
used for the primary analysis of anticancer activity.

Disease assessment modalities may include imaging (e.g., CT scan, MRI, bone 
scan, plain radiography) and physical examination (as indicated for 
palpable/superficial lesions). 

The baseline disease assessment will be completed within 4 weeks prior to the 
first dose of GSK3174998, then every 12 weeks thereafter, and at the final study 
visit.  For subjects enrolled in the Part A “Pharmacodynamic Cohort” and in all 
Part B expansion cohorts an additional disease assessment will be performed at 
Week 6. See the Time and Events Table (Section 7.1, Table 13) for the schedule 
of assessments of anticancer activity. 

Assessments must be performed on a calendar schedule and should not be affected 
by dose interruptions/delays. 

For post-baseline assessments, a window of 7 days is permitted to allow for 
flexible scheduling.  If the last radiographic assessment was more than 12 weeks 
prior to the subject’s withdrawal from study and PD has not been documented, a 


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disease assessment should be obtained at the time of withdrawal from the study.
Upon implementation of Protocol Amendment 4, no future disease assessments 
are required. 

Subjects whose disease responds (either CR or PR) should have a confirmatory 
disease assessment performed at least 4 weeks after the date of assessment during 
which the response was demonstrated. 

Subjects whose disease progresses (PD) must have a confirmatory scan performed 
at least 4 weeks after the date of assessment during which the first indication of 
PD was demonstrated.    

To ensure comparability between the baseline and subsequent assessments, the 
same method of assessment and the same technique will be used when assessing 
response.  

Pre-baseline scans (within 24 weeks before the baseline scan) may be collected to 
assess tumor growth rate in selected subjects to support exploratory investigation 
of tumor growth kinetics.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1, Table 13 and Table 14).  
7.4.1.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 8.  
The investigator and their designees are responsible for detecting, documenting, and 
reporting events that meet the definitions of an AE or SAE.  
7.4.1.1.
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information

AEs and SAEs will be collected from the start of study treatment until the follow-
up contact (see Section 7.4.1.3) at the time points specified in the Time and 
Events Table (Section 7.1, Table 13 ).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any AESI and SAEs assessed as related to study participation (e.g., protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a 
GSK product will be recorded from the time a subject consents to participate in 
the study up to 90 days after the last dose of study drug(s). If another anti-cancer 
agent is started during the 90 day reporting period, only AESI and SAEs that 
occur within 30 days from the last dose of study drug(s) should be recorded.  
SAEs must be reported within 24 hours to the Sponsor either by electronic media 
or paper


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
All AESI and SAEs will be recorded and reported to GSK within 24 hours, as 
indicated in Appendix 8.  

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating, and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in
Appendix 8.  
7.4.1.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs and non-serious AESI (as defined in
Appendix 8) will be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or until the subject is lost to follow-up (as defined in 
Section 5.4).  Further information on follow-up procedures is given in Appendix 8.  
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular (CV) events (as defined in Section 7.4.1.4.1) and all deaths, 
whether or not they are considered SAEs, specific CV and Death sections of the eCRF 
will be required to be completed. These sections include questions regarding CV 
(including sudden cardiac death) and non-CV death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific CV section of the eCRF within one week of receipt of a CV 
Event data query prompting its completion.
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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7.4.1.4.1.
Definition of Cardiovascular Events
A cardiovascular event (CV) is defined as:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
7.4.1.5.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE.
Death due to disease under study is to be recorded on the death eCRF form.
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE.
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as an SAE (instead of a disease-related event [DRE]):

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with study treatment(s).
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non-interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 


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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.  
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects
will be collected after the start of dosing until 120 days after the last dose of study 
medication.

If a pregnancy is reported, then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 9.  
7.4.3.
Physical Exams

A complete physical examination will be done at screening and will include 
assessments of the Cardiovascular, Respiratory, Gastrointestinal and Neurological 
systems. Height and weight will also be measured and recorded.  

A brief, targeted physical examination will be done at all other timepoints, unless 
physician’s judgement requires a full exam. 

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.  

For melanoma subjects, a full body dermatological examination will be performed 
by a dermatologist (or suitably qualified physician) to identify abnormal skin 
lesions within the 28 day screening period.  All findings will be photographed and 
identified during screening.  Subsequently, brief skin examinations will be 
included in the PE exams as per the Time and Events Table (Section 7.1, Table 
13) or more frequently as necessitated.  Wherever possible, the same physician 
should perform these examinations.  Follow-up skin examinations by a referral 
dermatologist should be conducted if clinically indicated ECOG PS.  
The PS will be assessed using the ECOG scale (Appendix 6) as specified in the Time and 
Events Table (Section 7.1, Table 13).


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7.4.4.
Vital Signs

Vital sign measurements to be measured in semi-supine position after 5 minutes rest 
will include temperature, systolic and diastolic blood pressure, and pulse rate. 

Vital signs will be measured more frequently if warranted by clinical condition of the 
subject.  On days where vital signs are measured multiple times, temperature does 
not need to be repeated unless clinically indicated.  

If a subject develops a fever, refer to Section 6.3.1 for fever management guidelines.  
7.4.5.
Electrocardiogram (ECG)
12-lead ECGs will be obtained at each planned ECG assessment during the study using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTcF intervals.  Refer to Section 5.4.3 for QTcF stopping criteria and additional 
QTcF readings that may be necessary.  
Before each ECG test, the subject should be at rest for approximately 10 minutes. The 
subject should be in the semi-recumbent or supine position; the same position must be 
used for all subsequent ECG tests.
For Part 1A of the study, ECG measurements will be performed in triplicate at specified
times (see Table 13, including footnotes). All other measurements may be performed as 
single ECG measurements.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 15, must be conducted 
in accordance with the laboratory manual, and Time and Events Schedule. Laboratory 
requisition forms must be completed and samples must be clearly labeled with the subject 
number, protocol number, site/center number, and visit date. Details for the preparation 
and shipment of samples will be provided by the laboratory and are detailed in the SRM. 
Reference ranges for all safety parameters will be provided to the site by the laboratory 
responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.  
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology

Clinical Chemistry

Hepatitis B and C


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
Pregnancy Test

Urinalysis, calculated creatinine clearance (CrCl)

Thyroid Function Tests

The results of each test must be entered into the eCRF.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 15.
Table 15
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistrya
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Calculated creatinine clearance (CrCl)
Chloride
Carbon Dioxide
Thyroid function 
Thyroid stimulating hormone, free T4, free T3
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Serum or urine -hCG Pregnancy test (as needed for women of child bearing potential) 
a.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 5.4.2 and Section 6.3.1.3
RBC = red blood cells; WBC = white blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular 
hemoglobin; BUN = blood urea nitrogen; AST = aspartate aminotransferase; ALT = alanine aminotransferase; HBsAg 
= Hepatitis B surface antigen; -hCG = beta-human chorionic gonadotropin; 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the Sponsor notified.  


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7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for PK analysis of GSK3174998 and pembrolizumab will be collected at 
the time points described in Section 7.1, Time and Events Table (Table 14). The actual 
date and time of each blood sample collection will be recorded in the eCRF.  The timing 
of PK samples may be altered and/or PK samples may be obtained at additional time 
points to ensure thorough PK monitoring.  Details on PK blood sample collection, 
processing, storage, and shipping procedures are provided in the SRM.
Blood samples (1 mL) for analysis of plasma GSK3174998 concentrations and blood 
samples (3 mL) for analysis of serum pembrolizumab concentrations will be collected 
from all subjects at the times indicated in Table 14.
Processing, storage and shipping procedures are provided in the SRM.  
7.5.2.
Blood Sample Analysis
Plasma or serum analysis for GSK3174998 and pembrolizumab will be performed under 
the control of Department of Bioanalysis, Immunogenicity and Biomarkers (BIB), 
IVIVT, PTS, GSK or Merck Sharp & Dohme Corp the details of which will be included 
in the SRM. Concentrations of GSK3174998 and pembrolizumab will be determined in
plasma and serum samples, respectively, using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).  
Once the plasma or serum has been analyzed for GSK3174998 and pembrolizumab any 
remaining plasma may be analyzed for other compound-related metabolites and the 
results reported under a separate BIB, PTS, GSK or Merck Sharp & Dohme protocol.  
7.6.
Biomarkers/Pharmacodynamic Markers
7.6.1.
Blood Biomarkers
Blood samples will be collected and analyzed by flow cytometry to evaluate the binding 
of GSK3174998 to the OX40 receptor, and its pharmacodynamic effect on lymphocytes. 
OX40 receptor occupancy will be determined prior to dosing of GSK3174998, after
treatment, and at selected treatment intervals. The numbers of T cells, B cells, and NK
cells as well as subsets of T cells will be simultaneously evaluated in whole blood by 
flow cytometry. The activation and proliferation status of T cells will also be 
simultaneously assessed in the same sample.
Blood samples will also be collected for isolation of PBMC, plasma, and serum.  Plasma 
and serum samples will be used for an analysis of circulating soluble factors in relation to 
T-cell activation, cfDNA, exosomes circulating proteins, and may be analyzed for soluble 
OX40 and soluble OX40-drug complex depending on the availability of the assays. 
Factors to be analyzed may include but are not limited to: the presence of IFN-γ, TNF-α, 
IL-2, IL-4, IL-5, IL-6, IL 10, IL-8, IL-12p70, IL-13, and IL-17 as well as antibodies 
against tumor, self tumor mutations, i.e., tumor mutational load, gene expression (RNA 
or protein) or viral antigens.  


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PBMCs isolated from whole blood will be preserved and stored for flow cytometry of 
additional cell types such as immune regulatory populations which may include but are 
not limited to myeloid derived suppressor cells, subsequent functional analysis or 
assessment of the diversity of the T-cell repertoire, its relationship to clinical responses, 
and changes in response to treatment with GSK3174998.  The functional state of PBMCs 
may be analyzed for expression of cytokines which may include but not limited to IFN-, 
IL-2, TNF, IL-17, Granzyme B, and CD107a.  PBMCs may also be evaluated for 
genomic (DNA) and gene expression (RNA or protein) alterations to determine 
treatment-related changes in immune-related signatures.  
7.6.2.
Tumor Tissue
Archival tumor tissue, as well as fresh pre- and on-treatment biopsies in subjects in the 
pharmacodynamic cohorts, dose-expansion cohorts, and if possible in the dose escalation 
cohorts will be evaluated by IHC for expression of phenotypic and functional immune 
cell markers on tumor infiltrating lymphocytes (TILs) and other immune cells and as well 
as immune signaling markers on the surface of tumor cells (e.g. including, but not limited 
to PD-L1), to understand antitumor immune responses. In addition, when possible, 
similar analyses will be performed on tumor tissue samples obtained upon progression. 
Additionally, tumor tissue may be sequenced to assess TCR diversity as well as evaluated 
for any DNA/RNA/protein changes correlating with response, such as but not limited to 
tumor mutational burden.
In the pharmacodynamic cohort and expansion cohorts, mandatory fresh pre- and on-
treatment biopsies are required (see Table 13 for timing). These mandatory biopsy 
samples will be evaluated as previously described for the archival, pre- and on-treatment
and progression biopsies.
If feasible, for all of the fresh pre-and on-treatment biopsies, both samples should be 
obtained from the same tumor lesion.  If not possible, the on-treatment biopsy should be 
obtained from the same organ as the pre-treatment biopsy. The tumor site chosen for 
biopsy must not be the used as an indicator lesion for assessment of disease unless 
otherwise discussed and agreed upon with the GSK medical monitor.
With subject consent and agreement by the PI and GSK Medical Monitor, additional, 
optional fresh biopsies may be obtained during the study. One example of when this may 
be considered is when a mixed response occurs and tumor biomarker data are anticipated 
to inform why some lesions are, and some are not, responding to the treatment. In this 
case, the additional biopsies are not required to be obtained from the same lesion or organ 
as the pre-treatment biopsy. .
Other biomarkers may be evaluated as determined by additional data. Details for sample 
collection, processing, storage, and shipment will be provided in the SRM.  
Blood and tumor samples may be used for purposes related to the quality assurance of the 
laboratory tests described in this protocol, or for the development of a diagnostic assay.


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7.7.
Anti-Drug Antibodies
7.7.1.
Blood Sample Collection
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3174998 and pembrolizumab. Serum samples for testing anti-GSK3174998 and 
anti-pembrolizumab antibodies will be collected as described in the Time and Events 
schedule (Section 7.1). The actual date and time of each blood sample collection will be 
recorded. Details of blood sample collection (including volume to be collected), 
processing, storage, and shipping procedures are provided in the SRM.
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring. In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing at 
the time of the event and again 30 days, 12 weeks, and 24 weeks after. For subjects who 
prematurely withdraw from the study, immunogenicity testing will occur at withdrawal 
and at follow-up 30 days, 12 weeks, and 24 weeks after the last dose.
7.8.
Genetics
Information regarding genetic research is included in Appendix 7.
8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee, and combined with data provided from other sources 
in a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
AEs and concomitant medications terms will be coded using MedDRA (Medical 
Dictionary for Regulatory Activities) and an internal validated medication dictionary, 
GSKDrug.  
eCRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy.


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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
9.1.1.
Part 1: Monotherapy Dose Escalation (GSK3174998)
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, the safety profile, and antitumor activity of GSK3174998.  
9.1.2.
Part 2: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab)
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
study will be focused on comparison between dose cohorts and only descriptive methods 
will be used in analysis of the data obtained from this study. 
9.1.3.
Part 2: Combination Dose Expansion (GSK3174998 + 
Pembrolizumab)
The expansion cohorts of GSK3174998 + pembrolizumab are designed to evaluate 
preliminary clinical activity. Futility assessments will be conducted to evaluate 
accumulating data including safety, responses, PK and pharmacodynamics. The 
methodology is based on the predictive probability of success if enrollment continues 
until all planned subjects are recruited [Lee, 2008].
There are mutiple dose expansion cohorts being planned for STS, melanoma and other 
cancers types in the dose-expansion phase. For each cohort the objective is to test the null 
hypothesis that the overall response rate for the combination of GSK3174998 +
pembrolizumab is equal to the historical response rate of monotherapy pembrolizumab.
The observed monotherapy pembrolizumab overall response rate was approximately 18% 
for STS [Burgess, 2017]. The observed monotherapy pembrolizumab overall response 
rate was assumed to be approximately 10% for melanoma in the pretreated population
[Robert, 2014].
The sample size is chosen based on an improvement of 20% in the overall response rate 
on the combination therapy over the null hypothesis, with power of at least 80% and no 
more than a 10% type 1 error rate. In the population previously treated with
pembrolizumab, the goal would be to observe a response rate of 30% after treatment with
the combination of GSK3174998 and pembrolizumab.


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Therefore, the hypotheses for both PD-(L)1 naïve and PD-(L)1 pretreated cohorts are 
shown as below:
For PD-(L)1 naïve dose expansion cohorts (e.g., STS), 
the null hypothesis for ORR is:
H0: p=18%
and the alternative hypothesis is:
HA:p=38%
For PD-(L)1 pretreated dose expansion cohorts (e.g., melanoma),
the null hypothesis for ORR is:
H0: p=10%
and the alternative hypothesis is:
HA:p=30%
9.2.
Sample Size Considerations
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data according to the 
objectives of each part of the study.  
The study will enroll up to approximately 264 subjects with tumor types that may include
NSCLC, SCCHN, RCC, melanoma, STS, bladder cancer, TNBC, and MSI CRC.
Up to 72 subjects will be enrolled in each of the two dose escalation parts of the study 
(Parts 1A and 2A); up to 30 subjects will be enrolled in each of dose expansion cohorts. 
The sample size of each expansion cohort at a given dose level will be minimum of 10
subjects and maximum of 30 subjects based on the overall response assessments.
The trial is not designed to stop early for efficacy but is designed to continuously assess
futility if the predictive probability of success is 10% or less.  The type I error rate, 
power, and predictive probability for assessing futility were determined from stating the 
minimum and maximum sample size, futility stopping rate, and the optimizing criterion 
as minimizing the sample size under null hypothesis.  A weak informative prior 
distribution with a mean response rate equal to the target response rate is assumed. Thus, 
the predictive probability for the response rate will be primarily driven by the data. The 
detailed decision criteria for all cohorts are documented in Section 9.3.2.


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Table 16
Expansion Cohorts Power and Type I Error
Power
Type I error
STS PD-(L)1 naïve population: p0=18% and 
p1=38%
0.802
0.062
Melanoma pretreated PD1/PDL1 population: 
p0=10% and p1=30%
0.831
0.051
For the PD-(L)1 naïve combination expansion cohorts in STS, starting with 10 subjects in 
each cohort and allowing for a maximum sample size of 30 for each cohort, this design 
will have approximately 80.2% power with an overall type I error rate (α) of 6.2%. Under 
null hypotheses with an 18% ORR, the probability of early termination (PET) is 43% 
after data from 10 subjects evaluable for response are available and 77% after data from 
20 evaluable subjects are available. Under the alternative hypothesis, if the true response 
rate is 38%, PET is 6% after data from 10 evaluable subjects are available and 13% after
data from 20 evaluable subjects are available.
For the expansion cohorts in PD-(L)1 pretreated melanoma, starting with 10 subjects in 
each cohort and allowing for a maximum sample size of 30 for each cohort, this design 
will have approximately 83.1% power with an overall type I error rate (α) of 5.1%. Under 
null hypotheses with a 10% ORR, PET is 35% and 80% when data for 10 and 20
evaluable subjects are available. Under the alternative hypothesis, if the true response rate 
is 30%, PET is 3% by 10 subjects evaluated and 13% by 20 subjects evaluated.
9.2.1.
Sample Size Re-estimation or Adjustment
Up to 30 subjects/cohort are expected to be enrolled in each dose-expansion phase of Part 
2.  There is no other sample size re-estimation or adjustment planned. 
9.3.
Data Analysis Considerations
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including biomarker and PK data and the safety profile of prior cohorts.  In addition, the 
recommended dose from a Continuous Reassessment Method (N-CRM) analysis 
[Neuenschwander, 2008] will be calculated.  The N-CRM is a type of Bayesian adaptive 
dose-escalation scheme.  The method is fully adaptive and makes use of all the DLT 
information available at the time of each dose assignment. The Fixed and Adaptive 
Clinical Trial Simulator (FACTS) will be used to conduct the N-CRM analysis. The DLT 
information on all subjects enrolled in the trial are used to update the estimated dose-
toxicity relationship and provide supportive information in addition to the 3+3 design in 
the next escalation/de-escalation decision.
The expansion phases are designed to evaluate preliminary efficacy.  A futility 
assessment will be conducted and enrollment may be paused in order to evaluate 
accumulating data including safety, responses and pharmacodynamic data. The 


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methodology is based on the predictive probability of success if enrollment continues 
until all planned subjects are recruited [Lee, 2008]. 
In addition, a Bayesian hierarchical model may be used to share information across 
cohorts if PK and biomarker data suggest a strong similarity in clinical activity among 
cohorts.
9.3.1.
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK3174998. Safety and anticancer activity will be evaluated based on this analysis 
population.  
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.  
9.3.2.
Interim Analysis
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in Section 4.1.1 and Section 9.3. The Steering Committee will 
guide the transition of the study from dose escalation to cohort expansion for both 
monotherapy and combination therapies
For dose expansion cohorts, continuous assessment of efficacy and safety was planned to
be performed after first interim analysis based upon a minimum of 10 subjects in at least 
one of the disease-specific cohorts with available unconfirmed overall response data for 
at least 12 weeks. However, after implementation of Amendment 4, no further subjects 
were enroled in the study; therefore, no futility analyses were performed.
Planned futility interim analysis decision rules for the 10th to 30th evaluable subjects are 
presented in Table 17 and Table 18, which specify the number of subjects with an 
unconfirmed response required for continuing enrolment when total sample size is up to 
30. Additional futility looks may have been performed, if necessary. These rules were 
intended as a guideline only. If applicable, appropriated data from dose escalation may 
have been integrated into dose expansion decisions.
Actual decisions will depend on the totality of the data. Any additional decision rules will 
be documented in the RAP before the interim analysis. Should the recommendation to 
stop for futility be disregarded in favor of a decision to continue the trial based on the 
totality of the data, the overall type I error rate of the expansion phase will be inflated. 
The Steering Committee will monitor safety and efficacy over the course of the study 
following the randomization and futility rules for expansion cohorts. 


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Table 17
Futility Boundary for PD(L)-1 naive Pembrolizumab Combination 
Therapy Expansion Cohorts in STS.
Number 
of 
subjectsa
Number of Responders
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a.
Shaded regions indicate enrollment pause based on meeting futility


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Table 18
Futility Boundary for PD(L)-1 Experienced Pembrolizumab 
Combination Therapy Expansion Cohorts in Melanoma
Number of 
Subjectsa
Number of Responders
0
1
2
3
4
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a.
Shaded regions indicate enrollment pause based on meeting futility.
9.4.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.  
9.4.1.
Primary Analyses
9.4.1.1.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP.


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9.4.1.2.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy.  
9.4.1.3.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class.  AEs 
will be graded by the investigator according to the NCI-CTCAE (version 4.0).  
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, SAEs and AEs leading to discontinuation of study treatment.  AEs, if listed 
in the NCI-CTCAE (version 4.0) will be summarized by the maximum grade.  Otherwise, 
the AEs will be summarized by maximum intensity.  
Characteristics (e.g., number of occurrences, action taken, grade, etc) of AESI (see 
Section 6.3.1.3 and Appendix 11) will be summarized separately.  
The incidence of deaths and the primary cause of death will be summarized.  
9.4.1.4.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (version 4.0).  Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criteria will be summarized 
using proportions.  Further details will be provided in the RAP.  
9.4.1.5.
Other Safety Measures
Data for vital signs and ECGs will be summarized based on pre-determined criteria 
identified to be of potential clinical concern.  Further details will be provided in the RAP.  
9.4.2.
Secondary Analyses
9.4.2.1.
Anticancer Activity Analyses
The All Treated Population will be used for anticancer activity analyses. Since this is a 
Phase I study, anticancer activity will be evaluated based on clinical evidence and 
response criteria.  If data warrant, the response data will be summarized by dose level. 
irRECIST is the primary measure of clinical activity for response endpoints; RECIST 
v1.1 guidelines are used for disease measurements. 
If the data warrant, ORR, DCR, TTR, and DOR will be calculated and listed for each 
subject. 
ORR is defined as the percentage of subjects with a best overall confirmed CR or PR at 
any time as per disease-specific criteria (refer to Appendix 5). DCR is defined as the 
percentage of subjects with a confirmed CR + PR at any time, plus SD 12 weeks.


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DOR will be calculated and listed for subjects with a confirmed CR or PR and is defined 
as the first documented evidence of CR or PR until disease progression or death due to 
any cause among subjects who achieve an overall response (i.e., unconfirmed or 
confirmed CR or PR). TTR is defined as the interval from the first dose of study 
treatment to the date of the first documented CR or PR.  DOR and TTR are considered as 
exploratory endpoints.  No summary tables for DOR and TTR will be provided.
Further details will be provided in the RAP.  
9.4.2.2.
Pharmacokinetic Analyses
9.4.2.2.1.
Pharmacokinetic Parameters
PK analysis of GSK3174998 and pembrolizumab will be the responsibility of the Clinical 
Pharmacology Modeling and Simulation (CPMS) Department, GSK or Merck Sharp and 
Dohme Corp.
PK analysis of drug concentration-time data will be conducted by non-compartmental 
methods under the direction of CPMS, Quantitative Sciences, GSK.  The following PK 
parameters will be determined if data permit:  

Cmax

time to Cmax (tmax)

Cmin

area under the plasma concentration-time curve, AUC(0-τ) (repeat dosing)

apparent terminal phase half-life (t½) (single dose)

systemic clearance of parent drug (CL)

steady-state volume of distribution (Vss)
9.4.2.2.2.
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK.
Drug concentration-time data will be listed for each subject and summarized by 
descriptive statistics at each time point by cohort. PK parameter data will be listed for 
each subject and summarized by descriptive statistics by cohort. 
The data from this study may be combined with the data from other studies for a 
population PK analysis, which will be reported separately.
9.4.2.3.
Pharmacokinetic/Pharmacodynamic Analyses
Data obtained from the pharmacodynamic samples will be descriptively and/or 
graphically summarized, and if warranted, exploratory PK/Pharmacodynamic analyses 
will be conducted to inform dose selection decisions.


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9.4.2.4.
Immunogenicity Analyses
Serum samples will be tested for the presence of anti-GSK3174998 antibodies using the 
currently approved analytical methodology using a tiered testing schema: screening, 
confirmation and titration steps. The presence of treatment emergent ADA will be 
determined using a GSK3174998 bridging style ADA assay with a bio-analytically 
determined cut-point determined during assay validation. Samples taken after dosing 
with GSK3174998 that have a value at or above the cut-point will be considered 
treatment-emergent ADA-positive. These ADA positive samples will be further 
evaluated in a confirmatory assay, and confirmed positive samples will be further 
characterized by assessment of titer. Results of anti-GSK3174998 antibody testing will 
be reported at the end of the study and will include incidence and titer. The presence or 
absence of antibodies to GSK3174998 in dosed subjects will be analyzed, then 
summarized descriptively and/or graphically presented.
9.4.3.
Other Analyses
9.4.3.1.
Translational Research Analyses
The results of translational research investigations may be reported in the main clinical 
study report (CSR) or in a separate report from the CSR. All endpoints of interest from 
all comparisons will be descriptively and/or graphically summarized as appropriate to the 
data.
Further details on the translational research analyses will be addressed in the RAP.  
9.4.3.2.
Novel Biomarker(s) Analyses
The results of these biomarker investigations may be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.  
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.
9.4.3.3.
Longitudinal tumor size modeling
Longitudinal tumor size data may be analyzed using a non-linear mixed effects model to 
determine tumor kinetic constants. These parameters may be related to other patient 
characteristics, such as dose group, GSK3174998 exposure, or biomarkers.
9.4.3.4.
Pharmacogenetic Analyses
Further details on PGx analyses will be addressed in Appendix 7 and the PGx RAP.  


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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.  
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.  

Obtaining signed informed consent.  

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).  

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.  

Signed informed consent must be obtained for each subject prior to participation 
in the study.  

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.  

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK designated monitors will contact the site prior to the start of the study to 


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review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement, and documentation of data items for which the eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.  
10.3.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. 
In the event of an assessment, audit, or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues, and to implement any corrective and/or 
preventative actions to address any findings/issues identified.  
10.4.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK designated monitor 
will conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP and GSK Standard Operating 
Procedures.  
GSK reserves the right to temporarily suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance. For multicenter studies, this can occur at one or more or at all sites.  
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action.  
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 


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regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.  
10.5.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including regenerating 
a hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions.  
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, GSK standards/procedures, and/or institutional 
requirements.  
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator is no longer associated with the site.  
10.6.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables and relevant reports and will have the opportunity to 
review the complete study results at a GSK site or other mutually-agreeable location.  
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.  
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.  


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11.
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACT
Adoptive cell transfer
ADA
Antidrug antibody
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event(s)
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC(0-t)
Area under the plasma concentration-time curve from time 0 
to the time of the last quantifiable concentration)
AUC(0-)
Area under the concentration-time curve over the dosing 
interval
BAL
Bronchoalveolar lavage
-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CL
Systemic clearance of parent drug
CrCl
Calculated creatinine clearance
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modeling and Simulation
CR
Complete response
CRM
Continual reassessment method
CRP
C-reactive protein
CRS
Cytokine release syndrome
CSR
Clinical Study Report
CT
Computed tomography
CTC
Circulating Tumor Cell
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CV
Cardiovascular
DCR
Disease Control Rate
DFS
Disease-free survival
DFSFU
Disease-free survival follow-up
DILI
Drug-induced liver injury
dL
Deciliter
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid


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DOR
Duration of Response
DRE
Disease-related event
ECG
Electrocardiogram(s)
ECOG
Eastern Cooperative Oncology Group
EOI
End of infusion
EOPI
End of pembrolizumab infusion
eCRF
Electronic case report form
FACTS
Fixed and Adaptive Clinical Trial Simulator
FcR
Antibody receptor crystalizable fragments gamma
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron-emission tomography
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
FTIH
First time in human
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GITR
Glucocorticoid-induced TNFR family related gene
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GSK
GlaxoSmithKline
HED
Human equivalent dose
HNSTD
Highest non-severely toxic dose
HPLC
High-performance liquid chromatography
h
Hour(s)
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL-10
Interleukin 10
INR
International normalized ratio
IP
Intraperitoneal
irAE
Immune-related adverse event(s)
IRB
Institutional Review Board(s)
irRECIST
Immune-related RECIST
ITIM
Immunoreceptor tyrosine-based inhibition motif
ITSM
Immunoreceptor tyrosine-based switch motif
IV
Intravenous
Kd
Equilibrium dissociation constant
kg
Kilogram(s)
L
Liter
LDH
Lactate dehydrogenase
LFT
Liver function Tests


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mg
Microgram
mAb
Monoclonal antibody
MABEL
Minimum anticipated biological effect level
MAD
Maximum administered dose
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
min
Minute(s)
mL
Milliliter(s)
mmHg
Millimeters of mercury
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
MSI CRC
Colorectal carcinoma displaying high microsatellite 
instability
MTD
Maximum tolerated dose
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria 
for Adverse Events
NK
Natural killer
NOAEL
No observed adverse effect level
NSCLC
Non-small cell lung cancer
nTregs
Natural Tregs
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PD-1
Programmed death receptor-1
PD
Progressive disease
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
PGx
Pharmacogenetics
PI
Principal investigator
PK
Pharmacokinetic(s)
PR
Partial response
PS
Performance status
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QTc
Corrected QT interval duration
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RANKL
Receptor activator of nuclear factor-kappaB ligand
RBC
Red blood cells
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid


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RP2D
Recommended Phase 2 dose
SAE
Serious adverse event(s)
SCCHN
Squamous cell carcinoma of the head and neck
sCRS
Severe cytokine release syndrome
SD
Stable disease
SFU
Survival follow-up
SLD
Sum of the longest diameters
SRM
Study Reference Manual
STS
Soft Tissue Sarcoma
TCR
T-cell receptor
TDV
Treatment discontinuation visit
TILs
Tumor infiltrating lymphocytes
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor
TNFR
Tumor necrosis factor receptor
Tregs
Regulatory T cells
Tr1
Type 1 regulatory
TSH
Thyroid stimulating hormone
TTR
Time to Response
ULN
Upper limit of normal
WBC
White blood cells
WNL
Within normal limits
Trademark Information
Trademarks of the GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Keytruda
Opdivo
Yervoy


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12.2.
Appendix 2: Immune-related Diseases
Table 19
List of Potential Immune-mediated Diseases
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, 
including 
paralyses/paresis (e.g. 
Bell’s palsy)

Optic neuritis

Multiple sclerosis

Transverse myelitis

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants

Acute disseminated 
encephalomyelitis, 
including site specific 
variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis

Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome 

Immune-mediated 
peripheral neuropathies 
and plexopathies, 
(including chronic 
inflammatory 
demyelinating 
polyneuropathy, multifocal 
motor neuropathy and 
polyneuropathies 
associated with 
monoclonal gammopathy).

Narcolepsy

Systemic lupus 
erythematosus and 
associated conditions

Systemic Scleroderma
(Systemic sclerosis),
including diffuse systemic 
form and CREST 
syndrome

Idiopathic inflammatory 
myopathies, including
Dermatomyositis, 
Polymyositis,

Antisynthetase syndrome

Rheumatoid arthritis and 
associated conditions
including Juvenile chronic 
arthritis and Still’s 
disease)

Polymyalgia rheumatica

Spondyloarthritis, 
including ankylosing 
spondylitis, reactive 
arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis)

Alopecia areata

Lichen planus

Sweet’s syndrome

Localized Scleroderma
(Morphoea)
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing 
cholangitis

Autoimmune cholangitis.

Inflammatory Bowel 
disease, including
Crohn’s disease, 
ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)

Grave's or Basedow’s disease

Diabetes mellitus type I

Addison’s disease

Polyglandular autoimmune 
syndrome

Autoimmune hypophysitis


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Vasculitides
Blood disorders
Others

Large vessels vasculitis 
including: giant cell 
arteritis such as 
Takayasu's arteritis and
temporal arteritis. 

Medium sized and/or small 
vessels vasculitis 
including: polyarteritis 
nodosa, Kawasaki's 
disease, microscopic 
polyangiitis, Wegener's 
granulomatosis, Churg–
Strauss syndrome (allergic 
granulomatous angiitis), 
Buerger’s disease 
(thromboangiitis 
obliterans), necrotizing 
vasculitis and anti-
neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type 
unspecified), Henoch-
Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune hemolytic 
anemia

Autoimmune 
thrombocytopenia

Antiphospholipid 
syndrome

Pernicious anemia

Autoimmune aplastic 
anemia

Autoimmune neutropenia 

Autoimmune 
pancytopenia

Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)

Ocular autoimmune diseases 
(including autoimmune uveitis 
and autoimmune retinopathy)

Autoimmune 
myocarditis/cardiomyopathy

Sarcoidosis

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome

Raynaud’s phenomenon


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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow-up assessments.  
Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane re-administered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR 1.5

SAE or fatality has earlier been observed with drug rechallenges [Papay, 2009; 
Hunt, 2010]

evidence of drug-related nonclinical liability (e.g. reactive metabolites;  
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug-induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favorable.  
Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available.  


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
Ethics Committee or IRB approval for rechallenge with study treatment must be 
obtained, as required.  

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the Ethics Committee or IRB as required, must be 
informed of the subject’s outcome following study treatment rechallenge. 

GSK to be notified of any AEs, as per Section 7.4.1.
AND/OR
Restart Following Transient Resolving Liver Stopping Events NOT Related 
to Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has a 
human leukocyte antigen (HLA) genetic marker associated with liver injury (e.g., 
lapatinib, abacavir, amoxicillin/clavulanate) are reviewed and excluded.  

Ethics Committee or IRB approval of study treatment restart must be obtained, as 
required.


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
If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or IRB as required, must be 
informed of the subject’s outcome following study treatment restart. 

GSK to be notified of any AEs, as per Section 7.4.1.


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12.4.
Appendix 4: NYHA Functional Classification System for 
Heart Failure
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994] 
provides a simple way of classifying the extent of heart failure. It places subjects in one 
of four categories based on the level of limitation experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is increased.


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12.5.
Appendix 5: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 
version 1.1
12.5.1.
Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion.  Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.

All measurements should be taken and recorded in millimeters (mm), using a ruler 
or calipers.

Ultrasound is not a suitable modality of disease assessment.  If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments 
of disease.  However FDG-PET can be useful in confirming new sites of disease 
where a positive FDG-PET scans correlates with the new site of disease present 
on CT/MRI or when a baseline FDG-PET was previously negative for the site of 
the new lesion. FDG-PET may also be used in lieu of a standard bone scan 
providing coverage allows interrogation of all likely sites of bone disease and 
FDG-PET is performed at all assessments.

If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast.  The method of 
assessment should be noted as CT on the eCRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required.
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations.  Whenever possible, the same 
scanner should be used.
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray.


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Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.  
12.5.2.
Guidelines for Evaluation of Disease
12.5.2.1.
Measurable and Non-measurable Definitions
12.5.2.1.1. Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm.  
If the slice thickness is greater than 5 mm, the minimum size of a measurable 
lesion must be at least double the slice thickness (e.g., if the slice thickness is 
10 mm, a measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest X-ray.

Additionally lymph nodes can be considered pathologically enlarged and 
measurable if
15 mm in the short axis when assessed by CT or MRI (slice thickness recommended to 
be no more than 5 mm).  At baseline and follow-up, only the short axis will be measured.
12.5.2.1.2. Non-measurable lesion: 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques 
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. Note: non-
measurable only disease is not allowed per protocol.  


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12.5.2.2.
Immune-Related RECIST Response Criteria
12.5.2.2.1. Evaluation of target lesions
New, measurablea lesions Incorporated into tumor burden
New, nonmeasurable 
lesions 
Do not define progression (but preclude irCR)
irCR
Disappearance of all lesions in two consecutive observations not less 
than 4 weeks apart.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.
irPR
30% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart
irSD
30% decrease in tumor burden compared with baseline cannot be 
established nor 20% increase compared with nadir
irPDb
At least 20% increase in tumor burden compared with nadir (at any 
single time point) in two consecutive observations at least 4 weeks 
apart.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
a.
Measureable according to RECIST v1.1.  
b.
Treatment decisions will be based upon the immune-related RECIST criteria.  
12.5.2.2.2. Antitumor response based on total measurable tumor burden
For the Modified RECIST criteria based on RECIST v1.1 and Immune-Related RECIST
Criteria [Wolchok, 2009], the initial index and measurable new lesions are taken into 
account. At the baseline tumor assessment, the sum of the longest diameters (SLD) in the 
plane of measurement of all index lesions (maximum of five lesions total (and a 
maximum of two lesions per organ) representative of all involved) is calculated. Note: If 
lymph nodes are included in the SLD, only the short axis of the lymph node(s) is added 
into the sum. The short axis is the longest perpendicular diameter to the longest diameter 
of a lymph node or nodal mass. At each subsequent tumor assessment, the SLD of the 
baseline index lesions and of new, measurable lesions (10 mm; up to 5 new lesions per 
organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the 
total tumor burden:
Tumor Burden = SLDindex lesions + SLDnew, measurable lesions
12.5.2.2.3. Time-point response assessment using the Immune-Related RECIST 
criteria
Percentage changes in tumor burden per assessment time point describe the size and 
growth kinetics of both conventional and new, measurable lesions as they appear. At each 
tumor assessment, the response in index and new, measurable lesions is defined based on 
the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be 


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assessed relative to baseline measurements (i.e., the SLD of all index lesions at 
screening).  
12.5.2.2.4. Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response (CR): The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. 
<10 mm short axis).

Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline 10 mm short axis.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 

Not Applicable (NA): No non-target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.

Sites of non-target lesions, which are not assessed at a particular time point based 
on the assessment schedule, should be excluded from the response determination 
(e.g. non-target response does not have to be "Not Evaluable").  
12.5.2.2.5. New lesions
New malignancies denoting disease progression must be unequivocal.  Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions.
Any equivocal new lesions should continue to be followed.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.  
12.5.3.
Evaluation of overall response
Table 20 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.


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Table 20
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = Complete response, PR = Partial response, SD = Stable disease, PD = Progressive disease, NA = Not 
applicable, and NE = Not Evaluable
12.5.3.1.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after the first dose at a minimum interval of 77 days.  

If the minimum time for SD is not met, best response will depend on the 
subsequent assessments.  For example if an assessment of PD follows the 
assessment of SD and SD does not meet the minimum time requirement the best 
response will be PD.  Alternatively, subjects lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered not 
evaluable.  
12.5.3.2.
Confirmation Criteria:
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.  


