Conditions: Neoplasms
Keywords: ICOS receptor agonist antibody Pembrolizumab KEYNOTE-478 GSK3359609 Cohort expansion Dose escalation Dostarlimab Cobolimab Bintrafusp alfa
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 829
Healthy volunteers: no

Brief summary:
GSK3359609 is an anti-Inducible T cell Co-Stimulator (ICOS) receptor agonist antibody intended for the treatment of cancers of different histology. This is a first-time-in-human (FTIH), open-label, multicenter study designed to investigate the safety, pharmacology, and preliminary antitumor activity in participants with selected, advanced or recurrent solid tumors with the aim to establish recommended dose(s) of GSK3359609 for further exploration as monotherapy and in combination with pembrolizumab or chemotherapy regimens. The study is comprised of two primary parts, each composed of two phases: Part 1: GSK3359609 monotherapy with Part 1A as dose escalation phase and Part 1B as cohort expansion phase; Part 2: GSK3359609 combination therapy with Part 2A pembrolizumab or GSK3174998 or chemotherapy or pembrolizumab plus chemotherapy or dostarlimab plus cobolimab or Bintrafusp alfa combination dose escalation phase and Part 2B expansion phase with pembrolizumab. The primary objective of the study is to determine the safety, tolerability, maximum tolerated dose or the maximum administered dose of GSK3359609 alone or in combination.

Detailed description:

Arms:
arm 1: Participants will receive feladilimab (GSK3359609) administered continuously at a dose level dependent on to which dose level the participant is accrued. arm 2: Participants will receive feladilimab (GSK3359609) administered continuously at a dose level chosen for further exploration in dose expansion cohorts. arm 3: Participants will receive feladilimab (GSK3359609) administered continuously in combination with pembrolizumab. arm 4: Participants will receive feladilimab (GSK3359609) administered continuously in combination with GSK3174998. arm 5: Participants participating in Part 2A chemotherapy combination cohorts will receive feladilimab (GSK3359609) in combination with chemotherapy at doses and schedules based on standard of care practice. arm 6: Participants will receive feladilimab (GSK3359609) administered continuously in combination with pembrolizumab. arm 7: Participants will receive feladilimab (GSK3359609) administered continuously in combination with dostarlimab. arm 8: Participants will receive feladilimab (GSK3359609) administered continuously in combination with dostarlimab followed by cobolimab. arm 9: Participants will receive feladilimab (GSK3359609) administered continuously in combination with bintrafusp alfa.

Interventions: intervention 1: feladilimab (GSK3359609) intervention 2: GSK3174998 intervention 3: Pembrolizumab intervention 4: Docetaxel intervention 5: Pemetrexed intervention 6: Paclitaxel plus Carboplatin intervention 7: Gemcitabine plus Carboplatin intervention 8: Fluorouracil (5-FU) plus carboplatin or cisplatin intervention 9: Dostarlimab intervention 10: Cobolimab intervention 11: Bintrafusp alfa
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None intervention 10: None intervention 11: None

Protocol document:
Prot_000.pdf: 
 
CONFIDENTIAL 
TMF-11734800 
The GlaxoSmithKline group of companies 
 
204691 
 
1 
 
TITLE PAGE 
Division: Worldwide Development 
 
Information Type: Protocol Amendment 
Title: 
A Phase I Open Label study of GSK3359609 (feladilimab) 
administered alone and in combination with anticancer agents 
in subjects with selected advanced solid tumors 
Compound 
Number: 
GSK3359609 
Development Phase: I 
Effective Date: 
20-AUG-2021 
 
Protocol Amendment Number:  9 
Author (s): 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited. 
 
PPD


 
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Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2015N238345_00 
2016-JAN-26 
Original 
2015N238345_01 
2016-MAR-14 
Amendment No. 1 
Amendment 1 includes the following revisions: 
• Updates to the definitions of dose-limiting toxicities presented in Section 
4.1.1.3, Dose-Limiting Toxicities 
• Inclusion of the requirement for subjects to remain under observation following 
completion of study treatment infusions in Section 6.1. 
• Clarification on the study treatment management for adverse events in 
subsections of Section 7 
Inclusion of additional requirements for study treatment rechallenge following Grade 3 
or Grade 4 infusion reactions in Section 7.12.3 
2015N238345_02 
2016-NOV-14 
Amendment No. 2 
Amendment 2 includes the following revisions: 
• Updates to pembrolizumab background and dose rationale language 
• Requirement for the number of GSK3359609 doses during the 28-day dose 
escalation DLT observation period amended from two to at least one to account 
for delays due to reasons other than AEs. 
• Language allowing for the potential to investigate pembrolizumab at doses 
other than 200 mg deleted. 
• Revisions to eligibility criteria that address prior therapies or allowed 
concomitant medications, tumor histology, clarification on prior malignancies 
and required labs.  Additional revisions include deleting the requirement for age 
of archival tumor specimen and revising pneumonitis history exclusions. 
• Non-serious AESI do not require 24-hour notification to GSK; introduced term 
events of clinical interest which do require 24 notifications. 
• Infusion reaction management guidelines revised to address discrepancies and 
simplify. 
• Updated language to allow MUGA in lieu of ECHO in the assessment of 
LVEF. 
General clarifications and typos were addressed, and assessment windows were added 
if missing. 
2015N238345_03 
2017-DEC-13 
Amendment No. 3 
Amendment 3 included the following major revisions: 
• Updated subject numbers based on increase in size of the study 


 
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• Design revised to include chemotherapy safety run-in cohort and indicate 
GSK3359609 (feladilimab) dosing will transition to fixed dose.  In addition, 
included specifics on the tumor indications selected for expansion cohorts. 
• Dose justification for GSK3359609 (feladilimab) fixed dosing and 
chemotherapy doses 
• Implementation of Quality of Life and symptomatic toxicity instruments in 
expansion cohorts 
• Update with requirement for disease assessments in subjects who discontinue 
study treatment due to durable CR. 
• Updated Safety Management Guidelines to include myocarditis guidelines and 
chemotherapy guidelines 
• Revised Benefit:Risk assessment to include reference to chemotherapy risks 
• Revised study treatment sections and concomitant medication section with 
chemotherapy language 
• Eligibility criteria revised to define target population for Part 1B and Part 2B 
cohorts. Criteria added based on chemotherapy safety run-in cohorts. Minor 
clarifications were also made. 
• Revised Section 8.1 tables to include chemotherapy administration assessments, 
PK assessments and updates to GSK3359609 (feladilimab) PK sampling. 
• Defined hypothesis for escalation phases and for specific expansion cohorts; 
sample size estimations, and futility decisions rules. 
 
2015N238345_04 
2018-OCT-30 
Amendment No. 4 
Amendment 4 included the following major revisions: 
• Updated Nonclinical Safety to include findings from the GSK3359609 
(feladilimab) (anti-ICOS agonist/GSK3174998 (anti-OX40 agonist) cytokine 
release assay  
• Included background on OX40, GSK3174998 mechanism of action and clinical 
experience to support the combination with GSK3359609 (feladilimab) 
• Revised design to include: combination of GSK3359609 (feladilimab) and 
GSK3174998; combination of fluorouracil (5-FU)/platinum with GSK3359609 
(feladilimab); combination of GSK3359609 (feladilimab) with pembrolizumab 
and the platinum doublets. 
• Included GSK3359609 (feladilimab) combination with GSK3174998 dose 
escalation decision using the 2D-NCRM. 
• Updates to design justification and dose justifications to support the 
combination of GSK3359609 (feladilimab) and GSK3174998; 5-FU/platinum 
chemotherapy combinations 
• Revised inclusion criterion 4 to define requirements for prior therapy 
• Revised inclusion criterion 10 requirement for renal function using calculated 
creatinine clearance from the minimum of 50 to 30 mL/min 
• Revised dose and safety management guidelines to include GSK3174998 
• Updated study assessments (refer to Table 24 and Table 25) to include 
GSK3174998, 5-FU and cisplatin administration, PK sampling, and 
GSK3174998 immunogenicity testing 


 
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• Updated statistical considerations and analysis to include GSK3359609 
(feladilimab) combination with GSK3174998 
Minor updates to include correction of typos and clarifications 
2015N238345_06 
2019-MAR-14 
Amendment No. 5 
Amendment 5 included the following major revisions: 
• Increased the total number of subjects that will be enrolled in the study to 698 
and appropriate corresponding changes were added.  
• Provided detailed dose information for the HNSCC randomization cohort in the 
Part 2B 
• Removed the eligibility requirement of absolute lymphocyte count   
• Modified ALT requirement at the baseline, to allow subjects with documented 
liver metastases to be eligible if ALT is ≤5xULN and the liver stopping criteria 
for those subjects.  
• Defined the subjects eligible to enroll in the Part 2A 5FU-platinum combination 
with GSK3359609 (feladilimab) and pembrolizumab  
• Added exclusion criterion to address subjects with tumors invading major 
vessels due to bleeding risk 
• Updates to the Statistical Analysis Sections corresponding to the increase of the 
total number of subjects 
2015N238345_11 
2020-FEB-27 
Amendment No. 6 
• Added HNSCC combination cohort of GSK3359609 (feladilimab) and 
pembrolizumab for subjects with CPS <1 
• Added investigation of GSK3359609 (feladilimab) and pembrolizumab Q6W 
as a new HNSCC randomized cohort 
• Added additional information on dose expansion of combination GSK3359609 
(feladilimab) (anti-ICOS agonist) and GSK3174998 (anti-OX40 agonist) at 24 
mg of each agent 
• Updated relevant sections including the time and events table to reflect the new 
cohorts that include GSK3359609 (feladilimab) Q6W dosing schedule  
• Updated GSK3359609 (feladilimab) clinical experience with safety update 
from the GSK3359609 (feladilimab) IB. 
• Added language to protocol describing retreatment option 
2015N238345_13 
2020-APR-08 
Amendment No. 7 
• Increased the total number of subjects that will be enrolled in the study to 873 
and appropriate corresponding changes were added.  
 
