Clinical trial NCT03447314
Conditions: Neoplasms
Keywords: pembrolizumab GSK1795091 Dose-escalation 204686 Immunotherapies GSK3359609 Phase I anticancer agent OX40 201212 204691 ICOS TLR4 GSK3174998 Advanced Solid Tumors
Sponsor: GlaxoSmithKline
Start date: 2018-03-26; Completion date: 2022-03-11
Enrollment: 54 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
GSK1795091 is being developed for administration in combination with other immune system modulators for the treatment of cancers. The study will be conducted in two parts. In Part 1, dose escalation will be performed to identify combination dose levels comprising GSK1795091 with either 24 milligrams (mg) GSK3174998 (Part 1a), 80 mg GSK3359609 (Part 1b), or 200 mg pembrolizumab (Part 1c). One dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. In Part 2 (dose-expansion), subjects will receive a single dose level of GSK1795091 as identified based on data from Part 1, in combination with either GSK3174998, GSK3359609, or pembrolizumab.

Detailed description:

Arms: arm 1: Participants will be administered GSK1795091 50 nanogram (ng) intravenously (IV) on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3174998 24 milligram (mg) administered at 3-week intervals (Q3W) via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval. arm 2: Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval. arm 3: Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval. arm 4: Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval. arm 5: Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval. arm 6: Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval. arm 7: Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval. arm 8: Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval. arm 9: Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval. arm 10: Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval. arm 11: Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval. arm 12: Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval. arm 13: Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval. arm 14: Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval. arm 15: Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval. arm 16: Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3174998 24 mg. arm 17: Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3359609 80 mg. arm 18: Participants will be administered GSK1795091 at a dose identified in Part 1 along with pembrolizumab 200 mg.
Interventions: intervention 1: GSK1795091 intervention 2: GSK3174998 intervention 3: GSK3359609 intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: GSK1795091 will be available as solution for injection intervention 2: GSK3174998 will be available as lyophilized powder to be reconstituted for infusion. intervention 3: GSK3359609 will be available as solution for infusion. intervention 4: Pembrolizumab will be available as solution for infusion or lyophilized powder for reconstitution.

Protocol documents:
Prot_000.pdf: 
2017N327572_07
CONFIDENTIAL
GlaxoSmithKline group of companies
204686
1
TITLE PAGE
Protocol Title: A Phase I, Open-Label Study of GSK1795091 Administered in 
Combination with Immunotherapies in Participants with Advanced Solid Tumors
Protocol Number: 204686 Amendment 06
Short Title: Study of a combination of GSK1795091 and immunotherapies in 
participants with advanced solid tumors
Compound 
Numbers:
GSK1795091
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
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.   
Medical Monitor Name and Contact Information
Medical Monitor contact information can be found in the Study Reference Manual 
(SRM)
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) number: IND136203
EudraCT number: 2017-003545-23
Approval Date: 08-SEP-2020
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


1
From:
Sent:
Thursday, September 10, 2020 7:29 PM
To:
Cc:
Subject:
FW: Prot-Amend6-204686-sponsign
From: Hesham Abdullah
 
Sent: Tuesday, September 08, 2020 3:04 PM 
To:
 
Cc:
Subject: RE: Prot‐Amend6‐204686‐sponsign 
Dear 
, 
As Chair of the Oncology PRF and Head of Oncology Clinical Development, I approve Amendment 6 to Protocol 204686. 
Best, 
Hesham 
From:
 
Sent: Tuesday, September 8, 2020 2:32 PM 
To: Hesham Abdullah 
Subject: Prot‐Amend6‐204686‐sponsign 
Dear Sponsor, 
To approve the clinical protocol indicated below, reply to this email and state your approval. 
PROTOCOL NUMBER:       
  204686 
DOCUMENT IDENTIFIER: 
 2017N327572_07 
AMENDMENT NUMBER:  
  6PROTOCOL TITLE:  
   A Phase I, Open‐Label Study of GSK1795091 
Administered in Combination with Immunotherapies in Participants with Advanced Solid Tumors 
Name of Sponsor Signatory:     Hesham 
Abdullah, MD, MSc, RAC 
 
Title of Sponsor Signatory: 
  SVP, Head 
Clinical Development, Oncology R&D 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2017N327572_07
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3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 6
08-SEP-2020
Amendment 5
02-MAR-2020
Amendment 4
12-AUG-2019
Amendment 3
14-SEP-2018
Amendment 2
25-JUL-2018
Amendment 1 CAN-1
06-MAR-2018
Amendment 1
08-DEC-2017
Original Protocol
28-SEP-2017
Amendment 6: 08-SEP-2020
Overall Rationale for the Amendment: There will be no further enrolment and Part 2 
of the study will not open as the development of GSK1795091 was discontinued by GSK.  
This decision was based on strategic prioritorization of the portfolio and is not due to the 
safety profile of GSK1795091.


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Section # and 
Name
Description of Change
Brief Rationale
Section 1, 
Synopsis

Language is added to close enrolment, 
discontinue efficacy follow-up and specify 
that one survival follow-up is required (if 
applicable). 

Discontinue plans for Part 2 and deleted 
language regarding Part 2.
The development of GSK1795091 
has been discontinued. This decision 
was based on strategic prioritization 
of the portfolio and is not due to the 
safety profile of GSK1795091.
Section 2, 
Schedule of 
Activities

Updates made to reflect closed enrolment,
discontinued efficacy follow-up and 
specify that one survival follow-up is 
required (if applicable).

Table 3 Part 2 is removed. 

Table 4 Part 2 is removed.
As above.
Section 5 Study 
Design

Language is added to close enrolment, 
discontinue efficacy follow-up and specify 
that one survival follow-up is required (if 
applicable). 

Discontinue plans for Part 2

Number of participants is updated to 
reflect removal of Part 2. 

End of study language is updated to be 
defined as when the last subject has 
completed/discontinued study treatment, 
completed the Treatment Discontinuation 
Visit (TDV) assessments, and the OS FU 
visit is completed (as applicable).

Study Schematic is updated to reflect Part 
2 removal. 
As above.
Section 7 
Treatments

Language updated to reflect removal of 
Part 2.
As above.
Section 8 
Discontinuation 
Criteria

Language is added to close enrolment, 
discontinue efficacy follow-up and specify 
that one survival follow-up is required (if 
applicable). 
As above.


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Section # and 
Name
Description of Change
Brief Rationale
Section 9

Time period for collection AE and SAE 
data is updated to reflect collection will be 
from the time a participant consents to 
participate in the study up to 90 days after 
the last dose of study treatment(s) or until 
the start of another anti-cancer therapy, 
whichever is first. 

PK will no longer be collected; however, 
event driven collections will be performed. 

Biomarkers will no longer be collected.
As above.
Section 10 Stats

Language Updated to reflect removal of 
Part 2.

Definition of study populations updated to 
accomodate generation of screen failure 
summaries.
As above
Appendix 14 : 
COVID-19

Appendix added.
This appendix has been added to 
outline the changes that have been 
made in response to the COVID-19 
pandemic


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................15
3.
INTRODUCTION....................................................................................................24
3.1.
Study Rationale ..........................................................................................24
3.2.
Brief Background ........................................................................................26
3.2.1.
GSK1795091 Background ...........................................................26
3.2.1.1.
GSK1795091 Nonclinical Activity................................26
3.2.1.2.
GSK1795091 Development Plan and Clinical 
Experience .................................................................27
3.2.1.2.1.
Hepatic adverse events ..........................29
3.2.2.
GSK3174998 Background ...........................................................30
3.2.2.1.
GSK3174998 Nonclinical Activity................................31
3.2.2.2.
GSK3174998 Clinical Experience...............................31
3.2.3.
GSK3359609 Background ...........................................................32
3.2.3.1.
GSK3359609 Nonclinical Activity................................32
3.2.3.2.
GSK3359609 Clinical Experience...............................33
3.2.4.
Pembrolizumab Background........................................................35
3.2.4.1.
Pembrolizumab Clinical Experience in 
Combination with other TLR Agonists.........................35
3.2.5.
GSK1795091 Combination Background ......................................35
3.2.5.1.
GSK1795091 In Vivo Studies .....................................35
3.2.5.2.
GSK1795091 In Vitro Studies.....................................40
3.2.5.2.1.
GSK1795091 and GSK3174998.............40
3.2.5.2.2.
GSK1795091 and GSK3359609.............41
3.2.5.2.3.
GSK1795091 and pembrolizumab..........41
3.2.5.3.
Clinical Combinations of GSK1795091 and 
GSK3174998..............................................................41
3.3.
Benefit/Risk Assessment ............................................................................42
3.3.1.
Risk Assessment .........................................................................43
3.3.2.
Overall Benefit: Risk Conclusion..................................................47
4.
OBJECTIVES AND ENDPOINTS...........................................................................48
5.
STUDY DESIGN ....................................................................................................50
5.1.
Overall Design ............................................................................................50
5.1.1.
Part 1: Dose Escalation of GSK1795091 administered in 
combination with either GSK3174998, GSK3359609, or 
pembrolizumab ............................................................................52
5.1.1.1.
Description of the Continual Reassessment 
Method .......................................................................53
5.1.1.2.
Logistic Model for N-CRM...........................................54
5.1.2.
PK/Pharmacodynamic Cohort(s)..................................................54
5.1.3.
Dose-Limiting Toxicity..................................................................54
5.1.4.
Part 2: Expansion Cohort.............................................................56
5.1.5.
Oversight .....................................................................................56


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5.1.6.
Tumor Types Enrolled During Parts 1..........................................56
5.1.7.
Intra-Participant Dose Escalation.................................................56
5.1.8.
Study Treatment ..........................................................................56
5.2.
Number of Participants ...............................................................................57
5.3.
Participant and Study Completion...............................................................57
5.4.
Scientific Rationale for Study Design ..........................................................57
5.5.
Dose Justification........................................................................................58
5.5.1.
Overview......................................................................................58
5.5.1.1.
Starting dose for TLR4 agonist GSK1795091.............58
5.5.1.2.
Dose for OX-40 agonist GSK3174998........................59
5.5.1.3.
Dose for ICOS agonist GSK3359609 .........................60
5.5.1.4.
Pembrolizumab dose..................................................61
5.5.1.5.
Combination considerations .......................................61
5.5.1.5.1.
Combination of GSK1795091 and 
GSK3174998..........................................62
5.5.1.5.2.
Combination of GSK1795091 and 
GSK3359609..........................................62
5.5.1.5.3.
Combination of GSK1795091 and 
pembrolizumab.......................................63
5.5.2.
Dose Escalation and Top Dose....................................................64
6.
STUDY POPULATION...........................................................................................64
6.1.
Inclusion Criteria.........................................................................................65
6.2.
Exclusion Criteria........................................................................................67
6.3.
Lifestyle Restrictions...................................................................................70
6.3.1.
Meals and Dietary Restrictions ....................................................70
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................70
6.3.3.
Activity .........................................................................................70
6.4.
Screen Failures...........................................................................................70
7.
TREATMENTS.......................................................................................................70
7.1.
Treatments Administered............................................................................70
7.2.
Dose Modification .......................................................................................72
7.2.1.
General Guidelines for Cytokine-Related Adverse Events 
and Infusion Reactions ................................................................74
7.2.1.1.
Management of Cytokine Related Adverse 
Events and Cytokine Release Syndrome....................75
7.2.1.2.
Management of Infusion Reactions ............................77
7.2.2.
General Guidelines for Immune-Related Adverse Events ............80
7.2.2.1.
General Principles of Immune-Related Adverse 
Events Identification and Evaluation...........................81
7.2.2.2.
General Guidelines for Clinically Significant 
Toxicities Not Otherwise Specified .............................81
7.2.2.3.
Management of Hepatotoxicity ...................................82
7.2.2.4.
Management of Gastrointestinal Events 
(Diarrhea or Colitis) ....................................................82
7.2.2.5.
Management of Skin Toxicity......................................84
7.2.2.6.
Management of Endocrine Events..............................84
7.2.2.7.
Management of Pneumonitis......................................85
7.2.2.8.
Management of Hematologic Events..........................87
7.2.2.9.
Uveitis/Iritis.................................................................87
7.2.2.10.
Management of Left Ventricular Dysfunction ..............88


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7.2.2.11.
Management of Valvular Toxicity................................89
7.3.
Method of Treatment Assignment ...............................................................89
7.4.
Blinding.......................................................................................................89
7.5.
Preparation/Handling/Storage/Accountability..............................................89
7.6.
Treatment Compliance................................................................................90
7.7.
Concomitant Therapy..................................................................................90
7.8.
Treatment after the End of the Study ..........................................................90
7.9.
Dose Delay.................................................................................................91
8.
DISCONTINUATION CRITERIA.............................................................................91
8.1.
Discontinuation of Study Treatment ............................................................91
8.1.1.
Liver Chemistry Stopping Criteria ................................................92
8.1.1.1.
Study Treatment Restart or Rechallenge....................93
8.1.2.
QTcF Stopping Criteria ................................................................93
8.1.3.
Stopping Rules for Clinical Deterioration......................................94
8.2.
Withdrawal from the Study..........................................................................95
8.3.
Lost to Follow Up........................................................................................95
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................96
9.1.
Efficacy Assessments.................................................................................97
9.1.1.
Evaluation of Anti-Cancer Activity ................................................97
9.2.
Adverse Events...........................................................................................98
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................99
9.2.2.
Method of Detecting AEs and SAEs.............................................99
9.2.3.
Follow-up of AEs and SAEs.......................................................100
9.2.4.
Regulatory Reporting Requirements for SAEs ...........................100
9.2.5.
Cardiovascular and Death Events..............................................100
9.2.5.1.
Cardiovascular and Death Events ............................101
9.2.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs.............................................101
9.2.7.
Pregnancy .................................................................................101
9.2.8.
Guidelines for Events of Special Interest ...................................102
9.3.
Treatment of Overdose.............................................................................102
9.4.
Safety Assessments .................................................................................102
9.4.1.
Physical Examinations...............................................................102
9.4.2.
Vital Signs..................................................................................103
9.4.3.
Electrocardiograms....................................................................103
9.4.4.
Clinical Safety Laboratory Assessments ....................................103
9.5.
Pharmacokinetics .....................................................................................105
9.5.1.
Blood Sample Collection............................................................105
9.5.2.
Blood Sample Analysis ..............................................................105
9.6.
Pharmacodynamics ..................................................................................105
9.7.
Genetics ...................................................................................................105
9.8.
Biomarkers/Pharmacodynamic Markers ...................................................106
9.8.1.
Blood Biomarkers ......................................................................106
9.8.2.
Tumor Tissue.............................................................................106
9.8.3.
Stool Collection for Microbiome Analysis ...................................107
9.9.
Medical Resource Utilization and Health Economics ................................107
9.10.
Qualitative Telephone Interview................................................................107
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ...............................108


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10.1.
Sample Size Determination ......................................................................108
10.2.
Populations for Analyses ..........................................................................108
10.3.
Statistical Analyses...................................................................................109
10.3.1.
Primary Analyses.......................................................................109
10.3.1.1.
Safety Analyses........................................................109
10.3.1.2.
Extent of Exposure ...................................................109
10.3.1.3.
Adverse Events ........................................................110
10.3.1.4.
Clinical Laboratory Evaluations ................................110
10.3.1.5.
Other Safety Measures.............................................110
10.3.2.
Secondary Analyses ..................................................................111
10.3.2.1.
Anticancer Activity Analyses.....................................111
10.3.2.2.
Pharmacokinetic Analyses........................................111
10.3.2.2.1.
Pharmacokinetic Parameters................111
10.3.2.2.2.
Statistical Analysis of 
Pharmacokinetic Data...........................112
10.3.2.3.
Immunogenicity Analyses.........................................112
10.3.3.
Other Analyses ..........................................................................113
10.3.3.1.
Translational Research Analyses .............................113
10.3.3.1.1.
PK/Pharmacodynamic/ Analyses..........113
10.3.3.1.2.
Biomarker(s) Analyses..........................113
10.3.3.2.
Pharmacogenetic Analyses ......................................114
10.3.3.3.
Qualitative Telephone Interviews..............................114
10.3.4.
Interim Analyses ........................................................................114
10.4.
N-CRM Analysis for Dose Escalation........................................................114
10.4.1.
Implementation of N-CRM .........................................................114
10.4.2.
Bayesian Prior for the Logistic Model.........................................114
11. REFERENCES.....................................................................................................116
12. APPENDICES......................................................................................................121
12.1.
Appendix 1: Abbreviations and Trademarks..............................................121
12.2.
Appendix 2: Clinical Laboratory Tests.......................................................124
12.3.
Appendix 3: Study Governance Considerations........................................125
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................129
12.5.
Appendix 5: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................135
12.6.
Appendix 6: Genetics................................................................................138
12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines ....................140
12.7.1.
Liver Safety Drug Restart or Rechallenge Guidelines ................142
12.8.
Appendix 8: Country-specific requirements: Canada ................................146
12.9.
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST version 
1.1 ............................................................................................................148
12.10. Appendix 10: CKD-EPI Formula ...............................................................154
12.11. Appendix 11: Adverse Events of Special Interest......................................155
12.12. Appendix 12: ECOG Performance Statusa................................................157
12.13. Appendix 13: mAb Monotherapy Dosing Period........................................158
12.14. Appendix 14: COVID-19 ...........................................................................159
12.15. Appendix 15 : Protocol Amendment History..............................................160


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1.
SYNOPSIS
Protocol Title: A Phase I, Open-Label Study of GSK1795091 in Combination with 
Immunotherapies in Participants with Selected Advanced Solid Tumors
Short Title: Study of combinations of GSK1795091 and immunotherapies in participants 
with advanced solid tumors
Rationale: The combination of two or more immunotherapies holds promise in treating 
patients with cancer.  One model of a “cancer-immune cycle” describes a series of feed-
forward steps by which the immune system recognizes and kills tumor cells, a cycle 
which is counterbalanced by tumor and host derived factors which suppress anti-tumor 
immune activation.  These steps include:
-
Release of cancer cell antigens
-
Cancer antigen presentation
-
Priming and activation
-
Trafficking of T-cells to tumors
-
Infiltration of T-cells into tumors
-
Recognition of cancer cells by T-cells
-
Killing of cancer cells
Rational combination strategies, such as immunotherapies acting at different steps in the
immune cycle, could produce meaningful and synergistic activity compared to
monotherapies.  Combining a TLR4 agonist with a checkpoint modulator targets two 
complementary steps in the cancer-immunity cycle; TLR engagement results in the 
production of various inflammatory cytokines/chemokines such as tumor necrosis factor 
(TNF), interleukin (IL) 6, granulocyte colony-stimulating factor (G-CSF), and type I 
interferons (i.e., IFN, IFN) and enhanced uptake, processing, and presentation of 
antigens.  Based on nonclinical data, the combinations of GSK1795091 (a TLR4 agonist) 
and GSK3174998 (an OX40 agonist), GSK3359609 (an ICOS agonist) or 
pembrolizumab (a PD-1 inhibitor) is anticipated to have antitumor activity greater than 
any of the monotherapies.  
Objectives and Endpoints:
With the implementation of amendment 06, the study is closed to enrolment and Part 2 
will not be opened.
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab.

Adverse events (AEs), serious adverse 
events, dose-limiting toxicities, 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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Objectives
Endpoints
Secondary

To evaluate the antitumor activity of 
GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab

Objective response rate (ORR) and 
disease control rate (DCR) (complete 
response [CR]+ partial response [PR]+ 
stable disease [SD] ≥12 weeks), time to 
response, duration of response, 
progression-free survival (PFS), and 
overall survival..

To characterize the pharmacokinetics (PK)
of GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab.

GSK1795091 concentrations in plasma 
and assessment of PK parameters (e.g.,
maximum observed concentration [Cmax], 
AUC(0-τ) and trough plasma concentration 
[Ctrough]) if data permit.

To evaluate the immunogenicity of 
GSK3174998, GSK3359609, or 
pembrolizumab when administered in 
combination with GSK1795091.  

Number and percentage of participants 
who develop detectable anti-drug 
antibodies against GSK3174998, 
GSK3359609, or pembrolizumab.
Exploratory

To evaluate the immunologic effects of 
GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab.  

Assessments of OX40 or ICOS receptor 
expression and occupancy of 
GSK3174998 or GSK3359609 on immune 
cells in the peripheral blood.  

Assessment of the phenotype, quantity, 
and activation state of T cells and other 
immune cells in peripheral blood.

Assessment of tumor biopsies by
immunohistochemistry or related 
technologies which may include but is not 
limited to the numbers of tumor-infiltrating 
lymphocytes and other cells expressing 
key phenotypic markers.

To explore the association between 
treatment with GSK1795091 when 
administered in combination with either
GSK3174998, GSK3359609, or 
pembrolizumab and measures of gene 
expression and immune function.  

Assessment of gene expression and 
immune function from study participants 
tumor tissue and/or blood samples may 
include but is not limited to immune related 
gene expression (RNA expression or 
RNAseq), gene signatures, and T-cell 
receptor DNA sequences. 

Assessment of soluble factors from study 
participants blood samples and/or tumor 
may include but is not limited to cytokines 
and stress-related proteins, cell free DNA 


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Objectives
Endpoints
(cfDNA), and exosomes.

To explore the association between 
treatment with GSK1795091 when 
administered in combination with either 
GSK3174998, GSK3359609, or 
pembrolizumab and biomarkers which may 
be associated with response. To explore 
the utility of these measures to enrich for 
clinical efficacy and/or development of a 
diagnostic test.

Comparison between antitumor activity and 
baseline biomarker samples from study 
participants blood and/or tumor which may 
include but are not limited to DNA, gene 
expression (RNA), proteins, immune cell 
phenotypes, and immune response 
markers.

Analysis of the data to identify potential 
selection biomarkers for participant 
enrichment.

To characterize the PK of GSK3174998, 
GSK3359609, or pembrolizumab when 
administered in combination with 
GSK1795091.  

GSK3174998, GSK3359609, or
pembrolizumab concentrations in 
plasma/serum and assessment of PK 
parameters (e.g., maximum observed 
concentration [Cmax], AUC(0-τ) and trough
concentration [Ctrough]) if data permit.

To explore PK-Pharmacodynamic 
relationships, such between PK 
parameters and antitumor activity, safety or 
pharmacodynamic markers after treatment 
with GSK1795091 when administered in 
combination with either GSK3174998, 
GSK3359609, or pembrolizumab.

Evaluation of the relationship of antitumor 
activity as assessed by ORR, DCR, safety
and/or pharmacodynamic markers with PK 
parameters (e.g., Cmax). 

Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host 
DNA and response to therapy.

Germline genetic evaluations may be 
conducted to test for association with:
Response to treatment, including 
GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab or any 
concomitant medicines.
Disease susceptibility, severity, and 
progression and related conditions.

To explore the gut microbiome composition 
and relationship to treatment response.

Sequencing of the microbiome from stool 
samples.  Analysis of the data to identify 
potential selection biomarkers for 
participant enrichment

Evaluation of the relationship between 
antibiotic/probiotic use prior to treatment 
and antitumor activity

To evaluate disease- and treatment-related 

Qualitative telephone interview.


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Objectives
Endpoints
symptoms and impact on function and 
health-related quality-of-life.
Overall Design:
This is a Phase I, open-label, non-randomized, multicenter and multi-country study 
designed to evaluate the safety, tolerability, PK, pharmacodynamic, and preliminary 
clinical activity of GSK1795091 administered in combination with other 
immunotherapies to participants with advanced solid tumors.  
In Part 1, the safety and tolerability of escalating doses of GSK1795091 and a single dose 
level of a monoclonal antibody (mAb) combination partner (GSK3174998,
GSK3359609, or pembrolizumab) will be evaluated in separate cohorts of participants
with advanced solid tumor cancers according to an Neuenschwander-Continual 
Reassessment Method (N-CRM) design to identify doses for evaluation in Part 2.  Part 1 
will include a GSK1795091 run-in period of 2 weeks (i.e., GSK1795091 administration 
on Days 1 and 8) prior to administration of the combination partner beginning at Day 15.  
Approximately 5 dose levels of GSK1795091 in combination with a single fixed dose 
level of the combination partner are planned to be evaluated in Part 1. Following 
protocol amendment, GSK1795091 may also be further evaluated by additional routes of 
administration.
With the implementation of amendment 06, the study is closed to further enrollement and 
Part 2 will not be opened.
PK/Pharmacodynamic cohorts for each combination will be opened to enrollment during 
Part 1 to obtain additional PK and pharmacodynamic data, with an emphasis to obtain 
insight on the potential impact of the combination treatments on the immune cells and 
status of the tumor microenvironment, in conjunction with PK and pharmacodynamic 
markers obtained from blood. Tumor biopsies are required for enrollment to the 
PK/Pharmacodynamic cohorts, whereas biopsies are strongly encouraged but not 
mandatory for Part 1 dose escalation cohorts. For each combination, participants in the 
PK/Pharmacodynamic cohorts may be enrolled to any dose level which has already been
completed and supported by adequate safety and tolerability from dose escalation for that 
combination. Up to a maximum of 45 participants may be enrolled into the 
PK/Pharmacodynamic cohorts with approximately 6 per dose level for each combination.
Number of Participants:
Approximately 72 participants will be enrolled into Part 1 (dose-escalation) of the study.  
Additionally, for each combination, up to 6 participants in each dose cohort, and a 
maximum of approximately 45 participants in total, may be enrolled into the 
PK/Pharmacodynamic cohort of Part 1. Additional cohorts (up to a maximum of 12 total 
participants) may be enrolled in Part 1 to allow for evaluation of more dose levels.


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Treatment Groups and Duration:
Participants will receive the combination of GSK1795091 with either GSK3174998, 
GSK3359609, or pembrolizumab.  In Part 1, escalating doses of GSK1795091 will be 
evaluated as guided by the N-CRM approach.  
The study includes a screening period, a treatment period, and a follow-up period.  
Participants will be screened for eligibility beginning 4 weeks before the start of 
treatment. The duration of study treatment is expected to be up to 2 years. With the 
implementation of amendment 06, participants who discontinue study treatment for any 
reason will no longer be followed for disease assessments.  For the purpose of safety 
follow-up, one Survival FU visit will be performed 12wks after the last dose of study 
treatment or prior to the start of the next anti-cancer therapy, whichever occurs first.  If a 
new anti-cancer therapy is started before the TDV, the OS visit is not required.  The study 
will conclude when the last subject has completed/discontinued study treatment, 
completed the Treatment Discontinuation Visit (TDV) assessments, and the OS FU visit 
is completed (as applicable).


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2.
SCHEDULE OF ACTIVITIES (SOA)

Two bullets below do not apply to those sites in Canada.

The timing and number of planned study assessments, including safety, 
laboratory, imaging, tumor biopsy, pharmacokinetic (PK), and 
pharmacodynamic/biomarker assessments included in the tables below 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. 
Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The Institutional Review Board (IRB)/
Independent Ethics Committees (IEC) will be informed of any safety issues that 
require alteration of the safety monitoring scheme or amendment of the informed 
consent form (ICF).
With the implementation of Amendments 5 and 6, specific assessments are not 
required. Please see Table 1 and Appendix 13 for further details.


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Table 1
Part 1 Dose Escalation and PK/Pharmacodynamic Cohorts: Safety, Laboratory, Efficacy, Study Treatment 
Proceduresv   (Darker Gray denotes activities that are discontinued based on amendment 06)
Scrna/b
GSK1795091 
Monotherapy
Combination Treatment: GSK1795091 + treatment mAba
Follow-up
Weeka
≤4
1
2
3
4
5
6
7
8
9
10
11
12
>12 -
105c
TDVd
PFS 
FUe
SFUf
Day
≤28
1
2s
8
15
16s
22
29
36
43
50
57
58s
64
71
78
>78-
736
Q12W Q12W 
Informed Consent
X
Record all antibiotics and 
probiotics taken 60 days prior 
to dosing
X
Inclusion/Exclusion
X
X
Demographics, Medical History, 
Prior Medications, Disease 
Characteristics
X
Concomitant Medications
Continuous: assess at each visit from first dose of study treatment
Participant Registration
X
Anti-Cancer Treatment
X
X
X
Study Treatment (note: administer GSK1795091 at least 1 hour after the end of the treatment mAb infusion)
Administer mAb treatmentg
(GSK3174998, 
GSK3359609, or 
pembrolizumab)
X
X
X
X
Q3W
Administer GSK1795091g
X
X
X
X
X
X
X
X
X
X
X
X
Q3W
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
X
X
X
Q6W
X


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Scrna/b
GSK1795091 
Monotherapy
Combination Treatment: GSK1795091 + treatment mAba
Follow-up
Weeka
≤4
1
2
3
4
5
6
7
8
9
10
11
12
>12 -
105c
TDVd
PFS 
FUe
SFUf
Day
≤28
1
2s
8
15
16s
22
29
36
43
50
57
58s
64
71
78
>78-
736
Q12W Q12W 
Physical Examination h
X
X
X
X
X
X
Q6W
X
Vital Signsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q3W
X
12-lead ECGl
X
X
X
X
X
X
X
X
Q12W
X
Echocardiogramq
X
Laboratory Assessments (Safety) – perform assessments pre-dose on each dosing day (-1 day window)
Hepatitis B and C
X
Pregnancy Test Serum β-
hCG at screeningr
≤3d
Monthly (urine or serum)
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Q3W
24 hr,
Wk 15 
onlys
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Q3W
X
Thyroid function
X
X
X
Q6W
X
Calculated CrCl
X
X
X
X
X
X
Q3W
X
Urinalysis
X
X
X
X
X
X
Q3W
X
Lipid panelu
X
Disease Assessments
Tumor imaging j
X
Xp
X
Q12W
X
Patient Reported Outcomes
Telephone Interview
Xm
Xn
Telephone call for survival 
statusf
X


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Scrna/b
GSK1795091 
Monotherapy
Combination Treatment: GSK1795091 + treatment mAba
Follow-up
Weeka
≤4
1
2
3
4
5
6
7
8
9
10
11
12
>12 -
105c
TDVd
PFS 
FUe
SFUf
Day
≤28
1
2s
8
15
16s
22
29
36
43
50
57
58s
64
71
78
>78-
736
Q12W Q12W 
Tumor Biopsies
Archived tumor k
X
Fresh tissue samplek
X
X
X
Progressive disease tissue 
sampleo
X
Microbiome Specimen
Stool Samplet
X
X
Abbreviations: AE = Adverse Event; AESI = Adverse Events of Special Interest; -hCG = Beta-Human Chorionic Gonadotropin; CrCl = Creatinine Clearance; ECG = 
Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; PFS FU = Progression-Free Survival Follow-up; Q3W = every 3 weeks; Q6W = every 6-
weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; SAE = Serious Adverse Event; Scrn = Screen; SFU = Survival Follow-up; TDV = Treatment Discontinuation Visit
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.  Laboratory assessments for Safety will have a -1 day window at all visits.
b.
Screening assessments or procedures to be performed up to 4 weeks (28 days) before the first dose (unless otherwise specified, with the exception of the screening serum
pregnancy test which must be performed within 3 days of the first dose of study treatment). Informed consent must be signed before any study specific assessments are 
performed.
c.
The frequency of assessments collected at the intervals stated “beginning from Week 12 onwards” will be as follows (unless stated otherwise in the table):
1.
Every dosing day (pre-dose every 3 weeks): clinical chemistry, hematology, urinalysis, calculated CrCl, vital signs (predose and EOI+2h)
2.
Every 6 weeks: thyroid function tests, ECOG PS assessments, physical examination (including weight) 
3.
Every 12 weeks: 12-lead ECG, tumor imaging.
d.
The TDV must be completed within 30 days from the last dose of study treatment and must be completed prior to the start of subsequent anti-cancer therapy. 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 or the start of a new anti-cancer therapy, 
whichever occurs first. 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 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 Section 9.2.1.
e.
With the implementation of amendment 06, Progression-free survival FU data will no longer be collected. 


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f.
With the implementation of amendment 06, one Survival FU visit will be performed 12wks after the last dose of study treatment or prior to the start of the next anti-cancer 
therapy, whichever occurs first. If a new anti-cancer therapy is started before the TDV, the OS visit is not required. See Appendix 13 for amendment 05 changes. Particpants 
can opt out of the telephone interview. 
g.
As of amendment 05, dosing with GSK1795091 was suspended. Dosing of treatment mAb (GSK3174998, GSK3359609, or pembrolizumab) will be at every 3-week intervals. Dosing of 
GSK1795091 will be at every 1-week intervals (Q1W) from Week 1 through Week 12 including the 2-week monotherapy run in period (Week 1 and Week 2). Starting at Week 12, 
GSK1795091 will be administered at every 3-week intervals (Q3W) to coincide with treatment mAb dosing. Participants will be dosed for a maximum of 2 years.

Infusion/injection of one or both study treatments may be up to 3 days before or after the planned date for administrative reasons only (e.g., routine scheduling, scheduling an 
infusion around a holiday).  However, such changes from the planned date should not result in consecutive doses of GSK1795091 being administered within 3 days.
h.
Physical exam must be completed per the SoA. A complete physical examination (including height and weight) must be performed at screening and TDV per Section 9.4.1. A 
brief physical examination (including weight) may be performed at other visits. 
i.
Vital Sign Schedule: See Appendix 13 for amendment 05 updated schedule. 

On Day 1, vital signs must be collected predose GSK1795091 and at the following times after the end of injection (EOI) of GSK1795091:  EOI +30m, EOI +2h, EOI 
+4h, EOI +6h. Vital signs should be assessed (and recorded) at all timepoints later than EOI +6h as clinically indicated (optional EOI +8h, EOI +12h, EOI +16h)
until changes in body temperature, heart rate, and/or blood pressure attributable to cytokine production are resolving. 

On Day 15 and 36, vital signs must be collected at predose treatment mAb infusion (GSK3174998, GSK3359609, or pembrolizumab) predose GSK1795091, EOI 
GSK1795091+ 2h, +4h, and +6h. Vital signs should be assessed (and recorded) at timepoints later than EOI +6h as clinically indicated (optional EOI +8h, EOI 
+12h, EOI +16h).

On Days 2, 16, and 58, vital signs corresponding to approximately EOI +24h will be assessed.

On all other visits, vital signs must be collected predose treatment mAb infusion (GSK3174998, GSK3359609, or pembrolizumab) (when administered), predose 
GSK1795091 and EOI GSK1795091 + 2h. Additional timepoints should be collected as clinically indicated (optional EOI +4h, EOI +6h, EOI +8h, EOI +12h, EOI 
+16h). From week 12, these will be taken Q3W correspo nding to dosing days.
j.
Tumor Imaging Schedule:

Screening tumor imaging must be obtained up to 4 weeks (28 days) before the first dose.

Tumor imaging will be performed every 12 weeks (±1 week) until disease progression has been confirmed by irRECIST; Participants whose disease progresses are 
encouraged to 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 may be used to determine treatment decisions for PD.

Participants in the PK/Pharmacodynamic Cohort have an additional tumor imaging assessment on Week 9

If a participant has achieved a complete response (CR) or partial response (PR) in the previous radiologic assessment, a repeat scan should be performed as a part of
the confirmation of response, no less than 4 weeks (28 days) after the criteria for response are first met

At the TDV, tumor imaging is only required if the last disease assessment did not show PD and was performed 6 weeks before TDV.

With the implementation of Amendment 6 PFS assessment is no longer required. During the PFS FU visits (performed when a participant 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.  
k.
Tumor Biopsies: With the implementation of amendment 06, tumor biopsies on treatment are no longer required.  


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
NOTE: 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.

Archived tissue sample is required for all participants at the time of screening. If archival sample is not available, a fresh biopsy is required. 

For Part 1 (Dose Escalation), Screening and on-treatment fresh biopsies are strongly encouraged but otherwise optional for participants in Part 1.

Part 1 PK/Pharmacodynamic Cohort: a fresh tumor biopsy is required at screening (before first dose) and Week 9 (±7 days). Tumor biopsy at Week 12 (±7 days) 
should be attempted if feasible but is not mandatory.  

If a biopsy sample collection is missed due to a treatment delay, it may be collected at the next possible study visit or timepoint.
l.
See Appendix 13 for amendment 05 updated ECG assessments schedule:  Day 1 ECG measurements will be performed in triplicate predose GSK1795091 and at the 
following times after the injection (EOI) of GSK1795091: EOI +10m, EOI +2h, EOI +4h, EOI +6hr, EOI +24h.  All other ECG measurements are performed predose treatment
mAb infusion (GSK3174998, GSK3359609, or pembrolizumab), predose GSK1795091, EOI GSK1795091 +2h, and at screening as single ECG measurements.
m.
See Appendix 13 for amendment 05 changes. Particpants can opt out of the telephone interview. Qualitative Telephone Interview to be completed via telephone within 21 
days following Day 64. 
n.
See Appendix 13 for amendment 05 changes. Participants can opt out of the telephone interview. Interview to be completed via telephone within 21 days following the 
treatment discontinuation visit.  Participants who have the TDV within 30 days of the Day 64 interview are not required to repeat the interview
o.
With the implementation of amendment 06, tumor biopsies are no longer required.  
p.
Tumor imaging at Week 9 is for participants in the PK/Pharmacodynamic Cohort only; and is timed to coincide with the on-treatment tumor biopsy at Week 9.  The disease 
assessment must be performed after the tumor biopsy.
q.
Multigated acquisition scan (MUGA) is acceptable if ECHO is not available. Assessments after Screening visit should be performed as clinically indicated.
r.
Perform only in women of child-bearing potential (WOCBP).  A serum pregnancy test must be performed at screening, and subsequent pregnancy tests may be either serum 
or urine. 
Final pregnancy test (serum or urine) must be performed in WOCBP 120 days after last study treatment.
s.
See 24hr sample collection on the Part 1 PK/Pharmacodynamic Table 2.  24 hour assessments for Vital Signs, Clinical Chemistry and ECG measurements will have a 8
hour window. At Week 15 only, Clinical Chemistry assessment corresponding to EOI+24 hr will also be assessed
t.
The stool sample can be collected at any time during the screening period either at the participants home or during clinic visits using the provided collection kit.  The 
collection kit will also be provided at the Week 8 visit and the sample may be collected during the week leading up to the Week 9 visit
u.
The lipid panel includes the following tests: Cholesterol(Total), Triglycerides, HDL Cholesterol, LDL-Cholesterol (calculated), Cholesterol/HDL Ratio (calculated), and Non-
HDL Cholesterol (calculated)
v.
See Appendix 13 for instructions on activities during mAb monotherapy.


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Table 2
Part 1 Dose Escalation and PK/Pharmacodynamics Cohorts: Pharmacokinetic, Pharmacodynamic, Anti-drug 
Antibody, and Genetic Assessmentsk (Based on amendment 05 and Appendix 13 the assessments in this table
and post treatment visits will no longer be collected)
Treatment
GSK1795091 
monotherapy
Post 
treatment
Week
1
2
3
3
4
6
9
9
10
12
>12
Day
1
2
8
15
16
22
36
57
58
64
78
>78
Within 
30d 
after 
last 
dosef
12 
WK 
after 
last 
doseg
Pharmacodynamic / Immunogenicity Blood Specimens
Whole blood (Receptor 
occupancy/Immune 
phenotyping)a
Pre091
Pre,
4h
24h
Pre
4hd
24h
Xb
Xb
PBMCs
Pre091
Pre
Pre
Pre
Pre
Pre
(Wk15 
onlyj)
Xb
Xb
Plasma 
(cytokines/ chemokines)
Pre091, 
2h, 4h, 
6h
24h
Pre091, 
2h, 4hd
Pre, 2h, 4h, 
6h
24h
Pre, 
2h, 
4h, 
6h
Pre, 
2h, 4hd
24h
Pre, 
2h, 
4hd
Pre, 2h, 
4hd, 24h
(Wk15 
only)j
Xb
Xb
Plasma (biomarkers)
Pre091
Pre
Pre
(Wk15 
only)j
Xb
Serum (biomarkers)
Pre091
Pre
Pre
(Wk15 
only)j
Xb
Serum ADA 
(GSK3174998, 
GSK3359609, or 
pembrolizumab)h,i
Pre
Pre
Pre
Pre
Pree
(Q12W)
X
X
Pharmacokinetic Blood Specimens
Treatment mAb PK
(GSK3174998, 
GSK3359609, or 
pembrolizumab)
Pre,
EOI, EOI+4h
EOI+24h
X
Pre 
Pre, 
EOI, 
EOI+4h
EOI+24h
X
Pre
Pree
(Q12W)
X
X
GSK1795091 PK
Pre091,
24h
Pre091,
Pre,
24h
Pre091
Pre, 
24h
Pre091, 
10min
10mine


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Treatment
GSK1795091 
monotherapy
Post 
treatment
Week
1
2
3
3
4
6
9
9
10
12
>12
Day
1
2
8
15
16
22
36
57
58
64
78
>78
Within 
30d 
after 
last 
dosef
12 
WK 
after 
last 
doseg
10min, 
2h, 4h, 
6h
10min, 
4hd
10min, 4h 
10min, 
4hd
10min
(Q12W)
Genetics Research Blood Specimen
Genetics samplec
X
Abbreviations: Ab = antibody; ADA = anti-drug antibody; EOI = end of infusion; PBMC = peripheral blood mononuclear cell; PK = Pharmacokinetics.
Dark gray denotes discontinued activities based on Amendment 06.
Timepoint Definitions for assessments associated with treatment mAb (GSK3174998, GSK3359609, or pembrolizumab) dosing:
X = Anytime during visit (sampling date/time must be recorded)
Pre = within 60 minutes before the start of the GSK3174998, GSK3359609, or pembrolizumab infusion
EOI= within 5-30 minutes after the end of GSK3174998, GSK3359609, or pembrolizumab infusion
EOI+2h = within 2 hours 30 minutes of the end of the GSK3174998, GSK3359609, or pembrolizumab infusion
EOI+4h = within 4 hours 1 hour of the end of the GSK3174998, GSK3359609, or pembrolizumab infusion
EOI+6h = within 6 hours 1 hour of the end of the GSK3174998, GSK3359609, or pembrolizumab infusion
EOI+24h = 24 hours 8 hours after the end of the GSK3174998, GSK3359609, or pembrolizumab infusion
Timepoint Definitions for assessments associated with GSK1795091 dosing:
X = Anytime during visit (sampling date/time must be recorded)
Pre091 = within 60 minutes before the start of the GSK1795091 injection
10min = within 10 minutes of the end of the GSK1795091 injection
2h = within 2 hours 30 minutes of the end of the GSK1795091 injection
4h = within 4 hours 1 hour of the end of the GSK1795091 injection
6h = within 6 hours 1 hour of the end of the GSK1795091 injection
24h = 24 hours 8 hours after the end of the GSK1795091 injection (sample intended to be drawn at same time as the EOI+24h sample associated with 
GSK3174998, GSK3359609, or pembrolizumab) 


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a.
Procedures for the blood sample collection, processing, storage, and shipping are described in the Study Reference Manual.
b.
The whole blood sample, plasma, serum, and PBMCs must be collected prior to the start of subsequent anti-cancer therapy.
c.
Informed consent for optional genetics research must be obtained before collecting a sample. It is recommended that the blood sample be taken at the first 
opportunity after a participant has met all eligibility requirements, and can be done up to 28 days before Day 1 or on Day 1.  Appendix 6 describes 
requirements for genetic research.
d.
Sample to be taken as clinically feasible within the protocol window (i.e., if participant has been discharged from the clinic prior to the allowed sample 
procurement window, this sample is not mandatory). 
e.
Week 12 and then every 12 weeks.
f.
Procedures at this visit must be completed within 30 days from the last dose of study treatment and must be completed prior to the start of subsequent anti-
cancer therapy. Procedures can be done 7 days, unless otherwise indicated.
g.
Procedures can be done 7 days, unless otherwise indicated.
h.
Serum samples are required to be collected prior to dosing (i.e., pre-dose) on each dosing day and at the indicated assessment visits following study 
treatment discontinuation, and one sample collected 12 weeks post last dose of study treatment. In addition to these scheduled immunogenicity assessments, 
“event-driven” testing will also be employed for those participants that experience anaphylaxis, serious hypersensitivity, or AEs related to study treatment 
administered that led to withdrawal from study treatment. See Section 10.3.2.3 for full details.
i.
In the event of a hypersensitivity reaction that is either 1) clinically-significant in the opinion of the investigator, or 2) leads to the participant withdrawing from 
study treatment, serum samples should be taken from the participant for immunogenicity testing at the time of the event and again 30 days, 12 weeks, and 24 
weeks after. 
j.
After week 12, PBMCs, Plasma (cytokines/chemokines), Plasma (biomarkers) and Serum taken at Week 15 only.  At Week 15, a plasma 
(cytokines/chemokines) assessment corresponding to EOI+24 hr will also be collected.
k.
See Appendix 13 for instructions on activities during mAb monotherapy.