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12.6.
Appendix 6: ECOG Performance Statusa
Grade
Descriptions
a.
Oken, 1982.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.7.
Appendix 7: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including GSK3174998 or pembrolizumab  or any 
concomitant medicines;

NSCLC, SCCHN, RCC, melanoma, bladder, STS, TNBC or MSI CRC, 
susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
12.7.1.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
12.7.2.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 mL blood sample will be taken for deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has met all 
eligibility requirements and provided informed consent for genetic research. 
Instructions for collection and shipping of the genetic sample are described in the 
laboratory manual. The DNA from the blood sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is 
taken on a single occasion unless a duplicate sample is required due to an inability 
to utilize the original sample.  


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The genetic sample is labeled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or the study closure/termination.  GSK or those working with GSK 
(for example, other researchers) will only use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form.  Samples may be used 
as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
12.7.3.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood sample for genetic 
research being taken.
12.7.4.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
12.7.5.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 


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instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
12.7.6.
Provision of Study Results and Confidentiality of Subject’s 
Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.  


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12.8.
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.8.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including 
those that worsen from baseline, and felt to be clinically significant in the medical and 
scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even though it may 
have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment 
or a concomitant medication (overdose per se will not be reported as an AE/SAE unless this is 
an intentional overdose taken with possible suicidal/self-harming intent.  This should be 
reported regardless of sequelae). See Section 6.8.2 for details on an overdose with 
pembrolizumab

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE.  However, the signs and symptoms and/or clinical sequelae resulting from lack 
of efficacy will be reported if they fulfill the definition of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition.


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Events NOT meeting definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
12.8.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
a.
Results in death
b. Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at 
risk of death at the time of the event.  It does not refer to an event, which hypothetically might have 
caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or out-patient setting.  
Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.

This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 


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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition.  These should also be considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse
g. Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, measure 
urinary bilirubin via dipstick.  If fractionation is unavailable and ALT  3xULN and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to subjects 
receiving anticoagulants.  If INR measurement is obtained, the value is to be recorded on the SAE 
form.

Refer to Section 6.3.1.3 for the required liver chemistry follow-up instructions
12.8.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the following 
AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack


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Cardiovascular Events (CV) Definition:

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.8.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory, and diagnostics reports) relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the eCRF

It is not acceptable for the investigator to send photocopies of the subject’s medical records to 
GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are requested by 
GSK.  In this instance, all subject identifiers, with the exception of the subject number, will be 
blinded on the copies of the medical records prior to submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  In such cases, the diagnosis will be documented as the 
AE/SAE and not the individual signs/symptoms.
12.8.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and will grade it according to the NCI-CTCAE v4.0.:


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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or arguments to 
suggest a causal relationship, rather than a relationship cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant therapy, 
other risk factors, and the temporal relationship of the event to the study treatment will be 
considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product Information, for 
marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that the 
investigator always make an assessment of causality for every event prior to the initial 
transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to elucidate 
as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up period, the 
investigator may be asked to provide GSK with a copy of any post-mortem findings, including 
histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated reporting 
time frames.


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12.8.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection tool

If the electronic system is unavailable for greater than 24 hours, the site will use the paper 
SAE data collection tool and  email to 
 or fax to 
 
.Site will enter the SAE data into the electronic system as soon as it becomes available.

The investigator will be required to confirm review of the SAE causality by ticking the 
‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., InForm 
system) will be taken off-line to prevent the entry of new data or changes to existing data

If a site receives a report of a new SAE from a study subject or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, the 
site can report this information to the Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
PPD
PPD
PPD


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12.9.
Appendix 9: Collection of Pregnancy Information
12.9.1.
Action to be taken if pregnancy occurs

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to GSK.
While the investigator is not obligated to actively seek this information in former 
study participants, he or she may learn of an SAE through spontaneous reporting.  
12.9.2.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
Any female subject who becomes pregnant while participating

Will discontinue study medication or be withdrawn from the study.


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12.10.
Appendix 10: Country Specific Requirements
No country-specific requirements exist.


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12.11.
Appendix 11: Adverse Events of Special Interest
The list of terms and reporting requirements for GSK AESI are provided below.  These 
are selected non-serious AEs and SAEs that must be reported to GSK regardless of 
relationship to study treatment.  Any event that meets the criteria described below must 
be reported regardless of investigator-determined relationship to study treatment or if 
considered immune-related (unless otherwise specified).   Investigators/study 
coordinators/designated site personnel are required to record these experiences in the 
eCRF (as described in the eCRF completion guidance document) and to provide 
supplemental information (such as medical history, concomitant medications, 
investigations, etc.) about the event. Please note this table lists known AESI, additional 
events may be identified during the course of the study.
Pneumonitis (reported as AESI if  ≥ Grade 2)
Acute interstitial pneumonitis
Interstitial lung disease
Pneumonitis
Colitis (reported as AESI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE)
Intestinal Obstruction
Colitis
Colitis microscopic
Enterocolitis
Enterocolitis hemorrhagic
Gastrointestinal perforation
Necrotizing colitis
Diarrhea
Endocrine (reported as AESI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE)
Adrenal Insufficiency
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Thyroid disorder
Thyroiditis
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA)
Endocrine (reported as AESI)
Type 1 diabetes mellitus (if new 
onset)
Hematologic (reported as AESI if  ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE)
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic 
Purpura (TTP)
Idiopathic (or immune) 
Thrombocytopenia Purpura  (ITP)
Disseminated Intravascular 
Coagulation (DIC)
Hemolytic Uremic Syndrome 
(HUS)
Any Grade 4 anemia regardless of underlying mechanism
Hepatic (reported as AESI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic 
steroids to treat the AE)
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT 
and/or AST)
Infusion Reactions (reported as AESI for any grade)
Allergic reaction
Anaphylaxis
Cytokine release syndrome
Serum sickness
Infusion reactions
Infusion-like reactions


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Neurologic (reported as AESI for any grade)
Autoimmune neuropathy
Guillain-Barré syndrome
Demyelinating polyneuropathy
Myasthenic syndrome
Ocular (report as AESI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE)
Uveitis
Iritis
Renal (reported as AESI if  ≥ Grade 2)
Nephritis
Nephritis autoimmune
Renal Failure
Renal failure acute
Creatinine elevations (report as AESI if ≥Grade 3 or any grade 
resulting in dose modification or use of systemic steroids to treat 
the AE)
Skin (reported as AESI for any grade)
Dermatitis exfoliative
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Skin (reported as AESI if ≥ Grade 3)
Pruritus
Rash
Rash generalized
Rash maculo-papular
Any rash considered clinically significant in the physician’s judgment 
Other (reported as AESI for any grade)
Myocarditis
Pancreatitis
Pericarditis
Any other Grade 3 event which is considered immune-related by the physician
Pembrolizumab-specific events of clinical interest for this trial include:

An overdose of pembrolizumab, as defined in Section 6.8.2 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is 
not associated with clinical symptoms or abnormal laboratory results. 

An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 


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12.12.
Appendix 12:  CKD-EPI Formula
CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 
defined by eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula 
[Levey, 2009].
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black]
where:
Scr is serum creatinine in mg/dL,
κ is 0.7 for females and 0.9 for males,
α is -0.329 for females and -0.411 for males,
min indicates the minimum of Scr /κ or 1, and
max indicates the maximum of Scr /κ or 1.


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12.13.
Appendix 13: Protocol Amendment Changes
12.13.1.
Amendment 1
12.13.1.1.
Where the Amendment Applies
This amendment applies to all sites and countries.
12.13.1.2.
Summary of Amendment Changes with Rationale
Amendment 1 incorporates changes to Section 4.1.4, Dose-Limiting Toxicities; 5.4 
Withdrawal/Stopping Criteria; and 6.3.1.12, Dose Delay as requested by the United 
States FDA.
Additionally, the SAE contact information was updated due to internal departmental 
changes.
12.13.1.3.
List of Specific Changes
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
REVISED TEXT:
Medical Monitor/Serious Adverse Event (SAE) Contact Information: 
Role
Name
Office Phone
Email Address
Mobile
Fax 
Primary 
Medical 
Monitor 
, MD
Secondary 
Medical 
Monitor
, MD, 
PhD
SAE 
contact 
information 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section 4.1.4 Dose-Limiting Toxicity
REVISED TEXT:
Table 4
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Febrile neutropenia 

Grade 4 neutropenia of >7 days’ duration or requiring G-CSF

Grade 4 anemia of any duration

Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding
Non-
hematologic

Grade 4 toxicity

Grade 3 toxicity that does not downgrade to Grade 1 Grade 2 or baseline within 3 
days despite optimal supportive carea, with the following exceptions:

Laboratory abnormality that is not clinically significant according to the investigators 
(for example, isolated Grade 3 elevation of amylase or lipase not associated with 
clinical or radiographic evidence of pancreatitis)

Grade 3 endocrinopathy that is adequately controlled by hormonal replacement

Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 ocular 
toxicity
Other

Toxicity that results in permanent discontinuation of GSK3174998 or GSK3174998 
and pembrolizumab during the first 4 weeks of treatment

Any other toxicity considered to be dose-limiting that occurs beyond 4 weeks will be 
considered in the selection of the dose for expansion cohorts

Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT
a.
Suggested management guidelines described in Section 6.3.1 for toxicity and may include systemic 
corticosteroids for immune-related toxicities; if use of systemic corticosteroids delays administration of 
the second dose of study treatment but the event does not otherwise meet the DLT criteria for non-
hematologic toxicity, the dose delay will not be considered a DLT. 
b.
DLT = Dose-limiting toxicity; G-CSF = Granulocyte colony-stimulating factor; AST = Aspartate 
aminotransferase; ALT = Alanine aminotransferase; ULN = Upper limit of normal; GSK = 
GlaxoSmithKline
Section 5.4 Withdrawal/Stopping Criteria
REVISED TEXT:
Subjects will receive study treatment for the scheduled time period, unless one of the 
following occurs earlier: disease progression (as determined by irRECIST), death, or
unacceptable toxicity, including meeting stopping criteria for liver chemistry defined in 
Section 5.4.1.  In addition, study treatment might be permanently discontinued for any of 
the following reasons:

Deviation(s) from the protocol

Request of the subject or proxy (withdrawal of consent by subject or proxy)

Investigator’s discretion


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
Subject is lost to follow-up 

Study is closed or terminated

Subjects with infusion delays greater than 3 weeks due to toxicity >49 days (i.e., 
2 missed doses + 7 days) should discontinue study drug(s) unless the treating 
investigator and Sponsor/Medical Monitor agree there is strong evidence 
supporting continued treatment. 
Note: Subjects who require permanent discontinuation of one of the study 
treatments due to toxicity in a given treatment combination must permanently 
discontinue both treatments (unless continued treatment with the remaining 
agent is agreed upon by the treating investigator and Sponsor/Medical Monitor)
in that combination and the reason for discontinuation must be recorded. The 
treatment discontinuation visit (TDV) should be conducted within 30 days of 
the decision to discontinue study drug(s).

Intercurrent illness that prevents further administration of study treatment(s)

Criteria for discontinuation of study drug(s) as described in Section 6.3.1 (Safety 
Management Guidelines) have been met

Criteria described in Section 5.4.2 (QTcF Stopping Criteria) have been met

Criteria described in Section 5.4.3 (Stopping Rules for Clinical Deterioration)
have been met
Section 6.3.1.12 Dose Delay
REVISED TEXT:
If there is a dose delay between 1 and 7 days, the procedures at the original scheduled 
visit (including dosing) should be performed as soon as possible.  If the delay is 8 days, 
the visit and dose(s) will be considered missed.  The procedures at the next scheduled 
visit should be performed, and subsequent visits will follow Q3W.  Subjects with 
infusion delays greater than 3 weeks due to toxicity >49 days (i.e., 2 missed doses + 7 
days) should discontinue study drug(s) unless the treating investigator and 
Sponsor/Medical Monitor agree there is strong evidence supporting continued treatment.  
For subjects requiring elective surgery or radiation therapy, every effort should be made 
to wait 1 to 2 weeks after the last dose of study drug(s) before performing surgery or 
starting radiation.  Study drug(s) should not be administered again until 1 to 2 weeks after 
recovery from surgery or radiation (see Section 6.10.1. for details on permitted 
medications and non-drug therapies).


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12.13.2.
Amendment 2 Protocol Changes for Amendment 2 (16-AUG-
2016) from the Protocol Amendment 1 (17-AUG-2015)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 2 includes the addition of preliminary clinical data to support the initiation 
of Part 2/combination with pembrolizumab, the addition of a new Pharmacodynamic 
Cohort to allow collection of additional tumor biopsies, removal of Soft Tissue Sarcoma 
from the targeted tumor types, extension of GSK3174998 dosing up to 2 years or 35 
cycles, definitions of analyses for anticancer activity, addition and clarifications of 
procedures in the T&E table, clarification on the use of CRM for dose escalation, as well 
as minor typographical and/or inconsistent language throughout the protocol.
List of Specific Changes
Section 1 PROTOCOL SYNOPSIS FOR STUDY 201212 (ENGAGE-1)
REVISED TEXT:
Objectives/Endpoints:
The primary objectives of the study are to evaluate the safety and tolerability and to 
identify the maximum tolerated dose (MTD) or maximum administered dose (MAD) of 
GSK3174998 when administered intravenously as monotherapy (Part 1) or in 
combination with pembrolizumab (Part 2) to subjects with selected advanced or recurrent 
solid tumors.  Secondary objectives include: the evaluation of antitumor activity;
characterization of pharmacokinetics (PK) for GSK3174998 when administered alone; 
characterization of PK for GSK3174998 and pembrolizumab when administered in 
combination;
evaluation of pharmacodynamic activity in the blood and tumor 
microenvironment;  and determination of the immunogenicity of GSK3174998 when 
administered alone or for GSK3174998 and pembrolizumab when administered in 
combination. Exploratory objectives include evaluation of pharmacodynamic activity in 
the blood and tumor microenvironment.
2 nd point:
Antitumor activity endpoints: Objective response rate (ORR) and Disease Control Rate 
(DCR) (complete response [CR]+partial response [PR]+stable disease [SD] ≥12 weeks), 
time to response (TTR), duration of response (DOR), progression-free survival (PFS), 
and overall survival (OS).  Unless otherwise specified, all response endpoints will be 
assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and by
irRECIST (immune-related RECIST); the primary endpoint analysis will use irRECIST.


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3rd point:
Pharmacodynamic endpoints: Assessment of lymphocyte OX40 receptor membrane 
expression and occupancy by GSK3174998, along with the phenotype, quantity, and 
activation state of T cells in the periphery, expression of circulating soluble factors, and 
changes in genomic DNA and gene expression. Assessment of tumor biopsies via 
immunohistochemistry (IHC) for the numbers of tumor-infiltrating lymphocytes and 
other immune cells expressing key phenotypic markers.
Treatment Arms and Duration:
The study includes a screening period, a treatment period, and a follow-up period.  
Subjects will be screened for eligibility beginning approximately 4 weeks before the start 
of treatment. The maximum duration of treatment with GSK3174998 will be 48 weeks; 
the maximum duration of treatment with pembrolizumab will be 2 years or 35 cycles, 
whichever comes first. The follow-up period for safety assessments will be a minimum of 
3 months from the date of the last dose. The post-treatment follow-up period includes 
disease assessments every 12 weeks until confirmed disease progression (PD). Following 
PD, subjects will be contacted every 3 months to assess survival status.
In Part 1, dose escalation for GSK3174998 monotherapy will begin with a starting dose 
of 0.003 mg/kg GSK3174998 administered once every 3 weeks (Q3W).  In Part 2, dose 
escalation for GSK3174998 + pembrolizumab combination therapy will begin with a 
fixed dose of 200 mg pembrolizumab administered Q3W and a starting dose of 
0.003 mg/kg GSK3174998 that is two dose levels below a tolerated dose of GSK3174998 
monotherapy that has also demonstrated pharmacodynamic activity in Part 1A of the 
study. Dose adjustments are allowed to address tolerability and safety issues.
Type and Number of Subjects:
The study will enroll up to approximately 264 180 subjects with tumor types that may 
include NSCLC, squamous cell carcinoma of the head and neck (SCCHN), renal cell 
carcinoma (RCC), melanoma, bladder cancer, soft tissue sarcoma (STS), triple-negative 
breast cancer (TNBC), and colorectal carcinoma displaying microsatellite instability 
(MSI CRC).
Section 2.3.1 Background
REVISED TEXT:
An overview of the nonclinical studies of GSK3174998 and preliminary clinical data 
from Protocol 201212 (ENGAGE-1) are is provided below.  Detailed information 
concerning the biology, pharmacology, PK, and safety can be found in the Investigators’ 
Brochure (IB) [GlaxoSmithKline Document Number 2014N212091_00.


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ADDED SECTIONS:
Section 2.3.5 Preliminary Clinical Data for GSK3174998
Data are summarized for the ongoing first time in human study with a clinical data cut-
off of 17 May 2016. Data are reported for six subjects enrolled at the following 
GSK3174998 dose levels: 0.003 mg/kg (Cohort 1, n=1), 0.01 mg/kg (Cohort 2, n=1), and 
0.03 mg/kg (Cohort 3, n=4).  At the time of reporting, three subjects had discontinued 
treatment due to disease progression (one at each dose level).
Section 2.3.5.1 Preliminary Safety Data (ENGAGE-1: Part 1)
No dose-limiting toxicities, no treatment-related Grade 3 or 4 toxicities, and no treatment 
discontinuations due to AEs were reported.  One SAE was reported (Grade 3 urinary tract 
infection and Grade 4 hydronephrosis) in a subject with bladder cancer treated at the 
0.003 mg/kg dose level; the SAE was attributed to disease progression.  The subject 
discontinued study treatment due to disease progression and at that time had received 2 
doses of GSK3174998.  All other AEs were Grade 1 or 2 in severity. One AE (fatigue) 
was reported in two subjects; all other events were reported once each: Actinic keratosis, 
anemia, arthralgia, asthenia, blood creatinine increased, cough, diarrhea, dizziness, dry 
mouth, fall, headache, hernia, hyperkalemia, hypoesthesia, myalgia, nausea, pain in 
extremity, vomiting.  Two events (Grade 1 dry mouth, Grade 1 nausea) were considered 
treatment-related.
For further details on the safety of GSK3174998, please refer to the IB [GlaxoSmithKline 
Document Number GlaxoSmithKline Document Number 2014N212091.
Section 2.3.5.2 Preliminary Pharmacokinetic Data (ENGAGE-1: Part 1)
Maximum observed concentrations (Cmax) of GSK3174998 in plasma were in the 
predicted range anticipated for each dose level (44 ng/mL for 0.003 mg/kg, 267 ng/mL 
for 0.01 mg/kg, 458 – 1624 ng/mL for 0.03 mg/kg). Clearance was greater than 
anticipated at the lower dose levels; this was considered to be due to target mediated 
clearance.  Subject 4, dosed at 0.03 mg/kg was the heaviest subject treated (119 kg), thus 
received the largest dose and had the highest GSK3174998 exposure (1624 ng/mL).
Section 2.3.5.3 Preliminary Receptor Occupancy Data (ENGAGE-1: Part 1)
Receptor occupancy (RO) was assessed for CD3+ cells from peripheral blood.  
Preliminary receptor occupancy (RO) data after the first dose was higher than predicted; 
approximately 85% RO was seen in Subject 1 who received the lowest dose of 
GSK3174998 (0.003 mg/kg). Subject 4, who had the largest GSK3174998 exposure, had 
>90% RO throughout the first dosing period (21 days); while Subjects 6, 7, and 502, 
treated with the same dose level (0.03 mg/kg) had >90% RO for approximately 8 days 
during the first dosing period.


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Section 2.3.5.4 Preliminary Clinical Activity Data (ENGAGE-1: Part 1)
Due to the frequency of disease assessments (every 12 weeks), few subjects had their first 
post-baseline disease assessments performed at the time of clinical data cut-off (17 May 
2016) and no objective responses were observed. Subject 1 (0.003 mg/kg), 3 (0.01 
mg/kg) and 4 (0.03 mg/kg) discontinued treatment due to disease progression after 2, 4, 
and 3 doses of GSK3174998, respectively.
Section 2.4 Pembrolizumab  
DELETED SECTION:
Section 2.4.1 PD-1 as a Therapeutic Target:
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control [Pedoeem, 2014].  The normal function of PD-1, expressed on the cell 
surface of activated T cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the 
gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4, which has been 
shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2).  The structures of murine PD-1 alone [Zhang, 2004] and in 
complex with its ligands were first resolved [Lazar Molnar, 2008;Lin, 2008], and more 
recently the NMR-based structure of the human PD-1 extracellular region and analyses of 
its interactions with its ligands were also reported [Cheng, 2013].  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-
1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules, such as CD3ζ, 
PKCθ and ZAP70, which are involved in the CD3 T-cell signaling cascade [Sheppard,
2004].  The mechanism by which PD-1 down-modulates T-cell responses is similar to, 
but distinct from that of CTLA-4 [Ott, 2013].  PD-1 was shown to be expressed on 
activated lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, Tregs and 
NK cells [Yao, 2014]. Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T cells [Nishimura, 1996], as well as subsets of 
macrophages [Huang, 2009] and dendritic cells [Pea Cruz, 2010]. The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types [Keir, 2008].  PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments [Keir, 2008].  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and short cytoplasmic regions 
with no known signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor. PD-L2 is thought to control immune T-
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell 


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function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor 
[Karim, 2009, Taube, 2012], which, via its interaction with the PD-1 receptor on tumor-
specific T cells, plays a critical role in immune evasion by tumors [Sanmamed, 2014].  
As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in cancer [Topalian, 2012].
REVISED TEXT:
2.4.2 2.4.1 Pembrolizumab Background and Clinical Trials:
Pembrolizumab [KEYTRUDA (US); previously known as lambrolizumab, MK-3475 and 
SCH 9000475] is a potent and highly selective humanized mAb of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 
and PD-L2.  Pembrolizumab was recently approved in the US and is indicated for the 
treatment of subjects with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor 
[KEYTRUDA Prescribing Information, 2014,Poole, 2014].  It is the first anti-PD-1 
therapy to receive regulatory approval in the US, and is currently under regulatory review 
in the EU.
Pembrolizumab, a humanized monoclonal antibody against the PD-1 protein, has been 
developed by Merck & Co for the treatment of patients with cancer. Pembrolizumab is 
approved for treatment of patients with melanoma in several countries; in the US and EU 
it is approved for the treatment of patients with advanced (unresectable or metastatic) 
melanoma in adults. Pembrolizumab has also been approved for treatment of patients 
with NSCLC in several countries; in the US it is indicated for the treatment of patients 
with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-
approved test and who have disease progression on or after platinum-containing 
chemotherapy. Patients with NSCLC and EGFR or ALK genomic tumor aberrations 
should also have disease progression on FDA-approved therapy for these aberrations 
prior to receiving pembrolizumab. In the US, pembrolizumab is also approved for the 
treatment of patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck with disease progression on or after platinum-containing chemotherapy.
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy 
trials in subjects with non-small cell lung cancer, head and neck squamous cell 
carcinoma, urothelial cancer, gastric cancer, triple negative breast cancer and Hodgkin’s 
Lymphoma as determined by response rate. Ongoing clinical trials are being conducted in 
advanced melanoma, NSCLC, head and neck cancer, urothelial cancer, gastric cancer, 
TNBC, Hodgkin’s lymphoma and a number of other advanced solid tumor indications 
and hematologic malignancies.  For study details please refer to the IB [Merck Sharp & 
Dohme Corp, 2015]


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2.4.2 Rationale for Pembrolizumab Dose Selection
DELETED TEXT:
An open-label Phase I trial (KEYNOTE-001) is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab.  The dose escalation portion of this 
trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
pembrolizumab showed evidence of target engagement and objective evidence of tumor 
size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has 
been identified.
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life [Merck Sharp & Dohme 
Corp, 2014]. Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q3W dosing schedule. Because Q3W dosing is more 
convenient for subjects, Q3W dosing will be furthered studied.
ADDED TEXT:
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose 
recently approved in the United States and several other countries for treatment of 
melanoma subjects is 2 mg/kg Q3W. Information on the rationale for selecting 200 mg 
Q3W is summarized below.
In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor activity 
of pembrolizumab when administered as monotherapy. The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 
2 weeks (Q2W) and dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W 
in subjects with advanced solid tumors. All dose levels were well tolerated and no dose-
limiting toxicities were observed. This first-in-human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels. No maximum tolerated dose (MTD) has been identified. In addition, two 
randomized cohort evaluations of melanoma subjects receiving pembrolizumab at a dose 
of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one randomized cohort 
evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been completed. The clinical 
efficacy and safety data demonstrate a lack of important differences in efficacy or safety 
profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected 
to provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.
Previously, a flat pembrolizumab exposure-response relationship for efficacy and safety 
has been found in subjects with melanoma in the range of doses between 2 mg/kg and 10 
mg/kg. Exposures for 200 mg Q3W are expected to lie within this range and will be 
close to those obtained with 2 mg/kg Q3W dose.


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A population pharmacokinetic (PK) model, which characterized the influence of body 
weight and other patient covariates on exposure, has been developed. The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution. The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those 
obtained with the 2 mg/kg dose and importantly will maintain individual patient 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response. Pharmacokinetic properties of pembrolizumab, and specifically the 
weight-dependency in clearance and volume of distribution are consistent with no 
meaningful advantage to weight-based dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 
tumor type. In addition, available PK results in subjects with melanoma, NSCLC, and 
other tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at tested doses among tumor types. Thus the 200 mg Q3W fixed-dose regimen 
is considered an appropriate fixed dose for other tumor indications as well.
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. The 
existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab
Section 3. Objectives and Endpoints
REVISED TEXT:
Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously to 
subjects with selected advanced or 
recurrent solid tumors.  

AEs, SAEs, DLT, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).  
Secondary

To evaluate the antitumor activity of 
GSK3174998 in subjects with selected 
advanced or recurrent solid tumors.

To characterize the PK of GSK3174998 
monotherapy.

ORR and DCR (CR+ PR+ SD ≥12 weeks), 
time to responseTTR, duration of response
DOR, PFS, and OS.b

GSK3174998 concentrations in plasma 
and PK parameters including Cmax, 
AUC(0-), and Cmin.

To evaluate the pharmacodynamic activity 

Assessment of lymphocyte OX40 receptor 


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Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
of GSK3174998 in the periphery, i.e., blood 
and in the tumor microenvironment
membrane expression and occupancy by 
GSK3174998, along with the phenotype, 
quantity, and activation state of T cells in 
the periphery.

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers

To determine the immunogenicity of 
GSK3174998. 

Number and percentage of subjects who 
develop detectable ADA.
Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
Exploratory

To explore the relationship between 
antitumor activity, PK parameters, and 
pharmacodynamic activity and other 
patient characteristics. response after 
treatment with GSK3174998.

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, and pharmacodynamic 
activity, and other patient characteristics.

To  evaluate the pharmacodynamic activity 
of GSK3174998 in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

To explore the association between 
treatment with GSK3174998 and changes 
in genomic DNA, gene expression (RNA 
and protein), measures of immune function 
in tissue and blood and antitumor activity

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, expression of circulating soluble 
factors such as cytokines and stress-related 
proteins). Changes in genomic DNA, gene 
expression (RNA and protein), (e.g, using 
cfDNA, exosomes or circulating tumor cells 
[CTCs]).

Correlation between antitumor activity and 
expression of immune related genes, e.g., 
but not limited to TCR sequences and gene 
signatures, along with the expression of 
circulating soluble factors such as cytokines 
and stress-related proteins in both tissues 
and blood. 

To evaluate the pharmacodynamic activity 
of GSK3174998 in the tumor 

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 


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microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test. 

To explore the immune response 
biomarkers in tumor tissue and their 
association with the antitumor activity with 
GSK3714998. 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein),TCR diversity or mutational load 
(genomic DNA).

Determination of the correlation between 
the immune response in tumor samples 
and antitumor activity of GSK3174998 to 
identify potential selection biomarkers for 
subject enrichment. 

Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host 
DNA and response to therapy.

Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 or any concomitant 
medicines.
Disease susceptibility, severity, and 
progression and related conditions.
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
In the final determination of the MTD, all available safety and tolerability data will be considered
Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 and by irRECIST (immune-related RECIST); irRECIST will be used to determine treatment
decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid
Objectives
Endpoints
Part 2: Combination GSK3174998 plus pembrolizumab
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of GSK3174998 
administered intravenously in combination with 
IV pembrolizumab to subjects with selected 
advanced or recurrent solid tumors. 

AEs, SAEs, DLTs, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate the antitumor activity of 
GSK3174998 in combination with 
pembrolizumab in subjects with selected 
advanced or recurrent solid tumors.

To characterize the PK of GSK3174998 
monotherapy when administered in 
combination.

ORR and DCR (CR+ PR+ SD ≥12 weeks), 
time to responseTTR, duration of response
DOR, PFS, and OS.b

Plasma GSK3174998 and serum 
pembrolizumab concentrations and PK 
parameters including Cmax, AUC(0-), and 
Cmin.


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Objectives
Endpoints
Part 2: Combination GSK3174998 plus pembrolizumab

To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the periphery, i.e., blood and 
in the tumor microenvironment

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998, along with the phenotype, 
quantity, and activation state of T cells in the 
periphery.

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating lymphocytes 
and other immune cells expressing key 
phenotypic markers

To determine the immunogenicity of 
GSK3174998 and pembrolizumab when 
administered in combination. 

Number and percentage of subjects who 
develop detectable ADA.


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Objectives
Endpoints
Part 2: Combination GSK3174998 plus pembrolizumab
Exploratory

To explore the relationship between 
antitumor activity, PK parameters, and 
pharmacodynamic activity and other patient 
characteristics. response after treatment with 
GSK3174998 in combination with 
pembrolizumab

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, and pharmacodynamic activity, and 
other patient characteristics.

To  evaluate the pharmacodynamic 
activity of GSK3174998 in combination with 
pembrolizumab in the peripheral blood and to 
explore the utility of these measures to enrich 
for clinical efficacy and development of a 
diagnostic test.

To explore the association between 
treatment with GSK3174998 and changes in 
genomic DNA, gene expression (RNA and 
protein), measures of immune function in tissue 
and blood and antitumor activity

Assessment of lymphocyte OX40 
receptor membrane expression and occupancy 
by GSK3174998. Measures of immune function 
in blood (e.g. phenotype, quantity, and 
activation state of T cells in the periphery, 
expression of circulating soluble factors such as 
cytokines and stress-related proteins). Changes 
in genomic DNA, gene expression (RNA and 
protein), (e.g, using cfDNA, exosomes or 
circulating tumor cells [CTCs]).

Correlation between antitumor activity 
and expression of immune related genes, e.g., 
but not limited to TCR sequences and gene 
signatures, along with the expression of 
circulating soluble factors such as cytokines and 
stress-related proteins in both tissues and 
blood. 

To evaluate the pharmacodynamic 
activity of GSK3174998 in combination with 
pembrolizumab in the tumor microenvironment
and to explore the utility of these measures to 
enrich for clinical efficacy and development of a 
diagnostic test. 

To explore the immune response 
biomarkers in tumor tissue and their association 
with the antitumor activity with GSK3714998. 

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating lymphocytes 
and other immune cells expressing key 
phenotypic markers. Changes in gene 
expression (RNA and protein), TCR diversity or 
mutational load (genomic DNA).

Determination of the correlation between 
the immune response in tumor samples and 
antitumor activity of GSK3174998 to identify 
potential selection biomarkers for subject 
enrichment. 

(PGx): To evaluate the association of 
genetic variations in the host DNA and 
response to therapy.

Germline genetic evaluations may be 
conducted for:

Medicine response, including 
GSK3174998 and pembrolizumab or any 
concomitant medicines.

Disease susceptibility, severity, and 
progression and related conditions.


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Objectives
Endpoints
Part 2: Combination GSK3174998 plus pembrolizumab
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
a.
In the final determination of the MTD, all available safety and tolerability data will be considered
b.
Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and by irRECIST (immune-related RECIST); irRECIST will be used to determine
treatment decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid
Section 4.1 Overall Design
REVISED TEXT:
2nd, 3 rd , 4 th Paragraph and figure 3:
The study will be conducted in 2 parts, each part consisting of a dose-escalation phase 
followed by a cohort expansion phase (see Figure 3).  Part 1 will evaluate GSK3174998
monotherapy, while Part 2 will evaluate GSK3174998 in combination with 
pembrolizumab. As shown in Figure 3, GSK3174998 will first be evaluated as 
monotherapy in escalating doses.  Once a dose of GSK3174998 has been identified that is 
both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may 
begin.  In Part 2, escalating doses of GSK3174998 will first be evaluated with fixed doses 
of pembrolizumab. Part 1A and 2A will also include a Pharmacodynamic Cohort, which 
requires mandatory fresh pre- and on-treatment biopsies and an additional disease 
assessment at week 6. Each part will also include expansion cohorts for up to three 
different tumor types.
The study will enroll up to approximately 180 264 subjects with tumor types that may 
include NSCLC, SCCHN, RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.  
In the dose-escalation phase of the study, subjects with any of the aforementioned tumor 
types may be included; whereas in the cohort expansion phase of the study, each 
expansion cohort will enroll subjects with one specific tumor type selected from the 
aforementioned list.  Up to three expansion cohorts may be included for each part of the 
study.
A subject’s disease status and determination of disease progression at postbaseline visits 
will be evaluated by the local investigators’ assessments of radiology by RECIST v1.1 
and irRECIST; a decision to discontinue treatment due to disease progression will be 
based upon irRECIST; however,
and the primary endpoint analysis will use 
irRECISTv1.1. Scans will be collected centrally and stored to allow for the option of 
central radiologic audit or review.


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Figure 4
ENGAGE-1 Study Design
a) Part 1A and Part 2A Design
b) Part 1A and Part 2A Dose Escalation
Figure 3a shows the overall study design: Part 1A GSK3174998 monotherapy dose escalation, Part 1B GSK3174998 monotherapy 
cohort expansion, Part 2A GSK3174998 + pembrolizumab dose escalation, Part 2B GSK3174998 + pembrolizumab cohort expansion.  
Figure 3b shows dose escalation (Parts 1A and 2A) including the “pharmacodynamic cohort”.  Note: An example of 3 dose levels 
being expanded in the pharmacodynamic cohort is provided to illustrate it is possible not all dose levels will be explored in the 
pharmacodynamic cohort, which mandates pre- and on-treatment tumor biopsies in order to further explore dose-response with 
biomarkers in the tumor microenvironment.  


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Section 4.1.1 Dose Escalation
REVISED TEXT:
2 nd paragraph:
For subsequent dose levels, a modified 3+3 design will be used for dose escalation as 
shown in Table 1.  The first three subjects treated at the third dose level will begin 
treatment 1 week apart to allow assessment of initial safety data in each subject before 
beginning the next subject’s treatment. Evaluation of the available safety data over the 
first 4 weeks of treatment is required from at least 3 subjects before a decision is made 
whether to enroll additional subjects at the same, or the next higher dose level.  Subjects 
who withdraw from the study before the completion of 4 weeks treatment and 2 doses for 
reasons other than DLT may be replaced. After the third dose level cohort is completed, 
subsequent dose levels may initially enroll up to 4 subjects and subjects will begin 
treatment at least 24 hours one calendar day apart.
Table 1  3 + 3 Dose-Escalation Guidelines
REVISED TEXT:
Number of Subjects with DLT 
at a Given Dose Level
Actiona
0 out of 3 subjects
Escalate to next dose level and enter 3 subjects
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects.
If 0 of the 3 additional subjects experience a DLT, proceed to next 
dose level.
If 1 or more of the additional subjects experience a DLT, the dose 
escalation is stopped and this dose is declared the MTD.
1 out of 6 subjects
Escalate to next dose level
2 or more subjects in a dosing cohort 
(up to 6 subjects)
Dose escalation will be stopped.  At this dose level, the MTD has 
been exceeded (highest dose administered).
a.The  Steering Committee may propose that a given dose-escalation cohort be expanded up to a total of 12 subjects if 
(i) further evaluation of the frequency of a given toxicity is warranted, based upon the observed safety profile in the 6 
subjects already recruited in the cohort or (ii) further evaluation of pharmacodynamic markers to aid dose selection is 
warranted; in either case, the incidence of confirmed DLT must not equal or exceed 33%.
DLT = Dose-limiting toxicity; MTD = Maximum tolerated dose
In alignment with the guidance prospectively established in the Protocol (see above), the 
Steering Committee proposed that dose-escalation cohorts be expanded up to a total of 12 
subjects in order to further evaluate pharmacodynamic markers to aid dose selection. This 
proposal was agreed and implemented at the time of opening Cohort 4 (0.1 mg/kg) and 
documented in writing.  Since the incidence of confirmed DLT must not exceed 33% in 
this study, the recommended dose from a Continuous Reassessment Method (N-CRM) 
analysis [Neuenschwander, 2008] will be calculated (as prospectively described in 
Section 9.3).  The N-CRM is a type of Bayesian adaptive dose-escalation scheme.  The 
method is fully adaptive and makes use of all the DLT information available at the time 
of each dose assignment. 


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From Part 1 Cohort 4 (0.1mg/kg) onwards and for all Part 2 dose levels, each dose level 
may initially enroll up to 4 subjects. Once at least 3 of these subjects have completed the 
DLT evaluation period (4 weeks), a decision may be made to initiate the next higher dose 
level, pending the evaluation of safety data using the N-CRM methodology.  Subjects 
identified as eligible for enrollment after the enrollment of 4 subjects in current dose level 
and before next higher dose level is open may be assigned to a lower dose level. 
A maximum of 12 subjects will be enrolled at any given dose level in Part 1A and Part 
2A; up to 6 of these subjects at any given dose level maybe part of a “Pharmacodynamic 
Cohort” (Figure 3).  Subjects entering the “Pharmacodynamic Cohort” will have the 
following additional eligibility requirements (as described in Section 5.1):

Mandatory fresh biopsy collection at baseline, on treatment (at 6 weeks), and if 
feasible at the time of disease progression

Additional 6-week disease assessment and availability of a pre-baseline scan 
(within 24 weeks before the baseline scan), if feasible, to support exploratory 
investigation of tumor growth kinetics
Exploration of lower dose levels than recommended by N-CRM (or expansion of a 
previously-tested dose level) is allowed if agreed upon by the Medical Monitor and 
treating investigators. The final dose escalation decision will be made by study team on 
all available data, including biomarker and PK data and the safety profile of prior cohorts.  
Dose-escalation decisions will be documented in writing with copies maintained at each 
site and the study files.