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• Added three new combination cohorts of GSK3359609 (feladilimab) plus 
bintrafusp alfa (M7824), GSK3359609 (feladilimab) plus dostarlimab, and 
GSK3359609 (feladilimab) plus dostarlimab plus cobolilmab with dose 
escalation and pharmacokinetic/pharmacodynamic phases in advanced solid 
tumors 
• Updated relevant sections including the time and events table to reflect the new 
cohorts that include the new combination agents 
• Updated relevant sections of biomarker cohort with additional details on 
screening and testing procedures and statistical analysis 
 
• Clarified difference between Adverse Event of Special Interest and Event of 
Clinical Interest. Included in the list of Events of Clinical Interest infection with 
COVID-19 
 
• Referenced Country Specific Amendment to incorporate Japanese sites 
2015N238345_15 
2020-OCT-09 
Amendment No. 8 
• Adjusted the total number of subjects that will be enrolled in the study to 867 
and appropriate corresponding changes were added.  
 
• Updated relevant sections including the time and events table to remove 
dostarlimab, cobolimab, and bintrafusp alfa cohorts. 
• Updated relevant sections of biomarker cohort with additional details on 
screening and testing procedures and statistical analysis 
 
• Updated 2A cohorts to remove dostarlimab, cobolimab, and bintrafusp alfa 
containing arms 
TMF-11734800 
2021-AUG-20 
Amendment No. 9 
• Reduced collection burden by eliminating pembrolizumab pharmacokinetics 
assay and pembrolizumab anti-drug antibody (ADA) 
• Eliminate second course of therapy following relapse  
• Clarification of End of Study and Off Study criteria 
• Clarification of reporting process for hepatic toxicity 
 
 
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SPONSOR SIGNATORY: 
Protocol Title: A Phase I Open Label study of GSK3359609 (feladilimab) administered 
alone and in combination with anticancer agents in subjects with selected advanced solid 
tumors 
Protocol Number: 204691/Amendment 09 
Compound Number 
or Name: 
GSK3359609 
 
 
 
 
 
 
Steven Hirschfeld, MD PhD 
Physician Project Lead 
  
 
Date 
The signed page is a separate document. 


 
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MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information:  
Role 
Name 
Office Phone  
Email Address 
Mobile 
Medical Monitor 
SAE Reporting 
 
OAX37649@gsk.com 
 
 
Sponsor Legal Registered Addresses:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
GlaxoSmithKline 
1250 South Collegeville Road 
Collegeville, PA 19426, USA 
Telephone: +1 610 917 7000 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application. 
Regulatory Agency Identifying Number(s):  
Investigational New Drug Number: 126353 
European Drug Regulatory Authorities Clinical Trials Number: 2016-000148-32 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol number 204691 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 


 
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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
SPONSOR SIGNATORY: ............................................................................................... 6 
INVESTIGATOR PROTOCOL AGREEMENT PAGE ....................................................... 8 
TABLE OF CONTENTS .................................................................................................. 9 
1. 
PROTOCOL SYNOPSIS FOR STUDY 204691 ...................................................... 13 
2. 
INTRODUCTION .................................................................................................... 18 
2.1. 
Study Rationale .......................................................................................... 18 
2.2. 
Brief Background ........................................................................................ 18 
2.3. 
GSK3359609 (feladilimab) (Antibody with ICOS Agonist Activity) ............... 20 
2.3.1. 
Background ................................................................................. 20 
2.3.2. 
Nonclinical Pharmacokinetics ...................................................... 21 
2.3.3. 
Nonclinical Safety ........................................................................ 21 
2.3.4. 
Nonclinical Activity and Pharmacodynamics ................................ 25 
2.3.5. 
GSK3359609 (feladilimab) Clinical Experience ............................ 28 
2.4. 
Pembrolizumab ........................................................................................... 32 
2.5. 
GSK3174998 (Anti-OX40 Agonist) .............................................................. 32 
2.5.1. 
GSK3174998 (Anti-OX40) Clinical Experience ............................ 33 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 34 
4. 
STUDY DESIGN .................................................................................................... 39 
4.1. 
Overall Design ............................................................................................ 39 
4.1.1. 
Dose Escalation Phase ................................................................ 43 
4.1.2. 
Dose Expansion Phase ................................................................ 54 
4.2. 
Study Treatment and Duration .................................................................... 57 
4.3. 
Study Population ......................................................................................... 58 
4.4. 
Design Justification ..................................................................................... 59 
4.5. 
Dose Justification ........................................................................................ 60 
4.5.1. 
Part 1A: GSK3359609 (feladilimab) (ICOS) Monotherapy 
Dose Rationale ............................................................................ 60 
4.5.2. 
Part 2A: GSK3359609 (feladilimab) (ICOS) Starting Dose 
in Combination with Pembrolizumab ............................................ 61 
4.5.3. 
Part 2A:  GSK3359609 (feladilimab) (ICOS) Starting Dose 
in Combination with Chemotherapy Pembrolizumab .................. 62 
4.5.4. 
Part 2A: GSK3359609 (feladilimab) (ICOS) Starting Doses 
in Combination with GSK3174998 (OX40) ................................... 62 
4.5.5. 
GSK3359609 (feladilimab) Dosing Frequency ............................. 63 
4.5.6. 
GSK3359609 (feladilimab) Fixed Dose Rationale ........................ 63 
4.5.7. 
Part 2: Pembrolizumab Dose Rationale ....................................... 64 
4.5.8. 
Part 2: Chemotherapy Dose Rationale ......................................... 66 
4.5.9. 
Part 2: GSK3174998 (OX40) Dose Rationale .............................. 66 
4.6. 
Benefit:Risk Assessment ............................................................................ 67 
4.6.1. 
Risk Assessment ......................................................................... 68 
4.6.2. 
Overall Benefit:Risk Conclusion ................................................... 69 


 
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5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ............. 69 
5.1. 
Inclusion Criteria ......................................................................................... 69 
5.2. 
Exclusion Criteria ........................................................................................ 73 
5.3. 
Screening/Baseline/Run-in Failures ............................................................ 76 
5.4. 
Withdrawal/Stopping Criteria....................................................................... 76 
5.4.1. 
Liver Chemistry Stopping Criteria ................................................ 78 
5.4.2. 
Stopping Rules for Clinical Deterioration ...................................... 80 
5.5. 
Participant and Study Completion ............................................................... 81 
6. 
STUDY TREATMENT ............................................................................................ 81 
6.1. 
Investigational Product and Other Study Treatment .................................... 81 
6.2. 
Treatment Assignment ................................................................................ 84 
6.3. 
Blinding ....................................................................................................... 85 
6.4. 
Packaging and Labeling .............................................................................. 85 
6.5. 
Preparation/Handling/Storage/Accountability .............................................. 85 
6.5.1. 
Preparation .................................................................................. 85 
6.5.2. 
Handling ...................................................................................... 85 
6.5.3. 
Storage ........................................................................................ 85 
6.5.4. 
Accountability .............................................................................. 85 
6.6. 
Compliance with Study Treatment Administration ....................................... 86 
6.7. 
Treatment of Study Treatment Overdose .................................................... 86 
6.7.1. 
GSK3359609 (feladilimab) (ICOS) or GSK3174998 
(OX40) Overdose ......................................................................... 86 
6.7.2. 
Pembrolizumab Overdose ........................................................... 86 
6.7.3. 
Chemotherapy Overdose ............................................................. 87 
6.8. 
Treatment after the End of the Study .......................................................... 87 
6.9. 
Concomitant Medications and Non-Drug Therapies .................................... 87 
6.9.1. 
Permitted Medications and Non-Drug Therapies .......................... 87 
6.9.2. 
Prohibited Medications and Non-Drug Therapies ......................... 88 
7. 
DOSE AND SAFETY MANAGEMENT GUIDELINES ............................................. 88 
7.1. 
General Guidelines for Immune-Related Adverse Events ........................... 90 
7.2. 
General Principles of Immune-Related Adverse Events Identification 
and Evaluation ............................................................................................ 91 
7.3. 
General Guidelines for Clinically Significant Toxicities Not 
Otherwise Specified .................................................................................... 91 
7.4. 
Management of Hepatotoxicity .................................................................... 91 
7.5. 
Management of Gastrointestinal Events (Diarrhea or Colitis) ...................... 96 
7.6. 
Management of Renal Toxicity .................................................................... 98 
7.7. 
Management of Skin Toxicity .................................................................... 100 
7.8. 
Management of Endocrine Events ............................................................ 101 
7.9. 
Management of Pneumonitis .................................................................... 103 
7.10. 
Management of Hematologic Events ........................................................ 105 
7.11. 
Management of Uveitis/Iritis ...................................................................... 105 
7.12. 
Management of Infusion Reactions or Severe Cytokine Release 
Syndrome (sCRS) ..................................................................................... 107 
7.12.1. 
Infusion Reaction ....................................................................... 107 
7.12.2. 
Cytokine Release Syndrome ...................................................... 107 
7.12.3. 
Guidelines for Management of Infusion Reactions/CRS ............. 108 
7.13. 
Management of Myocarditis ...................................................................... 111 
7.14. 
Management of Neurotoxicity ................................................................... 112 
7.15. 
Management of QTc Events ..................................................................... 112 