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3.
INTRODUCTION
3.1.
Study Rationale
The model of a “cancer-immune cycle” describes a series of feed-forward steps by which 
the immune system recognizes and kills tumor cells, a cycle which is counterbalanced by 
tumor and host derived factors which suppress anti-tumor immune activation [Chen, 
2013; Chen, 2017].  The steps of tumor immune recognition and killing include release of 
cancer cell antigens, cancer antigen presentation, priming and activation, trafficking of T-
cells to tumors, recognition of cancer cells by T-cells, and killing of cancer cells. Immune 
suppressive factors which may be operative in tumor microenvironment include 
checkpoint pathways (e.g., programmed death receptor-1 [PD-1], cytotoxic T-
lymphocyte-associated antigen 4 [CTLA-4]) and a range of immunosuppressive factors 
(e.g., IDO, TGF-β), as well as immune inhibitory cell populations including T regulatory 
(Treg) cells, myeloid derived suppressor cells, and immune suppressive macrophages 
(M2-macrophages).  Thus, cancer persistence and growth results from aberrant cell 
replication together with a relative imbalance in favor of immune suppressive factors as 
compared to anti-tumor immune activating responses.
The therapeutic benefit of blocking the immuno-inhibitory checkpoint pathways PD-1
and CTLA-4 recently has been demonstrated across multiple tumor types, yielding 
durable responses in some patients.  However, a majority of patients do not respond to 
monotherapy with checkpoint inhibitors, and strategies to increase their activity by 
combination approaches are being actively explored.  It is also possible that 
immunotherapies acting at different steps in the cycle and on different cells and pathways 
could have improved therapeutic indices over currently available monotherapies. 
Furthermore, engaging novel pathways and combinations may provide therapeutic 
options for patients wherein the pre-existing host and tumor microenvironment factors do 
not favor response to PD-1 or CTLA-4.
Toll-like receptors (TLRs) are a family of ‘sensor’ proteins primarily expressed on 
certain immune and epithelial cells that function as activators of innate immunity in 
response to microbial-related molecules known as Pathogen-Associated Molecular 
Patterns (PAMPs).  PAMPs include molecules such as nucleic acids, flagellar proteins, 
and lipopolysaccharide (LPS), the prototypical ligand for TLR4.  Ligand-driven 
activation of TLRs results in the production of various inflammatory cytokines and 
chemokines such as tumor necrosis factor (TNF), IL-6, IL-8, IP-10, G-CSF, interferons 
(IFNs), and enhanced uptake, processing, and presentation of antigens by antigen 
presenting cells.  Further effects of TLR4 agonism observed in animal models of cancer 
include reduction of Treg cells and promotion of macrophage phenotypic switching from
an immunosuppressive M2 phenotype to an immune active M1 phenotype.  
GSK1795091 is a synthetic TLR4 agonist that is being developed by GlaxoSmithKline as 
an immunological adjuvant to be administered in combination with other immune system 
modulators for the treatment of cancers. GSK1795091 is not being developed as a 
monotherapy given the lack of robust anti-tumor activity that has been reported for the 
drug class in participants with advanced malignancies [Guha, 2012; Weihrauch, 2015; 
Pashenkov, 2006].  Therefore, the first-time in human (FTIH) study of GSK1795091 was 


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performed in healthy participants to evaluate preliminary safety, PK, pharmacodynamics, 
and to identify a pharmacologically active starting dose to initiate studies in cancer 
patients [Refer to GSK Document Number 2015N236402_03, Study 204685]. 
The adverse event (AE) profile in the GSK1795091 FTIH study was characterized by 
cytokine-related effects such as flu-like symptoms and changes in temperature and heart 
rate (Section 3.2.1.2). One (1) study participant experienced an elevation in 
transaminases (Section 3.2.1.2.1).  Overall, the clinical profile of GSK1795091 as 
evaluated in healthy participants was consistent with that anticipated by the repeat dose 
GLP toxicology studies in rats and monkeys and with the profiles of other TLR agonists 
reported in both healthy participants and cancer patients [Kanzler, 2007; Bahador, 2007; 
Schmoll, 2014; Northfelt, 2014; Isambert, 2013]. Data from the FTIH study was used to 
support the starting dose and dose rationale in the present study (Section 5.5).
Other attractive immunotherapy anticancer targets include costimulatory pathways that 
enhance T-cell function.  OX40 is one such 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 IgG1 anti-OX40 agonistic mAb being 
developed for the treatment of advanced malignancies. 
ICOS is another costimulatory receptor that is highly induced on CD4+ and CD8+ T cells 
upon TCR engagement and activation [Paulos, 2010; Wakamatsu, 2013].  A growing 
body of literature supports the concept that activating ICOS on CD4+ and CD8+ T cells 
has antitumor potential, and multiple lines of nonclinical and clinical evidence have 
established the rationale for targeting ICOS in cancer.  GSK3359609 is a modified 
humanized IgG4 anti-ICOS mAb currently under study in patients with advanced solid 
tumors.
Pembrolizumab is a humanized IgG4 kappa monoclonal antibody that blocks the 
interaction between the PD-1 receptor found on T cells and its ligands, PD-L1 and PD-
L2.  Upregulation of PD-1 ligands occurs in some tumors and signaling through this 
pathway can contribute to inhibition of active T-cell immune surveillance of tumors.  
Pembrolizumab releases the PD-1 pathway-mediated inhibition of the immune response, 
including the anti-tumor immune response. Pembrolizumab is in clinical development as 
an IV immunotherapy for advanced malignancies and indicated for the treatment of 
patients across a number of conditions. For more details on specific indications refer to 
pembrolizumab IB [KEYTRUDA SPC, 2019] and approved labelling.
This study will assess the safety, PK, pharmacodynamics, and preliminary clinical 
activity of GSK1795091 administered in combination with other immunotherapies to 
participants with advanced solid tumors. GSK3174998, GSK3359609, and 
pembrolizumab are well-suited for combination with GSK1795091 based on mechanisms 
of action targeting complementary nodes of the cancer-immunity cycle and compelling 
antitumor activity observed in preclinical models. Subsequent combination partners
and/or additional routes of administration may be evaluated (following protocol 


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amendment/s) based on biologic rationale, nonclinical data, and/or emerging clinical 
data.
3.2.
Brief Background
3.2.1.
GSK1795091 Background
An overview of GSK1795091 is provided below.  Detailed information concerning the 
biology, pharmacology, PK, and safety characteristics can be found in the Investigators’ 
Brochure (IB) for GSK1795091 [GSK Document Number 2015N239078_04].  Clinical 
information is aligned to that available at the time of protocol development.
GSK1795091 was initially developed in the course of structure-activity studies on LPS
(also known as ‘endotoxin’), the naturally occurring ligand of TLR4. GSK1795091 is a 
monosaccharide from the aminoalkyl glucosaminide 4-phosphate class of compounds 
intended for use as a vaccine adjuvant or an immune modulator. GSK1795091 is an 
agonist of TLR4 that induces immunologic responses in vitro and in vivo. GSK1795091, 
as a single-agent, stimulates cytokine production (in vitro and in vivo), changes in 
immune cell populations (in vivo) and generates fever response (in vivo).
3.2.1.1.
GSK1795091 Nonclinical Activity 
GSK1795091 has shown immunomodulatory activity in multiple in vitro and in vivo 
models.  GSK1795091 added to whole blood ex vivo induces cytokine production, and 
when administered to BALB/c mice, induces phenotypic trends in peripheral blood 
leukocytes including decreased regulatory T-cells (Tregs), increased T-cell activation, 
and expansion of myeloid cells and monocyte/macrophages.  GSK1795091 administered 
to CT-26 tumor-bearing BALB/c mice resulted in an increase in survival compared to 
control groups. 
The in vitro and in vivo pharmacology of GSK1795091 is consistent with other TLR 
agonists [Kanzler, 2007]. In vitro cytokine induction (IL-1, IL-6, IP-10 and TNF) by
GSK1795091 is similar to that of LPS. In rabbits, a species used for assessing endotoxin 
contamination of parenteral formulations due to their high sensitivity, GSK1795091 
produced a transient increase in body temperature similar to that which occurs following 
LPS administration. In the repeat dose intravenous toxicity studies in rats and monkeys, 
GSK1795091 was associated with the expected pro-inflammatory actions of a TLR4 
agonist. The primary systemic effect seen with weekly dosing of GSK1795091 in rat 
(dosing up to 4 weeks) and monkey (dosing up to 6 weeks) studies was increased levels 
of specific cytokines; all other findings were transient and considered secondary to this 
primary response.  Adverse findings were only noted in rat and include microscopic 
changes in the heart valves and lymphocytic inflammatory cell infiltrates in the liver. 
The no-observed-adverse-effect-level (NOAEL) is 15 g/kg/dose and 200 g/kg/dose, in 
the rat and monkey, respectively. Based on the predicted human exposure at the highest 
planned clinical dose of 250 ng (predicted maximum concentration [Cmax] is 
approximately 0.036 ng/mL, and predicted area under the plasma concentration-time 
curve [AUC] is approximately 1.21 ng·h/mL), the margin to the NOAEL dose in rat is 


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approximately 2061X for Cmax and 214X for AUC and in monkey is approximately 
40,000X for Cmax and 24,132X for AUC.
3.2.1.2.
GSK1795091 Development Plan and Clinical Experience
This protocol describes Study 204686, evaluating the combination of GSK1795091 with 
other immunotherapies.  The study will be the second evaluation of GSK1795091 in 
humans and the first in participants with cancer. 
GSK1795091 is not planned for development as a monotherapy in cancer participants 
given that the TLR agonist drug class has not produced robust monotherapy antitumor 
activity in multiple prior clinical trials of participants with advanced malignancies.
However, the safety, PK, and pharmacodynamics results from the FTIH study support the 
design and conduct of a clinical trial in cancer participants where the benefits of 
GSK1795091 are more likely to be realized as an adjuvant in combination with other 
immune therapies with complementary modes of action. Should the combination(s)
demonstrate robust anti-tumor activity and a favorable safety profile, monotherapy study 
arms could be added by future amendment to explore the relative contributions of the 
study treatments.
Like GSK1795091, other TLR agonists including the prototypical TLR4 agonist, LPS, 
have been evaluated in both healthy participants and cancer patients for experimental and 
therapeutic purposes. Administration causes dose-dependent increases in cytokines
including TNF, IL-6, and IL-8, which peak within 2 to 4 hours and return to normal 
within 24 hours. In cases where the same TLR agonist has been administered to both 
healthy participants and to cancer participants, the PK and pharmacodynamic profiles 
have been similar for the two populations [Schmidt, 2015; Dietsch, 2014].  Clinical safety 
data for the drug class is characterized by a predictable tolerability profile of transient 
fever and flu-like symptoms (e.g., chills, nausea, malaise, etc.) attributable to cytokine 
production [Bahador, 2007]. A review of studies comprising thousands of healthy 
participants that have been administered LPS notes that long-term toxicities have not 
been described [Bahador, 2007]. Although elderly participants have greater decreases in 
blood pressure as compared to young participants administered 2 ng/kg doses of LPS 
[Krabbe, 2001], the difference in sensitivity has not prevented administration of even 
higher doses (5 ng/kg) to cancer participants [Engelhardt, 1991]. At these doses, peak 
TNFand IL-6 levels can exceed 5000 pg/ml, and further dose escalation has been
limited by rising transaminase levels [Engelhardt, 1991]. In other trials of TLR4 agonists 
in participants with advanced malignancies, cytokine-associated SAEs such as 
bronchospasm and hypotension have been reported [Vosika, 1984; de Bono, 2000].  
Overall, the cytokine-associated adverse events associated with TLR agonists overlaps 
minimally with the profiles of checkpoint modulators. Thus, the safety profile of TLR 
agonists is well suited for administration in combination with other immune therapies 
such as checkpoint modulators.
The FTIH study of GSK1795091 was a randomized, double-blind (sponsor unblinded), 
placebo-controlled, ascending dose and parallel group study in healthy participants (GSK 
Document Number 2015N236402_03, Study 204685).  In Part 1, single IV bolus doses of 
placebo or GSK1795091 7, 21, 60, or 100 ng were administered (n=6 GSK1795091, n=2 
placebo per dose level, except the 60 ng cohort which was repeated, i.e., n=12 


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GSK1795091, n=4 placebo).  Dose escalation was stopped, per protocol, following the 
100 ng cohort, in which 3 of 6 participants experienced AEs of moderate intensity. In 
Part 2, participants were to receive repeat doses of GSK1795091.  However, Part 2 was 
not started following an elevation in transaminases on study day 30 for 1 participant in
cohort 4 (60 ng) of Part 1 (Section 3.2.1.2.1).  
Preliminary PK assessments of GSK1795091 were performed based on available data.  
No quantifiable concentrations were observed at the 7 ng dose (assay lower limit of 
quantification [LLOQ] = 2 pg/mL), and insufficient PK concentrations were above the 
LLOQ at the 21 ng dose to enable calculation of AUC.  Median peak concentrations 
(Cmax) at doses 21 (n=6), 60 (n=12) and 100 ng (n=6) doses were 3.90, 10.02 and 
23.26 pg/mL, respectively. The Cmax values from these three single doses were evaluated 
for dose-proportionality using the power model loge (PK parameter) = a + b * loge (dose) 
where “a” is the intercept and “b” is the slope and was fitted by restricted maximum 
likelihood using SAS Proc Mixed. An estimate of the slope with corresponding 90% 
confidence interval (CI) was obtained from the power model to assess the degree of dose-
proportionality, wherein a slope equal to 1.0 is indicative of dose-proportionality. The 
90% confidence interval for the slope was (0.84, 1.20) and (0.96, 1.24) with inclusion and 
without inclusion, respectively, of a participant from the 100 ng dose cohort who showed 
an approximately 3-fold lower Cmax compared to other participants from this cohort. 
These intervals were contained within the interval (0.8, 1.25) indicating that slope is 
around unity implying that dose-proportionality is observed for Cmax within this dose 
range.  Half-life could not be reliably estimated for lower dose groups due to limited data 
above the assay LLOQ.  The median half-life calculated from the 100 ng dose is ~72 h, 
which is in agreement with expectations based on extrapolation of preclinical data.
The safety profile of GSK1795091 in the FTIH study [GSK Document Number 
2015N236402_03], included AEs consistent with cytokine production and was generally 
qualitatively similar to profiles of other TLR agonists. Based on preliminary, unblinded 
safety data, as of 7 days after completing dosing in the 100 ng cohort, the most common 
clinical findings were influenza-like illness (10 participants), body temperature increased 
(4 participants), abdominal pain, back pain, dizziness, headache, oropharyngeal pain, 
presyncope, (2 participants).  No other AEs were observed in more than 1 participant.
The frequency of safety observations increased with dose as described below.  

Following administration of 7 or 21 ng GSK1795091 (6 participants in each 
group), the reported AEs and changes in vital signs resembled the placebo group.

Following administration of 60 ng GSK1795091 (12 participants), mild influenza-
like symptoms or headache were reported for 7 participants.  One (1) participant 
had moderate abdominal cramps considered possibly related to study treatment. 
One (1) participant experienced a 58 bpm increase in heart rate to a maximum of 
125 bpm. One (1) participant experienced a 12-fold increase in alanine 
aminotransferase (ALT) (described Section 3.2.1.2.1).

Following administration of 100 ng GSK1795091 (6 participants), influenza-like 
symptoms were reported for 5 participants.  Three (3) participants experienced 
moderate AEs considered at least possibly related to study treatment by the 


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investigator, including orthostatic presyncope, muscle tremor, back pain, nausea, 
dizziness, influenza-like symptoms.  Because 3 of 6 participants experienced AEs 
of moderate intensity dose escalation was stopped, per protocol. 
3.2.1.2.1.
Hepatic adverse events
In study 204685, 1 participant received a single 60 ng IV dose of GSK1795091 and 
experienced a 12-fold increase in ALT.  The time course of the increase was notable in 
that the participant had a slightly elevated ALT immediately prior to dosing (53 U/L; 
upper limit of normal [ULN] = 50 U/L), and the value remained of low grade but trended 
upward to 89.6 U/L on day 7 post-dose and 122.5 U/L on day 21.  On day 32, the ALT 
increased to 563.4 U/L, and it peaked on day 34 (626.7 U/L) before declining. Beginning 
with day 35, total bilirubin was elevated (29.9 mol/L; ULN = 21 mol/L). Day 35
aspartate aminotransferase (AST), indirect bilirubin, and direct bilirubin were 254.5 U/L 
(ULN = 50 U/L), 25.8 mol/L (ULN = 17.6 mol/L), and 4.1 mol/L (ULN = 3.4 
mol/L), respectively. The participant experienced no other AEs on the trial and only had 
mild increases in body temperature (0.6oC) and heart rate (14 bpm) relative to predose 
values. A thorough evaluation by a hepatologist including comprehensive laboratory 
studies and liver ultrasound provided no additional insight into the elevations in hepatic 
laboratory values.  Of note, the participant had multiple elevations in transaminases and 
total bilirubin before or during other clinical trials at the investigative site, although all 
were of low grade (maximum ALT <4-fold ULN; maximum total bilirubin < 1.5-fold 
ULN).
The elevation in transaminases and total bilirubin was considered possibly related to 
GSK1795091 by the investigator. In addition, the sponsor, in consultation with external 
hepatologists, considered an undefined, underlying, low-grade hepatic pathology to 
possibly have contributed to the elevation in transaminases, given the participant’s 
history. A potential role for GSK1795091 as contributing to the observed increases 
cannot be ruled out based on the available information.Transaminases were routinely 
measured in all participants in the study, and no other participant experienced an 
increase.
In study 204686, as of the cutoff date of June 25, 2019, 1 participant received study 
treatment (GSK1795091 150 ng and GSK3174998 24 mg) for 6 weeks and experienced a
serious adverse event of hepatitis which met liver stopping criteria and dose-limiting 
toxicity criteria. A 40-year-old male with no previous history of liver disease or liver 
metastases developed elevations in ALT 11x ULN (peak ALT 461 IU/L, ULN ALT 41 
IU/L), AST 11x ULN (peak AST 461 IU/L, ULN AST 40 IU/L) and ALP 7.7x ULN 
(peak ALP 994 IU/L, ULN ALP 129 IU/L). Total and direct bilirubin remained within 
normal limits. There was no nausea, vomiting, fever or abdominal pain. At the time of the 
hepatitis, the subject was also receiving antibiotic treatment (with ciprofloxacin and 
amoxycillin/clavulanate) for an intra-abdominal abscess. Viral serology, autoantibody 
panel and imaging did not reveal an alternative cause for the event. Study drugs were 
interrupted, the subject was treated with 1 mg/kg methylprednisolone and the 
transaminases were resolving (ALT 283, AST 68) three days after peak values. ALP 
remained elevated (865 IU/L). Disease progression was noted on the imaging and the 
subject elected to withdraw from the study.  The investigator and sponsor considered the 


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event possibly related to GSK1795091 and GSK3174998. The sponsor, in consultation 
with external expert hepatologists also considered concomitant amoxycillin/clavulanate 
as a possible cause.  A potential role for GSK1795019 and GSK3174998 cannot be ruled 
out based on available information.
3.2.2.
GSK3174998 Background
An overview of GSK3174998 is provided below.  Detailed information concerning the 
biology, pharmacology, PK, and safety characteristics can be found in the IB [GSK 
Document Number 2014N212091_05]. Clinical information is aligned to that available at 
the time of protocol development.
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 the fragment crystallizable region (Fc) receptor (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 which is supported by available clinical 
experience. 


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3.2.2.1.
GSK3174998 Nonclinical Activity
GSK3174998 (and mouse surrogate antibodies) have shown activity in multiple in vitro 
and in vivo models.  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. A surrogate mAb to murine OX40 (OX86) was 
administered to female BALB/c mice bearing CT26 mouse colon carcinoma tumors, and 
produced an increase in survival compared to control groups.  Together, these data 
provide rationale for GSK3174998 to be used as an immunotherapy for the treatment of 
cancer.
The cynomolgus monkey was demonstrated to be an appropriate toxicology species due 
to human comparability with OX40 protein sequence identity, GSK3174998 binding and 
activity. GSK3174998 was well tolerated in monkey toxicology studies following weekly 
IV dosing for up to 4 weeks at doses up to 100 mg/kg/week with no adverse test article-
related findings noted. Anti-GSK3174998 antidrug antibodies (ADAs) were detected in
most monkeys given 10 mg/kg; however, the ability to determine toxicity in the
terminal necropsy animals was not compromised by ADAs due to the fact that robust
target engagement was observed. No infusion reactions were observed in monkeys,
including those with ADA.
3.2.2.2.
GSK3174998 Clinical Experience
Eighty-two (82) participants with advanced solid tumors have been treated in the ongoing 
FTIH study 201212 as of 13 August 2017 [GSK Document Number 2014N225045_02, 
Study 201212]. Of the 82 participants, 45 were treated with GSK3174998 monotherapy 
across 6 dose levels of (0.003 0.01, 0.3, 1, 3, and 10 mg/kg), and 39 participants were 
treated with the combination of GSK3174998 and pembrolizumab 200 mg, at 
GSK3174998 doses of 0.003 0.01, 0.3, 1 mg/kg. Two participants crossed over from 
monotherapy to combination therapy. To date, GSK3174998 was well tolerated in 
humans with no indication of dose-related increases in AEs based on current data.
In the GSK3174998 monotherapy study arm, no dose-limiting toxicities or treatment-
related Grade 3, Grade 4, or Grade 5 toxicities were reported. A single event led to 
treatment discontinuation, Grade 3 aphasia due to Grade 5 stroke. The most common AEs 
were fatigue (11, 24%), back pain (9, 20%), diarrhea (9, 20%), nausea (8, 18%), asthenia 
(8, 18%), vomiting (8, 18%), anemia, (7, 16%), headache (5, 11%), dyspnoea (5, 11%), 
myalgia (4, 11%), pain in extremity (5, 11%), and pyrexia (5, 11%). The most common 
treatment related AEs included diarrhea (5, 11%) and fatigue (5, 11%).
In the GSK3174998 combination study arm, no treatment related Grade 4 or Grade 5 
toxicities were reported. Two patients reported Grade 3 treatment-related AEs. One 
patient with head and neck cancer treated with 1 mg/kg GSK3174998 and 200 mg 
pembrolizumab reported treatment related Grade 3 AEs of asthenia and infusion reaction, 
both attributed to study treatment and occurring over one month apart from another. A 
second patient with triple-negative breast cancer (TNBC) treated with 3 mg/kg 
GSK3174998 reported Grade 3 lymphopenia attributed to study treatment. One dose 
limiting toxicity of Grade 2 pleural effusion was reported in a patient with TNBC. The 


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only AE leading to treatment discontinuation was Grade 3 fatigue. The most common 
AEs were pleural effusion (9, 23%), fatigue (6, 15%), decreased appetite, (5, 13%), 
pyrexia (5, 13%), arthralgia (4, 10%), and dyspnoea (4, 10%). The most common 
treatment related AEs included fatigue (5, 13%) and nausea (3, 8%).
Of note, there was no evidence for an acute cytokine release syndrome (CRS) associated 
with GSK3174998 administration at any dose tested, despite having a measured receptor 
occupancy >80% in peripheral blood in the immediately post-dose timeframe for all 
tested doses (see Figure 8 for additional information on GSK3174998 receptor 
occupancy).  This is consistent with the mechanistic understanding of OX40 providing a 
costimulatory signal to T-cells dependent on a TCR engagement and not functioning as a 
super agonist.  Overall, the safety profile of GSK3174998 does not appear to have 
overlapping toxicity with TLR agonists.
For further details on the safety of GSK3174998, please refer to the IB [GSK Document 
Number 2014N212091_05].
3.2.3.
GSK3359609 Background
An overview of GSK3359609 is provided below.  Detailed information concerning the 
biology, pharmacology, PK, and safety characteristics can be found in the IB [GSK 
Document Number 2017N319717_02]. Clinical information is aligned to that available at 
the time of protocol development.
GSK3359609 is a humanized IgG4 anti-ICOS agonistic mAb with specific, high-affinity 
binding to and agonist activity of ICOS, which is expressed on CD4+ and CD8+ T cells.
The desired pharmacology of GSK3359609 is to expand the total number and increase 
the activity of tumor specific effector CD4+ and CD8+ T cell populations.  Tumor 
specific T cells must be first primed through contact with cognate antigens and activated 
into effector cells in order for induction of ICOS expression to occur and GSK3359609 to 
bind and elicit an agonist effect.  Therefore, it is expected that GSK3359609 will be most 
active in disease settings where an antitumor immune response is primed as an inherent 
feature of the tumor or by prior lines of therapy.  Additionally, GSK3359609 is expected 
to be active in combination with agents which prime or modulate tumor immunity.
3.2.3.1.
GSK3359609 Nonclinical Activity
GSK3359609 biophysical properties and pharmacology have been extensively 
characterized in a series of nonclinical experiments. In vitro binding and functional 
studies were performed with recombinant protein as well as cell lines or primary human 
immune cells cultured ex vivo. Because ICOS was weakly expressed on resting T cells 
yet upon TCR engagement and activation became highly induced on CD4+ and CD8+ T 
cells, all binding and functional studies performed were with anti-CD3 and/or anti-CD28 
activated PBMCs from healthy human donors.
GSK3359609 bound to recombinant human ICOS with an affinity of 1.34 nM as 
determined by Biacore methodology. GSK3359609 bound in a concentration-dependent 
manner to pre-activated primary CD4+ and CD8+ T cells from healthy human donors. 
As expected, minimal binding of GSK3359609 to T cells was noted in the absence of 
activation.


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The nonclinical toxicology program for GSK3359609 was conducted in cynomolgus 
monkeys which were shown to be an appropriate species since the mAb cross reacts 
equally well with human and cynomolgus monkey ICOS receptors. There was no binding 
of GSK3359609 with rodent ICOS receptors. Receptor occupancy (evidence of 
GSK3359609 binding and decreased free receptor) was demonstrated in vivo in monkeys 
on CD3+CD4+CD14- T cells in peripheral blood after administration of single and 
multiple doses of GSK3359609 and persisted throughout the dosing phase and off-dose 
period. Immunohistochemical assessment of ICOS distribution in normal human tissues 
showed positive membranous staining in specific cells or lymphoid cell aggregates 
considered likely to be T cells in the tissues examined including lymphoid tissues, 
gastrointestinal tract, liver, pancreas and testes.
A range of in vitro and in vivo studies have been conducted to investigate the primary 
pharmacology of GSK3359609.  The pharmacokinetics of GSK3359609 were
investigated in two repeat dose cynomolgus monkey IV toxicology studies. Systemic 
exposure generally increased proportionally as the dose increased. A decrease in plasma 
concentrations was observed after, typical of an immunogenicity response; all animals 
were confirmed to be positive for anti-drug antibody (ADA).
GSK3359609 is not a super-agonist; as the ICOS agonist function of GSK3359609 
required TCR engagement. In the absence of anti-CD3 antibodies, there was minimal to 
no detectable increase in T cell activation or induction of pro-inflammatory cytokines 
with either the immobilized or soluble form of GSK3359609. Activated CD4+ T cells 
treated with GSK3359609 resulted in a greater magnitude of T cell proliferation, and 
cytokine induction when the antibody was immobilized as opposed to being added as a 
soluble protein to the supernatant of the T cell cultures. It is known that antibody cross 
linking is required for T cell stimulation through other costimulatory receptors 
[Wacholtz, 1989]. Therefore, the bound-format in vitro assays mimic the in vivo 
condition wherein an ICOS antibody forms cell-to-cell cross-links through FcγR binding.
3.2.3.2.
GSK3359609 Clinical Experience
As of 16 March 2018, 63 subjects received at least one dose of GSK3359609 as a 
monotherapy and 42 subjects received at least one dose of GSK3359609 in combination
with 200 mg pembrolizumab in the ongoing FTIH study 204691 [GSK Document 
Number 2015N238345_03].  These subjects are included in the safety analysis. 
Subjects received GSK3359609 monotherapy in dose escalation and expansion phases at 
the following dose levels: 0.001 mg/kg (n=1), 0.003 mg/kg (n=1), 0.01 mg/kg (n=2), 
0.03 mg/kg (n=8), 0.10 mg/kg (n=11), 0.30 mg/kg (n=12), 1 mg/kg (n=18), and 3 mg/kg 
(n=10). One subject enrolled in the 0.03 mg/kg dose level received at Cycle 1 a 
GSK3359609 dose that equated to 0.15 mg/kg.
Among the dose levels of GSK3359609 monotherapy investigated (from 0.001 mg/kg to 
3 mg/kg), a dose limiting toxicity (DLT) was observed in 1 subject at the 3 mg/kg dose 
level. The subject that experienced the DLT following monotherapy GSK3359609, a 52-
year-old female, enrolled in the PK/PD cohort, experienced AEs of Grade 4 increases in 
AST, ALT, and gamma-glutamyltransferase (GGT); Grade 3 increases in lipase and 
bilirubin; Grade 2 increase in alkaline phosphatase; and Grade 1 increase in amylase. 


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The first of these events (AST increased) occurred 24 days after the start of study 
treatment. An ultrasound of the liver showed marked dilation of the biliary tract and the 
presence of a liver lesion measuring 51 x 41 mm. As of the clinical cutoff date, no event 
was considered serious. All the events were ongoing, considered related to study 
treatment, and led to treatment discontinuation.
In the overall Part 1 population, 56 of 63 subjects (89%) experienced at least one AE
regardless of causality; 46% of these AEs were Grade 1 or 2 in severity. Twenty-two 
subjects (35%) experienced at least one AE with a maximum severity Grade of 3 in dose 
levels with > 2 subjects enrolled.  The percentage of subjects who experienced at least 
one Grade 3 AE is: 50% (4 of 8 subjects) at 0.03 mg/kg; 36% (4 of 11 subjects) at 0.1 
mg/kg; 33% (4 of 12 subjects) at 0.3 mg/kg; 44% (8 of 18 subjects) at 1 mg/kg; 10% (1 
of 10 subjects) at 3 mg/kg. Four Grade 4 events were reported in two subjects (1 event 
each of increased AST, increased ALT, and increased GGT occurred in the same subject 
treated at 3 mg/kg, and tumor perforation in another subject treated at 0.1 mg/kg).  Three 
Grade 5 events of dyspnea, lower gastrointestinal hemorrhage, and sepsis were reported 
in 1 subject each at 3, 1, 0.03 mg/kg, respectively. SAEs reported in >1 subject each 
overall included abdominal pain, lung infection, pain, and urinary tract infection, all of 
which were reported in 2 subjects each. Three subjects had AEs leading to permanent 
discontinuation of study treatment.
Forty-two (42) subjects received at least one dose of GSK3359609 in combination with 
pembrolizumab 200mg; this includes the dose escalation and expansion phases at the 
following dose levels:  GSK3359609 0.01 mg/kg (n=5), GSK3359609 0.03 mg/kg (n=5), 
GSK3359609 0.10 mg/kg (n=5), GSK3359609 0.30 mg/kg (n=20), and GSK3359609 
1 mg/kg (n=7).
No DLTs were reported for any of the 5 dose levels of GSK 3359609 in combination 
with pembrolizumab 200 mg investigated thus far (from 0.010 mg/kg to 1 mg/kg).  
Grade 1 and 2 AEs were experienced by 21 subjects (50%) that received GSK3359609 in 
combination with pembrolizumab 200 mg. Twelve subjects (29%) experienced AEs that 
were Grade 3 or 4 and none were Grade 5. Among these 12 subjects, Grade 3 or 4 AEs 
were also considered serious for 7 and 1 subject(s), respectively. A Grade 3 event of 
diarrhea in 1 subject was considered related to study treatment by the investigator. At 
least one SAE was reported for 14 subjects in Part 2, of which 1 event of diarrhea was 
considered treatment related. No SAEs were reported in >1 subject each overall.  One 
subject had an AE leading to permanent discontinuation of study treatment in Part 2. 
For further details on the safety of GSK3359609, please refer to the IB [GSK Document 
Number 2017N319717_02].


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3.2.4.
Pembrolizumab Background
Pembrolizumab, a humanized monoclonal antibody against the PD-1 protein, has been 
developed by Merck & Co for the treatment of patients with cancer and has been 
approved for treatment of patients with multiple advanced malignancies. Refer to the 
pembrolizumab approved labelling for detailed background information [KEYTRUDA
SPC, 2019; KEYTRUDA PI, 2019].
3.2.4.1.
Pembrolizumab Clinical Experience in Combination with other TLR 
Agonists
Clinical trials of TLR agonists at doses associated with systemic cytokine-related AEs 
have not demonstrated frequent, severe, or unexpected toxicities when administered in 
combination with pembrolizumab [Flowers, 2017; Leung, 2017; Milhem, 2018]. For 
example, the TLR4 agonist G100 was administered alone and in combination with 
pembrolizumab [Flowers, 2017].  The overall frequency of treatment-related AEs was 
69% for G100 alone vs. 85% for G100 + pembrolizumab.  One (1) of 13 subjects 
experienced Grade 3 adrenal insufficiency with colitis, hyponatremia, and hypocalcemia, 
attributable to pembrolizumab.  No other Grade 3 or greater events were described. The 
authors concluded that all AEs considered possibly related to G100 were grade 1 or 2 and
the addition of pembrolizumab did not result in unexpected or worsening toxicity
[Flowers, 2017].  SD-101 administered by intratumoral injection with standard doses of 
pembrolizumab in subjects with metastatic melanoma experienced frequent AEs 
characteristic of TLR agonists, e.g. chills (17/22 subjects; 77.3%); headache (16/22 
subjects; 72.7%); myalgia (15/22 subjects; 68.2%); nausea (7/22 subjects; 31.8%); 
pyrexia (7/22 subjects; 31.8%); and influenza-like illness (6/22 subjects; 27.3%).  
Grade 3 AEs were observed in 59.1% of patients (most common: myalgia 13.6% and 
injection site pain 13.6%).  Immune-related AEs occurred in 2 patients.  [Leung, 2017].  
When SD-101 was administered to subjects with metastatic SCCHN in combination with 
pembrolizumab, potential irAEs were reported at a frequency of 3/22 subjects (14%) 
[Cohen, 2018].  The authors concluded that the combination neither exacerbated the 
adverse event profiles of the monotherapies nor resulted in a unique safety signal for the 
combination [Leung, 2017; Cohen, 2018].  In an ongoing phase Ib dose escalation trial 
evaluating intratumoral TLR9 agonist CMP-001 in combination with pembrolizumab in 
63 subjects with advanced melanoma, 15 Grade 3/4 related AEs were reported, including 
hypotension (n=7), anemia (n=2), chills (n=2), hypertension (n=2) and fever (n=2) 
[Milhem, 2018]. No maximum tolerated dose was identified during the dose escalation 
phase of the study. While acknowledging the limitations of direct comparisons to these 
studies, these results demonstrate that other TLR agonists administered at doses 
associated with systemic, cytokine-associated AEs have been well-tolerated in 
combination with pembrolizumab by subjects with advanced malignancies.
3.2.5.
GSK1795091 Combination Background
3.2.5.1.
GSK1795091 In Vivo Studies
Efficacy Studies
Based on the potentially complementary mechanisms of action of GSK3174998 and 
GSK1795091, the combination was evaluated in BALB/c mice implanted with syngeneic 
CT-26 tumor xenografts.  Four groups of 10 BALB/c mice with intact immune systems 


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were implanted with CT-26 tumors.  The mice received one of the following treatments: 
placebo, GSK1795091 (TLR4 agonist), OX86 agonist (mouse surrogate OX40 agonist 
antibody), or the combination of GSK1795091 and OX86 agonist.  While the 
monotherapies had modest effects on tumor growth (Figure 1), the combination treatment 
of GSK1795091 and OX86 produced greater activity and durable responses.
Figure 1
CT-26 Tumor Growth in Balb/c Mice Treated with GSK1795091 (TLR4 
agonist) and/or OX86 (mouse surrogate for OX40) agonist
The reduction in tumor volume translated to significant improvement in the survival of 
animals (Figure 2).  Approximately 70% of animals that received the combination of 
GSK1795091 and OX86 survived more than 100 days.  By contrast, 10-20% of the 
animals that received either monotherapy survived 100 days.
Figure 2
Survival of Balb/c Mice Implanted with CT-26 Tumors and Treated 
with GSK1795091 (TLR4 agonist) and/or OX86 agonist


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GSK1795091 and GSK3359609 combination was evaluated in BALB/c mice implanted 
with syngeneic CT-26 tumors.  Four groups of 10 BALB/c mice with intact immune 
systems were implanted with CT-26 tumors.  The mice received one of the following 
treatments: placebo, GSK1795091 (TLR4 agonist), 7E.17G9 agonist (mouse surrogate 
ICOS agonist antibody), or the combination of GSK1795091 and 7E.17G9 agonist.  
While the monotherapies had very modest effects on tumor growth (Figure 3), the 
combination treatment of GSK1795091 and 7E.17G9 produced greater activity and 
durable responses. GSK1795091 and 7E.17G9 monotherapies resulted in 10% and 40% 
of mice that survived more than 100 days respectively, while the combination therapy 
resulted in 60% tumor free mice that survived more than 100 days (Figure 4).
Figure 3
CT-26 Tumor Growth in Balb/c Mice Treated with GSK1795091 (TLR4 
agonist) and/or ICOS agonist antibody (7E.17G9, mouse surrogate 
for GSK3359609)


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Figure 4
Survival of Balb/c Mice Implanted with CT-26 Tumors and Treated 
with GSK1795091 (TLR4 agonist) and/or ICOS agonist antibody 
(7E.17G9, mouse surrogate for GSK3359609)
Figure 5
EMT-6 Tumor Growth in Balb/c Mice Treated with GSK1795091 
(TLR4 agonist) and/or PD-1 antibody (RMPI-14, mouse surrogate for 
pembrolizumab)


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Figure 6
Survival of Balb/c Mice Implanted with EMT-6 Tumors and Treated 
with GSK1795091 (TLR4 agonist) and/or PD-1 antibody (RMPI-14, 
mouse surrogate for pembrolizumab)
GSK1795091 and a PD-1 antibody in combination were evaluated in BALB/c mice 
implanted with syngeneic EMT-6 tumors.  Four groups of 10 BALB/c mice with intact 
immune systems were implanted with EMT-6 tumors.  The mice received one of the 
following treatments: placebo, GSK1795091 (TLR4 agonist), RMP1-14 (mouse surrogate 
PD-1 antibody), or the combination of GSK1795091 and RMP1-14.  While the 
monotherapies exhibited tumor growth inhibition (Figure 5), the combination treatment 
of GSK1795091 and RMPI-14 resulted in greater tumor growth inhibition. GSK1795091 
and RMPI-14 monotherapies resulted in 40% tumor free mice that survived 60 to 80 
days, while the combination therapy resulted in 90% tumor free mice that survived 60 to 
80 days (Figure 6).
These preclinical efficacy results for GSK1795091 have been reproducible across a range 
of studies (e.g., testing of different doses, dose frequencies, and routes of administration), 
and together with in vitro and in vivo pharmacologic data, provide rationale for 
evaluating the combination of GSK1795091 with either GSK3174998, GSK3359609, or 
pembrolizumab in a clinical trial for the treatment of cancer.
Safety Studies
In a Safety PK/Pharmacodynamic study, groups of 3 cynomolgus monkeys were 
administered GSK1795091 (2 µg/kg) monotherapy or GSK1795091 in combination with 
GSK3174998 (10 mg/kg).  Changes in IL-6, IL-8, IL-10, MCP-1, and IP-10 were 
observed, with peak cytokine values at 2 hours post-dose of test articles.  Minimal 
changes from baseline were observed for TNF, IFNγ, IL-2, and IL-1.  The ratios 
(combination:monotherapy) of median values (from lowest to highest) at 2 hours post-
dose were 0.59, 0.77, 1.4, 1.6, and 2.5 for MCP-1, IL-8, IP-10, IL-6, and IL-10, 
respectively.  Overall, cytokine values were variable and the distributions were generally 
overlapping when comparing the monotherapy and combination arms.  There were no 
changes in hematology or clinical pathology parameters.  


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A review of the nonclinical toxicology findings with both GSK1795091 and 
GSK3174998 given as single agents indicate that additional combination toxicology 
studies in monkeys would not likely provide additional relevant clinical risk assessment 
data.
A review of the data from the nonclinical combination efficacy studies of GSK1795091 
and anti-ICOS as well as the nonclinical toxicology findings for both GSK1795091 and 
GSK3359609 used as single agents was conducted and adequately provide support for 
their use in combination in the target patient population.  Additionally, the nonclinical 
toxicology findings for both GSK1795091 and GSK3359609 given as single agents 
indicate that a combination toxicology study in monkeys would not likely provide 
additional relevant clinical risk assessment data.
A review of the data from the nonclinical combination efficacy studies of GSK1795091 
and anti-PD1 as well as the nonclinical toxicology findings and clinical (pembrolizumab 
only) safety information for both GSK1795091 and pembrolizumab used as single agents 
was conducted and adequately provide support for their use in combination in the target 
patient population.  Additionally, the nonclinical toxicology findings for both 
GSK1795091 and pembrolizumab given as single agents indicate that a combination 
toxicology study in monkeys would not likely provide additional relevant clinical risk 
assessment data.
3.2.5.2.
GSK1795091 In Vitro Studies
The potential of GSK1795091 alone and in combination with GSK3174998, 
GSK3359609, or pembrolizumab to induce cytokine release in vitro was evaluated in 
PBMCs isolated from 10 healthy human donors (5 males and 5 females) under conditions 
of no anti-CD3 stimulation (resting) and with anti-CD3 stimulation (pre-stimulation), 
which was previously shown to upregulate OX40 surface expression on T-cells.  
Cytokines (IL-2, IL-6, IL-10, IFN, and TNF) were measured following 24 hours 
incubation with GSK1795091 (10, 100 or 1000 pg/mL) and either GSK3174998, 
GSK3359609, or pembrolizumab mAbs (0. 01, 0.1, 1 or 10 g/mL).  Anti-CD28 and 
human IgG1 or IgG4 (as appropriate) isotype control antibodies were included as positive 
and negative controls, respectively. Positive cytokine induction by GSK1795091 and 
GSK3174998, GSK3359609, or pembrolizumab combination was defined as 3-fold 
increase above that of GSK1795091 alone. 
3.2.5.2.1.
GSK1795091 and GSK3174998
No effects on cytokine responses in resting or pre-stimulated PBMCs were detected at 
10 pg/mL GSK1795091 in combination with any concentration of GSK3174998. For 
concentrations ≥100 pg/mL GSK1795091, addition of 1 µg/mL GSK3174998 to resting 
PBMCs produced minimal to mild increases (approx. 2-4 fold) in IL-6, IL-10, and/or 
TNFin 2/10 donors, and in 1/10 donors in pre-stimulated PBMCs incubated with 
1000 pg/mL GSK1795091 in combination with 1 g/mL GSK3174998.  There was high 
donor-to-donor variability in cytokine responses, and individual donors had inconsistent 
concentration-response curves amongst the various test conditions.  These results suggest 
that the potential for enhanced cytokine release when these agents are administered in 


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combination in patients appears to be low, but cannot be eliminated due to the high 
amount of data variability.
3.2.5.2.2.
GSK1795091 and GSK3359609
No increases greater than 3-fold over single treatment arm in IL-2, IL-6, IL-10, IFN-, or 
TNF-were detected in PBMCs treated with GSK1795091 in combination with 
GSK3359609 (at concentrations up to 1000 pg/mL and 10 g/mL, respectively) 
compared to GSK1795091 alone, either in the presence or absence of anti-CD3
stimulation.  These results suggest that the potential for enhanced cytokine release when 
these agents are administered in combination in patients appears to be low.
3.2.5.2.3.
GSK1795091 and pembrolizumab
When pembrolizumab (≥0.1 μg/mL) was combined with GSK1795091 (10, 100 or 
1000 pg/mL) in rested PBMCs, there was an increase in the anti-inflammatory cytokine 
IL-10 [median increase 3.1-fold (range 0.01- to 119-fold)] in up to 5 of 10 donors 
compared to the respective concentrations of GSK1795091 plus human IgG4 isotype 
control.  Enhanced responses were also observed in rested PBMCs of one to three donors
(out of 10) for at least one inflammatory cytokine: IL-2 [1.5-fold (0.01- to 4.5-fold)], IL-6 
[1.8-fold (1.1- to 8.2-fold)], or TNF-α [1.7-fold (0.2- to 7.8-fold)]. There was high 
donor-to-donor variability in cytokine responses, and individual donors had inconsistent 
concentration-response curves amongst the various test conditions.  Given that a subset of 
the donors had increases in one or more pro-inflammatory cytokines, IL-2, IL-6, and 
TNF-, the potential for enhanced cytokine release when GSK1795091 and 
pembrolizumab are administered in combination in patients cannot be eliminated (see the 
Investigator’s Brochure, GSK Document Number 2015N239078_04).
3.2.5.3.
Clinical Combinations of GSK1795091 and GSK3174998
As of 13 August 2018, preliminary clinical data were available for 4 subjects that 
received GSK1795091 50 ng and in combination with GSK3174998 24 mg. Three (3) 
participants completed the 6-week DLT evaluation period.  One (1) participant received 
the first doses of GSK1795091 and GSK3174998 in combination and remained on study 
without adverse events.  One (1) subject experienced a SAE (constipation), considered 
unrelated to study treatment by the investigator.  One (1) subject, with a history of 
hypertension, experienced Grade 3 hypertension that resolved with administration of 
Demerol 25 mg.  Based on preliminary data, no adverse events considered related to 
GSK1795091 during the monotherapy run-in period, increased in severity when 
administered in combination with GSK3174998.


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3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of GSK1795091, GSK3174998, and GSK3359609 may be 
found in the respective IBs [GSK Document Number 2015N239078_04 , GSK Document 
Number 2014N212091_05, and GSK Document Number 2017N319717_02]. Information 
for pembrolizumab is found in the KEYTRUDA Prescribing Information. The following 
section outlines the risk assessment and mitigation strategy for this protocol.


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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Products [GSK1795091, GSK3174998, GSK3359609, and pembrolizumab]
Cytokine release syndrome (CRS) and/or 
cytokine-associated symptoms (flu-like 
symptoms, fever, tachycardia, hypotension, etc.).
TLR agonists are known to increase serum 
cytokine levels based upon extensive preclinical 
and clinical data [Kanzler, 2007; Astiz, 1995; 
Dillingh, 2014; Isambert, 2013].

GSK1795091 starting dose selected as a 
minimally active dose based on clinical and 
pharmacodynamic data from the 
GSK1795091 FTIH study [GSK Document 
Number 2015N236402_03].  No further 
modification appears indicated given 
available in vivo and in vitro combination 
data for GSK1795091 and clinical data for 
the mAbs.

The first 3 participants at each dose level 
receive study treatment at least 3 days apart 

Evaluation of GSK1795091 tolerability during 
a 2-week run-in period before administration 
as a combination.

Conservative and progressively smaller 
relative dose increases of GSK1795091 
between cohorts (Section 5.1.1)

Adverse event management with supportive 
care and paracetamol.  In the event of 
unexpectedly severe cases, AE 
management with fluids, oxygen, 
vasopressor support, etc. Refer to 
Section 7.2.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Vagal reactions
Rare cases of severe vagal reactions, 
bradycardia and asystole have been described in 
healthy participants receiving LPS. Risks for 
these events may include prior history of 
syncope and inadequate hydration [van Eijk, 
2004].

Hydration of participants before and after 
study product administration.

Frequent vital sign and electrocardiogram 
(ECG) measurements in the immediate post-
dose time frame.

Adverse event management with fluids and, 
if necessary, vasopressor support (Section 
7.2.1).
Infusion reactions and hypersensitivity
Risk for infusion reactions and hypersensitivity is 
inherent to many mAbs [Brennan, 2010].

Exclusion of participants with history of 
severe hypersensitivity to another mAb.  
Refer to Section 6.2 for exclusions.

GSK3174998, GSK3359609, and 
pembrolizumab administration to be 
completed with no residual infusion-
associated events before GSK1795091 
administration. 
Refer to Section 7.2.1 for management of 
infusion reactions.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Immune-related AEs
Monoclonal antibodies which affect the adaptive 
immune-system and promote the killing of tumor 
cells (e.g., ipilimumab, pembrolizumab and 
nivolumab) have been associated with 
inflammatory AEs such as diarrhea/colitis, 
pneumonitis, nephritis, hypophysitis, adrenalitis, 
thyroiditis, severe skin reactions, uveitis, 
myocarditis and hepatotoxicity.  These are well 
established after treatment with checkpoint 
modulators, and are consistent with the immune-
stimulatory mechanism of action of these agents.  
Data are insufficient at this time to fully 
appreciate the characteristics of GSK3174998 or 
GSK3359609 in this regard; however, 
surveillance for events of this nature is 
warranted.  Risks of irAEs are well-described for 
pembrolizumab [KEYTRUDA PI, 2019].

Exclusion of participants with:

Toxicity (Grade 3) related to prior 
immunotherapy leading to study 
treatment discontinuation
Refer to Section 6.2.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Liver toxicity
One (1) participant with a history of transaminase 
and bilirubin elevations experienced a mild 
increase in ALT at study day 7 (>1.5-fold) and a 
significant increase in ALT (12-fold ULN), AST 
(5-fold ULN) and total bilirubin (1.4-fold ULN) 35 
days following a single dose of GSK1795091.  

Exclusion of participants with ALT or bilirubin 
1.5-times ULN or greater at screening.

Administration of GSK1795091 monotherapy 
during a 2-week run-in period.  Participants 
with an increase in ALT 1.5x baseline and 
1.5x ULN not attributable to another cause 
during the run-in will discontinue study 
treatment and not receive GSK1795091 and 
mAbs in combination.

Criteria for stopping dosing, monitoring and 
managing transaminase elevations, and 
rechallenging participants that experience a 
transaminase elevation (Appendix 7).
Embryofetal harm
Based on the mechanism of action, 
pembrolizumab can cause fetal harm 
[KEYTRUDA PI, 2019]. The risks of 
GSK1795091, GSK3174998 and GSK3359609 
are unknown. Based on the therapeutic targets 
for GSK1795091, GSK3359609, and 
GSK3174998, they have the potential to 
modulate maternal tolerance to the fetus and can 
therefore cause fetal harm. (Riella, 2013; Clark,
2004; Heikkinen, 2004).

Exclude pregnant woman from participation 
in the study and require highly effective 
contraceptive measures for WOCBP.
Immune complex disease
Immune complex formation and deposition were 
findings in nonclinical safety studies for 
GSK3359609 (refer to the GSK3359609 IB)
Clinical laboratory safety assessments and 
immunogenicity testing


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3.3.2.
Overall Benefit: Risk Conclusion
This is an open-label, dose escalation study and the first study of the combination of 
GSK1795091 with GSK3174998, GSK3359609, or pembrolizumab conducted in 
humans; this study will enroll participants with advanced solid tumors.  There is biologic 
rationale to study these combinations for the treatment of cancer based on complementary 
modes of action on the immune system, and antitumor activity of the combinations that 
exceeds activity of the monotherapies in preclinical models. However, it is unknown if 
the combinations will have clinical activity for patients with cancer. 
Based on nonclinical in vivo and ex vivo combination evaluations and clinical experience 
to date, and the conservative starting dose of GSK1795091, the safety profiles of the 
combinations are not expected to exceed that of the monotherapies at the starting doses.  
In contrast to experience to date with GSK3174998 and GSK3359609, it is expected that 
increasing the dose of GSK1795091 past a certain threshold will be associated with DLTs 
given the TLR4 agonist mechanism of action and experience with other TLR agonists 
including LPS.  As a checkpoint inhibitor, rather than a direct immune-stimulator, 
pembrolizumab is not expected to substantially increase the potential for DLTs with 
GSK1795091, but the potential for specific synergies cannot be excluded a priori.  
Consistent with other Phase 1 trials for the treatment of cancer, a target DLT frequency 
has been set as 16-33%, and a Bayesian adaptive dose escalation design for GSK1795091 
is employed to efficiently determine the dose(s) associated with this DLT frequency.  In 
addition, it is possible that infrequent events unrelated to GSK1795091 dose, such as 
increases in hepatic laboratory values, might be observed. This risk will, in part, be 
mitigated by a run-in period for GSK1795091 prior to the initiation of combination study 
treatment. The run-in provides an evaluation of monotherapy GSK1795091 safety and 
tolerability in participants with cancer and prevents the administration of combination 
therapy to participants that experience, with GSK1795091 alone, a DLT, unacceptable 
tolerability, or an increase in ALT to 1.5x ULN and 1.5x baseline. Overall, the benefit: 
risk is typical of a Phase I study of participants with advanced cancer.


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of 
GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or
pembrolizumab.

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 GSK1795091 
when administered in combination with either
GSK3174998, GSK3359609, or pembrolizumab

Objective response rate (ORR) and disease control 
rate (DCR) (complete response [CR]+ partial 
response [PR]+ stable disease [SD] ≥12 weeks), 
time to response, duration of response, 
progression-free survival (PFS), and overall survival 
(OS).

To characterize the pharmacokinetics (PK) of 
GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or 
pembrolizumab.

GSK1795091, concentrations in plasma and 
assessment of PK parameters (e.g., Cmax, AUC(0-
τ) and Ctrough) if data permit.

To evaluate the immunogenicity of GSK3174998, 
GSK3359609, and pembrolizumab when 
administered in combination with GSK1795091.  

Number and percentage of participants who 
develop detectable ADA against GSK3174998, 
GSK3359609, or pembrolizumab.
Exploratory

To evaluate the immunologic effects of 
GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or
pembrolizumab.  

Assessments of OX40 or ICOS receptor expression 
and occupancy of GSK3174998 or GSK3359609 on 
immune cells in the peripheral blood.  

Assessment of the phenotype, quantity, and 
activation state of T cells and other immune cells in 
peripheral blood.

Assessment of tumor biopsies by 
immunohistochemistry or related technologies 
which may include but is not limited to the numbers 
of tumor-infiltrating lymphocytes and other cells 
expressing key phenotypic markers.

To explore the association between treatment with 
GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or 
pembrolizumab and measures of gene expression 
and immune function.  

Assessment of gene expression and immune 
function from study participants tumor tissue and/or 
blood samples may include but is not limited to 
immune related gene expression (RNA expression 
or RNAseq), gene signatures, and T-cell receptor 
DNA sequences. 

Assessment of soluble factors from study 
participants blood samples and/or tumor may 
include but is not limited to cytokines and stress-
related proteins, cell free DNA (cfDNA), and 
exosomes. 


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Objectives
Endpoints

To explore the association between treatment with 
GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or 
pembrolizumab and biomarkers which may be 
associated with response. To explore the utility of 
these measures to enrich for clinical efficacy and/or 
development of a diagnostic test.

Comparison between antitumor activity and 
baseline biomarker samples from study participants 
blood and/or tumor which may include but are not 
limited to DNA, gene expression (RNA), proteins, 
immune cell phenotypes, and immune response 
markers. 

Analysis of the data to identify potential selection 
biomarkers for participant enrichment.

To characterize the PK of GSK3174998, 
GSK3359609, or pembrolizumab when 
administered in combination with GSK1795091.  

GSK3174998, GSK3359609, or pembrolizumab 
concentrations in plasma/serum and assessment of 
PK parameters (e.g., maximum observed 
concentration [Cmax], AUC(0-τ) and trough 
concentration [Ctrough]) if data permit.

To explore PK-Pharmacodynamic relationships, 
such between PK parameters and antitumor 
activity, safety or pharmacodynamic markers after 
treatment with GSK1795091 when administered in 
combination with either GSK3174998,
GSK3359609, or pembrolizumab.

Evaluation of the relationship of antitumor activity 
as assessed by ORR, DCR, safety and/or 
pharmacodynamic markers with PK parameters 
(e.g., Cmax). 

Pharmacogenetics (PGx): To evaluate the 
association of genetic variations in the host DNA 
and response to therapy.

Germline genetic evaluations may be conducted to 
test for association with:

Response to treatment, including GSK1795091 
when administered in combination with either 
GSK3174998, GSK3359609, or pembrolizumab.

Disease susceptibility, severity, and progression 
and related conditions.

To explore the gut microbiome composition and 
relationship to treatment response.

Sequencing of the microbiome from stool samples.  
Analysis of the data to identify potential selection 
biomarkers for participant enrichment

Evaluation of the relationship between 
antibiotic/probiotic use prior to treatment and 
antitumor activity

To evaluate disease and treatment related 
symptoms and impact on function and health-
related quality-of-life.

Qualitative telephone interview.