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Section 4.1.2  Part 1A: Monotherapy Dose Escalation
REVISED TEXT:
Table 2  Part 1A Dose Levels
Dose 
Level
GSK3174998 (mg/kg)a
Dose Escalation 
Cohort (n)
Pharmacodynamic 
Cohort (n)
1
0.003
1
6
2
0.01
1
6
3
0.03
3-6
6
4
0.1
3-6
6
5
0.3
3-6
6
6
1.0
3-6
6
7
3.0
3-6
6
8
10.0
3-6
6
a.
Lower dose intensities may be explored if exposure is significantly higher than predicted, if there is excessive 
toxicity, or if further evaluation of pharmacodynamic markers to aid dose selection is warranted. This may be 
achieved by reducing the dose or by alternate dosing schedules. 
Section 
4.1.3 
Part 
2A: 
Combination 
Dose 
Escalation 
(GSK3174998 
+ 
Pembrolizumab)
REVISED TEXT:
Dose escalation for GSK3174998 + pembrolizumab combination therapy will begin with 
a fixed dose of 200 mg pembrolizumab administered Q3W and a starting dose of 0.003 
mg/kg GSK3174998. that is at least 2 dose levels below a tolerated dose of GSK3174998 
monotherapy that has also demonstrated pharmacodynamic activity in Part 1A of the 
study.
GSK3174998 dose levels that may be administered in combination with pembrolizumab 
are An example of potential combinations of GSK3174998 and pembrolizumab is 
described in Table 3.  In this example, a dose of 1 mg/kg GSK3174998 alone was 
tolerated in at least 3 subjects in Part 1A of the study.


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Table 25
Example of Part 2A Dose Levels
Dose 
Level
GSK3174998 
(mg/kg)
Pembrolizumab 
(mg)
Dose Escalation 
Cohort (n)
Pharmacodynamic 
Cohort (n)
1
0.003
200
3-6
6
2
0.01
200
3-6
6
3
0.03
200
3-6
6
4 1
0.1
200
3-6
6
25
0.3
200
3-6
6
36
1.0
200
3-6
6
47
3.0
200
3-6
6
58
10.0
200
3-6
6
If the combination doses in the starting dose cohort of Part 2A are not tolerable, lower 
dose intensities of GSK3174998 may be evaluated in combination with 200 mg 
pembrolizumab. This may be achieved by reducing the dose or alternate dosing 
schedules. The dose of pembrolizumab will remain fixed at 200 mg throughout the study.
Dose escalation will proceed until the MTD or MAD of the combination regimen is 
identified, as described in Section 4.1.1.  Dose-escalation decisions will take into account 
all available data, including the safety profile of prior cohorts throughout the time 
subjects are on study, which will be reviewed by the investigator(s), GSK Medical 
Monitor, pharmacokineticist, and statistician.  The dose-escalation decision for the 
subsequent cohort and rationale will be documented in writing with copies maintained at 
each site and the study files.
Any cohort may be expanded beyond the 3 to 6 subjects enrolled during dose escalation, 
to a maximum of 12 to facilitate collection of additional safety, PK, and 
pharmacodynamic data (Figure 3).  A total of up to 12 subjects may be treated at the dose 
of GSK3174998 selected for Parts 1B and 2B to better characterize the safety, PK, and 
pharmacodynamic data at that dose, before opening the Dose-Expansion phase.
Section 4.2. Treatment Arms and Duration
REVISED TEXT:
1 st paragraph:
The study includes a screening period, a treatment period, and a follow-up period.  
Subjects will be screened for eligibility beginning approximately 4 weeks before the start 
of treatment.  The maximum duration of treatment with GSK3174998 will be 48 weeks; 
the maximum duration of treatment with and pembrolizumab will be 2 years (Table 5) or 
35 cycles whichever comes first. The follow-up period for safety assessments will be a 
minimum of 3 months from the date of the last dose.  The post-treatment follow-up 
period includes disease assessments every 12 weeks until documented PD.  Following 
PD, subjects will be contacted every 3 months to assess survival status.


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Table 5 Study Treatments
REVISED TEXT:
Study Part
Study Treatment
Part 1: GSK3174998 Monotherapy
1A – Dose escalation
GSK3174998 IVa Q3W for up to 48 weeks 2 years or 35 cycles, 
whichever comes first
1B – Cohort expansion
GSK3174998 IVb Q3W for up to 48 weeks 2 years or 35 cycles, 
whichever comes first
Part 2: GSK3174998 in combination with pembrolizumab 
2A – Dose escalation
GSK3174998 IVc Q3W for up to 48 weeks 2 years or 35 cycles, 
whichever comes first
Pembrolizumab 200mg IV Q3W for up to 2 years or 35 cycles, 
whichever comes first
2B – Cohort expansion
GSK3174998 IVb Q3W for up to 48 weeks 2 years or 35 cycles, 
whichever comes first
Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 cycles, 
whichever comes first
a.     For dose levels see Table 2.
b.     At one or two dose levels shown to be tolerable in dose escalation of each part. 
d.
For dose levels see Table 3.
IV = Intravenous; Q3W = Every 3 weeks
Section 4.3  Type and Number of Subjects
REVISED TEXT:
1 st paragraph
The number of dose levels and the level at which the MTD is reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish the recommended dose(s) for further study. It is estimated that a total of up to 
approximately 180 264 subjects will be enrolled in this two-part study (approximately 
60144 subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects in Parts 
1B and 2B [cohort expansion])
Section 4.4 Design Justification
REVISED TEXT:
This study evaluates the safety, tolerability, pharmacodynamic effects, and preliminary 
clinical activity of GSK3174998 as a monotherapy (Part 1) and in combination with anti-
PD-1, pembrolizumab (Part 2).  The safety, tolerability, and pharmacodynamics of 
monotherapy GSK3174998 will be evaluated in a modified 3+3 dose escalation that 


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includes an accelerated titration design for the first two dose levels.  The dose escalation 
will be followed by expansion cohorts in defined subject populations.  Upon 
demonstration of clear pharmacodynamic immune activation, exploration of the 
combination of GSK3174998 with pembrolizumab may commence, in parallel with the 
continuing monotherapy exploration.  Dose escalation of GSK3174998 in combination 
with a 200 mg fixed dose of pembrolizumab will begin at a dose of 0.003 mg/kg 
GSK3174998 as described in Section4.5.2.that is at least 2 dose levels below a dose of 
GSK3174998 that has been demonstrated to be safe at that point in time.  
In order to ensure sufficient safety and pharmacodynamic data were available before 
beginning enrollment to Part 2 of the study, available clinical data (clinical data cut-off: 
17 May 2016; (see Section 2.3.5) from Part 1 of the study, including safety, PK, 
pharmacodynamics and efficacy, were reviewed by the Steering Committee.  The 
Steering Committee also considered available data for other OX40 agonist antibodies as 
relevant background information [Hamid, 2016;Hansen, 2016;Infante, 2016].  GSK 
Medical Governance reviewed the same data as the Steering Committee and endorsed 
initiation of Part 2 of the study.  The decision to initiate Part 2 was documented and 
reported to all participating PIs and IRBs/ IECs.
In the dose escalation phase, subjects will be enrolled with selected solid tumors that are 
likely to respond to anti-OX40 therapy (e.g., indications previously reported to have a 
response to immunotherapies, predicted immunogenicity, and/or expression of OX40).  
The tumor types to be evaluated in dose escalation are as follows: NSCLC, SCCHN, 
RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.
Almost all of these histologies have demonstrated prior response to anti-CTLA-4 and/or 
anti-PD-1/PD-L1 therapies [Zamarin, 2015].  In addition, gene expression data [TCGA, 
2014] suggest that all of these tumor types have at least moderate expression of OX40.
The inclusion of the combination with pembrolizumab is based on the preference to 
identify potential transformational activity early in development.  Although GSK3174998 
is expected to have meaningful clinical activity as a monotherapy, the full potential of the 
molecule is likely to be discovered in combination with other agents, particularly 
immunotherapies.  Pembrolizumab is an ideal combination partner for GSK3174998 
because it targets a different aspect of the cancer-immunity cycle, has a toxicity profile of 
mainly Grade 1 or 2 events, and preclinical data strongly supports the potential for 
synergy.
Recently reported data with OX40 agonists and other TNFR agonists [Hamid, 2016;
Hansen, 2016; Infante, 2016] has highlighted the importance of understanding the impact 
of treatment with these agents on the tumor microenvironment.   To date TNFR agonist
antibodies appear to saturate receptors in the periphery at low doses, be well-tolerated, 
have demonstrated biological effects in the tumor microenvironment in some but not all 
tumors where serial fresh biopsies were available (e.g., increased CD8 infiltration, 
decreased Tregs), and have demonstrated modest clinical activity.  In order to better 
understand dose-response and variables that may influence clinical response to treatment 
with GSK3174998 alone or in combination with pembrolizumab, it is critical that 
immune biomarkers in the tumor microenvironment are assessed in this study across a 


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range of doses and, if feasible, correlated with clinical response.  In alignment with the 
guidance prospectively established in the Protocol, the Steering Committee proposed that 
dose-escalation cohorts be expanded up to a total of 12 subjects in order to further 
evaluate pharmacodynamic markers to aid dose selection. In order to address the need to 
explore the potential relationships between dose, biological effects in the tumor 
microenvironment, and tumor response, a “pharmacodynamic cohort” is included in each 
of the dose-escalation parts of the study (Part 1A and Part 2A).  In order to be eligible to 
be enrolled in the pharmacodynamic cohorts, subjects must consent to mandatory fresh 
biopsy collection at baseline, on treatment (at 6 weeks), and if feasible at the time of 
disease progression. An additional disease assessment (at 6 weeks) and availability of a 
pre-baseline scan (within 24 weeks before the baseline scan), if feasible, will support 
exploratory investigation of tumor growth kinetics in this cohort.
In order to ensure sufficient safety and pharmacodynamic data are available before 
beginning enrollment to the GSK3174998/pembrolizumab combination (Part 2), 
available clinical data, including safety, pharmacodynamics and efficacy, will be 
reviewed by the Steering Committee.  The study team will also seek endorsement from 
GSK Medical Governance in order to initiate Part 2 of the study.  Upon deciding to open 
Part 2, the decision will be documented and reported to all participating PIs and IRBs/ 
IECs.
Section 4.5.2  Part 2: Starting Dose
REVISED TEXT:
2 nd paragraph:
The starting dose of GSK3174998 for the Part 2/Combination Dose-Escalation phase will 
was planned to be at least 2 dose levels below a dose that has been shown to be tolerated
during the monotherapy dose escalation. 
This determination is was based on an 
allowance that a 10-fold lower dose of GSK3174998 should provide a sufficient safety 
margin when pembrolizumab is added. Using these criteria, data from Part 1 Cohort 3 
(0.03 mg/kg), with a clinical data cut-off of 17 May 2016, supported a Part 2 starting 
dose of 0.003 mg/kg GSK3174998.  The 0.03 mg/kg dose level was tolerated and 
transient peripheral OX40 receptor saturation was observed in 3 of 4 subjects with the 
fourth subject having 100% OX40 receptor saturation throughout the first dosing period 
(21 days).  These data were reviewed by the Steering Committee and GSK Medical 
Governance (as described in Section 4.4) and are briefly summarized in Section 2.3.5 of 
the protocol.
Section 5.1 Inclusion Criteria
REVISED TEXT:
Inclusion criteria 4, 5 and 9:
4. Subjects with the following solid tumors are eligible for screening: NSCLC, SCCHN, 
RCC, melanoma, bladder, STS, TNBC, and MSI CRC


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1.
5.A biopsy of the tumor tissue obtained at anytime from the initial diagnosis to study 
entry. Although a fresh biopsy obtained during screening is preferred, archival tumor 
specimen is acceptable, if it is not feasible to obtain a fresh biopsy.  For Part 1B and 
Part 2B, any archival tumor specimen must have been obtained within 3 months of 
starting study drug.
Note: Subjects enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts must provide a 
fresh biopsy of a tumour lesion not previously irradiated during the screening period and 
must agree to provide at least one additional on-treatment biopsy.
Table 26
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
ANC
≥1.5x109/L
Lymphocyte count
>1,000/mm3
Hemoglobin
≥9 g/dL
Platelets
≥100x109/L
Hepatic
Total bilirubin
For subjects with Gilbert’s Syndrome (only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
ALT
≤1.5xULN
Renal
Serum Creatinine
OR
Calculated CrCla
≤1.5xULN
> 50 mL/min
Endocrine
TSHb
WNL
ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal; WNL = within normal limits
a.
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula (see Appendix 12) or per institutional standard.
b.
If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 are 
within the normal limits.
Section 5.2 Exclusion Criteria
REVISED TEXT:
Exclusion criteria 1:
1. Prior treatment with the following agents (from last dose of prior treatment to first 
dose of GSK3174998): 

TNFR agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at 
any time. 
NOTE: Subjects treated in Part 1/monotherapy with GSK3174998 may be 
enrolled into Part 2/combination with pembrolizumab upon disease progression 
and upon discussion and approval from the GSK Medical Monitor.


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
Checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors: within 8 
4 weeks.  
Exclusion criteria 2: 
2. Prior treatment with Receptor activator of nuclear factor-kappaB ligand (RANKL) 
inhibitors (e.g., denosumab) within 4 weeks of the start of study drug.
Exclusion criteria 3, third point:
4.3. Subjects whose toxicity related to prior treatment has not resolved to Grade 1 
(except alopecia, hearing loss, grade 2 neuropathy or endocrinopathy managed with 
replacement therapy) are not eligible.
5. Central nervous system (CNS) metastases, with the following exception:

Subjects who have previously-treated CNS metastases, are asymptomatic, and 
have had no requirement for steroids or anti-seizure medication for 2 weeks 
prior to first dose of study drug.
13. 12 Known, current drug or alcohol abuse.
18. Current or Hhistory of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung 
disease, or organizing pneumonia., or evidence of active, non-infectious pneumonitis. 
that required steroids.  Note: post-radiation changes in the lung related to prior 
radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment 
may be permitted if agreed by the investigator and Medical Monitor.
19. History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
Section 5.4.  Withdrawal/Stopping Criteria
REVISED TEXT:
Addition of Sub-Heading:
5.4.1 Treatment Discontinuation:
1st paragraph:
Subjects will receive study treatment for the scheduled time period, unless one of the 
following occurs earlier: disease progression (as determined by irRECIST), death, or 
unacceptable toxicity, including meeting stopping criteria for liver chemistry defined in 
Section 5.4.2.  In addition, study treatment might be permanently discontinued for any of 
the following reasons:

Major deviation(s) from the protocol
6th paragraph:
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be re-treated, except as described in Section 5.4.2.1 and in the following 


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scenario. Re-treatment of subjects who progress after a best overall response of PR or CR 
may be considered on a case-by-case basis for up to 1 year after discussion between the 
treating investigator and the Sponsor/Medical Monitor if:

No cancer treatment was administered since the last dose of GSK3174998 
pembrolizumab

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria

The trial is open.  
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation.  Response or progression in this Second Course Phase will not count 
towards the primary efficacy endpoint in this trial.
5.4.2 5.4.3 QTcF Stopping Criteria:
2nd paragraph:
The QTcF should be based on single or averaged QTcF values of triplicate ECGs 
obtained over a brief (e.g., 5-10 minute) recording period. (i.e. single QTcF is used when 
a single ECG is performed, and averaged QTcF is used when triplicate ECGs are 
performed)
Section 5.5 Subject and Study Completion
REVISED TEXT:
Since subjects will be followed for survival in this study, only when a subject dies is 
he/she considered to have completed the study; consequently “death” is not listed as a 
reason for withdrawal from the study. Furthermore, disease progression, discontinuation 
of study treatment, and AEs, are not by themselves reasons for withdrawal from the study 
as follow-up for OS is desired. If a subject dies a copy of the death certificate should be 
available for review, if possible, and the cause of death should be evaluated and 
documented.
A subject will be considered to have completed the study if they complete screening 
assessments, received at least one dose of study treatment(s), and the TDV, or are 
receiving ongoing study treatment at the time of the Sponsor’s decision to close the 
study.
For both Part 1 (dose-escalation phase) and Part 2 (expansion cohort), a completed 
subject is one who has discontinued study treatment for reasons listed in Section 5.4 and 
completed a TDV or has died while receiving study treatment.
The end of the study is defined as the last subject’s last visit.


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Section 6.1 Investigational Product and Other Study Treatment
REVISED TEXT:
Table 27
Investigational Product Dosage/Administration
Study Treatment
Product name:
GSK3174998
Pembrolizumab
Dosage form:
Lyophilized powder for 
reconstitution
Solution for infusion or 
Lyophilized powder for 
reconstitutionc
Unit dose strength(s)/ Dosage 
level(s):
40 mg lyophilized powder
Dose range: 0.003 to 
≤10 mg/kg
100 mg/ 4 mL solution or
50 mg lyophilized powder
Dose range: 200 mg
Route of Administration
IV infusion – 30 mina, b
IV infusion – 30 mina
Frequency of Administration
Q3Wb
Q3Wb
Dosing instructions:
Make every effort to target 
infusion timing to be as close 
to 30 min as possible. 
However, given the variability 
of infusion pumps from site to 
site, a window of -5 min and 
+10 min is permitted (i.e., 
infusion time is 30 min: -5 
min/+10 min or 25 to 40 min).
Make every effort to target 
infusion timing to be as close to 
30 min as possible. However, 
given the variability of infusion 
pumps from site to site, a 
window of -5 min and +10 min 
is permitted (i.e., infusion time 
is 30 min: -5 min/+10 min or 25 
to 40 min).
Manufacturer/ source of 
procurement
GSK
Merck
a.
Infusions may be prolonged in the event of an infusion reaction.  If multiple subjects experience clinically 
significant infusion reactions, the infusion rate may be slowed for all future administrations of study drug(s) for all 
subjects. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
b.
Dose levels 1 and 2 will be administered less than 30 min, please refer to the SRM for infusion directions
c.
The dosage form of pembrolizumab will be either solution or lyophilized powder for all subjects/doses. This will be 
decided and communicated prior to start of the combination phase of the study.
Q3W = Every 3 weeks; GSK = GlaxoSmithKline


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Section 6.3.1 Dose and Safety Management Guidelines
REVISED TEXT:
Table 9 General Dose Modification and Management Guidelines for Drug- related 
Non-Hematologic Adverse Events Not Otherwise Specified
Severity
Management
Follow-up
Grade 1

Administer symptomatic 
treatment as appropriate

Continue study drug(s)a
Symptoms resolve to baseline within 7 days:

Provide close follow-up to evaluate for increased severity
Symptoms ongoing >7 days:

Consider following algorithm for Grade 2 events
Grade 2

Administer symptomatic 
treatment

Investigate etiology

Consider consulting 
subspecialist, biopsy, and/or 
diagnostic procedure

Discuss with Sponsor/Medical 
Monitor
Symptoms ongoing >7 days or worsening

Consider interruption of study drug(s)a
o Resume study drug(s) at the same dose if symptoms 
have improved to Grade 1 and steroid dose is 10 mg 
prednisone/day or less
o If symptoms persist at Grade 2 for greater than 6 
weeks, permanently discontinue study drug. See 
Section 6.3.1.13

Consider starting moderate dose systemic corticosteroids 
(e.g., 0.5 mg/kg/day of prednisone or equivalent)
o Continue steroids until improvement to Grade 1 or 
resolution; taper steroids as medically appropriate

If symptoms continue or worsen to Grade 3-4, see below
Grade 3-4

Interrupt or permanently 
discontinue study drug(s)a

Consult subspecialist

Administer 1-2 mg/kg/day IV 
methylprednisolone 

Discuss with Sponsor/Medical 
Monitor
Symptoms improve to Grade 2:

Continue steroids until improvement to ≤Grade 1 or 
baseline; taper steroids over at least 1 month, then if 
symptoms have improved to Grade 1 and steroid dose is 
10 mg prednisone/day or less, consider resumption of 
study drug(s) at the next lower dose level
Symptoms ongoing: 

Discuss further management with consultant and 
Sponsor/Medical Monitor

Consider alternative immunosuppressive therapy
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor.  


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Table 10 Guidelines for Dose Modification and Management of Hepatotoxicity
Severity
Management
Follow-up
Grade1
ALT > ULN to 3x 
ULN
OR
Total bilirubin 
> ULN to 1.5x ULN
MONITOR
Assess liver function at least 
weekly
Monitor the subject at least weekly until liver chemistries 
resolve, stabilize, or return to within baseline
Hepatotoxicity improves to ≤ Grade 1 or baseline or 
remains stable: 
Provide close follow-up to evaluate for increased 
severity.
Hepatotoxicity worsens to ≥ Grade 2:
see below
Grade 2
ALT >3-5x ULN 
OR
Total bilirubin  >1.5-
3xULN
INTERRUPT/HOLD
Consider interruption of
Interrupt study drug(s) after and
discussion  with 
Sponsor/Medical Monitora
Consider treatment with IV or 
oral corticosteroids
Assess for infection and liver 
metastases
Repeat liver chemistries 
(include ALT, AST, alkaline 
phosphatase, bilirubin) and 
perform liver event follow-up 
assessmentswithin 24-72 
hours (see below)
Assess liver function at least 
twice weekly
Discuss with Sponsor/Medical 
Monitor within 24 hours 
Consider consultation with a 
hepatologist
Monitor the subject at least twice weekly until liver 
chemistries resolve, stabilize, or return to within baseline
Hepatotoxicity improves to ≤ Grade 1 or baseline within 7 
days: 
Resume study drug(s) (note: requirements specified in 
Section 5.4.2.1 must be met before treatment can 
restart)
Provide close follow-up to evaluate for recurrence
Hepatotoxicity ongoing > 7 days:
Start systemic corticosteroids (e.g., 0.5 mg/kg/day of 
prednisone or equivalent)
Continue steroids until improvement to ≤Grade 1 or 
baseline or resolution; taper steroids over at least one 
month
Resume study drug(s) if hepatotoxicity improves to 
≤Grade 1 or baseline and steroid dose is 10 mg 
prednisone/day or less (note: requirements specified in 
Section 5.4.2.1 must be met before treatment can 
restart)
Provide close follow-up to evaluate for recurrence
Discontinue study treatment if:
Hepatotoxicity continues or worsens to ALT >5x ULN or 
total bilirubin to >3x ULN (follow instructions below)
ALT 3xULN but <5xULN persists for 4 weeks
ALT 3xULN but <5xULN and cannot be monitored 
weekly for 4 weeks
Unable to reduce corticosteroid dose to 10 mg or less 
of prednisone or equivalent per day within 12 weeks
Recurrence after rechallenge:
Discontinue study drug(s) permanently
Monitor subject closely for clinical signs and symptoms
Perform full panel LFTs a weekly or more frequently if 
clinically indicated until ALT decreases to Grade 1
At the time of the recurrence, complete the eCRF liver 
event forms.


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Severity
Management
Follow-up
Grade 3
ALT >5 x ULN
OR
Total bilirubin >3x 
ULN
DISCONTINUE
Immediately discontinue study 
drug(s)a
Assess for infection and liver 
metastases
Repeat liver chemistries 
(include ALT, AST, alkaline 
phosphatase, bilirubin) and 
perform liver event follow-up 
assessment within 24 hours 
(see below)
Assess liver function at least 
twice weekly
Consider Administration of 1-
2  mg/kg/day IV 
methylprednisolone 
Discuss with Sponsor/Medical 
Monitor within 24 hours
Consider consultation with a 
hepatologist
Monitor the subject at least twice weekly until liver 
chemistries resolve, stabilize, or return to within baseline
If ALT or bilirubin have not decreased within 72 hours in 
the absence of other etiologies and steroid treatment 
has not been administered, initiate treatment with 1-
2 mg/kg/day IV methylprednisolone
Continue steroids until improvement to ≤Grade 1 or 
baseline or resolution; taper steroids over at least one 
month
If serum transaminase levels do not decrease 48 hours 
after initiation of systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be given. Infliximab
is not recommended due to its potential for 
hepatotoxicity.
Grade 4
ALT >20 x ULN
OR
Total bilirubin >10x 
ULN
Additional Stopping 
Criteria: ALT 3x 
ULN AND Total 
bilirubin 2x ULN 
(>35% direct 
bilirubin)b
ALT3xULN and 
INR>1.5, if INR 
measuredc
ALT  3xULN 
associated with 
symptoms (new or 
worsening) believed 
to be related to liver 
injury or 
hypersensitivityd
DISCONTINUE
Immediately discontinue study 
drug(s)a
Assess for infection and liver 
metastases
Repeat liver chemistries 
(include ALT, AST, alkaline 
phosphatase, bilirubin) and 
perform liver event follow-up 
assessment within 24 hours 
(see below)
Assess liver function at least 
twice weekly
Administer 1-2 mg/kg/day IV 
methylprednisolone 
Discuss with Sponsor/Medical 
Monitor within 24 hours
Consider consultation with a 
hepatologist
Monitor the subject at least twice weekly until liver 
chemistries resolve, stabilize, or return to within baseline
Continue steroids until improvement to ≤Grade 1 or 
baseline or resolution; taper steroids over at least one 
month
If serum transaminase levels do not decrease 48 hours 
after initiation of systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be given. Infliximab 
is not recommended due to its potential for 
hepatotoxicity.
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor.
b.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin 
on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
c.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 


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measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
d.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
ALT = Alanine aminotransferase; ULN = Upper limit of normal; AST = Aspartate aminotransferase; IV = Intravenous 
LFT = liver function tests; INR = International Normalized Ratio
Section 6.3.1.5 Management of Gastrointestinal Events (Diarrhea or Colitis)
REVISED TEXT:
Signs/symptoms may include, but are not limited to: diarrhea, constipation, abdominal 
pain, cramping and/or bloating, nausea and/or vomiting, blood and/or mucus in stool with 
or without fever, rectal bleeding, peritoneal signs consistent with bowel perforation, and 
ileus. All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.


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Table 11 Guidelines for Dose Modification and Management of Gastrointestinal 
Events (Diarrhea or Colitis)
REVISED TEXT:
Severity
Management
Follow-up
Grade 1

Administer anti-diarrheal and 
symptomatic treatment as 
appropriate
Symptoms resolve to baseline within 7 days:

Provide close follow-up to evaluate for increased severity.
Symptoms ongoing > 7 days:

Consider following algorithm for Grade 2 events
Grade 2

Interrupt study drug(s)a

Administer antidiarrheal and 
symptomatic treatment

Consider corticosteroids

Discuss with Sponsor/Medical 
Monitor
Symptoms resolve to ≤ Grade 1 or baseline within 3 days:

resume study drug(s)
Symptoms ongoing >3 days, blood or mucus in stool, or 
ulceration/bleeding on endoscopy:

consider GI consultation and endoscopy to confirm or rule 
out colitis 

Start systemic corticosteroids (e.g. 0.5 mg/kg/day of 
prednisone or equivalent)

Continue steroids until improvement to Grade 1 or 
resolution; taper steroids as medically appropriate

Resume study drug(s) if symptoms have improved to 
Grade 1 and steroid dose is 10 mg prednisone/day or less

If symptoms continue or worsen to Grade 3-4, see below
Grade 3

Interrupt study drug(s)a

Assess for bowel perforation; 
do not administer 
corticosteroids if present

Consult gastrointestinal (GI) 
service, perform endoscopy 
with biopsy

Administer 1-2 mg/kg/day IV 
methylprednisolone  

Discuss with Sponsor/Medical 
Monitor

When symptoms improve to ≤Grade 1, taper steroids over 
at least 1 month, then consider restarting treatment

If corticosteroid therapy does not reduce initial symptoms 
within 48 to 72 hours, treat with additional anti-
inflammatory measures. Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a 
prolonged steroid taper over 45-60 days.  

If symptoms worsen during steroid taper, retaper starting at 
a higher dose followed by a more prolonged taper.  
Recurrence after rechallenge:

Discontinue study drug(s) permanently unless 
otherwise agreed upon by the Sponsor/Medical Monitor 
and Investigators
Grade 4

Discontinue study drug(s)

Immediately inform 
Sponsor/Medical Monitor

Management as per Grade 3
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor.  
IV = Intravenous


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Section 6.3.1.7 Management of Endocrine Events
REVISED TEXT:
Signs/symptoms may include, but are not limited to: fatigue, weakness, headache, mental 
status and/or behavior changes, fever, vision disturbances, cold intolerance, abdominal 
pain, unusual bowel habits, loss of appetite, nausea and/or vomiting, and hypotension.  
Endocrine events may include the following AE terms: new-onset type 1 diabetes
mellitus, adrenal insufficiency, hyperthyroidism, hypophysitis, hypopituitarism, 
hypothyroidism, thyroid disorder, and thyroiditis.
Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and/or electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes an adrenal crisis and must be considered a medical emergency
Dose modification guidelines for endocrine events are provided in Table 13.  


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Table 13
Guidelines for Dose Modification and Management of Endocrine 
Events
Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and/or electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes an adrenal crisis and must be considered a medical emergency.
Severity
Management
Follow-up
ModerateGrade 2

Signs and/or 
symptoms of 
dysfunction

Endocrinopathies 
requiring hormone 
replacement or 
medical intervention

Consider interruption of study 
drug(s)a if symptomatic

Assess endocrine function

Consider pituitary imaging

Administer up to 1-2 mg/kg/day IV 
methylprednisolone if clinically 
indicated

Initiate appropriate hormone-
replacement therapy

Consider consultation with 
endocrinology

Discuss with Sponsor/Medical 
Monitor

Consider resuming study agent(s) 
when:

Taper steroids as clinically indicated

Consider resuming study agent(s) 
when Ssubject is stable (on hormone-
replacement therapy if indicated), 
symptoms have resolved or return to 
baseline, and the subject is receiving 
≤10 mg prednisone or equivalent per 
day

Subject is receiving ≤10 mg 
prednisone or equivalent per day
SevereGrades 3-4

Adrenal crisis or 
other adverse 
reactions requiring 
hospitalization, 
urgent medical 
intervention.

Consider interruption of study 
drug(s)a

Discuss with Sponsor/Medical 
Monitor

Consider immediate initiation of 1-
2 mg/kg/day IV 
methylprednisolone

Consult endocrinology

Other management as above

Taper steroids over at least 1 month
Consider resuming study agent(s) when:

Subject is stable (on hormone-
replacement therapy if indicated) 
and symptoms have resolved or 
return to baseline

Subject is receiving ≤10 mg 
prednisone or equivalent per day
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor.  
IV = Intravenous


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ADDED SECTION:
Section 6.3.1.11 Renal Failure or Nephritis
Table 17
Guidelines for Dose Modification & Management of Renal Failure or 
Nephritis
Severity
Management
Follow-up
Grade 1
Symptomatic treatment as appropriate
Symptoms resolve to baseline within 7 days:

Provide close follow-up to evaluate for increased 
severity.
Symptoms ongoing > 7 days:

Consider following algorithm for Grade 2 events
Grade 2

Interrupt study drug(s)a

Consultation with nephrology is 
strongly recommended

Consider administration of oral or IV 
corticosteroids

Discuss with Sponsor/Medical 
Monitor
Symptoms resolve to baseline within 7 days: 

resume study drug(s)
Symptoms ongoing > 7 days:

Discontinue study drugs

If symptoms continue or worsen to Grade 3-4, see 
below
Grade 3

Interrupt study drug(s) a

Administer 1-2 mg/kg/day IV 
methylprednisolone 

Consultation with nephrologist is 
strongly recommended

Discuss with Sponsor/Medical 
Monitor
Symptoms improve to ≤ Grade 2:

continue steroids until improvement to ≤ Grade 1 or 
baseline; taper steroids over at least one month
Symptoms ongoing ≥12 weeks

permanently discontinue study drugs
Grade 4

Discontinue study drug(s)

Immediately inform Sponsor/Medical 
Monitor

Management as per Grade 3
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor.  
IV = Intravenous


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Section 6.3.1.12, Table 18
REVISED TEXT
Table 18
Biomarker Panel
Biomarker
Relationship to Adverse Event
Serum tryptasea
IgE-related infusion reaction (Allergic/anaphylaxis) 
[Schwartz, 2006]
Serum CRPa
Elevated in CRS [Lee, 2014]
Serum ferritina
Elevated in CRS [Lee, 2014]
Serum Plasma cytokine 
panelb
(IFN-γ*^, TNF-α*^, IL-2*, 
IL-4, IL-5*, IL-6*^, IL-8*, 
IL-10*, IL-12p70, IL-13, and 
IL-17)
* Reported to be elevated in CRS [Lee, 2014]
^ consistently reported as elevated in CRS [Lee, 2014]
CRP=C-reactive protein; CRS= Cytokine release syndrome; IFN-= Interferon gamma; TNF-= Tumor necrosis factor 
alpha; IL = Interleukin. 
a.
Performed by PI designated local laboratory
b.
Performed by GSK designated laboratory
Section 6.8.2 Pembrolizumab Overdose
REVISED TEXT:
An overdose of pembrolizumab will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any overdose of pembrolizumab, or follow up to an 
overdose, whether or not related to the Sponsor’s product, must be reported within 5 days
to GSK as an AESI, either by electronic media or paper.
Section 6.10 Concomitant Medications and Non-Drug Therapies
ADDED TEXT:
Medications or vaccinations specifically prohibited (see Section 6.10.2) are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director.  The final decision on any supportive therapy or vaccination 


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rests with the investigator and/or the subject's primary physician.  However, the decision 
to continue the subject on trial therapy or vaccination schedule requires the mutual 
agreement of the investigator, the Sponsor and the subject
Section 6.10.1 Permitted Medications and Non-Drug Therapies
REVISED TEXT:
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusion of blood and blood products, and treatment with antibiotics, 
antiemetics, antidiarrheals, and analgesics, as appropriate. Seasonal flu vaccine is 
permitted as an injection only. Intra-nasal flu vaccine is excluded. Elective palliative 
surgery or palliative radiation may be permitted on a case-by-case basis in agreement 
with the Medical Monitor, if these do not include any "target" lesions.are not performed 
to alleviate symptoms resulting from disease progression.
Growth Factors and Bisphosphonates:  The use of growth factors, RANK-L inhibitors,
and bisphosphonates (if on a stable dose for at least 4 weeks) is permitted while 
participating in this study.  However, the initiation of growth factors and bisphosphonates 
is not allowed during the first 4 weeks of study treatment, unless used in the management 
of toxicity and agreed upon by the investigator and Medical Monitor.
Section 6.10.2 Prohibited Medications and Non-Drug Therapies
4th bullet:
DELETED TEXT:
RANKL inhibitors (e.g. denosumab).
Section 7 Study Assessments and Procedures
REVISED TEXT:
If assessments are scheduled for the same nominal time, it is recommended that then the 
assessments should occur in the following order: 12-lead ECG, vital signs, and blood 
draws.  The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.
Section 7.1 Time and Events Table
REVISED TEXT:
Table 19 Time and Events Table – Monotherapy and Combination Therapy


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Scrna/b
Treatmenta
Follow-up
Weeka
≤4
0
1
2
3
4
5
6
9
12
> 12 - 48c
≥49 -105c
TDVd
DFS FUe
SFUf
Day
≤28
1
8
15
22
29
36
43
64
85
106-337
≥344-736
30d after 
last dose
Q12W
Q12W
Dose
1
2
3
4
5
6-17
18-36
Informed Consent
X
Inclusion/Exclusion
X
X
Demographics, Medical History, 
Prior Medications
X
Concomitant Medications
Assess at each visit from first dose until the TDV visit
Subject Registration
X
Anti-Cancer Treatment
X
X
X
Part I Study Treatment Monotherapy
Administer GSK3174998 (± 23
days)g
X
X
X
X
X
X
X
Part 2 Study Treatment Combination Therapy (note: administer pembrolizumab 1 hour after the end of the GSK3174998 infusion)
Administer GSK3174998g
X
X
X
X
X
X
X
Administer Pembrolizumabg
X
X
X
X
X
X
X
Safety
AE/SAE Assessment
Assess at each visit from first dose until the TDV visit for AEs and until 90 days after last dose for AESI and SAEsd
ECOG PS
X
X
X
X
X
X
X
X
X
X
Q6w
Q6w
X
Physical Examination
X
X
X
X
X
X
Q6w
Q6w
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECGkECGl
X
X l
X l
X
X
Xl
Q12w
Q12w
X
Laboratory Assessments (Safety) – perform assessments pre-dose on each dosing day
Hepatitis B and C
X
Pregnancy Test: Serum β-hCG
≤3d
As clinically indicated Monthly (urine or serum)
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid function tests
X
X
X
XQ6W
Q6W
X
Calculated CrCl
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessments
Tumor imaging h
X
Xj
X
Q12W
Telephone call for survival 
X


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Scrna/b
Treatmenta
Follow-up
Weeka
≤4
0
1
2
3
4
5
6
9
12
> 12 - 48c
≥49 -105c
TDVd
DFS FUe
SFUf
Day
≤28
1
8
15
22
29
36
43
64
85
106-337
≥344-736
30d after 
last dose
Q12W
Q12W
Dose
1
2
3
4
5
6-17
18-36
statusf
Tumor Biopsies
Archived tumor i
X
Fresh tissue samplei
X
X
X
PD tissue sampleki
Xki
Foot notes d, g, h, i and j
d.   The treatment discontinuation visit should be completed 30 days from the last dose of study treatment. The window for this visit is +10 days. All AEs and concurrent medications will
be collected until at least 30 days after the last dose of study treatment. All AESIs and SAEs and any concurrent medications relevant to the reported AESIs and SAEs will be 
collected until at least 90 days after the last dose of study treatment. If another anti-cancer agent is started during the 90 day reporting period, only AESI and SAEs that occur 
within 30 days from the last dose of study drug(s) should be recorded. or until the start of new anticancer therapy, whichever occurs first. Any drug or study-related SAEs occurring
after the 90-day window will be reported according to directions provided in(see Section7.4.1.1)
g.    Dosing of GSK3174998 and pembrolizumab at every 3-week intervals is shown in the Time and Events Table; however, dosing of GSK3174998 may be delayed due to toxicity. 
During the combination phase, GSK3174998 should be administered first, and pembrolizumab should be administered at least 1 hour and no more than 2 hours following the end 
of the GSK3174998 infusion. GSK3174998 will be dosed for a maximum of 48 weeks. Pand pembrolizumab will be dosed for a maximum of 2 years or 35 cycles, whichever 
comes first
h.    Screening tumor imaging must be obtained within 28 days of the first dose. Tumor imaging will be performed every 12 weeks (1 week) until disease progression has been 
confirmed by irRECIST; Subjects whose disease progresses must have a confirmatory scan performed at least 4 weeks after the date of assessment during which the first 
indication of PD was demonstrated. additional scans may be obtained if PD is suspected but not confirmed Immune-related RECIST will be used to determine treatment decisions 
for PD and the primary endpoint analysis will use irRECIST. If a subject has achieved a CR or PR in the previous radiologic assessment, a repeat scan should be performed as a 
part of the confirmation of response, within at least 4 6 weeks to confirm the response. At the TDV, tumor imaging is only required if the last disease assessment did not show PD 
and was performed 6 weeks before TDV. During the DFS FU visits (performed when a subject has permanently discontinued study treatment before disease progression has 
been documented), tumor imaging will be obtained every 12 weeks (1 week) until PD, initiation of a new anticancer treatment, or death, whichever comes first
i.     A fresh tumor biopsy should be attempted at screening (before first dose) and at Week 6 (after the 3rd dose of study treatment +1 week). Fresh biopsies are mandatory for all 
patients  in the Pharmacodynamic Cohort and the Dose Expansion phase.  During the Dose Expansion phase, Oonce evaluable paired tumor biopsies are collected for up to 10 
subjects in the dose expansion phases, this requirement may be waived. Tumor lesions planned for biopsy must not be used as indicator lesions for assessment of disease, unless 
discussed and agreed with the GSK Medical Monitor. For subjects in the initial dose escalation cohorts, where biopsy is not mandatory, , a recent archival tumor specimen is 
acceptable if it is not feasible to obtain a fresh biopsy.
j.    The 6-week disease assessment for patients in the Pharmacodynamic Cohort is timed to coincide with the on-treatment (6 week) tumor biopsy. The disease assessment should 
be performed after the tumor biopsy.