 
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7.16. 
Management of Left Ventricular Dysfunction ............................................. 113 
7.17. 
Management of Valvular Toxicity .............................................................. 113 
7.18. 
Management Guidance of Chemotherapy-related Toxicities ..................... 113 
7.19. 
Dose Delay ............................................................................................... 116 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 116 
8.1. 
Time and Events Tables ........................................................................... 117 
8.2. 
Screening and Critical Baseline Assessments .......................................... 126 
8.3. 
Efficacy ..................................................................................................... 127 
8.3.1. 
Evaluation of Anti-Cancer Activity .............................................. 127 
8.4. 
Safety ....................................................................................................... 129 
8.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) ........ 129 
8.4.2. 
Pregnancy ................................................................................. 131 
8.4.3. 
Physical Examinations ............................................................... 131 
8.4.4. 
Performance Status ................................................................... 131 
8.4.5. 
Vital Signs .................................................................................. 131 
8.4.6. 
Electrocardiogram ...................................................................... 132 
8.4.7. 
Echocardiograms ....................................................................... 132 
8.4.8. 
Clinical Safety Laboratory Assessments .................................... 132 
8.5. 
Pharmacokinetics ..................................................................................... 133 
8.6. 
Immunogenicity......................................................................................... 134 
8.7. 
Biomarkers/Pharmacodynamic Markers ................................................... 134 
8.7.1. 
Blood Biomarkers ...................................................................... 134 
8.7.2. 
Tumor Tissue ............................................................................. 134 
8.8. 
Genetics ................................................................................................... 135 
9. 
DATA MANAGEMENT ......................................................................................... 136 
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................... 136 
10.1. 
Hypotheses ............................................................................................... 136 
10.1.1. 
Part 1A and Part 2A Dose Escalation/Safety Run-in .................. 136 
10.1.2. 
Part 1B GSK3359609 (feladilimab) Monotherapy 
Expansion/ Part 2B GSK3359609 (feladilimab) 
Combination with Pembrolizumab Expansion of PD-1/L1 
Experienced Participants ........................................................... 136 
10.1.3. 
Part 2B GSK3359609 (feladilimab) Combination with 
Pembrolizumab Expansion of PD-1/L1 Naïve Participants ......... 137 
10.2. 
Dose Escalation ........................................................................................ 138 
10.2.1. 
Modified Toxicity Probability Interval  (mTPI) ............................. 138 
10.2.2. 
2D-CRM..................................................................................... 138 
10.3. 
Dose Expansion........................................................................................ 139 
10.4. 
Sample Size Considerations ..................................................................... 139 
10.4.1. 
Sample Size Assumptions ......................................................... 139 
10.4.2. 
Dose Escalation ......................................................................... 139 
10.4.3. 
Dose Expansion......................................................................... 141 
10.4.4. 
Sample Size Sensitivity .............................................................. 145 
10.4.5. 
Sample Size Re-estimation or Adjustment ................................. 145 
10.5. 
Data Analysis Considerations ................................................................... 146 
10.5.1. 
Analysis Populations .................................................................. 146 
10.6. 
Interim Analysis ........................................................................................ 146 
10.7. 
Key Elements of the Analysis Plan............................................................ 149 
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10.7.1. 
Primary Analyses ....................................................................... 149 
10.7.2. 
Secondary Analyses .................................................................. 150 
10.7.3. 
Pharmacokinetic Analyses ......................................................... 151 
10.7.4. 
Pharmacokinetic/Pharmacodynamic Analyses ........................... 152 
10.7.5. 
Immunogenicity.......................................................................... 153 
10.7.6. 
Other Analyses .......................................................................... 153 
11. STUDY GOVERNANCE CONSIDERATIONS ...................................................... 153 
11.1. 
Posting of Information on Publicly Available Clinical Trial Registers .......... 153 
11.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...................................................................................... 154 
11.3. 
Quality Assurance ..................................................................................... 154 
11.4. 
Study and Site Closure ............................................................................. 155 
11.5. 
Records Retention .................................................................................... 155 
11.6. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................. 156 
11.7. 
Steering Committee .................................................................................. 156 
12. REFERENCES ..................................................................................................... 157 
13. APPENDICES ...................................................................................................... 164 
13.1. 
Appendix 1:  Abbreviations and Trademarks ............................................. 164 
13.2. 
Appendix 2: Immune-related Diseases ..................................................... 168 
13.3. 
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ........................... 170 
13.4. 
Appendix 4: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines ................................................................................................. 172 
13.5. 
Appendix 5: NYHA Functional Classification System for Heart 
Failure ...................................................................................................... 175 
13.6. 
Appendix 6: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST version 
1.1 ............................................................................................................ 176 
13.7. 
Appendix 7: ECOG Performance Status ................................................... 181 
13.8. 
Appendix 8: Events of Clinical Interest ...................................................... 182 
13.9. 
Appendix 9: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ............................................. 183 
13.9.1. 
Definition of Adverse Events ...................................................... 183 
13.9.2. 
Definition of Serious Adverse Events ......................................... 184 
13.9.3. 
Definition of Cardiovascular Events ........................................... 185 
13.9.4. 
Recording of AEs and SAEs ...................................................... 186 
13.9.5. 
Evaluating AEs and SAEs .......................................................... 186 
13.9.6. 
Reporting of SAEs to GSK ......................................................... 187 
13.9.7. 
Collection of Pregnancy Information .......................................... 188 
13.10. Appendix 10: CKD-EPI Formula ............................................................... 190 
13.11. Appendix 11: Genetic Research ............................................................... 191 
13.12. Appendix 12 - Country Specific Requirements .......................................... 194 
13.12.1. COUNTRY SPECIFIC REQUIREMENTS (JAPAN) ................... 194 
13.13. Appendix 13 – Substantial Protocol Changes from Previous 
Amendment .............................................................................................. 196 


 
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1. 
PROTOCOL SYNOPSIS FOR STUDY 204691 
Rationale 
GSK3359609 (feladilimab) is an anti-Inducible T cell Co-Stimulator (ICOS) receptor 
agonist monoclonal antibody (mAb) intended for the treatment of cancers of different 
histology. It is expected to differentiate from first generation immunomodulatory 
antibodies directed against immune checkpoint modulators by targeting a different axis in 
the antitumor T cell response cascade and promoting activation of a co-stimulatory 
receptor instead of blocking an inhibitory checkpoint receptor. 
The desired pharmacology of GSK3359609 (feladilimab) 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 (feladilimab) to bind and elicit an agonist effect. Therefore, it is expected 
that GSK3359609 (feladilimab) 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 (feladilimab) is expected to be active in 
combination with agents which prime or modulate tumor immunity. Therefore, both 
single agent therapy and combination therapies will be evaluated in the first-time-in-
human (FTIH) clinical study. 
Primary and Secondary Objective(s)/Endpoint(s) 
Objectives 
Endpoints 
Part 1 GSK3359609 (feladilimab) (anti-ICOS mAb) Monotherapy 
Primary 
• To determine the safety, tolerability, 
MTD or the MAD of GSK3359609 
(feladilimab) 
• AEs, SAEs, DLTs, changes in 
safety/laboratory assessment 
parameters, dose modifications 
Secondary 
• To determine the recommended dose 
of GSK3359609 (feladilimab) for 
further exploration 
• To evaluate the antitumor activity of 
GSK3359609 (feladilimab)  
• To characterize the PK properties of 
GSK3359609 (feladilimab) 
• To determine immunogenicity 
• AEs, SAEs, DLTs, changes in 
safety/laboratory assessment 
parameters, dose modifications, PK, 
pharmacodynamic activity, antitumor 
activity 
• ORR1, DCR1, PFS1, OS, TTR1, 2, 
DoR1, 2 
• Plasma PK parameters such as Cmax, 
Ctau, AUC (0-) as data permit 
•  ADA incidence by dose level/dose 


 
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Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; 
Cmax=maximum observed concentration; Ctau=minimum observed concentration; DCR=disease control 
rate; DLT=dose limiting toxicity; DoR=duration of response; irRECIST=immune-related RECIST; 
MAD=maximum administered dose; MTD=maximum tolerated dose; ORR=overall response rate; 
OS=overall survival; PFS=progression-free survival; PK; pharmacokinetic; RECIST=Response Evaluation 
Criteria in Solid Tumors; SAE; serious adverse events; TTR=time to response 
1. irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, 
DCR);RECISTv1.1 guidelines are used for PFS, DoR, TTR and disease assessments.  
2. 
 