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5.
STUDY DESIGN
5.1.
Overall Design
This is a Phase I, open-label, non-randomized, multicentre, multi-country study designed 
to evaluate the safety, tolerability, PK, pharmacodynamic, and preliminary clinical 
activity of GSK1795091 administered in combination with other immunotherapies to 
participants with advanced solid tumors.  
With the implementation of amendment 06, the study is closed to enrolment and Part 2 
will not be opened.
Figure 7
Study Design
Part 1 is divided into 3 treatment arms based on the GSK1795091 combination partner;
Part 1a, Part 1b, or Part 1c.  Each of the three treatment arms may have up to 5 dose 
escalation cohorts to investigate the safety and tolerability of escalating doses of 
GSK1795091with a single dose level of the combination partner. GSK1795091 
combination partners are:


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
GSK3174998 24 mg (Part 1a)

GSK3359609 80 mg (Part 1b)

Pembrolizumab 200 mg (Part 1c)
Part 1 will include a GSK1795091 run-in period of 2 weeks (i.e., GSK1795091 
administration on days 1 and 8) prior to administration of the combinations beginning on 
day 15 (Week 3). Following protocol amendment, GSK1795091 may also be evaluated 
by additional routes of administration. Safety data will be evaluated according to a 
Neuenschwander-Continual Reassessment Method (N-CRM) design [Neuenschwander, 
2008].
With the implemention of amendment 06, enrolment into the study is now closed and 
Part 2 of the study will not open.
For each combination of GSK1795091 in Part 1, PK/Pharmacodynamic cohorts will be 
opened at cleared dose levels for that combination (i.e. the most recent investigated dose 
level that supported dose escalation) to explore the potential relationships between dose, 
biological effects in the tumor microenvironment, and tumor response.  A particular 
emphasis in the PK/Pharmacodynamic cohort is placed on evaluating the possible effects 
of the combination on the immune cells and immune status within the tumor 
microenvironment.  Thus, to be eligible for the PK/Pharmacodynamic cohort, participants 
must consent to mandatory fresh biopsy collection at baseline and on treatment (see
Section 2, SoA). An additional radiographic disease assessment (see Section 2, SoA) will 
support exploratory investigation of tumor growth kinetics in this cohort.  Note that while 
consent to fresh tumor biopsy is not required for participation in the dose escalation 
cohorts in Part 1, it is strongly encouraged. Up to 6 participants per dose level may be 
enrolled into the PK/Pharmacodynamic cohort for each combination and a maximum of 
approximately 45 participants in total.
The study includes a screening period, a treatment period, and a follow-up period.  
Participants will be screened for eligibility beginning 4 weeks before the start of 
treatment.  The duration of study treatment will be up to 2 years.  . 
With the implementation of  amendment 06, participants who discontinue study treatment 
for any reason will no longer be followed for disease assessments.  One Survival FU visit 
will be performed 12wks after the last dose of study treatment or prior to the start of the 
next anti-cancer therapy, whichever occurs first. If a new anti-cancer therapy is started 
before the TDV, the OS visit is not required.  The study will conclude when the last
subject has completed/discontinued study treatment, completed the Treatment 
Discontinuation Visit (TDV) assessments, and the OS FU visit is completed (as
applicable). Following protocol amendment(s), additional participants may be enrolled to 
evaluate additional routes of study treatment administration (e.g., intratumoral 
administration), additional agents to be used in combination with GSK1795091, or 
additional indications, based on emerging nonclinical and/or clinical data.


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5.1.1.
Part 1: Dose Escalation of GSK1795091 administered in 
combination with either GSK3174998, GSK3359609, or 
pembrolizumab
In Part 1, dose escalation will be performed to identify combination dose levels 
comprising GSK1795091 with either 24 mg GSK3174998 (Part 1a), 80 mg GSK3359609
(Part 1b), or 200 mg pembrolizumab (Part 1c).  One (1) dose level of GSK3174998, 
GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned 
for evaluation, pending emerging safety and tolerability information as dose escalation 
proceeds. 
Part 1 will include a run-in period of 2 weeks in which GSK1795091 is administered 
once-weekly [i.e., administration on day 1 (Week 1) and day 8 (Week 2)] prior to 
initiation of combination treatment with either GSK3174998, GSK3359609, or 
pembrolizumab beginning on day 15 (Week 3).  During the run-in period, participants
that experience a DLT, unacceptable toxicity, or an increase in ALT (1.5x ULN and 1.5x 
baseline) and not attributable to another cause will be discontinued from the study and
will not receive GSK1795091 in combination. (See Section 5.1.3).
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 7.2.
The starting schedule for GSK1795091 will be at every 1-week intervals (Q1W) from 
Week 1 through Week 12 including the 2-week monotherapy run in period (Week 1 and 
Week 2) (see SoA Table 1). Subsequently, GSK1795091 will be administered at every 3-
week intervals (Q3W) to coincide with GSK3174998, GSK3359609, or pembrolizumab
dosing.  Thus, beginning with Week 12 for Part 1 and Week 13 for Part 2, both 
GSK1795091 and combination partners will be administered on the same study day at a 
frequency of Q3W. 
Cohorts will be opened beginning with 50 ng GSK1795091 administered in combination 
with either 24 mg GSK3174998, 80 mg GSK3359609, or 200 mg pembrolizumab. Three
(3) or more participants will be enrolled in each cohort. The total number of participants 
enrolled into each cohort and dose assignments will be guided by safety information
(Section 5.1.3) from participants receiving the study treatment combinations according to 
N-CRM modelling (Section 5.1.1.1, [Neuenschwander, 2008]).  
Sequential groups of 3-4 participants will be enrolled and dose escalation (or de-
escalation) will proceed guided by an N-CRM design.  Dose escalation for each cohort
will proceed independently of the other cohorts, e.g. dose escalation for Part 1a is not 
required prior to dose escalation for Part 1b or Part 1c. The first 3 participants at each 
dose level will receive study treatment at least 3 days apart (e.g., if the participant in a 
cohort were dosed on Monday, the earliest the next participant could be dosed is 
Thursday). Once the 6-week DLT evaluation period has been completed for at least 3 
subjects in each group (Section 5.1.3), N-CRM analysis will be performed to guide the 
dose level to which the next 3-4 participants will be assigned based on DLT frequency 
(Section 5.1.1.1). The number of participants allocated to any cohort is an estimate; 
participants may also be allocated to PK/Pharmacodynamic cohorts at a previous dose 
level that supported dose escalation.


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Dose levels -1 are available for GSK3174998 (8 mg +50 ng GSK1795091) and 
GSK3359609 (24 mg + 50 ng GSK1795091) if the target toxicity level is exceeded in 
Cohort 1 and a dose reduction is needed below planned doses.  No dose reductions for 
pembrolizumab will be implemented.
5.1.1.1.
Description of the Continual Reassessment Method
The N-CRM model-based design is a Bayesian adaptive dose escalation scheme that 
assumes a 2-parameter logistic model for the toxicity rate as a function of dose. It is a 
modified version of the original Continual Reassessment Method proposed by 
[O’Quigley, 1990]. The N-CRM method is fully adaptive and makes use of all DLT 
information, therefore is expected to locate the target dose level efficiently. In this case, 
the model will be applied to the dose escalation decision for GSK1795091, which will be 
performed independently for each combination.
Dose escalation decisions will be held after participants within any given cohort have 
been observed for at least 6 weeks after starting the study treatment (per Section 5.1.3). 
At the time of each dose escalation decision, the Fixed and Adaptive Clinical Trial 
Simulator (FACTS [Tessella, Abington, United Kingdom]) will be used to obtain the 
posterior probabilities for the DLT rate. The N-CRM estimates for each potential dose
will provide the posterior probabilities that the DLT rate lies in each of four toxicity 
ranges:

[0%, 16%] Underdosing

[16%, 33%] Target toxicity

[33%, 60%] Excessive toxicity

[60%, 100%] Unacceptable toxicity
The recommended dose for dose escalation, based on the N-CRM model, will be the dose 
with the highest posterior probability of lying in the target toxicity interval with the 
additional requirement that the sum of the posterior probabilities of the DLT rate lying in 
the excessive toxicity or unacceptable toxicity range is less than 25%. An updated 
estimate of the toxicity curve will be provided at the time of each dose escalation 
meeting.  Note that de-escalation as well as escalation is possible using this method. 
Dose escalation will continue until conditions for either scenario (i) or (ii) are met:
i) Six participants have been treated at the current target dose 
AND
For the current dose level, the posterior probabilities of the DLT rate lying within the 
excessive toxicity interval or within the unacceptable toxicity interval sum to less 
than 25% 
AND
For the next higher dose, the posterior probabilities of the DLT rate lying within the 
excessive toxicity interval or within the unacceptable toxicity interval sum to greater 
than 25%.


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ii) No doses are usable (i.e., for all doses, the posterior probabilities of the DLT rate 
lying within the excessive toxicity interval or within the unacceptable toxicity interval 
sum to more than 25%) 
AND 
At least 2 DLTs have been observed.
Dose recommendations based on the N-CRM analysis will be used as guidance. To 
ensure safety of participants, additional participants may be enrolled at a current dose 
level at the discretion of the study investigators and sponsor, even though a higher dose is 
recommended by N-CRM analysis.
5.1.1.2.
Logistic Model for N-CRM
A two-parameter logistic model will be used for N-CRM analysis for dose level selection
during the dose escalation phase. This model will estimate the probability of observing a 
DLT at each dose level in the study as DLT information becomes available.
The logistic model that used for describing the dose-toxicity relationship is: 
,
where pd is the probability of DLT at dose d, and dm is a reference dose, and α and β are 
Bayesian priors.
5.1.2.
PK/Pharmacodynamic Cohort(s)
Characterizing the effects of treatment on the tumor microenvironment is essential to the 
understanding the mechanism of action of GSK1795091 and its combination partners at 
the site of action. Thus, for each combination of GSK1795091 in Part 1, 
PK/Pharmacodynamic cohorts will be opened to characterize the biological effects in the 
tumor microenvironment and explore the potential relationships between dose and tumor 
response.  PK/Pharmacodynamic cohorts, with up to 6 participants per dose level, will be 
opened for GSK1795091 dose levels previously cleared for dose escalation.
Pre- and on-treatment tumor biopsies are required for enrollment to this cohort. PK, 
pharmacodynamic markers, and safety samples will be drawn according to Section 2 to 
obtain additional PK and pharmacodynamic data.  Following the selection of a 
recommended combination dose for Part 2, participants in the Part 1 
PK/Pharmacodynamic cohort may have the dose escalated to a higher completed dose 
level (not exceeding the target toxicity level) after Week 9 once the necessary 
PK/Pharmacodynamic procedures and tissue biopsies have been completed. See 
Section 5.1.7 for further instructions on intra-participant dose escalation.
5.1.3.
Dose-Limiting Toxicity
All toxicities will be graded using National Cancer Institute - Common Toxicity Criteria 
for AEs (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 and meets 


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at least 1 of the criteria listed in Table 3.  If an AE is considered related to the underlying 
disease, it is not a DLT.
Table 3
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 neutropenia of >7 days’ duration or febrile neutropenia 

Grade 4 anemia 

Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding
Non-
hematologic

Grade 4 toxicity

Grade 3 toxicity that does not resolve to Grade 1 or baseline within 14 days despite optimal 
supportive care 

Immune-related toxicity requiring >10 mg prednisone (or equivalent) per day after 12 weeks 
from the last dose of study treatment

Cardiopulmonary or hemodynamic toxicity starting within 24 hours of study treatment injection 
that requires >40% fraction inspired oxygen (FiO2), vasopressor administration, antiarrhythmic 
agent or other significant medical intervention.

ECG changes showing asystole or bradycardia that is symptomatic and requires medical 
intervention.

Liver toxicity (see Appendix 7) including 
o
ALT 5xULN
o
ALT 3xULN persists for 4 weeks
o
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
o
ALT 3xULN and INR >1.5, if INR measured
o
ALT 3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity

Following events are not considered DLTs
o
Changes in leukocyte parameters within 48 hours of GSK1795091 administration
o
Grade 1 changes in ALT 
o
≥ Grade 3 electrolyte abnormalities that are corrected within 24 hours without clinical 
sequelae
o
Grade 3 tumor flare (defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor)
o
Grade 3 fatigue
Other (not 
addressed 
above)

Toxicity that results in permanent discontinuation or dose reduction of GSK1795091 during 
the first 6 weeks of treatment

Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT
For participants to be considered evaluable for dose escalation decisions, missed study 
treatments must be limited during the first 6 weeks of dosing. Participants may not miss 
any study treatment administered Q3W and may not miss more than 1 study treatment 
administered Q1W.
Participants who withdraw from study treatment before completing 6 weeks of treatment 
for reasons other than DLT or who are not evaluable for dose escalation decisions may be 
replaced.  If a participant experiences a DLT during this period, the participant will be 
discontinued from the study.  
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 7.2.


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5.1.4.
Part 2: Expansion Cohort
With the implementation of amendment 06, the study is closed to enrolment and Part 2 
will not be opened.
5.1.5.
Oversight
The active study investigators, GSK medical monitor, GSK pharmacovigilance physician, 
GSK statistician, GSK physician(s) independent of the study team and contract 
organization physicians will be responsible for decisions to escalate doses.  Prior to the 
dose escalation decision, the attendees will review critical safety information defined in 
Section 5.1.3, and in the Dose Escalation Plan. Decisions will be based on safety 
information and other available data from ongoing and prior cohorts.
The dose-determination decision and rationale for each cohort will be discussed with 
investigators during teleconference(s) and documented in writing, with copies maintained 
at each study site and in the study master file.
Although the N-CRM will be used to recommend the next dosing level, clinical judgment 
by the study investigators and GSK study team can override this recommendation or halt 
enrollment into any cohorts as deemed appropriate at any time during the trial.
5.1.6.
Tumor Types Enrolled During Parts 1 
In Part 1, participants with advanced solid tumors will be enrolled.  
5.1.7.
Intra-Participant Dose Escalation
Intra-participant dose escalation will be considered on a case-by-case basis provided the 
participant has completed at least 6 weeks of study treatment without the occurrence of a 
SAE or ≥Grade 2 drug-related toxicity.  Approval by the Sponsor is required for intra-
participant dose escalation.
5.1.8.
Study Treatment
Study Part
Study Treatment: GSK1795091 in combination with GSK3174998, GSK3359609, 
or pembrolizumab
Part 1: Dose Escalation
1a
GSK3174998 24 mg IV and GSK1795091 IV 
1b
GSK3359609 80 mg IV and GSK1795091 IV
1c
pembrolizumab 200 mg IV and GSK1795091 IV


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5.2.
Number of Participants
Approximately 72 participants will be enrolled into Part 1 (dose-escalation) of the study
with approximately 24 participants in each combination.  .  
Additionally, for each combination, up to 6 participants in each dose cohort and a 
maximum of approximately 45 participants in total may be enrolled into the 
PK/Pharmacodynamic cohorts of Part 1. Additional cohorts (up to a maximum of 12 total 
participants) may be enrolled in Part 1 to allow for evaluation of additional dose levels of 
GSK1795091.
In Part 1, if a participant prematurely discontinues before the completion of 6-weeks 
treatment for reasons other than DLT, a replacement participant may be enrolled at the 
discretion of the Sponsor in consultation with the investigator.
5.3.
Participant and Study Completion
In Part 1, participants will be considered to have completed the study if they complete 
screening assessments and receive at least 1 study treatment and experience a DLT or 
complete the 6-week DLT observation period, and the treatment discontinuation visit 
(TDV).
Cause of death must be documented in the case report form (CRF)/electronic CRF
(eCRF). A participant will be considered to have withdrawn from the study if the 
participant has not died and is lost to follow-up, has withdrawn consent, at the 
investigator’s discretion is no longer being followed or if the study is closed/terminated.
Disease progression and AEs, are not by themselves reasons for withdrawal from the 
study. The end of the study is defined as the last participant has completed/discontinued 
study treatment and completed the TDV assessments, and the OS follow-up visit is 
completed (as applicable). See SoA (Section 2) .
5.4.
Scientific Rationale for Study Design
The combination of GSK1795091 with either GSK3174998, GSK3359069, or
pembrolizumab was selected based on complementary mechanisms of action and robust 
antitumor activity in preclinical models. 
Eligibility criteria require that participants have progressed after standard therapies or are 
otherwise unsuitable for standard therapies, and the criteria are intended to minimize the 
risk of adverse reactions to treatment with immunotherapies.
In Part 1, dose escalation of GSK1795091, with a fixed dose of the combination partners,
will be performed using an N-CRM model to optimize the allocation of participants to 
dose levels with a 16-33% DLT frequency. The DLT criteria are based on typical 
oncology rules with additional modifications for toxicities expected for the study 
treatments.


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In Part 1, a 2-week run-in period for GSK1795091 precedes the administration of the 
combination therapy.  The run-in provides an evaluation of monotherapy GSK1795091 
safety and tolerability in participants with cancer and prevents the administration of 
combination therapy to participants that experience, with GSK1795091 alone, a DLT, 
unacceptable tolerability, or an increase in ALT to 1.5x ULN and 1.5x baseline.
5.5.
Dose Justification
5.5.1.
Overview
GSK1795091, GSK3174998, and GSK3359609 have been previously administered as 
monotherapies in studies 204685 (GSK Document Number 2015N236402_03), 201212
(GSK Document Number 2014N225045_02), and 204691 (GSK Document Number 
2015N238345_03), respectively.  
The selection of starting combination doses has taken into consideration all available 
data, including the safety, tolerability, and pharmacology data of monotherapy 
GSK1795091, monotherapy GSK3174998, and monotherapy GSK3359609 observed in 
the respective FTIH studies [GSK Document Number 2015N236402_03, GSK Document 
Number 2014N225045_02, and GSK Document Number 2015N238345_03] and for 
pembrolizumab as summarized in the Prescribing Information [KEYTRUDA PI, 2019], 
together with pharmacology and safety data from animal models and human ex vivo 
(peripheral blood mononuclear cell [PBMC]) assays, conducted under monotherapy and 
combination conditions.   
5.5.1.1.
Starting dose for TLR4 agonist GSK1795091
The starting dose of GSK1795091 is 50 ng administered once-weekly IV. Previously 
GSK1795091 was administered at doses up to 100 ng IV to healthy participants in the 
FTIH Study (204685).  Based on data from the FTIH study, the starting dose in the 
current study (50 ng) is expected to produce low level pharmacological effects consistent 
with TLR4 agonism based on data from the FTIH study (Section 3.2.1.2).  
Because robust TLR receptor saturation assays are not available, target engagement by 
GSK1795091 in the FTIH study (204685) was monitored using representative 
inflammatory cytokine biomarkers. Based on review of available preliminary data (dose 
levels up to 100 ng), post-dose elevations of cytokines following administration of
GSK1795091 in the FTIH study were of a low magnitude compared to historical clinical 
studies of TLR agonists administered to cancer patients.  For example, the peak levels of 
inflammatory cytokines at 2h, such as TNF(median:12 pg/ml; min: 6 pg/ml; max: 23
pg/ml) and IL-6 (median: 132 pg/ml; min: 81 pg/ml; max: 184 pg/ml pg/ml, 
respectively), associated with administration of 100 ng GSK1795091 are below levels 
reported in previous studies of TLR agonists in cancer patients (>1000 pg/ml) [Chow, 
2017; Engelhardt, 1991]. These differences are likely not a function of differences in 
study populations, given that prior comparisons of TLR agonists in healthy participants 
and cancer participants have shown similar cytokine responses between populations 
[Schmidt, 2015; Dietsch, 2014]. Even acknowledging possible differences in 
pharmacodynamic assay performance, the greater than 10–100 fold margin between 


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cytokine concentrations associated with 100 ng doses of GSK1795091 versus
concentrations reported in other studies of cancer patients provides reassurance that a 
significant margin separates the starting dose of GSK1795091 and maximum tolerated 
dose of other TLR agonists.  
Consistent with the mechanism of action of GSK1795091, body temperature and heart 
rate increased with dose in Study 204685 (GSK Document Number 2015N236402_03). 
Mean maximum change with 95% CI in body temperature in the participants that 
received placebo was 0.4 0.2oC. For GSK1795091 dose levels, 7 ng, 21 ng, 60 ng, and 
100 ng, mean maximum change with 95% CI in body temperature was 0.5 0.3, 0.6 
0.4, 0.8.5, and 1.3 0.3 oC, respectively. Mean maximum change with 95% CI in heart 
rate in the participants that received placebo was 6 5 beats per minute.  For 
GSK1795091 dose levels, 7 ng, 21 ng, 60 ng, and 100 ng, mean maximum change with 
95% CI in heart rate was 8 9, 10 18, 18 15, 21 5 beats per minute, respectively.  
Thus, a 50 ng starting dose is expected to be associated with modest changes in body 
temperature and heart rate. 
Based on preliminary, unblinded safety data (described in Section 3.2.1.2), the most 
common clinical findings were influenza-like symptoms and increased body temperature. 
Predominantly mild AEs were reported when doses up to 60 ng were administered.  
Three (3) participants experienced moderate AEs following administration of 100 ng 
GSK1795091. 
In addition to the aforementioned dose-related AEs, 1 out of the 12 participants that 
received a 60 ng dose of GSK1795091 experienced a 12-fold ULN increase in ALT, 5-
fold ULN increase in AST, and 1.4-fold ULN increase in total bilirubin on day 35.  As 
only 1 event was observed and the dose administered was below the maximum 
administered, 100 ng, the data are too limited to relate elevations in hepatic laboratories
to dose. Because of the possible risk of infrequent or idiosyncratic transaminase 
elevations, a 2-week GSK1795091 run-in period will be performed in Part 1, including 
monitoring and study treatment discontinuation criteria for ALT elevations, before 
GSK1795091 and combination partners are administered.
In summary, at the GSK1795091 starting dose of 50 ng, minimal pharmacodynamic 
effects and dose-related cytokine-associated clinical effects are expected. The risk of 
infrequent events of uncertain relationship to GSK1795091 dose will be mitigated by a 2-
week monotherapy run-in period.
5.5.1.2.
Dose for OX-40 agonist GSK3174998
The starting dose of GSK3174998 is 24 mg (~0.3 mg/kg) IV administered every 3 weeks
(Q3W).  No DLTs were observed over a range from 0.003 mg/kg (~0.24 mg) to 10 mg/kg 
(~800 mg) in cancer patients receiving GSK3174998 monotherapy in GSK Document 
Number 2014N225045_02, Study 201212.  Thus, the starting dose of 24 mg is 1/33 of the 
top dose of GSK3174998 that was evaluated and produced no DLTs in Study 201212.
OX40 receptor occupancy (RO) in the central circulation is expected to be near maximal
over the whole 3-week dosing interval with 24 mg GSK3174998 based on measured RO 


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in Study 201212 (see the 0.3 mg/kg dose level in Figure 8). Efficacy responses to OX40 
agonism have been observed at widely varying dose levels, including 0.3 mg/kg.
Figure 8
Median Receptor Occupancy Profiles for Varying Doses of 
GSK3174998
Preliminary measured RO data from Study 201212 (GSK Document Number 2014N225045_02) Part 1A 
(GSK3174998 monotherapy).
Based on the totality of available data, including receptor occupancy, efficacy and safety, 
a 24 mg dose level was selected for GSK3174998. Based on emerging safety, exposure 
and/or pharmacodynamic data, the dose for GSK3174998 may be adjusted lower, to 8 
mg, if agreed by the study investigators and GSK study team.
5.5.1.3.
Dose for ICOS agonist GSK3359609
The starting dose of GSK3359609 is 80 mg (~1 mg/kg) IV administered Q3W. In the 
FTIH study (Study 204691) of GSK3359609, doses up to 3mg/kg (~240 mg) Q3W were 
evaluated as monotherapy or in combination with pembrolizumab 200 mg Q3W. Based
on the available clinical exposure and safety data from Study 204691 as listed in the IB 
[GSK Document Number 2017N319717_02], GSK3359609 can be dosed up to 3 mg/kg 
(~240 mg). One DLT was reported in one out of 10 participants treated at this dose (see 
Section 3.2.3.2).  The planned dose of GSK3359609 for evaluation in the present study is 
80 mg, or approximately 1/3 the top dose studied to date. 
GSK3359609 systemic concentrations at different dose levels have been simulated with a 
population pharmacokinetic model developed with available clinical data.


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ICOS receptor occupancy (RO) in the central circulation has been estimated based on 
predicted GSK3359609 systemic exposures and potency values for the functional effects
of GSK3359609 characterized from in vitro binding/activation assays.  Potency values 
generated from three different binding/activation assays (Kd, T-cell binding, IFN-
release) were in the range of 0.09 to 4.14 µg/mL. The corresponding ICOS RO levels 
with predicted GSK3359609 systemic exposures at different dose levels are listed in 
Table 4. The predicted RO demonstrates that the 80 mg dose (~1 mg/kg) provides 
adequate level of target engagement across all three approaches.  The currently planned 
80mg GSK3359609 dose may be adjusted lower to 24mg based on emerging safety, 
exposure and/or pharmacodynamic data if agreed by the study investigators and GSK 
study team. 
Table 4
Projected CD4+ receptor occupancy in central circulation from 
population PK predicted median steady-state peak and trough 
exposures of GSK3359609 (Q3W regimen) based on in vitro potency 
estimates
Dose
(mg)
Cmax
(g/mL)
C
(g/mL)
RO based on Kd
[0.09 g/mL] (%)
RO based on T-
cell binding 
[0.989 g/mL] 
(%)
RO based on 
IFNrelease 
(bound) [4.14 
g/mL] (%)
At Cmax
At C
At Cmax
At C
At Cmax
At C
8
3.47
0.919
97.5
91.1
77.8
48.2
45.6
18.2
24
10.3
2.73
99.1
96.8
91.3
73.4
71.4
39.8
80
34.7
9.23
99.7
99.0
97.2
90.3
89.3
69.0
240
103.6
27.3
99.9
99.7
99.1
96.5
96.2
86.8
Note:  8 (~0.01mg/kg) to 240mg (~3mg/kg) Q3W regimen evaluated as monotherapy and in 
combination with pembrolizumab 200mg Q3W in Clinical study 206491
5.5.1.4.
Pembrolizumab dose
The dose regimen for pembrolizumab, 200 mg IV Q3W, is the approved dosing scheme 
as described in the Prescribing Information [KEYTRUDA PI, 2019].  No reduction in 
dose is planned given that pembrolizumab has been administered in combination with 
other TLR agonists to subjects with advanced cancers without causing a notable change 
in the safety and tolerability profile [Flowers, 2017; Leung, 2017; Milhem, 2018].  
Moreover, the safety and efficacy profile of the approved dose regimen for 
pembrolizumab is well established, whereas the efficacy of lower doses is not fully 
characterized. 
5.5.1.5.
Combination considerations
At the 50 ng starting dose of GSK1795091, only minimal clinical and pharmacodynamic
effects are expected. Therefore, at the starting dose, GSK1795091 is not expected to 
significantly alter the safety and tolerability profile of GSK3174998, GSK3359609, or
pembrolizumab. Conversely, these mAb combination partners are not expected to 
significantly alter the safety and tolerability profile of GSK1795091 based on available in 
vitro data, in vivo data, clinical data for GSK1795091, and reported clinical data for other 
TLR agonists.


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5.5.1.5.1.
Combination of GSK1795091 and GSK3174998
Collectively, in vitro, in vivo, and preliminary clinical data suggest that GSK3174998 is 
unlikely to significantly alter the safety profile of GSK1795091.  
In vitro studies of GSK1795091 and GSK3174998 in PBMCs produced increases in IL-6, 
IL-10 or TNF-for 6 of 10 healthy donors treated with GSK3174998 (≥0.1 pg/mL) in 
combination with GSK1795091 (≥100 pg/mL) compared to either GSK3174998 or 
GSK1795091 alone. No effect of GSK3174998 at concentrations up to 10 pg/mL was 
observed on cytokine responses at 10 pg/mL GSK1795091. There was high donor-to-
donor variability in cytokine responses, and individual donors had inconsistent 
concentration-responses of the various test conditions. Therefore, the potential for 
enhanced cytokine release when these agents are administered in combination in patients 
cannot be eliminated due to the high amount of data variability.
GSK3174998 did not enhance cytokine induction by GSK1795091 in cynomolgus 
monkeys. Overall, when GSK1795091 was evaluated alone or in combination with 
GSK3174998, cytokine values were variable and the distributions were generally 
overlapping. Based on these nonclinical data, GSK3174998 is not expected to
significantly alter the safety and tolerability profile of GSK1795091.
As of the cut-off date of 13 August 2018, 4 study participants have received 
GSK1795091 and GSK3174998, in combination.  The tolerability for the combination 
was not diminished as compared to the monotherapies.  Specifically, no exacerbation of 
acute, cytokine-related events was observed.  
In summary, in vitro data and preliminary clinical data for GSK1795091 and 
GSK3174998 support the ongoing combination of these agents.  On average, 
GSK3174998 has a modest effect on GSK1795091-induced cytokines in vitro.  However, 
variability in response is significant and the potential for enhanced cytokine release when 
these agents are administered in combination in patients cannot be eliminated.  This risk 
is mitigated by the 2-week GSK1795091 monotherapy run-in period that prevents 
administration of combination therapy to participants that do not tolerate GSK1795091 
monotherapy (See Section 5.1.3). Preliminary clinical data reaffirm that the combination 
of GSK1795091 with GSK3174998 is tolerated at the starting doses.
5.5.1.5.2.
Combination of GSK1795091 and GSK3359609
Collectively, in vitro and in vivo data suggest that GSK3359609 is unlikely to 
significantly alter the safety profile of GSK1795091.  
In vitro studies of GSK1795091 and GSK3359609 in PBMCs were performed. No 
increases in IL-2, IL-6, IL-10, IFN-, or TNF-were detected in PBMCs treated with 
GSK3359609 in combination with GSK1795091 (at concentrations up to 1000 pg/mL 
and 10 pg/mL, respectively) compared to GSK3359609 alone, either in the presence or 
absence of sub-optimal anti-CD3 stimulation.
In vivo, the anti-ICOS 7E.17G9 clone was evaluated in the CT26 murine syngeneic 
tumor model in combination with the TLR4 agonist GSK1795091 in two separate in vivo 
studies.  Female BALB/c mice bearing CT26 mouse colon carcinoma tumors 


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(n=10/group) were given twice weekly IP doses of 7E.17G9 at 10 or 100 g/mouse for 
3 weeks alone and in combination with GSK1795091 at 5, 10 or 25 g/mouse.  The 
treatments were well-tolerated with no significant loss of body weight.
Overall, the nonclinical data for GSK1795091 and GSK3359609 administered as 
monotherapies support the starting combination of low doses of GSK1795091 and 
GSK3359609.
5.5.1.5.3.
Combination of GSK1795091 and pembrolizumab 
Collectively, in vitro, in vivo, and clinical data reported for TLR agonists and 
pembrolizumab suggest that pembrolizumab is unlikely to significantly alter the safety 
profile of GSK1795091.  
In vitro, when pembrolizumab (≥0.1 μg/mL) was combined with GSK1795091 (10, 100 
or 1000 pg/mL) in rested PBMCs, there was an increase in the anti-inflammatory
cytokine, IL-10 [median increase 3.1-fold (range 0.01- to 119-fold)], in up to 5 of 10 
donors compared to the respective concentrations of GSK1795091 plus human IgG4 
isotype control.  Enhanced responses were also observed in rested PBMCs of one to three 
donors (out of 10) for inflammatory cytokines IL-2 [1.5-fold (0.01- to 4.5-fold)], IL-6 
[1.8-fold (1.1- to 8.2-fold)], or TNF-α [1.7-fold (0.2- to 7.8-fold)]. There was high 
donor-to-donor variability in cytokine responses, and individual donors had inconsistent 
concentration-response curves amongst the various test conditions.  Given that a subset of 
the donors had increases in one or more of the pro-inflammatory cytokines, IL-2, IL-6, 
and TNF-, the potential for enhanced cytokine release when GSK1795091 and 
pembrolizumab are administered in combination in patients cannot be eliminated.
The anti-PD-1 RMP1-14 clone was evaluated in the EMT6 murine syngeneic tumor 
model in combination with GSK1795091.  BALB/c mice were given twice weekly IP 
doses of RMP1-14 at 200 µg/mouse for 3 weeks alone and in combination with 
GSK1795091 at 2.5 or 25 µg/mouse. The treatments were well-tolerated with no 
significant loss of body weight.
Clinical trials of other TLR agonists at doses associated with systemic cytokine-related 
AEs have not demonstrated unexpected toxicities when administered in combination with 
pembrolizumab [Flowers, 2017; Leung, 2017; Milhem, 2018].  Flowers et al. evaluated 
the AE profile of G100, a TLR4 agonist, alone and in combination with pembrolizumab 
and reported that all AEs considered possibly related to G100 were grade 1 or 2 and the 
addition of pembrolizumab did not result in unexpected or worsening toxicity.  Leung et 
al., similarly concluded that the combination did not exacerbate adverse events associated 
with the monotherapies.  Conversely, the authors of these reports have concluded that the 
combination the TLR agonists, at doses associated with systemic cytokine-related effects, 
did not result in a diminished safety profile for pembrolizumab [KEYTRUDA PI, 2019].
See Section 3.2.4.1 for further details.
In summary, in vitro data for GSK1795091 and pembrolizumab along with clinical data 
for other TLR agonists and pembrolizumab support the combination of these agents.  On 
average, pembrolizumab has a minimal effect on GSK1795091-induced inflammatory 


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cytokines in vitro, with high donor-to-donor variability noted.  However, the potential for 
enhanced cytokine release when these agents are administered in combination in patients 
cannot be eliminated.  This risk is mitigated by the 2-week GSK1795091 monotherapy 
run-in period that prevents administration of combination therapy to participants that do 
not tolerate GSK1795091 monotherapy (See Section 5.1.3). Clinical reports for multiple 
TLR agonists administered at doses associated with systemic cytokine related AEs do not 
indicate a heightened risk of combining with pembrolizumab (Section 3.2.4.1). In 
general, the nonclinical data for GSK1795091 and pembrolizumab and clinical data 
reported for other TLR agonists with pembrolizumab support the starting combination of 
low doses of GSK1795091 with pembrolizumab.  
Overall, the clinical and nonclinical data for GSK1795091, GSK3174998, GSK3359609, 
and pembrolizumab administered as monotherapies and in combination support the 
starting combination of low doses of GSK1795091 with either GSK3174998, 
GSK3359609, or pembrolizumab.
5.5.2.
Dose Escalation and Top Dose
Based on available clinical data, the tolerability of GSK1795091 approximates that of 
LPS.  Therefore, the top dose of GSK1795091 for study participants with cancer is 
expected to be similar to doses of LPS studied in similar populations, namely 2 to 4 ng/kg 
(i.e., 160 to 320 ng).  The top dose of GSK1795091 will not exceed approximately 250 
ng, which would represent a less than 3-fold escalation beyond the 100 ng dose which has 
been studied in the FTIH healthy volunteer study.  The dose escalation step size of 50 ng 
increments results in a dose escalation scheme with progressively more conservative
relative increases (e.g., 50 ng to 100 ng = 100% increase; 100 to 150 ng = 50% increase; 
150 ng to 200 ng = 33% increase; 200 ng to 250 ng = 25% increase).
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact participant eligibility is provided in the IBs/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 participant 
safety.  Therefore, adherence to the criteria as specified in the protocol is essential.


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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1.
Participant must be 18 years of at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
Histological documentation of advanced solid tumor.
3.
Archival tumor tissue obtained at any time 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.  
Note: Participants enrolled in a PK/Pharmacodynamic Cohort 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.
4.
Disease that has progressed after standard therapies or for which standard 
therapy is otherwise unsuitable (e.g., intolerance). 
5.
Measurable disease, i.e., presenting with at least 1 measurable lesion per 
Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).  See 
Appendix 9 for definition of a measurable lesion.
6.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.  
7.
Life expectancy of at least 12 weeks.  
8.
Adequate organ function (see Table 5):
9.
In France, a participant will be eligible for inclusion in this study only if either 
affiliated to or a beneficiary of a social security category.


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Table 5
Organ Function
System
Laboratory Values
Hematologic
ANC
≥1.5x109/L
Hemoglobina
≥9 g/dL
Plateletsa
≥100x109/L
PT/INR and PTT (unless participant is receiving anticoagulant)
<1.5xULN
Hepatic
Total bilirubin
For participants with Gilbert’s Syndrome (only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
ALT
≤1.5xULN
Renal
Calculated CrClb
> 50 mL/min
Endocrine
TSHc
WNL
Cardiac
Ejection fraction
≥ 50% by echocardiogram d
ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; INR = 
International Normalized Ratio; TSH = thyroid-stimulating hormone; ULN = upper limit of normal; WNL = 
within normal limits; PT = prothrombin time; PTT = partial thromboplastin time
a.
Participants must maintain hemoglobin and/or platelet values for at least 2 weeks without transfusion or 
growth factor support.
b.
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) formula (see Appendix 10)
c.
If TSH is not within normal limits at baseline, the participant may still be eligible if total T3 or free T3 and free 
T4 are within the normal limits
d.
Multigated acquisition scan (MUGA) is acceptable if echocardiography is not available
Sex
10.
Male or female
a.
Female participants: 
A female participant is eligible to participate if she is not pregnant (see 
Appendix 5), not breastfeeding, and at least 1 of the following conditions 
applies:
i.
Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 5
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 5 during the treatment period and for at least 120 days after the 
last dose of study treatment.
Informed Consent
11. Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol.


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Additional Inclusion Criteria for Participants in Part 2a (GSK3174998 expansion) 
and Part 2b (GSK3359609 expansion)
12. Histological or cytological documentation of SCCHN (oral cavity, 
oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or 
metastatic and is not amenable to curative treatment options, surgery or 
definitive chemoradiation therapy.
13. Received, ineligible for, or otherwise unsuitable for platinum-based therapy 
and anti-PD-1/PD-L1 therapy.
14. Received no more than 3 prior lines of systemic therapy for metastatic disease.
Additional Inclusion Criteria for Participants in Part 2c (pembrolizumab 
expansion)
15.
Histological or cytological documentation of SCCHN (oral cavity, 
oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or 
metastatic and is not amenable to curative treatment options, surgery or 
definitive chemoradiation therapy.
16. Received no more than 2 prior lines of systemic therapy for metastatic disease.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Malignancy other than disease under study with the exception of those from 
which the participant has been disease-free for more than 2 years and not 
expected to affect the safety of the participant or the endpoints of the trial.  
2.
Symptomatic central nervous system (CNS) metastases or asymptomatic CNS 
metastases that have required steroids within 2 weeks prior to first dose of 
study treatment.
3.
Active autoimmune disease that has required systemic disease modifying or 
immunosuppressive treatment within the last 2 years.
Note: Replacement therapy (e.g., thyroxine or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is permitted.
4.
Concurrent medical condition requiring the use of systemic 
immunosuppressive treatment within 28 days before the first dose of study 
treatment.  
5.
Known human immunodeficiency virus infection.
6.
Current unstable liver or biliary disease per investigator assessment defined by 
the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, persistent jaundice, or cirrhosis. 
NOTE: Stable chronic liver disease (including Gilbert’s syndrome or 
asymptomatic gallstones) or hepatobiliary involvement of malignancy is 
acceptable if participant otherwise meets entry criteria.


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7.
Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 
months prior to first dose of study treatment
8.
Positive Hepatitis C test result at screening or within 3 months prior to first 
dose of study treatment. 
NOTE: Participants with positive Hepatitis C antibody due to prior resolved 
disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test 
is obtained. Participants with negative Hepatitis C antibody test are not 
required to also undergo Hepatitis C RNA testing 
9.
QTcF >450 msec or QTcF >480 msec for participants 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.
10. Recent history (within the past 6 months) of acute diverticulitis, inflammatory 
bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
11. Recent history of allergen desensitization therapy within 4 weeks of starting 
study treatment.  
12. History of severe hypersensitivity to mAbs.  
13. History or evidence of cardiovascular (CV) 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.  

Cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting, or 
bypass grafting within the past 6 months before enrollment.  

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.  
14. History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung 
disease, or organizing pneumonia, or evidence of active, non-infectious 
pneumonitis.  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 
Sponsor.
15. Recent history (within 6 months) of uncontrolled symptomatic ascites or 
pleural effusions.
16. Any serious and/or unstable pre-existing medical, psychiatric disorder, or 
other condition that could interfere with the participant’s safety, obtaining 
informed consent, or compliance to the study procedures.  


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17. 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 Institutional Review Board (IRB) approval 
(by chair or designee) is given allowing exception to this criterion for a 
specific participant.
Prior/Concomitant Therapy
18. Prior treatment with the following agents: 

OX40, ICOS agonist at any time.

Prior systemic or intratumoral therapy with TLR agonist.

Anticancer therapy or investigational therapy within 30 days or 5 half-lives of 
the drug, whichever is shorter.

Prior radiation therapy:  permissible if at least 1 non-irradiated measurable 
lesion is available for assessment according to RECIST version 1.1 or if a 
solitary measurable lesion was irradiated, objective progression is 
documented. A wash out of at least 14 days before start of study treatment for 
radiation of any intended use to the extremities for bone metastases and 28 
days for radiation to the chest, brain, or visceral organs is required.
19. Prior allogeneic or autologous bone marrow transplantation or another solid 
organ transplantation.  
20. Toxicity from previous treatment including:

Toxicity Grade ≥3 related to prior immunotherapy and that lead to study 
treatment discontinuation.  

Toxicity related to prior treatment has not resolved to Grade 1 (except 
alopecia, or endocrinopathy managed with replacement therapy).  
21. Received transfusion of blood products (including platelets or red blood cells) 
or administration of colony stimulating factors (including G-CSF, 
granulocyte-macrophage colony-stimulating factor, and recombinant 
erythropoietin) within 2 weeks before the first dose of study treatment.  
Other Exclusions
22. Major surgery 4 weeks before the first dose of study treatment.  Participants 
must have also fully recovered from any surgery (major or minor) and/or its 
complications before initiating study treatment.  
23. Known drug or alcohol abuse.  
24. Receipt of any live vaccine within 4 weeks. 
Additional Exclusion Criteria for Participants in Part 2c
25. Received prior anti-PD-1/PD-L1 therapy.


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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
No dietary restrictions are required. Note that participants should be well-hydrated before 
receiving study treatment (see Section 7.1)
6.3.2.
Caffeine, Alcohol, and Tobacco
Participants who use products containing caffeine, alcohol, or tobacco are not required to
change their habits of using these products during the study treatment.
6.3.3.
Activity
Participants may experience orthostatic dizziness following administration of 
GSK1795091. Precautions should be taken to avoid falls after rising from a lying or 
seated position for several hours after administration of study treatment.  In addition, 
participants will abstain from strenuous exercise for 8 hours before each blood collection 
for clinical laboratory tests. Participants may participate in light recreational activities 
during studies (e.g., watching television, reading).
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once.  This includes retesting specific vital sign measurements, 
laboratory assessments, etc. that may not have met eligibility criteria.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study treatment’ is used throughout the protocol to 
describe any combination of products received by the participant as per the protocol 
design.  
7.1.
Treatments Administered
Participants receiving study treatment should be well-hydrated (TLR agonists have rarely 
been associated with severe bradycardia or asystole in clinical trials, attributed to poor 
hydration and/or history of syncope) [van Eijk, 2004]. Oral hydration should be 
encouraged in the days prior to study treatment and/or IV fluids (e.g., 1 L or as clinically 
indicated) administered before GSK1795091. Participants with a history of syncope


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and/or uncertain compliance with hydration recommendations should receive additional 
pre-dose and/or post-dose fluids at the discretion of the investigator. 
Treatment with GSK1795091 was suspended as of Protocol amendment 05. Participants 
may continue to receive either GSK3174998, GSK3359609 or pembrolizumab as 
monotherapy. 
Following administration of GSK1795091, assessments must be performed as noted in 
the SoA. Cytokine-related AEs including changes in vital signs commonly begin within 
several hours of administration of GSK1795091.  Participants must be monitored for 6
hours after administration of the first dose of GSK1795091 or longer as clinically 
indicated. Similarly, participants must be monitored for 6 hours after administration of 
the first 2 study treatments of GSK1795091 and combination partners. Participants that 
tolerate GSK1795091 without adverse changes in heart rate or blood pressure may have 
the duration of observation with subsequent study treatment reduced to 2 hours, provided 
the dose and schedule has not been changed. Guidelines for monitoring cytokine-related 
AEs are summarized in Section 7.2.1.1.
GSK1795091 and mAb combination partners GSK3174998, GSK3359609, or 
pembrolizumab will be administered to participants at each study site under medical 
supervision of an investigator or designee.  GSK3174998, GSK3359609, or 
pembrolizumab will be administered first, and GSK1795091 will be administered at least 
1 hour after the completion of the mAb infusion.  The date and time of administration 
will be recorded in the source documents and reported in the eCRF.  
If a participant experiences an infusion reaction with the administration of the mAb
combination partner, associated AEs should resolve before GSK1795091 is administered.  
If AEs associated with the mAb are slow to resolve, it is acceptable to administer 
GSK1795091 on the following day. Should further delay be required, the participant will 
be discontinued from study treatment. Any participant who experiences an infusion 
reaction attributable to the mAb may receive GSK1795091 on the following day for all 
subsequent study treatments.
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.  See Section 2 for dosing timepoints and 
visit windows and Section 7.9 for additional details regarding dosing delays.
The Study Reference Manual (SRM) contains specific instructions for the preparation of 
GSK1795091, GSK3174998, GSK3359609, and pembrolizumab and the unit dose 
strength of each formulation.  


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Table 6
Investigational Product Dosage/Administration
Study 
Treatment 
Name:
GSK1795091
GSK3174998
GSK3359609
Pembrolizumab
Dosage 
formulation:
Solution for 
injection
Lyophilized powder for
solution (reconstitution) 
for infusion
Solution for 
infusion
Solution for 
infusion or 
lyophilized 
powder for 
reconstitutionb
Dosage 
level(s):
Dose Level: 
50-250 ng
Dose level: 24mg
Dose Level:
80 mg
Dose Level:
200 mg every 3 
weeks
Route of 
Administration:
IV injection 
IV infusion – 30 mina
IV infusion -
30 mina
IV infusion -
30 mina
Packaging and 
Labeling
Study 
Treatment 
will be 
provided in 
container. 
Each 
container will 
be labeled as 
required per 
country 
requirement.
Study Treatment will be 
provided in container. 
Each container will be 
labeled as required per 
country requirement.
Study 
Treatment 
will be 
provided in 
container. 
Each 
container will 
be labeled as 
required per 
country 
requirement.
Commercial 
Supply
Labeled as 
required per 
country 
requirement
Manufacturer:
GSK
GSK
GSK
Merck
Note:  Refer to the SRM for detailed information on the investigational products
a.   Infusions may be prolonged in the event of an infusion reaction.  If multiple participants experience clinically 
significant infusion reactions, the infusion rate may be slowed for all future administrations of study treatment(s) 
for all participants. Should this global change in infusion rate be required, it will be communicated to the sites in 
writing.
b.   The dosage form of pembrolizumab will be either solution or lyophilized powder for all subjects/doses. This 
will be dependent on country or site formulary requirements.
7.2.
Dose Modification
Safety management guidelines, including dose modification algorithms, are provided
below. Please note, in cases where the investigator is directed to permanently discontinue 
study treatment, these instructions are mandatory as described in Section 7 and Section 8.
An overview of the dose modification guidelines is presented in Table 7.


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All AEs are to be graded according to NCI-CTCAE, version 4.0 (http://ctep.cancer.gov)
and unless otherwise specified (e.g., Section 7.2.1.1).  All dose modifications and the 
reason(s) for the dose modification must be documented in the eCRF. 
The major classes of toxicity described in Section 7 include “cytokine-related AEs and 
infusion reactions” (Section 7.2.1) and “immune-related AEs” (irAE) (Section 7.2.2).  
Even though both cytokine production and immune activity play roles in both categories 
of events, the nomenclature is intended to describe distinct classes of AEs, as described 
below. 
Investigators should refer to the IBs for GSK1795091 [GSK Document Number 
2015N239078_04], GSK3174998 [GSK Document Number 2014N212091_05], and 
GSK3359609 [GSK Document Number 2017N319717_02] for additional information 
regarding the background of each drug and the management of other AEs or potential 
safety-related issues.  Refer to the approved labelling for pembrolizumab-related 
background information and management of AEs [KEYTRUDA SPC, 2019; 
KEYTRUDA PI, 2019].
In case a dose reduction is necessary, the dose level of GSK1795091, the mAb or both 
may be changed as determined by the investigator and sponsor.  If either study treatment 
is deemed intolerable and requires discontinuation despite optimal management, as 
described below, the participant must be discontinued from both study treatments.  If one 
study treatment is not continued for reasons beside safety or tolerability, the other study 
treatment may be continued following approval by the sponsor and investigator.  Refer to 
Appendix 13 and SOA (Section 2) for instructions regarding participant activity if only 
mAb monotherapy is administered.
GSK1795091 may be restarted at the next lower dose level, and/or the mAb 
(GSK3174998 or GSK3359609) at the next lower dose level described in Section 5.1.1.  
Pembrolizumab must always be administered at the fixed 200 mg dose level.


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Table 7
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 treatment
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 treatment
o Resume study treatment at the same dose if 
symptoms have improved to Grade 1 and steroid 
dose is 10 mg prednisone/day or less

For immune-related events, 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, follow 
algorithm for Grade 3-4 events
Grade 3-4

Interrupt or discontinue study 
treatment

Consult subspecialist

For possible immune-related 
events, administer 1-
2 mg/kg/day IV 
methylprednisolone 

Discuss with Sponsor/Medical 
Monitor
Symptoms improve to Grade 2:

For possible immune-related events, 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 
treatment at the next lower dose level of GSK1795091 
and/or mAb
Symptoms ongoing: 

Discuss further management with consultant and 
Sponsor/Medical Monitor

Consider alternative immunosuppressive therapy
7.2.1.
General Guidelines for Cytokine-Related Adverse Events and 
Infusion Reactions
Cytokine-related AEs and infusion reactions are toxicities with sometimes similar 
underlying pathology. However, for the purposes of this protocol, the 2 terms should not 
be used interchangeably. “Cytokine-related AEs” describe the common and expected 
spectrum of flu-like symptoms that are associated with administration of TLR agonists, 
such as GSK1795091, and are attributable to cytokine induction. The AEs may be related 
to the dose level of study treatments.  “Cytokine release syndrome” describes a severe 
form of a cytokine-related AE. “Infusion reactions” describe the less common and 
typically idiosyncratic reactions to mAbs and other proteins that can occur by several 
mechanisms including, in some circumstances, IgE. The AEs are not necessarily related 
to the dose level of study treatments. The verbatim terms used to report “cytokine-related 


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AEs” or “infusion reactions” should describe the specific clinical signs or symptoms 
experienced by the study participant (e.g. chills, hypotension, rash, etc.) rather than non-
descriptive, high-level terms (e.g. cytokine release syndrome, infusion reaction, etc.).  
The management recommendations for both cytokine-related AEs and for infusion 
reactions are summarized below.
7.2.1.1.
Management of Cytokine Related Adverse Events and Cytokine 
Release Syndrome
The TLR agonists (including TLR4 agonists) are known to increase serum cytokine 
levels based upon evaluations in laboratory animals, healthy participants and patients 
[Kanzler, 2007; Astiz, 1995; Dillingh, 2014; Isambert, 2013]. Drugs in this class have 
generally caused mild to moderate toxicities associated with systemic cytokine 
production such as flu-like symptoms, fever, tachycardia, headache, nausea, and 
vomiting. The severity of cytokine-related AEs associated with TLR agonists generally 
peaks within several hours and subsides within a day. In a case report of a participant that 
self-administered a very high dose (1 mg) of LPS, supportive care was provided in an 
Intensive Care Unit (ICU). Reported treatment included fluids and vasopressors to 
maintain hemodynamic stability and diuresis for pulmonary edema [Taveira da Silva,
1993].
Recent experiences of CRS with cell therapies may or may not be relevant to managing 
CRS associated with other immunotherapies.  Guidelines for managing CRS associated 
with cell therapies have been published [Lee, 2014]. Patients with mild or moderate AEs 
have been managed with supportive care, including fluids, vasopressors, and/or oxygen. 
Patients with high grade CRS have been managed in an intensive care unit and received 
immunosuppressive treatment. Anecdotally, tocilizumab (anti-IL-6 receptor antibody) 
has produced rapid and complete correction of CRS associated with cellular therapies 
[Maude, 2014].  Tocilizumab was recently approved by the FDA for the treatment of 
chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine 
release syndrome (8 mg/kg given as a 60-minute intravenous infusion for patients at or 
above 30 kg, with doses not to exceed 800 mg per infusion). 
The attribution of signs and symptoms to cytokine production should be influenced by 
the timing with respect to administration of study treatment. The grading of cytokine-
related AEs according to NCI-CTCAE criteria and according to Lee et al [Lee, 2014] is 
based on the requirement for intervention and the responsiveness to treatment.  
Recommendations for managing AEs are provided in Table 8.