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Table 19 Time and Events Table – Pharmacokinetics, Antidrug Antibodies, and Pharmacodynamics (Parts 1 and 2).
Treatment
Day
1
2
8
15
22
23
29
36
43
64
85
106
≥148
30 D 
after 
Last 
Dose
12 Wks 
Post-
Treatment 
1 week
Dose
1
2
3
4
5
6
≥8
Pharmacogenetics 
(6 mL)a
X
Receptor 
occupancy and 
phenotyping 
panels(10 mL)
Pre
EOI+4hg
EOI+24h
X
X
Pre
EOI+4hg
Pre
EOI + 4hg
X
X
Plasma + PBMC 
prep (20 mL)b
Pre
X
Pre
Pre
X
X
Cytokines (5 mL)
Pre
EOI+4h
EOI+24h
X
Pre
EOI+4h
Pre
EOI+4h
Plasma for cfDNA + 
exosomes (10 mL)
Pre
At time of 
biopsy if 
done
Serum (5 mL)
Pre
GSK3174998
Pharmacokinetics 
(1 mL)
Pre
EOI+30m
EOI+4h
EOI+24hd
X
X
Pre
EOI+30m
EOI+4h
EOI+24
X
X
Pre
EOI+30m
Pre
EOI+30m
Pre
EOI+30m
Pre
EOI+30m
Pree
X
X
Part 2 only: 
Pembrolizumab 
Pharmacokinetics 
(3  mL)
Pre
EOPI+30m
EOI+24h
X
X
Pre
Pre
Pre
Pree
X
X
Anti- GSK3174998 
antibodiesc,f (5 mL)
Pre
Pre
Pre
Pre
Pree
X
Xf
Part 2 only: Anti-
Pembrolizumab 
antibodiesc,f (56
mL)
Pre
Pre
Pre
Pre
Pree
X
Xf


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Foot note no. f and g:
f. In the event of a hypersensitivity reaction that is either 1) clinically-significant in the opinion of the investigator, or 2) leads to the subject withdrawing from the study, blood samples 
should be taken from the subject for immunogenicity testing at the time of the event and again 30 days, 12 weeks, and 24 weeks after.
g.  If the EOI+4h RO sample is scheduled to be collected after the last lab courier pick-up time of the day, the sample should be collected as late as possible to enable processing and 
shipping on the same day as collection.


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Section 7.2.2 Baseline Documentation of Target and Non-Target Lesions
Last paragraph
REVISED TEXT:
Confirmation of CR and PR are required per protocol.  Confirmation assessments must be 
performed within 4 to at least 4 weeks after the criteria for response have initially been 
met and may be performed at the next protocol scheduled assessment.  If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required (e.g., evaluations must occur at each protocol 
scheduled time point regardless of unscheduled assessments).
Section 7.3.1 Evaluation of Anticancer Activity
REVISED TEXT:
7 and 8 bullet points:

Subjects whose disease responds (either CR or PR) should have a confirmatory disease 
assessment performed at least 4 weeks after the date of assessment during which the 
response was demonstrated. More frequent disease assessments may be performed at the 
discretion of the investigator.  

Subjects whose disease progresses (PD) must have a confirmatory scan performed at least 
4 weeks after the date of assessment during which the first indication of PD was 
demonstrated.
Section 7.4.1.1 Time Period and Frequency for Collecting Adverse Events and 
Serious Adverse Events Information.
REVISED TEXT:
Any AESI and SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will 
be recorded from the time a subject consents to participate in the study up to 90 days after
the last dose of study drug(s). If another anti-cancer agent is started during this time the 
90 day reporting period, only AESI and SAEs that occur within 30 days from the last 
dose of study drug(s) should be recorded.  until 30 days after the last dose, or initiation of 
other anti-cancer agent (whichever is later). SAEs must be reported within 24 hours to the 
Sponsor either by electronic media or paper.
Section 7.4.2 Pregnancy
REVISED TEXT:
1 st bullet point:

Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of dosing until 120 days after the last dose of study medication.


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Section 7.4.3 Physical Exams
REVISED TEXT:

A complete physical examination will be done at screening and will include assessments 
of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.  

A brief, targeted physical examination will be done at all other timepoints, unless 
physician’s judgement requires a full exam include assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

For melanoma subjects, a full body dermatological examination will be performed by a 
dermatologist (or suitably qualified physician) to identify abnormal skin lesions within 
the 28 day screening period.  All findings will be photographed and identified during 
screening.  Subsequently, Bbrief skin examinations will be performed as indicated in the
will be included in the PE exams as per the Time and Events Table (Section7.1, Table 19) 
or more frequently as necessitated.
Section 7.4.4  Vital Signs
REVISED TEXT:
2 nd point:
Three readings of blood pressure and pulse rate should be taken, the first reading should 
be rejected and the second and third averaged to give the measurement to be recorded in 
the eCRF.
Section 7.4.6  Clinical Safety Laboratory Assessments
REVISED TEXT:
Added Thyroid Function Tests
Table 29   Clinical Laboratory Assessments
Added Chloride and Carbon Dioxide in Clinical chemistry assessment
Added urine -hCG Pregnancy test to Other Screening Tests


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Section 7.6.1 Blood Biomarkers:
REVISED TEXT:
2 nd paragraph:
Blood samples will also be collected for isolation of PBMC and plasma, and serum. 
Plasma and serum samples will be used for an analysis of circulating soluble factors in 
relation to T-cell activation, cfDNA, exosomes circulating proteins, and may be analyzed 
for soluble OX40 and soluble OX40-drug complex depending on the availability of the 
assays. Factors to be analyzed may include but are not limited to: the presence of IFN-γ, 
TNF-α, IL-2, IL-4, IL-5, IL-6, IL 10, IL-8, IL-12p70, IL-13, and IL-17 as well as 
antibodies against tumor, self tumor mutations, gene expression (RNA or protein) or viral 
antigens.
Section 7.6.2  Tumor Tissue
REVISED TEXT:
Archival tumor tissue,  as well as fresh pre- and post on-treatment biopsies in subjects in 
the pharmacodynamic cohorts, at least 10 subjects of the dose-expansion cohorts and if 
possible in the dose escalation cohorts will be evaluated by IHC for expression of 
phenotypic and functional immune cell markers on tumor infiltrating lymphocytes (TILs) 
and other immune cells and as well as immune signaling markers on the surface of tumor 
cells (e.g. including, but not limited to PD-L1), to understand antitumor immune 
responses. In addition, when possible, similar analyses will be performed on tumor tissue 
samples obtained upon progression. Additionally, tumor tissue may be sequenced to 
assess TCR diversity as well as evaluated for any DNA/RNA/protein changes correlating 
with response.
In the pharmacodynamic cohort mandatory fresh pre- and on treatment biopsies are 
required (see Table 18 for timing). These mandatory biopsy samples will be evaluated as 
previously described for the archival, pre and post treatment, and progression biopsies.  
If feasible, for all of the fresh pre-and on-treatment biopsies the same tumor site should 
be used for both samples.  If not possible, the post treatment biopsy should be obtained 
from the same anatomical site as the pre-dose biopsy.   The tumor site chosen for biopsy 
must not be the used as an indicator lesion for assessment of disease unless otherwise 
discussed and agreed upon with the GSK medical monitor.
Other biomarkers may be evaluated as determined by additional data. Details for sample 
collection, processing, storage, and shipment will be provided in the SRM
Blood and tumor samples may be used for purposes related to the quality assurance of the 
laboratory tests described in this protocol, or for the development of a diagnostic assay.


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ADDED SECTIONS:
Section 7.7  Anti-Drug Antibodies
Section 7.7.1  Blood Sample Collection
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3174998 and pembrolizumab. Serum samples for testing anti-GSK3174998 and 
anti-pembrolizumab antibodies will be collected as described in the Time and Events 
schedule (Section 7.1). The actual date and time of each blood sample collection will be 
recorded.
Details of blood sample collection (including volume to be collected), 
processing, storage, and shipping procedures are provided in the SRM.  
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.
In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing at 
the time of the event and again 30 days, 12 weeks, and 24 weeks after. For subjects who 
prematurely withdraw from the study, immunogenicity testing will occur at withdrawal 
and at follow-up 30 days, 12 weeks, and 24 weeks after the last dose.
Section 9.1.2 Part 1: Monotherapy Dose Expansion (GSK3174998)
REVISED TEXT:
The null hypothesis for the secondary endpoint- overall response rate is:
H0: p≤10%.
The alternative hypothesis is:
HA: p>10%.
Section 9.2 Sample Size Considerations
REVISED TEXT:
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data according to the 
objectives of each part of the study.  
The study will enroll up to approximately 186 264subjects with tumor types that may 
include NSCLC, SCCHN, RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC


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Section 9.3 Data Analysis Considerations
REVISED TEXT:
1 st paragraph:
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including biomarker and PK data and the safety profile of prior cohorts.  In addition, the 
recommended dose from a Continuous Reassessment Method (N-CRM) analysis 
[Neuenschwander, 2008] willmay be calculated.  The N-CRM is a type of Bayesian 
adaptive dose-escalation scheme.  The method is fully adaptive and makes use of all the 
DLT information available at the time of each dose assignment. The Fixed and Adaptive 
Clinical Trial Simulator (FACTS) will be used to conduct the N-CRM analysis. The DLT 
information on all subjects enrolled in the trial are used to update the estimated dose-
toxicity relationship and provide supportive information in addition to the 3+3 design in 
the next escalation/de-escalation decision. ; the 3+3 algorithm is expected to be used as 
the primary criteria for dose escalation.
Section 9.3.2   Interim Analysis
ADDED TEXT:
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in section 4.1 and section 9.3. The Steering Committee will 
guide the transition of the study from dose escalation to cohort expansion for both 
monotherapy and combination therapies. 
For dose expansion cohorts, continuous assessment of efficacy and safety will be 
performed after first interim analysis based upon a minimum of 10 subjects in at least one 
of the disease-specific cohort with available unconfirmed Overall Response data. The 
Steering Committee will monitor safety and efficacy over the course of the study 
following the randomization and futility rules for expansion cohorts as described in
section 4.1 and section 9.3.
Section 9.4.1.6 Primary Analyses
DELETED SECTION:
9.4.1.6   Anticancer Activity Analyses
The All Treated Population will be used for anticancer activity analyses. Since this is a 
Phase I study, anticancer activity will be evaluated based on clinical evidence and 
response criteria.  If data warrant, the response data will be summarized by dose level.  


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If the data warrant, PFS and duration of response will be calculated and listed for each 
subject.  PFS is defined as time from the date of first dose to the date of disease 
progression according to clinical or radiological assessment or death due to any causes, 
whichever occurs earliest.  Duration of response is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause 
among subjects who achieve an overall response (i.e., unconfirmed or confirmed CR or 
PR). If the subject does not have a documented date of event, PFS will be censored at the 
date of the last adequate assessment.  Further details on rules of censoring will be 
provided in the RAP.  PFS will be summarized using the Kaplan-Meier method if the 
data warrant.
Section 9.4.2   Secondary Analyses
ADDED  SECTION:
9.4.2.1 Anticancer Activity Analyses
The All Treated Population will be used for anticancer activity analyses. Since this is a 
Phase I study, anticancer activity will be evaluated based on clinical evidence and 
response criteria.  If data warrant, the response data will be summarized by dose level.  
irRECIST is the primary measure of clinical activity for response endpoints and PFS; 
RECIST v1.1 guidelines are used for disease measurements. 
If the data warrant, ORR, DCR, TTR, DOR, PFS and OS  will be calculated and listed for 
each subject. 
ORR is defined as the percentage of subjects with a best overall confirmed CR or PR at 
any time as per disease-specific criteria (refer to Appendix 12.5). DCR is defined as the 
percentage of subjects with a confirmed CR + PR at any time, plus SD 12 weeks.
DOR will be summarized for subjects with a confirmed CR or PR and is defined as the 
first documented evidence of CR or PR until disease progression or death due to any 
cause among subjects who achieve an overall response (i.e., unconfirmed or confirmed 
CR or PR). Censoring rules will follow those of the PFS analysis. TTR is defined as the 
interval from the first dose of study treatment to the date of the first documented CR or 
PR.
PFS is defined as time from the date of first dose to the date of disease progression 
according to clinical or radiological assessment or death due to any cause, whichever 
occurs earliest. For the analysis of PFS, if the subject received subsequent anti-cancer 
therapy prior to the date of documented events, PFS will be censored at the last adequate 
assessment (e.g. assessment where visit level response is CR, PR or SD) prior to the 
initiation of therapy. Otherwise, if the subject does not have a documented date of event, 
PFS will be censored at the date of the last adequate assessment.
OS is defined as the interval from the first dose of study treatment to the date of death, 
irrespective of the cause of death. If a subject does not have a documented date of death, 
time of death will be censored at the date of last contact.  


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Further details on rules of censoring will be provided in the RAP.  PFS and OS will be 
summarized using the Kaplan-Meier method if the data warrant.
Section 9.4.2.4   Immunogenicity Analyses
DELETED TEXT:
First two paragraphs:
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3174998 and pembrolizumab. Serum samples for testing anti-GSK3174998 and 
anti-pembrolizumab antibodies will be collected as described in the Time and Events 
schedule (Section7.1). The actual date and time of each blood sample collection will be 
recorded.
Details of blood sample collection (including volume to be collected), 
processing, storage, and shipping procedures are provided in the SRM.  
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.
In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing at 
the time of the event and again 30 days, 12 weeks, and 24 weeks after. For subjects who 
prematurely withdraw from the study, immunogenicity testing will occur at withdrawal 
and at follow-up 30 days, 12 weeks, and 24 weeks after the last dose.
Section 9.4.3   Other Analyses
ADDED SECTION:
9.4.3.3 Longitudinal tumor size modelling
Longitudinal tumor size data will be analyzed using a non-linear mixed effects model to 
determine tumor kinetic constants. These parameters may be related to other patient 
characteristics, such as dose group, GSK3174998 exposure, or biomarkers.
Section 11   References
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structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. 
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ADDED REFERENCES:
Hamid O, Thompson JA, Dlab A, Ros W, Eskens ALM, et al. First in Human Study of an 
OX40 Agonist Monoclonal Antibody PF-04518600 (PF-8600) in Adult Patients With 
Select 
Advanced 
Solid 
Tumors: 
Preliminary 
Safety 
and 
Pharmacokinetic 
/Pharmacodynamic Results.  Abstract J Clin Oncol 34, 2016 (suppl; abstr 3079)


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Hansen AR, et al. A first-in-human phase I dose escalation study of the OX40 agonist 
MOXR0916 in patients with refractory solid tumors. In: Proceedings of the 107th Annual 
Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New 
Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract CT097.
Infante JR, Hansen AR, Pishvaian MJ, Chow LQ, McArthur G,  et al. A phase Ib dose 
escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab 
in patients with advanced solid tumors. J Clin Oncol 34, 2016 (suppl; abstr 101).
REVISED REFERENCES:
KEYTRUDA (pembrolizumab) prescribing information. Merck Sharp & Dohme 
Corporation, Whitehouse Station, New Jersey, USA, September 2014 October 2015.  
Merck Sharp & Dohme Corp.  Investigator’s brochure for pembrolizumab. 19-Dec-2014
31-Aug-2015.
Section 12.1 Appendix 1 Abbreviations and Trademarks
REVISED TEXT:
Added Abbrevations
Deleted abbrevations
CTC
Circulating Tumor Cell
DOR
Duration of Response
STS
Soft tissue sarcoma
TTR
Time to Response


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Section 12.5 Appendix 5: Guidelines for Assessment of Disease, Disease  Progression 
and Response Criteria – adapted from RECIST version 1.1.
REVISED TEXT:
Evaluation of target lesions
New, measurablea lesions Incorporated into tumor burden
New, nonmeasurable 
lesions 
Do not define progression (but preclude mCR irCR)
irCR
Disappearance of all lesions in two consecutive observations not less 
than 4 weeks apart.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to <10 mm.
irPR
c.
30% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart
irSD
30% decrease in tumor burden compared with baseline cannot be 
established nor 20% increase compared with nadir
irPDb
At least 20% increase in tumor burden compared with nadir (at any 
single time point) in two consecutive observations at least 4 weeks 
apart.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
a.
Measureable according to RECIST v1.1.  
b.
Treatment decisions will be based upon the immune-related RECIST criteria.  
Table 23 Evaluation of Overall Response for Subjects with Measurable Disease at 
Baseline.
REVISED TEXT:
Evaluation of best overall response:
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after the first dose at a minimum interval of 84 days.  
If the minimum time for SD is not met, best response will depend on the subsequent 
assessments.  For example if an assessment of PD follows the assessment of SD and SD 
does not meet the minimum time requirement the best response will be PD.  
Alternatively, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.


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Section 12.7  Appendix 7: Genetic Research
REVISED TEXT:
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including GSK3174998 or pembrolizumab  or any 
concomitant medicines;

NSCLC, SCCHN, RCC, melanoma, bladder, STS, TNBC or MSI CRC, 
susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate
Section 12.8.1 Definition of Adverse Events
2nd box, 5th bullet
REVISED TEXT:

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae). See Section 6.8.2
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Section 12.8 Appendix 8 Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.
REVISED TEXT:
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and  email to usnaps
or fax to 
.Site will enter the SAE data into the 
electronic system as soon as it becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information to the Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
Section 12.11 Appendix 11: Adverse Events of Special Interest
REVISED TEXT:
1 st paragraph
The list of terms and reporting requirements for GSK AESI are provided below.  These 
are selected non-serious AEs and SAEs that must be reported to the GSK medical 
monitor within 24 hours regardless of relationship to study treatment.  Any event that 
meets the criteria described below must be reported regardless of investigator-determined 
relationship to study treatment or if considered immune-related (unless otherwise 
specified).   Investigators/study coordinators/designated site personnel are required to 
record these experiences in the eCRF (as described in the eCRF completion guidance 
document) and to provide supplemental information (such as medical history, 
concomitant medications, investigations, etc.) about the event.
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Added Text following the table:
Pembrolizumab-specific events of clinical interest for this trial include:

An overdose of pembrolizumab, as defined in Section 6.8.2 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is 
not associated with clinical symptoms or abnormal laboratory results. 

An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.


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12.13.3.
Amendment 3 Protocol Changes for Amendment 3 (16-MAR-
2018) from the Protocol Amendment 2 (16-AUG-2016)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 3 includes the addition of preliminary clinical, safety, PK and PD data;
updated pembrolizumab background and dose rationale, study design, with description of 
cohort expansion populations for Part 2B, modified dose rationale for cohort expansion 
(Part 2B). Updated risk assessment, Inclusion/Exclusion Criteria to define cohort 
expansion population. Consolidated Section 6.3 Dose and Safety Management Guidelines
and minor changes to Time & Events tables. Modified Section 9 (Statistical 
Considerations and Data Analysis) – updated hypothesis, sample size considerations, 
futility analysis and stopping rules. Throughout the document minor editorial and 
document formatting revisions were made (minor, therefore have not been summarized
[e.g. Table no., figure no., section no. etc]).
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Specific Changes
Section TITLE PAGE
Rationale for Change
The sponsor information was updated based on internal GSK team personnel changes.
REVISED TEXT:
 
 
Section MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Rationale
Medical monitor information was updated
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REVISED TEXT:
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event (SAE) Contact Information:
Role
Name
Office Phone Email Address
Mobile
Fax 
Primary 
Medical 
Monitor 
, 
MD
Secondary 
Medical 
Monitors
, 
MD, PhD
, 
MD
SAE contact 
information 
 
Section PROTOCOL SYNOPSIS Objective/Endpoints
Rationale for Change
Additional pharmacodynamic endpoints added
REVISED TEXT:

Pharmacodynamic endpoints: Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by GSK3174998, along with the 
phenotype, quantity, and activation state of T cells in the periphery, T-cell 
receptor (TCR) diversity, expression of circulating soluble factors, and changes 
in genomic DNA and gene expression, and mutational load. Assessment of 
tumor biopsies via immunohistochemistry (IHC) for the numbers of tumor-
infiltrating lymphocytes and other immune cells expressing key phenotypic 
markers. Changes in gene expression (RNA and protein), TCR diversity or 
mutational load (genomic DNA)..  
Section PROTOCOL SYNOPSIS Type and Number of Subjects
Rationale for Change
Added new tumor type
REVISED TEXT
The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma 
PPD
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(RCC), melanoma, bladder cancer, soft tissue sarcoma (STS), triple-negative breast 
cancer (TNBC), and colorectal carcinoma displaying high microsatellite instability (MSI 
CRC).  
Section 2.3.5. Preliminary Clinical Data for GSK3174998
Rationale for Change
Preliminary clinical data updated based on data from the ongoing study
REVISED TEXT
Data are summarized for the ongoing first time in human study with a clinical data cut-
off of 17 May 2016 09 Jan 2018. Data are reported for 104 subjects. 45 subjects received 
doses up to 10 mg/kg of GSK3174998 monotherapy and 61 subjects received doses up to 
1.0 10 mg/kg of GSK3174998 + 200 mg of pembrolizumab.  Two subjects crossed over 
from monotherapy to combination therapy.
Data are reported for six subjects enrolled at the following GSK3174998 dose levels: 
0.003 mg/kg (Cohort 1, n=1), 0.01 mg/kg (Cohort 2, n=1), and 0.03 mg/kg (Cohort 3, 
n=4).  At the time of reporting, three subjects had discontinued treatment due to disease 
progression (one at each dose level).  
Section 2.3.5.1.1. Safety Data - Part 1
Rationale for Change
Preliminary safety data updated based on data from the ongoing study
REVISED TEXT:
No dose-limiting toxicities, or treatment-related Grade 4, or Grade 5 toxicities were 
reported. Grade 3 asthenia and Grade 3 lymphocytopenia were reported in a single patient 
and attributed to study treatment. A single event in another subject led to treatment 
discontinuation,; Grade 5 stroke manifested as aphasia, attributed to disease progression. 
No dose-limiting toxicities, treatment-related Grade 3 or 4 toxicities,The most common 
AEs regardless of attribution were fatigue (13, 29%), back pain (9, 20%), diarrhea (9, 
20%), nausea (9, 20%), vomiting (9, 20%), asthenia (8, 18%), anemia, (7, 16%), 
headache (6, 13%), constipation (5, 11%), cough (5, 11%), dyspnoea (5, 11%), myalgia 
(5, 11%), pain in extremity (5, 11%), and pyrexia (5, 11%). The most common AEs
attributed to treatment by the investigator included diarrhea (5, 11%) and fatigue (5, 
11%). and no treatment discontinuations due to AEs were reported.  One SAE was 
reported (Grade 3 urinary tract infection and Grade 4 hydronephrosis) in a subject with 
bladder cancer treated at the 0.003 mg/kg dose level; the SAE was attributed to disease 
progression.  The subject discontinued study treatment due to disease progression and at 
that time had received 2 doses of GSK3174998.  All other AEs were Grade 1 or 2 in 
severity. One AE (fatigue) was reported in two subjects; all other events were reported 
once each: Actinic keratosis, anemia, arthralgia, asthenia, blood creatinine increased, 


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cough, diarrhea, dizziness, dry mouth, fall, headache, hernia, hyperkalemia, hypoesthesia, 
myalgia, nausea, pain in extremity, vomiting.  Two events (Grade 1 dry mouth, Grade 1 
nausea) were considered treatment-related.
Section: 2.3.5.1.2.
Safety Data - Part 2
Rationale for Change
Preliminary safety data updated based on data from the ongoing study
REVISED TEXT:
No treatment related Grade 4 or Grade 5 toxicities were reported. Three patients reported 
Grade 3 treatment-related AEs. Two dose limiting toxicities were reported. One patient 
with bladder cancer reported asymptomatic Grade 3 cardiac troponin and Grade 1 
myocarditis occurring 16 days after the first and only dose of study treatments. Both 
events were attributed to study treatments, resulted in discontinuation of treatment, and 
resolved with a short course of 500 mg methylprednisolone. Other treatment-related 
Grade 3 events included Grade 3 fatigue in one patient with colorectal cancer (resulting 
in treatment discontinuation), and Grade 3 diarrhea in a patient with bladder cancer.  The 
diarrhea lasted a single day, three days after the second dose of study drugs. A second 
dose limiting toxicity of Grade 2 pleural effusion was reported in a patient with triple 
negative breast cancer (0.03 mg/kg dose cohort).  Adverse events leading to treatment 
discontinuation included the Grade 3 myocarditis and Grade 3 fatigue described above, 
and Grade 3 abdominal pain not related to treatment in a patient with colorectal cancer. 
The most common AEs regardless of attribution were fatigue (15, 25%), decreased 
appetite, (12, 20%), pleural effusion (9, 15%), arthralgia (8, 13%), nausea (7, 11%), 
asthenia (6, 10%), cough (6, 10%), and diarrhea (6, 10%). The most common AEs
attributed to treatment by the investigator included fatigue (12, 20%), nausea (4, 7%), and 
pruritus (4, 7%).
For further details on the safety of GSK3174998, please refer to the IB [GlaxoSmithKline 
Document Number GlaxoSmithKline Document Number 2014N212091_00]
Section 2.3.5.2. Preliminary Pharmacokinetic Data (ENGAGE-1, Part 1A and 2A)
Rationale for Change
Preliminary PK data updated based on data from the ongoing study
REVISED TEXT:
Section 2.3.5.2 Preliminary Pharmacokinetic Data (ENGAGE-1, Part 1A and 2A: 
Part 1)
Maximum observed concentrations (Cmax) of GSK3174998 in plasma were in the 
predicted range anticipated for each dose level (44 ng/mL for 0.003 mg/kg, 267 ng/mL 
for 0.01 mg/kg, 458 1624 ng/mL for 0.03 mg/kg). Clearance was greater than anticipated 


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at the lower dose levels; this was considered to be due to target mediated clearance.  
Subject 4, dosed at 0.03 mg/kg was the heaviest subject treated (119 kg), thus received 
the largest dose and had the highest GSK3174998 exposure (1624 ng/mL).The PK of 
GSK3174998 was evaluated after IV administration at doses of 0.003 mg/kg to 10 mg/kg 
every 3 weeks in patients with solid tumors in Study 201212. Plasma PK samples (cut-off 
date 28 July 2017) were analyzed with a validated analytical method based on 
immunocapture and trypsin digestion, followed by ultra-high pressure liquid 
chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis with a lower 
limit of quantitation (LLOQ) of 10 ng/mL.
The median first cycle concentration-time profiles for Part 1A and Part 2A presented in 
Figure 2 initially exhibited a biexponential decline typical for mAbs- administered IV.  
At lower GSK3174998 concentrations, faster elimination and shorter half-lives were 
observed, indicating target-mediated disposition.  Consequently, AUC and trough 
concentrations were increasing more than proportionally with dose. Concentration-time 
profiles were similar between GSK3174998 alone and combination therapy, indicating 
that co-administration of pembrolizumab did not affect the PK of GSK3174998. Cmax 
values were approximaely dose-proportional and typical for mAbs.
At the time of data cut off (22 June 2017) 49% of subjects with available post-treatment 
data tested positive for anti-GSK3174998 anti-drug antibodies (ADA) across dose levels 
0.003–10 mg/kg GSK3174998 in Part 1A and 0.003–0.1 mg/kg in Part 2A. Positive ADA 
titers were detectable as early as three weeks after the first dose of GSK3174998.  Of the 
30 subjects with positive ADA titers, two subjects experienced infusion related reactions 
beginning with administration of the third dose of GSK3174998; no other infusion 
reactions were reported in the study.


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Figure 2 Median (range) time-concentrations profiles by dose group for GSK3174998 
alone or in combination with pembrolizumab
Notes: 
1. Preliminary data from Study 201212 (cut-off date 28 July 2017).
2. Samples reported below the limit of quantitation (0.01 g/mL) were assigned a value of 0.005 g/mL for the 
purposes of this graphical summary.
Section 2.3.5.3. Preliminary Receptor Occupancy Data (ENGAGE-1, Part 1A and 
2A) 
Rationale for Change
Preliminary receptor occupancy data updated based on data from the ongoing study
REVISED TEXT:
Section 2.3.5.3. Preliminary Receptor Occupancy Data (ENGAGE-1, Part 1A and 
2A: Part 1)
Receptor occupancy (RO) was assessed for CD3+ cells from peripheral blood.  
Preliminary receptor occupancy (RO) data after the first dose was higher than predicted; 
approximately 85% RO was seen in Subject 1 who received the lowest dose of 
GSK3174998 (0.003 mg/kg). Subject 4, who had the largest GSK3174998 exposure, had 
>90% RO throughout the first dosing period (21 days); while Subjects 6, 7, and 502, 
treated with the same dose level (0.03 mg/kg) had >90% RO for approximately 8 days 
during the first dosing period.Receptor occupancy (RO) was assessed for peripheral 


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blood CD3+ T cells in Part1A and 2A. Preliminary data indicated that a high degree 
(80%) of receptor occupancy is achieved initially (1 day after dosing) even for the 
lowest dose of 0.003 mg/kg GSK3174998 (Figure 3). For doses of 0.1 mg/kg or smaller 
receptor occupancy subsequently declines towards the end of the dosing cycle. Starting 
with 0.3 m/kg GSK3174998 continuously high receptor occupancy levels are observed 
over the whole 21-day dosing cycle. Qualitatively similar receptor occupancy profiles 
were observed when GSK3174998 was administered in combination with 200 mg 
pembrolizumab Q3W (Figure 3)
Figure 43 Median receptor occupancy profiles for varying doses of 
GSK3174998 alone or in combination with pembrolizumab
Notes: 
1. Preliminary data from Study 201212.
Section 2.3.5.4.
Preliminary Clinical Activity Data (ENGAGE-1)
Rationale for Change
Preliminary clinical data updated based on data from the ongoing study
REVISED TEXT:
2.3.5.4. Preliminary Clinical Activity Data (ENGAGE-1: Part 1)
Due to the frequency of disease assessments (every 12 weeks), few subjects had their first 
post-baseline disease assessments performed at the time of clinical data cut-off (17 May 


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2016) and no objective responses were observed. Subject 1 (0.003 mg/kg), 3 (0.01 
mg/kg) and 4 (0.03 mg/kg) discontinued treatment due to disease progression after 2, 4, 
and 3 doses of GSK3174998, respectively.
2.3.5.4.1.
Clinical Activity - Part 1A
At the time of the clinical data cut-off (09 Jan2018), one confirmed PR was reported at 
week 24 in a subject with STS (0.3 mg/kg GSK3174998), who subsequently discontinued 
treatment for PD at week 30. A subject with NSCLC (0.3 mg/kg GSK3174998) was 
reported to have SD for 24 weeks, and discontinued treatment with PD after 39 weeks. 
An additional 5 subjects were reported to have SD at week 12, but subsequently 
discontinued treatment for PD prior the next imaging assessment.
2.3.5.4.2.
Clinical Activity - Part 2A
At the time of the clinical cut-off (09 Jan 2018), clinical responses were reported for the 
combination of GSK3174998 and pembrolizumab. At the 0.01 mg/kg GSK3174998 + 
200 mg pembrolizumab dose level, one subject demonstrated a CR (MSI-CRC) and one 
subject with SCCHN demonstrated SD at week 24, and continues on treatment at week 
54. At the 0.1 mg/kg GSK3174998 + 200 mg pembrolizumab dose level, 3 subjects 
demonstrated a PR (melanoma, bladder and MSI-CRC). At the 0.3 mg/kg GSK3174998 
+ 200 mg pembrolizumab dose level, 1 subject with NSCLC demonstrated a PR, while a 
second subject with NSCLC demonstrated SD at week 15 and remained on treatment as 
of week 27.
Section 2.4 Pembrolizumab
Rationale for Change
Updated language as required
REVISED TEXT:
2.4.1 Pembrolizumab Background and Clinical Trials
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, 
thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an intravenous (IV) immunotherapy for advanced malignancies.  Keytruda™ 
(pembrolizumab) is indicated for the treatment of patients across a number of indications.  
For more details on specific indications refer to the Investigator brochure.[Merck Sharp 
& Dohme Corp, 2015] . 
Pembrolizumab, a humanized monoclonal antibody against the PD-1 protein, has been 
developed by Merck & Co for the treatment of patients with cancer. Pembrolizumab is 
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it is approved for the treatment of patients with advanced (unresectable or metastatic) 
melanoma in adults. Pembrolizumab has also been approved for treatment of patients 
with NSCLC in several countries; in the US it is indicated for the treatment of patients 
with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-
approved test and who have disease progression on or after platinum-containing 
chemotherapy. Patients with NSCLC and EGFR or ALK genomic tumor aberrations 
should also have disease progression on FDA-approved therapy for these aberrations 
prior to receiving pembrolizumab. In the US, pembrolizumab is also approved for the 
treatment of patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck with disease progression on or after platinum-containing chemotherapy.
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy 
trials in subjects with non-small cell lung cancer, head and neck squamous cell 
carcinoma, urothelial cancer, gastric cancer, triple negative breast cancer and Hodgkin’s 
Lymphoma as determined by response rate. Ongoing clinical trials are being conducted in 
advanced melanoma, NSCLC, head and neck cancer, urothelial cancer, gastric cancer, 
TNBC, Hodgkin’s lymphoma and a number of other advanced solid tumor indications 
and hematologic malignancies.  For study details please refer to the IB 
2.4.2 Rationale for Pembrolizumab Dose Selection
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). 
Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from 
physiologically-based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different 
disease settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) 
and different treatment settings (monotherapy and in combination with chemotherapy). 
Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 
Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
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Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, 
PK data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 
mg Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over 
a wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-
dosing provides similar control of PK variability as weight based dosing, with 
considerable overlap in the distribution of exposures from the 200 mg Q3W fixed dose 
and 2 mg/kg Q3W dose. Supported by these PK characteristics, and given that fixed-dose 
has advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols.
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W. The dose 
recently approved in the United States and several other countries for treatment of 
melanoma subjects is 2 mg/kg Q3W. Information on the rationale for selecting 200 mg 
Q3W is summarized below.
In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor activity 
of pembrolizumab when administered as monotherapy. The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 
2 weeks (Q2W) and dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W 
in subjects with advanced solid tumors. All dose levels were well tolerated and no dose-
limiting toxicities were observed. This first-in-human study of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels. No maximum tolerated dose (MTD) has been identified. In addition, two 
randomized cohort evaluations of melanoma subjects receiving pembrolizumab at a dose 
of 2 mg/kg versus 10 mg/kg Q3W have been completed, and one randomized cohort 
evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been completed. The clinical 
efficacy and safety data demonstrate a lack of important differences in efficacy or safety 
profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected 
to provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.
Previously, a flat pembrolizumab exposure-response relationship for efficacy and safety 
has been found in subjects with melanoma in the range of doses between 2 mg/kg and 10 
mg/kg. Exposures for 200 mg Q3W are expected to lie within this range and will be 
close to those obtained with 2 mg/kg Q3W dose.
A population pharmacokinetic (PK) model, which characterized the influence of body 
weight and other patient covariates on exposure, has been developed. The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution. The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably overlap those 
obtained with the 2 mg/kg dose and importantly will maintain individual patient 


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exposures within the exposure range established in melanoma as associated with maximal 
clinical response. Pharmacokinetic properties of pembrolizumab, and specifically the 
weight-dependency in clearance and volume of distribution are consistent with no 
meaningful advantage to weight-based dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 
tumor type. In addition, available PK results in subjects with melanoma, NSCLC, and 
other tumor types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at tested doses among tumor types. Thus the 200 mg Q3W fixed-dose regimen 
is considered an appropriate fixed dose for other tumor indications as well.
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. The 
existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab.
Section 3 OBJECTIVE AND ENDPOINTS
Rationale for Change
Addition of TCR diversity and mutational load
REVISED TEXT:
Second and Fourth Exploratory Objective and Endpoint
Exploratory

To evaluate the pharmacodynamic activity 
of GSK3174998 in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, TCR diversity, expression of 
circulating soluble factors such as 
cytokines and stress-related proteins). 
Assessment of changes in genomic DNA, 
gene expression (RNA and protein), (e.g.,
using cfDNA, exosomes or circulating 
tumor cells [CTCs]), and mutational load. 


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
Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host 
DNA and response to therapy or disease 
characterization.


Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 or any concomitant 
medicines.
Disease susceptibility, severity, and 
progression and related conditions.
Section 4.1 Overall Design
Rationale for Change
Additional tumor type of STS added
REVISED TEXT:
Second paragraph 
The study will be conducted in 2 parts, each part consisting of starting with a dose-
escalation phase followed by a cohort expansion phase. Part 1 will evaluate GSK3174998
monotherapy, while Part 2 will evaluate GSK3174998 in combination with 
pembrolizumab.  As shown in Figure 5 , GSK3174998 will first be evaluated as 
monotherapy in escalating doses.  Once a dose of GSK3174998 has been identified that is 
both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may 
begin.  In Part 2, escalating doses of GSK3174998 will first be evaluated with fixed doses 
of pembrolizumab. Part 1A and 2A will also include a Pharmacodynamic Cohort, which 
requires mandatory fresh pre- and on-treatment biopsies and an additional disease 
assessment at week 6. Each Part 2 part will also include expansion cohorts for up to three 
differentspecified tumor types.
Third paragraph
The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, SCCHN, RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.  In the 
dose-escalation phase of the study, subjects with any of the aforementioned tumor types 
may be included; whereas in the cohort expansion phase of the study, each expansion 
cohort will enroll subjects with one specific tumor type selected from the aforementioned 
list.  Up to three expansion cohorts may be included for each part of the study.  
Figure 5 Information of part 1B is deleted 
Section 4.1.4 Dose Limiting Toxicity
Rationale for Change
Consolidated dose modifications guidelines


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REVISED TEXT:
Last Paragraph
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 6.3.1 and is based on the experience of management of immune-
related adverse events (irAEs) since the development of ipilimumab and PD-1 inhibitors 
such as pembrolizumab.  Section 6.3.1 includes general guidance for the management of  
non-hematologic AEs (Table 9), general guidance for the management of irAEs (Section 
6.3.1.1), general principles of irAE identification and evaluation (Section 6.3.1.2), and 
specific guidance for: hepatotoxicity (Section 6.3.1.4), gastrointestinal events (Section 
6.3.1.5), skin toxicity (Section 6.3.1.6), endocrine events (Section 6.3.1.7), pneumonitis 
(Section 6.3.1.8), hematologic events (Section 6.3.1.9), uveitis/iritis (Section 6.3.1.10), 
infusion reactions or severe cytokine release (Section 6.3.1.11) and dose delay (Section 
6.3.1.13).
Section 4.1.5. Cohort Expansion
Rationale for Change
New details added to define the dose expansion cohorts
REVISED TEXT:
Any dose level(s) in Parts 1A and 2A (dose escalation) may be selected for cohort 
expansion in Parts 1B and 2B of the study in order to collect additional data on safety, 
PK, pharmacodynamic activity, and clinical activity.  
Each expansion cohort will include subjects with a single tumor type and will enroll up to 
approximately 20 subjects who will be treated at the selected dose level.  In both Part 1B 
and Part 2B, up to three expansion cohorts will be enrolled with one indication per 
cohort.  Selection of tumor indications will be based in part on data generated in Part 1A 
and Part 2A, respectively. The Steering Committee will review the available preliminary 
safety, PK, pharmacodynamic, and clinical activity data before selecting the dose level 
indications for all 3 cohorts. Criteria that may be In accordance with the Steering 
Committee Charter and based upon a review of pertinent data with input from the study 
team and investigators, the Steering Committee recommended initiation of Part 2B 
expansion cohorts, including the selection of tumor types and the dose of GSK3174998 to 
be administered to subjects who enter the expansion cohorts as described below. Criteria
considered in the determination of which dose level(s) to expand and which tumor types 
to select for cohort expansion may includeincluded:

Target engagement and pharmacodynamic activity:  Observed OX40 receptor 
occupancy and pharmacodynamic activity.  Pharmacodynamic activity will be 
determined by an evaluation of markers of T-cell activation and proliferation in whole 
blood.  The changes in numbers and activation state of lymphocytes will also be 
assessed and correlated with individual responses as well as immune cell populations 
within the tumor (see Section 7.6).  