 
Objectives 
Endpoints 
Part 2 GSK3359609 (feladilimab) (anti-ICOS mAb) in Combination with 
Pembrolizumab (anti-PD-1 mAb) or GSK3174998 (anti-OX40 mAb) 
Primary 
• To determine the safety, tolerability, 
MTD or the MAD of GSK3359609 
(feladilimab) in combination with 
pembrolizumab or GSK3174998 
• AEs, SAEs, DLTs, changes in 
safety/laboratory assessment 
parameters, dose modifications 
Secondary 
• To determine the recommended 
dose(s) and schedule of GSK3359609 
(feladilimab) in combination with 
pembrolizumab for further exploration 
• To determine the recommended 
dose(s) of GSK3359609 (feladilimab) 
and GSK3174998 in combination 
• To evaluate the antitumor activity of 
GSK3359609 (feladilimab) in 
combination with pembrolizumab or 
GSK3174998  
• AEs, SAEs, DLTs, changes in 
safety/laboratory assessment 
parameters, dose modifications, PK, 
pharmacodynamic activity, antitumor 
activity 
 
 
• ORR1, DCR1, PFS1, OS, TTR1, 2, 
DoR1, 2 
 
• To characterize the PK properties of 
GSK3359609 (feladilimab), 
pembrolizumab, and  GSK3174998 
when administered in combination 
• GSK3359609 (feladilimab), 
GSK3174998, and serum 
pembrolizumab PK parameters such 
as Cmax, Ctau, AUC (0-) as data 
permits 
• To determine immunogenicity of 
GSK3359609 (feladilimab), 
• ADA  
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Objectives 
Endpoints 
pembrolizumab or GSK3174998 when 
administered in combination 
• incidence of each drug by dose 
level/dose 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; Cmax= 
maximum observed concentration; Ctau=minimum observed concentration; DCR=disease control rate; 
DLT=dose limiting toxicity; DoR=duration of response; irRECIST=immune-related RECIST; 
MAD=maximum administered dose; MTD=maximum tolerated dose; ORR=overall response rate; 
OS=overall survival; PFS=progression-free survival; PK; pharmacokinetic; RECIST=Response 
Evaluation Criteria in Solid Tumors; SAE; serious adverse events; TTR=time to response 
1. irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, 
DCR);RECISTv1.1 guidelines are used for PFS, DoR, TTR and disease assessments.  
2. 
 
 
Objectives 
Endpoints 
Part 2A3 GSK3359609 (feladilimab) (anti-ICOS mAb) Combinations with 
Chemotherapies (Pembrolizumab) 
Primary 
• To determine the safety, tolerability, 
of GSK3359609 (feladilimab) in 
combination with standard of care 
chemotherapies 
• AEs, SAEs, changes in 
safety/laboratory assessment 
parameters, dose modifications 
Secondary 
• To determine the recommended dose 
of GSK3359609 (feladilimab) for 
further exploration 
 
• To characterize the PK properties of 
GSK3359609 (feladilimab), 
chemotherapies, and pembrolizumab 
• To determine immunogenicity of 
GSK3359609 (feladilimab) and 
pembrolizumab 
• AEs, SAEs, DLTs, changes in safety/ 
laboratory assessment parameters, 
dose modifications, PK, 
pharmacodynamic activity, antitumor 
activity 
• Plasma PK parameters such as Cmax, 
and Ctau as data permit 
• ADA incidence by dose level/dose 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; Cmax= maximum observed concentration; 
Ctau=minimum observed concentration; DLT=dose limiting toxicity; PK; pharmacokinetic; SAE; serious 
adverse events 
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Overall Design 
This is an open-label, multicenter study designed to evaluate the safety, tolerability, 
pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of 
GSK3359609 (feladilimab) administered intravenously to participants with selected 
advanced or recurrent solid tumors. The study will be conducted in two parts with each 
part consisting of a dose escalation phase and expansion phase. Part 1 will evaluate 
GSK3359609 (feladilimab) as a monotherapy, while Part 2 will evaluate GSK3359609 
(feladilimab) (anti-ICOS agonist mAb) in combination with pembrolizumab (anti-PD-1 
mAb), or GSK3174998 (anti-OX40 mAb), or chemotherapy regimens; GSK3359609 
(feladilimab) combinations with chemotherapies will only consist of safety run-in 
cohorts. 
The aim of the dose escalation phases (Part 1A and 2A) is to identify recommended dose 
or doses of GSK3359609 (feladilimab) for further investigation either as a monotherapy 
or combination therapy. GSK3359609 (feladilimab) in combination with other agents is 
planned to be investigated in the dose escalation phase to identify recommended dose 
combination(s); recommended doses may be explored in the expansion phase. The 
recommended dose(s)/dose combination(s) will be based on the observed safety and 
tolerability, PK, pharmacodynamic profiles, and any preliminary anticancer activity. 
The purpose of the chemotherapy safety run-in cohorts is to evaluate the safety, and 
preliminary efficacy, of the 24 mg and 80 mg GSK3359609 (feladilimab) doses in 
combination with standard of care doses of chemotherapies (pembrolizumab); 
additional GSK3359609 (feladilimab) doses within the planned doses may be 
investigated to establish the recommended GSK3359609 (feladilimab) dose 
(pembrolizumab). 
In the dose expansion phases (Part 1B and 2B), the expansion cohorts include participants 
defined by a single tumor histology. Additionally, several expansion cohorts have been 
defined by a specific characteristic such as tumors exhibiting high microsatellite 
instability, deficiency in DNA mismatch repair processes, or viral-mediated pathology. 
GSK3359609 (feladilimab) monotherapy is being investigated in a biomarker defined 
cohort (ICOS expression); GSK3359609 (feladilimab) in combination with 
pembrolizumab or other agents also may be investigated in biomarker defined cohorts. 
Further cohorts may be defined by other features such as response to prior treatment with 
an immune checkpoint inhibitor, a disease characteristic, molecular/genetic alteration or 
pathology. The aim is to further explore the clinical activity of GSK3359609 
(feladilimab) monotherapy and in combination with pembrolizumab or other agents in 
defined cohorts. 
Treatment Arms and Duration 
In Part 1 of the study, all participants will receive GSK3359609 (feladilimab) 
monotherapy. In Part 2 of the study, all participants will receive GSK3359609 
(feladilimab) in combination with: 
• Pembrolizumab  


 
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• or Standard of care chemotherapy regimens with and without pembrolizumab  
or  
•  GSK3174998  
Participants may continue treatment until disease progression, unacceptable toxicity, or 
withdrawal of consent up to a maximum initial treatment duration of approximately 2 
years, up to 35 cycles. For participants enrolling in HNSCC dose optimization cohort the 
maximum treatment duration is approximately 2 years, or up to 17 cycles for both 
GSK3359609 (feladilimab) and pembrolizumab. After permanent discontinuation of 
study treatment, the follow-up period for safety assessments will be a minimum of 90 
days after the last dose of study treatment or until the start of subsequent anti-cancer 
treatment. 
Type and Number of Participants 
Overall it is estimated a total of 867 participants may be enrolled in this two-part study 
(Part 1 [monotherapy: Parts 1A, 1B, 1C and Part 1D] and Part 2 [combination therapy: 
Parts 2A, 2B, and 2C]). Approximately 166 participants are planned to be enrolled in 
Parts 1A and 2A [dose escalation/safety run-in], approximately 20 participants per cohort 
enrolled in Part 1C and Part 2C in a Japan country specific amendment, and 
approximately 20 participants enrolled in Part 1D in a China country specific 
amendment; approximately 641 participants are planned to be enrolled in Parts 1B and 
2B (cohort expansion) to include approximately 60 participants in the biomarker training 
cohort. In many cohorts a seamless design occurs between Part 2A and Part 2B, the dose 
escalation and the expansion phase. Cohorts may be expanded to include additional 
participants to evaluate subpopulations based on parameters such as histology, genetics, 
or other criteria. 
The Part 1B PK/pharmacodynamics cohort will enroll approximately 52 participants. The 
average sample size in Part 1B is 171 participants in all cohorts excluding the 
PK/PD/ADA cohort under the null hypothesis; the average sample size in Part 2B is 343 
in all cohorts under the null hypothesis. The average sample size in Part 1B excluding the 
PK/PD cohort is 210 participants if two cohorts (non-biomarker) are under the alternative 
hypothesis; the average sample size in Part 2B is 379 participants if three cohorts are 
under the alternative hypothesis. 
Analysis 
In the GSK3359609 (feladilimab) monotherapy and pembrolizumab combination dose 
escalation/chemotherapy combination safety run-in phases, a modified Toxicity 
Probability Interval method will be used to guide dose decisions [Ji, 2010]. In the 
GSK3359609 (feladilimab) combination with GSK3174998 (anti-OX40) dose escalation 
phase, a two-dimensional continual reassessment method (2D-CRM) [Neuenschwander, 
2014] will be used to guide the dose combination decisions. Dose decisions will be based 
primarily on dose limiting toxicities however the totality of clinical safety assessments 
will be considered. No formal statistical hypotheses will be tested, and analyses will be 
descriptive. In dose expansion phases, a Bayesian adaptive design with independent 