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Table 8
Cytokine Related Adverse Event Dose Modification and Treatment 
Guidelines
Treatment
Premedication at 
Subsequent Dosing
Grades 1 or 2
Mild reaction; intervention may be 
indicated
Grade 1: e.g., fever, constitutional 
symptoms
Grade 2: e.g., hypotension 
responsive to fluids, hypoxia 
responsive to <40% FiO2 or other 
cytokine-related AEs responsive to 
intervention.

Monitor vital signs until any 
changes in body temperature, 
heart rate, and blood pressure 
attributable to cytokine 
production are resolving.  In 
some circumstances, 
monitoring overnight may be 
required.  

Provide 
symptomatic/supportive care, 
including paracetamol, fluids, 
supplemental oxygen, etc., as 
required. 
Premedication may be 
considered with subsequent 
study treatment.
Participants that tolerate 
initial study treatment may 
have the duration of 
observation with subsequent 
study treatments reduced at 
the discretion of the 
investigator
Grades 3 or 4
Grade 3: AEs requiring aggressive 
intervention such as vasopressor 
administration, > 40% FiO2 or 
other cytokine-related AEs 
unresponsive to intervention.
Grade 4: life threatening symptoms 
or severe organ toxicities with 
interventions including mechanical 
ventilation

Monitor vital signs until any 
changes in body temperature, 
heart rate, and blood pressure 
attributable to cytokine 
production are resolving.  In 
some circumstances, 
monitoring overnight may be 
required.

Perform ECG and/or 
echocardiographic monitoring 
as indicated based on medical 
history and cardiac function. 

Provide 
symptomatic/supportive care, 
including paracetamol, fluids, 
supplemental oxygen, 
vasopressor administration, 
diuresis etc. as indicated. 

Consider tocilizumab if 
conventional supportive 
measures are inadequate to 
control a declining clinical 
course or potentially life-
threatening toxicities. 

Obtain serum for C-reactive 
protein (CRP), tryptase, ferritin, 
and plasma for the cytokine 
panel (see Table 9 and SRM) 
within 3 hours of the event.  
Should the cytokine-related 
event be attributed to 
GSK1795091 and further 
study treatment administered, 
the dose of GSK1795091 will 
be reduced to the next lower 
dose level.


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Treatment
Premedication at 
Subsequent Dosing

Do not administer further study 
treatment, unless approved by 
Sponsor/Medical Monitor.
Appropriate resuscitation equipment and a physician should be readily available during the period of drug 
administration.
Table 9
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-1, IL-
1Ra, GCSF, IP-10, MCP-1, 
RANTES)
* 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
Note: Serum and plasma to be drawn within 3 hours of a Grade 3 or 4 cytokine 
related AE, as per Table 8
7.2.1.2.
Management of Infusion Reactions
Infusion reactions are a well-documented AE associated with the administration of mAbs
and other therapeutic proteins. 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. 
Clinically infusion reaction may present as 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.


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Should any of these symptoms or signs be observed with administration of GSK3174998, 
GSK3359609, or pembrolizumab, all must resolve before the administration of 
GSK1795091.  Administration of GSK1795091 may be delayed until the following day.  
Should further delay be required for symptoms of the infusion reaction to resolve, the 
participant will be discontinued from study treatment. If a participant experienced an 
infusion reaction attributable to GSK3174998, GSK3359609, or pembrolizumab with 
prior administration, it is acceptable to administer GSK1795091 on the following day.
Guidelines for the management of infusion reactions are provided in Table 10.
Table 10
Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; requires infusion 
rate to be decreased; intervention 
may be indicated

Decrease the rate of the mAb 
infusion to 25% or less of the 
original infusion rate until 
recovery from symptoms.  

The participant must be 
closely monitored until 
resolution of symptoms. 

Diphenhydramine 50 mg may 
be administered at the 
discretion of the treating 
physician.  

When symptoms resolve, 
resume the infusion at 50% of 
the original infusion rate; if no 
further complications ensue 
after 30 minutes, the rate may 
be increased to 100% of the 
original infusion rate. 

GSK1795091 may be 
administered following 
complete resolution of 
symptoms.

The amount of mAb infused 
must be recorded.  
Diphenhydramine 50 mg (or 
equivalent) and/or 
paracetamol (acetaminophen) 
325 mg to 1000 mg should be 
administered at least 30 
minutes before additional 
study treatment 
administration. Study 
treatments may continue to be 
administered on the same 
day.
Grade 2
Moderate reaction such as 
generalized pruritus, flushing, rash, 
dyspnea, or hypotension with 
systolic blood pressure > 80 mmHg
Stop Infusion.

Begin an IV infusion of 
normal saline.  

Administer diphenhydramine 
50 mg IV (or equivalent) 
and/or paracetamol 
(acetaminophen) 325 mg to 
1000 mg.

The participant must be 
closely monitored until 
resolution of symptoms. 
Corticosteroid therapy may be 
administered at the discretion 
of the treating physician.

When symptoms resolve, 
restart the infusion at 50% of 
the original infusion rate; if no 
Diphenhydramine 50 mg (or 
equivalent) and/or 
paracetamol (acetaminophen) 
325 mg to 1000 mg should be 
administered at least 30 
minutes before additional 
study treatment 
administration.  GSK1795091 
may be administered the 
following day.


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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
further complications ensue 
after 30 minutes, the rate may 
be increased to 100% of the 
original infusion rate. 

Monitor participant closely.  If 
symptoms recur, immediately 
discontinue the infusion; no 
further study treatment will be 
administered at that visit.  
Administer diphenhydramine 
50 mg IV and continue to 
monitor the participant closely 
until resolution of symptoms.  

Participants who develop 
Grade 2 toxicity despite 
adequate premedication must 
be permanently discontinued 
from further study treatment 
administration. 

The amount of mAb infused 
must be recorded.
Grades 3 or 4
Severe reaction [e.g., 
bronchospasm, generalized 
urticaria, systolic blood pressure < 
80 mm Hg, hypoxemia, or 
angioedema]
Grade 3: prolonged [i.e., requiring 
6 or more hours to respond to 
symptomatic medication and/or 
discontinuation 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

Immediately discontinue the 
mAb infusion.  No further 
study treatment will be 
administered, unless approved 
by Sponsor/Medical Monitor 
(criteria for rechallenge 
include but are not limited to 
participants who are receiving 
compelling benefit with study 
treatment that exceeds risk, 
and no effective alternative 
therapy is available).

The amount of mAb infused 
must be recorded on the eCRF.  

Investigators should follow 
their institutional guidelines 
for the treatment of 
anaphylaxis (e.g., epinephrine 
0.2 mg to 1.0 mg of a 1: 1,000 
solution for subcutaneous 
administration or 0.1 mg to 
0.25 mg of a 1: 10,000 
solution injected slowly for IV 
administration, and/or 
diphenhydramine 50 mg IV 
with methylprednisolone 
100 mg IV (or equivalent), as 
needed.) 

Consider additional 
intervention in consultation 
with the Sponsor (e.g., 
Diphenhydramine 50 mg (or 
equivalent) and/or 
paracetamol (acetaminophen) 
325 mg to 1000 mg should be 
administered at least 30 
minutes before additional 
study treatment 
administration.  GSK1795091 
may be administered the 
following day.


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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
tocilizumab).  

Obtain serum for CRP, 
tryptase, ferritin, and plasma 
for the cytokine panel (see 
Table 9 and SRM) within 3 
hours of the event.  

The participant must be 
closely monitored until 
resolution of symptoms.
Appropriate resuscitation equipment and a physician should be 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
7.2.2.
General Guidelines for Immune-Related Adverse Events
An “immune-related AE” (irAE) is defined as a clinically significant AE of any organ 
that is associated with study treatment exposure, is of unknown etiology, and is consistent 
with an immune-related mechanism. The classification refers to the traditional spectrum 
of AEs associated with checkpoint modulators (e.g., colitis, pneumonitis, etc.)  The term 
is not intended to describe the acute cytokine-related AEs or infusion reactions described 
in Section 7.2.1.  Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.
Early recognition of irAEs and initiation of treatment are critical to reduce the risk of 
complications, since the majority of irAEs are reversible with the use of steroids and 
other immune suppressants [Pardoll, 2012; Weber, 2012].  If an irAE is suspected, the 
participant must return to the study site as soon as possible instead of waiting for his/her 
next scheduled visit.  Participants who experience a new or worsening irAE must be 
contacted and/or evaluated at the study site more frequently.  
If an irAE is suspected, a thorough evaluation must be conducted in an effort to possibly 
rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes before 
diagnosing an irAE.  Serological, immunological, and histological (biopsy) data should 
be considered to support the diagnosis of an immune-related toxicity.  Consultation with 
the appropriate medical specialist should be considered when investigating a possible 
irAE.  
Organs most frequently affected by irAEs include the skin and the colon due to their 
rapid regeneration rate. Less frequently affected tissues are lung, liver, and the pituitary 
and thyroid glands.  Mild irAEs are usually treated symptomatically and do not require 
dosing delays or discontinuation.  Higher grade and persistent lower grade irAEs 
typically necessitate interrupting or discontinuing treatment and administration of 
systemic steroids or other immunosuppressive agents (such as TNF blockers) when 
systemic steroids are not effective.  


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7.2.2.1.
General Principles of Immune-Related Adverse Events Identification 
and Evaluation
Before administration of study treatment, investigators are to review a participant's AEs, 
concomitant medications, and clinical evaluation results e.g., vital signs, lab results, 
ECGs, ECOG PS, physical exam findings, responses, etc. as outlined in the Schedule of 
Activities (SoA) (Section 2)to monitor for new or worsening irAEs and ensure continued 
dosing is appropriate.  
Adverse events of special interest (AESIs) are defined as events of potential immunologic 
etiology. Such events reported after treatment with other immune modulatory therapy 
include Grade 2 colitis, uveitis, hepatitis, pneumonitis, Grade 3 diarrhea, endocrine 
disorders, and specific cutaneous toxicities, as well as other events that may be immune 
mediated, including but not limited to demyelinating polyneuropathy, myasthenia gravis-
like syndrome, non-infectious myocarditis, or non-infectious pericarditis [see
Appendix 11 for a listing of AESIs].  
For participants who experience signs or symptoms that may be consistent with an AESI, 
sites must notify the Sponsor of the event within 24 hours via email and/or phone.  
Documentation of events potentially qualifying for AESI must occur after discussion 
between the investigator and the Sponsor.  
7.2.2.2.
General Guidelines for Clinically Significant Toxicities Not Otherwise 
Specified
While specific guidance is provided for AESI, it is possible that other clinically 
significant drug-related toxicities that are not specifically described may occur and 
warrant dose modification.  Table 7 provides general guidance for the management of 
clinically significant toxicities that are not otherwise specifically described in this section.  
Investigators must contact the Sponsor within 24 hours of being notified of the event for 
all Grade 3 clinically significant non-hematological drug-related toxicities where 
interruption or permanent discontinuation of study treatment may be warranted according 
to the guidelines provided.  Otherwise, investigators are encouraged to contact the 
Sponsor as needed to discuss any case that warrants separate discussion outside of the 
scope of current guidelines.  
For events that do not resolve to less than or equal to Grade 1 within 12 weeks after the 
last infusion/injection, study treatment must be permanently discontinued after 
consultation with the Sponsor. With investigator and Sponsor agreement, participants 
with a laboratory AE still at Grade 2 after 12 weeks may continue treatment in the trial 
only if asymptomatic and controlled.  
For participants who experience a recurrence of the same AE(s) at the same grade or 
greater with rechallenge of study treatment, a consultation between the Sponsor and 
investigator will occur to determine whether the participant should continue in the study.  
Recurrence of an SAE at the same grade or greater with rechallenge of study treatment 
must result in permanent discontinuation of the study treatment.  


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7.2.2.3.
Management of Hepatotoxicity
In the event of treatment-emergent hepatotoxicity, potential contributing factors such as 
concomitant medications, viral hepatitis and other infectious causes, choledocholithiasis, 
and hepatic metastases, and myositis should be investigated. Concomitant medications 
known to be hepatotoxic which may be contributing to liver dysfunction should be 
discontinued or replaced with alternative medications to allow for recovery of liver 
function. As generally understood, AST or ALT >3x ULN and concomitant bilirubin 
≥2.0x ULN (>35% direct bilirubin), in the absence of elevated alkaline phosphatase or 
biliary injury, suggests significant liver injury. Record alcohol use on the liver event 
alcohol intake form in the eCRF. Liver dysfunction must be fully evaluated even if 
clinical signs and symptoms indicate progression of liver tumor lesions. Imaging studies 
must be obtained to document potential progression of malignancy. Guidelines for 
management of emergent hepatotoxicity are shown in Section 8.1.1 and Appendix 7.
Report hepatotoxicity events to GSK within 24 hours.  Complete liver event eCRF forms 
and SAE forms if the event also meets the criteria for SAE reporting.  
If treatment is held or discontinued do not restart/rechallenge the participant with study 
treatment unless all of the requirements described in Section 8.1.1.1 have been met. Liver 
chemistry stopping criteria are provided in Section 8.1.1.
In Canada, if liver chemistry stopping criteria are met, participants will not be 
allowed to restart study drugs or be rechallenged.
7.2.2.4.
Management of Gastrointestinal Events (Diarrhea or Colitis)
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.
Differential diagnosis: All attempts should be made to rule out other causes such as 
metastatic disease, bacterial or parasitic infection, viral gastroenteritis, or the first 
manifestation of an inflammatory bowel disease by examination for stool leukocytes, 
stool cultures, and a Clostridium difficile titer.  Dose modification guidelines for 
gastrointestinal events are provided in Table 11.


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Table 11
Guidelines for Dose Modification and Management of 
Gastrointestinal Events (Diarrhea or Colitis)
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 treatment

Administer antidiarrheal and 
symptomatic treatment

Discuss with Sponsor/Medical 
Monitor
Symptoms resolve to Grade ≤1 or baseline within 3 days: 

resume study treatment
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 treatment 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, follow 
algorithm for Grade 3-4 events
Grade 3

Interrupt study treatment

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.  

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.  

Resume study treatment(s) if toxicity has resolved to 
Grade 1 and steroid dose is 10 mg prednisone or 
equivalent per day within 12 weeks of last dose. If the 
last dose was administered >12 weeks, study 
treatment(s) must be permanently discontinued.
Recurrence after rechallenge:

Discontinue study treatment permanently unless 
otherwise agreed upon by the Sponsor/Medical 
Monitor and Investigators
Grade 4

Permanently discontinue 
study treatment

Immediately inform 
Sponsor/Medical Monitor

Management as per Grade 3


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7.2.2.5.
Management of Skin Toxicity
Differential diagnosis: All attempts should be made to rule out other causes such as 
metastatic disease, infection, or allergic dermatitis. Dose modification guidelines for skin 
toxicity are provided in Table 12.
Table 12
Guidelines for Dose Modification and Management of Skin Toxicity
Severity
Management
Follow-up
Grade 1 

Symptomatic 
management
Provide close follow-up
Grade 2

Interrupt study 
treatment

Discuss with 
Sponsor/Medical 
Monitor

Consider dermatology 
consultation and biopsy
Symptoms resolve to baseline within 7 days: 

resume study treatment
Symptoms ongoing > 7 days:

Start topical or systemic corticosteroids (e.g., 0.5-
1 mg/kg/day of prednisone or equivalent)

Continue steroids until improvement to Grade 1 or 
resolution; taper steroids as medically appropriate

Resume study treatment if symptoms have improved 
to Grade 1 and steroid dose is 10 mg 
prednisone/day or less

If symptoms continue or worsen, follow algorithm for 
Grade ≤3 events
Grade 3 or greater 
or Stevens-Johnson 
syndrome, toxic 
epidermal 
necrolysis, or rash 
complicated by full 
thickness dermal 
ulceration, or 
necrotic, bullous, or 
hemorrhagic 
manifestations

Permanently 
discontinue study 
treatment

Administer 1-
2 mg/kg/day IV 
methylprednisolone 

Discuss with 
Sponsor/Medical 
Monitor

Consider dermatology 
consultation and biopsy

When dermatitis is controlled, taper steroids over at 
least 1 month 
IV = Intravenous
7.2.2.6.
Management of Endocrine Events
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: 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.


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Dose modification guidelines for endocrine events are provided in Table 13.
Table 13
Guidelines for Dose Modification and Management of Endocrine 
Events
Severity
Management
Follow-up
Grade 1 or 2

Signs and/or 
symptoms of 
dysfunction

Endocrinopathies 
requiring hormone 
replacement or 
medical 
intervention

Consider interruption of study 
treatment 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:

Participant is stable (on hormone-
replacement therapy if indicated) and 
symptoms have resolved or return to 
baseline

Participant is receiving ≤10 mg 
prednisone or equivalent per day
Grade 3 or greater

Adrenal crisis or 
other adverse 
reactions requiring 
hospitalization, 
urgent medical 
intervention.

Consider interruption of study 
treatment

Discuss with Sponsor/Medical 
Monitor

Consider immediate initiation of 
1-2 mg/kg/day IV 
methylprednisolone

Consult endocrinology

Other management as above
Consider resuming study agent(s) when:

Participant is stable (on hormone-
replacement therapy if indicated) and 
symptoms have resolved or return to 
baseline

Participant is receiving ≤10 mg 
prednisone or equivalent per day
7.2.2.7.
Management of Pneumonitis
Signs/symptoms may include, but are not limited to: dyspnea, dry cough, hemoptysis, 
fever, chest pain and/or tightness, abnormal breath sounds, and fatigue.  If symptoms 
indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered.  Pneumonitis events may include the 
following AE terms: pneumonitis, interstitial lung disease, and acute interstitial 
pneumonitis. 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered.
Differential diagnosis: All attempts should be made to rule out other causes such as 
metastatic disease, and bacterial or viral infection. It is important that participants with a 
suspected diagnosis of pneumonitis be managed as per the guidance below until 
treatment-related pneumonitis is excluded.  Treatment of both a potential infectious 
etiology and pneumonitis in parallel may be warranted.  Management of the treatment of 


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suspected pneumonitis with steroid treatment should not be delayed for a therapeutic trial 
of antibiotics.  If an alternative diagnosis is established, the participant does not require 
management as below; however, the AE should be reported regardless of etiology. Dose 
modification guidelines for pneumonitis are provided in Table 14.
Table 14
Guidelines for Dose Modification and Management of Pneumonitis
Severity
Management
Follow-up
Grade 1
(asymptomatic with 
radiographic findings 
only)

Discuss continued 
treatment with study 
treatment with 
Sponsor/Medical Monitor

Consider pulmonary 
consultation and/or 
bronchoscopy if clinically 
indicated

Serial imaging
Grade 2
First episode:

Interrupt study treatment

Consider pulmonary 
consultation with
bronchoscopy and 
bronchoalveolar lavage 
(BAL) 

Administer 1-2 mg/kg/day IV 
methylprednisolone 

Discuss with 
Sponsor/Medical Monitor
Second episode:

Permanently discontinue 
study treatment

When symptoms improve to ≤ Grade 1, taper 
steroids over at least 1 month. Permanently 
discontinue study treatment if unable to 
reduce corticosteroid dose to ≤10 mg 
prednisone or equivalent daily.  

Rechallenge with study treatment at the 
same dose(s) may be considered if a first 
event improves to Grade 1 or resolves within 
12 weeks of onset. Repeat chest imaging 
monthly as clinically indicated.  
Grade 3 and 4

Permanently discontinue study 
treatment

Bronchoscopy with biopsy and 
BAL is recommended

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.  

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.  

Add anti-infective prophylaxis as appropriate.


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7.2.2.8.
Management of Hematologic Events
Dose modification guidelines for hematologic events are provided in Table 15.
Table 15
Guidelines for Dose Modification and Management of Hematologic 
Events
Severity
Management
Follow-up
Grade 1-2

As clinically indicated

Provide close follow-up to evaluate for increased 
severity
Grade 3

Consider interruption of study 
treatment

Discuss with Medical Monitor

Obtain flow cytometry study of 
T and B lymphocytes

Consult hematology

Further management as 
clinically indicated

As clinically indicated
Grade 4

Consider discontinuation of
study treatment for any 
severe or life-threatening
event 

Consult hematology

Obtain flow cytometry study of 
T and B lymphocytes.

Discuss with Sponsor/Medical 
Monitor

As clinically indicated
7.2.2.9.
Uveitis/Iritis
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. Dose modification guidelines for uveitis/iritis are provided in 
Table 16.


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Table 16
Guidelines for Dose Modification and Management of Uveitis/Iritisa
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 treatment

Consultation with ophthalmologist is 
strongly recommended

Treat with topical steroids such as 
1% prednisolone acetate 
suspension and iridocyclitics

Discuss with Sponsor/Medical 
Monitor
Symptoms resolve to baseline within 7 days: 

resume study treatment
Symptoms ongoing > 7 days:

Discontinue study treatments

If symptoms continue or worsen to Grade 3-4, 
follow algorithm for Grade 3-4 events
Grade 3

Interrupt study treatment

Administer 1-2 mg/kg/day IV 
methylprednisolone (local 
administration of 
corticosteroids may be 
considered after consultation 
with an ophthalmologist)

Consultation with 
ophthalmologist 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 1 month
Symptoms ongoing ≥12 weeks

permanently discontinue study treatments
Grade 4

Permanently discontinue study 
treatment

Immediately inform 
Sponsor/Medical Monitor

Management as per Grade 3
a.
If multiple study treatments are administered per protocol, guidance may apply to 1 or more study agents; 
discuss management on a case-by-case basis with the Sponsor/Medical Monitor.  
7.2.2.10.
Management of Left Ventricular Dysfunction
Echocardiography (ECHO) or MUGA must be performed at Screening, and if clinically 
indicated as outlined in the SoA (Section 2).
Participants with Grade 3 or Grade 4 (symptomatic) left ventricular (LV) systolic 
dysfunction that includes left ventricular ejection fraction (LVEF) decrease of >10% 
from baseline should interrupt study treatment and have repeat echocardiogram 
performed. LVEF should be monitored every 4 weeks for a total of 16 weeks or until 
resolution. If recovery occurs (LVEF >institutional lower limit of normal [LLN] and 
symptom resolution) within 4 weeks, study treatment may be restarted at a reduce dose in 
consultation with the Sponsor.


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Participants with symptoms of LV systolic dysfunction without an accompanying 
decrease in LVEF by echocardiogram should have a full evaluation performed as 
appropriate (e.g., cardiology consult, additional workup for swelling/shortness of breath) 
and symptoms should resolve to <Grade 2 prior to discussion of restarting study 
treatment at the same or reduced dose with the Sponsor.
Copies of all ECHO and cardiology consultations performed on participants who 
experience a >10% decrease in LVEF from baseline and whose cardiac ejection fraction 
is <institution’s LLN will be required by the Sponsor for review. Instructions for 
submitting qualifying ECHOs are provided in the SRM.
7.2.2.11.
Management of Valvular Toxicity
Participants with a Grade 3 or Grade 4 (symptomatic, severe regurgitation/stenosis by 
imaging with symptoms controlled by medical intervention) valvular toxicity must 
interrupt study treatment. Valvular toxicity should continue to be monitored every 4 
weeks for 16 weeks or until resolution.  If recovery occurs (return to baseline via imaging 
AND symptom resolution) within 4 weeks, the participant may restart study treatment at 
a reduced dose in consultation with and after approval of the Sponsor.
Copies of all ECHO and cardiology consultations performed on participants who 
experience valvular toxicity will be required by the Sponsor for review.  Instructions for 
submitting qualifying ECHOs are provided in the SRM.
7.3.
Method of Treatment Assignment
All screened participants will be identified by a unique participant number that will 
remain consistent for the duration of the study.  Upon completion of all the required 
screening assessments, eligible participants will be registered into the study by the 
investigator or authorized site staff. See SRM for additional information on screening and 
enrollment procedures.
7.4.
Blinding
This is an open label study; there is no blinding.
7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants 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.


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
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 the 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/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.
7.6.
Treatment Compliance
GSK1795091 in combination with either GSK3174998, GSK3359609, or pembrolizumab
will be intravenously administered to participants at the site.  When participants are dosed 
at the site, they will receive study treatment directly from the investigator or designee, 
under medical supervision. Administration will be documented in the source documents 
and reported in the CRF.
7.7.
Concomitant Therapy
Participants 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 antibiotic and probiotic use 
within 60 days prior to first dose, 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.  
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.  
If future changes are made to the 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.  
7.8.
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 participant’s medical condition.


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7.9.
Dose Delay
GSK1795091 in combination with either GSK3174998, GSK3359609, or pembrolizumab 
may be interrupted for treatment-related AEs or other reasons such as medical / surgical 
events or logistical reasons not related to study therapy.
During the first 12 weeks (Part 1) of study participation (GSK1795091 Q1W dosing), if 
there is a dose delay between 1 and 3 days, the procedures at the original scheduled visit 
(including dosing) should be performed as soon as possible.  If the delay is >3 days, the 
visit and dose(s) will be considered missed and the procedures at the next scheduled visit 
should be performed.  After Week 12 (Part 1) of study participation (Q3W dosing), 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 >7 days, the 
visit and dose(s) will be considered missed and the procedures at the next scheduled visit 
should be performed.
If a biopsy sample collection is missed, it may be collected at the next possible visit.  
Participants with infusion delays equivalent to 2 consecutive missed doses should 
discontinue study treatment(s) unless the treating investigator and Sponsor agree there is 
strong evidence supporting continued treatment. Administration of GSK1795091 the day 
following the treatment mAb infusion is not considered a dose delay.
8.
DISCONTINUATION CRITERIA
Participants will receive study treatment for the scheduled time period, unless 1 of the 
following occurs earlier: disease progression (as determined by immune-related RECIST 
[irRECIST]), death, unacceptable toxicity or stopping criteria are met, including meeting 
criteria for liver chemistry defined in Section 8.1.1.
8.1.
Discontinuation of Study Treatment
In addition to the above, study treatment might be permanently discontinued for any of 
the following reasons:

Deviation(s) from the protocol

Withdrawal of consent by participant or proxy

Discretion of the investigator 

Participant loss to follow-up by the investigative site

Closure or termination of the study 

Criteria described in Section 7.9 (Dose Delay)

Female participant who becomes pregnant while on study treatment

Criteria for discontinuation of study treatment(s) as described in Section 7.2
(Dose Modification Guidelines) have been met

Criteria described in Section 8.1.2 (QTcF) Stopping Criteria) have been met


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
Criteria described in Section 8.1.3 (Stopping Rules for Clinical Deterioration) 
have been met
Note: Participants who require permanent discontinuation of one of the study treatments 
due to toxicity in a given treatment combination must permanently discontinue both 
treatments in that combination and the reason for discontinuation must be recorded.. The 
TDV must be conducted within 30 days of the last dose of study treatment(s).
The primary reason for discontinuation must be documented in the participant’s medical 
records and eCRF. If the participant voluntarily discontinues from treatment due to 
toxicity, ‘AE’ will be recorded as the primary reason for permanent discontinuation on 
the eCRF. 
Once a participant has permanently discontinued from study treatment(s), the participant 
will not be allowed to be retreated. 
The assessments required at the TDV must be completed within 30 days of the last dose 
of study treatment(s).
Participants who permanently discontinue from study treatment(s) will no longer be 
followed for for PFS FU. One Survival FU visit will be performed 12wks after the last 
dose of study treatment or prior to the start of the next anti-cancer therapy, whichever 
occurs first.  If a new anti-cancer therapy is started before the TDV, the OS visit is not 
required.  The study will conclude when the last subject has completed/discontinued 
study treatment, completed the Treatment Discontinuation Visit (TDV) assessments, and 
the OS FU visit is completed (as applicable).
All participants 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 
SoA (Section 2).
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when a participant 
meets the conditions outlined in Figure 9.


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Figure 9
Liver Chemistry Stopping Criteria
Refer to Appendix 7 for required Liver Safety Actions and Follow up Assessments.
8.1.1.1.
Study Treatment Restart or Rechallenge
In Canada, if liver chemistry stopping criteria are met, participants will not be allowed to
restart study drugs or be rechallenged.
If a participant meets liver chemistry stopping criteria do not restart/rechallenge the 
participant 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 participant
Refer to Appendix 7 for full guidance.
8.1.2.
QTcF Stopping Criteria

The QTcF correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the participant 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 minutes) recording period (i.e., single QTcF is 


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used when a single ECG is performed, and averaged QTcF is used when triplicate 
ECGs are performed).

Withdrawal of subjects is to be based on an average QTcF value of triplicate 
ECGs. If a single ECG demonstrates a prolonged QTcF interval, then obtain 2 
more ECGs over a brief period of time (e.g., 5-10 minutes) and then use the 
averaged QTcF values of the 3 ECGs to determine whether the subject should be
discontinued from the study.
If a participant meets either of the following criteria, they must be discontinued from 
study treatment.  

QTcF >500 msec
OR

Change from baseline of QTcF >60 msec
For participants with underlying bundle branch block, proceed with the following 
discontinuation criteria:
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
See the SoA (Section 2) for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that need to be completed.
8.1.3.
Stopping Rules for Clinical Deterioration
As indicated in Section 9.1, in order to adequately assess the antitumor effect of 
immunotherapeutic agents, participants experiencing apparent progression as defined by 
RECIST version 1.1 guidelines may continue to receive treatment until progression is 
confirmed at the next imaging assessment at least 4 weeks later as indicated by irRECIST 
guidelines. These considerations should be balanced by clinical judgment as to whether 
the participant is clinically deteriorating and unlikely to receive benefit from continued 
study treatment. 
In cases where deterioration was assessed in the investigator’s opinion to have occurred 
after a clinical event and is attributable to disease progression, is unlikely to reverse with 
continued study treatment or managed by supportive care (e.g., bisphosphonates and/or 
bone directed radiotherapy, thoracentesis, or paracentesis for accumulating effusions), 
study treatment should be discontinued. 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

Skeletal related events defined by the following:


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
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 participant even in the absence of any such documented clinical 
event.
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA (Section 2) for data to be collected at the time of study 
discontinuation and follow-up  for any further evaluations that need to be 
completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 


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9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA 
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA (Section 2).
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, pharmacodynamics/biomarker, or other assessments (not applicable for 
participants in Canada).  

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 550 mL of blood for the purposes of this study, will be collected over the 
first 12 weeks of the study. The total volume will depend on how long the participant
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 SoA (Section 2), 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 SoA (Section 2).


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9.1.
Efficacy Assessments

Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] as outlined below and in Appendix 9
of this protocol.

Disease assessment modalities may include imaging (e.g., computed tomography 
[CT] scan, magnetic resonance imaging [MRI], bone scan, plain radiography) and 
physical examination (as indicated for palpable/superficial lesions). Scans will be 
collected centrally during the study and may be reviewed or analyzed by an 
independent central reviewer. Details will be provided in the SRM.

The baseline disease assessment will be completed up to 28 days prior to the first 
dose of study treatment.  See the Schedule of Activities Tables (Section 2) for the 
schedule of assessments of anti-cancer activity subsequent to the baseline disease 
assessment. 

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 6 weeks or more prior to 
the participant’s withdrawal from study treatment and PD has not been documented, 
a disease assessment should be obtained at the time of withdrawal from study
treatment.

To ensure comparability between the baseline and subsequent assessments, the same 
method of assessment and the same technique will be used when assessing response.
9.1.1.
Evaluation of Anti-Cancer Activity

RECIST version 1.1 guidelines will be used to determine the overall tumor burden at 
baseline, select target and non-target lesions, and in the disease assessments 
throughout the duration of the study [Eisenhauer, 2009] as further outlined in 
Appendix 9 of this protocol. irRECIST assessments will be evaluated as well. 
Treatment decisions according to irRECIST are encouraged, including confirmatory 
disease assessments at least 4 weeks after the date disease progression was declared.
Similarly, new lesions should be measured, as feasible, and may be incorporated into 
assessments of tumor burden according to irRECIST guidelines.  

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 and 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 


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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 CT or MRI can be considered measurable.   
Bone scans, fluorodeoxyglucose (FDG)-positron-emission tomography (PET) scans 
or X-rays are not considered adequate imaging techniques to measure bone lesions.

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 (up to 28 days before first dose, see 
Section 2): CT scan with contrast of the chest, abdomen, and pelvis is required. For 
participants with SCCHN, a scan of the head and neck area is required. Other areas 
should be evaluated as indicated by the participant’s underlying disease prior to 
screening, including clinical disease assessment for palpable/visible lesions. 
Although CT scan is preferred, MRI may be used as an alternative method of 
baseline disease assessment, especially for those participants 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. At each post baseline assessment, evaluations of the sites of disease 
identified by these scans are required.  Refer to RECIST version 1.1 guidelines for 
use of FDG-PET/CT [Eisenhauer, 2009].  
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue GSK1795091 and combination partners (see 
Section 8). 


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9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study treatment until the follow-up
visit at the time points specified in the SoA (Section 2).  (However, any SAEs 
assessed as related to study participation [e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy] or related to a GSK 
product will be recorded from the time a participant consents to participate in the 
study).

All AEs will be collected from the start of treatment until the follow-up visit at
the time points specified in the SoA (Section 2).  

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF not the AE section.

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 participant consents to participate 
in the study up to 90 days after the last dose of study treatment(s) or until the start 
of another anti-cancer therapy, whichever is first. SAEs must be reported within 
24 hours to the Sponsor either by electronic media or paper.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant 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?”


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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, [and non-serious AESIs (as defined in 
Section 9.2.8)], will be followed until the event is resolved, stabilized, otherwise
explained, or the participant is lost to follow-up (as defined in Section 8.3). Further 
information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRB/IEC, and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the IB and will notify the IRB/IEC, 
if appropriate according to local requirements.
9.2.5.
Cardiovascular and Death Events
For any CV events detailed in Appendix 4 and all deaths, whether or not they are 
considered SAEs, specific CV and Death sections of the CRF will be required to be 
completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death. 
The CV CRFs 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 CRF within 1 week of receipt of a CV Event 
data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported.


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9.2.5.1.
Cardiovascular and Death Events
A CV event 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
9.2.6.
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 
a 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 participant, 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 a SAE.
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as a SAE (instead of a disease-related event):

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with study treatment(s).
9.2.7.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until 120 days after the last dose of study medication.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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9.2.8.
Guidelines for Events of Special Interest
The severity of AEs will be graded utilizing the NCI-CTCAE, version 4.0. Guidelines for 
dose modifications and interruptions for management of common toxicities associated 
with the study treatment(s) are provided in Section 7.  
9.3.
Treatment of Overdose
For this study, any dose of GSK1795091 or combination partners greater than 50% of the 
intended dose within a 24-hour time period will be considered an overdose.
There is no specific antidote for overdose with GSK1795091, GSK3174998, 
GSK3359609, or pembrolizumab.  In the event of a suspected overdose, it is 
recommended that the appropriate supportive clinical care should be instituted, as 
dictated by the participant’s clinical status. 
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities for 
at least 130 days.
3.
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).
4.
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 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are listed in the SoA (Section 2).
9.4.1.
Physical Examinations

A complete physical examination will be done at screening and TDV and will 
include assessments of the CV, Respiratory, Gastrointestinal and Neurological
systems. Height and weight will also be measured and recorded.

A brief physical examination will be done at all other timepoints and will include 
assessments of the skin, lungs, CV system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

For melanoma participants, a full body dermatological examination will be 
performed by a dermatologist (or suitably qualified physician) to identify 


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abnormal skin lesions within the 28-day screening period.  All findings will be 
photographed and identified during screening.  Brief skin examinations will be 
performed as indicated in the SoA (Section 2) 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 by the ECOG PS.  

The PS will be assessed using the ECOG scale (Appendix 12) as specified in the 
SoA (Section 2).
9.4.2.
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 participant.  On days where vital signs are measured multiple times, 
temperature does not need to be repeated unless clinically indicated.  

If a participant develops a fever, refer to Section 7.2.1.1 for fever management 
guidelines.
9.4.3.
Electrocardiograms
Twelve-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 8.1.2 for QTcF stopping criteria and 
additional QTcF readings that may be necessary.  
Before each ECG test, the participant should be at rest for approximately 10 minutes. The 
participant should be in the semi-recumbent or supine position; the same position must be 
used for all subsequent ECG tests.
For Part 1 of the study, ECG measurements will be performed in triplicate at specified 
times (see SoA [Section 2] including footnotes). All other measurements may be 
performed as single ECG measurements.
At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes apart. 
The full set of triplicates should be completed in less than 4 minutes.
ECGs will be collected centrally during the study and may be reviewed or analyzed. 
Details will be provided in the SRM.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of local clinical laboratory tests to be performed 
and to the SoA for all protocol-required laboratory assessments, including timing 
and frequency. 


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
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment must be repeated until the values return to normal or baseline or are no 
longer considered significantly abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology must be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the participant 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 participant 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

Pregnancy Test

Urinalysis, calculated creatinine clearance (CrCl)

Thyroid Function Tests

Lipid Panel

The results of applicable tests must be entered into the eCRF as required.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Appendix 2.


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9.5.
Pharmacokinetics
With the implementation of Amendments 05 and 06, PK will no longer be collected.
However, event-driven collections (e.g. in response to hypersensitivity including infusion 
reactions) will be performed per Table 2 (footnote h and i) and Section 10.3.2.3.
9.5.1.
Blood Sample Collection
Blood samples for PK analysis of GSK1795091, GSK3174998, GSK3359609, and 
pembrolizumab will be collected at the time points described in the SoA (Section 2). 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.  Any change to the number and timing of 
PK samples is not applicable for participants enrolled in Canada.  Details on PK blood 
sample collection, processing, storage, and shipping procedures are provided in the SRM.  
Processing, storage and shipping procedures are provided in the SRM.
9.5.2.
Blood Sample Analysis
Concentrations of GSK1795091, GSK3174998, GSK3359609, and pembrolizumab will 
be determined in blood samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site.  Once the sample has been analyzed 
for study drugs any remaining sample may be analyzed for other compound-related 
metabolites and the results reported under a separate PTS-DMPK/Scinovo or GSK 
protocol.  
9.6.
Pharmacodynamics
See Section 9.8 below.  
9.7.
Genetics
Information regarding genetic research is included in Appendix 6
An important exploratory objective of the clinical study is genetic research.  Participation 
in genetic research is optional, but all participants who are eligible for the clinical study 
will be given the opportunity to participate.  Participants may decline participation 
without effect on their medical care or care during the clinical study.  A separate consent 
signature is required for genetic research
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
Details on processes for collection and shipment and destruction of these samples can be 
found in the SRM.


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9.8.
Biomarkers/Pharmacodynamic Markers
With the implementation of Amendments 05 and 06, samples for biomarkers will no 
longer be collected.
9.8.1.
Blood Biomarkers
Blood samples will be collected and analyzed by flow cytometry to evaluate the
pharmacodynamic effects of all treatments on various immune cell populations.  In 
addition, the binding of GSK3174998 to the OX40 receptor and GSK3359609 to the 
ICOS receptor may be measured in blood by flow cytometry analysis as described in 
Table 2.
Blood samples will also be collected for the isolation of PBMCs, plasma and serum. 
Plasma and serum samples may be used for an analysis of circulating soluble factors and 
soluble OX40, soluble ICOS, soluble OX40-drug complex, and soluble ICOS-drug 
complex depending on the availability of the assays. Plasma samples may also be 
analyzed for cell-free DNA (cfDNA), or exosomes or for novel biomarkers of immune 
activation or response to treatment.  Additional factors to be analyzed from plasma and 
serum may include but are not limited to several cytokines, as well as antibodies against 
tumor, self, or viral antigens.  
Based on the availability of sample, PBMCs will be isolated from whole blood. Isolated 
PBMCs will be preserved and stored for other relevant experiments, which may include 
but are not limited to flow cytometry of additional immune cell types, subsequent 
functional analysis or assessment of the diversity of the T-cell repertoire by DNA 
sequencing, its relationship to clinical responses, and changes in response to treatment 
with GSK1795091 when administered in combination with either GSK3174998, 
GSK3359609, or pembrolizumab.  The functional state of PBMCs may be analyzed for 
expression of cytokines.  PBMCs may also be evaluated for genomic (DNA), gene 
signature analysis and gene expression (RNA) alterations to determine treatment-related 
changes in immune-related signatures.  
Other biomarkers may be evaluated as determined by additional research and data. If 
predictive biomarkers are identified in samples, they may be used for the development of 
a diagnostic test. Details for sample collection, processing, storage, and shipment will be 
provided in the SRM.
9.8.2.
Tumor Tissue
Based on the availability of sample, tumor biopsies and/or archival tissue will be 
evaluated by IHC or related technologies for expression of phenotypic and functional 
immune cell markers on tumor infiltrating lymphocytes and other immune cells as well as 
immune signaling markers (on both the surface and internal) of tumor cells, to understand 
antitumor immune responses. In addition, when possible, similar analyses will be 
performed on tumor tissue samples obtained upon progression. Additionally, tumor tissue 
DNA may be sequenced to assess mutational burden and/or TCR diversity, and RNA 
expression analysis may be performed by RNAseq or related technologies.  Further 


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research may also evaluate changes in any DNA/RNA/protein correlating in response to 
treatment with GSK1795091 when administered in combination with either
GSK3174998, GSK3359609, or pembrolizumab.  
Other biomarkers may be evaluated as determined by additional research and data. If 
predictive biomarkers are identified in samples, they may be used for the development of 
a diagnostic test.  Details for sample collection, processing, storage, and shipment will be 
provided in the SRM.
9.8.3.
Stool Collection for Microbiome Analysis
Stool specimens offer accessible means of evaluating the gut microbial community.  
Association of the stool microbiome composition with physiological and medical 
conditions and response to treatments has been reported in patients with various diseases, 
including cancer. Stool samples may be evaluated for changes in the gut microbial 
community as a response to treatment, and may also assess the relationship between 
antibiotic/probiotic use prior to treatment and antitumor response.
Details for sample collection, processing, storage, and shipment will be provided in the 
SRM.
9.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.10.
Qualitative Telephone Interview
To further evaluate disease and treatment related symptoms and associated impacts on 
function and health-related quality of life, participants will have the option to participate 
in a qualitative interview via telephone.  The interview will be conducted by a trained 
interviewer in the participant’s native language and will be audio recorded for 
transcription and analysis.
The telephone interview is to be completed within 21 days following completion of Day 
64 and following the TDV.  Participants who have the TDV within 30 days of the Day 64 
interview are not required to repeat the interview.
Additional details on the optional qualitative telephone interview can be found in the 
SRM.


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10.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
Part 1: Dose Escalation
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested.  The dose escalation part of the study will be focused on the
determination of the recommended dose for dose expansion and further exploration, the 
safety profile, and antitumor activity of the combination of GSK1795091 with 
GSK3174998, GSK3359609, or pembrolizumab.
Part 2: Cohort Expansion
With the implementation of amendment 06, the study is closed to enrolment and Part 2 
will not be opened.
10.1.
Sample Size Determination
The planned sample size for the study was chosen to allow adequate characterization
of safety, clinical activity, PK, and PD profile based on the study objectives.  For dose 
escalation, the total sample size depends on the number needed to adequately characterize 
the DLT profile and determine the recomendend Part 2 dose.
With the implementation of amendment 06, the study is closed to enrolment and Part 2 
will not be opened.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Enrolled 
All participants who sign the ICF to participate in the clinical trial.
All Treated
All participants who receive at least 1 dose of GSK1795091, GSK3174998, 
GSK3359609, or pembrolizumab.
Pharmacokinetic
All participants from the All Treated population for whom a PK sample is obtained,
analysed, measureable, and valid.  
Pharmacodynamic
All participants from the All Treated population for whom a 
pharmacodynamic/biomarker sample is obtained, analysed, and measureable.


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10.3.
Statistical Analyses
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.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given participant will depend on efficacy and 
tolerability, the duration of follow-up will vary between participants. Consequently, there 
will be no imputation for missing data. 
Demographic and baseline characteristics will be summarized.
10.3.1.
Primary Analyses
10.3.1.1.
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.
10.3.1.2.
Extent of Exposure
The number of participants administered study treatment will be summarized according 
to the duration of therapy.


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10.3.1.3.
Adverse Events
Adverse events will be coded using the standard MedDRA and grouped by system organ 
class.  Adverse events will be graded by the investigator according to the NCI-CTCAE 
(version 4.0).  
Events will be summarized by frequency and proportion of total participants, 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.  Adverse 
events, 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 7.2.2.1 and Appendix 12 will be summarized separately.  
The incidence of deaths and the primary cause of death will be summarized.
10.3.1.4.
Clinical Laboratory Evaluations
Change of hematology and clinical chemistry will be descriptively summarized by 
cohort. These summaries will include sample size, mean, median, standard deviation, 
minimum, and maximum.
The toxicity grades and the worst-case toxicity grade of 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.  
10.3.1.5.
Other Safety Measures
Vital signs (body temperature and pulse rate) and ECGs (QT and QTcF) measurements 
change from baseline will be descriptively summarized by cohort. These summaries will 
include sample size, mean, median, standard deviation, minimum, and maximum.
Vital signs and ECGs will also be tabulated according to the categories specified below. 
The summaries will include frequencies and corresponding percentages. Further details 
will be provided in the RAP.  
Vital Signs:
-
Increased body temperature to: ≤38.0, 38.1-38.5, 38.6-39.0, ≥39.1 oC
-
Change in body temperature from baseline by: ≤1.0, 1.1-1.5, 1.6-2.0, ≥2.1 oC
-
Increased pulse rate to: ≤100, 101-115, 116-130, ≥131 bpm
-
Change in pulse rate from baseline by: ≤20, 21-35, 36-50, ≥51 bpm
-
Decreased pulse rate to: <45 bpm
-
Increased systolic blood pressure to: ≤140, 141-160, 161-180, ≥181 mmHg
-
Decreased systolic blood pressure to: <80 mmHg
-
Increased diastolic blood pressure to: ≤90, 91-100, 101-110, ≥111 mmHg
-
Decreased diastolic blood pressure to: <50 mmHg


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ECGs:
-
PR interval: >200 msec
-
QRS interval: >120 msec
-
QT interval: ≤450, 451-480, 481-500, ≥501 msec
-
QTcF interval: ≤450, 451-480, 481-500, ≥501 msec
-
Change in QT from baseline by: ≤30, 31-60, ≥61 msec
-
Change in QTcF from baseline by: ≤30, 31-60, ≥61 msec
10.3.2.
Secondary Analyses
10.3.2.1.
Anticancer Activity Analyses
The All Treated Population will be used for anticancer activity analyses. Anticancer 
activity will be evaluated based on clinical evidence and response criteria as assessed by 
RECIST v1.1 and specified in Appendix 9.  Immune related response criteria (irRECIST) 
will be evaluated as an exploratory endpoint.  If data warrant, the response data will be 
summarized by cohort.  
If the data warrant, PFS, time to response, duration of response and overall survival will 
be calculated and listed for each participant, and be summarized by cohort.  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.  
Time to response is defined as the time from the date of first dose to the date of the first 
documented evidence of response (PR or CR). 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 participants who achieve an overall response (i.e., unconfirmed or 
confirmed CR or PR). If the participant 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. Overall survival is defined as time from the date of first dose 
to the date of death due to any cause. For participants who do not die, time of death will 
be censored at the date of last contact.
Objective response rate (ORR) and disease control rate (DCR) will be summarized by 
cohort. ORR is defined as percentage of participants with complete response or partial 
response. DCR is defined as percentage of participants with complete response or partial 
response or at least 12 weeks of stable disease. If data warrant, the corresponding 95% CI 
for ORR and DCR will also be provided. Participants with unknown or missing responses 
will be treated as non-responders, i.e., these participants will be included in the 
denominator when calculating percentages of response.
10.3.2.2.
Pharmacokinetic Analyses
10.3.2.2.1. Pharmacokinetic Parameters
Pharmacokinetic analysis of study treatments will be the responsibility of the Clinical 
Pharmacology Modeling and Simulation (CPMS) Department.