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
TolerabilityTarget engagement and PK:  Observed OX40 receptor occupancy and 
GSK3174998 exposure. 

Safety and tolerability: The frequency of DLT, and frequency and severity of 
treatment-related AEsof special interest (AESI), and the extent of dose modifications 
for either GSK3174998 or the combination agent.  

Clinical activity: Evidence of clinical response, including SD of at least 12 weeks 
and/or minor responses.  
After 10 subjects have been enrolled in a given The preliminary clinical data supporting 
initiation of the expansion cohort, the Steering Committee may recommend continued 
accrual in that cohorts are summarized in Section 2.3.5.
The initial expansion cohort up to a total of cohorts in Part 2B will evaluate one dose 
level of 0.3 mg/kg GSK3174998 (see Section 4.5.3) in tumor types where confirmed
response or prolonged SD (12 weeks) was observed in Part 1A or 2A of this study. 
Tumor types selected for initial evaluation in expansion cohorts are melanoma and 
dedifferentiated liposarcoma (seeTable 5).  Additional tumor types may be included in 
Part 2B in accordance with existing inclusion/exclusion criteria. A maximum of 
approximately 20120 subjects.  While it iswill be included in Part 2B. 
Table 5
Part 2B Expansion Cohorts 
Study Part 2B
Population
Prior PD-(L)1 
Treatment
GSK3174998
Dose
N
Melanoma
Yes
0.3 mg/kg
10-30
Dedifferentiated liposarcomaa
No
0.3 mg/kg
10-30
Additional tumor types b
TBD
TBD
10-60
a. Dedifferentiated liposarcoma will be the initial target; however, additional sarcoma sub-types may be included 
b. Any of the tumor types studied in Part A (may be enriched for selected biomarkers if validated biomarker selection 
assays are available)
Subsequent expansion cohorts are anticipated that the additional 10 subjects in each 
cohort will be treated at the same dose level asto receive 0.3 mg/kg GSK3174998, unless 
emerging data from Parts A or B of the initial 10 subjects, the Steering Committee may 
recommendstudy support further exploration of a differentan alternative tested dose level. 
These cohorts may include any of the tumor types studied in Part A, including additional 
subtypes of STS, and may be enriched for selected biomarkers if validated biomarker 
selection assays are available (e.g., PD-(L)1 expression, OX40 expression on the basis of 
emerging data. selected T cell populations, high mutational load, etc). The selection of 
any additional dose level(s) or dosing schedules and tumor types for cohort expansion 
will be communicated to the sites in writing. 
A minimum of 10 subjects will be enrolled in each cohort. The first futility analysis of 
each expansion cohort will be conducted after approximately 10 subjects are enrolled for 


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whom overall response data at approximately week 12 is available. Enrollment will 
continue while evaluating the tumor responses from the first 10 evaluable subjects. 
Any expansion cohort passing futility criteria may be selected to expand up to a total of 
30 subjects per cohort. Interim analyses for futility will be conducted with decision rules 
for the 10th to 30th evaluable subjects (see Table 17 and Table 18).  These decision rules 
provide a guideline only; actual decisions will depend upon the totality of the data. For 
example, a cohort may be expanded if at least 1 melanoma subject or 2 STS subjects of 
the initial 10 subjects enrolled in each cohort demonstrate a confirmed response (per 
cohort). Please refer to Section 9.3.2 for details of the futility analysis.
The selection of dose level(s) and tumor types selected for cohort expansion will be 
communicated to the sites in writing. For any of the expansion cohorts tested, if the 
observed clinical benefit appears to be associated with specific patient characteristics 
and/or biomarkers, a new cohort may be opened for further investigation with subjects 
enriched with these specific patient characteristics and/or biomarkers. Expansion cohorts 
will require mandatory fresh pre- and on-treatment biopsies (see Secition 7.6.2) and an 
additional disease assessment at Week 6. This disease assessment is timed to coincide 
with the on-treatment (Week 6) tumor biopsy. If feasible, the disease assessment should 
be performed after the tumor biopsy. 
Section 4.1.6 Intra-Subject Dose Escalation
Rationale for Change
Part 1B was removed from the study design
REVISED TEXT:
There will be no intra-subject dose escalation., except as follows.  Upon determination of 
the dose selected for Part 1B, subjects being treated at lower doses in Part 1A may be 
considered for escalation/titration to the Part 1B dose. For such subjects, the decision 
whether to dose escalate will be made on a case-by-case basis after agreement by the 
investigator and the GSK Medical Monitor.
There will be no intra-subject dose escalation in Part 2 of the study. 
Section 4.2.
Treatment Arms and Duration
Rationale for Change
Part 1B was removed from the study design


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REVISED TEXT:
Table 6
Study Treatments
Study Part
Study Treatment
Part 1: GSK3174998 Monotherapy
1A – Dose escalation
GSK3174998 IVa Q3W for up to 2 years or 35 cycles, whichever comes 
first
1B – Cohort expansion
GSK3174998 IVb Q3W for up to 2 years or 35 cycles, whichever 
comes first
Part 2: GSK3174998 in combination with pembrolizumab 
2A – Dose escalation
GSK3174998 IVc IVb Q3W for up to 2 years or 35 cycles, whichever 
comes first Pembrolizumab 200mg IV Q3W for up to 2 years or 35 
cycles, whichever comes first
2B – Cohort expansion
GSK3174998 IVb IVb Q3W for up to 2 years or 35 cycles, whichever 
comes first Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 
cycles, whichever comes first
a.
For dose levels see Table 2.
b.
At one or two dose levels shown to be tolerable in dose escalation of each part. 
c.
For dose levels see Table 3. 
Alternative dosing schedules may be explored if the data warrants. This will be communicated to the sites in writing 
prior to implementation.
IV = Intravenous; Q3W = Every 3 weeks
Section 4.3
Type and Number of Subjects
Rationale for Change
Part 1B was removed from the study design
REVISED TEXT:
First paragraph second sentence
It is estimated that a total of up to approximately 264 subjects will be enrolled in this 
two-part study (approximately 144 subjects in Parts 1A and 2A [dose escalation]; 
approximately 120 subjects in Parts 1B and Part 2B [cohort expansion]).  
Section 4.4.
Design Justification
Rationale for Change
Minor corrections and addition of STS


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REVISED TEXT:
First paragraph second sentence
The safety, tolerability, and pharmacodynamics of monotherapy GSK3174998 will be 
evaluated in a modified CRM3+3 dose escalation that includes an accelerated titration 
design for the first two dose levels.
Third paragraph second sentence
The tumor types to be evaluated in dose escalation are as follows: NSCLC, SCCHN, 
RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.
Section 4.5.3 Dose Rationale for Cohort Expansion (Part 2B)
Rationale for Change
Data added to support dose selection decision for expansion cohorts.
REVISED TEXT:
GSK3174998 will be administered intravenously at a dose of 0.3 mg/kg once every 3 
weeks (Q3W) on Day 1 of each 21-day cycle in combination with 200 mg 
pembrolizumab Q3W.
For GSK3174998 doses of ( 0.3 mg/kg and higher appears to be the threshold for linear 
PK and peripheral receptor occupancy saturation over the whole dose interval was
observed (see Figure 3 Figure 2 and Figure 3)..  Peripheral OX40 receptor occupancy on 
circulating CD3+ T cells, provides a measure of target engagement. While the 
relationship between the extent of peripheral receptor occupancy and clinical response 
has not been established, clinical activity was observed in Part 1A at this dose level for 
monotherapy as described in Section 2.3.5.4.1 2.3.5.4. In Part 2A at GSK3174998 dose 
levels 0.01 to 0.3 mg/kg in combination with pembrolizumab (see Section 2.3.5.4.2 ) at 
the time of the clinical data cut off (09 Jan 2018). 
Safety data were reported for the full dose range of GSK3174998 monotherapy (0.003 to 
10 mg/kg) and for GSK3174998 (0.003 to 10 mg/kg) when administered in combination 
with pembrolizumab 200 mg at the time of the clinical data cut-off (09 Jan 2018). No 
DLTs were reported for monotherapy. Two DLTs (pleural effusion and myocarditis) 
were reported in the combination setting. Out of 9 subjects dosed at GSK31748998 0.03 
mg/kg + pembrolizumab, one DLT of pleural effusion was reported. Out of 4 subjects 
dosed at GSK3174998 10 mg/kg + pembrolizumab, one DLT of myocarditis was 
reported.  Overall, there did not appear to be a dose-relationship for AEs and the 0.3 
mg/kg dose level for the combination treatment was well tolerated. Safety data are 
described in more detail in Section 2.3.5.1.
In summary, the 0.3 mg/kg GSK3174998 dose level was well tolerated during dose 
escalation, demonstrated target engagement on circulating T cells and clinical activity 


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was observed at this dose level for both monotherapy and in combination with 
pembrolizumab.
Section 4.6.1 Risk Assessment GSK3174998 pembrolizumab
Rationale for Change
Addition of embryo-fetal toxicity risk and mitigation strategy.
REVISED TEXT:
Section 4.6.1. Risk Assessment GSK3174998 pembrolizumab
Table 67
Risk Assessment
Potential Risk of 
Clinical 
Significance
Summary of Data/Rationale for
Risk
Mitigation Strategy
Hypersensitivity 
reaction
Risk for infusion reactions and 
hypersensitivity is inherent to 
many mAbs [Brennan, 2010]
Subjects Severe hypersensitivity 
to another mAb are not eligible for 
participation in this study
See Section 6.3.1.11 6.3.1.2
Severe cytokine 
release syndrome 
(sCRS)
OX40 is a costimulatory receptor 
that can stimulate proliferation 
and activation of T cells
GSK3174998 is an OX40 agonist 
that can costimulate T-cell 
activation in the context of TCR 
signal and CD28 cosignal.
An anti-CD28 super agonist 
(TGN1412) induced rapid-onset 
catastrophic CRS in 6 healthy 
volunteers
See Section 6.3.1.11 6.3.1.2
Other immune-
related AEs
Inflammatory AEs such as 
diarrhea/colitis, pneumonitis, and 
hepatotoxicity are well established 
after treatment with immune-
modulating agents, and are consistent 
with the immune-stimulatory 
mechanism of action of these agents. 
Subjects with the following 
medical history are not eligible
for participation in this study
o Toxicity (Grade 3) related 
to prior immunotherapy 
leading to study treatment 
discontinuation 
o Severe hypersensitivity to 
another mAb
See Table 9, Non-Hematologic 
AEs; Table 10, Hepatotoxicity; 
Table 11, Gastrointestinal Events; 
Table 12, Skin Toxicity; Table 13, 
Endocrine Events; Table 14, 
Pneumonitis; Table 16, 


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Uveitis/IritisSee Section 6.3.1.1
Embryo-fetal toxicity
Currently there are a number of 
monoclonal antibodies targeting 
immune checkpoints approved for use 
in humans (e.g., ipilimumab, 
nivolumab, durvalumab and 
pembrolizumab). These agents have 
embryo-fetal toxicity documented in 
the Warnings and Precautions section 
of the USPI and in Section 4.6 of the 
EU-SPC. This risk has been 
identified in a variety of animal 
species (generally cynomolgus 
monkeys or experiments in mice with 
PD-(L)1 antagonism), and link the 
PD-1/PD-L1 signaling pathway with 
maintenance of pregnancy through
induction of maternal immune 
tolerance to fetal tissue. Human IgG4 
(immunoglobulins) are known to cross 
the placenta; therefore, 
pembrolizumab has the potential to be 
transmitted from the mother to the 
developing fetus. There are no 
available human data informing the 
risk of embryo-fetal toxicity.
Advise females of 
reproductive potential of the 
potential risk to a fetus. 
Women of child-bearing 
potential and their male 
partners are required to use 
highly effective contraception 
as described in Section 5.1
TCR = T-cell receptor; mAb = Monoclonal antibody; AEs = Adverse Events
Section 5.1.
Inclusion Criteria
Rationale for Change
Criteria updated to define expansion cohorts
REVISED TEXT:
Subjects eligible for enrollment in the study must meet all of the following criteria: 
1. Provide signed, written informed consent.  
2. Male and female subjects, age 18 years (at the time consent is obtained).  


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3. Histological documentation of locally advanced, recurrent or metastatic solid 
malignancy that has progressed after standard therapy appropriate for the specific 
tumor type, or for which standard therapy has proven to be ineffective, 
intolerable, or is considered inappropriate (with the possible exception of the PD-
(L)1 naive populations described in inclusion criterion 4).  Subjects should not 
have received more than 5 prior lines of therapy for advanced disease including 
both standards of care and investigational therapies.  Subjects whose cancers 
harbor molecular alterations for which targeted therapy is standard of care should 
have received health authority-approved appropriate targeted therapy for their 
tumor types before enrollment. 
4. Subjects with the following solid tumors are eligible for screening: NSCLC, 
SCCHN, RCC, melanoma, bladder, STS, TNBC, and MSI CRC.
In Part 2B (Cohort Expansion), specific subgroups of the above solid tumors will 
be studied. These subgroups may be defined by specific lines of treatment, types 
of prior treatment, histological subtypes, and may be enriched for selected 
biomarkers or patient characteristics. Populations to be studied in Amendment 3 
include but are not limited to the following. Enrolment of additional populations 
will be communicated in writing.

Subjects with dedifferentiated liposarcoma who have not received prior 
treatment with a PD-(L)1 inhibitor

Subjects with melanoma who have received a prior PD-(L)1 inhibitor, had 
a CR, PR or SD and subsequently progressed while on PD-(L)1 therapy.

Subjects who have received prior treatment with a PD-(L)1 inhibitor must 
have documented disease progression as defined by meeting all of the 
following criteria:
Has received at least 2 doses of an approved PD-(L)1 inhibitor
Has demonstrated disease progression as defined by RECIST v1.1. 
The initial evidence of disease progression is to be confirmed by a 
second assessment no less than four weeks from the date of the 
first documented PD, in the absence of rapid clinical progression.
Progressive disease has been documented within 18 weeks from 
the last dose of the PD-(L)1 inhibitor.
5. In Parts 1A and 2A, Aa biopsy of the tumor tissue obtained at anytime from the 
initial diagnosis to study entry. Although a fresh biopsy obtained during screening 
is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a 
fresh biopsy..  For Part 1B and Part 2B, any archival tumor specimen must have 
been obtained within 3 months of starting study drug.
Note: Subjects enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts 
or in Part 2B of the study must provide a fresh biopsy of a tumour lesion 
not previously irradiated during the screening period and must agree to 
provide at least one additional on-treatment biopsy. In addition, an 
archived tumor tissue should be submitted for subjects in Part 2B, if 
available.


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The criterion for collection of fresh biopsies may be waived once GSK has 
determined an appropriate number of viable tissue samples have been 
analysed.
6. Measurable disease per RECIST version 1.1 - please refer to Appendix 5. 
Palpable lesions that are not measurable by radiologic or photographic evaluations 
may not be utilized as the only measurable lesion
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.  
8. Life expectancy of at least 12 weeks.  
9. Adequate organ function (see Table 8):
Table 8
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
ANC
≥1.5x109/L
Lymphocyte count
>1,000800/mm3
Hemoglobin
≥9 g/dL
Platelets
≥100x109/L
Hepatic
Total bilirubin
For subjects with Gilbert’s Syndrome (only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
Part 1A and 2A: ALT
≤1.5xULN
Part 2B: ALT
≤2.5xULN
Renal
Serum Creatinine
OR
Calculated CrCla
≤1.5xULN
> 50 mL/min
Endocrine
TSHb
WNL
ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal; WNL = within normal limits
c.
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula (see Appendix 12) or per institutional standard.
d.
If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 are 
within the normal limits.
10. QT duration corrected for heart rate by Fridericia’s formula (QTcF) <450 msec or 
QTcF <480 msec for subjects with bundle branch block.  
The QTcF is the QT interval corrected for heart rate according to Fridericia’s 
formula, machine-read or manually over-read.
Section 5.2.
Exclusion Criteria
Rationale for Change
Criteria updated to define expansion cohorts


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REVISED TEXT:
First Exclusion criteria second bullet point

Checkpoint inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors: within 4 
weeks. NOTE: Subjects entering the PD-(L)1 naive expansion cohort may not 
have received any prior PD-(L)1 anti-cancer treatment.
Twenty third Exclusion criteria
History of severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients
Section 5.4.1. Treatment Discontinuation
Rationale for Change
Addition of window for TDV
REVISED TEXT:
Second Paragraph (NOTE) second sentence 
The treatment discontinuation visit (TDV) should be conducted within 30 days (+10 
days) of the decision to discontinue study drug(s).
Section 6.1.
Investigational Product and Other Study Treatment
Table 89
Investigational Product Dosage/Administration
Study Treatment
Product name:
GSK3174998
Pembrolizumab
Dosage form:
Lyophilized powder for 
reconstitution
Solution for infusion 
Unit dose strength(s)/ Dosage 
level(s):
40 mg lyophilized powder
Dose range: 0.003 to 
≤10 mg/kg
100 mg/ 4 mL solution 
Dose range: 200 mg
Route of Administration
IV infusion – 30 mina, b
IV infusion – 30 mina
Frequency of Administration
Q3Wb, c
Q3Wb
Dosing instructions:
Make every effort to target 
infusion timing to be as close 
to 30 min as possible. 
However, given the variability 
of infusion pumps from site to 
site, a window of -5 min and 
+10 min is permitted (i.e., 
infusion time is 30 min: -5 
min/+10 min or 25 to 40 min).
Make every effort to target 
infusion timing to be as close to 
30 min as possible. However, 
given the variability of infusion 
pumps from site to site, a 
window of -5 min and +10 min 
is permitted (i.e., infusion time 
is 30 min: -5 min/+10 min or 25 
to 40 min).


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Manufacturer/ source of 
procurement
GSK
Merck
a.
Infusions may be prolonged in the event of an infusion reaction.  If multiple subjects experience clinically 
significant infusion reactions, the infusion rate may be slowed for all future administrations of study drug(s) for all 
subjects. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
b.
Dose levels 1 and 2 will be administered less than 30 min, please refer to the SRM for infusion directions
c.
Alternative dosing schedules may be explored if emerging data warrants. This will be communicated to the sites in 
writing prior to implementation.
Q3W = Every 3 weeks; GSK = GlaxoSmithKline
Section 6.3. Planned Dose Adjustments
Rationale for Change
Dose modification guidelines consolidated for sake of efficiency.
REVISED TEXT:
Section 6.3 of previous amendment (Amendment 2) is modified extensively (many sections 
have been deleted or modified) in the current amendment (Amendment 3).
6.3.1
Dose and Safety Management Guidelines
6.3.1.1. Dose modification and toxicity management for immune-related AEs 
associated with GSK3174998 pembrolizumab
AEs associated with treatment with GSK3174998 pembrolizumab exposure may be 
immune-mediated. These immune-related AEs (irAEs) may occur shortly after the first 
dose or several months after the last dose of GSK3174998 pembrolizumab treatment, or 
anywhere in between, and may affect more than on body system simultaneously. 
Therefore, early recognition of and initiation of treatment for these events is critical to 
reduce potential complications. Based on existing data from study 201212, most irAEs 
were reversible and could be managed with interruptions of GSK3174998 
pembrolizumab, administration of corticosteroids and/or other supportive care. For 
suspected irAEs, ensure adequate evaluation to confirm the etiology or exclude other 
causes. Additional procedures or tests such as, but not limited to bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue GSK3174998 pembrolizumab 
and administer corticosteroids. Dose modification and toxicity management guidelines 
for ir AEs associated with GSK3174998 pembrolizumab are provided in Table 10.


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Table 10
Dose modification and toxicity management guidelines for immune-
related AEs 
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
For situations where GSK3174998 pembrolizumab has been withheld, GSK3174998 pembrolizumab 
can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
GSK3174998 pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 
12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv4.0)
Action taken to 
GSK3174998 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-
up 
Pneumonitis 
Grade 2
Withhold 

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone 
or equivalent) 
followed by taper

Monitor subjects 
for signs and 
symptoms of 
pneumonitis

Evaluate subjects 
with suspected 
pneumonitis with 
radiographic 
imaging and 
initiate 
corticosteroid 
treatment

Add prophylactic 
antibiotics for 
opportunistic 
infections
Grade 3 or 4, 
or recurrent 
grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone 
or equivalent) 
followed by taper

Monitor subjects 
for signs and 
symptoms of 
enterocolitis (i.e. 
diarrhea, 
abdominal pain, 
blood or mucus in 
stool with or 
without fever) 
and of bowel 
perforation (i.e. 
peritoneal signs 
and ileus).

Subjects with ≥ 
Grade 2 diarrhea 
suspecting colitis 
Grade 4
Permanently 
discontinue


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should consider 
GI consultation 
and performing 
endoscopy to rule 
out colitis. 

Subjects with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If 
sufficient oral 
fluid intake is not 
feasible, fluid and 
electrolytes 
should be 
substituted via IV 
infusion.
AST / ALT 
elevation or 
increased 
bilirubin
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
methylprednisolone 
or equivalent) 
followed by taper

Monitor with liver 
function tests 
(consider weekly 
or more 
frequently until 
liver enzyme 
value returned to 
baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
methylprednisolone 
or equivalent) 
followed by taper
Type 1 diabetes 
mellitus 
(T1DM) or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold

Initiate insulin 
replacement therapy 
for subjects with 
T1DM 

Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia 

Monitor subjects 
for hyperglycemia 
or other signs and 
symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.

Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue
Hyperthyroidism 
Grade 2
Continue 

Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs 
and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently 


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discontinue
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs 
and symptoms of 
thyroid disorders. 
Nephritis and 
renal 
dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(methylprednisolone 
1-2mg/kg or 
equivalent) followed 
by taper.

Monitor changes 
of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of 
AE administer 
corticosteroids
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes

Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Grade 3, or 
intolerable/ 
persistent 
Grade 2
Withhold

Based on severity of 
AE administer 
corticosteroids 

Ensure adequate 
evaluation to 
confirm etiology 
or exclude other 
causes
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
NOTES: 
1.
The decision whether to withhold or permanently discontinue GSK3174998 pembrolizumab is at 
the discretion of the investigator or treating physician.
2.
For subjects with Grade 3 or 4 immune-related endocrinopathy where interruption of GSK3174998 
pembrolizumab is required, treatment with GSK3174998 pembrolizumab may be resumed when 
the event resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or, for T1DM,
metabolic control has been achieved.


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Table 11
Biomarker Panel
Biomarker
Relationship to Adverse Event
Serum tryptasea
IgE-related infusion reaction (Allergic/anaphylaxis) 
[Schwartz, 2006]
Serum CRPa
Elevated in CRS [Lee, 2014]
Serum ferritina
Elevated in CRS [Lee, 2014]
Plasma cytokine panelb
(IFN-γ*^, TNF-α*^, IL-2*, 
IL-4, IL-5*, IL-6*^, IL-8*, 
IL-10*, IL-12p70, IL-13, and 
IL-17)
* Reported to be elevated in CRS [Lee, 2014]
^consistently reported as elevated in CRS [Lee, 2014]
CRP=C-reactive protein; CRS= Cytokine release syndrome; IFN-= Interferon gamma; TNF-= Tumor necrosis factor 
alpha; IL = Interleukin. 
a.
Performed by PI designated local laboratory
b.
Performed by GSK designated laboratory
These guidelines are suggestions, and investigators and site staff may also follow their 
site’s standard operating procedures for the treatment of these events.


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Table 12 GSK3174998 Pembrolizumab Infusion Reaction Dose Modification and 
Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be 
held until symptoms resolve and 
the subject should be 
premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of study drugs with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
No subsequent dosing


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**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Subject is permanently 
discontinued from further 
study drug treatment.
Appropriate resuscitation equipment should be available at the bedside and a physician 
readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) at http://ctep.cancer.gov
6.3.1.3 Dose Delay
GSK3174998 pembrolizumab may be interrupted for situations other than treatment-
related AEs such as medical / surgical events or logistical reasons not related to study 
therapy. Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
If there is a dose delay between 1 and 49 days (2 dosing cycles + 7 days), the procedures 
at the original scheduled visit (including dosing) should be performed as soon as possible.   
All subsequent visits will follow a Q3W calendar schedule.  Subjects with infusion delays 
causing 2 consecutive missed doses due to toxicity should discontinue study drug(s) 
unless the treating investigator and Sponsor/Medical Monitor agree there is strong 
evidence supporting continued treatment.  While no washout from study treatments is 
required for subjects requiring elective surgery or palliative radiation therapy while on 
study, investigators and site staff are encouraged to schedule these procedures to fall in 
between dosing days (see Section 6.10.1. for details on permitted medications and non-
drug therapies).  
Section 6.8.1. GSK3174998 Overdose
Rationale for Change
Length of follow up adjusted to be consistent with the T&E table
REVISED TEXT:
Second bullet point

Closely monitor the subject for AEs/SAEs and laboratory abnormalities for at least 
13090 days. 
Section 6.10.1.
Permitted Medications and Non-Drug Therapies
Rationale for Change
Adjustments to guidelines for palliative radiation


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REVISED TEXT:
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusion of blood and blood products, palliative radiation to non-target 
lesions, and treatment with antibiotics, antiemetics, antidiarrheals, and analgesics, as 
appropriate. Seasonal flu vaccine is permitted as an injection only. Intra-nasal flu vaccine 
is excluded. Elective surgery or non-palliative radiation may be permitted on a case-by-
case basis in agreement with the Medical Monitor. , if these do not include any "target" 
lesions. 
Growth Factors and Bisphosphonates:  The use of growth factors, RANK-L inhibitors, 
and bisphosphonates (if on a stable dose for at least 4 weeks) is permitted while 
participating in this study.  However, the initiation of growth factors and bisphosphonates 
is not allowed during the first 4 weeks of study treatment, unless used in the management 
of toxicity and agreed upon by the investigator and Medical Monitor.
Steroids: Use of steroids is permitted for treatment of AEs (as per Table 9, Non-
Hematologic AEs; Table 10, Hepatotoxicity; Table 11, Gastrointestinal Events;Table 
12, Skin Toxicity;Table 13, Endocrine Events; Table 14, Pneumonitis, and Table 16,
Uveitis/Iritis) while the subject is undergoing treatment on this study. Table 10 and 
Table 12, Dose Modification Guidelines for Immune-Related AEs or Infusion 
Reactions. 


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Section 7.1 Time and Events Table
Rationale for Change
Minor changes to clarify footnotes and define expansion cohorts
REVISED TEXT:
Time and Evnts Table and Footnotes
Table 13
Time and Events Table – Monotherapy and Combination Therapy
Tumor Biopsies
Archived tumor i
X
Fresh tissue samplei, m
X
X
PD tissue samplek
Xk
g.
Dosing of GSK3174998 and pembrolizumab at every 3-week intervals is shown in the Time and Events Table; however, dosing of GSK3174998 may be delayed due to 
toxicity. During the combination phase, GSK3174998 should be administered first, and pembrolizumab should be administered at least 1 hour and no more than 2 hours 
following the end of the GSK3174998 infusion. GSK3174998 and pembrolizumab will be dosed for a maximum of 2 years or 35 cycles, whichever comes first. Alternative 
dosing schedules of GSK3174998 and pembrolizumab may be explored if the data warrants. This will be communicated in writing to sites prior to implementation.
h.
Screening tumor imaging must be obtained within 28 days of the first dose. Tumor imaging will be performed every 12 weeks (1 week) until disease progression has been 
confirmed by irRECIST; Subjects whose disease progresses must have a confirmatory scan performed at least 4 weeks after the date of assessment during which the first 
indication of PD was demonstrated. Immune-related RECIST will be used to determine treatment decisions for PD and the primary endpoint analysis will use irRECIST. If a 
subject has achieved a CR or PR in the previous radiologic assessment, a repeat scan should be performed as a part of the confirmation of response, within at least 4 weeks 
to confirm the response. At the TDV, tumor imaging is only required if the last disease assessment did not show PD and was performed 6 weeks before TDV. During the 
DFS FU visits (performed when a subject has permanently discontinued study treatment before disease progression has been documented), tumor imaging will be obtained 
every 12 weeks (1 week) until PD, initiation of a new anticancer treatment, or death, whichever comes first. Pre-baseline scans (within 24 weeks before the baseline scan) 
may be collected to assess tumor growth rate in selected subjects to support exploratory investigation of tumor growth kinetics.
i.
A fresh tumor biopsy should be attempted at screening (before first dose) and at Week 6 (after the 3rd dose of study treatment +1 week). Fresh biopsies are mandatory for all 
patients in the Pharmacodynamic Cohort and the Dose Expansion phase.  During the Dose Expansion phase, once evaluable paired tumor biopsies are collected for up to 10 
subjects in the dose expansion phases, this requirement may be waived. Tumor lesions planned for biopsy must not be used as indicator lesions for assessment of disease, 
unless discussed and agreed with the GSK Medical Monitor. For subjects in the initial dose escalation cohorts, where biopsy is not mandatory, a recent archival tumor 
specimen is acceptable if it is not feasible to obtain a fresh biopsy.  


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j.
The 6-week disease assessment will be performed for subjects enrolled in Part A for patients in the Pharmacodynamic Cohort and in all Part B expansion cohorts. This 
disease assessment is timed to coincide with the on-treatment (6 week) tumor biopsy. If feasible, tThe disease assessment should be performed after the tumor biopsy. 
k.
Progressive Disease Tissue Sample: An optional fresh tumor biopsy should be attempted at the time of disease progression.
l.
For Part 1A only: On Day 1 ECG measurements will be performed in triplicate predose and at the following times after the infusion: EOI+30m, EOI + 4h, EOI +24h, on Day 22 
ECG measurements will be performed in triplicate predose and on Day 85 ECG measurements will be performed in triplicate predose and at the following times after the 
infusion: EOI+30m.
m.
With subject consent and agreement by the PI and GSK Medical Monitor, additional, optional fresh biopsies may be obtained during the study. One example of when this 
may be considered is when a mixed response occurs and tumor biomarker data are anticipated to inform why some lesions are, and some are not, responding to the 
treatment. 
Time and Events Table – Pharmacokinetics, Antidrug Antibodies, and Pharmacodynamics (Parts 1 and 2)
Treatment
Day
1
2
8
15
22
23
29
36
43
64
85
106
≥148
30 D 
after 
Last 
Dose
12 Wks 
Post-
Treatment 
1 week
Dose
1
2
3
4
5
6
≥8
Pharmacogenetics 
(6 mL)a
X
Receptor 
occupancy and 
phenotyping 
panels(10 mL)i
Pre
EOI+4hg
EOI+24h
X
X
Pre
EOI+4hg
Pre
EOI + 4hg
X
X
Plasma + PBMC 
prep (20 mL)b
Pre
X
Pre
Pre
Pre
X
X
Cytokines (5 mL)
Pre
EOI+4h
EOI+24h
X
Pre
EOI+4h
Pre
EOI+4h
Pre
EOI+4h
Plasma for cfDNA + 
exosomes (10 20 
mL)h
Pre
At time of 
biopsy if 
done
Serum (5 mL)
Pre
GSK3174998
Pharmacokinetics 
(1 mL)
Pre
EOI+30m
EOI+4h
EOI+24h
d
X
X
Pre
EOI+30m
EOI+4h
EOI+2
4d
X
X
Pre
EOI+30m
Pre
EOI+30m
Pre
EOI+30
m
Pre
EOI+30m
Pree
X
X


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Part 2 only: 
Pembrolizumab 
Pharmacokinetics 
(3  mL)
Pre
EOPI+30
m
EOI+24h
X
X
Pre
Pre
Pre
Pree
X
X
Anti- GSK3174998 
antibodiesc,f (45
mL)
Pre
Pre
Pre
Pre
Pre
Pre
Pree
X
Xf
Part 2 only: Anti-
Pembrolizumab 
antibodiesc,f (6 mL)
Pre
Pre
Pre
Pre
Pree
X
Xf
Timepoint Definitions:
X = Anytime during visit
Pre = within 60 min before the start of the GSK3174998 infusion
EOI+30m = within 30 minutes of the end of the GSK 3174998 infusion
EOPI+30m = within 30 minutes of the end of the pembrolizumab infusion
EOI +4h = within 4 hours 10 minutes of the end of the GSK3174998 infusion
EOI+24h = 24 hours 4 hours after the end of the GSK3174998 infusion
a.
Informed consent for optional pharmacogenetics research must be obtained before collecting a sample. It is recommended that the blood sample be taken at the first opportunity 
after a subject has met all eligibility requirements, and can be done up to 28 days before Day 1.
b.
If the baseline/pre-dose sample is not viable, samples for PBMCs are not needed at subsequent visits.
c.
In addition to these scheduled immunogenicity assessments, “event-driven” testing will also be employed for those subjects that experience anaphylaxis, serious 
hypersensitivity, or AEs related to study drug administration that led to withdrawal from the study. See Section 9.4.2.4 for full details.
d.
Day 2 PK samples are only required during the dose-escalation phases of the study.
e.
Dose 8 and every 4 dosing cycles
f.
In the event of a hypersensitivity reaction that is either 1) clinically-significant in the opinion of the investigator, or 2) leads to the subject withdrawing from the study, blood 
samples should be taken from the subject for immunogenicity testing at the time of the event and again 30 days, 12 weeks, and 24 weeks after. 
g.
If the EOI+4h RO sample is scheduled to be collected after the last lab courier pick-up time of the day, the sample should be collected as late as possible to enable processing 
and shipping on the same day as collection.
h.
If a tumor biopsy is taken at the time of PD, then a plasma sample should also be collected for cfDNA + exosomes, 
i.
Receptor Occupancy and phenotyping panels will only be collected in Parts 1A and 2A of the study
D = Days; PBMC = Peripheral blood mononuclear cell; EOI = End of infusion
Procedures for blood sample collection, processing, storage, and shipping are described in the SRM.


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Section 7.3.1. Evaluation of Anticancer Activity
Rationale for Change
Additional details needed for expansion cohorts
REVISED TEXT:
Third Bullet point and last bullet point

The baseline disease assessment will be completed within 4 weeks prior to the 
first dose of GSK3174998, then every 12 weeks thereafter, and at the final study 
visit.  For subjects enrolled in the Part A “Pharmacodynamic Cohort” and in all 
Part B expansion cohorts an additional disease assessment will be performed at 
Week 6. See the Time and Events Table (Section 7.1, Table 13) for the schedule 
of assessments of anticancer activity.  