 
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tumor type modeling will be implemented. Additional analysis with hierarchical 
modeling across disease-specific participant cohorts may be explored. The design permits 
the trial to be frequently monitored for clinical activity with the constraint of both Type I 
and Type II error rates [Berry, 2013]. 
2. 
INTRODUCTION 
2.1. 
Study Rationale 
GSK3359609 (feladilimab) is intended to be a first-in-class anti-ICOS agonist antibody 
for the treatment of cancers of different histology. It is expected to differentiate from first 
generation immunomodulatory antibodies directed against Cytotoxic T-Lymphocyte-
Associated Protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/PD-Ligand-
1 (PD-L1) by targeting a different axis in the antitumor T cell response cascade and 
promoting activation of a co-stimulatory receptor instead of blocking an inhibitory 
checkpoint receptor. The effect of ICOS agonist activity is to promote the expansion and 
function of cytotoxic CD8+, and effector CD4+ T cells, resulting in improved antitumor 
immune responses that are durable. Due to the restricted expression of ICOS on activated 
T cells, it is expected that GSK3359609 (feladilimab) may result in a more favorable 
safety profile as compared with other antibodies that target co-stimulatory T cell 
receptors constitutively expressed on naïve T cells. 
Nevertheless, some tumors may engage multiple mechanisms to escape immune-
mediated antitumor effects thus combining an ICOS agonist with agents that target 
different pathways within the immune cascade may be required for achieving the desired 
clinical effect. Accordingly, as ICOS agonists stimulate IFN production which induces 
PD-L1 expression on tumor cells and within the tumor microenvironment [Mimura, 
2018], this may facilitate the therapeutic benefit of PD-1/L1 blockade within tumors that 
have low levels of PDL1 expression. Several studies have underscored the co-expression 
of PD-1 and ICOS on tumor--infiltrating lymphocytes (TILs) and anti-PD-1-responsive 
peripheral T cells, as well as complementarity between inhibition of the PD-1/L1 axis and 
co-stimulation via the ICOS/L axis [Kamphorst, 2017; Gros, 2014; Beyrend, 2019]. 
Clinical studies and a series of nonclinical studies support the combination approach of 
an anti-ICOS agonist with immune checkpoint inhibitors or other agents that modulate 
the immune system distinct from ICOS biology (refer to Section 2.2, through Section 
2.5). 
The purpose of this FTIH, open-label study is to investigate the safety, pharmacology, 
PK, immunogenicity, biomarker identification, and preliminary antitumor activity in 
participants with selected, advanced or recurrent solid tumors with an aim to establish 
recommended dose(s) of GSK3359609 (feladilimab) for further exploration as a 
monotherapy and in combination with pembrolizumab, chemotherapy, or other agents. 
2.2. 
Brief Background 
A model of cancer immunity is described as a cyclic multistep process that functions to 
elicit an effective antitumor response [Chen, 2013]. Each step can be negatively 
regulated, thus providing the tumor with redundant mechanisms by which to block an 


 
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antitumor immune response. In some cases, tumors will be highly dependent on a single 
mechanism, and in these cases, there is the potential to achieve significant clinical 
activity with a single agent immunomodulatory therapy. However, it is expected that 
tumors often utilize redundant mechanisms to evade antitumor immune responses and in 
these cases, combination therapies are likely required. 
Robust antitumor responses including complete cure in some cancers have been achieved 
by modulating a patient’s immune system. Antibodies targeting the checkpoint receptors 
or their cognate ligands engaged in negative regulation of T cell responses, such as 
CTLA-4 and PD-1/PD-L1, have demonstrated efficacy and are proven effective as 
anticancer immunotherapies in a broad range of tumors including some solid tumors 
otherwise considered poorly immunogenic. Moreover, the PD-1 inhibitor, 
pembrolizumab, as a single agent in a biomarker selected NSCLC population offers 
patients in the first-line setting a chemotherapy-free regimen with a significant overall 
survival benefit [Reck, 2016]. 
Nevertheless, a majority of tumors are unresponsive to this class of agents as 
monotherapies because they may possess features that enable them to evade immune 
surveillance, suppress immune reactivity, proliferate and survive within an inflammatory 
microenvironment. In addition, multiple mechanisms of immune suppression could exist 
which may prohibit effective antitumor immune responses. In these instances, 
combination therapies will likely be required to improve clinical benefit. The 
combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with 
metastatic melanoma is an example of the practice-changing clinical benefit of such 
combinations with two immune checkpoint inhibitors [Wolchok, 2013; Larkin , 2015]. 
In some patients, however, inhibition of a select set of immune checkpoint pathways (e.g. 
PD-1/L1 or CTLA-4) alone may not elicit an effective antitumor response. To reinstate 
immunosurveillance, effective therapeutic intervention may require combinations with 
agents that provide co-stimulatory signals or target different processes within the immune 
cascade. These regimens may include chemotherapies which elicit advantageous 
immunological effects [Galluzzi, 2015] as evidenced by improved progression-free 
survival and overall survival in combination of PD-1/L1 therapies [Gandhi, 2018; 
Socinski, 2018]. Another approach would be to target co-stimulatory receptors (e.g. 
ICOS and OX40) to potentially enhance immune activation. Apart from its role in 
augmenting T cell activation, proliferation, and survival through direct and indirect 
mechanisms [Betting, 2009; Croft, 2010], OX40 signaling has been shown to block the 
activity of induced regulatory T (Tregs) cells, thereby further promoting T cell effector 
immune responses [Ito, 2006]. 
Immunomodulatory agents that target other components of the cancer immunity cycle are 
needed to expand the population of patients and range of tumor types that may respond to 
immunotherapy as well as enhance the magnitude and duration of antitumor responses in 
patients whose tumors are already sensitive to current immunotherapy approaches. 
Ultimately the aim is to improve patient survival outcome in all disease settings including 
the advanced setting which is considered non-curative by nature. 


 
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ICOS is a co-stimulatory receptor belonging to the CD28/CTLA immunoglobulin super 
family with expression restricted to T cells [Hutloff, 1999]. ICOS is weakly expressed on 
resting TH17, follicular helper T and Treg cells yet is highly induced on CD4+ and CD8+ 
T cells upon T cell receptor (TCR) engagement and activation [Paulos, 2010; 
Wakamatsu, 2013]. Upregulation of ICOS leads to both Th1 and Th2 cytokine secretion 
and sustained effector T cell proliferation and function [Sharpe, 2002]. A growing body 
of evidence supports the concept that activating ICOS on CD4+ and CD8+ effector T 
cells has antitumor potential. 
As evident from the clinical efficacy of anti-PD-1/L1 agents indicated for the treatment 
of cancers, targeting immune checkpoint modulators is an established concept that has 
resulted in patients deriving transformational clinical benefit. The unique mechanistic 
profile of an anti-ICOS agonist antibody provides an opportunity to investigate the 
antitumor potential of targeting a T cell co-stimulator as a single agent and to combine 
with other immune-targeted agents that regulate key immune pathways or immune cell 
populations as well as tumor targeted agents, either in development or already in clinical 
use. 
2.3. 
GSK3359609 (feladilimab) (Antibody with ICOS Agonist 
Activity) 
2.3.1. 
Background 
GSK3359609 (feladilimab) is a humanized anti-ICOS monoclonal antibody (mAb) 
selected for its nanomolar (nM) binding to and agonist activity in ICOS-expressing CD4+ 
and CD8+ effector T cells. GSK3359609 (feladilimab) is specifically engineered as an 
Immunoglobulin (Ig)G4 hinge-stabilized isotype, IgG4PE, to markedly decrease binding 
affinity of the Fc (Fragment crystallizable) region of the mAb to activating Fcγ receptors 
and C1q, and thereby diminish the cytotoxic potential of GSK3359609 (feladilimab) that 
would result in depletion of ICOS-positive T cells through antibody-dependent or 
complement-dependent cellular cytotoxicity, respectively. Moreover, the IgG4PE isotype 
retains functional binding to the Fc inhibitor receptor, FcRIIb, a feature described as 
critical for modulating antibody agonist activity [Li, 2011], which also may be essential 
for optimal ICOS agonist activity and its associated antitumor effects in humans. 
The desired pharmacology of GSK3359609 (feladilimab) is the expansion in the total 
number as well as an increase in the activity of tumor specific CD4+ and CD8+ T cell 
populations. Tumor specific T cells must be primed and activated in order for the 
induction of ICOS expression to occur, and thereby for GSK3359609 (feladilimab) to 
bind and function. Therefore, the expectation is GSK3359609 (feladilimab) may be most 
active in settings where an antitumor immune response was primed by prior lines of anti-
cancer therapy and/or in combination with agents that prime or modulate tumor 
immunity. Nevertheless, there is the potential for monotherapy activity in patients with 
tumors that exhibit intrinsic primed/activated effector T cells. 
As indicated in Section 2.3.4 the biophysical and mechanistic properties of GSK3359609 
(feladilimab) have been characterized across multiple in vitro systems. GSK3359609 
(feladilimab) exhibits binding properties consistent with other successful therapeutic 


 
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antibodies. It binds with sub nanomolar affinity to human ICOS and cross-reacts with 
cynomolgus monkey ICOS (1.34 and 0.95 nM, respectively). GSK3359609 (feladilimab) 
induces activation, proliferation and cytokine production in a dose-dependent manner in 
activated T cells. 
2.3.2. 
Nonclinical Pharmacokinetics 
The pharmacokinetics of GSK3359609 (feladilimab) was investigated in two cynomolgus 
monkey IV toxicology studies (refer to Section 2.3.3.1). The large molecular size of 
GSK3359609 (feladilimab) (approximately 150 kilodaltons) and its composition of 
naturally occurring amino acids and a large molecular weight polymer preclude the 
requirement to perform standard distribution, metabolism and excretion studies in 
nonclinical species. 
In the repeat dose study in cynomolgus monkeys in which two doses of GSK3359609 
(feladilimab) were administered two weeks apart, systemic exposure on Day 1 generally 
increased proportionally as the dose increased from 0.3 to 3 milligram (mg)/kilogram 
(kg). However, as the dose of GSK3359609 (feladilimab) increased from 3 to 30 mg/kg, 
a greater than proportional increase in systemic exposure was observed. There was a 
decrease in plasma concentrations in monkeys given 3 mg/kg, typical of an 
immunogenicity response; all animals were confirmed to be positive for anti-drug 
antibody (ADA) in an ADA bridging assay. 
In the second repeat dose study in which GSK3359609 (feladilimab) was administered 
once weekly for 4 weeks, the systemic exposure to GSK3359609 (feladilimab) increased 
dose-proportionally with increasing dose. Following 4 weeks of repeat dosing at both 
dose levels (10 mg/kg and 100 mg/kg), the increases in the gender-averaged AUC 0-168h 
and Cmax (maximum observed concentration) values of GSK3359609 (feladilimab) from 
Week 1 to Week 4 ranged from 1.6 to 2.1-fold. Instances of decreased plasma 
concentrations were observed in individual monkeys after the fourth dose at 
10 mg/kg/week due to primate ADA formation; ADA was detected in a single female at 
100 mg/kg/week. 
Refer to the GSK3359609 (feladilimab) Investigator’s Brochure (IB) for further details 
[GlaxoSmithKline Document Number RPS-CLIN-015202, 2021]. 
2.3.3. 
Nonclinical Safety 
The nonclinical toxicology program for GSK3359609 (feladilimab) 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 (feladilimab) with rodent ICOS receptors. 
 