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Pharmacokinetic analysis of GSK1795091 drug concentration-time data will be 
conducted by non-compartmental methods under the direction of CPMS, Quantitative 
Sciences, GSK.  PK parameters including but not limited the following will be 
determined if data permit:

Maximum observed concentrations (Cmax)

Trough plasma concentrations(Ctrough)

AUC(0-τ) (repeat dosing)
10.3.2.2.2. Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics and Programming.
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by cohort. PK parameter data will be listed for 
each participant and summarized by descriptive statistics by cohort. 
If data warrants, the data from this study may be combined with the data from other 
studies for a population PK analysis, which will be reported separately. A nonlinear 
mixed effects model will be used to determine population pharmacokinetic parameters 
and identify relevant covariates (e.g., age, weight, or disease related covariates).
10.3.2.3.
Immunogenicity Analyses
Serum samples to assess the presence of anti-drug antibodies (ADA) will be collected as 
described in the SoA (Section 2). All samples will be assessed for anti-GSK3174998 and
anti-GSK3359609 antibodies using validated immunoassays. Analysis for the presence 
of anti-pembrolizumab antibodies will be performed contingent on availability of a 
validated assay, and if considered clinically relevant.  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 (any change to the number and timing of immunogenicity samples is not 
applicable for participants enrolled in Canada). In the event of a hypersensitivity reaction 
that is either 1) clinically-significant in the opinion of the investigator, or 2) leads to the 
participant withdrawing from study treatment, blood samples should be taken from the 
participant for immunogenicity testing at the time of the event and again 30 days, 12 
weeks, and 24 weeks after. For participants who 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 ADA using a tiered testing schema: screening, 
confirmation and titration steps. The presence of treatment emergent ADA will be 
determined using a drug-specific bridging style ADA assay with a bio-analytically 
determined cut-point determined during assay validation. Samples taken after dosing 


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with treatment mAb combination partners 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. A neutralizing ADA assay may be developed for 
characterization of selected, stored samples. Results of ADA testing will be reported at 
the end of the study and will include incidence and titer.
10.3.3.
Other Analyses
10.3.3.1.
Translational Research Analyses
The results of translational research investigations may be reported in the main clinical 
study report (CSR) or in a separate 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. 
10.3.3.1.1. PK/Pharmacodynamic/ Analyses
Observed or predicted concentrations or summary exposure measure (e.g., Cmax, Ctrough, 
and AUC) may be combined with safety, efficacy, or pharmacodynamic measures of 
interest to examine potential exposure-response relationships.  Descriptive and graphical 
evaluation will first be performed. 
Where evidence of relationship is seen, statistical models may be fitted to further explore 
PK/Pharmacodynamic relationship. Further model details will be provided in the RAP.
10.3.3.1.2. Biomarker(s) Analyses
The results of biomarker investigations, which may include but is not limited to immune 
cell phenotypes in blood and tumor, abundance of soluble factors such as cytokines and 
stress-related proteins, DNA sequence alterations, gene expression (RNA) in immune 
cells and tumor, tumor mutational burden, and microbiome analysis may be reported 
separately from the main CSR.  All analyses will be descriptively and/or graphically 
summarized as appropriate to the data.  
Performance of these investigations may be conditional on the results of the clinical trial 
principally, but not exclusively, on the primary measures of the clinical trial outcome and 
samples may be selected for analysis on the basis of the clinical outcome.
OR
These investigations may be performed irrespective of whether a response to
GSK1795091 when administered in combination with either GSK3174998, 
GSK3359609, or pembrolizumab is observed.
Additionally, comparative examination of post-dosing profiles in conjunction with pre-
dosing profiles may yield known and novel candidate biomarkers/profiles and new 
insights which relate to the action of GSK1795091 when administered in combination 
with either GSK3174998, GSK3359609, or pembrolizumab.


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All samples may be retained for the length of time described in participant informed 
consent forms after the last participant completes the trial.
Where evidence of association between anticancer activity or immunologic effects and 
biomarkers is seen, additional exploratory analyses may be performed to further 
characterize the biomarker(s). Full details will be addressed in the RAP.
10.3.3.2.
Pharmacogenetic Analyses
Further details on PGx analyses will be addressed in Appendix 6 and the PGx RAP.  
10.3.3.3.
Qualitative Telephone Interviews
The results of these qualitative telephone interviews will be descriptively summarized 
and may be reported separately from the main CSR.  
10.3.4.
Interim Analyses
No formal interim analysis is planned for this study.
10.4.
N-CRM Analysis for Dose Escalation
10.4.1.
Implementation of N-CRM
The N-CRM model implementation will be performed using the FACTS (Version 4.0 or 
higher).
10.4.2.
Bayesian Prior for the Logistic Model
The N-CRM methodology requires that a Bayesian prior distribution for the dose-toxicity 
curve be pre-specified.  The Bayesian prior used for this design was determined using the 
quantile method.  For each dose, the most likely (median) presumed probability of DLT 
was specified, along with a 95% credible interval – an interval within which the team is 
95% a priori certain the probability of a DLT lies.  The 95% credible intervals are 
intentionally wide due to limited information about the toxicity profile of GSK1795091
in humans and to allow the accumulating data to have more influence on dose 
recommendations than the prior.  
The Bayesian prior (, ln()) is assumed to follow bivariate normal distribution. The 
Bayesian prior means (standard deviations) for dosing scheme shown in Table 17 are 
determined to be: E[]=-1.889 (1.0079), E[ln()]=0.1807 (0.6682), with correlation 
between and ln() as ρ=-0.3644, and use 100 ng as the reference dose. 
Table 17 and Figure 10 shows the median prior probability of experiencing a DLT at the 
given dose along with a 95% credible interval around the median:


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Table 17
Table of Specified Prior Probability of DLT (with 95% Credible 
Interval)
Anticipated Dose for 
GSK1795091 (ng)
Median Probability 
of Toxicity
2.5% Quantile for 
Probability of Toxicity
97.5% Quantile for 
Probability of Toxicity
50
0.075
0.005
0.4
100
0.15
0.01
0.5
150
0.225
0.02
0.65
200
0.30
0.04
0.75
250
0.375
0.05
0.85
Figure 10
Graphical Display of the Prior Distribution for the Probability of DLT 
Given Dose (Median with 95% Credible Interval)
Note: x-axis is natural log (dose/reference dose).


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADA
Antidrug antibody
AE
Adverse event(s)
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC(0-)
Area under the concentration-time curve over the dosing 
interval
BAL
Bronchoalveolar lavage
cfDNA
Cell-free DNA
CI
Confidence interval
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CrCl
Calculated creatinine clearance
Cmax
Maximum observed concentration
CNS
Central nervous system
CPMS
Clinical Pharmacology Modeling and Simulation
CR
Complete response
CRP
C-reactive protein
CSR
Clinical Study Report
CT
Computed tomography
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CV
Cardiovascular
DILI
Drug-induced liver injury
dL
Deciliter
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram(s)
ECOG
Eastern Cooperative Oncology Group
EOI
End of infusion
eCRF
Electronic case report form
FACTS
Fixed and Adaptive Clinical Trial Simulator
Fc
Fragment crystallizable region
FcR
Fragment crystallizable region receptor
FDG-PET
Fluorodeoxyglucose-positron-emission tomography
FSH
Follicle stimulating hormone
FTIH
First time in human
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomular filtration rate
GGT
Gamma-glutamyltransferase
GSK
GlaxoSmithKline


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h
Hour(s)
HPV
Human papillomavirus
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
IFN
Interferon
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL-10
Interleukin 10
INR
International normalized ratio
irAE
Immune-related adverse event(s)
IRB
Institutional Review Board(s)
irRECIST
Immune-related RECIST
IV
Intravenous
kg
Kilogram(s)
L
Liter
LPS
lipopolysaccharide
g
Microgram
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
min
Minute(s)
mL
Milliliter(s)
mmHg
Millimeters of mercury
MRI
Magnetic resonance imaging
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria 
for Adverse Events
ng
Nanogram
NOAEL
No-observed-adverse-effect-level
nTregs
Natural Tregs
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PAMP
Pathogen-associated molecular pattern
PBMC
Peripheral blood mononuclear cell
PD-1
Programmed death receptor-1
PD
Progressive disease
pg
Picogram
PFS
Progression-free survival
PGx
Pharmacogenetics
PK
Pharmacokinetic(s)
PR
Partial response


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PS
Performance status
Q1W
Every 1 week
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
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SRM
Study Reference Manual
TCR
T-cell receptor
TDV
Treatment discontinuation visit
TLR4
Toll-like receptor 4
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor
TNFR
Tumor necrosis factor receptor
Tregs
Regulatory T-cells
Tr1
Type 1 regulatory
ULN
Upper limit of normal
WOCBP
Women of childbearing potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
FACTS
KEYTRUDA


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 18 will be performed by local laboratories.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 18
Clinical Safety 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
CrCl (Calculated)                     C-reactive protein
Lipid panel
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 WOCBP) 
a.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8 and Section 7.2.2.3 . Laboratory assessments required for follow up after 
a liver event may require submission to the central lab.  Details came be found in the SRM and Central 
Laboratory Manual.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; -hCG = beta-human chorionic gonadotropin; 
BUN = blood urea nitrogen; HBsAg = Hepatitis B surface antigen; MCV = mean corpuscular volume; MCH = mean 
corpuscular hemoglobin; RBC = red blood cells; WBC = white blood cells


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the CSR.  The investigator will be provided 
reasonable access to statistical tables, figures, 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 participants, 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.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or eCRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
CSR/equivalent summary or as locally agreed. No records may be destroyed 
during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written 
notification to the sponsor. 


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Data Management

For this study participant 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 and an 
internal validated medication dictionary, GSKDrug.  

The eCRFs (including queries and audit trails) will be retained by GSK, and 
copies will be made available to the investigator to maintain as the investigator 
copy.  Participant initials will not be collected or transmitted to GSK according to 
GSK policy.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available.

Definition of what constitutes source data can be found in the SRM.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

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 study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to underlying disease).

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 before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug 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 it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
Events NOT Meeting the AE Definition 

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 participant’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 


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participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Definition of SAE
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).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant 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 inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant 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 
outpatient setting. Hospitalization to satisfy protocol-recommended observation of vital 
sign trends should not be considered a SAE if done for logistical purposes alone.
Complications that occur during hospitalization are AE. 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 persistent disability/incapacity

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 trauma (e.g., sprained ankle) which may interfere with or prevent 


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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 SAE 
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 participant or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include 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 International harmonized ratio (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 
participants receiving anticoagulants.  If INR measurement is obtained, the value is 
to be recorded on the SAE form.

Refer to Section 7.2.2.3 for the required liver chemistry follow-up instructions
Definition of Cardiovascular Events
CV Events Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism


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
Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE 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) 
related to the event.

The investigator will then record all relevant AE/SAE information in the eCRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
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
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/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 underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in 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.


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
There may be situations in which 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 before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

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 participant 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.
Reporting of SAE 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, the site will use the paper SAE data collection 
tool as outlined in the SRM. 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 participant 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 


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telephone.

Contacts for SAE reporting can be found in the SRM.


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12.5.
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
Female participant: is eligible to participate if she is not pregnant (as confirmed by a 
negative serum beta-human chorionic gonadotrophin), not lactating, and at least one of 
the following conditions applies:
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormone replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement 
is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.


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Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 19. 
Table 19
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the 
treatment period and for at least 120 days after the last dose of study treatment 
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 participants understand how to properly use these methods of contraception. 
This list does not apply to WOCBP with same sex partners, when this is their preferred 
and usual lifestyle or for participants who are and will continue to be abstinent from 
penile-vaginal intercourse on a long term and persistent basis.


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Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test 

Additional pregnancy testing should be performed at monthly intervals during the 
treatment period and at 120 days after the last dose of study treatment and as 
required locally 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.

Participant 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 for medical reasons 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.
Any female participant who becomes pregnant while participating

Will discontinue study medication or be withdrawn from the study.


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12.6.
Appendix 6: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis.

DNA samples will be used for research related to GSK1795091, GSK3359609, 
GSK3174998, and pembrolizumab in combination with GSK1795091 or advanced 
solid tumors and related diseases. They may also be used to develop tests/assays 
including diagnostic tests related to GSK1795091, GSK3359609, GSK3174998, and 
pembrolizumab combination treatment or study treatments of this drug class, and 
advanced solid tumors. Genetic research may consist of the analysis of 1 or more 
candidate genes or the analysis of genetic markers throughout the genome or analysis 
of the entire genome as appropriate.

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data.

DNA samples will be analyzed by using appropriate descriptive and/or statistical 
analysis methods. A detailed description of any planned analyses will be documented 
in a RAP prior to initiation of the analysis. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK1795091, GSK3359609, pembrolizumab and 
GSK3174998 or study treatments of this class. The results of genetic analyses may 
be reported in the CSR or in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK1795091, GSK3359609, 
GSK3174998, and pembrolizumab combination treatment or study treatments of this 
class or advanced solid tumors and related diseases continues but no longer than 15 
years after the last participant last visit or other period as per local requirements.
US Food and Drug Administration states that an in vitro companion diagnostic device 
(IVD) could be essential for the safe and effective use of a corresponding therapeutic 
product to:

Identify participants who are most likely to benefit from a particular therapeutic 
product;

Identify participants likely to be at increased risk for serious adverse reactions as 
a result of treatment with a particular therapeutic product;

Monitor response to treatment for the purpose of adjusting treatment (e.g., 
schedule, dose, discontinuation) to achieve improved safety or effectiveness


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
Identify participants in the population for whom the therapeutic product has 
been adequately studied, and found safe and effective, i.e., there is insufficient 
information about the safety and effectiveness of the therapeutic product in any 
other population
Global regulatory requirements for IVD companion diagnostic tests are evolving.  If a 
DNA-based IVD companion diagnostic device might be needed to identify participants 
who are appropriate for the GSK medicinal product(s) under investigation in this 
protocol, then GSK should collect and retain DNA samples from participants who carry 
the genetic variant of interest as well as DNA samples from participants who do not carry 
the genetic variants of interest to validate the performance of the companion diagnostic. 
Therefore, where local regulations and IRB/IEC allow, a sample will be collected for 
DNA analysis. Any IVD companion diagnostic research objectives should be described 
in participant informed consent forms.


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12.7.
Appendix 7: Liver Safety: Required Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
Phase I/II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT - absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately discontinue study treatment 
Report the event to GSK within 24 hours
Complete the liver event CRF and complete 
SAE data collection tool if the event also meets 
the criteria for an SAE2
Perform liver event follow up assessments 
Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline6
(see MONITORING below)
Do not restart/rechallenge participant with 
study treatment unless allowed per protocol and 
GSK Medical Governance approval is granted
(refer to Section 12.7.1) 
If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
Viral hepatitis serology4
Obtain INR and recheck with each liver chemistry 
assessment until the transaminases values show 
downward trend
Only in those with underlying chronic hepatitis B at 
study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody5.
Blood sample for PK analysis, obtained within 28 
days after last dose6.
Serum creatine phosphokinase and lactate 
dehydrogenase.
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 


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MONITORING:
For bilirubin or INR criteria:
Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs
Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline6
A specialist or hepatology consultation is 
recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-72 
hrs 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline6
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications
Record alcohol use on the liver event alcohol 
intake CRF
For bilirubin or INR criteria:
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins)
Serum acetaminophen adduct high-performance
liquid chromatography assay (quantifies potential 
acetaminophen contribution to liver injury in 
participants with definite or likely acetaminophen 
use in the preceding week [James, 2009]). 
NOTE: not required in China
Liver imaging (ultrasound, MRI, or CT) and /or 
liver biopsy to evaluate liver disease; complete 
Liver Imaging and/or Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant 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. 
2.
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 participants receiving anticoagulants
3.
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)
4.
Includes: 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 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior 
to first dose of study treatment


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Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity and who can be monitored 
weekly for 4 weeks
Notify the medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 
Participant can continue study treatment
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 1
If at any time participant meets the liver chemistry 
stopping 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline1.
1.
for the purpose of these guidelines “baseline” refers to laboratory assessments performed closest 
and prior to first dose of study treatment
12.7.1.
Liver Safety Drug Restart or Rechallenge Guidelines
In Canada, if liver chemistry stopping criteria are met, participants will not be allowed to
restart study drugs or be rechallenged.
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
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 participant
If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then participant must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments.
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane re-administered within 1 month of 
initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  


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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)

participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious AE or fatality has earlier been observed with drug rechallenges [Papay, 
2009; Hunt, 2010]
evidence of drug-related preclinical liability (e.g., reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following DILI. Because of the risks 
associated with rechallenge after DILI this should only be considered for a participant 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 favourable.
Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a 
participant who is receiving compelling benefit (partial response or complete 
response) with study treatment that exceeds risk, and no effective alternative therapy 
is available.  
  The ALT at the time of rechallenge is <3xULN.
The participant did not have additional risk factors for a fatal outcome following the 
initial injury including hypersensitivity, jaundice, bilirubin >2xULN (direct bilirubin 
>35% of total), or INR >1.5.

IRB or IEC approval for rechallenge with study treatment must be obtained, as 
required.   

If the rechallenge is approved by GSK Medical Governance in writing, the 
participant 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 participant 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.

Participants 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.


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
If after study treatment rechallenge, participant meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the IRB or IEC as required, must be informed of the 
participant’s outcome following study treatment rechallenge. 

GSK to be notified of any AEs, as per Appendix 4. 
2. 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
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).

Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 8.1.1.1 will apply.

There is no evidence of alcoholic hepatitis.

IRB or IEC approval of study treatment restart must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
participant 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 participant 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.

Participants 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, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.


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
Medical Monitor, and the IRB or IEC as required, must be informed of the 
participant’s outcome following study treatment restart. 

GSK to be notified of any AEs, as per Appendix 4.


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12.8.
Appendix 8: Country-specific requirements: Canada
The following country specific requirements apply to Canada only:
Section # and 
Name
Country Requirement
Section 5.1, 
Overall Design
Participants with confirmed PR or CR will be followed for response 
duration and may be eligible (outside of Canada) for continued 
study treatment at the time of relapse/progression. The decision 
whether a participant 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.
Section 2, 
Schedule of 
Activities and 
Section 9, 
Study 
Assessments 
and 
procedures, 
Section 9.5.1, 
Blood Sample 
Collection and 
Section 
10.3.2.3, 
Immunogenicity
Section 2:

Two bullets below do not apply to those sites in 
Canada.

The timing and number of planned study assessments, 
including safety, laboratory, imaging, tumor biopsy, 
pharmacokinetic (PK), and pharmacodynamic/biomarker 
assessments included in the tables below 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. 

Any changes in the timing or addition of time points for any 
planned study assessments must be documented and 
approved by the relevant study team member and then 
archived in the sponsor and site study files, but will not 
constitute a protocol amendment. The Institutional Review 
Board (IRB)/ Independent Ethics Committees (IEC) will be 
informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the informed 
consent form (ICF).
Section 9:
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, pharmacodynamics/biomarker, or other 
assessments (not applicable for participants in Canada).  
Section 9.5.1:
The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring.  
Any change to the number and timing of PK samples is not 
applicable for participants enrolled in Canada.


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Section # and 
Name
Country Requirement
Section 10.3.2.3:
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 (any change to the number 
and timing of immunogenicity samples is not applicable for 
participants enrolled in Canada).
Section 7.2.2.3, 
Management of 
Hepatotoxicity, 
Section 8.1.1.1, 
Study 
Treatment 
Restart and 
Rechallenge 
and Section 
12.7.1, Liver 
Safety Drug 
Restart or 
Rechallenge 
Guidelines
In Canada, if liver chemistry stopping criteria are met, 
participants will not be allowed to restart study drugs or be 
rechallenged.


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12.9.
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 
version 1.1
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 CRF.
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 [Eisenhauer, 2009].
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 [Eisenhauer, 2009].
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 [Eisenhauer, 2009].


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Guidelines for Evaluation of Disease
Measurable and Non-Measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least 1 dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5mm.  If
the slice thickness is greater than 5mm, 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

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm).  At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009].
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 [Eisenhauer, 2009].
Measurable disease: The presence of at least 1 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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Immune-Related RECIST Response Criteria
Table 20
Evaluation of Target Lesions
New, measurablea lesions 
Incorporated into tumor burden
New, non-measurable lesions 
Do not define progression (but preclude CR)
irCR
Disappearance of all lesions in 2 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 2 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 2 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.
Measurable according to RECIST version 1.1.
b.
Treatment decisions may be based upon the immune-related RECIST guidelines.
Antitumor response based on total measurable tumor burden
For Modified RECIST based on RECIST version 1.1 and irRECIST [Wolchok, 2009;
Nishino, 2013], the initial target (‘index”) and measurable new lesions are taken into 
account. At the baseline tumor assessment, the sum of the diameters in the plane of 
measurement of all target lesions (maximum of 5 lesions in total and a maximum of 2
lesions per organ representative of all involved organs) is calculated.
Note: If pathological lymph nodes are included in the sum of diameters, 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 sum of diameters of the baseline target lesions and of new, 
measurable nodal and non-nodal lesions (10 mm), up to 2 new lesions per organ are 
added together to provide the total tumor burden:
Tumor Burden = Sum of diameterstarget lesions + sum of diametersnew, measurable lesions
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 
assessed relative to baseline measurements (i.e., the sum of diameters of all target lesions 
at screening).  


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Response Criteria
Evaluation of target lesions
Definitions for assessment of response for target lesion(s) are as follows:

CR:  Disappearance of all target lesions.  Any pathological lymph nodes must be 
<10mm in the short axis.

PR:  At least a 30% decrease in the sum of the diameters of target lesions, taking as a 
reference, the baseline sum of the diameters (e.g., percent change from baseline).

SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD.

PD: At least a 20% increase in the sum of the diameters of target lesions, taking as a 
reference, the smallest sum of diameters recorded since the treatment started (e.g., 
percent change from nadir, where nadir is defined as the smallest sum of diameters 
recorded since treatment start). In addition, the sum must have an absolute increase 
from nadir of 5mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by 1 of the 5 preceding definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g., sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions).  When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments.  However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented.  If an assessment of 
PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g., 2 mm). If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured.  The response at the time when the lesion reappears will depend upon 
the status of the other lesions.  For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance.  However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.


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Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response:  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: Unequivocal progression of existing non-target lesions. 

Not Applicable (NA):  No non-target lesions at baseline.

Not Evaluable (NE):  Cannot be classified by 1 of the 4 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 timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g., 
non-target response does not have to be "Not Evaluable"). 
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.
Evaluation of overall response
Table 21 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 participants with measurable disease at baseline.


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Table 21
Evaluation of Overall Response for Participants 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
Note:

Participants with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) 
to confirm the CR.
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 the first 
scheduled tumor evaluation.  

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, participants lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered not 
evaluable.  
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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12.10.
Appendix 10: CKD-EPI Formula
Chronic Kidney Disease (CKD) stage: Kidney Disease Outcomes Quality Initiative CKD 
stages 3/4/5 defined by estimated glomular filtration rate (GFR) using the CKD 
Epidemiology Collaboration 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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12.11.
Appendix 11: Adverse Events of Special Interest
The list of terms and reporting requirements for 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.
Cytokine-related AEs
Cardiopulmonary or hemodynamic toxicity starting within 24 hours of study treatment 
that requires >40% FiO2, vasopressor administration, antiarrhythmic agent or other 
significant medical intervention. Asystole, as measured by ECG, or bradycardia that is 
symptomatic and requires medical intervention.
Immune-related AEs
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


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Serum sickness
Infusion reactions
Infusion-like reactions
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


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12.12.
Appendix 12: 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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12.13.
Appendix 13: mAb Monotherapy Dosing Period
The following information is a guidance for participants who are treated with mAb 
monotherapy.
Schedule of Activities in Section 2 should be followed with the following clarifications:
Table 1: Part 1 Dose Escalation and PK/Pharmacodynamic Cohorts: Safety, Laboratory, 
Efficacy, Study Treatment Procedures
1. Vital Signs: Predose mAb and mAb EOI+2h. After 2h, as clinically indicated.
2. ECG: As single measurement, Predose mAb and mAb EOI+2h. After 2h as 
clinically indicated.
3. Optional Consent Procedures
a.
Tumor Biopsies: Participants can opt out of the optional procedure 
including those in the PK/PD cohort.
b. Telephone Interview: Participants can opt out of the optional procedure
4. PK/PD subjects: Participants can opt out of the mandatory fresh biopsy required 
at Week 9. Optional Week 12 fresh biopsy is not mandatory per protocol.
Table 2: Part 1 Dose Escalation and PK/Pharmacodynamics Cohorts: Pharmacokinetic, 
Pharmacodynamic, Anti-drug Antibody, and Genetic Assessments
Scheduled assessments will not be collected. However, event-driven collections 
(e.g. in response to hypersensitivity including infusion reactions) will be 
performed per Table 2 (footnote h and i) and Section 10.3.2.3.  


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12.14.
Appendix 14: COVID-19 
STUDY PROCEDURES DURING COVID-19 PANDEMIC
During the special circumstances caused by the current COVID-19 pandemic, you should 
consider specific public health guidance, the impact of any travel restrictions 
implemented by local/regional health authorities and local institutions, and individual 
benefit /risk when making enrollment and treatment decisions for trial participants.
Every effort should be made to adhere to protocol-specified assessments for participants 
on study intervention, including follow up however when not possible, for the duration of 
these special circumstances, the following measures may be implemented for enrolled 
participants.Clinical investigators should document in [site files and in participant 
notes/Electronic Heath Records as appropriate] how restrictions related to COVID-19 led 
to the changes in study conduct and duration of those changes and indicate which trial 
participants were impacted and how those trial participants were impacted (as per the 
current local COVID-19 related regulatory guidance). 

Missing protocol required data/visits due to COVID-19 should be noted in participant 
notes and recorded as a COVID-19 protocol deviation.


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12.15.
Appendix 15 : Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Amendment 1 08-December-2017
Overall Rationale for the Amendment: Amendment 1 incorporates changes to the 
protocol as requested by the United States Food and Drug Administration (FDA).
Section # and 
Name
Description of Change
Brief Rationale
Whole 
Document

Administrative corrections 
of minor typographical, 
and/or inconsistent 
language throughout the 
protocol
Provide clarity and correction
Synopsis

Updated study design to 
remove 240 mg dose level of 
GSK3174998

Reduced overall number of 
study participants in line with 
the removal of the 
GSK3174998 240 mg dose 
level
Updated in line with main document
Section 2 SoA
Table 1 and Table 3:

Added additional vital sign and 
ECG monitoring at specified 
study visits

Removal of Circulating Tumor 
Cells (CTC) collection
Table 2 and Table 4:

Added additional GSK1795091 
PK assessments at 2 hours
and 4-hour post GSK1795091 
injection at Day 1 to align with 
ECG assessments
Table 1 and Table 3:

Additional monitoring and alignment of 
ECG assessments with PK 
GSK1795091 assessments as 
requested by FDA

Clarified timing of predose 
GSK1795091 and GSK3174998 vital 
sign and ECG assessments

Expected limited expression of CTCs 
in this patient pollution.
Table 2 and Table 4:

Request of FDA to capture the PK 
profile after intravenous injection 
coinciding with ECG assessments
Section 5, 
Section 5.1, Section 5.4, Section 
Updated as requested and agreed with 


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Section # and 
Name
Description of Change
Brief Rationale
Study Design
5.5:

Updates made through out 
section to remove 
GSK3174998 240 mg dose 
level in Part 1 Dose Escalation 
and Part 2 Expansion Cohort 
and confirm one dose of 
GSK3174998 (24 mg) to be 
used in combination with 
GSK1795091

Included GSK3174998 -1 dose 
level (8 mg) in case dose 
reduction is needed below 
GSK3174998 24 mg + 
GSK1795091 50 ng

Updated DLT criterial in Table 
6 
Section 5.2, Number of 
Participants:

Reduced overall number of 
study participants in line with 
the removal of the 
GSK3174998 240 mg dose 
level
FDA
Section 6, 
Study 
Population
Updated inclusion criteria for 
participants in Part 2
Provided additional inclusion criteria for 
prior lines of treatment
Section 7, 
Treatments 
Administered

Added additional safety 
monitoring following first dose 
of GSK1795091 and first two 
doses of combination
GSK3174998 and 
GSK1795091

Clarified meaning of phrase, 
“that requires oxygen > 40%” 
by replacing text with “oxygen 
>40% FiO2”. Also updated in 
Section 5/DLT criteria

Updated Table 8

Extended duration of monitoring for 
AEs including changes to vital signs 
and ECGs following first doses of 
GSK1795091 monotherapy and in 
combination with GSK3174998

Clarification supported by publication 
Lee et al

Table updated to remove 240 mg dose 


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Section # and 
Name
Description of Change
Brief Rationale
of GSK3174998
Section 7.3
Removed direction to register 
participants into GSK registration 
and medication ordering system  
System will not be used for participant 
registration.  Study Reference Manual will
include details for participant registration 
and enrollment
Section 10, 
Statistical 
Considerations 
and Data 
Analysis (10.1, 
10.3.4, 10.4.2)
Immunogenicity 
Analysis 
(10.3.2.3)

Removed reference to two 
cohorts in Part 2 Expansion 
Cohort

Added option for development 
of a neutralizing ADA assay

240 mg dose level of GSK3174998 
removed

Included per recommendation from 
FDA to allow for further 
characterization of stored samples
Section 12.7.1, 
Liver Safety 
Drug Restart or 
Rechallenge 
Guidelines
Added additional criteria for 
consideration of rechallenge with 
study treatment after a liver event
Criteria added to increase safeguards 
when considering possible study treatment 
rechallenge
Amendment 01, Country Specific (Canada) 06-MAR-2018
Overall Rationale for the Amendment: Prot-Ament1-CAN-1 incorporates changes to 
the protocol specific to sites in Canada only as requested by and agreed with Health
Canada.
Section # and 
Name
Description of Change
Brief Rationale
Section 5.1, 
Overall Design
Removed text to allow participants 
who progress after confirmed CR 
or PR to continue on study 
treatment if in agreement with 
sponsor and study investigator
Requested by Health Canada to follow 
stopping rules outlined in the protocol and 
remove Investigator discretion to request a 
participant continue to receive study drugs
Section 5.1.1, 
Part 1: Dose 
Escalation of 
GSK1795091 
and 
GSK3174998 
Removed text to allow participants 
who experienced a DLT, 
unacceptability or an increase in 
ALT, and not attributable to 
another cause, to continue on 
study treatment if in agreement 
with investigator and sponsor
Requested by Health Canada to follow 
stopping rules outlined in the protocol that 
a participant experiencing DLT or 
unacceptable toxicity stop study treatment


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Section # and 
Name
Description of Change
Brief Rationale
Section 5.1.3, 
Alternative 
Dosing 
Schedule
Removed text that an alternative 
dosing schedule for GSK1795091 
may be evaluated if emerging data 
suggest that the protocol-specified 
schedule will result in excessive 
toxicity or limited efficacy
Requested by Health Canada that any 
change to protocol dosing schedule will 
require a protocol amendment
5.1.4, Dose-
Limiting 
Toxicity
Removed text to allow participants 
who experienced a DLT to 
continue on study treatment if in 
agreement with sponsor and study 
investigator
Requested by Health Canada to follow 
stopping rules outlined in the protocol and 
remove Investigator discretion to request a 
participant continue to receive study drugs
Section 2, 
Schedule of 
Activities and 
Section 9, 
Study 
Assessments 
and 
procedures, 
Section 9.5.1, 
Blood Sample 
Collection and 
Section 
10.3.2.3, 
Immunogenicity
Removed text to allow adjustment 
for the timing and number of 
planned study assessments during 
the course of the study based on 
newly available data.
Requested by Health Canada that any 
change to timing or number of study 
assessments will require a protocol 
amendment
Section 7.2.2.3, 
Management of 
Hepatotoxicity, 
Section 8.1.1.1, 
Study 
Treatment 
Restart and 
Rechallenge 
and Section 
12.7.1, Liver 
Safety Drug 
Restart or 
Rechallenge 
Guidelines
Added text that the option to 
restart or rechallenge study 
treatment following meeting the 
liver chemistry stopping criteria will 
not apply for participants in 
Canada
Requested by Health Canada to follow 
stopping rules outlined in the protocol and 
remove option to restart or rechallenge
after liver stopping event
Section 10.1, 
Sample Size 
Added text describing the 
application of enrolment stopping 
rules to document how the criteria 
Clarify the proposed sample size and 
enrollment stopping rules for Part 2 


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Section # and 
Name
Description of Change
Brief Rationale
Determination
in Table 17 and assessment of 
futility will be applied for Part 2 
Expansion Cohort.
Expansion Cohort
Amendment 2 25-JUL-2018
Overall Rationale for the Amendment: Amendment 2 incorporates changes to the 
protocol to consolidate Canada country-specific amendment 01 CAN-1 and include two 
additional immunotherapy combination partners. 
Section # and 
Name
Description of Change
Brief Rationale
Whole 
Document

Administrative corrections of 
minor typographical, and/or 
inconsistent language 
throughout the protocol

Language updated throughout 
to add two treatment arms: 
GSK1795091 with 
GSK3359609, and 
GSK1795091 with 
pembrolizumab

Combined with country-specific 
(Canada) protocol amendment 

Provides clarity and correction

To expand the assessment of 
GSK1795091 administered in 
combination with other 
immunotherapies

Incorporates changes requested by 
Health Canada in the country-specific 
amendment into global document
Synopsis

Aligned with changes to study 
design and participant number 
in main text

Updated in line with main document
Section 2 SoA
Table 1, Table 3:

Added evaluations for new 
treatment arms

Added microbiome specimen 
collection
Table 2, Table 4:

Added assessments for new 
treatment arms
Table 1, Table 3:

Provides instruction for new treatment 
arms
Table 2, Table 4:

Provides instruction for new treatment 
arms 
Section 3 
Introduction

Added background information 
and rationale for targeting 
ICOS and PD-1 in combination 

Supports decision to include new 
treatment arms


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Section # and 
Name
Description of Change
Brief Rationale
with GSK1795091

Added risk considerations for 
GSK3359609 and 
pembrolizumab in Risk 
Assessment table
Section 4 
Objectives and 
Endpoints

Added exploratory endpoint for 
Microbiome Analysis

Added exploratory endpoint for 
PK of combination partners

Provides additional information for new 
treatment arms
Section 5, 
Study Design
Section 5.1, Overall Design

Study schematic updated

Exclusions to Canadian 
participants identified

Table 5 removed from
Section 5.2, Number of 
Participants

Part 2 numbers increased to 
reflect new treatment 
combinations

Provides specific instructions for 
conducting modified study
Section 6, 
Study 
Population

Updated inclusion and 
exclusion criteria for 
participants in Part 2c

Provides additional criteria for prior 
lines of treatment
Section 7, 
Treatments 
Administered

Updated Table 8 and Table 9

Added Table 10 and Table 11

Includes descriptions for GSK3359609 
and pembrolizumab

Dose Modification and Treatment 
Guidelines presented in table format
Section 8, 
Discontinuation 
Criteria

Added withdrawal of subjects 
is to be based on an average 
QTcF value of triplicate ECGs

Clarification of QTcF Stopping Criteria
Section 9, 
Study 
Assessments

Added description for Stool 
Specimen collection

Provides direction for sample collection
Section 10, 

Clarifications to sample size 

Provides updated numbers of study 


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Section # and 
Name
Description of Change
Brief Rationale
Statistical 
Considerations 
and Data 
Analysis
determination to account for 
new treatment arms
participants
Section 11, 
References

References added for ICOS 
and pembrolizumab 
information 

Supports new treatment arms
Amendment 3 14-SEP-2018
Overall Rationale for the Amendment: Amendment 3 incorporates changes to the 
protocol to include the most recent information for pembrolizumab combination studies 
and changes to biomarker sample collections to evaluate TLR4 responses. 
Section # and Name
Description of Change
Brief Rationale
Section 2 Schedule of 
Activities Tables
Biomarker sample collection 
aligned with TLR4 dosing
Ensures cytokine response data and 
flow cytometry data collected at 
consistent times post TLR4 
administration to evaluate TLR4 
responses as opposed to the 
combination partners
Section 3.2.4.1
Clinical Experience in 
Combination with other 
TLR Agonists
Conclusions from other 
pembrolizumab studies and 
the frequency of cytokine-
associated AEs and were 
included
Alignment with the updated CRA 
report
Section 3.2.5
Combination Background
Pembrolizumab survival 
curve duration updated
Alignment with published report
Section 3.3.1 Risk 
Assessment Table
Information added to CRS 
Mitigation Strategies
Provides additional information on 
risk mitigation
Section 5.5.1.5 
Combination 
Considerations
Dose justifications for 
combination treatments were 
added
Alignment with the updated CRA 
report
Section 7.2.1 General 
Guidelines for Cytokine-
Related Adverse Events 
and Infusion Reactions
Clarification of verbatim 
terms used to report 
“cytokine-related AEs” or 
“infusion reactions”
Provides instruction on AE 
terminology
Section 12.11 Adverse 
Events of Special Interest
Cytokine Release Syndrome 
removed from Infusion 
Reactions (reported as AESI 
for any grade)
Provides instruction on AE 
terminology
Whole Document
Minor typographical errors 
corrected, clarifications and 
formatting changes


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Amendment 4: 12-AUG-2019
Overall Rationale for the Amendment: Amendment 4 incorporates changes to the 
protocol to include the most recent safety information, changes to futility stopping 
criteria and biomarker sample collections. 
Section # and 
Name
Description of Change
Brief Rationale
Section 2 
Schedule of 
Activities Tables
Number of biomarker and clinical 
chemistry samples collected increased 
Ensures sufficient cytokine 
response data and flow cytometry 
data collected to evaluate TLR4 
responses 
Section 2 
Schedule of 
Activities Tables
Table 1:Footnote for tumor biopsy clarified 
to state biopsy can be collected next visit if 
missed for treatment delay 
Ensures appropriate biopsy 
sample may be collected 
Section 2 
Schedule of 
Activities Tables
Table 4:Footnotes for immunogenicity and 
hypersensitivity reactions clarified that 
participants will be with drawn from 
treatment, not study
Clarification
Section 
3.2.1.2.1
Descripton of another participant with 
elevated ALT added from new safety data
Accuracy and completeness of 
safety data
Section 5.1
Minimum number of participants in the Part 
2 expansion cohorts changed from 6 to 8
Improves chances of seeing 
efficacious response
Section 5.1.3
Text added to describe replacement of 
participants with DLT 
Clarification
Section 5.2
Text added to describe the replacement of 
participants in Part 2
Clarification
Section 6
Modified requirements for previous therapy
More reflective of real-world study 
population
Section 7 Table 
8
Removed unit dose strength and dosing 
instructions
Available in the investigator’s 
brochure
Section 7.2
Stated AEs wil be graded by NCI-CTCAE 
unless otherwise specified
Include Lee 2014 reference
Section 10
Alternative hypothesis adjusted based on 
change to minimum numbers, Table 19 
and Table 20 updated
Reflects change to minimum 
number of participants
Whole 
document
References updated
New references available
Amendment 5: 02-Mar-2020
Overall Rationale for the Amendment: Amendment 5 addresses mAb monotherapy 
(GSK3174998, GSK3359609, or pembrolizumab) and the activities that are modified for this 
occurrence.


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Section # and 
Name
Description of Change
Brief Rationale
Section 2 
Schedule of 
Activities 
Tables: Table 1 
and Table 2
Footnote added to direct reader to
Appendix 13 for SOA modifications. 
Ensures that only those activities 
that are required are collected 
from the participant. Reduces 
burden on participant.  
Section 7.2 
Dose 
Modification 
Included language allowing continued 
treatment if only mAb monotherapy is 
administered.
Provides instruction for continuing 
in the trial on mAb monotherapy
Appendix 13: 
mAb 
Monotherapy 
Dosing Period
Added guidance on modifications that 
should be taken if only mAb monotherapy 
is administered.
Provided details on the changes 
to the activities required. Reduces 
burden on participant.

SAP_001.pdf: 
 
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C o m p a n y: 
I Q VI A 
 
U p o n re vie w of t his d oc u me nt, t he u n dersi g ne d a p pr o ves t his versi o n of t he Statistical A nal ysis 
Pla n, a ut h orizi n g t hat t he c o nte nt is acce pta ble f or t he re p orti n g of t his st u d y. 
 
N a me  
Si g n at ure  
D ate  
A p pr o ve d B y:  
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Me dical Direct or, O nc ol o g y Cli nical De vel o p me nt 
  
C o m p a n y: 
Gla x o S mit h Kli ne  
 
A p pr o ve d B y:  
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Gl o bal Cli nical De vel o p me nt Ma na ger  
  
C o m p a n y: 
Gla x o S mit h Kli ne  
 
P P D
P P D
P P D
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A p pr o ve d B y: 
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Hea d of I m m u n ol o g y- O nc ol o g y Bi o mar kers 
  
C o m pa n y: 
Gla x o S mit h Kli ne  
 
A p pr o ve d B y: 
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Direct or, Cli nical P har mac ol o g y  
  
C o m pa n y: 
Gla x o S mit h Kli ne  
 
A p pr o ve d B y: 
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Pri nci pal Pr o gra m mer  
  
C o m pa n y: 
Gla x o S mit h Kli ne  
 
A p pr o ve d B y: 
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Statistics Lea der  
  
C o m pa n y: 
Gla x o S mit h Kli ne  
 
P P D
P P D
P P D
P P D
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
O U T P U T T E M P L A T E S S I G N A T U R E P A G E  
O ut p ut Te m plates V 1. 0 ( Date d 2 3 Dec 2 0 2 0 ) f or Pr ot oc ol 2 0 4 6 8 6. 
 
N a me  
Si g n at ure  
D ate  
A ut h or:  
 
 
2 3 Dec 2 0 2 0 
 
P ositi o n:  
Lea d Statisticia n  
  
C o m p a n y: 
I Q VI A 
U p o n re vie w of t his d oc u me nt, t he u n dersi g ne d a p pr o ves t his versi o n of t he O ut p ut Te m plates, 
a ut h orizi n g t hat t he c o nte nt is acce pta ble f or t he re p orti n g of t his st u d y. 
 
N a me  
Si g n at ure  
D ate  
A p pr o ve d B y:  
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Statistics Lea der  
  
C o m p a n y: 
Gla x o S mit h Kli ne  
 
A p pr o ve d B y:  
 
 
D D M M M Y Y Y Y  
 
P ositi o n:  
Pri nci pal Pr o gra m mer  
  
C o m p a n y: 
Gla x o S mit h Kli ne  
 
P P D
P P D
P P D
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
M O DI FI C A TI O N H I S T O R Y 
 
U ni q ue 
I de ntifier 
f or t his 
Versi o n  
D ate of t he 
D oc u me nt 
Versi o n  
A ut h or  
Si g nific a nt C h a n ges fr o m  
Pre vi o us A ut h orize d Versi o n  
1. 0 
2 3 Dec 2 0 2 0 
 
N ot A p plica ble – First Versi o n  
 
 
P P D
 
P P D
P P D


Gl a x o S mit h Kli n e  
P R O T O C O L 2 0 4 6 8 6  
A n al y si s Pl a n  
P a g e 6 of 7 0  
D o c u m e nt:  
 
A ut h or:  
V er si o n N u m b er:  
1. 0  
V er si o n D at e:  
   [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T A B L E O F C O N T E N T S  
1.
I N T R O D U C TI O N............................................................................................................. 1 1
2.
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  ................................................................... 1 1 
2. 1.  
Pri m ar y O bjecti ve a n d E n d p oi nts  ................................................................................................................ 1 1  
2. 2.  
Sec o n d ar y O bjecti ves a n d E n d p oi nts ........................................................................................................... 1 1  
2. 3.  
E x pl or at or y O bjecti ves a n d E n d p oi nts  ........................................................................................................ 1 2  
3.
S T U D Y D E SI G N  ............................................................................................................... 1 5 
3. 1.  
Ge ner al Descri pti o n  ....................................................................................................................................... 1 5  
3. 1. 1.  
Fi g ure 1: St u d y Desi g n  ............................................................................................................................ 1 5  
3. 2.  
St u d y Desi g n f or t he D ose Esc al ati o n P h ase  ................................................................................................ 1 6  
3. 3.  
St u d y Desi g n f or t he D ose E x p a nsi o n P h ase  ............................................................................................... 1 6  
3. 4.  
Sc he d ule of E ve nts  ......................................................................................................................................... 1 7  
3. 5.  
C h a n ges t o A n al ysis fr o m Pr ot oc ol  .............................................................................................................. 1 7  
4.
S T A TI S TI C A L H Y P O T H E S E S  ..................................................................................... 1 7 
4. 1.  
P art 1: D ose Esc al ati o n  ................................................................................................................................. 1 7  
4. 2.  
P art 2: D ose E x p a nsi o n  ................................................................................................................................. 1 7  
5.
P L A N N E D A N A L Y S E S  ................................................................................................... 1 7 
5. 1.  
I nteri m D ose Esc al ati o n Decisi o ns ............................................................................................................... 1 8  
5. 1. 1.  
Descri pti o n of t he Ne ue nsc h wa n der -C o nti n ual Reassess me nt Met h o d  ................................................... 1 8  
5. 1. 2.  
L o gistic Re gressi o n M o del f or N -C R M  .................................................................................................. 1 9  
5. 1. 3.  
Dis pla ys t o be Create d f or D ose Escalati o n Re vie w  ................................................................................ 2 0  
5. 2.  
Pri m ar y A n al ysis  ........................................................................................................................................... 2 1  
5. 3.  
Fi n al A n al ysis  ................................................................................................................................................. 2 1
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 7 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
6.  
A N A L Y SI S S E T S .............................................................................................................. 2 1  
6. 1.  
All E nr olle d A n al ysis Set [ E N R]  ................................................................................................................... 2 1  
6. 2.  
All Tre ate d A n al ysis Set [ T R T]  .................................................................................................................... 2 1  
6. 3.  
P h ar m ac o ki netic A n al ysis Set [ P K S]  ........................................................................................................... 2 2  
6. 4.  
P h ar m ac o d y n a mic A n al ysis Set [ P D S]  ........................................................................................................ 2 2  
7.  
P A R TI CI P A N T G E N E R A L C O N SI D E R A TI O N S  ...................................................... 2 2 
7. 1.  
Refere nce St art D ate a n d St u d y D a y  ........................................................................................................... 2 2  
7. 2.  
B aseli ne  ........................................................................................................................................................... 2 3  
7. 3.  
Retests, U nsc he d ule d Visits a n d E arl y Ter mi n ati o n D at a  ......................................................................... 2 4  
7. 4.  
St atistic al Tests  .............................................................................................................................................. 2 4  
7. 5.  
C o m m o n C alc ul ati o ns  ................................................................................................................................... 2 5  
7. 6.  
S oft w are Versi o n  ............................................................................................................................................ 2 5  
8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................................ 2 5 
8. 1.  
A dj ust me nts f or C o v ari ates a n d F act ors t o be I ncl u de d i n A n al yses  ....................................................... 2 5  
8. 2.  
M ultice nter St u dies  ........................................................................................................................................ 2 5  
8. 3.  
Missi n g d at a  ................................................................................................................................................... 2 6  
8. 4.  
M ulti ple C o m p aris o ns/ M ulti plicit y  ............................................................................................................. 2 6  
8. 5.  
E x a mi n ati o n of S u b gr o u ps  ............................................................................................................................ 2 6  
9.  
O U T P U T P R E S E N T A TI O N S  ......................................................................................... 2 6 
1 0.  
DI S P O SI TI O N A N D WI T H D R A W A L S  ........................................................................ 2 7 
1 1.  
P R O T O C O L D E VI A TI O N S  ........................................................................................... 2 7
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 8 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 2.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S ....................... 2 8 
1 2. 1.  
Deri v ati o ns  ................................................................................................................................................. 2 9  
1 3.  
E F FI C A C Y O U T C O M E S ................................................................................................ 2 9  
1 3. 1.  
Pri m ar y Effic ac y  ........................................................................................................................................ 2 9  
1 3. 2.  
Sec o n d ar y Effic ac y  .................................................................................................................................... 3 0  
1 3. 2. 1.  
Sec o n dar y Efficac y Varia bles & Deri vati o ns  .......................................................................................... 3 0  
1 3. 2. 1. 1.  
Best O verall Res p o nse  ..................................................................................................................... 3 0  
1 3. 2. 1. 2.  
O bjecti ve Res p o nse Rate  ................................................................................................................. 3 1  
1 3. 2. 1. 3.  
Disease C o ntr ol Rate  ....................................................................................................................... 3 1  
1 3. 2. 1. 4.  
Ti me t o Res p o nse ............................................................................................................................. 3 1  
1 3. 2. 1. 5.  
D urati o n of Res p o nse  ....................................................................................................................... 3 1  
1 3. 2. 1. 6.  
Pr o gressi o n Free S ur vi val  ................................................................................................................ 3 2  
1 3. 2. 1. 7.  
O verall S ur vi val  ............................................................................................................................... 3 3  
1 3. 2. 2 . 
Missi n g Data Met h o ds f or Sec o n dar y Efficac y Varia bles  ....................................................................... 3 4  
1 3. 2. 3.  
Strate g y f or I nterc urre nt E ve nts f or Sec o n dar y Efficac y Varia bles  ......................................................... 3 5  
1 3. 2. 4.  
A nal ysis of Sec o n dar y Efficac y Varia bles  ............................................................................................... 3 5  
1 3. 2. 4. 1.  
Best O verall Res p o nse  ..................................................................................................................... 3 5  
1 3 . 2. 4. 2. 
O bjecti ve Res p o nse Rate  ................................................................................................................. 3 5  
1 3. 2. 4. 3.  
Disease C o ntr ol Rate  ....................................................................................................................... 3 5  
1 3. 2. 4. 4.  
Ti me t o E ve nt E n d p oi nts  ................................................................................................................. 3 5  
1 4.  
S A F E T Y O U T C O M E S  .................................................................................................... 3 6 
1 4. 1.  
A d verse E ve nts  ........................................................................................................................................... 3 6  
1 4. 1. 1.  
All T E A Es  ............................................................................................................................................... 3 6  
1 4. 1. 1. 1.  
Relati o ns hi p t o St u d y Me dicati o n  .................................................................................................... 3 7  
1 4. 1. 2.  
C o m m o n N o n -seri o us T E A Es ................................................................................................................. 3 7  
1 4. 1. 3.  
T E A Es Lea di n g t o Disc o nti n uati o n of St u d y Me dicati o n  ....................................................................... 3 8  
1 4. 1. 4.  
T E A Es Lea di n g t o D ose M o dificati o ns  ................................................................................................... 3 8  
1 4. 1. 5.  
Seri o us A d verse E ve nts  ........................................................................................................................... 3 8  
1 4. 1. 6.  
Fatal A d verse E ve nts  ............................................................................................................................... 3 8  
1 4. 1. 7.  
A d verse E ve nts Of S pecial I nterest  ......................................................................................................... 3 9  
1 4. 1. 7. 1.  
I m m u ne-relate d A Es ........................................................................................................................ 3 9  
1 4. 2.  
De at hs  ......................................................................................................................................................... 4 1  
1 4. 3.  
St u d y Me dic ati o n E x p os ure  ...................................................................................................................... 4 1  
1 4. 3. 1.  
Deri vati o ns  ............................................................................................................................................... 4 1  
1 4. 4.  
D ose Li miti n g T o xicities  ............................................................................................................................ 4 2
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 9 of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4. 5.  
L a b or at or y E v al u ati o ns  ............................................................................................................................ 4 2  
1 4. 5. 1.  
I m m u n o ge nicit y ....................................................................................................................................... 4 3  
1 4. 5. 2.  
Deri vati o ns  ............................................................................................................................................... 4 4  
1 4. 5. 3.  
N CI -C T C A E Gra di n g f or La b orat or y Data  ............................................................................................. 4 4  
1 4. 6.  
E C G E v al u ati o ns  ....................................................................................................................................... 4 4  
1 4. 6. 1.  
E C G S pecific Deri vati o ns  ........................................................................................................................ 4 5  
1 4. 6. 2.  
E C G Mar ke dl y A b n or mal Criteria  ........................................................................................................... 4 6  
1 4. 7.  
Vit al Si g ns  ................................................................................................................................................... 4 6  
1 4. 7. 1.  
Vital Si g ns Mar ke dl y A b n or mal Criteria  ................................................................................................. 4 7  
1 5.  
P H A R M A C O KI N E TI C A N A L Y SI S  .............................................................................. 4 8 
1 5. 1.  
Pl as m a C o nce ntr ati o n D at a  ...................................................................................................................... 4 9  
1 5. 2.  
P h ar m ac o ki netic P ar a meters  .................................................................................................................... 5 0  
1 6.  
P H A R M A C O D Y N A MI C / BI O M A R K E R A N A L Y SI S  ............................................... 5 3 
1 6. 1.  
P h ar m ac o d y n a mic / Bi o m ar ker V ari a bles  .............................................................................................. 5 3  
1 6. 2.  
H a n dli n g of Missi n g D at a f or P h ar m ac o d y n a mic / Bi o m ar ker V ari a bles  ............................................ 5 4  
1 6. 3.  
A n al ysis of P h ar m ac o d y n a mic / Bi o m ar ker V ari a bles  ........................................................................... 5 4  
1 6. 4.  
A n al ysis of P h ar m ac o ki netic Vers us P h ar m ac o d y n a mic / Bi o m ar ker V ari a bles  ................................ 5 6  
1 7.  
D A T A N O T S U M M A RI Z E D O R P R E S E N T E D  .......................................................... 5 6 
1 8.  
R E F E R E N C E S  .................................................................................................................. 5 8 
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  .............................. 5 9 
I Q VI A O ut p ut C o n ve nti o ns ...................................................................................................................................... 5 9  
D ates & Ti mes  ............................................................................................................................................................ 6 2  
S pelli n g F or m at  ......................................................................................................................................................... 6 2  
Prese nt ati o n of Tre at me nt Gr o u ps  .......................................................................................................................... 6 2
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Prese nt ati o n of Visits  ................................................................................................................................................. 6 3  
Listi n gs  ....................................................................................................................................................................... 6 5  
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N TI O N S  ............................................................. 6 5 
Al g orit h m f or Tre at me nt E mer ge nce of A d verse E ve nts:  ..................................................................................... 6 6  
Al g orit h m f or Pri or / C o nc o mit a nt/ P ost Me dic ati o ns:  ........................................................................................... 6 8  
 