Pre-baseline scans (within 24 weeks before the baseline scan) may be collected to 
assess tumor growth rate in selected subjects to support exploratory investigation 
of tumor growth kinetics.
Section 7.4.5. Electrocardiogram (ECG)
Rationale for Change
Additional details needed for expansion cohorts
REVISED TEXT:
Third paragraph first sentence
For Part 11A of the study, ECG measurements will be performed in triplicate at specified 
times (see Table 13, including footnotes).
Section 7.5.2 Blood Sample Analysis
Rationale for Change
Name of analysis name changed
REVISED TEXT:
Plasma or serum analysis for GSK3174998 and pembrolizumab will be performed under 
the control of Department of Bioanalysis, Immunogenicity and Biomarkers (BIB), 
IVIVT, PTS, GSKPTS-DMPK/Scinovo, GSK or Merck Sharp & Dohme Corp the details 
of which will be included in the SRM. Concentrations of GSK3174998 and 
pembrolizumab will be determined in plasma and serum samples, respectively, using the 


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currently approved bioanalytical methodology. Raw data will be archived at the 
bioanalytical site (detailed in the SRM).  Once the plasma or serum has been analyzed for 
GSK3174998 and pembrolizumab any remaining plasma may be analyzed for other 
compound-related metabolites and the results reported under a separate BIB, PTSPTS-
DMPK/Scinovo, GSK or Merck Sharp & Dohme protocol.
Section 7.6.1. Blood Biomarkers  
Rationale for Change
Addition of tumor mutational load to be consistent with other sections of the protocol
REVISED TEXT:
Second paragraph third sentence 
Factors to be analyzed may include but are not limited to: the presence of IFN-γ, TNF-α, 
IL-2, IL-4, IL-5, IL-6, IL 10, IL-8, IL-12p70, IL-13, and IL-17 as well as antibodies 
against tumor, self tumor mutations, i.e., tumor mutational load, gene expression (RNA 
or protein) or viral antigens.  
Section 7.6.2.Tumor Tissue
Rationale for Change
Additional details needed for expansion cohorts
REVISED TEXT:
Archival tumor tissue, as well as fresh pre- and on-treatment biopsies in subjects in the 
pharmacodynamic cohorts, at least 10 subjects of the dose-expansion cohorts, and if 
possible in the dose escalation cohorts will be evaluated by IHC for expression of 
phenotypic and functional immune cell markers on tumor infiltrating lymphocytes (TILs) 
and other immune cells and as well as immune signaling markers on the surface of tumor 
cells (e.g. including, but not limited to PD-L1), to understand antitumor immune 
responses. In addition, when possible, similar analyses will be performed on tumor tissue 
samples obtained upon progression. Additionally, tumor tissue may be sequenced to 
assess TCR diversity as well as evaluated for any DNA/RNA/protein changes correlating 
with response, such as but not limited to tumor mutational burden.
In the pharmacodynamic cohort and expansion cohorts, mandatory fresh pre- and on on-
treatment biopsies are required (see Table 13 for timing). These mandatory biopsy 
samples will be evaluated as previously described for the archival, pre- and 
ontreatment,on-treatment and progression biopsies.
If feasible, for all of the fresh pre-and on-treatment biopsies, both samples should be 
obtained from the same tumor lesion site should be used for both samples.  If not 
possible, the on-treatment biopsy should be obtained from the same anatomical site organ 
as the pre-treatment biopsy. The tumor site chosen for biopsy must not be the used as an


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indicator lesion for assessment of disease unless otherwise discussed and agreed upon 
with the GSK medical monitor.
With subject consent and agreement by the PI and GSK Medical Monitor, additional, 
optional fresh biopsies may be obtained during the study. One example of when this may 
be considered is when a mixed response occurs and tumor biomarker data are anticipated 
to inform why some lesions are, and some are not, responding to the treatment. In this 
case, the additional biopsies are not required to be obtained from the same lesion or organ 
as the pre-treatment biopsy. . 
Section 9.1 Hypotheses
Rationale for Change
Additional details needed to define the analysis plan for the expansion cohorts
REVISED TEXT:
Section 9.1.1. to Section 9.3.2.
9.1.1. Part 1: Monotherapy Dose Escalation (GSK3174998)
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, the safety profile, and antitumor activity of GSK3174998.  
9.1.2.  Part 1: Monotherapy Dose Expansion (GSK3174998)
The null hypothesis for the secondary endpoint- overall response rate is:
H0: p≤10%.
The alternative hypothesis is:
HA: p>10%.
9.1.2. Part 2: Combination Dose Escalation (GSK3174998 + Pembrolizumab)
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
study will be focused on comparison between dose cohorts and only descriptive methods 
will be used in analysis of the data obtained from this study. 
9.1.3. Part 2: Combination Dose Expansion (GSK3174998 + Pembrolizumab)
In the dose-expansion phase, for each cohort the primary goal is to test the null 
hypothesis that the overall response rate for the combination of GSK3174998 + 
pembrolizumab is equal to the historical response rate of monotherapy pembrolizumab, 
expected to be 15% to 40% according to which tumor types are selected for study. The 


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goal will be to detect an improvement in the overall response rate on the combination 
therapy in the range of 25% over the null, with power of at least 80% and no more than a 
15% type 1 error rate.  In populations resistant to pembrolizumab, the goal would be to 
observe a response rate of 20% to 30% to the combination of GSK3174998 + 
pembrolizumab.
The expansion cohorts of GSK3174998 + pembrolizumab are designed to evaluate 
preliminary clinical activity. Futility assessments will be conducted to evaluate 
accumulating data including safety, responses, PK and pharmacodynamics. The 
methodology is based on the predictive probability of success if
enrollment continues until all planned subjects are recruited [Lee, 2008].
There are mutiple dose expansion cohorts being planned for STS, melanoma and other 
cancers types in the dose-expansion phase. For each cohort the objective is to test the null 
hypothesis that the overall response rate for the combination of GSK3174998 + 
pembrolizumab is equal to the historical response rate of monotherapy pembrolizumab. 
The observed monotherapy pembrolizumb overall response rate was apprioxmately 18% 
for STS [Burgess, 2017]. The observed monotherapy pembrolizumb overall response rate 
was assumed to be apprioxmately 10% for melanoma in the pretreated population[Robert, 
2014].
The sample size is chosen based on an improvement of 20% in the overall response rate 
on the combination therapy over the null hypotheiss, with power of at least 80% and no 
more than a 10% type 1 error rate. In the population previously treated with
pembrolizumab, the goal would be to observe a response rate of 30% to the combination 
of GSK3174998 and pembrolizumab.
Therefore, the hypothesis for both PD-(L)1 naïve and PD-(L)1 pretreated cohorts are 
shown as below:
For PD-(L)1 naïve dose expansion cohorts (e.g., STS), 
the null hypothesis for ORR is:
H0: p=18%
The alternative hypothesis is:
HA:p=38%
For PD-(L)1 pretreated dose expansion cohorts (e.g., melanoma),
the null hypothesis for ORR is:
H0: p=10%
The alternative hypothesis is:


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HA:p=30%
9.2. Sample Size Considerations
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data according to the 
objectives of each part of the study.  
The study will enroll up to approximately 264subjects264 subjects with tumor types that 
may include NSCLC, SCCHN, RCC, melanoma, STS, bladder cancer, TNBC, and MSI 
CRC.
Up to 72 subjects will be enrolled in each of the two dose escalation parts of the study 
(Parts 1A and 2A); up to 30 subjects will be enrolled in each of dose expansion cohorts. 
The sample size of each expansion cohort at a given dose level will be minimum of 10 
subjects and maximum of 30 subjects based on the overall response assessments.
The trial is not designed to stop early for efficacy but is designed to continusly assess 
futility if the predictive probability of success is 10% or less.  The type I error rate, 
power, and predictive probability for assessing futility were determined from stating the 
minimum and maximum sample size, futility stopping rate, and the optimizing criterion 
as minimizing the sample size under null hypothesis.  A weak informative prior 
distribution with a mean response rate equal to the target response rate is assumed. Thus, 
the predictive probability for the response rate will be primarily driven by the data. The 
detailed decision criteria for all cohorts are documented in section 9.3.2.
Table 16
Expansion Cohorts Power and Type I Error 
Power
Type I error
STS PD-(L)1 naïve population: p0=18% and 
p1=38%
0.802
0.062
Melanoma pretreated PD1/PDL1 population: 
p0=10% and p1=30%
0.831
0.051
For the PD-(L)1 naïve combination expansion cohorts in STS, starting with 10 subjects in 
each cohort and allowing for a maximum sample size of 30 for each cohort, this design 
will have approximately 80.2% power with an overall type I error rate (α) of 6.2%. Under 
null hypotheses with an 18% ORR, the probability of early termination (PET) is 43% 
after data from 10 subjects evaluable for response are available and 77% after data from 
20 evaluable subjects are available. Under the alternative hypothesis, if the true response 
rate is 38%, PET is 6% after data from 10 evaluable subjects are available and 13% after 
data from 20 evaluable subjects are available.


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For the expansion cohorts in PD-(L)1 pretreated melanoma, starting with 10 subjects in 
each cohort and allowing for a maximum sample size of 30 for each cohort, this design 
will have approximately 83.1% power with an overall type I error rate (α) of 5.1%. Under 
null hypotheses with a 10% ORR, PET is 35% and 80% when data for 10 and 20 
evaluable subjects are available. Under the alternative hypothesis, if the true response rate 
is 30%, PET is 3% by 10 subjects evaluated and 13% by 20 subjects evaluated.
9.2.1. Sample Size Re-estimation or Adjustment
Up to 2030 subjects/cohort are expected to be enrolled in each dose-expansion phase of 
Part 1 and Part 2.  In Part 2, theThere is no other sample size may be increased up to 
approximately 40 subjects per cohort, once the tumor types are chosen and the 
null/alternative hypotheses determined, to maintain power of at least 80% with no more 
than a 15% type 1 error rate.re-estimation or adjustment planned. 
9.3. Data Analysis Considerations
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including biomarker and PK data and the safety profile of prior cohorts.  In addition, the 
recommended dose from a Continuous Reassessment Method (N-CRM) analysis 
[Neuenschwander, 2008] will be calculated.  The N-CRM is a type of Bayesian adaptive 
dose-escalation scheme.  The method is fully adaptive and makes use of all the DLT 
information available at the time of each dose assignment. The Fixed and Adaptive 
Clinical Trial Simulator (FACTS) will be used to conduct the N-CRM analysis. The DLT 
information on all subjects enrolled in the trial are used to update the estimated dose-
toxicity relationship and provide supportive information in addition to the 3+3 design in 
the next escalation/de-escalation decision.
The expansion phases are designed to evaluate preliminary efficacy.  A futility 
assessment will be conducted and enrollment may be paused in order to evaluate 
accumulating data including safety, responses and pharmacodynamic data. The 
methodology is based on the predictive probability of success if enrollment continues 
until all planned subjects are recruited [Lee, 2008]. 
In addition, a Bayesian hierarchical model may be used to share information across 
cohorts if PK and biomarker data suggest a strong similarity in clinical activity among 
cohorts. 
For Part 1: MonotherapyIn the Dose Expansion cohorts, after 10 subjects have been 
enrolled in each cohort (for pre-treatment , the number of observed responses may be 
used to guide further enrollment according to the rules summarized in Table 22 Table 17
and Table 18.  However, all available data will be considered in making enrollment 
decisions.  


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Table 22
Monotherapy Expansion Cohort Enrollment Guidance
Number of Responses
Number of Subjectsa
0
1
2
3
4
10
11
12
13
14
15
16
17
18
19
20
a.
The shaded regions are the specific regions for pausing enrollment. 
Starting with 10 subjects and allowing for a maximum sample size of 20, this design will 
have a type I error rate () of 0.128 and 88% power when the true response rate is 30%. 
The trial is not designed to stop early for efficacy but is designed to assess futility if the 
predictive probability of success is 1% or less.  The type I error rate, power, and 
predictive probability of success to assess futility were derived from explicitly stating the 
minimum and maximum sample size, futility stopping rate, and selection of the 
optimizing criterion as the maximization of power under the alternative hypothesis.  The 
Bayesian prior used in determining the design was Beta (0.1, 0.9), a relatively non-
informative distribution with a mean response rate of 10%. Under the null hypothesis, if 
the true response rate is 10%, the expected sample size of the design is 16 subjects per 
expansion cohort and the probability of early termination is 73%.  Under the alternative 
hypothesis, if the true response rate is 30%, the expected sample size of the design is 20 
subjects per expansion cohort and the probability of early termination is 6%.
These operating characteristics assume that the futility assessment rules are followed. If 
not and the trial continues to enroll until 20 subjects are evaluated, the overall type 1 
error rate increases from 0.128 to 0.133, with an increase in power from 88% to 89%.
The statistical approach for creating futility assessment rules for the expansion phase of 
the combination cohorts will be similar to that of the monotherapy phase, determined 
according to which tumor types are selected for study. In addition, a Bayesian 
hierarchical model may be used to share information across cohorts if PK and biomarker 
data suggest a strong similarity in clinical activity among cohorts.
CRM-recommended dose-escalation levels, futility assessment rules, and posterior 
probabilities are only guidelines and the totality of the data will be considered by the 
team in decision making.  


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9.3.1. Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK3174998. Safety and anticancer activity will be evaluated based on this analysis 
population.  
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.  
9.3.2. Interim Analysis
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in Section 4.1.1 and Section 9.3. The Steering Committee will 
guide the transition of the study from dose escalation to cohort expansion for both 
monotherapy and combination therapies. 
For dose expansion cohorts, continuous assessment of efficacy and safety will be 
performed after first interim analysis based upon a minimum of 10 subjects in at least one
of the disease-specific cohort with available unconfirmed Overall Responseoverall 
response data.
Futility interim analysis decision rules for the 10th to 30th evaluable subjects are presented 
in Table 17 and Table 18, which specify the number of subjects with an unconfirmed 
response required for continuing enrolment when total sample size is up to 30. Additional 
futility looks may be performed, if necessary. These rules are intended as a guideline 
only. If applicable, appropriated data from dose escalation may be integrated into dose 
expansion decisions.
Actual decisions will depend on the totality of the data. Any additional decision rules will 
be documented in the RAP before the nterim analysis. Should the recommendation to 
stop for futility be disregardedp in favor of a decision to continue the trial based on the 
totality of the data, the overall type I error rate of the expansion phase will be inflated. 
The Steering Committee will monitor safety and efficacy over the course of the study 
following the randomization and futility rules for expansion cohorts. 


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Table 17
Futility Boundary for PD(L)-1 naive Pembrolizumab Combination 
Therapy Expansion Cohorts in STS.
Number 
of 
subjectsa
Number of Responders
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a.
Shaded regions indicate enrollment pause based on meeting futility


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Table 18
Futility Boundary for PD(L)-1 Experienced Pembrolizumab 
Combination Therapy Expansion Cohorts in Melanoma
Number of 
Subjectsa
Number of Responders
0
1
2
3
4
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
a.
Shaded regions indicate enrollment pause based on meeting futility
Section 11 References
Rationale for Change
New references added
REVISED TEXT:
Burgess MA, Bolejack V, Van Tine BA, et al. Multicenter phase II study of 
pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): final results 
of SARC028 and biomarker analyses. J Clin Oncol. 2017;35(suppl; abstr 11008)..
Garon EB, Rizvi NA, Hui R, Leighl NL, Balmanoukian AS, Eder JP, Patnaik A, 
Aggarwal A, et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N 
Engl J Med 2015; 372:2018-2028.
KEYTRUDA (pembrolizumab) prescribing information. Merck Sharp & Dohme 
Corporation, Whitehouse Station, New Jersey, USA, October 2015 November 2017.  


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Section 12.1. Appendix 1: Abbreviations and Trademarks
Rationale for Change
Clarification of MSI CRC and addition of STS
REVISED TEXT:
MSI CRC
Colorectal carcinoma displaying high microsatellite 
instability
STS
Soft Tissue Sarcoma
Section 12.5.3.1.
Evaluation of best overall response
Rationale for Change
Aligned wording to be consistent with T&E table
REVISED TEXT:
First bullet

To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after the first dose at a minimum interval of 84 77 days. 
Section 12.7 Appendix 7: Genetic Research
Genetic Research Objectives and Analyses
Rationale for Change
Addition of STS expansion cohort
REVISED TEXT:
Second bullet point

NSCLC, SCCHN, RCC, melanoma, bladder, STS, TNBC or MSI CRC, 
susceptibility, severity, and progression and related conditions
Section 12.11.Appendix 11: Adverse Events of Special Interest
Rationale for Change
Minor change to wording
REVISED TEXT:
First paragraph fifth sentence
Please note this table lists known AESI, additional events may be identified during the 
course of the study.


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12.13.4.
Amendment 4 Protocol Changes 
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 4 documents the closure of Part 2B expansion cohorts, removes the 
requirement for future disease assessments and survival follow-up, and clarifies the 
impact of ending enrolment of expansion cohorts on the study objectives and efficacy 
analysis.
For expansion cohorts, enrolment of 10 subjects/cohort was initially planned, with a 
possibility of further enrolment if the cohorts passed planned futility analyses. However, 
in February 2019, a strategic decision was made not to initiate any new clinical 
investigations with the GSK3174998/pembrolizumab combination, including halting 
further expansion beyond 10 subjects/cohort. This decision was based upon the modest 
clinical activity observed within the study at that time, in addition to published data for 
other OX40 agonist antibodies combined with PD-1 or PD-L1 inhibitors reporting 
low/modest clinical activity for these combinations. As a consequence, the futility 
analyses (described in Section 4.1.5) were deemed unnecessary. Ultimately, the three 
expansion cohorts in Melanoma, STS and NSCLC treated a total of 9, 9, and 5 subjects, 
respectively. As of 5 November 2019, all subjects have completed treatment and are in 
post-treatment follow-up; no responses were observed in subjects enrolled in the 
expansion cohorts. Given the lack of responses in the expansion cohorts (Part 2B) and the 
modest clinical activity observed in dose escalation (Part 1A and 2A), no time-to-event 
summaries and analyses (TTR, DOR, PFS, OS) will be performed for efficacy data.
Minor clarifications, formatting and typographical errors were also addressed in this 
amendment.
Changes are noted with strikethrough to identify deleted text and underlining to identify 
new or replacement text.
Overall change: The protocol has been updated to reflect the most recent IBs throughout 
the document.
Section TITLE PAGE
Rationale for Change
The sponsor information was updated based on internal GSK team personnel changes.
REVISED TEXT:
 
PPD


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Section Sponsor Signatory
Rationale for Change
The sponsor information was updated based on internal GSK team personnel changes.
REVISED TEXT:
Li Yan, MD
VP, Head Unit Physician
Hesham A. Abdullah, MD, MSc, RAC 
SVP, Head of Clinical Development, Oncology 
Section MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Rationale 
Medical monitor information was updated
REVISED TEXT:
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/Serious Adverse Event (SAE) Contact Information:
Role
Name
Office Phone Email 
Address
Mobile
Fax 
Primary 
Medical Monitor 
, MD
Secondary 
Medical Monitors
, MD, PhD
, MD
SAE contact 
information 
Section PROTOCOL SYNOPSIS Objectives/Endpoints (Antitumour activity)
Rationale for Change
Given the modest clinical activity observed in dose escalation (Part 1A and 2A), no time-
to-event summaries and analyses (TTR, DOR, PFS, OS) will be performed for efficacy 
data.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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REVISED TEXT

Antitumor activity endpoints: Objective response rate (ORR) and Disease 
Control Rate (DCR) (complete response [CR]+partial response [PR]+stable
disease [SD] ≥12 weeks), time to response (TTR), duration of response (DOR), 
progression-free survival (PFS), and overall survival (OS).  Unless otherwise 
specified, all response endpoints will be assessed by Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1 and by irRECIST (immune-related 
RECIST); the primary endpoint analysis will use irRECIST.
Section PROTOCOL SYNOPSIS Treatment Arms and Duration (Second paragraph)
Rationale for Change
This decision was based upon the modest clinical activity observed in the study.
REVISED TEXT
With the implementation of Amendment 04, there will be no requirement to perform 
future disease assessments or survival follow-up. In Part 1, dose escalation for 
GSK3174998 monotherapy will begin with a starting dose of 0.003 mg/kg GSK3174998
administered once every 3 weeks (Q3W).
Section 2.3.5. Preliminary Clinical Data for GSK3174998
Rationale for Change
Updates in the Investigators’ Brochure. Removal of text within the protocol that is a 
duplicate of the Investigators’ Brochure.
REVISED TEXT
2.3.5. Preliminary Clinical Data for GSK3174998
Data are summarized for the ongoing first time in human study with a clinical data cut-
off of 09 Jan 2018.13 August 2019 in the Investigator’s Brochure [2014N212091_06].
Data are reported for 104138 subjects.; 45 subjects received doses up to 10 mg/kg of 
GSK3174998 monotherapy and 6196 subjects received doses up to 1.0 10 mg/kg of 
GSK3174998 + 200 mg of pembrolizumab.  TwoThree subjects crossed over from 
monotherapy to combination therapy.
2.3.5.1.
Preliminary Safety Data (ENGAGE-1)
2.3.5.1.1.
Safety Data - Part 1
No dose-limiting toxicities, or treatment-related Grade 4, or Grade 5 toxicities were 
reported. Grade 3 asthenia and Grade 3 lymphocytopenia were reported in a single patient 
and attributed to study treatment. A single event in another subject led to treatment 
discontinuation; Grade 5 stroke manifested as aphasia, attributed to disease progression. 


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The most common AEs regardless of attribution were fatigue (13, 29%), back pain (9, 
20%), diarrhea (9, 20%), nausea (9, 20%), vomiting (9, 20%), asthenia (8, 18%), anemia, 
(7, 16%), headache (6, 13%), constipation (5, 11%), cough (5, 11%), dyspnoea (5, 11%), 
myalgia (5, 11%), pain in extremity (5, 11%), and pyrexia (5, 11%). The most common 
AEs attributed to treatment by the investigator included diarrhea (5, 11%) and fatigue (5, 
11%). 
2.3.5.1.2.
Safety Data - Part 2
No treatment related Grade 4 or Grade 5 toxicities were reported. Three patients reported 
Grade 3 treatment-related AEs.Two dose limiting toxicities were reported. One patient 
with bladder cancer reported asymptomatic Grade 3 cardiac troponin and Grade 1 
myocarditis occurring 16 days after the first and only dose of study treatments. Both 
events were attributed to study treatments, resulted in discontinuation of treatment, and 
resolved with a short course of 500 mg methylprednisolone. Other treatment-related 
Grade 3 events included Grade 3 fatigue in one patient with colorectal cancer (resulting 
in treatment discontinuation), and Grade 3 diarrhea in a patient with bladder cancer.  The 
diarrhea lasted a single day, three days after the second dose of study drugs. A second 
dose limiting toxicity of Grade 2 pleural effusion was reported in a patient with triple 
negative breast cancer (0.03 mg/kg dose cohort).  Adverse events leading to treatment 
discontinuation included the Grade 3 myocarditis and Grade 3 fatigue described above, 
and Grade 3 abdominal pain not related to treatment in a patient with colorectal cancer. 
The most common AEs regardless of attribution were fatigue (15, 25%), decreased 
appetite, (12, 20%), pleural effusion (9, 15%), arthralgia (8, 13%), nausea (7, 11%), 
asthenia (6, 10%), cough (6, 10%), and diarrhea (6, 10%). The most common AEs 
attributed to treatment by the investigator included fatigue (12, 20%), nausea (4, 7%), and 
pruritus (4, 7%).For further details on the safety of GSK3174998, please refer to the IB 
[GlaxoSmithKline Document Number GlaxoSmithKline Document Number 
2014N212091_00]
2.3.5.2.
Preliminary Pharmacokinetic Data (ENGAGE-1, Part 1A and 2A)
The PK of GSK3174998 was evaluated after IV administration at doses of 0.003 mg/kg 
to 10 mg/kg every 3 weeks in patients with solid tumors in Study 201212. Plasma PK 
samples (cut-off date 28 July 2017) were analyzed with a validated analytical method 
based on immunocapture and trypsin digestion, followed by ultra-high pressure liquid 
chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis with a lower 
limit of quantitation (LLOQ) of 10 ng/mL.
The median first cycle concentration-time profiles for Part 1A and Part 2A presented in 
Figure 2 initially exhibited a biexponential decline typical for mAbs  administered IV.  At 
lower GSK3174998 concentrations, faster elimination and shorter half-lives were 
observed, indicating target-mediated disposition.  Consequently, AUC and trough 
concentrations were increasing more than proportionally with dose. Concentration-time 
profiles were similar between GSK3174998 alone and combination therapy, indicating 
that co-administration of pembrolizumab did not affect the PK of GSK3174998. Cmax 
values were approximaely dose-proportional and typical for mAbs.


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At the time of data cut off (22 June 2017) 49% of subjects with available post-treatment 
data tested positive for anti-GSK3174998 anti-drug antibodies (ADA) across dose levels 
0.003–10 mg/kg GSK3174998 in Part 1A and 0.003–0.1 mg/kg in Part 2A. Positive ADA 
titers were detectable as early as three weeks after the first dose of GSK3174998.  Of the 
30 subjects with positive ADA titers, two subjects experienced infusion related reactions 
beginning with administration of the third dose of GSK3174998; no other infusion 
reactions were reported in the study.
Figure 2
Median (range) time-concentrations profiles by dose group for 
GSK3174998 alone or in combination with pembrolizumab
Notes: 
1. Preliminary data from Study 201212 (cut-off date 28 July 2017).
2. Samples reported below the limit of quantitation (0.01 g/mL) were assigned a value of 0.005 g/mL for the 
purposes of this graphical summary.
2.3.5.3.
Preliminary Receptor Occupancy Data (ENGAGE-1, Part 1A and 2A)
Receptor occupancy (RO) was assessed for peripheral blood CD3+ T cells in Part1A and 
2A. Preliminary data indicated that a high degree (80%) of receptor occupancy is 
achieved initially (1 day after dosing) even for the lowest dose of 0.003 mg/kg 
GSK3174998 (Figure 3). For doses of 0.1 mg/kg or smaller receptor occupancy 
subsequently declines towards the end of the dosing cycle. Starting with 0.3 m/kg 
GSK3174998 continuously high receptor occupancy levels are observed over the whole 
21-day dosing cycle. Qualitatively similar receptor occupancy profiles were observed 


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when GSK3174998 was administered in combination with 200 mg pembrolizumab Q3W 
(Figure 3)
Figure 3
Median receptor occupancy profiles for varying doses of GSK3174998 
alone or in combination with pembrolizumab
Notes: 
1. Preliminary data from Study 201212.
2.3.5.4. Preliminary Clinical Activity Data (ENGAGE-1)
2.3.5.4.1.
Clinical Activity - Part 1A
At the time of the clinical data cut-off (09 Jan2018), one confirmed PR was reported at 
week 24 in a subject with STS (0.3 mg/kg GSK3174998), who subsequently discontinued 
treatment for PD at week 30. A subject with NSCLC (0.3 mg/kg GSK3174998) was 
reported to have SD for 24 weeks, and discontinued treatment with PD after 39 weeks. 
An additional 5 subjects were reported to have SD at week 12, but subsequently 
discontinued treatment for PD prior the next imaging assessment.
2.3.5.4.2.
Clinical Activity - Part 2A
At the time of the clinical cut-off (09 Jan 2018), clinical responses were reported for the 
combination of GSK3174998 and pembrolizumab. At the 0.01 mg/kg GSK3174998 + 
200 mg pembrolizumab dose level, one subject demonstrated a CR (MSI-CRC) and one 
subject with SCCHN demonstrated SD at week 24, and continues on treatment at week 
54. At the 0.1 mg/kg GSK3174998 + 200 mg pembrolizumab dose level, 3 subjects 


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demonstrated a PR (melanoma, bladder and MSI-CRC). At the 0.3 mg/kg GSK3174998 
+ 200 mg pembrolizumab dose level, 1 subject with NSCLC demonstrated a PR, while a 
second subject with NSCLC demonstrated SD at week 15 and remained on treatment as 
of week 27.
Section 3 Objectives and Endpoints
Rationale for Change
Given the modest clinical activity in the study, no time-to-event summaries and analyses 
(TTR, DOR, PFS, OS) will be performed for efficacy data. TTR and DOR will be 
calculated and considered as exploratory endpoints.
REVISED TEXT
Objectives
Endpoints
Part 1: GSK3174998 Monotherapy
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously to 
subjects with selected advanced or 
recurrent solid tumors.  

AEs, SAEs, DLT, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate the antitumor activity of 
GSK3174998 in subjects with selected 
advanced or recurrent solid tumors.

To characterize the PK of GSK3174998 
monotherapy.

ORR and DCR (CR+ PR+ SD ≥12 weeks), 
TTR, DOR, PFS, and OS.)b

GSK3174998 concentrations in plasma 
and PK parameters including Cmax, 
AUC(0-), and Cmin.

To determine the immunogenicity of 
GSK3174998. 

Number and percentage of subjects who 
develop detectable ADA.
Exploratory

To explore the relationship between 
antitumor activity, PK parameters,
pharmacodynamic activity and other 
patient characteristics.

To explore onset and durability of response 

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, pharmacodynamic activity, 
and other patient characteristics.

TTR and DOR


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Objectives
Endpoints
Part 1: GSK3174998 Monotherapy

To evaluate the pharmacodynamic activity 
of GSK3174998 in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, TCR diversity, expression of 
circulating soluble factors such as 
cytokines and stress-related proteins). 
Assessment of changes in genomic DNA, 
gene expression (RNA and protein), (e.g. 
using cfDNA, exosomes or circulating 
tumor cells [CTCs]), and mutational load. 
Part 1: GSK3174998 Monotherapy
Exploratory

To evaluate the pharmacodynamic activity 
of GSK3174998 in the tumor 
microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test. 

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity, or mutational load 
(genomic DNA).

Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host 
DNA and response to therapy or disease 
characterization.

Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 or any concomitant 
medicines.
Disease susceptibility, severity, and 
progression and related conditions.
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
c.
In the final determination of the MTD, all available safety and tolerability data will be considered
d.
Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and by irRECIST (immune-related RECIST); irRECIST will be used to determine treatment
decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid


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Objectives
Endpoints
PART 2: Combination GSK3174998 plus pembrolizumab
Primary

To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously 
in combination with IV pembrolizumab to 
subjects with selected advanced or 
recurrent solid tumors. 

AEs, SAEs, DLTs, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate the antitumor activity of 
GSK3174998 in combination with 
pembrolizumab in subjects with selected 
advanced or recurrent solid tumors.

ORR and DCR (CR+PR+SD ≥12 weeks), 
TTR, DOR, PFS, and OS.).b

To characterize the PK of GSK3174998
and pembrolizumab when administered in 
combination. 

Plasma GSK3174998 and serum
pembrolizumab concentrations and PK 
parameters including Cmax, AUC(0-τ), and 
Cmin.

To determine the immunogenicity of 
GSK3174998 and pembrolizumab when 
administered in combination.  

Number and percentage of subjects who 
develop detectable ADA. 
Exploratory

To explore the relationship between 
antitumor activity, PK parameters,
pharmacodynamic activity and other 
patient characteristics. 

Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK
parameters, pharmacodynamic activity, 
and other patient characteristics.

To explore onset and durability of response

TTR and DOR

To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and development 
of a diagnostic test.

Assessment of lymphocyte OX40 receptor 
membrane expression and occupancy by 
GSK3174998. Measures of immune 
function in blood (e.g. phenotype, quantity, 
and activation state of T cells in the 
periphery, TCR diversity, expression of 
circulating soluble factors such as 
cytokines and stress related proteins). 
Assessment of changes in genomic DNA, 
gene expression (RNA and protein), (e.g. 
using cfDNA, exosomes or CTCs), and 
mutational load. 


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Objectives
Endpoints
PART 2: Combination GSK3174998 plus pembrolizumab
PART 2: Combination GSK3174998 plus pembrolizumab
Exploratory

To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the tumor 
microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test.

Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity, or mutational load 
(genomic DNA).

PGx: To evaluate the association of genetic 
variations in the host DNA and response to 
therapy or disease characterization. 

Germline genetic evaluations may be 
conducted for:
Medicine response, including 
GSK3174998 and pembrolizumab or 
any concomitant medicines. 

Disease susceptibility, severity, and 
progression and related conditions.
Hypothesis
For the primary objective, no formal statistical hypothesis will be tested; analysis will be descriptive 
and exploratory
d.
In the final determination of the MTD, all available safety and tolerability data will be considered
e.
Unless otherwise specified, all response endpoints will be assessed by RECIST v1.1 and by irRECIST; irRECIST
will be used to determine treatment decisions.
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid
Section 4.1.5. Cohort Expansion (Fifth paragraph onwards)
Rationale for Change
Given the modest clinical activity observed in the study a decision was made not to 
initiate any new clinical investigations with the GSK3174998/pembrolizumab 
combination.
REVISED TEXT
A minimum of 10 subjects will be enrolled in each cohort. TheUntil implementation of 
Amendment 4, the first futility analysis of each expansion cohort will be conductedwas 
planned to occur after approximately 10 subjects are enrolled for whom overall response 
data at approximately week 12 iswas available. Enrollment will continue while evaluating 


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the tumor responses from the first 10 evaluableAfter implementation of Amendment 4, 
no further subjects were enroled in the study, and no futility analyses were performed. 
Any expansion cohort passing futility criteria may be selected to expand up to a totalUntil 
implementation of 30 subjects per cohort. Interim analyses for futility will be conducted 
with decision rules for the 10th to 30th evaluable subjects (see Table 17 and Table 18).  
These decision rules provide a guideline only; actual decisions will depend upon the 
totality of the data.  For example, a cohort may be expanded if at least 1 melanoma 
subject or 2 STS subjects of the initial 10 subjects enrolled in each cohort demonstrate a 
confirmed response (per cohort). Please refer to Section 9.3.2 for details of the futility 
analysis.
For Amendment 4, for any of the expansion cohorts tested, if the observed clinical benefit 
appearsappeared to be associated with specific patient characteristics and/or biomarkers, 
a new cohort may behave been opened for further investigation with subjects enriched 
with these specific patient characteristics and/or biomarkers. After implementation of 
Amendment 4, no further subjects were enroled in the study.
Expansion cohorts will require mandatory fresh pre- and on-treatment biopsies (see 
SecitionSection 7.6.2) and an additional disease assessment at Week 6. This disease 
assessment is timed to coincide with the on-treatment (Week 6) tumor biopsy. If feasible, 
the disease assessment should be performed after the tumor biopsy. 
Section 4.2.
Treatment Arms and Duration (Second Paragraph onwards)
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT
The study includes a screening period, a treatment period, and a follow-up period.  
Subjects will be screened for eligibility beginning approximately 4 weeks before the start 
of treatment.  The maximum duration of treatment with GSK3174998 and
pembrolizumab will be 2 years (Table 6) or 35 cycles whichever comes first. The follow-
up period for safety assessments will be a minimum of 3 months from the date of the last 
dose.  The post-treatment follow-up period includes disease assessments every 12 weeks 
until documented PD.  Following PD, subjects will be contacted every 3 months to assess 
survival status. 
Subjects with confirmed PR or CR will be followed for response duration and may be 
eligible for additional treatment with GSK3174998 at the time of relapse/progression. 
The decision whether a subject will receive additional treatment will be discussed and 
agreed upon by the treating investigator and the Sponsor/Medical Monitor on a case-by-
case basis.
With the implementation of Amendment 04, there will be no requirement to perform 
future disease assessments or survival follow-up.


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Section 5.4.1. Treatment Discontinuation (Fourth Paragraph last point onward)
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT

Study closure/termination (with implementation of Protocol Amendment 4).
A subject with a CR requires confirmation of response via imaging at least 4 weeks after 
the first imaging showed a CR. Early discontinuation of GSK3174998 and/or 
pembrolizumab may be considered for subjects who have attained a confirmed complete 
response per RECIST 1.1 that have been treated for at least 6 months and had at least two 
treatments beyond the date when the initial CR was declared.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be re-treated, except as described in Section 5.4.2.1 and in the following 
scenario. Re-treatment of subjects who progress after a best overall response of PR or CR 
may be considered on a case-by-case basis for up to 1 year after discussion between the 
treating investigator and the Sponsor/Medical Monitor if:

No cancer treatment was administered since the last dose of GSK3174998 
pembrolizumab

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria

The trial is open.  
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Response or progression in this Second Course Phase will not count 
towards the primary efficacy endpoint in this trial.
All subjects who permanently discontinue study treatment will be followed for a 
minimum of 6 months from the date of the last dose. The follow-up period for safety 
assessments will be a minimum of 3 months from the date of the last dose. The post 
treatment follow-up period includes disease assessments every 12 weeks until 
documented PD.  Following PD, subjects will be contacted every 3 months to assess 
survival status. 
With the implementation of Amendment 04, there will be no requirement to perform 
future disease assessments or survival follow-up. If the subject voluntarily discontinues 
from treatment due to toxicity, ‘AE’ will be recorded as the primary reason for permanent 
discontinuation on the eCRF.  
All subjects who discontinue from study treatment will undergo safety assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in the 
Time and Events Table (see Section 7.1, Table 13 and Table 14).  
Section 5.5 Subject and Study Completion


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Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT
Since Upon Protocol Amendment 4 implementation, ongoing subjects will be considered 
withdrawn due to study closure and will be followed for survival in this study, onlyup to 
3 months after the last dose.  Only when a subject dies is he/she considered to have 
completed the study; consequently “death” is not listed as a reason for withdrawal from 
the study. Furthermore, disease progression, discontinuation of study treatment, and AEs, 
are not by themselves reasons for withdrawal from the study as follow-up for OS is 
desired.. If a subject dies a copy of the death certificate should be available for review, if 
possible, and the cause of death should be evaluated and documented.
Section 6.9. Treatment after the End of the Study
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition.
Refer to Section 5.4 and Section 7.1 for follow-up assessments of subjects who are to be 
followed for disease progression and/or survival after they permanently discontinue from 
study treatment.
Section 7.1. Time and Events Table
(Table 13 Time and Events Table – Monotherapy and Combination Therapy
Footnote e, f, h)
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT
e.
If study treatment has been permanently discontinued in the absence of PD, the subject will return for disease 
assessments every 12 weeks until PD is documented (by irRECIST), another anticancer treatment is initiated, or
death, whichever occurs first. These visits are described as Disease Free Survival Follow-up (DFS FU) visits.  
Upon implementation of Protocol Amendment 4, no future disease assessments are required. 


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f.
The Survival FU visit should be completed every 12 weeks after documented disease progression (or after 
initiation of another anticancer treatment).  Subjects should be contacted every 12 weeks (2 weeks) until death
occurs. Upon implementation of Protocol Amendment 4, no future survival follow-up is required.
h.
Screening tumor imaging must be obtained within 28 days of the first dose. Tumor imaging will be performed 
every 12 weeks (1 week) until disease progression has been confirmed by irRECIST; Subjects whose disease 
progresses must have a confirmatory scan performed at least 4 weeks after the date of assessment during which 
the first indication of PD was demonstrated. Immune-related RECIST will be used to determine treatment 
decisions for PD and the primary endpoint analysis will use irRECIST. If a subject has achieved a CR or PR in the 
previous radiologic assessment, a repeat scan should be performed as a part of the confirmation of response, 
within at least 4 weeks to confirm the response. At the TDV, tumor imaging is only required if the last disease 
assessment did not show PD and was performed 6 weeks before TDV. During the DFS FU visits (performed 
when a subject has permanently discontinued study treatment before disease progression has been 
documented), tumor imaging will be obtained every 12 weeks (1 week) until PD, initiation of a new anticancer 
treatment, or death, whichever comes first. Pre-baseline scans (within 24 weeks before the baseline scan) may be 
collected to assess tumor growth rate in selected subjects to support exploratory investigation of tumor growth 
kinetics. Upon implementation of Protocol Amendment 4, no future disease assessments are required.
Section 7.3.1. Evaluation of Anticancer Activity (Fifth bullet point)
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT

For post-baseline assessments, a window of 7 days is permitted to allow for 
flexible scheduling.  If the last radiographic assessment was more than 12 weeks 
prior to the subject’s withdrawal from study and PD has not been documented, a 
disease assessment should be obtained at the time of withdrawal from the study.
Upon implementation of Protocol Amendment 4, no future disease assessments 
are required.
Section 9.3.2. Interim Analysis
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses will be performed for efficacy data.
REVISED TEXT
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in Section 4.1.1 and Section 9.3. The Steering Committee will 
guide the transition of the study from dose escalation to cohort expansion for both 
monotherapy and combination therapies


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For dose expansion cohorts, continuous assessment of efficacy and safety willwas 
planned to be performed after first interim analysis based upon a minimum of 10 subjects 
in at least one of the disease-specific cohorts with available unconfirmed overall response 
data for at least 12 weeks. However, after implementation of Amendment 4, no further 
subjects were enroled in the study; therefore, no futility analyses were performed.
of the disease-specific cohort with available unconfirmed overall response data. 
Futility Planned futility interim analysis decision rules for the 10th to 30th evaluable 
subjects are presented in Table 17 and Table 18, which specify the number of subjects 
with an unconfirmed response required for continuing enrolment when total sample size 
is up to 30. Additional futility looks may behave been performed, if necessary. These 
rules arewere intended as a guideline only. If applicable, appropriated data from dose 
escalation may behave been integrated into dose expansion decisions.
Section 9.4.2.1
Anticancer Activity Analyses
Rationale for Change
Given the modest clinical activity observed in the study, no time-to-event summaries and 
analyses (TTR, DOR, PFS, OS) will be performed for efficacy data. TTR and DOR will 
be calculated and considered as exploratory endpoints.
REVISED TEXT
The All Treated Population will be used for anticancer activity analyses. Since this is a 
Phase I study, anticancer activity will be evaluated based on clinical evidence and 
response criteria.  If data warrant, the response data will be summarized by dose level. 
irRECIST is the primary measure of clinical activity for response endpointsand PFS; 
RECIST v1.1 guidelines are used for disease measurements. 
If the data warrant, ORR, DCR, TTR, DOR, PFS and OSDOR will be calculated and 
listed for each subject. 
ORR is defined as the percentage of subjects with a best overall confirmed CR or PR at 
any time as per disease-specific criteria (refer to Appendix 5). DCR is defined as the 
percentage of subjects with a confirmed CR + PR at any time, plus SD 12 weeks.
DOR will be summarized calculated and listed for subjects with a confirmed CR or PR 
and is defined as the first documented evidence of CR or PR until disease progression or 
death due to any cause among subjects who achieve an overall response (i.e.,
unconfirmed or confirmed CR or PR). Censoring rules will follow those of the PFS 
analysisTTR is defined as the interval from the first dose of study treatment to the date of 
the first documented CR or PR.  DOR and TTR are considered as exploratory endpoints.  
No summary tables for DOR and TTR will be provided.
PFS is defined as time from the date of first dose to the date of disease progression 
according to clinical or radiological assessment or death due to any cause, whichever 
occurs earliest. For the analysis of PFS, if the subject received subsequent anti-cancer 


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therapy prior to the date of documented events, PFS will be censored at the last adequate 
assessment (e.g. assessment where visit level response is CR, PR or SD) prior to the 
initiation of therapy. Otherwise, if the subject does not have a documented date of event, 
PFS will be censored at the date of the last adequate assessment.
OS is defined as the interval from the first dose of study treatment to the date of death, 
irrespective of the cause of death. If a subject does not have a documented date of death, 
time of death will be censored at the date of last contact.  
Further details on rules of censoring will be provided in the RAP.  PFS and OS will be 
summarized using the Kaplan-Meier method if the data warrant.
Section 9.4.2.2.1.
Pharmacokinetic Parameters
Rationale for Change
Update to PK analyses to be conducted.
REVISED TEXT
PK analysis of GSK3174998 and pembrolizumab will be the responsibility of the Clinical 
Pharmacology Modeling and Simulation (CPMS) Department, GSK or Merck Sharp and 
Dohme Corp.
PK analysis of drug concentration-time data will be conducted by non-compartmental 
methods under the direction of CPMS, Quantitative Sciences, GSK.  The following PK 
parameters will be determined if data permit:  

Cmax

time to Cmax (tmax)

Cmin

area under the plasma concentration-time curve (AUC(0-t), AUC(0-τ) (repeat 
dosing) and/or AUC(0-∞) (single dose)

apparent terminal phase elimination rate constant (z) (single dose)

apparent terminal phase half-life (t½) (single dose)

systemic clearance of parent drug (CL)

steady-state volume of distribution (Vss)
Section 12.7 Apeendix 7 Genetic Research (12.7.2. Study Assessments and Procedures)
Rationale for Change
Clarification on length of time for sample storage.