 (evidence of GSK3359609 (feladilimab) binding and decreased free receptor) 
was demonstrated in vivo on CD4+ T cells in peripheral blood after administration of 
single and multiple doses of GSK3359609 (feladilimab) in monkeys and persisted 
throughout the dosing phase and off-dose period. Immunohistochemical (IHC) 
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 
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tissues examined including lymphoid tissues, gastrointestinal tract, liver, pancreas and 
testes. 
The potential of immobilized GSK3359609 (feladilimab) to induce cytokine release was 
investigated in an in vitro assay using human peripheral blood mononuclear cells 
(PBMCs) from 10 healthy donors in the presence and absence of activation with 
immobilized anti-CD3. As expected, induction of one or more cytokines was detected in 
PBMCs incubated with GSK3359609 (feladilimab) in the presence of anti-CD3 which is 
consistent with the pharmacology of the drug. In non-activated PBMCs, weak induction 
of only one cytokine, interferon-gamma (IFN) was observed in 2 of 10 donors; and in 
anti-CD3 pre-stimulated PBMCs (but no anti-CD3 costimulation), weak induction of 
IFN was observed in 1 of 10 donors. In pharmacology studies, TCR engagement was 
required for induction of ICOS expression and for the ICOS agonist function of 
GSK3359609 (feladilimab). In the absence of TCR stimuli, such as anti-CD3 antibodies, 
there was minimal to no detectable increase in ICOS expression, GSK3359609 
(feladilimab) binding to T cells, T cell activation or induction of pro-inflammatory 
cytokines with either immobilized or soluble form of the ICOS antibody. While the 
potential for GSK3359609 (feladilimab) to induce cytokine release in T cells in the 
absence of TCR engagement in vivo cannot be completely discharged by these in vitro 
assays, the weak induction of only a single cytokine and the absence of increased 
cytokine levels following repeat dosing in monkey studies, suggest the risk is low. 
2.3.3.1. 
GSK3359609 (feladilimab) Monotherapy Studies 
The systemic toxicity of GSK3359609 (feladilimab) after IV administration was 
evaluated in monkeys on repeat dose studies of 4 and 13 weeks given weekly doses of 10 
and 100 mg/kg/dose. GSK33359609 was generally well tolerated with occasional 
transient clinical signs and mild changes in cytokine levels. There were no remarkable 
changes in T cell subsets, Treg cells or T cell activation markers, but decreases in 
monocyte count were seen in males given 100 mg/kg/week on the 13-week study. Anti-
GSK3359609 (feladilimab) antibodies (ADA) were noted in some animals at both dose 
levels. The presence of ADA detected in 3 monkeys from each study was associated with 
increased GSK3359609 (feladilimab) clearance and decreased GSK3359609 
(feladilimab) binding to ICOS receptors on circulating CD4+ T lymphocytes.  On the 13-
week study, all of the monkeys had evidence of circulating immune complexes (CIC). 
Adverse vascular/perivascular findings (lymphocytic infiltration and/or intimal 
thickening) in the heart, seminal vesicles, kidneys, cervix and vagina consistent with 
immune complex formation and deposition were noted in a total of 4 monkeys from both 
GLP toxicology studies. 
One female monkey given 100 mg/kg/week on the 4-week study exhibited adverse 
clinical signs consistent with an acute infusion reaction and was euthanized shortly after 
the completion of the fourth weekly dose. This animal had microscopic changes of multi-
organ inflammation associated with tissue vasculature (arteries, choroid plexus and 
glomerular predilection), was ADA positive, and stained positive for GSK3359609 
(feladilimab), monkey IgG, IgM and/or C3 at sites of vascular injury and inflammation as 
well as within phagocytosed granules/globules in monocytes/macrophages in the affected 
tissues. On the 13-week study at 100 mg/kg/week, vascular/perivascular findings 


 
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(lymphocytic infiltration and/or intimal thickening) were observed in the heart, seminal 
vesicles, and kidneys in 1 male, and in the cervix and vagina in 1 female. The nature and 
distribution of the microscopic inflammatory lesions at known predilection sites for 
immune complex deposition and the presence of CIC in the affected animals are 
consistent with ADA‑mediated immune complex disease. 
One male monkey given 10 mg/kg/week for 4 weeks had microscopic evidence of 
minimal focal inflammation of a coronary artery which was similar to, but less severe 
than the lesion noted in the animal given 100 mg/kg. Although there were no detectable 
ADAs (possibly due to high levels of circulating drug), this lesion was consistent with 
immune-complex deposition because of the similarity to the lesion noted in the 
aforementioned animal. IHC staining did not confirm the presence of immune complex 
deposition since the lesion of interest was not present in subsequent heart sections. 
These potential changes will be monitored in the clinic setting by assessing renal function 
tests, immunogenicity and electrocardiographs.  
Stage-specific evaluation of spermatogenesis was not performed on testes since most 
male monkeys were considered to be sexually immature on both the 4-and 13-week 
studies. However, as GSK3359609 (feladilimab) has high-affinity binding to ICOS, 
which is expressed on CD4+ and CD8+ T cells which did not exhibit binding to 
reproductive organs. With the exception of vascular inflammation attributed to immune 
complex deposition, no histopathology findings in reproductive tissue parenchyma of 
male or female monkeys were noted. 
In summary, GSK3359609 (feladilimab) was generally well tolerated in monkey 
toxicology studies following weekly dosing for up to 13 weeks at doses up to 100 
mg/kg/week. ADAs were detected in monkeys given 10 or 100 mg/kg, however the 
majority of monkeys had sustained systemic exposure and 
 throughout 
the dosing periods indicating that the ability to determine toxicity was not compromised 
by ADA. Adverse infusion reactions and vascular inflammation in the heart, kidney and 
other organs were not considered a direct effect of test article administration but indirect 
toxicity attributed to ADA and based on these findings a NOAEL was not determined 
across the 4-and 13 week-studies. 
Refer to the GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline 
Document Number RPS-CLIN-015202, 2021]. 
2.3.3.2. 
Combination Studies 
To support the combination of GSK3359609 (feladilimab) with other cancer therapies, 
such as pembrolizumab (anti-PD-1 mAb), and GSK3174998 (anti-OX40 mAb), the 
nonclinical toxicology findings with each given as single agents were reviewed. The 
nonclinical toxicology profiles of each agent alone are well characterized and indicate 
that combination toxicology studies in monkeys would not likely provide any relevant 
data that would inform clinical risk assessments. Risk mitigation measures for potential 
clinically relevant risks associated with GSK3359609 (feladilimab) combination therapy 
based on these nonclinical assessments or clinical safety data are described in this 
protocol. 
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2.3.3.2.1. GSK3359609 (feladilimab) Combination with Pembrolizumab 
For the planned combination with pembrolizumab, review of the principal nonclinical 
toxicology findings in monkeys associated with pembrolizumab consisted of generalized 
lymphocytic infiltration consistent with its pharmacologic activity, which was not 
associated with clinical toxicities. In a human PBMC cytokine release assay, 
pembrolizumab did not cause cytokine stimulation in non-stimulated cultures but did 
cause increases in interleukin (IL)-2, tumor necrosis factor-alpha (TNF), IFN IL-6 and 
IL-17 in staphylococcal enterotoxin B stimulated cells, suggesting the potential for 
inappropriate cytokine release under stimulated conditions [KEYTRUDA FDA 
Pharmacology Toxicology Review, 2014]. The potential for cytokine release by 
GSK3359609 (feladilimab) in combination with pembrolizumab was evaluated in PBMC 
and mixed lymphocyte reaction in vitro pharmacology assays. Under stimulated 
conditions, T cells showed enhanced cytokine production with the combination treatment 
compared to the single antibody treatments alone, consistent with expected pharmacology 
of a co-stimulator and checkpoint inhibitor. 
2.3.3.2.2. GSK3359609 (feladilimab) Combination with GSK3174998 (Anti-OX40 
Agonist) 
For the planned combination with GSK3174998, the principal nonclinical toxicology 
findings in monkeys associated with GSK3174998 single agent included detection of 
anti-GSK3174998 antibodies in most monkeys given 10 mg/kg; 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. Overall no adverse test article-related 
findings were noted. No infusion reactions were observed in monkeys, including those 
with ADA. Refer to the GSK3174998 IB for further details [GlaxoSmithKline Document 
Number 2014N212091_06, 2020]. 
The potential for cytokine release by GSK3359609 (feladilimab) and GSK3174998 
(defined as test articles) in combination relative to either test article alone was evaluated 
in vitro in PBMCs (n=10 donors) under assay conditions with or without anti-CD3 
(prestimulated or rested, respectively).  During the treatment period with the 
combination, rested PMBCs were tested with anti-CD3 costimulation, while 
prestimulated PMBCs were tested with or without anti-CD3 costimulation.  In rested 
PBMCs from 4 donors, there were IFN or TNF responses (3X of no drug control) 
with GSK3359609 (feladilimab) and GSK3174998 combinations (0.01 g/mL of at 
least one of the test articles) where no effect was observed with either test article alone at 
concentrations up to 10 g/mL, or at incrementally lower concentrations of GSK3359609 
(feladilimab) when combined with incrementally higher concentrations of GSK3174998. 
There was no evidence of a combination effect on cytokines in prestimulated PBMCs 
relative to the corresponding concentration of either GSK3359609 (feladilimab) or 
GSK3174998 alone. Refer to the GSK3359609 (feladilimab) IB for further details 
[GlaxoSmithKline Document Number RPS-CLIN-015202, 2021]. 