 
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 1  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1.  IN T R O D U C TI O N  
T his d oc u me nt descri bes t he r ules a n d c o n ve nti o ns t o be use d i n t he prese ntati o n a n d a nal ysis of 
efficac y , safet y, p har mac o ki netic ( P K) a n d p har mac o d y na mic data f or Pr ot oc ol 2 0 4 6 8 6. It 
descri bes t he data t o be s u m marize d a n d a nal yze d, i ncl u di n g s pecifics of t he statistical a nal yses 
t o be perf or me d.  
T his statistical a nal ys is pla n ( S A P) is base d o n pr ot oc ol a me n d me nt 6, date d 0 8 t h Se pte m ber  
2 0 2 0 . 
2.  S T U D Y O B J E C TI V E S  A N D E N D P OI N T S  
2. 1.  
P RI M A R Y O B J E C TI V E  A N D E N D P OI N T S  
T he pri mar y o bjecti ve a n d e n d p oi nt is t he f oll o wi n g: 
O bjecti ves  
E n d p oi nts  
T o e val uate t he safet y a n d t olera bilit y of 
G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b . 
A d verse E ve nts ( A Es ), Seri o us A d verse 
E ve nts ( S A Es ), D ose Li miti n g T o xicities 
(D L Ts ), wit h dra wals d ue t o A Es, d ose 
re d uctio ns or dela ys, a n d c ha n ges i n safet y 
assess me nts (e. g., la b orat or y para meters, vital 
si g ns, a n d car diac para meters). 
2. 2.  
S E C O N D A R Y O B J E C TI V E S  A N D E N D P OI N T S  
T he sec o n dar y o bjecti ves a n d e n d p oi nts are t he f oll o wi n g:  
O bjecti ves  
E n d p oi nts  
T o e val uate t he a ntit u m or acti vit y of 
G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
O bjecti ve res p o nse rate ( O R R) a n d disease 
c o ntr ol rate ( D C R) (c o m plete res p o nse [ C R] + 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 2  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
c o m bi nati o n wit h G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b 
partial res p o nse [ P R]  + sta ble disease [ S D] 
≥1 2 wee ks), ti me t o res p o nse, d urati o n of 
res p o nse, pr o gressi o n-free s ur vi val ( P F S), a n d 
o verall s ur vi val ( O S).  
T o c haracterize t he p har mac o ki netics ( P K) of 
G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h eit her G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or Pe m br oliz u ma b . 
G S K 1 7 9 5 0 9 1 c o nce ntrati o ns i n plas ma a n d 
assess me nt of P K para meters (e. g., C ma x, 
A U C( 0 -τ) a n d Ctr o u g h) if data per mit. 
T o e val uate t he i m m u n o ge nicit y of 
G S K 3 1 7 4 9 9 8, G S K 3 3 5 9 6 0 9, a n d 
P e m br oliz u ma b w he n a d mi nistere d i n 
c o m bi nati o n wit h G S K 1 7 9 5 0 9 1.   
N u m ber a n d perce nta ge of part ici pa nts w h o 
de vel o p detecta ble A nti - Dr u g A nti b o dies 
(A D A ) a gai nst G S K 3 1 7 4 9 9 8, G S K 3 3 5 9 6 0 9, 
or P e m br oliz u ma b . 
2. 3.  
 E X P L O R A T O R Y O B J E C TI V E S  A N D E N D P OI N T S  
T he e x pl orat or y o bjecti ves a n d e n d p oi nts are t he f oll o wi n g: 
O bjecti ves  
E n d p oi nts  
T o e val uate t he i m m u n ol o gic effects of 
G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b .   
Assess me nts of O X 4 0 or I C O S rece pt or 
e x pressi o n a n d occ u pa nc y of G S K 3 1 7 4 9 9 8 or 
G S K 3 3 5 9 6 0 9 o n i m m u ne cells i n t he 
peri p heral bl o o d.   
Assess me nt of t he p he n ot y pe, q ua ntit y, a n d 
acti vati o n state of T cells a n d ot her i m m u ne 
cells i n peri p heral bl o o d. 
Assess me nt of t u m or bi o psies b y 
i m m u n o hist oc he mistr y or relate d tec h n ol o gies 
w hic h ma y i ncl u de b ut is n ot li mite d t o t he 
n u m bers of t u m or-i nfiltrati n g l y m p h oc ytes 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
a n d ot her cells e x pressi n g ke y p he n ot y pic 
mar kers.  
T o e x pl ore t he ass ociati o n bet wee n treat me nt 
wit h G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b a n d 
meas ures of ge ne e x pressi o n a n d i m m u ne 
f u ncti o n.   
Assess me nt of ge ne e x pressi o n a n d i m m u ne 
f u ncti o n fr o m st u d y partici pa nts t u m or tiss ue 
a n d/ or bl o o d sa m ples ma y i ncl u de b ut is n ot 
li mite d t o i m m u ne relate d ge ne e x pressi o n 
( R N A e x pressi o n or R N Ase q), ge ne 
si g nat ures, a n d T-cell rece pt or D N A 
se q ue nces.  
Assess me nt of s ol u ble fact ors fr o m st u d y 
partici pa nts bl o o d sa m ples a n d/ or t u m or ma y 
i ncl u de b ut is n ot li mite d t o c yt o ki nes a n d 
stress-relate d pr otei ns, cell free D N A 
(cf D N A), a n d e x os o mes. 
T o e x pl ore t he ass ociati o n bet wee n treat me nt  
wit h G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b a n d 
bi o mar kers w hic h ma y be ass ociate d wit h 
res p o nse. T o e x pl ore t he utilit y of t hese 
meas ures t o e nric h f or cli nical efficac y a n d/ or 
de vel o p me nt of a dia g n osti c test. 
C o m paris o n bet wee n a ntit u m or acti vit y a n d 
baseli ne bi o mar ker sa m ples fr o m st u d y 
partici pa nts bl o o d a n d/ or t u m or w hic h ma y 
i ncl u de b ut are n ot li mite d t o D N A, ge ne 
e x pressi o n ( R N A), pr otei ns, i m m u ne cell 
p he n ot y pes, a n d i m m u ne res p o nse mar kers.  
A na l ysis of t he data t o i de ntif y p ote ntial 
selecti o n bi o mar kers f or partici pa nt 
e nric h me nt. 
T o c haracterize t he P K of G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or Pe m br oliz u ma b w he n 
a d mi nistere d i n c o m bi nati o n wit h 
G S K 1 7 9 5 0 9 1. 
G S K 3 1 7 4 9 9 8, G S K 3 3 5 9 6 0 9, or 
Pe m br oliz u ma b c o nce ntrati o ns i n 
plas ma/ser u m a n d assess me nt of P K 
para meters (e. g., ma xi m u m o bser ve d 
c o nce ntrati o n [ C ma x], A U C( 0-τ) a n d tr o u g h 
c o nce ntrati o n [ Ctr o u g h]) if data per mit. 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 4  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T o e x pl ore P K - P har mac o d y na mic 
relati o ns hi ps, s uc h as bet wee n P K para meters 
a n d a ntit u m or acti vit y, safet y or 
p har mac o d y na mic mar kers after treat me nt 
wit h G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h eit her G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or P e m br oliz u ma b . 
E val uati o n of t he relati o ns hi p of a ntit u m or  
acti vit y as assesse d b y O R R, D C R, safet y 
a n d/ or p har mac o d y na mic mar kers wit h P K 
para meters  (e. g., C ma x). 
P har mac o ge netics ( P G x): T o e val uate t he 
ass ociati o n of ge netic variati o ns i n t he h ost 
D N A a n d res p o nse t o t hera p y. 
Ger mli ne ge netic e val uati o ns ma y be 
c o n d ucte d t o test f or ass ociati o n wit h: 
- 
Res p o nse t o treat me nt, i ncl u di n g 
G S K 1 7 9 5 0 9 1 w he n a d mi nistere d i n 
c o m bi nati o n wit h eit her G S K 3 1 7 4 9 9 8, 
G S K 3 3 5 9 6 0 9, or Pe m br oliz u ma b . 
Disease s usce pti bilit y, se verit y, a n d 
pr o gressi o n a n d relate d c o n diti o ns. 
T o e x pl ore t he g ut micr o bi o me c o m p ositi o n 
a n d relati o ns hi p t o treat me nt res p o nse.  
Se q ue nci n g of t he micr o bi o me fr o m st o ol 
sa m ples. A nal ysis of t he data t o i de ntif y 
p ote ntial selecti o n bi o mar kers f or partici pa nt 
e nric h me n t 
 
E val uati o n of t he relati o ns hi p bet wee n 
a nti bi otic/ pr o bi otic use pri or t o treat me nt a n d 
a ntit u m or acti vit y 
T o e val uate disease a n d treat me nt relate d 
s y m pt o ms a n d i m pact o n f u ncti o n a n d healt h-
relate d q ualit y- of-life. 
Q ualitati ve tele p h o ne i nter vie w.  
 
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
3.  S T U D Y D E SI G N  
3. 1.  
G E N E R A L D E S C RI P TI O N  
T his is a P hase I, o pe n -la bel, n o n-ra n d o mize d, m ultice nt er, m ulti-c o u ntr y st u d y desi g ne d t o 
e val uate t he safet y, t olera bilit y, P K, p har mac o d y na mic, a n d preli mi nar y cli nical acti vit y of 
G S K 1 7 9 5 0 9 1 a d mi nistere d i n c o m bi nati o n wit h ot her i m m u n ot hera pies t o partici pa nts wit h 
a d va nce d s oli d t u m ors. 
T his st u d y c o nsists of 2 parts; Part 1 is t he d ose escalati o n p hase a n d Part 2 is t he d ose e x pa nsi o n 
p hase.  F oll o wi n g pr ot oc ol a me n d me nt 6,  f urt her e nr ol me nt was st o p pe d a n d  Part 2 of  t he st u d y 
was n ot o pe n as t he de vel o p me nt of G S K 1 7 9 5 0 9 1 was disc o nti n ue d b y G S K. 
3. 1. 1.  
F I G U R E 1:  S T U D Y D E SI G N  
 
 
 
 
 
 
 
 
 
 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
3. 2.  
S T U D Y D E SI G N F O R T H E D O S E E S C A L A TI O N P H A S E  
Part 1 is desi g ne d t o e val uate t he safet y a n d t olera bilit y of escalati n g d oses of G S K 1 7 9 5 0 9 1 wit h 
a si n gle d ose le vel of c o m bi nati o n part ners i n partici pa nts wit h a d va nce d ca ncers acc or di n g t o a 
Ne ue nsc h wa n der -C o nti n ual Reassess me nt Met h o d ( N - C R M) desi g n [Ne ue nsc h wa n der , 2 0 0 8] t o 
i de ntif y a d ose f or e val uati o n i n Part 2. Starti n g at 5 0 n g, u p t o 5 differe nt d ose le vels of 
G S K 1 7 9 5 0 9 1 are pla n ne d t o be e val uate d f or Part 1. D ose le vels of t he c o m bi nati o n part ners will 
re mai n fi xe d.  
G S K 1 7 9 5 0 9 1 c o m bi nati o n par t ners are: 
•  
G S K 3 1 7 4 9 9 8 2 4 m g ( Part 1a) 
•  
G S K 3 3 5 9 6 0 9 8 0 m g ( Part 1 b) 
•  
Pe m br oliz u ma b 2 0 0 m g ( Part 1c)  
Part 1 will i ncl u de a G S K 1 7 9 5 0 9 1 r u n-i n peri o d of 2 wee ks (a d mi nistrati o n o n Da ys 1 a n d 8) 
pri or t o t he a d mi nistrati o n of c o m bi nati o n t hera p y be gi n ni n g at Da y 1 5. G S K 1 7 9 5 0 9 1 will 
c o nti n ue t o be a d mi nistere d wee kl y u p t o wee k 1 2. Starti n g at wee k 1 2, G S K 1 7 9 5 0 9 1 will be 
a d mi nistere d at 3 -wee k i nter vals t o c oi nci de wit h t he a d mi nistrati o n of t he c o m bi nati o n part ner 
dr u g. T hree or m ore partici pa nts will be e nr olle d i n eac h c o h ort.  T he t otal n u m ber of 
partici pa nts e nr olle d i nt o eac h c o h ort a n d d ose assi g n me nts will be g ui de d b y safet y i nf or mati o n 
(Pr ot oc ol Secti o n 5. 1. 3) fr o m partici pa nts recei vi n g t he G S K 1 7 9 5 0 9 1 a n d st u d y treat me nt 
c o m bi nati o ns acc or di n g t o N- C R M.  
P K / P har mac o d y na mic c o h orts will be o pe ne d at cleare d d ose le vels f or t hat c o m bi nati o n (i.e. t he 
m ost rece nt i n vesti gate d d ose le vel t hat s u p p orte d d ose escalati o n). U p t o 6 partici pa nts per d ose 
le vel ma y be e nr olle d i nt o t he P K/ P har mac o d y na mic c o h ort f or eac h c o m bi nati o n.   
3. 3.  
S T U D Y D E SI G N F O R T H E D O S E E X P A N SI O N P H A S E  
F oll o wi n g pr ot oc ol a me n d me nt 6,  f urt her e nr ol me nt was st o p pe d a n d 
P P D
Part 2  of t he st u d y was  n ot 
o pe n as t he de vel o p me nt of G S K 1 7 9 5 0 9 1 was disc o nti n ue d b y G S K. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
3. 4.  
S C H E D U L E O F E V E N T S  
Sc he d ule of e ve nts ca n be f o u n d i n Secti o n 2 of t he pr ot oc ol. 
3. 5.  
C H A N G E S T O A N A L Y SI S F R O M P R O T O C O L  
N o c ha n ges. 
4.  S T A TI S TI C A L H Y P O T H E S E S  
4. 1.  
P A R T 1:  D O S E E S C A L A TI O N  
Wit h res pect t o t he pri mar y o bjecti ves a n d e n d p oi nts, n o s pecific statistical h y p ot heses are bei n g 
teste d. T he d ose escalati o n part of t he st u d y will be f oc use d o n t he deter mi nati o n of t he 
rec o m me n de d d ose f or d ose e x pa nsi o n a n d f urt her e x pl orati o n, t he safet y pr ofile, a n d a ntit u m or 
acti vit y of t he c o m bi nati o n of G S K 1 7 9 5 0 9 1 wit h G S K 3 1 7 4 9 9 8, G S K 3 3 5 9 6 0 9, or 
Pe m br oliz u ma b . 
4. 2.  
P A R T 2:  D O S E E X P A N SI O N  
F oll o wi n g pr ot oc ol a me n d me nt 6,  f urt her e nr ol me nt was st o p pe d a n d  Part 2 of t he st u d y was n ot 
o pe n as t he de vel o p me nt of G S K 1 7 9 5 0 9 1 was disc o nti n ue d b y G S K  
5.  P L A N N E D A N A L Y S E S  
T he st u d y will n ot utilize a n I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C). Cli nical trial 
data use d i n t he decisi o ns will be i n -strea m data o nl y; t hat is, t he data will n ot necessaril y be 
clea ne d i n a d va nce of t he i nteri m a nal yses. T he f oll o wi n g a nal yses will be perf or me d f or t his 
st u d y: 
•  
I nteri m d ose escalati o n decisi o n a nal yses d uri n g st u d y part 1a, 1 b a n d 1c.  
•  
P P D
Pri mar y  a nal ysis 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
Fi nal a nal ysis  
•  
N ote t hat f oll o wi n g pr ot oc ol a me n d me nt 6,  f urt her e nr olme nt  was st o p pe d a n d  Part 2  of t he 
st u d y was  n ot o pe n as t he de vel o p me nt of G S K 1 7 9 5 0 9 1 was disc o nti n ue d b y G S K.  Interi m 
f utilit y a nal yses f or part 2a a n d 2 b will n ot be perf or me d , a n d a pri mar y a nal ysis will  be 
perf or me d usi n g all data o btai ne d pri or t o 0 1J ul y 2 0 2 0.  
5. 1.  
IN T E RI M D O S E E S C A L A TI O N D E CI SI O N S   
F or t he d ose escalati o n p hase, t he D ose Li miti n g T o xicit y ( D L T) i nf or mati o n al o n g wit h 
preli mi nar y safet y data, i ncl u di n g A Es, c ha n ges i n la b orat or y val ues a n d ot her safet y para meters, 
a n d a vaila ble P K/ p har mac o d y na mic data will be e val uate d b y t he G S K st u d y tea m f or eac h d ose 
escalati o n c o h ort pri or t o ma ki n g d ose escalati o n decisi o ns. D ose escalati o n ( or de -escalati o n) 
will pr ocee d as g ui de d b y a n N- C R M desi g n.   
5. 1. 1.  
D E S C RI P TI O N O F T H E N E U E N S C H W A N D E R - CO N TI N U A L R E A S S E S S M E N T M
E T H O D  
T he N -C R M m o del -base d desi g n is a Ba yesia n a da pti ve d ose escalati o n sc he me t hat ass u mes a 
2- para meter l o gistic m o del f or t he t o xicit y rate base d o n d ose. It is a m o difie d versi o n of t he 
ori gi nal C o nti n ual Reassess me nt Met h o d pr o p ose d b y [ O’ Q ui gle y, 1 9 9 0]. T he N -C R M met h o d is 
f ull y a da pti ve a n d ma kes use of all D L T i nf or mati o n, a n d t heref ore, is e x pecte d t o l ocate t he 
tar get d ose le vel efficie ntl y. I n t his case, t he m o del will be a p plie d t o t he d ose escalati o n decisi o n 
f or G S K 1 7 9 5 0 9 1, w hic h will be perf or me d i n de pe n de ntl y f or eac h c o m bi nati o n. 
D ose escalati o n decisi o ns will be hel d after partici pa nts wit hi n a n y gi ve n c o h ort ha ve bee n 
o bser ve d f or at least 6 wee ks after starti n g t he st u d y treat me nt. At t he ti me of eac h d ose 
escalati o n  decisi o n, t he Fi xe d a n d A da pti ve Cli nical Trial Si m ulat or ( F A C T S [ Tessella, 
A bi n gt o n, U nite d Ki n g d o m]) will be use d t o o btai n t he p osteri or pr o ba bilities f or t he D L T rate. 
T he N - C R M esti mates, f or eac h p ote ntial d ose, t he p osteri or pr o ba bilities t hat t he D L T rate lies 
i n eac h of f o ur t o xicit y ra n ges: 
•  
( 0 %, 1 6 %) U n der d osi n g 
•  
( 1 6 %, 3 3 %) Tar get t o xicit y 
•  
P P D
( 3 3 %, 6 0 %) E xcessi ve t o xicit y 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 1 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
( 6 0 %, 1 0 0 %) U nacce pta ble t o xicit y 
T he rec o m me n de d d ose base d o n t he N- C R M m o del will be t he d ose wit h t he hi g hest p osteri or 
pr o ba b ilit y of l yi n g i n t he tar get t o xicit y i nter val wit h t he a d diti o nal re q uire me nt t hat t he s u m of 
t he p osteri or pr o ba bilities of t he D L T rate l yi n g i n t he e xcessi ve t o xicit y or u nacce pta ble t o xicit y 
ra n ge is less t ha n 2 5 %. A n u p date d esti mate of t he t o xicit y c ur ve will be pr o vi de d at t he ti me of 
eac h d ose escalati o n meeti n g.  N ote t hat de- escalati o n as well as escalati o n is p ossi ble usi n g t his 
met h o d. D ose escalati o n will c o nti n ue u ntil c o n diti o ns f or eit her sce nari o (i) or (ii) are met:  
i)  
Si x partici pa nts h a ve bee n treate d at t he c urre nt tar get d ose  
A N D  
F or t he c urre nt d ose le vel, t he p osteri or pr o ba bilities of t he D L T rate l yi n g wit hi n t he e xcessi ve 
t o xicit y i nter val or wit hi n t he u nacce pta ble t o xicit y i nter val s u m t o less t ha n 2 5 %  
A N D  
F or t he ne xt hi g her d ose, t he p osteri or pr o ba bilities of t he D L T rat e l yi n g wit hi n t he e xcessi ve 
t o xicit y i nter val or wit hi n t he u nacce pta ble t o xicit y i nter val s u m t o greater t ha n 2 5 %. 
ii)  
N o d oses are usa ble (i.e., f or all d oses, t he p osteri or pr o ba bilities of t he D L T rate l yi n g 
wit hi n t he e xcessi ve t o xicit y i nter val or wit hi n t he u nacce pta ble t o xicit y i nter val s u m t o m ore 
t ha n 2 5 %)  
A N D  
At least 2 D L Ts ha ve bee n o bser ve d. 
D ose rec o m me n dati o ns base d o n t he N- C R M a nal ysis will be use d as g ui da nce  a n d t he decisi o n 
a b o ut d ose will be base d o n t otalit y of t he data . T o e ns ure safet y of partici pa nts, a d diti o nal 
partici pa nts ma y be e nr olle d at a c urre nt d ose le vel at t he discreti o n of t he st u d y i n vesti gat ors 
a n d s p o ns or, e ve n t h o u g h a hi g her d ose is rec o m me n de d b y N- C R M a nal ysis.  
5. 1. 2.  
L O GI S TI C R E G R E S SI O N M
O D E L F O R N- C R M  
P P D
A t w o - para meter l o gistic m o del will be use d f or N - C R M a nal ysis f or d ose le vel selecti o n d uri n g 
t he d ose escalati o n p hase. T his m o del will esti mate t he pr o ba bilit y of o bser vi n g a D L T at eac h 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
d ose le vel i n t he st u d y as D L T i nf or mati o n bec o mes a vaila ble.  
T he l o gistic m o del t hat use d f or descri bi n g t he d ose- t o xicit y relati o ns hi p is:  
𝑙𝑙𝑙𝑙�p d ( 1 −p d )
�
�= 𝛼𝛼+  𝛽𝛽 ∗𝑙𝑙𝑙𝑙�𝑑𝑑𝑑𝑑𝑚𝑚
�
�, 
w here p d is t he pr o ba bilit y of D L T at d ose d , a n d d m  is a refere nce d ose, a n d α a n d β are Ba yesia n pri ors. 
5. 1. 3.  
D I S P L A Y S T O B E C R E A T E D F O R D O S E E S C A L A TI O N R E VI E W  
E val uati o n of D L Ts f or at least t hree partici pa nt s w h o ha ve c o m plete d 6 wee ks st u d y treat me nt 
(i ncl u di n g t he r u n-i n peri o d) is re q uire d pri or t o deter mi ni n g t he d ose f or t he ne xt c o h ort.  
Re vie w of preli mi nar y data will be perf or me d after c o m pleti o n of eac h d osi n g c o h ort i n Part 1 
usi n g pri maril y S p otfire a n d E D C if nee de d. Preli mi nar y safet y a n d st u d y p o p ulati o n data ma y 
i ncl u de a de m o gra p hic s u m mar y, a d verse e ve nt ( A E) s u m mar y, A E s u m mar y b y ma xi m u m 
gra de, S A E listi n g, listi n g of A Es t hat are re p orte d t o be D L Ts, a n d listi n g of A Es lea di n g t o 
per ma ne nt disc o nti n uati o n of st u d y treat me nt.  
F urt her, after t he first i nsta nce of a D L T a n d f or eac h s u bse q ue nt c o h ort, u p date d p osteri or 
esti mates of t he pr o ba bilities of D L T rate falli n g  i n eac h d ose-t o xicit y ra n ge will  be pr o vi de d. 
T he Fi xe d a n d A da pti ve Cli nic al Trial Si m ulat or ( F A C T S) ( Versi o n 4. 0 or hi g her) s oft ware fr o m 
Tessella will be use d t o perf or m N -C R M a nal yses.  
Pri or t o deter mi ni n g a d ose f or t he ne xt c o h ort, if data warra nt, e x pl orat or y a nal yses ma y  be 
c o n d ucte d t o assess t he relati o ns hi p of d ose le vels wit h safet y, P K, a n d p har mac o d y na mic 
para meters usi n g all data a vaila ble.  
T he G S K st u d y tea m, i n c olla b orati o n wit h st u d y i n vesti gat ors a n d I Q VI A st u d y tea m , will 
re vie w all rele va nt data t o s u p p ort: 
•  
w het her t he c urre nt d ose ha d acce pta ble t o xicit y  
•  
P P D
t he decisi o n re gar di n g t he ne xt d ose le vel base d o n t he t otalit y of t he data 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 1  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
5. 2.  
P RI M A R Y  A N A L Y SI S  
All pla n ne d a nal yses i de ntifie d i n t his S A P will be perf or me d b y I Q VI A Bi ostatistics f oll o wi n g 
c o m pleti o n of t he f oll o wi n g ste ps:  
•  
All data o btai ne d pri or t o 0 1J ul y 2 0 2 0 has bee n e ntere d i nt o t he e C R F. 
•  
F or data c ollecte d pri or t o 0 1J ul y 2 0 2 0, a ll re q uire d critical data base clea ni n g acti vities ha ve 
bee n c o m plete d a n d data base l oc k ( D B L) has bee n declare d b y Data Ma na ge me nt.  
•  
S p o ns or a ut h orizati o n of t his Statistical A nal ysis Pla n  
5. 3.  
F I N A L A N A L Y SI S  
All fi nal, pla n ne d a nal yses i de ntifie d i n t his S A P will be perf or me d b y I Q VI A Bi ostatistics 
f oll o wi n g c o m pleti o n of t he f oll o wi n g ste ps: 
•  
All partici pa nts ha ve c o m plete d t he st u d y as defi ne d pr ot oc ol a me n d me nt 6. 
•  
F or data c ollecte d after 0 1J ul y 2 0 2 0, all re q uire d critical data base clea ni n g acti vities ha ve 
bee n c o m plete d a n d fi nal data base  l oc k ( D B L)  has bee n declare d b y Data Ma na ge me nt.  
6.  A N A L Y SI S S E T S  
A gree me nt a n d a ut h orizati o n of partici pa nts i ncl u de d/e xcl u de d fr o m eac h a nal ysis set will be 
c o n d ucte d pri or t o eac h pla n ne d a nal ysis .  
6. 1.  
A L L E N R O L L E D A N A L Y SI S S E T [ E N R] 
T he All E nr olle d A nal ysis Set i ncl u des all partici pa nts w h o si g n t he I C F t o partici pate i n t he 
cli nical trial. Partici p a nts i n t his a nal ysis set  will be use d f or t he scree n fail ure s u m mar y.  
6. 2.  
A L L T R E A T E D A N A L Y SI S S E T [ T R T] 
P P D
T he All Treate d A nal ysis Set i ncl u des all partici pa nts w h o ta ke at least 1 d ose of a n y st u d y 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 2  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
treat me nt. A nal yses of de m o gra p hic, baseli ne c haracteristics, safet y a n d a ntica ncer acti vit y will 
be base d o n t his a nal ysis set . F or a nal yses a n d dis pla ys base d o n t he T R T, partici pa nt s will be 
classifie d acc or di n g t o act ual treat me nt recei ve d.  
6. 3.  
P H A R M A C O KI N E TI C A N A L Y SI S S E T [ P K S] 
T he P har mac o ki netic A nal ysis Set wil l i ncl u de partici pa nts fr o m t he T R T w h o recei ve d at least 
o ne d ose of G S K 1 7 9 5 0 9 1 treat me nt, a n d fr o m w h o m at least o ne p ost d ose P K sa m ple was 
o btai ne d, a nal yze d , meas ura ble  f or G S K 1 7 9 5 0 9 1, a n d vali d (i.e., n ot affecte d b y pr ot oc ol 
de viati o ns or e ve nts t hat warra nt e xcl usi o n) . T his a nal ysis set  will be t he pri mar y p o p ulati o n f or  
all P K s u m maries . F or a nal yses a n d dis pla ys base d o n t he P K S, partici pa nt s will be classifie d 
acc or di n g t o act ual treat me nt recei ve d.  
6. 4.  
P H A R M A C O D Y N A MI C A N A L Y SI S S E T [ P D S] 
T h e P har mac o d y na mic A nal ysis Set will i ncl u de partici pa nts i n t he T R T fr o m w h o m at least o ne 
p har mac o d y na mic sa m ple was o btai ne d, a nal yze d a n d was meas ura ble. T his a nal ysis set will be 
t he pri mar y p o p ulati o n f or p har mac o d y na mic a nal yses. F or a nal yses a n d dis pla ys base d o n t he 
P D S, partici pa nt s will be classifie d acc or di n g t o act ual treat me nt recei ve d. 
7.  P A R TI CI P A N T  G E N E R A L C O N SI D E R A TI O N S  
7. 1.  
R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y  
St u d y Da y will be calc ulate d fr o m t he refere nce start date a n d  will be use d t o s h o w relati ve ti me 
fr o m t he refere nce date t o start/st o p da y of assess me nts a n d e ve nts. St u d y da y will a p pear i n 
e ver y listi n g w here a n assess me nt date or e ve nt date a p pears .  
Refere nce start date is defi ne d as t he da y of t he first d ose of st u d y me dicati o n, ( Da y 1 is t he da y 
of t he first d ose of st u d y me dicati o n ).  
•  
If t he date of t he e ve nt is o n or after t he refere nce date, t he n:  
P P D
St u d y Da y = ( date of e ve nt – refere nce date) + 1. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
If t he date of t he e ve nt is pri or t o t he refere nce date,  t he n:  
St u d y Da y = ( date of e ve nt – refere nce date). 
I n t he sit uati o n w here t he e ve nt date is partial or missi n g, t he date will a p pear partial or missi n g 
i n t he listi n gs, a n d St u d y Da y a n d a n y c orres p o n di n g d urati o ns will be prese nte d base d o n t he 
i m p utati o ns s pecifie d i n A p pe n di x 2 : Partial Date C o n ve nti o ns.  
7. 2.  
B A S E LI N E  
F or all e n d p oi nts (e xce pt as n ote d i n baseli ne defi niti o ns) t he baseli ne val ue will be t he latest 
pre- d ose assess me nt wit h a n o n -missi n g val ue, i ncl u di n g t h ose fr o m u nsc he d ule d visits. If ti me 
is n ot c ollecte d, Da y 1 assess me nts are ass u me d t o be ta ke n pri or t o first d ose a n d use d as 
baseli ne. F or la b orat or y data, baseli ne will be t he latest n o n -missi n g pre -d ose val ue fr o m ce ntral 
la b. If n o ce ntral la b val ue is a vaila ble, t he latest n o n-missi n g pre -d ose val ue fr o m l ocal la b will 
be use d. If ti me is n ot c ollecte d a n d t here are m ulti ple assess me nts o n t he sa me da y, t he mea n 
will be use d as t he baseli ne val ue.  
P ar a m et er  
St u d y A s s e s s m e nt s C o n si d er e d a s B a s eli n e  
B a s eli n e U s e d i n 
D at a Di s pl a y  
S cr e e ni n g  
D a y -1  
D a y 1 ( Pr e -D o s e)  
Effi c a c y  
Dis e as e Ass ess m e nt  
X  
 
 
Scr e e ni n g  
S af et y  
Vit al Si g ns  
X  
 
X  
D ay 1 Pr e -d os e 
G S K 1 7 9 5 0 9 1  
E C O G  
X  
 
X  
D ay 1 Pr e -d os e 
G S K 1 7 9 5 0 9 1  
P hysic al Ex a mi n ati o n  
X  
 
X  
D ay 1 Pr e -d os e 
G S K 1 7 9 5 0 9 1 if 
c oll ect e d, ot h er wis e, 
us e scr e e ni n g  
1 2 -l e a d E C G 
X  
 
X  
M e a n of tri plic at e pr e -
d os e G S K 1 7 9 5 0 9 1 
m e as ur e m e nts o n 
D ay 1  
Ec h oc ar di o gr a m  
X  
 
 
Scr e e ni n g  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 4  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
P ar a m et er  
St u d y A s s e s s m e nt s C o n si d er e d a s B a s eli n e  
B a s eli n e U s e d i n 
D at a Di s pl a y  
S cr e e ni n g  
D a y - 1 
D a y 1 ( Pr e -D o s e)  
L a b or at ory 
Ass ess m e nt 
X  
 
X  
D ay 1 Pr e -d os e 
G S K 1 7 9 5 0 9 1 if 
c oll ect e d, ot h er wis e, 
us e scr e e ni n g  
 P h ar m a c o d y n a mi c s  
P h ar m ac o dy n a mics  / 
Bi o m ark er  
 
 
X  
D ay 1 Pr e -d os e  
 
U nless ot her wise state d, if baseli ne data is missi n g n o deri vati o n will be perf or me d a n d baseli ne 
will be set t o missi n g.  
T he baseli ne defi niti o n will be f o ot n ote d o n all c ha n ge fr o m baseli ne dis pla ys.  
7. 3.  
 R E T E S T S , U N S C H E D U L E D V I SI T S A N D E A R L Y 
T E R MI N A TI O N D A T A  
I n ge neral, f or b y-visit s u m maries, data rec or de d at t he n o mi nal visit will be prese nte d.  T his 
i ncl u des t he Treat me nt Disc o nti n uati o n Visit ( T D V), all T D V data will be s u m marize d u n der t he 
sa me visit, re gar dless of w he n partici pa nt s disc o nti n ue d treat me nt.  U nsc he d ule d meas ure me nts 
will n ot be i ncl u de d i n b y- visit s u m maries b ut will c o ntri b ute  t o t he e val uati o n of best res p o nse 
a n d best/ w orst case val ue w here re q uire d (e. g. s hift ta ble).  
I n t he case of rescree ne d partici pa nts, t he latest scree ni n g assess me nts will be use d.   
Listi n gs will i ncl u de all assess me nts, i ncl u di n g b ot h sc he d ule d a n d u n- sc he d ule d. 
7. 4.  
S T A TI S TI C A L T E S T S  
P P D
N o statistical c o m paris o ns will be c o n d ucte d f or t his st u d y.  C o nfi de nce i nter vals will be 9 5 %, 
a n d all i nter vals will be t w o -si de d, u nless ot her wise s pecifie d i n t he descri pti o n of t he a nal yses. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
7. 5.  
C O M M O N C A L C U L A TI O N S  
F or q ua nti tati ve meas ure me nts, c ha n ge fr o m baseli ne will be calc ulate d as:  
 
•  
C ha n ge fr o m Baseli ne = P ost -Baseli ne Visit Val ue – Baseli ne   
•  
Perce nta ge c ha n ge fr o m baseli ne will be s u m marize d as t he f oll o wi n g:  
•  
Perce nta ge  C ha n ge fr o m Baseli ne = 1 0 0 x ( P ost-Baseli ne Visit Val ue – Baseli ne) / Baseli ne   
•  
F ol d c ha n ge fr o m baseli ne = ( P ost -Baseli ne Visit Val ue) / Baseli ne  
•  
A ge  ( years) r o u n de d d o w n t o t he nearest i nte ger = ( Date of i nf or me d c o nse nt - Date of Birt h 
+ 1) / 3 6 5. 2 5 
If eit her t he Baseli ne or P ost-Baseli ne Visit Val ue is missi n g, C ha n ge fr o m Baseli ne a n d 
F ol d/ Perce nta ge C ha n ge fr o m Baseli ne is set t o missi n g.  
7. 6.  
S O F T W A R E V E R SI O N  
P har mac o ki netic a nal ysis will be c o n d ucte d usi n g P h oe ni x Wi n N o nli n Versi o n 8. 0 or hi g her. All 
a nal yses will be c o n d ucte d usi n g S A S versi o n 9. 4 or hi g her.  
8.  S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1.  
A D J U S T M E N T S F O R C O V A RI A T E S A N D F A C T O R S T O B E 
IN C L U D E D I N A N A L Y S E S  
N o a dj ust me nts f or c o variates will be a p plie d t o a n y of t he a nal yses descri be d i n t his Statistical  
A nal ysis Pla n. 
8. 2.  
M U L TI C E N T E R S T U DI E S  
P P D
I n t his m ultice nter a n d m ulti-c o u ntr y st u d y, all ce nters will be p o ole d pri or t o a nal ysis. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S u b -re gi o ns will n ot be defi ne d. 
8. 3.  
M I S SI N G D A T A 
Missi n g safet y data will n ot be i m p ute d, wit h t he e xce pti o n of missi n g baseli ne f or p ur p ose of 
s u m marizi n g gra de i ncrease fr o m baseli ne or c ha n ge fr o m baseli ne i n ter ms of n or mal ra n ges.  
A p pr oac hes t o missi n g data f or efficac y a nal yses are descri be d i n secti o n  1 3.   
8. 4.  
M U L TI P L E C O M P A RI S O N S / M U L TI P LI CI T Y  
T here will be n o c o m paris o ns c o n d ucte d bet wee n treat me nt c o h orts or st u d y parts f or t his st u d y. 
8. 5.  
E X A MI N A TI O N O F S U B G R O U P S  
•  
T he f oll o wi n g s u b gr o u ps will be e x pl ore d f or selecte d e n d p oi nts: 
•  Ori gi nal vs m o difie d f or m ulati o n  of G S K 1 7 9 5 0 9 1  
9.  O U T P U T P R E S E N T A TI O N S  
A p pe n di x 1  s h o ws c o n ve nti o ns f or prese ntati o n of data i n o ut p uts.  
T he te m plates pr o vi de d wit h t his S A P descri be t he prese ntati o ns f or t his st u d y a n d t heref ore t he 
f or mat a n d c o nte nt of t he s u m mar y ta bles, fi g ures, a n d listi n gs t o be pr o vi de d b y I Q VI A 
Bi ostatistics.  
P P D
Eac h treat me nt c o h ort ( G S K 1 7 9 5 0 9 1 + G S K 3 1 7 4 9 9 8, G S K 1 7 9 5 0 9 1 + G S K 3 3 5 9 6 0 9, 
G S K 1 7 9 5 0 9 1 + Pe m br oliz u ma b ) will be s u m marize d se paratel y ; h o we ver, listi n gs will i ncl u de 
data fr o m all treat me nt c o h orts. F or selecte d o ut p uts stratifie d b y f or m ulati o n of G S K 1 7 9 5 0 9 1,  a 
p o ole d treat me nt c o h ort ( G S K 1 7 9 5 0 9 1 + G S K 3 1 7 4 9 9 8 or G S K 1 7 9 5 0 9 1 + G S K 3 3 5 9 6 0 9 or 
G S K 1 7 9 5 0 9 1 + Pe m br oliz u ma b) ma y be prese nte d.  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 0.  D I S P O SI TI O N A N D W
I T H D R A W A L S 
All partici pa nts w h o pr o vi de i nf or me d c o nse nt will be acc o u nte d f or i n t his st u d y.  
P artici pa nts i n t he T R T a nal ysis set will be c o nsi dere d t o ha ve c o m plete d t he st u d y if t he y fall 
i nt o eit her of t he f oll o wi n g t w o cate g ories: 
•  Partici pa nts w h o e x perie nce a D L T ( d ose li mit i n g t o xicit y) a n d c o m plete t he treat me nt 
disc o nti n uati o n visit ( T D V)   
•  Partici pa nts w h o c o m plete t he 6 wee k visit a n d t he treat me nt disc o nti n uati o n visit ( T D V)   
Partici pa nt  dis p ositi o n a n d wit h dra wals fr o m treat me nt a n d t he st u d y, i ncl u di n g pri mar y reas o n 
f or wit h dra wal, will be prese nte d f or t he T R T b y c o h ort, st u d y part a n d o verall. I n a d diti o n, t he 
n u m ber of partici pa nt s scree ne d, t he n u m ber of scree n fail ures a n d t he reas o ns f or scree n fail ure 
will be prese nte d f or t he S C R b y st u d y part a n d o verall. Als o, i ncl usi o n i n all a nal ysis sets will 
be s u m marize d b y c o h ort, st u d y part a n d o verall f or t he T R T. A s u m mar y of partici pa nt s 
screene d a n d treate d b y c o u ntr y will als o be prese nte d f or t he S C R b y st u d y part a n d o verall.  
A nal ysis will be perf or me d  b y c o m bi nati o n part ner (se paratel y f or eac h part ner a n d acr oss all 
part ners p o ole d), d ose gr o u p, a n d f or m ulati o n ( Ori gi nal F or m ulati o n,  M o difie d F or m ulati o n, or 
All F or m ulati o ns).  
A listi n g will be pr o d uce d t o dis pla y t he i nf or mati o n c ollecte d i n t he e C R F re gar di n g patie nt 
dis p ositi o n. 
1 1.  P R O T O C O L D E VI A TI O N S  
I m p orta nt pr ot oc ol de viati o ns (i ncl u di n g de viati o ns relate d t o st u d y i ncl usi o n/e xcl usi o n criteria, 
c o n d uct of t he trial, patie nt ma na ge me nt or patie nt assess me nt) will be s u m marize d f or t he T R T 
b y c o h ort, st u d y part a n d o verall.  
•  
P P D
Pr ot oc ol de viati o ns are rec or de d i n t he C T M S, w hic h is c o nsi dere d as t he ori gi nal s o urce 
d oc u me nt . De viati o n cate g or y are selecte d a n d i m p orta nt de viati o ns are disc usse d i n a 
m o nt hl y de viati o ns meeti n g wit h t he s p o ns or a n d cli nical tea m w here i m p orta nt de viati o ns 
are deci de d a n d e ntere d i nt o t he C T M S l o g . Data will be re vie we d pri or t o freezi n g t he 
data base t o e ns ure all i m p orta nt de viati o ns are c orrectl y ca pt ure d a n d cate g orize d i n t he 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
pr ot oc ol de viati o ns dataset 
•  
T his dataset will be t he basis f or t he s u m maries a n d listi n gs of pr ot oc ol de viati o ns.  
Pr ot oc ol de viati o ns will be trac ke d b y t he st u d y tea m t hr o u g h o ut t he c o n d uct of t he st u d y i n 
acc or da nce wit h t h e Pr ot oc ol De viati o n Ma na ge me nt Pla n versi o n 2 ( 2 6 t h Ja n uar y 2 0 1 8). 
I m p orta nt pr ot oc ol de viati o ns a n d i ncl usi o n i n t he a nal ysis sets, i ncl u di n g reas o ns f or e xcl usi o n, 
will be liste d.  
1 2.  D E M O G R A P HI C A N D O T H E R  B A S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic data a n d ot her baseli ne c haracteristics will be prese nte d f or t he T R T.  
N o statistical testi n g will be carrie d o ut f or de m o gra p hic or ot her baseli ne c haracteristics.  
T he f oll o wi n g de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d b y c o h ort, st u d y 
part a n d o verall:  
•  
A ge ( years) - calc ulate d relati ve t o date of c o nse nt  
•  
A ge Gr o u p  ( < = 1 8, 1 8- 6 4, > = 6 5) 
•  
Se x  
•  
Race (Africa n A merica n/ Africa n Herita ge , A merica n I n dia n or Alas ka n Nati ve, Asia n, Blac k 
or Africa n A merica n, Nati ve Ha waiia n  or Ot her Pacific Isla n der , W hite, Mi xe d Race ) 
•  
Et h nicit y  
•  
C hil d - beari n g P ote ntial 
•  
Wei g ht at Baseli ne ( k g)  
•  
Hei g ht at Scree ni n g (c m)  
•  
B MI ( k g/ m 2) 
P P D
All de m o gra p hic a n d baseli ne c haracteristics data will be liste d.  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 2 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A nal ysis will be perf or me d  b y c o m bi nati o n part ner (se paratel y f or eac h part ner a n d acr oss all 
part ners p o ole d), d ose gr o u p, a n d f or m ulati o n ( Ori gi nal F or m ulati o n,  M o difie d F or m ulati o n, or 
All F or m ulati o ns).  
1 2. 1.  
D E RI V A TI O N S  
•  
B MI ( k g/ m 2) = wei g ht ( k g)/ hei g ht ( m)2 
•  
C reati ni ne C leara nce (Cr Cl ) ( m L/ mi n) fr o m ser u m creati ni ne will be base d o n C oc kcr oft-
Ga ult f or m ula : 
•  
Cr Cl ( male) = ([ 1 4 0 -a ge i n years] × wei g ht i n k g)/(ser u m creati ni ne i n m g/ d L × 7 2) 
•  
Cr Cl (fe male) = Cr Cl ( male) × 0. 8 5  
•  
If partial dates are prese nt, t he f oll o wi n g r ules will be a p plie d f or t he calc ulati o n of ti me 
varia bles:  
1.  If t he da y is missi n g t he date will be i m p ute d as t he first of t he m o nt h.  
2.  If t he da y a n d m o nt h are missi n g t he date will be i m p ute d as t he 1st Ja n uar y.   
1 3.  E F FI C A C Y O U T C O M E S  
U nless ot her wise state d , efficac y e n d p oi nts will b e s u m marize d f or t he T R T b y c o h ort a n d st u d y 
part ( w here a p plica ble). 
F or selecte d efficac y o utc o mes a nal ysis will be perf or me d b y c o m bi nati o n part ner (se paratel y f or 
eac h part ner a n d acr oss all part ners p o ole d), d ose gr o u p, a n d f or m ulati o n ( Ori gi nal F or m u lati o n,  
M o difie d F or m ulati o n, or All F or m ulati o ns).  
1 3. 1.  
P RI M A R Y E F FI C A C Y  
P P D
T here are n o pri mar y efficac y a nal yses pla n ne d f or t he st u d y. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 2.  
S E C O N D A R Y E F FI C A C Y  
T he sec o n dar y efficac y a nal yses i n v ol ve assessi n g t he a ntit u m or acti vit y of G S K 1 7 9 5 0 9 1 a n d its 
c o m bi nati o n part ners. T hese a nal yses will i ncl u de t he f oll o wi n g: o bjecti ve res p o nse rate ( O R R), 
disease c o ntr ol rate ( D C R), ti me t o res p o nse ( T T R), d urati o n of res p o nse, pr o gressi o n- free 
s ur vi val ( P F S) a n d o verall s ur vi val.  
T u m or res p o nse i.e., c o m plete res p o nse ( C R), partial res p o nse ( P R), sta ble disease ( S D), a n d 
pr o gressi ve disease ( P D) will be base d o n t he assess me nts fr o m t he i n vesti gat ors’ re vie w of 
o bjecti ve e vi de nce (e. g., ra di ol o gical sca n). O verall res p o nses were meas ure d i n acc or da nce wit h 
t he R E CI S T versi o n 1. 1 [W olc h o k,  2 0 0 9; Nis hi n o, 2 0 1 3]. 
Lesi o n assess me nt met h o d a n d ti mi n g, e val uati o n of disease, disease pr o gressi o n a n d res p o nse 
criteria will be c o n d ucte d acc or di n g t o R E CI S T ( versi o n 1. 1) as o utli ne d i n A p pe n di x 9 of t he 
pr ot oc ol.   
1 3. 2. 1.  
S E C O N D A R Y E F FI C A C Y V A RI A B L E S &  D E RI V A TI O N S  
1 3. 2. 1. 1.  
Best O verall Res p o nse  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me nt u ntil 
disease pr o gressi o n/rec urre nce a n d will be deter mi ne d pr o gra m maticall y base d o n t he 
i n vesti gat ors assess me nt of res p o nse at eac h ti me p oi nt.  
•  T o be assi g ne d a stat us of S D, f oll o w- u p disease assess me nt m ust ha ve met t he S D criteria at 
least o nce after t he first d ose at a mi ni m u m i nter val of 8 wee ks. 
•  If t he mi ni m u m ti me f or S D is n ot met, best res p o nse will de pe n d o n t he s u bse q ue nt 
assess me nts. F or e xa m ple, if a n assess me nt of P D f oll o ws t he assess me nt of S D a n d S D d oes 
n ot meet t he mi ni m u m ti me re q uire me nt t he best res p o nse will be P D. Alter nati vel y, 
partici pa nts l ost t o f oll o w -u p after a n S D assess me nt n ot meeti n g t he mi ni m u m ti me criteria 
will be c o nsi dere d n ot e val ua ble.  
P P D
T o be assi g ne d a stat us of P R or C R, a c o nfir mat or y disease assess me nt s h o ul d be perf or me d n o 
less t ha n 4 wee ks ( 2 8 da ys) after t he criteria f or res p o nse are first met. 
P P D


Gl a x o S mit h Kli n e  
P R O T O C O L 2 0 4 6 8 6  
A n al y s i s Pl a n 
P a g e 3 1  of 7 0  
D o c u m e nt:  
 