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REVISED TEXT
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples soonerstudy closure/termination.  
GSK or those working with GSK (for example, other researchers) will only use samples 
collected from the study for the purpose stated in this protocol and in the informed 
consent form.  Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.

SAP_001.pdf: 
Statistical Analysis Plan 
Official Title of Study: A Phase I, Open-Label Study of GSK3174998 Administered Alone and in 
Combination with Anticancer Agents including Pembrolizumab in Subjects with Selected Advanced Solid 
Tumors 
 
NCT ID: NCT02528357 
Other Identifiers:  2015-000152-14; ICON # 9018-0001 
Date of Document: 19May2020 
 


 
C O N FI D E N TI A L 
 
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2 0 1 2 1 2  
 
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Di visi o n: W orl d Wi d e De vel o p me nt 
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Title: 
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A p pr o ve d b y:  
 
  
Se ni or  Statistics Direct or 
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P P D


 
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TABLE OF CONTENTS 
PAGE 
ABBREVIATIONS ............................................................................................................... 4 
1. 
INTRODUCTION ......................................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................... 8 
2.1. 
Study Objective(s) and Endpoint(s)................................................................. 8 
3. 
STATISTICAL HYPOTHESES .................................................................................. 11 
3.1. 
Part 1: Monotherapy Dose Escalation (GSK3174998) ................................. 11 
3.2. 
Part 2: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab) ............................................................................................. 11 
3.3. 
Part 2: Combination Dose Expansion (GSK3174998 + 
Pembrolizumab) ............................................................................................. 12 
4. 
STUDY DESIGN ........................................................................................................ 12 
5. 
PLANNED ANALYSES .............................................................................................. 14 
5.1. 
Interim Analyses ............................................................................................ 14 
5.2. 
Analyses for Dose Escalation Cohorts and Expansion Phases ................... 15 
5.3. 
Final Analyses................................................................................................ 15 
6. 
SAMPLE SIZE CONSIDERATIONS ......................................................................... 15 
6.1. 
Sample Size Assumptions ............................................................................. 15 
7. 
ANALYSIS POPULATIONS ...................................................................................... 16 
7.1. 
All Treated Population ................................................................................... 16 
7.2. 
PK Population ................................................................................................ 16 
7.3. 
Analysis Datasets .......................................................................................... 16 
8. 
TREATMENT COMPARISONS ................................................................................ 16 
8.1. 
Data Display Treatment and Other Subgroup Descriptors ........................... 16 
9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ........................................ 16 
9.1. 
Other Strata and Covariates .......................................................................... 17 
9.2. 
Examination of Subgroups ............................................................................ 17 
9.3. 
Multiple Comparisons and Multiplicity ........................................................... 17 
10. DATA HANDLING CONVENTIONS .......................................................................... 17 
10.1. 
Premature Withdrawal and Missing Data ...................................................... 17 
10.2. 
Derived and Transformed Data ..................................................................... 18 
10.2.1. 
Reference dates ............................................................................. 18 
10.2.2. 
Study Day for Safety Measures ..................................................... 18 
10.2.3. 
Study Day for Efficacy .................................................................... 18 
10.2.4. 
Duration and Elapsed Time ........................................................... 18 
10.2.5. 
Imputation of Partial Dates............................................................. 19 
10.2.6. 
Imputation of Missing Exposure End Dates .................................. 23 
10.2.7. 
Baseline Definition ......................................................................... 23 
10.2.8. 
Change from baseline .................................................................... 23 
10.2.9. 
Multiple Assessments .................................................................... 24 
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10.2.10. Actual Treatment ............................................................................ 24 
10.2.11. Extended Loss to Follow-up or Extended Time without an 
Adequate Assessment ................................................................... 24 
10.2.12. Date Associated with Response .................................................... 25 
10.3. 
Values of Potential Clinical Importance ......................................................... 25 
10.3.1. 
Laboratory Parameters .................................................................. 25 
10.3.2. 
ECG Parameters ............................................................................ 25 
10.3.3. 
Vital Signs ...................................................................................... 26 
11. STUDY POPULATION .............................................................................................. 27 
11.1. 
Disposition of Subjects .................................................................................. 27 
11.2. 
Protocol Deviations ........................................................................................ 27 
11.3. 
Demographic and Baseline Characteristics .................................................. 28 
11.4. 
Concomitant Medications .............................................................................. 28 
11.5. 
Subsequent Anticancer Therapies ................................................................ 28 
12. EFFICACY ANALYSES ............................................................................................. 29 
12.1. 
Endpoints / Variables ..................................................................................... 29 
12.2. 
Summary Measure ........................................................................................ 30 
12.2.1. 
Best Overall Response (BOR) ....................................................... 30 
12.2.1.1. Confirmed Best Overall Response (BOR) ................... 30 
12.2.1.1.1. Confirmed Best Overall Response 
per RECIST (version 1.1) Criteria 
and irRECIST Criteria .............................. 30 
12.2.1.1.2. Confirmed Best Overall Response 
per irRECIST Criteria .............................. 31 
12.2.1.2. Unconfirmed Best Overall Response .......................... 31 
12.2.1.2.1. Unconfirmed Best Overall 
Response per RECIST V1.1 and 
irRECIST Criteria ..................................... 32 
12.2.1.2.2. Unconfirmed Best Overall 
Response per irRECIST .......................... 32 
12.2.2. 
Objective Response Rate (ORR) and Disease Control 
Rate (DCR)..................................................................................... 32 
12.2.3. 
Time to response (TTR) ................................................................. 32 
12.2.4. 
Duration of response (DOR) .......................................................... 33 
12.2.4.1. DOR per irRECIST ....................................................... 33 
12.2.4.2. DOR per RECIST ......................................................... 34 
13. SAFETY ANALYSES ................................................................................................. 36 
13.1. 
Extent of Exposure ........................................................................................ 36 
13.2. 
Adverse Events .............................................................................................. 36 
13.3. 
Adverse Events of Special Interest ............................................................... 37 
13.4. 
Deaths and Serious Adverse Events ............................................................ 38 
13.5. 
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events ............................................................................................................ 38 
13.6. 
Pregnancies ................................................................................................... 38 
13.7. 
Clinical Laboratory Evaluations ..................................................................... 38 
13.7.1. 
Analyses of Liver Function Tests ................................................... 39 
13.8. 
Other Safety Measures .................................................................................. 40 
13.8.1. 
Vital Signs ...................................................................................... 40 
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13.8.2. 
Performance Status ....................................................................... 40 
13.8.3. 
ECG ................................................................................................ 40 
14. HEALTH OUTCOMES ANALYSES .......................................................................... 40 
15. PHARMACOKINETIC ANALYSES ........................................................................... 40 
15.1. 
Drug Concentration Measures ...................................................................... 41 
15.2. 
Deriving and Summarizing Pharmacokinetic Parameters ............................ 41 
15.3. 
Statistical Analyses ........................................................................................ 42 
15.4. 
Population Pharmacokinetic Analyses .......................................................... 42 
16. PHARMACODYNAMIC AND BIOMARKERS ANALYSES ....................................... 42 
16.1. 
Pharmacodynamic and Biomarker Analyses ................................................ 42 
16.2. 
Immunogenicity Analyses .............................................................................. 43 
16.3. 
Translational Research Analyses .................................................................. 43 
17. PHARMACOGENETIC DATA ANALYSES ............................................................... 43 
18. REFERENCES .......................................................................................................... 44 
 
 
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Abbreviations 
ADA 
Antidrug antibody 
AE 
Adverse event(s) 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC(0-t) 
Area under the plasma concentration-time curve from time 
0 to the time of the last quantifiable concentration) 
AUC(0-W) 
Area under the concentration-time curve over the dosing 
interval 
E-hCG 
Beta-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CL 
Systemic clearance of parent drug 
CrCl 
Calculated creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
CNS 
Central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CR 
Complete response 
CRM 
Continual reassessment method 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CV 
Cardiovascular 
DCR 
Disease Control Rate 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
EOI 
End of infusion 
EOPI 
End of pembrolizumab infusion 
eCRF 
Electronic case report form 
FACTS 
Fixed and Adaptive Clinical Trial Simulator 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-positron-emission tomography 
FTIH 
First time in human 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
h 
Hour(s) 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
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ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
irAE 
Immune-related adverse event(s) 
irRECIST 
Immune-related RECIST 
IV 
Intravenous 
Kd 
Equilibrium dissociation constant 
kg 
Kilogram(s) 
L 
Liter 
LDH 
Lactate dehydrogenase 
LFT 
Liver function Tests 
Pg 
Microgram 
MAD 
Maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
mmHg 
Millimeters of mercury 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
MSI CRC 
Colorectal carcinoma displaying microsatellite instability 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria 
for Adverse Events 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PGx 
Pharmacogenetics 
PI 
Principal investigator 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance status 
Q3W 
Every 3 weeks 
QTc 
Corrected QT interval duration 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cells 
RCC 
Renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event(s) 
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SD 
Stable disease 
SFU 
Survival follow-up 
SRM 
Study Reference Manual 
STS 
Soft tissue sarcoma 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cells 
WNL 
Within normal limits 
 
Trademark Information 
Trademarks of the GlaxoSmithKline group 
of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
SAS 
 
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1.
INTRODUCTION
This reporting and analysis plan (RAP) details all planned analyses required for a Clinical 
Study Report of study 201212. This is a first time in human (FTIH), open-label, non-
randomized, multicenter study designed to evaluate the safety, tolerability, PK, 
pharmacodynamics, and preliminary clinical activity of GSK3174998 administered 
intravenously to subjects with selected advanced or recurrent solid tumors. 
For further information on the study design, see Protocol Amendment 04 dated 04-
FEB-2020 (2014N225045_04). 
The RAP was written by staff of ICON Clinical Research. The execution of the RAP, 
with exception to CRM-based analyses in FACTS, will be undertaken by staff of ICON 
Clinical Research. 
All decisions regarding final analysis, as defined in this RAP document, have been made 
prior to Database Freeze of the study data.  
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2. 
 SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Part 1: GSK3174998 Monotherapy 
Primary 
x To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously 
to subjects with selected advanced or 
recurrent solid tumors.   
x AEs, SAEs, DLT, withdrawals due to AEs, 
dose reductions or delays, and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).   
Secondary 
x 
To evaluate the antitumor activity of 
GSK3174998 in subjects with selected 
advanced or recurrent solid tumors. 
x 
To characterize the PK of GSK3174998 
monotherapy. 
x 
To determine the immunogenicity of 
GSK3174998.  
x 
ORR and DCR (CR+ PR+ SD ≥12 
weeks) b 
x 
GSK3174998 concentrations in plasma 
and PK parameters including Cmax, 
AUC(0-W), and Cmin. 
x 
Number and percentage of subjects who 
develop detectable ADA. 
Exploratory 
x 
To explore the relationship between 
antitumor activity, PK parameters, 
pharmacodynamic activity and other 
patient characteristics.  
x 
To explore onset and durability of 
response 
x 
Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK 
parameters, pharmacodynamic activity, 
and other patient characteristics.  
 
x 
TTR and DOR 
x To evaluate the pharmacodynamic activity 
of GSK3174998 in the peripheral blood 
and to explore the utility of these 
measures to enrich for clinical efficacy and 
development of a diagnostic test. 
x 
Assessment of lymphocyte OX40 
receptor membrane expression and 
occupancy by GSK3174998. Measures of 
immune function in blood (e.g. phenotype, 
quantity, and activation state of T cells in 
the periphery, TCR diversity, expression 
of circulating soluble factors such as 
cytokines and stress-related proteins). 
Changes in genomic DNA, gene 
expression (RNA and protein), (e.g. using 
cfDNA, exosomes or circulating tumor 
cells [CTCs]) and mutational load.  
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Objectives 
Endpoints 
Part 1: GSK3174998 Monotherapy 
Exploratory 
x To evaluate the pharmacodynamic activity 
of GSK3174998 in the tumor 
microenvironment and to explore the utility 
of these measures to enrich for clinical 
efficacy and development of a diagnostic 
test.  
x 
Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity or mutational load 
(genomic DNA). 
x Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the 
host DNA and response to therapy or 
disease characterization. 
 
x 
Germline genetic evaluations may be 
conducted for: 
x Medicine response, including 
GSK3174998 or any concomitant 
medicines. 
x Disease susceptibility, severity, and 
progression and related conditions. 
 
Hypothesis 
For the primary objective, no formal statistical hypothesis will be tested; analysis will be 
descriptive and exploratory 
a. 
In the final determination of the MTD, all available safety and tolerability data will be considered 
b. 
Unless otherwise specified, all response endpoints will be assessed by Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 and by irRECIST (immune-related RECIST); irRECIST will be used to determine 
treatment decisions.  
RNA = Ribonucleic acid; DNA = Deoxyribonucleic acid 
 
 
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Objectives 
Endpoints 
PART 2: Combination GSK3174998 plus pembrolizumab 
Primary 
x 
To evaluate the safety and tolerability and 
identify the MTDa or the MAD of 
GSK3174998 administered intravenously 
in combination with IV pembrolizumab to 
subjects with selected advanced or 
recurrent solid tumors.  
x 
AEs, SAEs, DLTs, withdrawals due to 
AEs, dose reductions or delays, and 
changes in safety assessments (e.g., 
laboratory parameters, vital signs, and 
cardiac parameters).  
Secondary 
x 
To evaluate the antitumor activity of 
GSK3174998 in combination with 
pembrolizumab in subjects with selected 
advanced or recurrent solid tumors. 
x 
ORR and DCR (CR+PR+SD ≥12 weeks)b  
 
x 
To characterize the PK of GSK3174998 
and pembrolizumab when administered in 
combination.  
x 
Plasma GSK3174998 and serum 
pembrolizumab concentrations and PK 
parameters including Cmax, AUC(0-τ), 
and Cmin.  
x 
To determine the immunogenicity of 
GSK3174998 and pembrolizumab when 
administered in combination.   
x 
Number and percentage of subjects who 
develop detectable ADA.  
Exploratory 
x 
To explore the relationship between 
antitumor activity, PK parameters, 
pharmacodynamic activity and other 
patient characteristics.  
x 
Evaluation of antitumor activity (CR, PR, 
SD, PD), tumor kinetic parameters, PK 
parameters, pharmacodynamic activity, 
and other patient characteristics.  
x 
To explore onset and durability of 
response 
x 
TTR and DOR 
x To evaluate the pharmacodynamic activity 
of GSK3174998 in combination with 
pembrolizumab in the peripheral blood and 
to explore the utility of these measures to 
enrich for clinical efficacy and 
development of a diagnostic test. 
x Assessment of lymphocyte OX40 
receptor membrane expression and 
occupancy by GSK3174998. Measures of 
immune function in blood (e.g. phenotype, 
quantity, and activation state of T cells in 
the periphery, TCR diversity, expression 
of circulating soluble factors such as 
cytokines and stress related proteins).  
Changes in genomic DNA, gene 
expression (RNA and protein), (e.g. using 
cfDNA, exosomes or CTCs) and 
mutational load.  
 
 
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Objectives 
Endpoints 
PART 2: Combination GSK3174998 plus pembrolizumab 
Exploratory 
x 
To evaluate the pharmacodynamic 
activity of GSK3174998 in combination 
with pembrolizumab in the tumor 
microenvironment and to explore the 
utility of these measures to enrich for 
clinical efficacy and development of a 
diagnostic test. 
x 
Assessment of tumor biopsies via IHC for 
the numbers of tumor-infiltrating 
lymphocytes and other immune cells 
expressing key phenotypic markers. 
Changes in gene expression (RNA and 
protein), TCR diversity or mutational load 
(genomic DNA). 
x PGx: To evaluate the association of 
genetic variations in the host DNA and 
response to therapy or disease 
characterization.  
 
x 
Germline genetic evaluations may be 
conducted for: 
x Medicine response, including 
GSK3174998 and pembrolizumab or 
any concomitant medicines.  
x 
Disease susceptibility, severity, and 
progression and related conditions.  
Hypothesis 
For the primary objective, no formal statistical hypothesis will be tested; analysis will be 
descriptive and exploratory 
a. 
In the final determination of the MTD, all available safety and tolerability data will be considered 
b. 
Unless otherwise specified, all response endpoints will be assessed by RECIST v1.1 and by irRECIST; 
irRECIST will be used to determine treatment decisions. 
RNA = Ribonucleic acid;  DNA = Deoxyribonucleic acid 
3. 
STATISTICAL HYPOTHESES 
3.1. 
Part 1: Monotherapy Dose Escalation (GSK3174998) 
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested.  The primary focus will be on determining the recommended dose for 
further exploration, the safety profile, and antitumor activity of GSK3174998.   
3.2. 
Part 2: Combination Dose Escalation (GSK3174998 + 
Pembrolizumab) 
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
study will be focused on comparison between dose cohorts and only descriptive methods 
will be used in analysis of the data obtained from this study.  
3.3. 
Part 2: Combination Dose Expansion (GSK3174998 + 
Pembrolizumab) 
The expansion cohorts of GSK3174998 + pembrolizumab are designed to evaluate 
preliminary clinical activity.  
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There are multiple dose expansion cohorts being planned for STS, melanoma and other 
cancers types in the dose-expansion phase. For each cohort the objective is to test the null 
hypothesis that the overall response rate for the combination of GSK3174998 + 
pembrolizumab is equal to the historical response rate of monotherapy pembrolizumab. 
The observed monotherapy pembrolizumab overall response rate was approximately 18% 
for STS. The observed monotherapy pembrolizumab overall response rate was assumed 
to be approximately 10% for melanoma in the pretreated population.  
The sample size is chosen based on an improvement of 20% in the overall response rate 
on the combination therapy over the null hypothesis, with power of at least 80% and no 
more than a 10% type 1 error rate. In the population previously treated with 
pembrolizumab, the goal would be to observe a response rate of 30% after treatment with 
the combination of GSK3174998 and pembrolizumab.  
Therefore, the hypotheses for both PD-(L)1 naïve and PD-(L)1 pretreated cohorts are 
shown as below: 
For PD-(L)1  naïve dose expansion cohorts (e.g., STS), the null hypothesis for ORR is: 
H0: p=18% 
 
and the alternative hypothesis is: 
HA: p=38% 
For PD-(L)1 pretreated dose expansion cohorts (e.g., melanoma), the null hypothesis for 
ORR is:  
H0: p=10% 
 
and the alternative hypothesis is: 
HA: p=30% 
4. 
STUDY DESIGN 
This is a first time in human (FTIH), open-label, non-randomized, multicenter study 
designed to evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary 
clinical activity of GSK3174998 administered intravenously to subjects with selected 
advanced or recurrent solid tumors.  
The study will be conducted in two parts (see Figure 1). Part 1 will evaluate 
GSK3174998 monotherapy, while Part 2 will evaluate GSK3174998 in combination with 
pembrolizumab.  As shown in Figure 1, GSK3174998 will first be evaluated as 
monotherapy in escalating doses.  Once a dose of GSK3174998 has been identified that is 
both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may 
begin.  In Part 2, escalating doses of GSK3174998 will first be evaluated with fixed doses 
of pembrolizumab. Part 1A and 2A will also include a Pharmacodynamic Cohort, which 
requires mandatory fresh pre- and on-treatment biopsies and an additional disease 
assessment at week 6. Part 2 will also include expansion cohorts for specified tumor 
types. 
 
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The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, SCCHN, RCC, melanoma, bladder cancer, STS, TNBC, and MSI CRC.  In the 
dose-escalation phase of the study, subjects with any of the aforementioned tumor types 
may be included; whereas in the cohort expansion phase of the study, each expansion 
cohort will enroll subjects with one specific tumor type selected from the aforementioned 
list. A subject’s disease status and determination of disease progression at postbaseline 
visits will be evaluated by the local investigators’ assessments of radiology by RECIST 
v1.1 and irRECIST; a decision to discontinue treatment due to disease progression will be 
based upon irRECIST and the primary endpoint analysis will use irRECIST. Scans will 
be collected centrally and stored to allow for the option of central radiologic audit or 
review.  
A Steering Committee will be established to review safety, PK, and other clinical data 
during the course of the study, to provide objective interpretation of study results, and 
guidance for key decisions. The remit of the Steering Committee will include guidance 
for the transition of the study from dose-escalation to cohort expansion and from Part 1 to 
Part 2, the selection of specific tumor types to include in the expansion cohorts, and the 
selection of the recommended Phase 2 dose (RP2D); the study team will also seek 
endorsement from GSK Medical Governance for the transition of the study from one part 
to another.  In the final determination of the MTD and RP2D, all available safety and 
tolerability data will be considered. Pending a review of emerging data from this study 
and under the guidance of the Steering Committee, the protocol may be subsequently 
amended to include investigation of additional anticancer agent combinations with 
GSK3174998. The remit, membership, roles and responsibilities of the Steering 
Committee are described in a Steering Committee Charter. Key decisions of the Steering 
Committee will be documented and reported to all participating principal investigators 
(PIs) and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs). 
The schedule of time and events can be found in the study protocol Section 7.1. Details 
regarding dose escalations can be found at the study protocol Section 4.1.1. 
 
 
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Figure 1 
Study Design 
 
5. 
PLANNED ANALYSES 
In line with ICH E9 [European Agency for the Evaluation of Medicinal Products, 1998], 
membership of the analysis populations will be determined using the definitions in 
Section 7 of this RAP. 
5.1. 
Interim Analyses 
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in protocol Section 4.1.1 and protocol Section 9.3. The Steering 
Committee will guide the transition of the study from dose escalation to cohort expansion 
for both monotherapy and combination therapies. 
For dose expansion cohorts, continuous assessment of efficacy and safety was planned to 
be performed after first interim analysis based upon a minimum of 10 subjects in at least 
one of the disease-specific cohorts with available unconfirmed overall response data for 
at least 12 weeks. However, after implementation of protocol Amendment 4, no further 
subjects were enrolled in the study; therefore, no futility analyses were performed. 
 
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5.2. 
Analyses for Dose Escalation Cohorts and Expansion 
Phases 
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including biomarker, PK data, and the safety profile of prior cohorts.  In addition, the 
recommended dose from a Continuous Reassessment Method (N-CRM) analysis 
[Neuenschwander, 2008] will be calculated.  The N-CRM is a type of Bayesian adaptive 
dose-escalation scheme.  The method is fully adaptive and makes use of all the DLT 
information available at the time of each dose assignment. The Fixed and Adaptive 
Clinical Trial Simulator (FACTS) will be used to conduct the N-CRM analysis. The 
DLT information on all subjects enrolled in the trial are used to update the estimated 
dose-toxicity relationship and provide supportive information in addition to the 3+3 
design in the next escalation/de-escalation decision. 
There is no futility analysis for dose expansion cohorts as specified in Section 5.1.  
5.3. 
Final Analyses 
The final analysis of the study will be performed when the study is completed or 
terminated.  Upon Protocol Amendment 4 implementation, ongoing subjects will be 
considered withdrawn due to study closure and will be followed for up to 3 months after 
the last dose.  Only when a subject dies is he/she considered to have completed the study; 
consequently, “death” is not listed as a reason for withdrawal from the study. 
Furthermore, disease progression, discontinuation of study treatment, and AEs, are not by 
themselves reasons for withdrawal from the study. If a subject dies a copy of the death 
certificate should be available for review, if possible, and the cause of death should be 
evaluated and documented. 
The end of the study is defined as the last subject’s last visit. 
6. 
SAMPLE SIZE CONSIDERATIONS 
6.1. 
Sample Size Assumptions 
The sample size for each part of the trial was chosen to adequately characterize 
the safety, clinical activity, PK, and pharmacodynamic marker data according to 
the objectives of each part of the study. 
 
The study will enroll up to approximately 264 subjects with tumor types that may include 
NSCLC, SCCHN, RCC, melanoma, STS, bladder cancer, TNBC, and MSI CRC. 
 
Up to 72 subjects will be enrolled in each of the two dose escalation parts of the study 
(Parts 1A and 2A); up to 30 subjects will be enrolled in each of dose expansion 
cohorts. The sample size of each expansion cohort at a given dose level will be 
minimum of 10 subjects and maximum of 30 subjects based on the overall response 
assessments. More details of sample size calculation are described in protocol Section 
9.2. 
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7. 
ANALYSIS POPULATIONS 
7.1. 
All Treated Population 
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK3174998.  Safety and anticancer activity will be evaluated based on this analysis 
population.   
7.2. 
PK Population 
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.   
7.3. 
Analysis Datasets 
Analysis datasets will be created according to CDISC/ADaM standards, and data will be 
listed and summarized according to GSK Integrated Data Standards Library (IDSL) 
reporting standards. Formatting for dates, times, and decimal places will follow GSK 
standards except where specified. 
8. 
TREATMENT COMPARISONS 
There are no treatment comparisons in the study. 
8.1. 
Data Display Treatment and Other Subgroup Descriptors 
 
For Part 1 (i.e., Part 1A), Monotherapy: Investigated doses of GSK3174998 will be 
displayed in summary tables and listings.  
 
For Part 2A, Combination Dose Escalation: Some AE and exposure tables and listings 
will be displayed for GSK3174998 and pembrolizumab separately, all other tables and 
listings will display by dose levels of both GSK3174998 plus pembrolizumab. 
 
For Part 2B, Combination Dose Expansion:  Data will be displayed by each cohort type at 
the recommended phase 2 dose; for combination therapy expansions, selected AE and 
exposure display requirements as noted in Part 2A will also apply. 
 
9. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
SAS 9.3 or higher version will be used to perform all data analyses, generate tables, 
figures, and listings. The exception would be CRM analyses, which are specified to take 
place in FACTS.  
All data within scheduled visits up to the time of study completion/withdrawal from 
study will be included in the analysis summaries, regardless of duration of treatment.  
Unscheduled visits will be considered for most extreme result reporting (e.g. worst grade 
post-baseline) and included in data listings. 
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Actual treatment derivation is specified in Section 10.2.10. Planned treatment is collected 
on dosing regimen eCRF page.  
Efficacy analysis will be based on planned treatment. 
For Part 1 and Part 2A, Safety and PK analysis will be based on actual treatment the 
subjects received and displayed by dose level. Efficacy analysis will be based on planned 
treatment and displayed by dose level.  
For Part 2B, tables and figures will be displayed by cohort type. The subject will be 
summarized in the cohort type though the actual dose level may be different from the 
planned dose level. A footnote will be added in the Safety and PK table or figure to 
explain the discrepancy. 
Unless otherwise noted, Safety and PK listings will be based on the actual treatment and 
efficacy listings will be based on the planned treatment. 
In addition, for PK and receptor occupancy analysis, if a subject received different   doses 
of treatment, the subject will be excluded from the analysis.  
Deviations from the analyses in the RAP will be identified in the CSR.  
Unless otherwise noted, the denominator for the percentage is the number of subjects in 
the analysis population used for the summary. 
9.1. 
Other Strata and Covariates 
In all efficacy analyses, there are no formal plans for any stratification. There are no 
formal plans for investigating any covariates. 
9.2. 
Examination of Subgroups 
There are no formal plans for examining subgroups. 
9.3. 
Multiple Comparisons and Multiplicity 
There is no adjustment for multiplicity in all primary and secondary analyses. 
10. 
DATA HANDLING CONVENTIONS 
10.1. 
Premature Withdrawal and Missing Data 
For endpoints which determine the percentage of responders, subjects with unknown/not 
evaluable or missing best overall response will be assumed to be non-responders, and will 
be included in the denominator when calculating the percentages.  
In the event that the study is terminated, all available data will be listed and a review 
carried out by the study team to assess which statistical analyses are still considered 
appropriate. 
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Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument. These data will be indicated by the use of a “blank” in subject 
listing displays. Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such. 
Subjects with the designation of treatment relationship for AEs and SAEs missing will 
have the worst case assumed to impute the relationship: if relationship to study treatment 
is missing it will be assumed to be “Yes”. There will be no other imputation for missing 
data other than what is described in Section 10.2 for partial dates. 
10.2. 
Derived and Transformed Data 
The following sections provide a general description of the derived and transformed 
variables used to describe and analyze the data. Separate analysis dataset specifications 
provide full details on all data derivations and transformations including descriptions of 
core standard algorithms and standard oncology algorithms. The analysis dataset 
specifications will clearly communicate the content and source of the datasets supporting 
the statistical analyses. 
10.2.1. 
Reference dates 
Unless otherwise stated, the safety reference (start) date will be the start of treatment of 
GSK3174998.  This will also be the efficacy reference date for this study.  The reference 
date for baseline characteristics (e.g. age) will be the date of screening. 
10.2.2. 
Study Day for Safety Measures 
If the date of interest occurs on or after the safety reference date then the safety study day 
will be calculated as (date of interest - safety reference date) + 1.  There is no safety study 
day 0. 
10.2.3. 
Study Day for Efficacy 
If the date of interest occurs on or after the efficacy reference date then efficacy study day 
will be calculated as (date of interest - efficacy reference date) + 1. If the date of interest 
occurs prior to the efficacy reference date then efficacy study day will be calculated as 
(date of interest – efficacy reference date). There is no efficacy study day 0.  
10.2.4. 
Duration and Elapsed Time 
Durations (e.g., the duration of an AE, duration of exposure, etc.) are calculated as the 
stop date minus the start date plus one. 
For elapsed time (e.g., the time since initial diagnosis): 
x 
If the reference date is on or after the event date, then the elapsed time is the 
reference date minus the event date + 1. 
x 
If the reference date is before the event date then the elapsed time is the reference 
date minus the event date. 
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When reporting time to event (TTE) durations in months, divide the number of days by 
30.4375; to report in weeks divide the number of days by 7; to report in years divide the 
number of days by 365.25. These algorithms for time to event return decimal numbers, 
and ignore the actual numbers of days in the months or years between start date and stop 
date. The "year" used in these algorithms is 365.25 days long, and the "month" is one 
twelfth of that year. 
For converting all other durations (e.g., duration of AEs, duration of exposure, age) to 
weeks, months or years use the following: 
x 
To report the duration in weeks, divide the number of days by 7. 
x 
To report the duration in months use: 
(YEAR(stopdate + 1) - YEAR(startdate)) * 12 + (MONTH(stopdate + 1) - 
MONTH(startdate) - 1) + (DAY(stopdate + 1) > = DAY(startdate)) 
x 
To report the duration in years use: 
INTCK('year', startdate, stopdate + 1) - (MONTH(stopdate + 1) < 
MONTH(startdate) or 
(MONTH(stopdate + 1) = MONTH(startdate) and DAY(stopdate + 1) < 
DAY(startdate))) 
The algorithms above for age and duration return whole numbers for months and years, 
accurately accounting for the actual numbers of days in the months or years between the 
start date and the stop date. 
10.2.5. 
Imputation of Partial Dates 
Imputed partial dates will not be used to derive study day, duration (e.g., duration of 
AEs), or elapsed time variables.  
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition, partial dates may be imputed for determining treatment-emergent AEs.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Example of Date Variables:  
XYZD_ - character date variable 
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XYZDT - numeric date variable 
XYZDTFL - flag variable 
Details on imputing partial dates for specific datasets are outlined below. 
Adverse Events (AE): 
Imputations in the adverse events dataset are used for determining treatment-emergent 
AEs and for sorting in data listings. 
Dataset 
Date 
Missing 
Element 
Rule 
Adverse 
Events 
(AE) 
 
 
 
Start 
Date 
day, month, 
and year 
x No Imputation for completely missing dates 
 
day, month 
x If study treatment start date is missing (i.e. 
subject did not start study treatment), then set 
start date = January 1. 
x Else if study treatment start date is not missing:  
o If year of start date = year of study treatment 
start date then  
- 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1.  
- 
Else set start date = study treatment start 
date.  
o Else set start date = January 1. 
 
day 
x If study treatment start date is missing (i.e. 
subject did not start study treatment), then set 
start date = 1st of month.  
x Else if study treatment start date is not missing:  
o If month and year of start date = month and 
year of study treatment start date then  
- 
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month.  
- 
Else set start date = study treatment start 
date. 
o Else set start date = 1st of month. 
End 
Date 
 
x No imputation for partial end dates will be 
performed 
 
 
 
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Surgery:   
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. 
Dataset 
Missing Element 
Rule 
Surgical 
Procedures 
 
 
day, month, and year 
x 
No Imputation for completely missing dates 
day, month 
x 
If partial date contains a year only set to 
January 1st. 
day 
x 
If partial date contains a month and year set to 
the 1st of the month 
 
Concomitant Medication and Blood and Blood Supportive Care Products: 
 
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only.  
Dataset 
Date Missing 
Element 
Rule 
Concomitant 
Medication 
Blood and Blood 
Supportive Care 
Products  
 
Start 
Date 
 
day, 
month, 
and year 
No Imputation for completely missing dates 
day, 
month 
x 
If study treatment start date is missing 
(i.e. subject did not start study treatment), 
then set start date = January 1.  
x 
Else if study treatment start date is not 
missing:  
o If year of start date = year of study 
treatment start date then  
- 
If stop date contains a full date 
and stop date is earlier than study 
treatment start date then set start 
date = January 1.  
- 
Else set start date = study 
treatment start date.  
Else set start date = January 1. 
day 
x 
If study treatment start date is missing 
(i.e. subject did not start study treatment), 
then set start date = 1st of month.  
 