 
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2.3.3.2.3. 
GSK3359609 (feladilimab) Combination with Chemotherapies 
Pembrolizumab 
To support the combination of GSK3359609 (feladilimab) with docetaxel, or the 
platinum-doublets (pemetrexed/carboplatin, paclitaxel/carboplatin, 
gemcitabine/carboplatin, or fluorouracil (5-FU)/carboplatin or cisplatin) with and without 
pembrolizumab, a review of the nonclinical toxicology findings with each given as single 
agents indicate that a combination toxicology study in monkeys would not likely provide 
any relevant clinical risk assessment data due to the frank toxicities of these 
chemotherapeutic agents. 
The nonclinical and clinical toxicity profiles of the cytotoxic chemotherapies are well 
characterized with extensive clinical experience for a range of oncological indications 
including combinations with immune checkpoint inhibitors, such as pembrolizumab, 
which have not identified overlapping toxicities across the two drug classes. Target 
organs/systems of toxicity are hematological, gastro-intestinal and reproductive; 
however, other systems such as cardiovascular, renal, pulmonary and nervous may 
exhibit findings consistent with inhibition of cellular repair and replication. These agents 
will be administered per approved product label. 
2.3.4. 
Nonclinical Activity and Pharmacodynamics 
2.3.4.1. 
GSK3359609 (feladilimab) Monotherapy 
GSK3359609 (feladilimab) 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 (feladilimab) bound to recombinant human ICOS with an affinity of 
1.34 nM as determined by Biacore methodology. GSK3359609 (feladilimab) 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 (feladilimab) to T 
cells was noted in the absence of activation. 
The ex vivo functional activity of GSK3359609 (feladilimab) was evaluated in isolated 
immune cell populations collected from healthy human donors. Isolated PBMCs were 
concurrently activated with anti-CD3 and treated with doses of GSK3359609 
(feladilimab) in the range of 0.1 µg/ml to 100 µg/ml as an immobilized form to emulate 
in vivo FcγR-mediated cross-linking. GSK3359609 (feladilimab) treatment resulted in 
concentration-dependent induction of cytokine production in healthy human donor 
PBMC which included IFN, TN, IL-17a, IL-10, IL-6 and to a lesser extent IL-2, IL-5 
and IL-13. GSK3359609 (feladilimab) significantly increased the levels of T cell 
activation markers such as CD69, OX40 and CD25 in a concentration-dependent manner. 
GSK3359609 (feladilimab) also showed a clear concentration-dependent increase in 
proliferation as measured by Ki67 staining of CD4+ and CD8+ T cells. Consistent with 


 
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the ICOS expression profile and biology, a more robust response was observed in CD4+ 
T cells compared to CD8+ T cells. These results were consistent across healthy human 
donor PBMC (n=4). Studies conducted with ex vivo treated PBMCs isolated from 
cynomolgus monkeys were comparable to that observed with ex vivo treated human 
PBMC. 
ICOS receptor signals through intracellular recruitment of phosphatidylinositol 3-kinase 
(PI3K) and via downstream activation of the mitogen activated protein kinases p38, JNK, 
and ERK [Chialda, 2005; Chen, 2013; Gigoux, 2014]. Treatment with GSK3359609 
(feladilimab) leads to increased phosphorylation of AKT, a key protein kinase in the 
PI3K signaling cascade, along with other proteins downstream of AKT, such as GSK3β 
and ribosomal protein S6 in a concentration and time dependent manner. 
GSK3359609 (feladilimab) is not a super-agonist; as the ICOS agonist function of 
GSK3359609 (feladilimab) 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 (feladilimab). Activated CD4+ T cells treated with GSK3359609 
(feladilimab) 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 co-stimulatory receptors [Wacholtz, 1989]. 
Therefore, the bound-format in vitro assays mimic the in vivo condition wherein an ICOS 
antibody forms cell-to-cell cross-linking through FcγR co-engagement. 
FcR-mediated cell-to-cell cross-linking enhanced GSK3359609 (feladilimab)-induced T 
cell activation, proliferation and function. GSK3359609 (feladilimab) was only able to 
effectively induce T cell proliferation in the presence of FcγR-expressing monocytes as a 
co-culture together with T cells. While an Fc blocking antibody had little or no effect on 
GSK3359609 (feladilimab)-induced cytokine production, it significantly inhibited 
GSK3359609 (feladilimab)-induced T cell proliferation further confirming that FcγR-
mediated cell-to-cell cross-linking is required for optimal activity of an anti-ICOS agonist 
antibody. 
Refer to the GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline 
Document Number RPS-CLIN-015202, 2021]. 
2.3.4.2. 
GSK3359609 (feladilimab) Combination with anti-PD-1 or anti-CTLA-4 
The T cell activating potential of GSK3359609 (feladilimab) was evaluated in multiple 
assay formats as a single agent and in combination with other immune checkpoint 
inhibitors. Ex vivo studies were conducted with PBMC isolated from healthy human 
donors pre-activated with anti-CD3 alone or anti-CD3/anti-CD28. Soluble GSK3359609 
(feladilimab) either alone or in combination with pembrolizumab or ipilimumab 
demonstrated a more robust pro-inflammatory cytokine response than either single agent 
alone. A modified allogenic mixed lymphocyte reaction assay, where lymphocytes from 
one donor were mixed ex-vivo with peptide-stimulated dendritic cells differentiated from 
freshly isolated monocytes from another donor, was also employed to evaluate 
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Significant increases in IFNγ secretion were observed for GSK3359609 (feladilimab) 
combined with pembrolizumab or ipilimumab as compared to either agent alone, 
supporting clinical evaluation of these combinations.  
In vivo experiments in different mouse models either using GSK3359609 
(feladilimab)/pembrolizumab or anti-mouse ICOS in combination with an anti-PD-1 
surrogate antibody demonstrated enhanced tumor growth inhibition and increased 
survivability of mice compared to either agent alone. Combination studies with 
GSK3359609 (feladilimab) and pembrolizumab in the human PBMC engrafted NSG 
mouse model with A2058 melanoma tumors show enhanced tumor growth inhibition and 
increased survivability of mice compared to either agent alone. Similar results were also 
observed with the anti-mouse ICOS and PD-1 surrogate antibodies in subcutaneously 
implanted syngeneic mouse CT26 colon carcinoma and EMT6 mammary carcinoma 
models, where combination treatment resulted in reduced tumor growth and 30 to 40% 
increased survival compared with the monotherapy groups. Furthermore, in vivo studies 
using ICOS-/- and ICOS-ligand (L)-/- mice demonstrated the requirement of ICOS 
signaling in mediating the anti-tumor activity of an anti-CTLA-4 antibody in the B16/F10 
melanoma syngeneic tumor model [Fu, 2011]. Mice lacking ICOS or ICOS-L had 
significantly decreased survival rates compared to wild-type mice after anti-CTLA-4 
antibody treatment suggesting a combination of anti-CTLA-4 treatment with an anti-
ICOS agonist may provide robust anti-tumor responses. In a separate study, B16 tumors 
engineered to overexpress ICOS-L were found to be significantly more sensitive to anti-
CTLA-4 treatment as compared to a B16/Bl6 tumor cells transduced with a control 
protein [Fan, 2014]. 
Treatment of tumor-bearing mice with anti-PD-1 antibodies upregulated ICOS on T cells. 
Treatment with mouse anti-PD-1 antibody in the A20 melanoma cell line model showed 
upregulation of ICOS+ CD4+ and CD8+ T cells in tumors as well as lymph nodes in the 
anti-PD-1 treated animals when compared to those treated with the vehicle or isotype 
control. Similarly, anti-mouse ICOS antibodies increased tumor PD-L1 expression, 
further support evaluating this combination. Finally, The Cancer Genome Atlas (TCGA) 
gene expression data demonstrates that tumors with higher ICOS expression also tend to 
have higher PD-L1 expression, with head and neck squamous cell carcinomas observed 
as having the highest ICOS expression suggesting that targeting both axes may result in 
greater anti-tumor immune response. Interplay between receptor induction also extended 
to CTLA-4. As an example, treatment with mouse anti-CTLA-4 mouse antibody induced 
ICOS on CD4+ and CD8+ T cells in the tumor, spleen and blood, a pattern comparable to 
the ipilimumab clinical response. 
2.3.4.3. 
GSK3359609 (feladilimab) Combination with GSK3174998 (OX40) 
In vivo combination studies using mouse monoclonal antibody surrogates of ICOS and 
OX40 agonists in multiple mouse syngeneic tumor models demonstrated enhanced 
activity (i.e., tumor growth inhibition and survival) of the combination in specific tumor 
models when compared to the single agent treated groups. In some models the 
combination effect was driven mainly by the OX40 mouse surrogate antibody.  
Refer to the GSK3359609 (feladilimab) IB for further details on study designs and results 
[GlaxoSmithKline Document Number RPS-CLIN-015202, 2021]. 