A ut h or:  
V er si o n N u m b er:  
1. 0  
V er si o n D at e:  
   [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 2. 1. 2.  
O bjecti ve Res p o nse Rate  
O bjecti ve Res p o nse Rate ( O R R) is defi ne d as t he perce nta ge of partici pa nt s ac hie vi n g a 
c o nfir me d best o verall res p o nse of  C R or P R w h o recei ve d at least o ne d ose of G S K 1 7 9 5 0 9 1 or 
its c o m bi nati o n part ners. O R R will be re p orte d b y R E CI S T v 1. 1. Parti ci pa nts wit h N ot E val ua ble 
or missi n g res p o nse will be treate d as n o n- res p o n ders (i.e. t he y will be i ncl u de d i n t he 
de n o mi nat or w he n calc ulati n g t he rate). 
1 3. 2. 1. 3.  
Disease C o ntr ol Rate  
Disease c o ntr ol rate ( D C R) is defi ne d as t he perce nta ge of partici pa nts wit h a c o nfir me d best 
o verall res p o nse of C R  or P R  or at least 1 2 wee ks of S D . F or t he p ur p ose of a nal ysis, a 2-wee k 
wi n d o w will be all o we d, i.e., a S D t hat is at least 1 0 wee ks after t he first d ose date will be 
i ncl u de d i n t he n u merat or f or D C R calc ulati o n. Part ici pa nts wit h N ot E val ua ble or missi n g 
res p o nse will be i ncl u de d i n t he de n o minat or w he n calc ulati n g t he rate . D C R will be re p orte d b y 
R E CI S T v 1. 1.  
1 3. 2. 1. 4.  
Ti me t o Res p o nse  
Ti me t o Res p o nse ( T T R) is defi ne d as t he ti me fr o m t he date of first d ose (i ncl u di n g r u n-i n) t o 
t he date of t he first d oc u me nte d e vi de nce of res p o nse (c o nfir me d P R or C R).  
T T R ( m o nt hs) = [ Date of o nset of  res p o nse – Date of first d ose + 1]/ 3 0. 4 3 7 5. 
If data per mits, ti me t o resp o nse will be s u m marize d f or res p o n ders acc or di n g t o R E CI S T 1. 1 . 
1 3. 2. 1. 5.  
D urati o n of Res p o nse  
D urati o n of Res p o ns e (D o R ) is de fi ne d as t he ti me fr om  first d ocu me nte d  evi de nce  o f CR  or PR  
u nti l d isease pr o gressi o n or de at h d ue to a n y ca us e am o n g partici pa nt s w h o ac hi eve an o ve rall 
res p o nse (i.e., a co nfir me d bes t o ve rall res p o nse of C R or  P R).  If data per mits, D o R w ill be  
s u m marize d acc or di n g t o R E CI S T 1. 1. 
D O R  (m o nt hs)  = [ Pr o gressi o n/ deat h  da te (ce ns or  da te) – D ate of  first d oc u me ntati o n  of  CR  or PR  
+ 1]/ 3 0. 4 3 7 5.
Ce ns ors hi p:   sa me as PF S  ce ns ors hi p (Ta bl e D
P P D
). 
P P D


Gl a x o S mit h Kli n e  
P R O T O C O L 2 0 4 6 8 6  
A n a l ysi s Pl a n  
P a g e 3 2  of 7 0  
D o c u m e nt:  
 
A ut h or:  
V er si o n N u m b er:  
1. 0  
V er si o n D at e:  
   [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 2. 1. 6.  
Pr o gressi o n Free S ur vi val  
Pr o gressi o n Free S ur vi val ( P F S) is defi ne d as t he i nter val of ti me (i n m o nt hs) bet wee n t he date 
of first d ose t o t he date of disease pr o gressi o n acc or di n g t o cli nical or ra di ol o gical assess me nt or 
deat h d ue t o a n y ca uses, w hic he ver occ urs earliest.  P F S wi ll be re p orte d acc or di n g t o R E CI S T  
1. 1. 
If t here is n o a de q uate baseli ne assess me nt, t he partici pa nts will be ce ns ore d at t heir date of first 
d ose. Partici pa nt s wit h o ut a n y a de q uate p ost-baseli ne t u m or assess me nts will be ce ns ore d at t he 
date of first d ose . If t he partici pa nt d oes n ot ha ve a d oc u me nte d date of e ve nt, P F S will be 
ce ns ore d at t he date of t he last a de q uate assess me nt.   
Partici pa nt s w h o pr o gresse d or die d after a n e xte n de d peri o d ( defi ne d as t he le n gt h of t w o 
sc he d ule d assess me nts) wit h o ut a deq uate assess me nt will be ce ns ore d at t heir date of last 
a de q uate assess me nt pri or t o pr o gressi o n or deat h e ve n if s u bse q ue nt i nf or mati o n is a vaila ble 
re gar di n g pr o gressi o n or deat h. A n a de q uate assess me nt is defi ne d as a n assess me nt w here t he 
res p o nse is CR, P R, or S D. T he date of res p o nse at t hat assess me nt will be use d f or ce ns ori n g. 
Ce ns ori n g r ules are defi ne d i n t he Ce ns ori n g R ules ta ble.  
If a partici pa nt has neit her pr o gresse d n or die d n or starte d ne w a nti-ca ncer t hera p y, t he n P F S will 
be ce ns ore d at t he date of t he last a de q uate assess me nt defi ne d as a n assess me nt w here t he 
res p o nse is C R, P R, S D. T he date of res p o nse will be use d as t he ce ns ori n g date. 
A s u m mar y of t he assi g n me nts f or pr o gressi o n a n d ce ns ori n g dates f or P F S are s pecifie d i n 
Ta ble A  bel o w. 
T a ble A:  
Ce ns ori n g R ules  
C e n s ori n g R ul e s  
Sit u ati o n  
D at e of E v e nt 
( Pr o gr e s si o n/ D e at h) 
or C e n s ori n g  
O ut c o m e: E v e nt 
( Pr o gr e s si o n/ D e at h) 
or C e n s ori n g  
N o ( or i n a d e q u at e) b as eli n e t u m or ass ess m e nts a n d t h e 
p artici p a nt  h as n ot di e d (if t h e p artici p a nt  h as di e d f oll o w 
t h e r ul es f or d e at h i n dict e d at t h e b ott o m of t h e t a bl e). A n 
a d e q u at e b as eli n e t u m or ass ess m e nt is d efi n e d as a n 
ass ess m e nt w h er e all i d e ntifi e d t ar g et l esi o ns h av e 
di a m et er r ec or d e d.  
First D os e D at e  
C e ns or e d  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
C e n s ori n g R ul e s  
Sit u ati o n  
D at e of E v e nt 
( Pr o gr e s si o n/ D e at h) 
or C e n s ori n g  
O ut c o m e: E v e nt 
( Pr o gr e s si o n/ D e at h) 
or C e n s ori n g  
N o p ost -b as eli n e ass ess m e nts a n d t h e p artici p a nt  h as n ot 
di e d (if t h e p artici p a nt  h as di e d f oll o w t h e r ul es f or d e at h 
i n dict e d at t h e b ott o m of t h e t a bl e) 
First D os e D at e  
C e ns or e d  
Pr o gr essi o n d oc u m e nt e d b et w e e n sc h e d ul e d visits  
D at e of ass ess m e nt of 
pr o gr essi o n 1 
Ev e nt 
N o pr o gr essi o n ( or d e at h)  
D at e of l ast ‘ a d e q u at e’ 
ass ess m e nt of 
r es p o ns e2 
C e ns or e d  
N e w a ntic a nc er tr e at m e nt st art e d ( pri or t o d oc u m e nt e d 
dis e as e pr o gr essi o n  or d e at h ).3  
D at e of l ast ‘ a d e q u at e’ 
ass ess m e nt of 
r es p o ns e2 ( o n or pri or t o 
st arti n g a nti-c a nc er 
t h er a py)  
C e ns or e d  
D e at h b ef or e first P D ass ess m e nt ( or D e at h pri or t o a ny 
a d e q u at e ass ess m e nts)  wit h o ut i niti ati n g a n e w a nti -
c a nc er t h er a py 
D at e of d e at h  
Ev e nt 
D e at h or pr o gr essi o n  ( w hic h ev er is e arli er) aft er m or e t h a n 
o n e miss e d visit  
D at e of l ast ‘ a d e q u at e’ 
ass ess m e nt of 
r es p o ns e2 ( pri or t o 
miss e d ass ess m e nts)  
C e ns or e d  
N O T E S :  
1 F or R E CI S T v 1. 1 Crit eri a: T h e earli est of (i) D at e of r a di ol o gic al ass ess m e nt s h o wi n g n e w l esi o n (if pr o gr essi o n is bas e d o n 
n e w l esi o n); or (ii) D at e of r a di ol o gic al ass ess m e nt s h o wi n g u n e q uiv oc al pr o gr essi o n i n n o n t ar g et l esi o ns, or (iii) Dat e of l ast 
r a di ol o gic al ass ess m e nt of m e as ur e d l esi o ns (if pr o gr essi o n is b as e d o n i ncr e as e i n s u m of m e as ur e d l esi o ns). 
2 A n a d e q u at e ass ess m e nt is d efi n e d as a n ass ess m e nt w h er e t he [r es p o ns e is C R, P R, or S D.  
3 If P D a n d N e w a nti-c a nc er t h er a py occ ur o n t h e s a m e d ay, ass u m e t h e pr o gr essio n w as d oc u m ent e d first ( e. g. outc o m e is 
pr o gr essi o n a n d t h e d at e is t h e d at e of t h e ass ess m e nt of pr o gr essi o n). If a nti -c anc er t h er a py is st art e d pri or t o a ny 
a d e q u at e ass ess m e n ts, c e ns orin g d at e s h o ul d b e t h e d at e of first d os e. 
1 3. 2. 1. 7.  
O verall S ur vi val  
P P D
O verall S ur vi val ( O S) is defi ne d as t he ti me fr o m date of first d ose of t he st u d y treat me nt 
( w hic he ver i n vesti gati o nal dr u g a d mi nistere d first) t o t he date of deat h f or a n y ca use. I n t he 
a bse nce of c o nfir mati o n of deat h, s ur vi val ti me will be ce ns ore d at t he last date t he partici pa nt is 
k n o w n t o be ali ve (i.e., at t heir last k n o w n ali ve date). 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 4  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T he le n gt h of O S will be calc ulate d as:  
O S ( m o nt hs) = [ deat h date or last k n o w n ali ve date – date of first d ose + 1]/ 3 0. 4 3 7 5. 
Partici pa nts lac ki n g data be y o n d date of first d ose will ha ve t heir s ur vi val ti mes ce ns ore d at date 
of first d ose.  
1 3. 2. 2.  
M
I S SI N G D A T A M
E T H O D S F O R S E C O N D A R Y E F FI C A C Y V A RI A B L E S  
If t he partici pa nt  starts a ne w a nti-ca ncer t hera p y w hil e still o n t he st u d y a n d t he start date of t he 
ne w t hera p y is partial t he f oll o wi n g r ules will be a p plie d : 
•  
If t he da y of t he m o nt h is missi n g a n d t he partial start date falls i n t he sa me m o nt h as t he last 
d ose of st u d y treat me nt, t he n assi g n t o earlier of ( date of last d ose of st u d y treat me nt + 1, last 
da y of m o nt h).  
•  
If t he da y of t he m o nt h is missi n g a n d t he partial start date falls i n t he sa me m o nt h as t he 
partici pa nt’s last assess me nt a n d t he partici pa nt’s last assess me nt is pr o gressi ve disease ( P D), 
t he n assi g n t o earlier of ( date of P D + 1, last da y of m o nt h).  
•  
If b ot h r ules a b o ve a p pl y, t he n assi g n t o latest of t he 2 dates.  
•  
Ot her wise, i m p ute missi n g da y t o t he first of t he m o nt h.  
•  
If t he da y of t he m o nt h a n d t he m o nt h is missi n g a n d t he partial start date  falls i n t he sa me 
year as t he last d ose of st u d y treat me nt, t he n assi g n t o earlier of ( date of last d ose of st u d y 
treat me nt + 1, 3 1 st Dece m ber ).  
•  
If t he da y of t he m o nt h a n d m o nt h is missi n g a n d t he partial start date falls i n t he sa me year  
as t he partici pa nt ’s last assess me nt a n d t he partici pa nt ’s last assess me nt is pr o gressi ve 
disease ( P D), t he n assi g n t o earlier of ( date of P D + 1, 3 1 st Dece m ber ).  
•  
If b ot h r ules a b o ve a p pl y, t he n assi g n t o latest of t he 2 dates.  
•  
Ot her wise, i m p ute missi n g da y a n d m o nt h t o t he 1 st Ja n uar y. 
P P D
I n ge neral, if a date is c o m pletel y missi n g, n o i m p utati o n will be perf or me d. I m p ute d dates will 
be st ore d i n t he ti me -t o-e ve nt dataset b ut will re mai n partial i n a n y ot her  rele va nt datasets.  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 3. 2. 3.  
S T R A T E G Y F O R IN T E R C U R R E N T E V E N T S F O R S E C O N D A R Y E F FI C A C Y V A RI A B L E S  
T he f oll o wi n g will be c o nsi dere d i nterc urre nt e ve nts f or t he a nal ysis of t he sec o n dar y efficac y 
e n d p oi nts: 
•  
I nitiati o n of a n alter nati ve a nti-ca ncer t hera p y 
All rec or de d disease assess me nts will be use d f or t he calc ulati o n of best c o nfir me d res p o nse  u ntil 
t he start of a ne w a nti-ca ncer t hera p y, re gar dless of t he st u d y treat me nt stat us.  
1 3. 2. 4.  
A N A L Y SI S O F S E C O N D A R Y E F FI C A C Y V A RI A B L E S  
1 3. 2. 4. 1.  
Best O verall Res p o nse  
T he n u m ber a n d perce nta ge of patie nts wit h a best o verall res p o nse of C R, P R, S D, P D or N E 
will be prese nte d.  
1 3. 2. 4. 2.  
O bjecti ve Res p o nse Rate  
O bjecti ve res p o nse rate a n d t he ass ociate d 2 -si de d 9 5 % e xact c o nfi de nce i nter vals will be 
pr o vi de d se paratel y f or eac h d o se usi n g a met h o d base d o n t he bi n o mial distri b uti o n. C o nfir me d 
res p o nse s u m maries will be pr o vi de d as per R E CI S T v 1. 1 . 
1 3. 2. 4. 3.  
Disease C o ntr ol Rate  
D C R will be s u m marize d i n t he sa me wa y as O R R. 
1 3. 2. 4. 4.  
Ti me t o E ve nt E n d p oi nts  
T he ti me t o e ve nt e n d p oi nts will be s u m marize d usi n g Ka pla n- Meier q ua ntile  esti mates al o n g 
wit h 2 -si de d 9 5 % CIs, wit h t he e xce pti o n of ti me t o res p o nse w hic h, will o nl y be s u m marize d 
wit h descri pti ve statistics ( mi n, ma x, me dia n, 1 st q ua ntile, 3r d q ua ntile). 
P P D
P F S will be gra p hicall y prese nte d usi n g K a pla n-Meier pl ots.  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4.  S A F E T Y O U T C O M E S  
U nless ot her wise s pecifie d, all safet y o ut p uts will be prese nte d i n t hree sets, o ne f or eac h 
c o m bi nati o n res pecti vel y . F or eac h ta ble f or a partic ular c o m bi nati o n, t he data will be prese nte d 
si de b y si de wit h Part 1 d ose le vel 1, Part 1 d ose le vel 2, a n d T otal.  
F or selecte d safet y o utc o mes a nal ysis will be perf or me d  b y c o m bi nati o n part ner (se paratel y f or 
eac h part ner a n d  acr oss all part ners p o ole d), d ose gr o u p, a n d f or m ulati o n ( Ori gi nal F or m ulati o n,  
M o difie d F or m ulati o n, or All F or m ulati o ns).  
1 4. 1.  
A D V E R S E E V E N T S  
A d verse E ve nts ( A Es) will be c o de d usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) ce ntral c o di n g dictio nar y, wit h t he latest versi o n pri or t o t he data base l oc k . 
Treat me nt e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as A Es t hat starte d or w orse ne d i n 
se verit y o n or after t he first d ose of st u d y me dicati o n. 
See A p pe n di x 2 f or ha n dli n g of partial dates f or A Es.  I n the case w here it is n ot p ossi ble t o 
defi ne a n A E as treat me nt e mer ge nt or n ot, t he A E will be classifie d b y t he w orst case (i.e. 
treat me nt e mer ge nt).  
Listi n gs  will i ncl u de T E A Es a n d N o n-T E A Es.  C yt o ki ne or m A B i nf usi o n relate d A Es will als o 
be pres e nte d. 
1 4. 1. 1.  
A L L T E A E S  
A n o ver vie w s u m mar y of A Es, i ncl u di n g c o u nts a n d perce nta ges of partici pa nt s wit h a n y A E, 
A Es relate d t o a n y st u d y treat me nt, A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y treat me nt, 
A Es relate d t o st u d y treat me nt lea di n g t o per ma ne nt treat me nt disc o nti n uati o n, Gra de 3/ 4 A Es,  
Relate d Gra de 3/ 4 A Es S A Es, S A Es relate d t o st u d y treat me nt, fatal S A Es, a n d fatal S A Es 
relate d t o st u d y treat me nt will be pr o d uce d. 
P P D
Se verit y is classe d acc or di n g t o t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( N CI -C T C A E  versi o n 4). T h e ma xi m u m gra de, as rec or de d i n t he e C R F will be 
use d f or t he s u m maries.  T E A Es starti n g after t he first d ose of st u d y me dicati o n wit h a missi n g 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
se verit y will be i ncl u de d i n t he s u m maries u n der gra de ‘ U n k n o w n’.  
A s u m mar y of n u m ber a n d perce nta ge of partici pa nts wit h a n y a d verse e ve nts b y ma xi m u m 
gra de will be pr o d uce d. A Es will be s orte d b y S O C a n d P T i n desce n di n g or der of t otal i nci de nce 
of S O C a n d b y al p ha betic or der f or a n y P T wit h e q ual i nci de nce wit hi n a S O C. T he s u m mar y 
will use t he f oll o wi n g al g orit h ms f or c o u nti n g t he partici pa nt s: 
•  
Preferre d ter m r o w : Partici pa nt s e x perie nci n g t he sa me A E preferre d ter m se veral ti mes 
wit h differe nt gra des will o nl y be c o u nte d o nce wit h t he ma xi m u m gra de.  
•  
S O C r o ws: Eac h partici pa nt is c o u nte d o nl y o nce at t he ma xi m u m gra de at eac h S O C le vel 
alt h o u g h t he y ma y ha ve se veral  differe nt preferre d ter m e ve nts wit hi n t he sa me S O C.  
•  
A n y e ve nt r o w : Eac h partici pa nt  wit h at least o ne a d verse e ve nt will be c o u nte d o nl y o nce at 
t he ma xi m u m gra de n o matter h o w ma n y e ve nts t he y ha ve. 
I n a d diti o n, t he fre q ue nc y a n d perce nta ge of A Es (all gra des) will be s u m marize d a n d dis pla ye d 
i n desce n di n g or der of t otal i nci de nce b y P T o nl y. 
1 4. 1. 1. 1.  
Relati o ns hi p t o St u d y Me dicati o n  
A “relate d” T E A E is defi ne d as a T E A E wit h a reas o na ble p ossi bilit y of bei n g relate d t o a n y 
st u d y me dicati o n as i n dicate d i n t he e C R F b y t he i n vesti gat or. Relate d T E A E’s will be 
cate g orize d as relate d t o G S K 1 7 9 5 0 9 1 o nl y, relate d t o c o m bi nati o n part ner o nl y or relate d t o 
b ot h. T E A Es wit h a missi n g relati o ns hi p t o st u d y me dicati o n will be re gar de d as relate d t o st u d y 
me dicati o n. If a p artici pa nt  re p orts t he sa me A E m ore t ha n o nce, t he A E wit h t he w orst case 
relati o ns hi p t o st u d y me dicati o n will be use d i n t he c orres p o n di n g relati o ns hi p s u m maries. T he 
treat me nt relate d A E s u m maries will be prese nte d b y ma xi m u m gra de b y P T o nl y. 
1 4. 1. 2.  
C O M M O N N O N -S E RI O U S T E A E S  
P P D
A s u m mar y ta ble of n o n-seri o us a d verse e ve nts b y s yste m or ga n class a n d preferre d ter m 
( n u m ber of partici pa nts a n d occ urre nces) wit h occ urre nces > = 5 %  of all s u bjects wit hi n a 
c o m bi nati o n c o h ort will be ge nerate d . N o r o u n di n g will be a p plie d f or i ncl u di n g a n e ve nt i n t his 
ta ble, i.e. a n e ve nt wit h i nci de nce of 4. 9 % will n ot be i ncl u de d. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4. 1. 3.  
T E A E S L E A DI N G T O D I S C O N TI N U A TI O N O F S T U D Y M
E DI C A TI O N  
T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y me dicati o n will be i de nti fie d fr o m t he 
A d verse E ve nt a n d Seri o us A d verse E ve nt e C R F pa ge s w here t he acti o n ta ke n wit h t he st u d y 
treat me nt was selecte d as “St u d y treat me nt  wit h dra w n”.  
F or T E A Es lea di n g t o disc o nti n uati o n of st u d y me dicati o n, s u m maries of i nci de nce rates 
(fre q ue ncies a n d perce nta ges) b y P T o nl y will be pre pare d. A se parate listi n g of T E A Es lea di n g 
t o disc o nti n uati o n of st u d y me dicati o n will be pr o d uce d.  
1 4. 1. 4.  
T E A E S L E A DI N G T O D O S E M O DI FI C A TI O N S  
T E A Es lea di n g t o d ose re d ucti o ns a n d T E A Es lea di n g t o d ose dela ys will be i de ntifie d fr o m t he 
A d verse E ve nt a n d Seri o us A d verse E ve nt e C R F pa ges b y t he acti o n ta ke n wit h t he st u d y 
treat me nt. A n A E lea di n g t o d ose m o dificati o n is a n A E f or w hic h eit her d ose re d uce d or d ose 
dela ye d was rec or de d o ne of t he acti o ns ta ke n f or t he A E . S u m mar y ta bles of T E A Es lea di n g t o 
d ose re d ucti o ns a n d d ose dela ys b y P T  o nl y will be pre pare d.  
1 4. 1. 5.  
S E RI O U S A D V E R S E E V E N T S  
Seri o us a d verse e ve nts ( S A Es) are t h ose e ve nts rec or de d o n t he Seri o us A d verse E ve nts pa ge of 
t he e C R F. A s u m mar y of seri o us T E A Es b y P T o nl y will be pre pare d.  I n a d diti o n S A Es will als o 
be s u m marize d b y relati o ns hi p t o G S K 1 7 9 5 0 9 1 o nl y, relati o ns hi p t o c o m bi nati o n part ner o nl y 
a n d relati o ns hi p t o b ot h .  Se parate listi n g s of fatal a n d n o n-fatal seri o us T E A Es will als o be 
pr o d uce d. F or c o m m o n S A Es, a  s u m mar y ta ble of seri o us a d verse e ve nts b y s yste m or ga n class 
a n d preferre d ter m ( n u m ber of partici pa nts a n d occ urre nces) wit h occ urre nces > = 5 %  of all 
s u bjects wit hi n a c o m bi nati o n c o h ort will be ge nerate d . N o r o u n di n g will be a p plie d f or 
i ncl u di n g a n e ve nt i n t his ta ble, i.e. a n e ve nt wit h i nci de nce of 4. 9 % will n ot be i ncl u de d. 
1 4. 1. 6.  
F A T A L A D V E R S E E V E N T S  
P P D
Fatal T E A Es are t h ose e ve nts w hic h are rec or de d as “Fatal” o n t he  Seri o us  A d verse E ve nts pa ge 
of t he e C R F. A s u m mar y of fatal T E A Es b y P T  o nl y will be pre pare d.  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 3 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4. 1. 7.  
A D V E R S E E V E N T S O F S P E CI A L IN T E R E S T  
A d verse e ve nts of s pecial i nterest ( A E SIs) are defi ne d as e ve nts of p ote ntial i m m u n ol o gic 
eti ol o g y. A Es will be c o nsi dere d A E SIs if i n dicate d b y t he c hec k b o x o n t he A d verse E ve nt a n d 
Seri o us A d verse E ve nt e C R F pa ges .  
T he f oll o wi n g A E SIs will be s u m marize d P T  o nl y. I n a d diti o n, t he s u m mar y of e ve nt 
c haracteristics f or eac h cate g or y of A E S I will als o be pr o vi de d, i ncl u di n g n u m ber of partici pa nts 
wit h a n y e ve nt, n u m ber of e ve nts, n u m ber of partici pa nts wit h a n y e ve nt t hat is seri o us, n u m ber 
of partici pa nt s wit h a n y e ve nt t hat is relate d t o st u d y treat me nt, t he o utc o me of t he e ve nt, 
ma xi m u m N CI -C T C A E gra de a n d t he acti o n ta ke n f or t he e ve nt. T he perce nta ge will be 
calc ulate d i n t w o wa ys, o ne wit h n u m ber o f partici pa nt s wit h a n e ve nt as t he de n o mi nat or a n d 
t he ot her wit h t otal n u m ber of partici pa nts as t he de n o mi nat or. T he w orst- case a p pr oac h will be 
a p plie d at partici pa nt  le vel f or t he e ve nt o utc o me a n d ma xi m u m gra de, i.e. a partici pa nt  will o nl y 
be c o u nte d o nce as t he w orst case  fr o m all t he e ve nts e x perie nce d b y t he partici pa nt . F or acti o n 
ta ke n t o a n e ve nt, partici pa nt will be c o u nte d o nce u n der eac h acti o n, e. g. if a partici pa nt has a n 
e ve nt lea di n g t o b ot h st u d y treat me nt disc o nti n uati o n a n d d ose re d uc ti o n, t he partici pa nt will be 
c o u nte d o nce u n der b ot h acti o ns.  A E SIs will be s u m marize d se paratel y as C yt o ki ne -relate d A Es 
a n d I m m u ne- relate d A Es as c ollecte d o n t he C R F. C yt o ki ne-relate d A Es 
Car di o p ul m o nar y or he m o d y na mic t o xicit y starti n g wit hi n 2 4 h o ur s of st u d y treat me nt t hat 
re q uires > 4 0 % Fi O 2, vas o press or a d mi nistrati o n, a ntiarr h yt h mic a ge nt or ot her si g nifica nt 
me dical i nter ve nti o n. As yst ole, as meas ure d b y E C G, or bra d ycar dia t hat is s y m pt o matic a n d 
re q uires me dical i nter ve nti o n. 
1 4. 1. 7. 1.  
I m m u ne-relate d A Es 
P n e u m o nitis (r ep ort e d as A E SI if  ≥ Gr a d e 2)  
Ac ut e i nt erstiti al p n e u m o nitis  
I nt erstiti al l u n g dis e as e 
P n e u m o nitis  
C olitis (r e p ort e d as A E SI if ≥ Gr ad e 2 or a ny gr a de r es ulti n g i n d os e m o dific ati o n or us e of syst e mic st er oi ds t o 
tr e at t h e A E) 
I nt esti n al O bstr ucti o n 
C olitis  
C olitis micr osc opic  
E nt er oc olitis  
E nt er oc olitis h e m orr h a gic  
G astr oi nt esti n al p erf or ati o n  
N ecr otizi n g c olitis  
Di arr h e a  
 
E n d ocri n e (r e p ort e d as A E SI if  ≥ Gr a d e 3 or ≥ Gr a d e 2 a n d r es ulti n g i n d os e m o dific ati o n or us e of syst e mic 
st er oi ds t o tr e at th e A E) 
A dr e n al I ns ufficie ncy  
Hy p ert hyr oi dis m  
Hy p o p hysitis  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Hy p o pit uit aris m  
Hy p ot hyr oi dis m  
T hyr oi d dis or d er  
T hyr oi ditis  
Hy p er glyc e mi a, if ≥Gr a d e 3 a n d ass oci at e d wit h k et osis or m et a bolic 
aci d osis ( D K A)  
E n d ocri n e (r e p ort e d as A E SI) 
Ty p e 1 di a b et es m ellit us (if n e w o ns et)  
 
 
H e m at ol o gic (r ep ort e d as A E SI if  ≥ Gr a d e 3 or any gr a d e r es ulti ng i n d os e m o dific ati o n or us e of syst e mic 
st er oi ds t o tr e at th e A E) 
A ut oi m m u n e h e m olytic a n e mi a  
A pl astic a n e mi a  
T hr o m b otic T hr o m b ocyt o p e nic 
P ur p ur a ( T T P)  
I di o p at hic ( or i m m u n e) 
T hr o m b ocyt o p eni a P ur p ur a  (I T P)  
Diss e mi n at e d I ntr av asc ul ar 
C o a g ul ati o n ( DI C)  
H e m olytic Ur e mic Sy n dr o m e 
( H U S) 
A ny Gr a d e 4 a ne mi a r e g ar dl ess of u n d erlyi n g m ec h a nis m  
H e p atic (r e p ort ed as A E SI if  ≥ Gr a d e 2, or a ny gr a d e r es ulti n g i n d os e m o dific ati o n or us e of syst e mic st er oi ds t o 
tr e at t h e A E) 
H e p atitis  
A ut oi m m u n e h e p atitis  
Tr a ns a mi n as e elev ati o ns ( A L T 
a n d/ or A S T)  
I nf usi o n R e acti ons (r e p ort e d as A E SI f or a ny gr ad e) 
All er gic r e acti o n  
A n a p hyl axis  
 
S er u m sick n ess  
I nf usi o n r e acti o ns 
I nf usi o n-lik e r e acti o ns 
N e ur ol o gic (r e p ort e d as A E SI f or a ny gr a d e)  
A ut oi m m u n e n e ur o p at hy  
G uill ai n -B arr é sy n dr o m e  
D e my eli n ati n g p oly n e ur o p at hy  
My ast h e nic sy n dr o m e  
 
 
Oc ul ar (r e p ort as A E SI if  ≥ Gr ad e 2 or a ny gr a de r es ulti n g i n d os e m o dific ati o n or us e of syst e mic st er oi ds t o tr eat 
t h e A E) 
Uv eitis  
Iritis 
 
R e n al (r e p ort e d as A E SI if  ≥ Gr a d e 2)   
N e p hritis  
N e p hritis a ut oi m m u n e  
R e n al F ail ur e  
R e n al f ail ur e ac ut e  
Cr e ati ni n e el ev ati o ns (r e p ort as A E SI if ≥Gr a d e 3 or a ny gr a d e r es ulti n g 
i n d os e m o dific ati o n or us e of syst e mic st er oi ds to tr e at t h e A E) 
Ski n (r e p ort e d as A E SI f or a ny gr a d e)  
D er m atitis exf oli ativ e  
Eryt h e m a m ultifor m e  
St ev e ns -J o h ns on sy n dr o m e 
T oxic e pi d er m al n ecr olysis  
 
 
Ski n (r e p ort e d as A E SI if ≥ Gr a de 3)  
Pr urit us  
R as h  
R as h g e n er aliz ed  
R as h m ac ul o -p ap ul ar  
 
 
A ny r as h c o nsi der e d cli nic ally sig nific a nt i n t h e p hysici a n’s j u d g m e nt  
Ot h er (r e p ort e d as A E SI f or a ny gr a d e)  
My oc ar ditis  
P a ncr e atitis  
P eric ar ditis  
A ny ot h er Gr a d e 3 ev e nt w hic h is c o nsi d er e d i m mu n e -r el at e d by th e p hysici a n 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 1  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 4. 2.  
D E A T H S  
I n t he e ve nt t hat a partici pa nt  has wit h dra w n c o nse nt, n o data after t he wit h dra wal of c o nse nt 
date fr o m t his partici pa nt  (i ncl u di n g deat h) will  a p pear i n t he data base . T his s h o ul d be e ns ure d as  
part of t he data clea ni n g pr ocess. All deat hs will be s u m marize d base d o n t he n u m ber a n d 
perce nta ge of partici pa nt s. T his s u m mar y will classif y partici pa nt s b y ti me of deat h relati ve t o 
t he last d ose of me dicati o n ( > 3 0 da ys or ≤3 0 da ys) a n d pri mar y ca use of deat h ( disease u n der 
st u d y, S A E relate d t o st u d y treat me nt, or ot her). A s u p p orti ve listi n g will be ge nerate d t o pr o vi de 
partici pa nt -s pecific details o n partici pa nts w h o die d. 
1 4. 3.  
S T U D Y M E DI C A TI O N E X P O S U R E  
T he n u m ber of d oses a d mi nistere d of st u d y treat me nt, t he d urati o n of e x p os ure , t he c u m ulati ve 
d ose, d ose i nte nsit y a n d relati ve d ose i nte nsit y will be s u m marize d  f or eac h of G S K 1 7 9 5 0 9 1 a n d 
its c o m bi nati o n part ners wit h mea n, me dia n, sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m.  
D ose dela ys, re d ucti o ns, a n d escalati o ns will be s u m marize d b y n u m ber of m o dificati o ns a n d 
reas o ns f or m o dificati o ns. T he s u m maries of d ose m o dificati o ns will be pr o vi de d o nl y if t he data 
warra nt. All t he d ose re d ucti o ns, d ose escalati o ns, a n d misse d d oses a n d d ose dela ys will be 
liste d se paratel y. 
A h oriz o ntal bar gra p h of d urati o n of treat me nt i n da ys will be pr o d uce d. T his gra p h will dis pla y 
o verall d urati o n of treat me nt i n da ys ( of a n y treat me nt) f or eac h partici pa nt , al o n g wit h t he 
treat me nt t hat t he partici pa nt  recei ve d, t heir pri mar y t u m or t y pe a n d t he partici pa nt ’s best 
res p o nse. 
1 4. 3. 1.  
D E RI V A TI O N S  
If t he d ose date is partial a n i m p ute d date will be use d f or a n y calc ulati o ns.  If t he da y is missi n g 
t he date will be i m p ute d  as t he first da y of t he m o nt h or t he date of first d ose, w hic he ver occ urs 
earliest. If t he da y a n d m o nt h are missi n g t he date will be i m p ute d as 1 st Ja n uar y or t he date of 
first d ose, w hic he ver occ urs earliest. 
P P D
T he d urati o n of e x p os ure t o st u d y treat me nt i n da ys will be calc ulate d acc or di n g t o t he f oll o wi n g 
r ules: 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 2  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  If t he last d ose is pri or t o wee k 1 3 da y 1, t he n D urati o n of E x p os ure i n Da ys = Treat me nt 
St o p Date – Treat me nt Start Date + 7 . 
•  If t he last d ose is wee k 1 3 da y 1 or later, t he n D urati o n of E x p os ure i n Da ys = Treat me nt 
St o p Date – Treat me nt Start Date + 2 1.  
C u m ulati ve d ose is e q ual t o t he s u m of all act ual d oses recei ve d d uri n g t he treat me nt peri o d. 
D ose i nte nsit y will be calc ulate d as t he act ual c u m ulati ve d ose / treat me nt d urati o n  i n 
wee k s.Relati ve d ose i nte nsit y is calc ulate d as ( D ose I nte nsit y / Pla n ne d D ose I nte nsit y) x 1 0 0. 
W here t he pla n ne d d ose i nte nsit y is t he pla n ne d c u m ulati ve d ose / treat me nt d urati o n i n wee ks. 
1 4. 4.  
D O S E L I MI TI N G T O XI CI TI E S  
T he n u m ber a n d perce nta ge of partici pa nts w h o e x perie nce a n y D ose Li miti n g T o xicit y ( D L T) 
f oll o wi n g t he first d ose of st u d y dr u g will be prese nte d .  
Listi n g will be pr o vi de d t o pr o vi de t he partici pa nts w h o e x perie nce a n y D ose Li miti n g T o xicit y 
( D L T) 
1 4. 5.  
L A B O R A T O R Y E V A L U A TI O N S  
Res ults fr o m t he ce ntral la b orat or y will be i ncl u de d i n t he re p orti n g of t his st u d y f or 
He mat ol o g y, Bl o o d C he mistr y a n d Uri nal ysis. A list of la b orat or y assess me nts t o be i ncl u de d i n 
t he o ut p uts is i ncl u de d i n t he pr ot oc ol, a p pe n di x 2.  
Prese ntati o ns will use SI U nits.  
Q ua ntitati ve la b orat or y meas ure me nts re p orte d as “ < X” (i.e. bel o w t he l o wer li mit of 
q ua ntificati o n ), or “ > X” (i.e. a b o ve t he u p per li mit of q ua ntificati o n), will be c o n verte d t o X/ 2 or 
X res pecti vel y f or t he p ur p ose of q ua ntitati ve s u m maries, b ut will be prese nte d as rec or de d (i.e. 
as “ < X” or “ > X” i n t he listi n gs, w here X has bee n c o n verte d i nt o t he SI u nit ). 
T he f oll o wi n g s u m maries will be pr o vi de d f or la b orat or y data: 
•  
P P D
I ncrease i n N CI -C T C A E  gra de fr o m baseli ne will be  s u m marize d at eac h sc he d ule d visit a n d 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
f or t he ma xi m u m p ost-baseli ne gra de i ncrease  (f or para meters w here N CI-C T C A E gra des are 
a p plica ble). T he i ncrease t o a ma xi m u m gra de of 3 a n d t he i ncrease t o a ma xi m u m gra de of 
4 , as well as a n y gra de i ncrease fr o m baseli ne, will be s u m marize d. Missi n g baseli ne gra des 
will be ass u me d as gra de 0. F or la b orat or y tests t hat  are gra de d f or b ot h l o w a n d hi g h val ues, 
s u m maries will be d o ne se paratel y a n d la bele d b y directi o n, e. g. s o di u m will be s u m marize d 
as h y p o natre mia a n d h y per natre mia. 
•  
F or la b tests t hat are n ot gra da ble b y N CI -C T C A E, s u m maries of w orst case c ha n ges fr o m 
baseli ne wit h res pect t o n or mal ra n ge will be ge nerate d. Decreases t o l o w, c ha n ges t o n or mal 
or n o c ha n ges fr o m baseli ne, a n d i ncreases t o hi g h will be s u m marize d at eac h sc he d ule d 
visit as well as f or t he w orst case p ost -baseli ne . If a partici pa nt  has a decrease t o l o w a n d a n 
i ncrease t o hi g h d uri n g t he sa me ti me i nter val, t he n t he partici pa nt is c o u nte d i n b ot h t he 
“ Decrease t o L o w” cate g ories a n d t he “I ncrease t o Hi g h” cate g ories.  
•  
B o x pl ots of c ha n ge fr o m baseli ne b y visit (f or q ua ntitati ve meas ure me nts) 
•  
Listi n g of partici pa nt s wit h la b orat or y res ults o utsi de t he n or mal ra n ge 
•  
Listi n gs of all la b orat or y para meters. Se parate listi n gs will be pr o d uce d f or  He mat ol o g y, 
Bl o o d C he mistr y a n d Uri nal ysis (i ncl u di n g res ults f or b ot h n u meric a n d cate g orical 
para meters).  
U nless ot her wise s pecifie d, t he de n o mi nat or i n perce nta ge calc ulati o n at eac h sc he d ule d visit 
will be base d o n t he n u m ber of partici pa nt s wit h n o n-missi n g val ue at eac h partic ular visit.  O nl y 
sc he d ule d visits  f or a partic ular la b para meter will be i ncl u de d i n t he s u m mar y of t he para meter.  
1 4. 5. 1.  
IM M U N O G E NI CI T Y  
I m m u n o ge nicit y res ults of a nti- G S K 3 1 7 4 9 9 8 a n d a nti- G S K 3 3 5 9 6 0 9 a nti b o d y testi n g will be 
re p orte d,. T he a nal ysis will be base d o n T R T a n d will i ncl u de t he f oll o wi n g s u m mar y ta bles:  
•  S u m mar y of I nci de nce of a nti-dr u g a nti b o dies ( A D A) :   fre q ue nc y of A D A i nci de nce  will 
be s u m marize d b y visit as well as o verall  A D A i nci de nce ( p ositi ve at a n y ti me). 
•  
P P D
S u m mar y of P ositi ve A nti - Dr u g A nti b o d y I nci de nce: T he n u m ber of partici pa nt s wit h 
tra nsie nt p ositi ve or persiste nt p ositi ve A D A will be s u m marize d. Tra nsie nt p ositi ve is 
defi ne d as si n gle p ost d ose p ositi ve or m ulti ple p ositi ves at n o n -se q ue ntial ti me p oi nts. 
P P D


Gl a x o S mit h Kli n e  
P R O T O C O L 2 0 4 6 8 6  
A n a l ysi s Pl a n  
P a g e 4 4  of 7 0  
D o c u m e nt:  
 
A ut h or:  
V er si o n N u m b er:  
1. 0  
V er si o n D at e:  
   [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
Persiste nt p ositi ve is defi ne d as p ositi ve f or at least t w o c o nsec uti ve visits or a si n gle 
p ositi ve  at t he last teste d visit . If a s u bject ca n be classifie d as b ot h tra nsie nt p ositi ve a n d 
persista nt p ositi ve t he y will be s u m marize d as persista nt p osi ti ve o nl y.  
•
If t he data all o ws, the titer will be s u m marize d wit h q uartile s. T he hi g hest titer val ue per
partici pa nt  will be use d i n t he s u m mar y. T he titer will o nl y be a vaila ble w he n it is A D A
p ositi ve.
T he i nci de nce a n d titer of A D A will be prese nte d at partici pa nt  le vel b y visit  i n a listi n g. 
1 4. 5. 2.  
 D E RI V A TI O N S  
W hite bl o o d cell differe ntials ( Ne utr o p hils, L y m p h oc ytes, M o n oc ytes, E osi n o p hils a n d 
Bas o p hils) s h o ul d be c o n verte d fr o m a bs ol ute val ues i nt o perce nta ges usi n g t he f oll o wi n g 
e q uati o n: 
𝑙𝑙𝑙𝑙𝛼𝛼𝛽𝛽𝑙𝑙𝑙𝑙𝑑𝑑𝑑𝑑𝑚𝑚𝐷𝐷𝐷𝐷𝑙𝑙 𝑃𝑃𝐷𝐷𝐷𝐷𝑃𝑃𝐷𝐷𝑙𝑙𝐷𝐷𝐷𝐷𝑃𝑃𝐷𝐷 = (( 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑙𝑙𝐷𝐷𝐷𝐷𝐷𝐷𝑙𝑙  𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝑙𝑙𝐴𝐴𝐷𝐷𝐷𝐷 𝐶𝐶𝐴𝐴𝐴𝐴𝑙𝑙𝐷𝐷) /(𝑊𝑊𝑊𝑊𝐶𝐶 𝐶𝐶𝐴𝐴𝐴𝐴𝑙𝑙𝐷𝐷))  × 1 0 0  
1 4. 5. 3.  
N CI -C T C A E  G R A DI N G  FO R L A B O R A T O R Y D A T A  
La b orat or y  meas ure me nts will  be gra de d  usi n g t he NCI -C T C A E,  Versi o n 4 s yste m as defi ne d  in  
t he f oll o wi n g li nk: 
htt ps:// w w w.e ortc. be/ser vices/ d oc/ctc/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6- 1 4 _ Q uic k Refere nce _ 5 x 7. p df  
1 4. 6.  
E C G  E V A L U A TI O N S  
Res ults fr o m t he ce ntral E C G ( Electr ocar di o gra m) Rea di n g Ce ntre will be i ncl u de d i n t he 
re p orti n g of t his st u d y.  
T he f oll o wi n g E C G para meters will be re p orte d f or t his st u d y:  
•
P R I nter val ( msec)
•
Q R S I nter val ( msec)
•
Q Tc F I nter val ( msec)
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
H R ( b p m)  
•  
R R ( msec)  
•  
O verall assess me nt of E C G (I n vesti gat or’s j u d g me nt):  
o  N or mal  
o  A b n or mal, N ot Cli nicall y Si g nifica nt ( A N C S)  
o  A b n or mal, Cli nicall y Si g nifica nt ( A C S)  
T he f oll o wi n g s u m maries will be pr o vi de d f or E C G data: 
•  
Act ual a n d c ha n ge fr o m baseli ne b y visit (f or q ua ntitati ve meas ure me nts) 
•  
Q T  a n d Q Tc F i nter val i ncrease  fr o m baseli ne t o a n y gra de, gra de 2 a n d gra de 3 b y sc he d ule d 
ti me p oi nt a n d f or t he w orst p ost-baseli ne res ult acc or di n g t o mar ke dl y a b n or mal criteria  (see 
secti o n 1 4. 6 . 2 bel o w) 
•  
I nci de nce of E C G a b n or malities b y visit 
•  
I nci de nce of mar ke dl y a b n or mal val ues at a n y ti me p ost- baseli ne f or P R a n d Q R S 
•  
A fi g ure pl otti n g t he baseli ne Q T, a n d Q Tc F val ues a n d t he w orst- case p ost -baseli ne val ues. 
T he fi g ure will ha ve refere nce li nes at 4 5 0 a n d 5 0 0 msec f or b ot h t he or di nate a n d t he 
a bscissa a xes. T here will be dia g o nal refere nce li nes at e q ualit y (i.e. a 4 5 de gree li ne), at 
e q ualit y pl us 3 0 msec, a n d at e q ualit y pl us 6 0 msec. 
•  
Listi n g of partici pa nt s meeti n g a n y of t he mar ke dl y a b n or mal criteria  defi ne d i n Secti o n 
1 4. 6. 2 . 
•  
All E C G para meters a n d fi n di n gs will be prese nte d i n a listi n g. W here c ollecte d i n tri plicate 
wit hi n a si n gle visit t he mea n  of t he re plica tes will be use d f or calc ulati n g t he s u m mar y 
statistics. 
1 4. 6. 1.  
E C G  S P E CI FI C D E RI V A TI O N S  
•  
P P D
Fri dericia’s C orrecti o n ( msec)  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
o  𝑙𝑙𝑙𝑙𝛼𝛼𝛽𝛽 (ms e c)  =
𝑙𝑙𝑙𝑙 (𝑑𝑑𝑑𝑑)
�𝑚𝑚𝐷𝐷 (𝐷𝐷𝑙𝑙) /1 0 0 0
3
 
 
1 4. 6. 2.  
E C G  M
A R K E D L Y A B N O R M A L C RI T E RI A  
Mar ke dl y a b n or mal q ua ntitati ve E C G meas ure me nts will be i de ntifie d  i n acc or da nce wit h t he 
f oll o wi n g pre defi ne d mar ke dl y a b n or mal criteria: 
•  
A bs ol ute val ues f or Q T, a n d Q Tc F will be classifie d as:  
o  > 4 5 0 - 4 8 0 msec ( Gra de 1) 
o  > 4 8 0 – 5 0 0 msec ( Gra de 2) 
o  > 5 0 0 msec ( Gra de 3) 
•  
C ha n ge fr o m Baseli ne f or Q T, a n d Q Tc F will be classifie d as: 
o  > 3 0 - 6 0 msec i ncrease fr o m baseli ne  
o  > 6 0 msec i ncrease fr o m baseli ne  
•  
A bs ol ute val ues f or P R i nter val will be classifie d as:  
o  > 2 0 0 msec 
•  
A bs ol ute val ues f or Q R S i nter val will be classifie d as:  
o  > 1 2 0 msec  
1 4. 7.  
V I T A L S I G N S 
T he f oll o wi n g Vital Si g ns meas ure me n ts will be re p orte d f or t his st u d y: 
•  
S yst olic Bl o o d Press ure ( m m H g)  
•  
Diast olic Bl o o d Press ure ( m m H g)  
•  
P P D
P ulse Rate ( b p m)  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
Te m perat ure ( ⁰C)  
•  
Wei g ht ( k g)  
•  
Hei g ht (c m) a n d B MI ( k g/ m 2) - liste d o nl y. 
T he f oll o wi n g s u m maries will be pr o vi de d f or vital s i g ns data: 
•  
Act ual a n d c ha n ge fr o m baseli ne b y visit  
•  
I ncrease/ decrease fr o m baseli ne t o a n y cate g or y, cate g or y 2 , a n d cate g or y 3 b y sc he d ule d 
ti me p oi nt a n d f or t he w orst p ost- baseli ne  res ult acc or di n g t o mar ke dl y a b n or mal criteria  
•  
B o x pl ots of c ha n ge fr o m ba seli ne b y visit (f or q ua ntitati ve meas ure me nts) 
•  
Listi n g of partici pa nts meeti n g mar ke dl y a b n or mal criteria  
1 4. 7. 1.  
V I T A L S I G N S M
A R K E D L Y A B N O R M A L C RI T E RI A  
Mar ke dl y a b n or mal q ua ntitati ve Vital Si g ns meas ure me nts will be i de ntifie d i n acc or da nce wit h 
t he f oll o wi n g pre defi ne d mar ke dl y a b n or mal criteria: 
V ari a ble 
U nit  
L o w  
R a n ge 
Hi g h  
R a n ge 
I ncrease d S B P  
m m H g  
> 1 4 0 
≥1 6 1 
≥1 8 1 
< 1 6 1 
< 1 8 1 
Decrease d S B P  
m m H g  
 
< 8 0 
I ncrease d D B P  
m m H g  
> 9 0 
≥1 0 1 
≥1 1 1 
< 1 0 1 
< 1 1 1 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
V ari a ble 
U nit  
L o w  
R a n ge 
Hi g h  
R a n ge 
Decrease d D B P  
m m H g  
 
< 5 0 
I ncrease d Heart rate  
B p m  
> 1 0 1 
≥1 1 6 
≥1 3 1 
< 1 1 6 
< 1 3 1 
Decrease d Heart rate  
B p m  
 