 
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Dataset 
Date 
Missing 
Element 
Rule 
Concomitant 
Medication 
 
Blood and 
Blood 
Supportive 
Care 
Products  
 
End 
Date 
day, 
month, 
and year 
x 
No Imputation for completely missing dates 
  
day, 
month 
x 
If partial end date contains year only, set end date = 
earliest of December 31 or date of last contact.  
  
day 
x 
If partial end date contains month and year, set end date 
= earliest of last day of the month or date of last contact 
 
Start Date of New Anticancer Therapy: 
Start dates for follow-up anticancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be temporarily imputed in order to define 
duration of response. Dates will only be imputed when a month and year are available but 
the day is missing. The imputed date(s) will not be stored on the anticancer therapy, 
radiotherapy, or surgical procedure datasets. The following rules will be used to impute 
the date when partial start dates are present on anticancer therapy radiotherapy, and/or 
surgical procedures dataset[s]: 
Dataset 
Date 
Missing 
Element 
Rule 
Anticancer 
Therapy  
 
Where 
applicable:  
Radiotherapy  
 
Surgical 
Procedures 
 
 
 
Start 
Date 
day, month, 
and year 
x 
No Imputation for completely missing 
dates 
 
day, month 
x 
No imputation for missing day and month 
(note the eCRF should only allow for 
missing day) 
 
day 
x 
If partial date falls in the same year and 
month as the last dose of study treatment, 
then assign to earlier of (date of last dose 
of study treatment+1, last day of month).  
x 
If partial date falls in the same year and 
month as the subject’s last assessment and 
the subject’s last assessment is PD, then 
assign to earlier of (date of PD+1, last day 
of month).  
x 
If both rules above apply, then assign to 
latest of the 2 dates  
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Dataset 
Date 
Missing 
Element 
Rule 
x 
Otherwise, impute missing day to the first 
of the month. 
End 
Date 
 
x 
No imputation for partial end dates will be 
performed 
The date of new anticancer therapy is derived as the earliest date of new anticancer 
therapy (e.g., chemotherapy), radiotherapy (where applicable), or cancer related surgical 
procedure (where applicable) and will include imputed dates. If the date of new 
anticancer therapy is an imputed date, then the date of new anticancer therapy flag 
variable is assigned the value of 'D' to indicate that the day portion of the date is imputed 
(following ADaM convention).  
As multiple dates are used to derive the date of new anticancer therapy ensure that the 
date of new anticancer therapy flag is only set to ‘D’ if the derived date is imputed. For 
example if the date of new radiotherapy is imputed but the date of new anticancer therapy 
is prior to date of new radiotherapy and the new anticancer therapy date is not a partial 
date then the flag should be set to missing as the date used for the new anticancer therapy 
is not an imputed date. 
10.2.6. 
Imputation of Missing Exposure End Dates 
Missing exposure end date will not be imputed. 
10.2.7. 
Baseline Definition 
Baseline will be defined as the most recent, non-missing value prior to or on the first 
study treatment dose date (this can be either GSK 3174998 or pembrolizumab). For 
laboratory data, baseline will be defined as the most recent, non-missing value from a 
central laboratory prior to or on the first study treatment dose date. If there are no central 
labs collected for a subject and lab test prior to or on the first dose of study treatment, the 
most recent, non-missing value from a local laboratory prior to or on the first dose of 
study treatment will be defined as the baseline value. 
If the latest pre-dose value is collected on the day of treatment, the time of treatment will 
be used to identify the baseline value.  If the pre-dose time point value is identified as 
baseline, and the data is recorded in triplicate the average will be used. 
For subjects who did not receive study treatment during the study, baseline will be 
defined as the latest, non-missing collected value. 
10.2.8. 
Change from baseline 
Change from baseline will be presented for safety data as described in Section 13.  
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Change from baseline is calculated as: 
x 
For records occurring after baseline: (visit value) – baseline value. 
Percent change from baseline is calculated as: 
x 
For records occurring after baseline: (change from baseline / baseline value) * 100 
Unless otherwise stated, if either the baseline or visit value is missing, the change from 
baseline and/or percent change from baseline is set to missing as well. 
10.2.9. 
Multiple Assessments 
All data will be reported according to the nominal visit date for which it was reported 
(that is, no visit windows will be applied during dataset creation). Unscheduled data will 
only be included in the display sections that report worst-case. For summaries that 
collapse data across multiple planned time intervals, the worst-case data at each collapsed 
interval will be selected.   
If multiple assessments on different days are reported for the same scheduled assessment, 
then the latest assessment for that scheduled assessment will be analyzed. 
If multiple assessments are reported on the same date for the same scheduled planned 
time, then the worst-case result will be analyzed, with the exception of laboratory data 
reported from both central and local laboratories.  
Furthermore, as quantitative ECG values will be measured in triplicate: 3 assessments are 
collected for each scheduled planned time, the first 3 measures will be used to compute 
the mean values for ECG intervals at each scheduled planned time.  
For vital signs, three readings of blood pressure (BP) and pulse rate will be taken and the 
first reading will be discarded. The second and third readings will be averaged and 
recorded on eCRF to give the measurement reported at each time point. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings.  
10.2.10. 
Actual Treatment 
The actual treatment of a subject will be derived from exposure data.  The first dose the 
subject received is used as actual treatment. 
10.2.11. 
Extended Loss to Follow-up or Extended Time without an 
Adequate Assessment 
If [two] or more scheduled disease assessments are missed and are then followed by an 
assessment of PD or death, PFS will be censored at the last adequate assessment prior to 
PD or death. As scheduled disease assessment is every 12 weeks, a window of 175 days 
(24 weeks + 7 day window) will be used to determine whether there was an extended 
time without adequate assessment. That is, if the time difference between PD/death and 
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last adequate assessment is more than 175 days, then PFS will be censored at the last 
adequate assessment prior to PD/death. 
10.2.12. 
Date Associated with Response 
For each disease assessment after baseline, a date will be associated with the response 
based on collective group of disease assessments made within the protocol visit window. 
For complete response (CR) and partial response (PR), this will be assigned to the latest 
date within the disease assessments. For stable disease (SD), Non-CR/Non-PD or Not 
Evaluable, this will be assigned to the earliest date within the disease assessments. For 
progressive disease (PD), assign to the earliest assessment date associated with the 
progression. Dates associated with irRECIST response values will be handled similarly. 
10.3. 
Values of Potential Clinical Importance 
10.3.1. 
Laboratory Parameters 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings. 
Laboratory grades will be reported, where applicable, using the Common Terminology 
Criteria for Adverse Events (CTCAE v4.0). 
10.3.2. 
ECG Parameters 
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance:  
To identify QTc (Fridericia’s) values of potential clinical importance, NCI-CTCAE v4.0 
will be used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’). Note that there is a slight inconsistency between NCI-CTCAE v4.0 and ICH 
E14 (Absolute QTc interval prolongation). It was decided to align with NCI-CTCAE v4.0 
for the oncology standard categories. 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute QTcF interval 
>450 to <481 (Grade 1) 
t481 to <501 (Grade 2) 
t501 (Grade 3) 
msec 
Increase from baseline 
QTcF  
Increase of t31 to d60                                               
Increase of >60 
msec 
 
The following criteria will be used to flag some ECG values that are values of potential 
clinical importance:  
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ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
PR interval 
<110 (L) and >220 (H) 
msec 
QRS interval 
<75 (L) and >110 (H) 
msec 
 
Averages (rounded to the integer) are the basis of analyses when time point data is 
collected in triplicate. 
10.3.3. 
Vital Signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’. 
The following criteria will be used to flag vital sign values (based on the averaged value) 
that are values of potential clinical importance: 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Decrease from baseline 
Heart Rate 
Decrease to <60 
bpm 
Increase from baseline 
Heart Rate 
Increase to >100 
bpm 
 
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will 
be used to assign categories that align with the grades for ‘Hypertension’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) 
Range 
Unit 
Increase from baseline 
Systolic Blood Pressure 
Increase to t120 to <140 (Grade 1) 
Increase to t140 to <160 (Grade 2) 
Increase to t160 (Grade 3) 
mmHg 
Increase from baseline 
Diastolic Blood 
Pressure 
Increase to t80 to <90 (Grade 1) 
Increase to t90 to <100 (Grade 2) 
Increase to t100 (Grade 3) 
mmHg 
 
Systolic blood pressure below 120 and diastolic blood pressure below 80 are considered 
as normal range and will receive Grade 0 designations. 
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’. 
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Vital Sign Parameter 
Potential Clinical Importance (PCI) 
Range 
Unit 
Increase from baseline 
temperature 
Increase to t38 
Degrees C 
Decrease from baseline 
temperature 
Decrease to d35 
Degrees C 
Additionally, temperature and heart rate will be further categorized for reporting based on 
the following: 
x 
Heart rate (beats/min): <60, 60-100, and >100; and  
x 
Temperature (°C): ≤35, 35<-38, ≥38. 
11. 
STUDY POPULATION 
Unless otherwise stated, all tables and listings in this section will be based on the All 
Treated Population, and all summaries and data listings will use treatment labels as 
specified in Section 7. 
11.1. 
Disposition of Subjects 
A summary of the number of subjects in each of the analysis populations described in 
Section 7 will be provided. In addition, the number of subjects enrolled by center will be 
summarized by treatment group using the All Treated Population.  A listing of subjects 
excluded from analysis populations will also be provided.  
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who withdrew from the study, 
including primary reasons for study withdrawal; the number and percentage of subjects 
who died will also be presented .  Reasons for study withdrawal will be presented in the 
order they are displayed in the eCRF. In addition, a summary table and listing identifying 
reasons for screening failures will be presented. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of subjects who have discontinued study treatment and a summary of the 
primary reasons for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF. A listing of 
study treatment discontinuation will be generated. The listing will include last dose date, 
and reasons for study treatment discontinuation as well as study part and phase of 
discontinuation.  
11.2. 
Protocol Deviations 
All protocol deviations will be summarized and listed and will include 
inclusion/exclusion deviations as well as other deviations.  
A separate listing of inclusion/exclusion deviations will also be provided. 
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11.3. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and 
baseline body weight) will be summarized and listed. Age, height and weight will be 
summarized using the mean, standard deviation, minimum, median, and maximum. In 
addition, age will also be categorized and summarized by 18-64, 65-74, and >74. The 
count and percentage will be computed for sex and ethnicity. Planned treatment, if 
different from actual treatment, will be listed in demographic characteristics listing.  In 
addition, for the re-enrolled subjects from Part 1 to Part 2, the information will be 
indicated in Part 2 demographic characteristics listing. 
Race and racial combinations will be summarized and listed. Family history, history of 
tobacco use and alcohol intake at screening will be listed. 
Disease history and characteristics: primary tumor type, histology, histologic grade, HPV 
status, time since initial diagnosis in months, stage at initial diagnosis, and time from last 
occurrence will be summarized. Indicators (yes/no) for the following, collected at 
screening, will also be summarized:  measurable disease, non-target lesions, and 
progression on previous therapy. Medical conditions present at screening will be listed 
and will be summarized by past and current. Disease history and characteristics, as well 
as these medical conditions, will be presented in data listings. 
Prior anticancer therapy will be coded using GSK Drug coding dictionary and will be 
classified by type (chemotherapy, immunotherapy, hormonal therapy, biologic therapy, 
small molecule targeted therapy, and vaccine, etc.). Some prior anticancer therapy may 
not have type available and will be summarized under “Missing” type. Prior anticancer 
therapy will be summarized by type of therapy. A subcategory immunotherapy - prior 
anti PD1/PD-L1 will be included in the summary table as well.  A summary of the 
number of prior anticancer therapy regimens by type will also be produced. Prior 
anticancer therapy will be listed. 
Prior anticancer radiotherapy will be listed. Prior cancer and non-cancer related surgeries 
will be summarized and listed.  
11.4. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary and listed. 
Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body System) 
information will be included in the dataset created but will not appear on the listing or 
summary. 
Blood products or blood supportive care products will be listed.  
11.5. 
Subsequent Anticancer Therapies 
Follow-up anticancer therapy will be coded using GSK Drug coding dictionary. A listing 
of follow-up anticancer therapy will show the relationship between preferred term and 
verbatim text; therapies will be classified by type (chemotherapy, immunotherapy, 
hormonal therapy, and biologic therapy, etc.).  
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On treatment and follow-up anticancer radiotherapy will be listed. 
On treatment and follow-up cancer and non-cancer related surgeries, together with prior 
cancer and non-cancer related surgeries will be summarized and listed. 
12. 
EFFICACY ANALYSES 
12.1. 
Endpoints / Variables 
Tumor response i.e., complete response (CR/irCR), partial response (PR/irPR), and stable 
disease (SD/irSD), and progressive disease (PD/irPD) will be based on the assessments 
from the investigators’ review of objective evidence (e.g., radiological scan). Overall 
responses were measured in accordance with the RECIST v1.1 and irRECIST. If the 
overall response reviewed by investigator is non-radiologic PD per RECIST v1.1 at a 
time point, the tumor response at that time point will be derived based on the assessments 
of target lesion, non-target lesion, and new lesion at that time point, using the below 
logic: 
Target Lesion 
Response 
Assessment per 
RECIST v1.1 
Non-target Lesion 
Assessment per 
RECIST v1.1 
New Lesion 
Assessment per 
RECIST v1.1 
Derived Overall 
Response per 
RECIST v1.1 
No target lesion at 
baseline 
CR 
No 
CR 
No target lesion at 
baseline 
NON-CR/NON-PD 
No 
NON-CR/NON-PD 
No target lesion at 
baseline 
NE 
No 
NE 
No target lesion at 
baseline 
PD 
No 
PD 
No target lesion at 
baseline 
PD 
Yes 
PD 
No target lesion at 
baseline 
Any  
Yes 
PD 
CR 
CR 
No 
CR 
CR 
NON-CR/NON-PD 
No 
PR 
PR 
NON-CR/NON-PD 
No 
PR 
PR 
NE 
No 
PR 
SD 
NON-CR/NON-PD 
No 
SD 
SD 
NE 
No 
SD 
SD 
No non-target lesion at 
baseline 
No 
SD 
NE 
NON-CR/NON-PD 
No 
NE 
NE  
No non-target lesion at 
baseline 
No 
NE 
PD 
any 
any 
PD 
any 
PD 
any 
PD 
any 
any 
Yes 
PD 
 
ORR, DCR, DOR and TTR will be reported by both RECIST v1.1 and irRECIST. 
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12.2. 
Summary Measure 
The evaluation of anticancer activity will be evaluated based on the All Treated 
Population as defined in Section 7 unless otherwise specified. Since this is a Phase I 
study, anticancer activity will be evaluated based on clinical evidence and response 
criteria.  If data warrant, the response data will be summarized by dose level or expansion 
cohort type. 
Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to RECIST (version 1.1) [Eisenhauer, 
2009] and irRECIST as outlined in Appendix 5 of the protocol.  irRECIST will be used to 
determine treatment decisions and will be used for the primary analysis of anticancer 
activity. 
12.2.1. 
Best Overall Response (BOR) 
Best response will be summarized. A swimmer plot of study duration and best response 
will be produced by cohort. 
12.2.1.1. 
Confirmed Best Overall Response (BOR) 
The confirmed best overall response is the best confirmed response recorded from the 
start of treatment until disease progression or start of new anti-cancer therapy, whichever 
earlier, and will be determined programmatically based on investigator assessment at 
each time point. Note that if the investigator assessment is non-radiologic PD by RECIST 
v1.1 at a time point, the overall response will be derived based on the logic specified in 
Section 12.1. The derived overall response at that time point will be used to derive BOR. 
If there are two assessments separated by not evaluable (NE) assessment(s) the best 
response shall be assessed applying the algorithm below, collapsing data by ignoring NE 
assessments.  
12.2.1.1.1. Confirmed Best Overall Response per RECIST (version 1.1) Criteria and 
irRECIST Criteria 
x To be assigned a status of SD/irSD, follow-up disease assessment must have met the 
SD/irSD criteria at least once after the first dose at a minimum interval of 77 days. 
x If the minimum of 77 days for SD/irSD is not met, the best overall response will 
depend on the subsequent assessments. For example, if an assessment of PD follows 
the assessment of SD and SD does not meet the minimum time requirement the best 
response will be PD. Alternatively, subjects lost to follow-up after an SD assessment 
not meeting the minimum time criteria will be considered not evaluable. 
x To be assigned a status of PR/irPR or CR/irCR, a confirmatory disease assessment 
should be performed no less than 4 weeks (28 days) after the criteria for response are 
first met. 
x Responses of CR/PR, irCR/irPR that do not meet the requirements of confirmed 
CR/PR, irCR/irPR are still eligible to be considered SD/irSD if it has met the 
SD/irSD criteria. 
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12.2.1.1.2. Confirmed Best Overall Response per irRECIST Criteria 
Besides the principles specified in Section 12.2.1.1.1, the below principle needs to be 
considered when deriving the confirmed BOR per irRECIST.  
x 
To be assigned a status of confirmed irPD, a confirmatory disease assessment should 
be performed at the next disease assessment no less than 4 weeks (28 days) after the 
criteria for irPD are first met. 
x 
irPD will not override a subsequent best overall response of irSD, irPR, or irCR, 
meaning that irPR or irSD can be assigned (timepoint response or BOR) even if new 
lesions have not regressed, or if unequivocal progression (non-target lesions) remains 
unchanged, providing that the criteria for confirmation of irPD are not met. 
Confirmed and confirmed BOR per irRECIST (irBOR) takes into account the 
requirement for confirmation of irCR, irPR, and irPD. If irBOR is irPD and is confirmed 
consecutively, irBOR will be termed as irCPD.  
If irBOR is irPD but not confirmed and there is no subsequent irSD, irPR, or irCR (e.g. 
NE or lost follow-up), the confirmed and unconfirmed irBOR will be termed as irUPD.  
If irBOR is irPD but not confirmed and there is no subsequent irSD, irPR, or irCR (e.g. 
NE or lost follow-up) due to study conclusion, the confirmed BOR will be termed as N/A 
(not applicable) and the unconfirmed irBOR will be termed as irUPD. 
Examples of Scenarios of Assignments of Confirmed/Unconfirmed Best Overall 
Response Using irRECIST (assuming the adjacent timepoints are 28 days apart at least): 
Case 
Timepoint 
Response 1 
Timepoint 
Response 2 
Timepoint 
Response 3 
Timepoint 
Response 4 
Timepoint 
Response 5 
Timepoint 
Response 6 
Confirmed 
BOR 
Unconfirmed 
BOR  
1 
irSD [1] 
irPR 
irPR 
irCR 
irCR 
irPD 
irCR 
irCR 
2 
irPR   
irSD [1] 
irPR 
 
 
 
irSD 
irPR 
3 
irSD [2] 
NE 
 
 
 
 
NE 
NE 
4 
irSD [2] 
irCR 
irCR 
irPD 
 
 
irCR 
irCR 
5 
irSD 
irSD 
irSD 
irPR 
 
 
irSD 
irPR 
6 
irPR 
irPR 
irPD 
irPD 
 
 
irPR 
irPR 
7 
irPD  
irPD [4] 
 
 
 
 
irCPD 
irCPD 
8 
irPD [3] 
irPD [4] 
 
 
 
 
N/A 
irUPD 
9 
irPD 
irSD [1] 
irPD 
 
 
 
irSD 
irSD 
10 
irPD [4] 
 
 
 
 
 
N/A 
irUPD 
11 
irSD [2] 
irPD [4] 
 
 
 
 
N/A 
irUPD 
12 
NE 
irPD [4] 
 
 
 
 
N/A 
irUPD 
13 
irPD 
NE 
NE 
NE 
NE 
NE 
N/A 
irUPD 
Assume any two adjacent assessments are at least 28 days apart 
[1] Assessment at least 77 days after the first dose 
[2] Assessment less than 77 days after the first dose 
[3] This assessment and next assessment is < 28 days 
[4] Last assessment before the subject died/discontinued from study 
12.2.1.2. 
Unconfirmed Best Overall Response 
The unconfirmed best overall response is the best overall response cross visits and will be 
determined programmatically based on investigator assessment at each time point. Note 
that if the investigator assessment is non-radiologic PD by RECIST v1.1 at a time point, 
the overall response will be derived based on the logic specified in Section 12.1. The 
derived overall response at that time point will be used to derive BOR. 
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If there are two assessments separated by not evaluable (NE) assessment(s), the best 
response shall be assessed applying the algorithm below, collapsing data by ignoring NE 
assessments.  
12.2.1.2.1. Unconfirmed Best Overall Response per RECIST V1.1 and irRECIST 
Criteria 
x 
To be assigned a status of SD/irSD, follow-up disease assessment must have met the 
SD/irSD criteria at least once after the first dose at a minimum interval of 77 days. 
x 
If the minimum of 77 days for SD/irSD is not met, the best overall response will 
depend on the subsequent assessments. For example, if an assessment of PD follows 
the assessment of SD and SD does not meet the minimum time requirement the best 
response will be PD. Alternatively, subjects lost to follow-up after an SD assessment 
not meeting the minimum time criteria will be considered not evaluable. 
12.2.1.2.2. Unconfirmed Best Overall Response per irRECIST  
Besides the principles specified in Section 12.2.1.2.1, irCPD and irUPD will be derived 
following the same principles described in Section 12.2.1.1.2. 
12.2.2. 
Objective Response Rate (ORR) and Disease Control Rate (DCR) 
ORR and DCR per RECIST v1.1 criteria are defined below. ORR and DCR per 
irRECIST criteria are defined similarly. 
x 
ORR is defined as the percentage of subjects achieving a (confirmed) CR/PR as 
BOR, as assessed by the investigator per RECIST 1.1 criteria (Note that if the 
investigator assessment is non-radiologic PD by RECIST v1.1 at a time point, the 
overall response will be derived based on the logic specified in Section 12.1). 
x 
DCR is defined as the percentage of subjects achieving a (confirmed) CR/PR, or SD 
as BOR, as assessed by the investigator per RECIST 1.1 criteria (Note that if the 
investigator assessment is non-radiologic PD by RECIST v1.1 at a time point, the 
overall response will be derived based on the logic specified in Section 12.1). A 
status of SD will be assigned if the follow-up disease assessment has met the SD 
criteria at least once after the date of first dose at a minimum of 77 days. 
x 
DCR with SD durability is defined as the percentage of subjects achieving a 
(confirmed) CR/PR, or SD≥161 days. A status of SD≥161 days will be assigned if 
the follow-up disease assessment has met the SD criteria at least once after the date 
of first dose at a minimum of 161 days. 
Confirmation of responses is required for the final analysis. 
ORR and DCR will be reported by both RECIST v1.1 and irRECIST. An adequate 
assessment is defined as an assessment where the Investigator determined response is 
irCR, irPR, or irSD.  
12.2.3. 
Time to response (TTR)  
Time to response (TTR) is defined as the time from the first dose of study treatment to 
the date of the first documented irCR or irPR. Only the subset of subjects who show a 
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confirmed irCR or irPR from All Treated Population will be included in this analysis. 
TTR per RECIST v1.1 criteria is defined similarly. 
Time to response will be listed.  
 
12.2.4. 
Duration of response (DOR)  
12.2.4.1. 
DOR per irRECIST 
DOR will be derived and listed for subjects with a confirmed irCR or irPR.  It is defined 
as the interval of time in months from the date of the first documented evidence of a 
confirmed response (irCR or irPR) to the date of first documented evidence of a 
confirmed disease progression according to radiological response from investigator 
assessment per irRECIST, or date of last adequate assessment of response, or the date of 
death due to any cause. An adequate assessment is defined as an assessment where the 
Investigator determined response is irCR, irPR, or irSD.   
 
A summary of the assignments for progression and censoring dates for DOR per 
irRECIST is specified in the following table. 
Assignments for Progression and Censoring Dates for DOR Analysis per irRECIST: 
Situation 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event 
(Progression/Death) 
Or Censored 
No (or inadequate) baseline 
tumor assessments and the 
subject has not died (if the 
subject has died follow the 
rules for death indicted at 
the bottom of the table) 
Start Date of Treatment
 
 
Censored 
No post-baseline 
assessments and the subject 
has not died (if the subject 
has died follow the rules 
for death indicted at the 
bottom of the table) 
Start Date of Treatment 
Censored 
Progression documented 
and confirmed at the next 
disease assessment and no 
less than 4 weeks apart 
Date of first assessment of 
irPD which is confirmed 
consecutively 
Event 
Unconfirmed irPD 
followed by NE or another 
PK less than 4 weeks apart, 
or not further assessment, 
Date corresponding irPD 
Event 
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Situation 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event 
(Progression/Death) 
Or Censored 
and subject dies or 
discontinues from the study 
No progression (or death) 
or initiation of new anti-
cancer therapy 
Date of last ‘adequate’ 
assessment of response1 
Censored 
Received subsequent anti-
cancer therapy prior to the 
date of documented events 
Date of last ‘adequate’ 
assessment of respnose1,2 
(prior to starting initiation 
of therapy) 
Censored 
Death before first irPD 
assessment  (or Death at 
baseline or prior to any 
adequate assessments) 
Date of death 
Event 
Death or progression after 
more than one missed visit 
Date of last ‘adequate’ 
assessment of response2 
(prior to missed 
assessments), refer to 
Section 10.2.11 
Censored 
1. 
An adequate assessment is defined as an assessment where the Investigator determined response is irCR, irPR, or irSD.  
2. 
If irPD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is 
progression and the date is the date of the assessment of progression). If anti-cancer therapy is started prior to any adequate 
assessments, censoring date should be the start date of treatment. 
 
12.2.4.2. 
DOR per RECIST 
DOR will be derived and listed for subjects with a confirmed CR or PR.  It is defined as 
the interval of time in months from the date of the first documented evidence of a 
confirmed response (CR or PR) to the date of first documented evidence of a confirmed 
disease progression according to radiological response from investigator assessment per 
RECIST, or date of last adequate assessment of response, or the date of death due to any 
cause. An adequate assessment is defined as an assessment where the Investigator 
determined response is CR, PR, or SD.   
 
A summary of the assignments for progression and censoring dates for DOR per RECIST 
is specified in the following table. 
 
 
 
 
 
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Assignments for Progression and Censoring Dates for DOR Analysis per RECIST: 
Situation 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event 
(Progression/Death) 
Or Censored 
No (or inadequate) baseline 
tumor assessments and the 
subject has not died (if the 
subject has died follow the 
rules for death indicted at 
the bottom of the table) 
Start Date of Treatment
 
 
Censored 
No post-baseline 
assessments and the subject 
has not died (if the subject 
has died follow the rules 
for death indicted at the 
bottom of the table) 
Start Date of Treatment 
Censored 
Progression documented 
between scheduled visits 
Date of assessment of 
progression1 
Event 
No progression (or death) 
or initiation of new anti-
cancer therapy 
Date of last ‘adequate’ 
assessment of response2 
Censored 
Received subsequent anti-
cancer therapy prior to the 
date of documented events 
Date of last ‘adequate’ 
assessment of respnose2,3 
(prior to starting initiation 
of therapy) 
Censored 
Death before first PD 
assessment  (or Death at 
baseline or prior to any 
adequate assessments) 
Date of death 
Event 
Death or progression after 
more than one missed visit 
Date of last ‘adequate’ 
assessment of response2 
(prior to missed 
assessments), refer to 
Section 10.2.11 
Censored 
3. 
The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or (ii) Date of 
radiological assessment showing unequivocal progression in non target lesions, or (iii) Date of last radiological assessment of 
measured lesions (if progression is based on increase in sum of measured lesions) 
4. 
An adequate assessment is defined as an assessment where the Investigator determined response is CR, PR, or SD.  
5. 
If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is 
progression and the date is the date of the assessment of progression). If anti-cancer therapy is started prior to any adequate 
assessments, censoring date should be the start date of treatment. 
 
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13. 
SAFETY ANALYSES 
Unless otherwise specified, all the safety analyses will be based on the All Treated  
Population as defined in Section 7 and summaries will include all events or assessments 
collected during the study. All the analyses will be performed by groups identified in 
Section 9. 
13.1. 
Extent of Exposure 
Extent of exposure to GSK3174998 and pembrolizumab will be summarized separately. 
The number of subjects and duration of exposure to study treatment in weeks (from first 
day to last day of treatment + 1 days) will be summarized. Descriptive statistics including 
mean, median, standard deviation, minimum, and maximum will be calculated for time 
on study treatment. Moreover, time on study treatment will be categorized in different 
time period: <3 months, 3 months to 6 months, >6 months to 12 months and >12 months. 
The number of infusions administered as study treatment will be summarised with mean, 
median, standard deviation, minimum, and maximum. 
Infusion dose intensity (the cumulative doses, divided by the total number of infusions) 
will be summarized using mean, median, standard deviation, minimum, and maximum.  
The cumulative dose is the sum of the doses administered during each infusion for a 
subject.   
The relative dose intensity (%) of GSK3174998 is the infusion dose intensity divided by 
the target dose. 
The number of dose delays and reasons for dose delays will be summarized.   
All infusion interruptions and dose delays will be listed separately. 
13.2. 
Adverse Events 
AEs will be coded to the preferred term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA dictionary) and grouped by system organ class (SOC).  
AEs will be graded by the investigator according to the NCI-CTCAE v4.0.   
An overview summary of on-treatment AEs, including counts and percentages of subjects 
with the below category will be produced: 
x Any AEs 
x Treatment-related AEs 
x AEs of special interest (AESI) 
x AEs leading to discontinuation of study treatment 
x AEs leading to dose reduction 
x AEs leading to dose interruption/delayed 
x and AEs leading to study withdrawal 
x SAEs 
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x Treatment-related SAEs 
x Fatal SAEs 
x Treatment-related fatal SAEs 
On-treatment AEs (or treatment-emergent AEs) include those with onset dates on or after 
the first study treatment dose date (this can be either GSK 3174998 or pembrolizumab).  
Treatment-related AE and AEs leading to discontinuation of study treatment will further 
be summarized by the treatment to which causality was attributed for Part 2. 
Events will be summarized by frequency and proportion of total subjects, by PT.  
Separate summaries will be given for: 
x All AEs 
x Treatment-related AEs (for Part 2, the summary will include AEs related to 
GSK3174998 or Pembrolizumab or both) 
x AEs leading to discontinuation of study treatment (for Part 2, the summary will 
include AEs leading to discontinuation of GSK3174998 or Pembrolizumab or 
both) 
x AEs leading to study withdrawal 
x SAEs 
x Treatment-related SAEs 
x AEs recorded as dose-limiting toxicities 
x AESI 
The summary by PT will be sorted by descending incidence. 
On-treatment AEs will be summarized by the maximum grade according to the NCI-
CTCAE v4.0 and sorted by PT and by PT in descending order of total incidence.  The 
summary will use the following algorithms for counting the subject: 
x 
Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade. 
x 
Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
All AEs will be listed.  
13.3. 
Adverse Events of Special Interest 
Characteristics (e.g., number of occurrences, action taken, grade, etc.) of AESI (also 
referred to as immune-related adverse event, see Appendix 11 in protocol) will be 
summarized separately. 
In addition, AESI will be listed separately. 
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13.4. 
Deaths and Serious Adverse Events 
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date from this subject including death is supposed to appear in the database, which should 
be part of the data cleaning process. All deaths will be summarised based on the number 
and percentage of subjects. This summary will classify subjects and primary cause of 
death as collected on the eCRF. A supportive listing will be generated to provide subject-
specific details on subjects who died.  
Summaries related to SAEs are specified in Section 13.2. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for 
x 
Fatal SAEs  
x 
Non-Fatal SAEs. 
13.5. 
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study and Other Significant 
Adverse Events 
AEs Leading to Discontinuation of Study Treatment will be summarized separately in 
descending order of total incidence by PT only and separate supportive listings will be 
generated with subject level details for those subjects: 
x 
AEs leading to discontinuation of study treatment  
x 
AEs leading to withdrawal from the study 
13.6. 
Pregnancies  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If female subjects or female partners of 
male subjects become pregnant while on the study, the information will be included in 
the narratives and no separate table or listing will be produced. 
13.7. 
Clinical Laboratory Evaluations 
The assessment of laboratory toxicities will examine the following laboratory tests:  
Clinical Chemistry: Total bilirubin, Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), Alkaline phosphatase, Total protein, Albumin, Sodium, 
Potassium, Calcium, Urea/Blood Urea Nitrogen (BUN), Creatinine, Creatinine 
Clearance, and Glucose. 
Hematology: Hemoglobin (HGB), Hematocrit (HCT), Platelet count, Red Blood Cell 
(RBC) count, White Blood Cell (WBC) count, Neutrophils (Absolute), Lymphocytes 
(Absolute), Monocytes (Absolute), Eosinophils (Absolute), Basophils (Absolute), 
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Neutrophils (%), Lymphocytes (%), Monocytes (%), Eosinophils (%) and Basophils (%); 
RBC indices (MCV and MCH). 
Thyroid Function Test: Thyroid-stimulating hormone (TSH) and free thyroxine (T4 and 
T3) test.  
Urinalysis: pH, Microscopic examination, Specific gravity, Ketones, Protein, and 
Glucose, Blood. 
Hepatitis Screening: Hepatitis B (HBsAg) and Hepatitis C (Hep C antibody). 
Pregnancy Screening: Serum β–hCG pregnancy test (as needed for women of child 
bearing potential). 
Laboratory grades will be reported using the NCI-CTCAE v4.0. 
Summaries of lab data by maximum toxicity grade will be provided. 
Summaries of worst case grade increase (including unscheduled assessments) from 
baseline grade will be provided for all the lab tests that are gradable by NCI-CTCAE 
v4.0. These summaries will display the number and percentage of subjects with a 
maximum post-baseline grade increasing from their baseline grade. Any increase in grade 
from baseline will be summarized along with any increase to a maximum grade of 3 and 
any increase to a maximum grade of 4. Missing baseline grade will be assumed as grade 
0. In addition, the summary will include grade increase from baseline by scheduled visits. 
For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia. 
Separate summary tables for hematology and clinical chemistry laboratory tests will be 
produced. 
A supporting listing of abnormal urinalysis data will be provided.  
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
13.7.1. 
Analyses of Liver Function Tests 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above.  
A plot of maximum total bilirubin versus maximum ALT will be generated. A trellis 
display of LFT shifts from baseline to maximum values will be provided. A matrix 
display of LFT results will also be produced. 
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13.8. 
Other Safety Measures 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
13.8.1. 
Vital Signs 
Values of vital signs will be listed. The categories defined in Section 10.3.3 will be 
flagged in listings.  
13.8.2. 
Performance Status 
ECOG performance status will be summarized at baseline and each post-baseline 
scheduled visit. Summaries will use frequency and percentage of subjects at each planned 
assessment time. A summary of change from baseline by scheduled visits will be 
performed, as well as the worst case post-baseline and the best case post-baseline changes 
during the study (improved, no change, deteriorated).  
A supporting listing will also be provided.  
13.8.3. 
ECG 
For numerical values measured in triplicate, averages at each visit will be the basis of 
analysis summaries. 
The QTc values based on Fridericia formula (QTcF) will be rounded to the integer and 
the values will be categorized into the ranges identified in Section 10.3.2.   
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: 31-60 and >60 msec.  Similarly, categories identified for PR 
interval and QRS interval will also be reported.   
Listings of abnormal ECG findings and a listing of ECG values will be provided with 
PCS records flagged. 
14. 
HEALTH OUTCOMES ANALYSES 
No health outcomes analyses were planned for the study. 
15. 
PHARMACOKINETIC ANALYSES 
Statistical analysis of GSK3174998 and pembrolizumab pharmacokinetic parameters will 
be performed by, or under the direct auspices of, Oncology Quantitative Sciences 
(Statistician), GSK or Merck. 
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15.1. 
Drug Concentration Measures 
PK analysis of GSK3174998 and pembrolizumab drug concentration-time data will be 
conducted by non-compartmental methods under the direction of CPMS, Quantitative 
Sciences, GSK or Merck. 
Drug concentration-time data will be listed for each subject and summarized by 
descriptive statistics at each time point by cohort. 
15.2. 
Deriving and Summarizing Pharmacokinetic Parameters 
For the calculation of individual pharmacokinetic profiles, if one or more non-
quantifiable (NQ) values occur in a profile before the first measurable concentration, they 
will be assigned a value of zero concentration. For linear plots, zero concentration 
value(s) before the first measurable concentration will be included in the plot. For log-
linear plots, zero concentration value(s) before the first measurable concentration will be 
assigned a missing value. 
If a single NQ value occurs between measurable concentrations in a profile, the NQ 
should generally be omitted (set to missing) in the derivation of pharmacokinetic 
parameters, statistical analysis, and the individual subject plots. If two or more NQ values 
occur in succession between measurable concentrations, the profile will be deemed to 
have terminated at the last measurable concentration prior to these NQs.  
For the purpose of individual subject plots, these NQs will be set to 0, and the subsequent 
measurable concentrations will be retained. For the derivation of pharmacokinetic 
parameters, these NQs and any subsequent measurable concentrations will be omitted (set 
to missing). 
NQs which occur after the last measurable concentration will be omitted (set to missing) 
in the derivation of pharmacokinetic parameters and from the individual subject plots. In 
some circumstances, there may be a pharmacokinetic rationale for fluctuation resulting in 
non-measurable concentrations in the middle of the concentration-time profile (e.g., 
entero-hepatic recycling, erratic absorption from transdermal/inhaled formulations). In 
these cases, the NQ values could be set to missing or to some other values (e.g., ½ LLQ) 
and subsequent valid concentrations may be retained. A reference line indicating LLQ 
will be included in plots. 
For the calculation of mean or median pharmacokinetic profiles, when estimating the 
mean or median value for the concentration at a given time point (i.e., descriptive mean 
or median curve), the following guidelines should be considered: 
All NQ values will be set to zero except when an individual NQ falls between two 
quantifiable values, in which case it will be omitted from the calculation of mean or 
median profiles. Measurable concentrations which follow more than one consecutive 
mid-profile NQ will be omitted (set to missing). 
The mean/median value at a time-point where one or more samples have NQ values will 
be reported (in tabular or graphical fashion) even if the mean/median value is below the 
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LLQ of the assay. For linear plots, zero concentration value(s) will be included in the 
plot. For log-linear plots, zero concentration value(s) will be assigned a missing value. 
Zero mean or median values will be included in summary tables. PK concentration values 
will be summarized. 
The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices. All calculations of non-compartmental 
parameters will be based on actual sampling times. The following PK parameters will be 
determined if data permit:   
x 
Cmax 
x 
CW 
x 
area under the plasma concentration-time curve AUC(0-τ) (repeat dosing)  
x 
apparent terminal phase elimination rate constant (Oz)  
x 
apparent terminal phase half-life (t½)  
x 
systemic clearance of parent drug (CL) 
x 
steady-state volume of distribution (Vss) 
All derived PK parameters will be listed. For each of these parameters, the following 
summary statistics will be calculated for each dose level: median, minimum, maximum, 
arithmetic mean, 95% confidence interval for the arithmetic mean, standard deviation,  
coefficient of variation (CV = sqrt (exp (SD2) - 1) * 100 [NOTE: SD = SD of log 
transformed data]), geometric mean, 95% confidence interval for the geometric mean and 
standard deviation of logarithmically transformed data. The first point, last point and 
number of points used in the determination of Oz will be included on the listing of the 
derived parameters. All PK parameters will be reported to at least 3 significant digits, but 
to no more significant digits than the precision of the original data.  
15.3. 
Statistical Analyses 
There’s no statistical analysis planned on PK data.  
15.4. 
Population Pharmacokinetic Analyses 
Population PK analyses may be conducted under the direction of CPMS, Quantitative 
Sciences, GSK.  The data from this study may be combined with the data from other 
studies for a population PK analysis, which may be reported separately. 
16. 
PHARMACODYNAMIC AND BIOMARKERS ANALYSES 
16.1. 
Pharmacodynamic and Biomarker Analyses 
Receptor occupancy data will be summarized and plotted.  
Other biomarker data may be reported separately from the main clinical study report, 
generated by GSK biomarker team if applicable.  All endpoints of interest from all 
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comparisons will be descriptively and/or graphically summarized as appropriate to the 
data.   
16.2. 
Immunogenicity Analyses 
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3174998 and pembrolizumab.  Serum samples for testing anti-GSK3174998 and 
anti-pembrolizumab antibodies will be collected as described in the Time and Events 
schedule (protocol Section 7.1).  The actual date and time of each blood sample 
collection will be recorded.  Details of blood sample collection (including volume to be 
collected), processing, storage, and shipping procedures are provided in the SRM. 
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring.  In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the subject withdrawing from 
the study, blood samples should be taken from the subject for immunogenicity testing at 
the time of the event and again 30 days, 12 weeks, and 24 weeks after.  For subjects who 
prematurely withdraw from the study, immunogenicity testing will occur at withdrawal 
and at follow-up 30 days, 12 weeks, and 24 weeks after the last dose. 
Serum will be tested for the presence of anti-GSK3174998 antibodies using the currently 
approved analytical methodology using a tiered testing schema: screening, confirmation 
and titration steps.  The presence of treatment emergent ADA will be determined using a 
GSK3174998 bridging style ADA assay with a bio-analytically determined cut-point 
determined during assay validation.  Samples taken after dosing with GSK3174998 that 
have a value at or above the cut-point will be considered treatment-emergent ADA-
positive.  These ADA positive samples will be further evaluated in a confirmatory assay, 
and confirmed positive samples will be further characterized by assessment of 
titer.  Number and percentage of subjects with confirmed positive immunogenicity at 
each visit will be summarized. Denominator for the percentage is number of subjects with 
non-missing Screening, Confirming or Titer results at each visit. Results of anti-
GSK3174998 antibody testing will be listed. 
16.3. 
Translational Research Analyses 
The results of translational research investigations may be reported in the main clinical 
study report (CSR).  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data. 
17. 
PHARMACOGENETIC DATA ANALYSES 
Further details on PGx analyses discussed in the protocol Appendix 7 may be 
identified/addressed in a separate PGx RAP, if applicable. 
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18.
REFERENCES
Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, et al. 
OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 
2013; 73:7189-7198. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). 
Eur J Cancer. 2009; 45:228-247.  
GlaxoSmithKline Document Number 2014N225045_04. A Phase I, Open-Label Study 
of GSK3174998 Administered Alone and in Combination with Anticancer Agents 
including Pembrolizumab in Subjects with Selected Advanced Solid Tumors. 04-
FEB-2020. 
GlaxoSmithKline Document Number 2014N212091_00. Investigator’s Brochure for 
GSK3174998. 29-Apr-2015 
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clin 
Trials. 2008; 5:93-106.  
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statistics Med. 2008; 27:2420-2439. 
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