< 4 5 
C ha n ge i n Heart Rate 
B p m  
> 2 0 
≥3 6 
≥5 1 
< 3 6 
< 5 1 
I ncrease d B o d y te m perat ure 
˚ C 
> 3 8. 0 
≥3 8. 6 
≥3 9. 1 
< 3 8. 6 
< 3 9. 1 
C ha n ge i n B o d y te m perat ure 
˚ C 
> 1. 0 
≥1. 6 
≥2. 1 
< 1. 6 
< 2. 1 
1 5.  P H A R M A C O KI N E TI C A N A L Y SI S  
P P D
All s u m maries  a n d p har mac o ki netic ( P K) a nal yses will be base d o n t he P K S a n d will be 
prese nte d b y treat me nt , d ose le vel , f or m ulati o n ( w here a p plica ble), a n d st u d y part. P K 
c o nce ntrati o ns are e x pecte d f or G S K 1 7 9 5 0 9 1, G S K 3 1 7 4 9 9 8, a n d G S K 3 3 5 9 6 0 9, a n d P K 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 4 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
para meters are e x pecte d  f or G S K 1 7 9 5 0 9 1. C o m bi nati o n part ner c o nce ntrati o ns ( G S K 3 1 7 4 9 9 8 
a n d G S K 3 3 5 9 6 0 9 o nl y) will be liste d. 
A n y data e xcl u de d fr o m a nal yses d ue t o pr ot oc ol de viati o ns t hat affect P K will be liste d b ut will 
n ot be i ncl u de d i n s u m maries. I m p orta nt pr ot oc ol de viati o ns or e ve nts t hat c o ul d affect P K are 
c ha n ges t o t he pr oce d ures t hat ma y i m pact t he q ualit y of t he data or a n y circ u msta nces t hat ca n 
alter t he e val uati o n of t he P K.   
1 5. 1.  
P L A S M A C O N C E N T R A TI O N D A T A  
G S K 1 7 9 5 0 9 1 p las ma c o nce ntrati o ns will be s u m marize d b y c o m bi na ti o n part ner (se paratel y f or 
eac h part ner a n d acr oss all part ners p o ole d), d ose gr o u p, f or m ulati o n ( O ri gi nal F or m ulati o n, 
M o difie d F or m ulati o n, or All F or m ulati o ns ), a n d n o mi nal ti me p oi nt usi n g descri pti ve statistics 
( n, n B L O Q ,  mea n, sta n dar d de viati o n, ge o metric mea n, ge o metric % C V  a n d 9 5 % CI f or 
ge o metric mea n, me dia n, mi ni m u m, ma xi m u m). S u bjects w h o u n der we nt a f or m ulati o n s witc h 
d uri n g t he st u d y will o nl y be i ncl u de d i n t he All F or m ulati o ns s u m maries. C o nce ntrati o ns t hat 
are bel ow t he li mit of q ua ntitati o n ( B L O Q) will be treate d as zer o  or L L O Q/ 2  f or t he 
c o m p utati o n of n o n- tra nsf or me d a n d tra nsf or me d descri pti ve statistics , res pecti vel y. If n = 2, 
o nl y n, me dia n, mi ni m u m a n d ma xi m u m will be re p orte d; if n = 1 , o nl y n a n d me dia n wi ll be 
re p orte d.  
T he f oll o wi n g fi g ures will be prese nte d  f or G S K 1 7 9 5 0 9 1 wit h refere nce li ne (s) t o re prese nt t he 
L L O Q :  
•  Me dia n c o nce ntrati o n vers us n o mi nal ti me ( o n c o nti n u o us scale) fi g ures, ge nerate d o n li near 
a n d se mi -l o garit h mic scales f or t he ti me perio d Da y  1 t o Da y 2 1. T hese fi g ures will be 
pre pare d b y c o m bi nati o n part ner (se parate pl ots f or eac h part ner a n d se parate pl ots f or all 
part ners p o ole d) a n d f or m ulati o n (se parate pl ots f or eac h f or m ulati o n). O nl y s u bjects w h o 
recei ve d a si n gle f or m ulati o n t hr o u g h o ut t he treat me nt peri o d ( Ori gi nal or M o difie d) will be 
i ncl u de d i n t hese pl ots. 
•  
P P D
Me dia n c o nce ntrati o n vers us n o mi nal ti me ( o n cate g orical scale) fi g ures, ge nerate d o n li near 
scale f or t he f ull P K assess me nt peri o d . T hese fi g ures will be pre pare d f or all c o m bi nati o n 
part ners p o ole d o nl y, se paratel y b y f or m ulati o n (se parate pl ots f or eac h f or m ulati o n). O nl y 
s u bjects w h o recei ve d a si n gle f or m ulati o n t hr o u g h o ut t he treat me nt peri o d ( Ori gi nal or 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
M o difie d) will be i ncl u d e d i n t hese pl ots. 
•  I n di vi d ual c o nce ntrati o n vers us n o mi nal ti me ( o n cate g orical scale) fi g ures, ge nerate d o n 
li near scale f or t he f ull P K assess me nt peri o d. Fi g ures will be la bele d b y c o m bi nati o n 
part ner, d ose gr o u p, a n d f or m ulati o n ( Ori gi nal, M o difie d, or B ot h). F or s u bjects w h o 
u n der we nt a f or m ulati o n s witc h d uri n g treat me nt  (ie, B ot h), a vertical d otte d li ne will be 
a d de d t o i n dicate t he ti me relati ve ti me of s witc h. 
A listi n g of P K bl o o d sa m ple c ollecti o n ti mes , sa m pli n g ti me de viati o ns, a n d meas ure d 
c o nce ntrati o ns will be pr o vi de d f or G S K 1 7 9 5 0 9 1, G S K 3 1 7 4 9 9 8, a n d G S K 3 3 5 9 6 0 9 ; t he listi n g 
f or G S K 1 7 9 5 0 9 1 will als o i n dicate t he G S K 1 7 9 5 0 9 1 f or m ulati o n use d. A partici pa nt  listi n g of 
all G S K 1 7 9 5 0 9 1 c o nce ntrati o n -ti me data f or eac h treat me nt will be prese nte d. 
1 5. 2.  
P H A R M A C O KI N E TI C P A R A M E T E R S  
P har mac o ki netic para meters f or G S K 1 7 9 5 0 9 1 will be calc ulate d b y sta n dar d n o n- c o m part me ntal 
a nal ysis acc or di n g t o c urre nt w or ki n g practices a n d usi n g t he c urre ntl y s u p p orte d versi o n of 
P h oe ni x Wi n N o nli n Versi o n 8. 3 or hi g her, or S A S Versi o n 9. 4 or hi g her.  
All calc ulati o ns of n o n- c o m part me ntal para meters will be base d o n act ual sa m pli n g ti mes 
relati ve t o t he d osi n g ti me f or G S K 1 7 9 5 0 9 1. P har mac o ki netic para meters liste d bel o w will be 
deter mi ne d fr o m t he plas ma c o nce ntrati o n -ti me data, as data per mit. All A U Cs will be calc ulate d 
usi n g t he li near tra pez oi dal r ule f or eac h i ncre me ntal tra pez oi d a n d t he l o g tra pez oi dal r ule f or 
eac h decre me ntal tra pez oi d.  
P P D
Pre d ose N Q val ues a n d N Q val ues pri or t o t he first q ua ntifia ble c o nce ntrati o n i n a c o nce ntrati o n-
ti me pr ofile will be set t o zer o f or P K a nal ysis, calc ulati o n of descri pti ve statistics, a n d 
i n di vi d ual partici pa nt  pl ots. N Q val ues after t he last q ua ntifia ble c o nce ntrati o n i n a pr ofile will 
be set t o missi n g f or P K a nal ysis a n d i n di vi d ual partici pa nt  pl ots, b ut will be set t o zer o f or 
calc ulati o n of descri pti ve statistics. If a si n gle N Q val ue occ urs bet wee n meas ura ble 
c o nce ntrati o ns i n a pr ofile, t he N Q s h o ul d ge nerall y be o mitte d (set t o missi n g) i n t he deri vati o n 
of p har mac o ki netic para meters, statistical a nal ysis, a n d t he i n di vi d ual s u bject pl ots . If t here are 2 
or m ore s uccessi ve e m be d de d N Q val ues bet wee n q ua ntifia ble c o nce ntrati o ns, t he N Q val ues 
will be set t o missi n g f or calc ulati o n of descri pti ve statistics a n d set t o 0 f or i n di vi d ual 
partici pa nt  pl ots . S u bse q ue nt q ua ntifia ble c o nce ntrati o ns i n t he pr ofile will be set t o missi n g f or 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 1  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
calc ulati o n of descri pti ve statistics  b ut i ncl u de d i n t he i n di vi d ual partici pa nt pl ots. F or t he 
deri vati o n of p har mac o ki netic para meters, t hese N Qs a n d a n y s u bse q ue nt meas ura ble 
c o nce ntrati o ns will be o mitte d (set t o missi n g).  
T he f oll o wi n g P K p ara meters will be calc ulate d .  
P ar a m et er  
P ar a m et e r D e s cri pti o n 
A U C( 0 -τ) 
Ar e a u n d er t h e c o nc e ntr ati o n -ti m e c urv e ov er t h e d osi n g i nt erv al (i. e., 0 t o 16 8  h o urs p ost d os e  f or 
G S K 1 7 9 5 0 9 1 ), c alc ul at e d fr o m ti m e z er o ( pr e d os e) t o pr e d os e of t h e n ext d os e. T his p ar a m et er will b e 
esti m at e d o n D ay 1 (i. e., D ay 1- 8) , D ay 1 5 (i. e., D ay 1 5 -2 2 ) a n d D ay 5 7 (i. e., D ay 5 7 -6 4 ) f or G S K 1 7 9 5 0 9 1. 
Act u al ti m es a n d ass oci at e d c o nc e ntr ati o ns at pr e d os e of t h e n ext d os e will b e us e d f or c alc ul ati o n of t his 
p ar a m et er. If t h e ti m e d evi ati o n fr o m t h e e n d of t h e sc h e d ul e d d osi n g i nt erv al is gr e at er t h a n 1 c al e n d ar d ay , t his 
p ar a m et er a n d r el at e d p ar a m et er s will b e list e d b ut excl u d e d fr o m s u m m ari es. 
A U C( 0 -τ)/ D os e 
D os e -n or m aliz e d A U C( 0 -τ), c alc ul at e d as A U C( 0-τ) divi d e d by d os e. T his p ar a m et er will b e esti m at e d f or all 
c as es w h er e A U C( 0-τ) is esti m at e d. 
A U C( 0 -∞)  
Ar e a u n d er t h e c o nc e ntr ati o n-ti m e c urv e fr o m ti m e z er o ( pr e d os e) extr a p ol at e d t o i nfi nity. T his p ar a m et er will b e 
esti m at e d o n D ay 1 (i. e., D ay 1- 8 ) o nly, if esti m a bl e.  
A U C( 0 -∞)/ D os e  
D os e -n or m aliz e d  A U C( 0 -∞) , c alc ul at e d as A U C( 0 -∞) divi d e d by d os e. T his p ar a m et er will b e esti m at e d w h e n  
A U C( 0 -∞) is esti m at e d. 
C m ax  
M axi m u m o bs erv e d pl as m a c o nc e ntr ati o n, d et er mi n e d dir ectly fr o m t h e c o nc e ntr ati o n -ti m e d at a. T his p ar a m et er 
will b e c alc ul at e d f or all d ays o n w hic h a s a m pl e is c oll ect e d at 1 0 mi ns aft er d osi n g  f or G S K 1 7 9 5 0 9 1, as t h e 
c o nc e ntr ati o n m e as ur e d at t h at ti m e p oi nt. If t h e s a m pl e is t ak e n m or e t h a n 1 5 mi n ut es aft er d osi n g  f or 
G S K 1 7 9 5 0 9 1 , t his p ar a m et er a n d r el at e d p ar a m et ers will b e list e d b ut excl u d e d fr o m s u m m ari es. 
C m ax/ D os e  
D os e -n or m aliz e d C m ax, esti m at e d as C m ax divi d e d by d os e. T his p ar a m et er will b e esti m at e d f or all c as es 
w h er e C m ax is esti m at e d.  
t m ax 
T h e act u al ti m e at w hic h C m ax is m e as ur e d, d et er mi n e d dir ectly fr o m t h e c o nc e ntr ati o n -ti m e d at a. T his 
p ar a m et er will b e esti m at e d f or all c as es w h er e C m ax is esti m at e d.  
λ z  
A p p ar e nt t er mi n al r at e c o nst a nt f or G S K 1 7 9 5 0 9 1, d et er mi n e d by l o g -li n e ar r e gr essi o n of t h e t er mi n al p h as e. 
T h e B est Fit m et h o d wit hi n P h o e nix Wi n N o nli n  will b e us e d f or s el ecti o n of d at a poi nts f or t h e 
r e gr essi o n, f oll o w e d by m a n u al a dj ust m e nt if vis u ally w arr a nt e d. 
t 1/ 2 
A p p ar e nt t er mi n al h alf -lif e ( h) f or G S K 1 7 9 5 0 9 1, d et er mi n e d as l n 2/λ z. 
C L  
Syst e mic cl e ar a nc e aft er i ntr av e n o us d osi n g ( L/ h  f or G S K 1 7 9 50 9 1 ), c alc ul at e d as d os e divi d e d by A U C( 0 -∞) o n 
D ay  1 a n d d os e divi d e d by A U C( 0 -τ) o n D ay  1 5 a n d D ay  5 7 . 
Vss 
V ol u m e of distri b uti o n at st e a dy st at e f oll o wi n g i ntr av e n o us d osi n g ( L), c alc ul at e d as m e a n r esi d e nc e ti m e 
( M R T) extr a p ol at e d t o i nfi nity m ulti pli e d by cl e ar a nc e ( M R Ti nf* C L) o n D ay  1, D ay  1 5, a n d D ay  5 7  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 2  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
P ar a m et er  
P ar a m et e r D e s cri pti o n 
C pr e  
Pr e d os e c o nc e ntr ati o n (tr o u g h c o nc e ntr ati o n at t h e e n d of a d osi n g i nt erv al ), d et er mi n e d dir ectly fr o m t h e 
c o nc e ntr ati o n-ti m e d at a o n all sc h e d ul e d st u dy d ays. If t h e ti m e d evi ati o n fr o m t h e e n d of t h e sc h e d ul e d d osi n g 
i nt erv al is gr e at er t h a n 1 c al e n d ar d ay, t his p ar a m et er a n d r el at e d p ar a m et ers will b e list e d b ut excl u d e d fr o m 
s u m m ari es. 
C pr e/ D os e  
D os e -n or m aliz e d C pr e , esti m at e d as Cpr e  divi d e d by d os e. T his p ar a m et er will b e esti m at e d f or all c as es w h er e 
C τ is esti m at e d. 
R A U C( 0 -τ) 
Acc u m ul ati o n r ati o f or A U C( 0 -τ), c alc ul at e d as [{ A U C( 0-τ) ( D ay Y) / A U C( 0-τ) ( D ay X)} * 1 0 0], w h er e X is t h e 
first d osi n g d ay f or t h e dr u g a n d Y is e ac h s u bs e q u e nt d osi n g d ay > X o n w hic h A U C( 0-τ) is esti m at e d.  
R C m ax  
Acc u m ul ati o n r ati o f or C m ax, c alc ul at e d as [{ C m ax( D ay Y) / C m ax( D ay X)} * 1 0 0], w h er e X is t h e first d osi n g 
d ay f or t h e dr u g a n d Y is e ac h s u bs e q u e nt d osi n g d ay > X o n w hic h C m ax is esti m at e d.   
R C pr e  
Acc u m ul ati o n r ati o f or C pr e , c alc ul at e d as [{ Cpr e ( D ay Y) / Cpr e ( D ay X)} * 1 0 0], w h er e Cpr e ( D ay X) is t h e tr o u g h 
m e as ur e m e nt aft er t h e first d osi n g d ay f or t h e dr u g a n d C pr e ( D ay Y) is t h e tr o u g h m e as ur e m e nt o n e ac h 
s u bs e q u e nt d osi n g d ay.  
 
T he f oll o wi n g dia g n ostic P K para meters will be liste d b ut will n ot be s u m marize d: 
P ar a m et er  
P ar a m et er D e s cri pti o n  
t 1/ 2 St art a n d 
St o p ti m e, 
I nt erv al 
T h e st art a n d st o p ti m e a n d t h e ti m e i nt erv al of t h e l o g -li n e ar r e gr essi o n t o d et er mi n e λ z will b e r e p ort e d. 
H o w ev er, esti m at es of λ z a n d r el at e d p ar a m et ers will n ot b e excl u d e d fr o m s u m m ari es, ev e n if t h e d ur ati o n of 
ti m e ov er w hic h λ z is esti m at e d is < 2 ti m es t h e s u bs e q u e ntly esti m at e d t 1/ 2. 
t 1/ 2 N 
N u m b er of d at a p oi nts i ncl u d e d i n t h e l o g -li n e ar r e gr essi o n t o d et er mi n e λ z.  A mi ni m u m of 3 d at a 
p oi nts will b e us e d f or d et er mi n ati o n.  
Rs q _ a dj  
G o o d n ess of fit st atistic f or c alc ul ati o n of λ z. If t h e Rs q _ a dj v al u e is l ess t h a n 0. 8 5 0 ( w h e n r o u n d e d t o 
3 si g nific a nt fi g ur es), λ z a n d r el at e d p ar a m et ers [A U C( 0 -∞) , C L, a n d Vss] will b e list e d b ut excl u d e d 
fr o m s u m m aries. 
% A U C ex  
P erc e nt a g e of A U C( 0 -∞) o bt ai n e d by extr a p ol ati o n, c alc ul at e d as  
[(A U C( 0 -∞) - A U C( 0 -l ast))/ A U C( 0 -∞)  × 1 0 0].  If t h e % A U C ex is gr e at er t h a n 2 0. 0 % of A U C( 0 -∞)  ( w h e n 
r o u n d e d t o 3 si g nific a nt fi g ur es), t h e n A U C( 0 -∞) a n d r el at e d p ar a m et ers ( C L a n d Vss) will b e list e d b ut 
excl u d e d fr o m su m m ari es . 
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
P K para meters will be s u m marize d b y c o m bi nati o n part ner (se paratel y f or eac h part ner a n d 
acr oss all part ners p o ole d), d ose gr o u p, a n d f or m ulati o n ( O ri gi nal F or m ulati o n,  M o difie d  
F or m ulati o n, or A ll F or m ulati o ns ) usi n g descri pti ve statistics ( n, mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, ma xi m u m, ge o metric mea n, ge o metric % C V  a n d 9 5 % CI f or ge o metric 
mea n ) if n f or t hat le vel of s u m marizati o n is ≥ 3 (if n = 2, o nl y n, me dia n, mi ni m u m , a n d 
ma xi m u m will be re p orte d; if n = 1 , o nl y n a n d me dia n will be re p orte d) .  Ge o metric mea n, 
ge o metric % C V  a n d 9 5 % CI f or ge o metric mea n  will n ot be calc ulate d f or ti me para meters. 
S u bjects w h o u n der we nt a f or m ulati o n s witc h d uri n g t he st u d y will o nl y be i ncl u de d i n t he A ll 
F or m ulati o ns s u m maries . 
Scatter pl ots (i n di vi d ual val ues ; ge o metric mea n  a n d 9 5% CI  if n > 3) of G S K 1 7 9 5 0 9 1 P K 
para meters [ C ma x, A U C( 0 -∞), A U C( 0 -τ), C pre, a n d c orres p o n di n g d ose-n or malize d para meters  
f or all c o m bi nati o n part ners p o ole d ] vers us d ose le vel (c o nti n u o us a xis) will be ge nerate d 
se paratel y b y st u d y da y o n Da ys 1, 1 5, a n d 5 7 of Part 1, if s ufficie nt data are a vaila ble . O nl y 
s u bjects w h o recei ve d a si n gle f or m ulati o n t hr o u g h o ut t he treat me nt peri o d ( Ori gi nal or 
M o difie d) will b e i ncl u de d i n t hese pl ots. B ot h f or m ulati o ns will be s h o w n o n t he sa me pl ot 
usi n g differe nt s y m b ols. W he n data are a vaila ble f or b ot h f or m ulati o ns wit hi n a d ose gr o u p, data 
f or t he t w o f or m ulati o ns will be s h o w n sli g htl y offset o n eit her si de of t he d ose le vel. 
A partici pa nt  listi n g of i n di vi d ual P K para meters will als o be pr o vi de d ; t he listi n g will i n dicate 
t he G S K 1 7 9 5 0 9 1 f or m ulati o n use d.  
 
1 6.  P H A R M A C O D Y N A MI C / B I O M A R K E R A N A L Y SI S  
All p har mac o d y na mic a n d bi o mar ker a nal yses will be base d o n t he P D S. All s u m maries will be 
prese nte d b y c o h ort a n d st u d y part u nless state d ot her wise. 
1 6. 1.  
P H A R M A C O D Y N A MI C / B I O M A R K E R V A RI A B L E S  
P P D
T he f oll o wi n g gr o u ps of p har mac o d y na mic a n d b i o mar ker para meters will be c o vere d i n t his 
S A P . All ot her p har mac o d y na mic / bi o mar ker varia bles ma y be a nal yze d b y G S K a n d if d o ne 
w o ul d be i ncl u de d i n a se parate Bi o mar ker R A P . 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 4  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
C yt o ki nes/ C he m o ki nes : I L- 1 0, I L- 1β , I L- 1 Ra, I F Nγ, I L- 1 2 p 7 0, I L- 2, I L-4, I L - 5, I L-6, I L - 8, 
G C S F, I P- 1 0, M C P-1, R A N T E S , T N Fα  
•  
W B C c o u nt wit h differe ntials: n e utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils  
•  
C- reacti ve pr otei n ( C R P)  
1 6. 2.  
H A N D LI N G O F M I S SI N G D A T A F O R P H A R M A C O D Y N A MI C / 
B I O M A R K E R V A RI A B L E S  
Missi n g p har mac o d y na mic a n d bi o mar ker res ults will n ot be i m p ute d , h o we ver ce ns ore d res ults 
will be i m p ute d f or t he p ur p ose of t he a nal yses . Ce ns ore d res ults are val ues w hic h ca n n ot be 
prese nte d n u mericall y beca use t he y fall o utsi de t he ra n ge of q ua ntificati o n ( Bel o w t he Li mit of 
Q ua ntificati o n ( B L O Q)  or A b o ve t he Li mit of Q ua ntificati o n ( A L O Q)). F or t he calc ulati o n of 
c ha n ge fr o m baseli ne B L O Q val ues will be set t o t he L o wer Li mit of Q ua ntificati o n ( L L O Q) / 2 
a n d A L O Q val ues will be set t o t he U p per Li mit of Q ua ntificati o n ( U L O Q). T hese sa me 
i m p utati on r ules will be a p plie d f or t he calc ulati o n of s u m mar y statistics of t he a bs ol ute val ues 
w here a p pr o priate, as descri be d i n secti o n 1 6. 3.   
1 6. 3.  
A N A L Y SI S O F P H A R M A C O D Y N A MI C / B I O M A R K E R 
V A RI A B L E S  
P har mac o d y na mic a n d bi o mar ker  para meters s pecifie d i n Secti o n 1 6. 1  will be s u m marize d usi n g 
descri pti ve statistics ( n,  n B L O Q, n A L O Q,  mea n, sta n dar d de viati o n, me dia n, mi ni m u m, 
ma xi m u m a n d ge o metric mea n)  b y sc he d ule d ti me p oi nt  if n f or t hat le vel of s u m marizati o n is ≥ 
3 (if n = 2 , o nl y n, n B L OQ, n A L O Q,  mi ni m u m a n d ma xi m u m will be re p orte d; if n = 1 , o nl y n, 
n B L O Q a n d n A L O Q  will be re p orte d) . A bs ol ute a n d f ol d c ha n ge fr o m baseli ne val ues will be 
s u m marize d, h o we ver t he ge o metric mea ns will o nl y be calc ulate d f or a bs ol ute val ues.    
Met h o ds of a nal ysis f or a bs ol ute p har mac o d y na mic a n d b i o mar ker para meters will de pe n d o n 
v ol u m e of a vaila ble data a n d t he pr o p orti o n of ce ns ore d res ults.   
•  
P P D
If less t ha n 2 0 % of res ults are ce ns ore d, t he n t he mea n, sta n dar d de viati o n a n d ge o metric 
mea n will be calc ulate d usi n g t he tra diti o nal a p pr oac h , wit h ce ns ore d val ues i m p ute d usi n g 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
t he a p pr oac h descri be d i n secti o n 1 6 . 2.  
•  If 2 0 % t o 5 0 % of res ults are ce ns ore d, t he n t he mea n, sta n dar d de viati o n a n d ge o metric mea n 
will be calc ulate d usi n g a para metric m o delli n g a p pr oac h i n S A S P R O C LI F E R E G, usi n g 
i nter val ce ns ori n g. Eac h val ue will be defi ne d b y a ra n ge of p ossi ble val ues. F or res ults 
w hic h are n ot ce ns ore d , t he l o wer a n d u p per li mit of t he i nter val will be e q ual t o t he rec or de d 
res ult. B L O Q res ults will be assi g ne d a n u p per i nter val li mit of t he L L O Q a n d a l o wer 
i nter val li mit of 0. A L O Q res ults will be assi g ne d a l o wer i nter val li mit of t he U L O Q, a n d 
t he u p per i nter val li mit will be missi n g t o si g nif y t hat a n y val ue a b o ve t he l o wer i nter val 
li mit is p ossi ble. T he mea n a n d sta n dar d de viati o n will be esti mate d as t he i nterce pt a n d scale 
para meters res pecti vel y of t he para metric m o del , ass u mi n g a n or mal distri b uti o n f or t he 
para meter res ult. T he ge o metric mea n will be esti mate d as t he bac k -tra nsf or me d i nterce pt 
p ara meter of t he para metric m o del , ass u mi n g a l o g n or mal distri b uti o n of t he para meter 
res ult. Se parate a nal yses will be r u n f or eac h para meter, treat me nt gr o u p a n d ti me p oi nt a n d 
n o a dj ust m e nts f or c o variates will be ma de .     
•  If m ore t ha n 5 0 % of res ults are ce ns ore d , t he n, n B L O Q a n d n A L O Q will be prese nte d 
o nl y. 
If B L O Q val ues e xist wit hi n a le vel of s u m marizati o n, t he mi ni m u m a n d me dia n will n ot be 
prese nte d i n t he s u m mar y ta ble. If A L O Q val ues e xist wit hi n a le vel of s u m marizati o n , t he 
ma xi m u m a n d me dia n will n ot be prese nte d i n t he s u m mar y ta ble.  
As c ha n ge fr o m baseli ne varia bles will n ot c o ntai n ce ns ore d val ues after i m p utati o n, s u m mar y 
statistics will be calc ulate d usi n g tra diti o nal met h o ds.  
T he f oll o wi n g pl ots will be create d f or eac h c yt o ki ne res pecti vel y:  
•  Li ne pl ot f or i n di vi d ual partici pa nt  le vel val ue o ver ti me 
•  Me dia n o ver ti me wit h err or bars re prese nti n g 2 5 perce ntile a n d 7 5 perce ntile 
•  Me dia n f ol d c ha n ge fr o m baseli ne o ver ti me (f or eac h ti me p oi nt, t he f ol d c ha n ge is 
defi n e d as ( visit val ue - baseli ne val ue)/ baseli ne val ue  
P P D
T he visit o n t he x- a xis will be e q uall y s pace d i g n ori n g t he ti me scale c o m pare d t o t he first d ose 
s o t hat t he earl y ti me p oi nts ca n be better vie we d fr o m t he pl ot. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T he f oll o wi n g pl ot will be create d f or C R P : 
•  Me dia n o ver ti me wit h err or bars re prese nti n g 2 5 perce ntile a n d 7 5 perce ntile 
1 6. 4.  
A N A L Y SI S O F P H A R M A C O KI N E TI C V E R S U S 
P H A R M A C O D Y N A MI C / B I O M A R K E R V A RI A B L E S  
Scatter pl ots of i n di vi d ual s u bject  Da y 1  ma xi m u m c ha n ge-fr o m baseli ne P D val ues (f or I L- 6, 
T N F -al p ha, I L-1 R A, I L - 1 0, M C P- 1, I P- 1 0, C R P, b o d y te m perat ure, p ulse, a n d s yst olic bl o o d 
press ure) vers us G S K 1 7 9 5 0 9 1 C ma x will be pre pare d. Differe nt s y m b ols will be use d t o 
disti n g uis h bet wee n G S K 1 7 9 5 0 9 1 f or m ulati o ns, a n d tre n d li nes will be o verlai d f or eac h 
f or m ulati o n. 
1 7.  D A T A N O T S U M M A RI Z E D O R P R E S E N T E D  
T he ot her d o mai ns n ot s u m marize d or prese nte d are:  
•  
C o m me nts  
•  
L ocal La b orat or y Scree ni n g Assess me nts (f or he patitis B a n d C ) a n d T h yr oi d f u ncti o n. 
•  
Li ver I ma gi n g  
•  
Pri or Me dical Hist or y/ S ur geries  
•  
C o nc o mita nt me dicati o ns/s ur geries  
•  
Pri or/ P ost -treat me nt a nti-ca ncer me dicati o ns  
•  
ir R E CI S T,  
•  
P D ot her t ha n c yt o ki nes a n d c he m o ki nes, bi o mar ker, tele p h o ne i nter vie w 
•  
St o ol,  
•  
L i ver e ve nts  
•  
P P D
E C O G  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  
P E  
•  
L V E F  
T hese d o mai ns a n d/ or var ia bles will n ot be s u m marize d or prese nte d b ut will be a vaila ble i n t he 
cli nical st u d y data base, S D T M a n d/ or A Da M datasets .
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
1 8.  R E F E R E N C E S  
1.  Lee JJ, Li u D D. A pre dicti ve pr o ba bilit y desi g n f or P hase II ca ncer cli nical trials. Cli n 
Trials. 2 0 0 8; 5: 9 3- 1 0 6. 
2.  N CI -C T C A E, Versi o n 4. 0 3: htt ps:// w w w.e ortc. be/ser vices/ d oc/ctc/ C T C A E _ 4. 0 3 _ 2 0 1 0-
0 6- 1 4 _ Q uic k Refere nce _ 5 x 7. p df  
3.  Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he Ba yesia n a p pr oac h t o 
p hase I ca ncer trials. Statistics Me d. 2 0 0 8; 2 7: 2 4 2 0- 2 4 3 9. 
4.  Nis hi n o M, Gi o b bie - H ur der A, Gar ga n o M, S u da M, Ra mai ya N H, H o di F S. De vel o pi n g 
a c o m m o n la n g ua ge f or t u m or res p o nse t o i m m u n ot hera p y: i m m u ne- relate d res p o nse 
criteria usi n g u ni di me nsi o nal meas ure me nts. Cli n Ca ncer Res. 2 0 1 3; 1 9: 3 9 3 6- 3 9 4 3. 
5.  O’ Q ui gle y J, Pe pe M, Fis her L. C o nti n ual Reassess me nt Met h o d: A Practical Desi g n f or 
P hase I Cli nical Trials i n Ca ncer. Bi o metrics. 1 9 9 0; 4 6: 3 3 - 4 8. 
6.  W olc h o k J D, H o os A, O’ Da y S, We ber J S, Ha mi d O, Le b be C, et al. G ui deli nes f or t he 
E val uati o n of I m m u ne T hera p y Acti vit y i n S oli d T u m ors: I m m u ne- Relate d Res p o nse 
Criteria. Cli n Ca ncer Res. 2 0 0 9; 1 5( 2 3): 7 4 1 2- 2 0. 
 
 
 
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 5 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  
I Q VI A O U T P U T C O N V E N TI O N S  
1.  O U T P U T FI L E N A MI N G C O N V E N TI O N S  
File na mes s h o ul d o nl y c o nsist of u p percase letters, l o wercase letters, di gits ( 0 t o 9) a n d 
u n dersc ores. A peri o d s h o ul d o nl y be use d t o i n dicate a se parat or bet wee n t he file na me a n d t he 
e xte nsi o n. N o s paces, ot her s pecial c haracters or p u nct uati o n mar ks are per mitte d.  
As far as p ossi ble, o ut p ut files s h o ul d be i n Ric h Te xt File ( R T F ) f or mat, alt h o u g h . D O C files are 
als o per mitte d.  
T he pr o gra m, pr o gra m l o g a n d o ut p ut file na me s h o ul d reflect t he t y pe a n d n u m ber of t he 
statistical o ut p ut. If t his is n ot p ossi ble, t he n t he o ut p ut na me s h o ul d be at least as descri pti ve as 
p ossi ble. A prefi x ca n be use d t o disti n g uis h bet wee n a Ta ble, Listi n g a n d Fi g ure d oc u me nt (‘ T’ 
f or ta ble, ‘ L’ f or listi n g a n d ‘ F’ f or fi g ure). If t here is o nl y 1 di git i n t he n u m ber of t he ta ble, 
listi n g or fi g ure i n t he place w here 2 di gits are p ossi ble, a lea di n g zer o s h o ul d be a d de d i n t he file 
na me t o ma ke s orti n g c o nsiste nt wit h t he se q ue nce (e . g. T 1 4 _ 3 _ 0 1 _ 1. R T F) 
2.  P A P E R SI Z E, O RI E N T A TI O N A N D M A R GI N S  
T he size of pa per will be Letter f or t he U nite d States, ot her wise  it will be A 4.  
T he pa ge orie ntati o n s h o ul d prefera bl y be la n dsca pe, b ut p ortrait is als o per mitte d. 
Mar gi ns s h o ul d pr o vi de at least 1 i nc h ( 2. 5 4 ce nti meters) of w hite s pace all ar o u n d t he pa ge, 
re gar dless of t he pa per size. 
T he n u m ber of c ol u m ns per pa ge (li nesize) s h o ul d be 1 4 5 f or A 4 a n d 1 3 4 f or Letter. 
T he n u m ber of r o ws per pa ge ( pa gesize) s h o ul d be 4 9 f or A 4 a n d 5 1 f or Letter. 
 
 
P P D
 
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
 
3.  F O N T S  
T he f o nt t y pe ‘ C o urier Ne w’ s h o ul d be use d as a defa ult f or ta bles a n d listi n gs, wit h a f o nt size 
of 8. T he f o nt c ol or s h o ul d be blac k. Si n gle s paci n g s h o ul d be use d f or all te xt. 
Fi g ures s h o ul d ha ve a defa ult f o nt of “ Ti mes R o ma n”, “ Hel vetica”, or “ C o urier Ne w”  wit h a f o nt 
size of 1 2. 
4.  T A B L E A N D LI S TI N G O U T P U T C O N V E N TI O N S  
Ge neral:  
•  T he first r o w i n t he b o d y of t he ta ble or listi n g s h o ul d be bla n k 
•  T he left ha n d c ol u m n s h o ul d start i n c ol u m n 1. N o i n de nti n g or ce nteri n g of t he o ut p ut 
s h o ul d occ ur. 
•  R o u n di n g s h o ul d be d o ne wit h t he S A S f u ncti o n R O U N D.  
•  N u m bers i n ta bles s h o ul d be r o u n de d, n ot tr u ncate d. 
•  Al p ha n u meric o ut p ut s h o ul d be left ali g ne d. 
•  N u m bers s h o ul d be deci mal p oi nt ali g ne d. 
•  Te xt val ues s h o ul d be left ali g ne d. 
•  T he first letter of a te xt e ntr y s h o ul d be ca pitalize d . 
•  T he wi dt h of t he e ntire o ut p ut s h o ul d matc h t he li nesize. 
U ni variate Statistics:  
•  Ta ble statistics s h o ul d li ne u p u n der t he N part of t he ( N = X X X) i n t he ta ble hea der. All 
deci mal p oi nts s h o ul d li ne u p. F or ‘Mi ni m u m, Ma xi m u m ’ t he c o m ma s h o ul d li ne u p wit h t he 
deci mal p oi nt. 
•  If t he ori gi nal data has N deci mal places, t he n t he s u m mar y statistics s h o ul d ha ve t he 
f oll o wi n g deci mal places: 
•  
P P D
Mi ni m u m a n d ma xi m u m: N  
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 1  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  Mea n, me dia n a n d % C V: N + 1  
•  S D: N + 2  
Fre q ue ncies a n d perce nta ges ( n a n d %):  
•  Perce nt val ues s h o ul d be re p orte d i nsi de pare nt hes es, wit h o ne s pace bet wee n t he c o u nt a n d 
t he left pare nt hesis of t he perce nta ge. Pare nt heses s h o ul d be j ustifie d t o acce pt a ma xi m u m of 
1 0 0. 0 as a val ue a n d pa d de d wit h bla n k s pace if t he perce nt is less t ha n 1 0 0. 0. A n e xa m ple is 
gi ve n bel o w: 
7 7  ( 1 0 0 . 0 % )  
5 0  (  6 4 . 9 % )  
0   (   0 . 0 % )  
•  Perce nta ges will be re p orte d t o o ne deci mal place . 
•  W here c o u nts are zer o, perce nta ges of 0. 0 % s h o ul d a p pear i n t he o ut p ut. 
C o nfi de nce I nter vals:  
•  As a r ule , c o nfi de nce i nter vals are o ut p ut t o o ne place m ore t ha n t he ra w data, a n d sta n dar d 
de viati o ns a n d sta n dar d err ors t o t w o places m ore t ha n t he ra w data 
•  C o nfi de nce i nter vals s h o ul d be j ustifie d s o t hat pare nt heses dis pla ye d o n c o nsec uti ve li nes of 
a ta ble “li ne u p”.  
•  B o u n dar y val ues s h o ul d be pa d de d as necessar y t o acce pt ne gati ve val ues a n d t o all o w 
ali g n me nt of t he deci mal place.  A n e xa m ple is gi ve n bel o w: 
( - 0 . 1 2 ,  - 0 . 1 0 )  
(  9 . 5 4 ,  1 2 . 9 1 )  
Rati os:  
•  Rati os s h o ul d be re p orte d t o o ne m ore deci mal place t ha n t he ori gi nal data. 
S paci n g: 
•  T here m ust be a mi ni m u m of 1 bla n k s pace bet wee n c ol u m ns ( prefera bl y 2) 
P P D
Missi n g val ues : 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 2  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
•  A “ 0” s h o ul d be use d t o i n dicate a zer o fre q ue nc y. 
•  A bla n k will be use d t o i n dicate missi n g data i n a partici pa nt  listi n g. 
 
5.  FI G U R E O U T P U T C O N V E N TI O N S  
 
•  Fi g ures s h o ul d be pr o vi de d i n R T F files usi n g t he S A S O ut p ut Deli ver y S yste m ( O D S), as 
C o m p uter Gra p hics Metafile ( C G M) f or matte d gra p hical o ut p ut ge nerate d b y S A S. 
•  T he C G M file itself s h o ul d c o ntai n t he title or f o oter.  
•  I n ge neral, b o xes ar o u n d t he fi g ures s h o ul d be use d. 
D A T E S &  T I M E S 
De pe n di n g o n data a vaila ble, dates a n d ti mes will ta ke t he f or m y y y y- m m - d d T h h: m m:ss. 
S P E L LI N G F O R M A T  
E n glis h U S. 
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S  
Se parate o ut p uts will be ge nerate d f or eac h c o m bi nati o n part ner, w hic h will be i de ntifie d b y a 
s uffi x o n t he o ut p ut n u m ber, w hich will refer t o t he st u d y part. F or o ut p uts, treat me nt gr o u ps will 
be re prese nte d as f oll o ws:  
C o m bi n ati o n P art ner 
( St u d y P art) 
C o h ort L a bel  
Or der i n T L F  
G S K 3 1 7 4 9 9 8 ( A)  
5 0 n g G S K 1 7 9 5 0 9 1  + 8 m g G S K 3 1 7 4 9 9 8  
1 
5 0 n g G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 1 7 4 9 9 8  
2 
1 0 0 n g G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 1 7 4 9 9 8  
3 
1 5 0 n g  G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 1 7 4 9 9 8  
4 
2 0 0 n g  G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 1 7 4 9 9 8  
5 
2 5 0 n g G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 1 7 4 9 9 8  
6 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 3  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
T otal - O verall ( Safet y Ta bles O nl y)  
7 
G S K 3 3 5 9 6 0 9  ( B) 
5 0 n g G S K 1 7 9 5 0 9 1 + 2 4 m g G S K 3 3 5 9 6 0 9  
1 
5 0 n g G S K 1 7 9 5 0 9 1 + 8 0 m g G S K 3 3 5 9 6 0 9  
2 
1 0 0 n g G S K 1 7 9 5 0 9 1 + 8 0 m g G S K 3 3 5 9 6 0 9  
3 
1 5 0 n g G S K 1 7 9 5 0 9 1 + 8 0 m g G S K 3 3 5 9 6 0 9  
4 
2 0 0 n g G S K 1 7 9 5 0 9 1 + 8 0 m g G S K 3 3 5 9 6 0 9  
5 
2 5 0 n g G S K 1 7 9 5 0 9 1 + 8 0 m g G S K 3 3 5 9 6 0 9  
6 
T otal - O verall ( Safet y Ta bles O nl y)  
7 
Pe m br oliz u ma b ( C)  
5 0 n g G S K 1 7 9 5 0 9 1 + 2 0 0 m g Pe m br oliz u ma b  
1 
1 0 0 n g G S K 1 7 9 5 0 9 1 + 2 0 0 m g Pe m br oliz u ma b  
2 
1 5 0 n g G S K 1 7 9 5 0 9 1 + 2 0 0 m g Pe m br oliz u ma b  
3 
2 0 0 n g G S K 1 7 9 5 0 9 1 + 2 0 0 m g Pe m br oliz u ma b  
4 
2 5 0 n g G S K 1 7 9 5 0 9 1 + 2 0 0 m g Pe m br oliz u ma b  
5 
T otal - O verall ( Safet y Ta bles O nl y)  
7 
All C o m bi nati o n 
Part ners P o ole d  B y 
f or m ulati o n ( D) 
5 0 n g G S K 1 7 9 5 0 9 1  + Part ner ( P o ole d)  
1 
 
1 0 0 n g G S K 1 7 9 5 0 9 1  + Part ner ( P o ole d)  
2 
 
1 5 0 n g G S K 1 7 9 5 0 9 1  + Part ner ( P o ole d)  
3 
 
2 0 0 n g G S K 1 7 9 5 0 9 1  + Part ner ( P o ole d)  
4 
 
2 5 0 n g G S K 1 7 9 5 0 9 1  + Part ner ( P o ole d)  
5 
 
T otal  
6 
D L = D ose Le vel t o be deter mi ne d fr o m N -C R M d ose escalati o n.  
P R E S E N T A TI O N O F V I SI T S 
F or o ut p uts, visits will be re prese nte d as f oll o ws a n d i n t hat or der: 
L o n g Na me ( defa ult) 
S h ort Na me  
Scree ni n g  
Scree ni n g  
Da y 1  
D 1  
Da y 2  
D 2  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 4  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
L o n g Na me ( defa ult) 
S h ort Na me  
Da y 8  
D 8  
Da y 1 5  
D 1 5  
Da y 1 6  
D 1 6  
Da y 2 2  
D 2 2  
Da y 2 9  
D 2 9  
Da y 3 6  
D 3 6  
Da y 4 3  
D 4 3  
Da y 5 0  
D 5 0  
Da y 5 7  
D 5 7  
Da y 5 8  
D 5 8  
Da y 6 4  
D 6 4  
Da y 7 1  
D 7 1  
Da y 7 8  
D 7 8  
Da y 8 5  
D 8 5  
Da y 1 0 6  
D 1 0 6 
Da y 1 2 7  
D 1 2 7 
… C o nti n ue at 2 1- da y i nter vals u ntil e n d of treat me nt 
D X X X  
Treat me nt Disc o nti n uati o n Visit 
T D V  
1 2 Wee k P F S F U  
W 1 2 P F S F U  
2 4 Wee k P F S F U  
W 2 4 P F S F U  
… C o nti n ue at 1 2- wee k i nter vals u ntil pr o gressi ve disease  W X X P F S F U  
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 5  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
L o n g Na me ( defa ult) 
S h ort Na me  
1 2 Wee k S F U 
W 1 2 S F U  
2 4 Wee k S F U 
W 2 4 S F U  
… C o nti n ue at 1 2- wee k i nter vals u ntil deat h or 2 years 
after first d ose  
W X X S F U  
L I S TI N G S 
All listi n gs will be or dere d b y t he f oll o wi n g ( u nless ot her wise i n dicate d i n t he te m plate):  
•  
St u d y Part ( 1a, 1 b, 1c – w here 1 refers t o t he d ose escalati o n p ha se, , a t he G S K3 1 7 4 9 9 8 
c o h ort, b t he G S K 3 3 5 9 6 0 9 c o h ort a n d c t he Pe m br oliz u ma b c o h ort) 
•  
Treat me nt gr o u p i n asce n di n g or der of d ose le vel f or G S K 1 7 9 5 0 9 1  
•  
Dr u g ( w here a p plica ble - G S K 1 7 9 5 0 9 1 t he n c o m bi nati o n part ner)  
•  
C e nter-partici pa nt  I D  
•  
Para meter ( w here a p p lica ble) 
•  
Date ( w here a p plica ble)  
•  
Ti me p oi nt ( w here a p plica ble) 
 
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N TI O N S  
P P D
I m p ute d dates will N O T be prese nte d i n t he listi n gs. 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 6  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A L G O RI T H M F O R T R E A T M E N T E M E R G E N C E O F A D V E R S E E V E N T S : 
S T A R T D A T E  
S T O P 
D A T E  
A C TI O N  
K n o w n  
K n o w n  
If start date < st u d y me d start date, t he n n ot T E A E. 
If start date > = st u d y me d start date, t he n T E A E. 
 
Partial  
If start date < st u d y me d start date, t he n n ot T E A E. 
If start date > = st u d y me d start date, t he n T E A E. 
 
Missi n g  
If start date < st u d y me d start date, t he n n ot T E A E . 
If start date > = st u d y me d start date, t he n T E A E. 
 
 
 
Partial, b ut k n o w n 
c o m p o ne nts s h o w t hat it 
ca n n ot be o n or after 
st u d y me d start date 
K n o w n  
N ot T E A E  
 
Partial  
N ot T E A E  
 
Missi n g  
N ot T E A E  
 
 
 
Partial, c o ul d be o n or 
after st u d y me d start date 
K n o w n  
If st o p date < st u d y me d start date, t he n n ot T E A E. 
If st o p date > = st u d y me d start date, t he n T E A E. 
 
Partial  
I m p ute st o p date as latest p ossi ble date (i.e. last da y 
of m o nt h if da y u n k n o w n or 3 1st Dece m ber if da y 
a n d m o nt h are u n k n o w n), t he n: 
If st o p date < st u d y me d start date, t he n n ot T E A E. 
If st o p date > = st u d y me d start date, t he n T E A E. 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 7  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A R T D A T E  
S T O P 
D A T E  
A C TI O N  
 
Missi n g  
Ass u me d T E A E  
 
 
 
Missi n g  
K n o w n  
If st o p date < st u d y me d start date, t he n n ot T E A E. 
If st o p date > = st u d y me d start date, t he n T E A E. 
 
Partial  
I m p ute st o p date as latest p ossi ble date (i.e. last da y 
of m o nt h if da y u n k n o w n or 3 1st Dece m ber if da y 
a n d m o nt h are u n k n o w n), t he n: 
If st o p date < st u d y me d start date, t he n n ot T E A E. 
If st o p date > = st u d y me d start date, t he n T E A E . 
 
Missi n g  
Ass u me d T E A E  
 
 
 
P P D
 
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 8  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
A L G O RI T H M F O R P RI O R / C O N C O MI T A N T / PO S T  M
E DI C A TI O N S :  
 
S T A R T 
D A T E  
S T O P 
D A T E  
A C TI O N  
K n o w n  
K n o w n  
If st o p date < st u d y me d start date, assi g n as pri or.  
Ot her wise:  
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks , 
assi g n as c o nc o mita nt .  
Ot her wise assi g n as p ost treat me nt. 
 
Partial  
I m p ute st o p date as latest p ossi ble date (i.e. last da y of m o nt h if 
da y u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are 
u n k n o w n), t he n: 
If st o p date < st u d y me d start date, assi g n as pri or. 
Ot her wise:  
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks , 
assi g n as c o nc o mita nt .  
Ot her wise assi g n as p ost treat me nt. 
 
Missi n g  
If st o p date is missi n g, c o ul d ne ver be ass u me d a pri or 
me dicati o n . 
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks  , 
assi g n as c o nc o mita nt . 
Ot her wi se assi g n as p ost treat me nt. 
 
 
 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 6 9  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A R T 
D A T E  
S T O P 
D A T E  
A C TI O N  
Partial  
K n o w n  
I m p ute start date as earliest p ossi ble date (i.e. first da y of m o nt h 
if da y u n k n o w n or 1st Ja n uar y if da y a n d m o nt h are u n k n o w n), 
t he n: 
If st o p date < st u d y me d start date, assi g n as pri or 
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks , 
assi g n as c o nc o mita nt .  
Ot her wise assi g n as p ost treat me nt. 
 
Partial  
I m p ute start date as earliest p ossi ble date (i.e. first da y of m o nt h 
if da y u n k n o w n or 1st Ja n uar y if da y a n d m o nt h are u n k n o w n) 
a n d i m p ute st o p date as latest p ossi ble date (i.e. last da y of 
m o nt h if da y u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are 
u n k n o w n), t he n: 
If st o p date < st u d y me d start date, assi g n as pri or. 
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks , 
assi g n as c o nc o mita nt .  
Ot her wise assi g n as p ost treat me nt. 
P P D
P P D


 
Gl a x o S mit h Kli n e   
P R O T O C O L 2 0 4 6 8 6  
 
A n al y si s Pl a n  
P a g e 7 0  of 7 0  
 
D o c u m e nt:  
 
A ut h or:  
 
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
                                     [2 3 D E C 2 0 2 0]  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 5  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 1 A pr 2 0 1 8  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d pr o pri et ar y 
t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d. 
S T A R T 
D A T E  
S T O P 
D A T E  
A C TI O N  
 
Missi n g  
I m p ute start date as earliest p ossi ble date (i.e. first da y of m o nt h 
if da y u n k n o w n or 1st Ja n uar y if da y a n d m o nt h are u n k n o w n), 
t he n: 
If st o p date is missi n g c o ul d ne ver be ass u me d a pri or 
me dicati o n . 
If start date < = e n d of G S K 1 7 9 5 0 9 1 treat me nt + 1 wee k, or a n d 
start date < = e n d of c o m bi nati o n part ner treat me nt + 3 wee ks , 
assi g n as c o nc o mita nt .  
Ot her wise assi g n as p ost treat me nt. 
 
 
 
Missi n g  
K n o w n  
If st o p date < st u d y me d start date, assi g n as pri or. 
Ot her wise  assi g n as c o nc o mita nt . 
 
Partial  
I m p ute st o p date as latest p ossi ble date (i.e. last da y of m o nt h if 
da y u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are 
u n k n o w n), t he n: 
If st o p date < st u d y me d start date, assi g n as pri or. 
Ot her wise  assi g n as c o nc o mita nt . 
 
Missi n g  
Assi g n as c o nc o mita nt . 
P P D
 
P P D


St atistic al A n al ysis Pl a n - v 1. 0 - S A P or P K- P D Secti o ns T here of - 2 3- Dec- 2 0 2 0
Electr o nic Si g n at ure M a nifest ati o n
T his pa ge is a ma nifestati o n of t he electr o nic si g nat ure(s) use d i n c o m plia nce wit h t he or ga nizati o n's
electr o nic si g nat ure p olicies a n d pr oce d ures.
P a ge 7 1 - O bject 1 0 0 0 5 5 1 A 0 0 0 0 0 0 0 0 3 1 0 C 6 0 B B
Si g ner F ull N a me
Me a ni n g of Si g n at ure
D ate a n d Ti me
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 1 1: 2 5 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 1 4: 2 0 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 1 5: 5 8 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 2 1: 0 2 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 2 3: 1 7 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
2 3 Dec 2 0 2 0 1 6: 3 0: 2 9 U T C
D oc u me nt A p pr o val (I certif y t hat I ha ve t he
e d ucati o n, trai ni n g a n d e x perie nce t o perf or m
t his tas k)
P P D
2 3 Dec 2 0 2 0 1 7: 1 9: 5 1 U T C
P P D
P P D
P P D
P P D
P P D
P P D