 
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2.3.5. 
GSK3359609 (feladilimab) Clinical Experience 
Analysis from the dose escalation phases of GSK3359609 (feladilimab) monotherapy 
(Part 1A, n=22) and GSK3359609 (feladilimab) combination with pembrolizumab (Part 
2A, n=36), and GSK3359609 (feladilimab) monotherapy pharmacokinetic 
(PK)/pharmacodynamic cohort (n=47) demonstrated GSK3359609 (feladilimab) alone 
and in combination with pembrolizumab was well tolerated across the 0.001–3 mg/kg 
dose range. Maximum tolerated dose (MTD) was not reached in Part 1A and Part 2A; 
maximum administered dose of GSK3359609 (feladilimab) as a monotherapy and in 
combination with pembrolizumab was 3 mg/kg. A range of GSK3359609 (feladilimab) 
doses (≥0.1-1 mg/kg) demonstrated biological and clinical activity supporting the 
mechanism of action of a non-depleting ICOS agonist as a clinical target [Hansen, 2018; 
Maio, 2019]. 
As of 16 March 2020, 249 participants received at least 1 dose of GSK3359609 
(feladilimab) as a monotherapy, 340 participants received at least 1 dose of GSK3359609 
(feladilimab) in combination with 200 mg pembrolizumab, 69 participants received at 
least 1 dose of GSK3359609 (feladilimab) in combination with chemotherapy 
(pembrolizumab), and 19 participants received at least 1 dose of GSK3359609 
(feladilimab) in combination with GSK3174998 in this current, ongoing 204691 study 
(refer to Section 2.3.5.2 for summary of safety). These participants are included in the 
preliminary safety analysis summarized below. 
Refer to GSK3359609 (feladilimab) IB for updated details [GlaxoSmithKline Document 
Number RPS-CLIN-015202, 2021].  
2.3.5.1. 
GSK3359609 (feladilimab) Monotherapy 
Overall in the Part 1 population, 231 of 249 participants (93%) experienced at least 1 AE 
regardless of causality. Overall, 98 out of 249 participants (39%) experienced at least 1 
AE of maximum severity Grade 3. Of the 249 participants treated in Part 1, 69 
participants (28%) experienced at least 1 SAE.  
Anemia was the most common AE (n=56, 22%). Sixteen of 249 participants (16%) 
experienced maximum Grade 3 anemia, 1 participant experienced a maximum Grade 4 
anemia, and no participant experienced a maximum Grade 5 anemia. Anemia occurred 
across dose levels, with 1 of 7 participants (14%) at 0.03 mg/kg; 7 of 25 participants 
(28%) at 0.1 mg/kg; 9 of 56 participants (16%) at 0.3 mg/kg; 35 of 126 participants 
(28%) at 1.0 mg/kg; and 2 of 24 participants (8%) at 3.0 mg/kg. Overall, 9 participants 
(4%) experienced at least 1 AE of maximum Grade 4 and 7 participants (3%) experienced 
at least 1 AE of maximum Grade 5. In order to elucidate the adverse event of special 
interest (AESI) profile of immune-mediated events, a very broad net of preferred terms 
was included in the various categories as these are potential terms that may be 
representative of signs/symptoms or conditions of the respective broader category; not all 
terms reflect true cases of immune-mediated events and should not be construed as such. 
Overall, in Part 1 GSK3359609 (feladilimab) monotherapy, 44 participants (18%) 
experienced at least 1 AESI subsumed under the AESI class of skin reactions, with 
pruritis as the most common event reported (20 participants [(8%]; all events were low 


 
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grade). No cases of pneumonitis were reported or identified in monotherapy. In the AESI 
subclass of hepatitis, no participant experienced an event of immune-mediated hepatitis, 
nor hepatitis, however, there was one Grade 3 event of hepatic function abnormal. Four 
participants experienced a Grade 3 event that was subsumed under the infusion-related 
reaction subclass: 3 participants experienced Grade 3 hypotension and 1 participant 
experienced a Grade 3 infusion-related reaction. One participant (<1%) experienced an 
event of colitis (Grade 3).  
Among the dose levels of GSK3359609 (feladilimab) monotherapy investigated in the 
dose escalation phase (from 0.001 mg/kg to 10 mg/kg), no dose limiting toxicities 
(DLTs) were observed during the 28-day DLT observation period. One participant in the 
PK/pharmacodynamic cohort receiving 3 mg/kg GSK3359609 (feladilimab) experienced 
DLTs of Grade 3 or Grade 4 elevations in alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, gamma-glutamyl 
transferase (GGT), impaired liver function that was considered serious, lipase and Grade 
1 amylase during the 28-day observation period. Factors relevant in the assessment of 
these events include: the participant was receiving paracetamol as a concomitant 
treatment for pain and an ultrasound of the liver showed marked dilation of the biliary 
tract and the presence of liver lesion measuring 51 x 41 mm; the participant underwent 
biliary stent placement. All events were considered related to study treatment and led to 
treatment discontinuation. 
Refer to GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline Document 
Number RPS-CLIN-015202, 2021]. 
2.3.5.2. 
GSK3359609 (feladilimab) in Combination with Pembrolizumab 
Overall in the Part 2 GSK3359609 (feladilimab) combination with pembrolizumab 
200 mg, 327 of 340 participants (96%) experienced at least 1 AE regardless of causality. 
The most common AEs (occurring in 15% of participants overall regardless of 
GSK3359609 (feladilimab) dose level in combination with pembrolizumab 200 mg or 
relationship to the study treatment) were anemia (20%); nausea (19%), fatigue (18%), 
asthenia (17%), diarrhea (17%), dyspnea (16%), decreased appetite (16%), and cough 
(15%). One hundred and fifty-nine participants (47%) experienced at least 1 AE of 
maximum Grade 3.  
Of the 340 participants treated in the Part 2 combination with pembrolizumab, 150 
participants (44%) experienced at least 1 SAE, of which 17 participants (5%) experienced 
at least 1 SAE considered by the investigator as treatment related. SAEs reported in >1 
participant each overall were dyspnea, pneumonitis, pneumothorax, fatigue, pneumonia, 
arthralgia, asthenia, general physical health deterioration, hypercalcemia, intestinal 
obstruction, lung infection, pain in extremity, pyelonephritis, pyrexia, tumor hemorrhage, 
acute kidney injury, ataxia, hyperglycemia, ileus, non-cardiac chest pain, pleural effusion, 
sepsis, small intestinal obstruction, and urinary tract infection. 
In the Part 2 GSK3359609 (feladilimab) combination with pembrolizumab, 67 
participants (20%) experienced at least 1 AESI subsumed under the AESI class of skin 
adverse reactions, with pruritis as the most common event reported (30 participants 


 
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[(9%]; 5 participants [1%] experienced at least 1 Grade 3 skin reaction event). Twelve 
participants (4%) experienced an event of pneumonitis; Grade 3 events were reported in 
1 of these participants (Grade 3). In the AESI subclass of hepatitis, 2 participants (<1%) 
experienced an event of hepatitis (Grade 2 and Grade 3), and 1 participant (<1%) 
experienced an event of Grade 1 immune-mediated hepatitis. Three participants 
experienced a Grade 3 event that was subsumed under the infusion-related reaction 
subclass: 2 participants experienced Grade 3 hypotension and 1 participant experienced a 
Grade 3 rash. Two participants (<1%) experienced an event of colitis, Grade 3 events 
were reported in 1 of these participants. 
In the 6 dose levels of GSK3359609 (feladilimab) (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 
mg/kg) investigated in combination with 200 mg pembrolizumab in the dose escalation 
phase, 1 participant receiving 3 mg/kg GSK3359609 (feladilimab) in combination with 
200 mg pembrolizumab experienced a DLT of Grade 3 pneumonitis that occurred 18 
days after the first dose of study treatment; the event resolved within 28 days. 
Refer to GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline Document 
Number RPS-CLIN-015202, 2021]. 
2.3.5.2.1. GSK3359609 (feladilimab) Monotherapy and Combination with 
Pembrolizumab in HNSCC 
The ongoing expansion phase in Study 204691 is investigating GSK3359609 
(feladilimab) as a monotherapy (Part 1B) and GSK3359609 (feladilimab) in combination 
with pembrolizumab (Part 2B) in participants with HNSCC. At a clinical data cut-off date 
of 26 July 2019, 17 participants with anti-PD-1/L1 treatment experienced HNSCC 
received at least 1 dose of 1 mg/kg GSK3359609 (feladilimab) in Part 1B cohort. In the 
treated population (n=17), the median age was 56 years (range: 41-73 years); 82% were 
male and 82% received ≥1 prior lines of systemic therapy in the advanced/metastatic 
setting. Sixteen of the 17 dosed participants were considered evaluable for efficacy 
analysis; the overall response rate (ORR) in the evaluable population was 6% with 1 of 
the 16 participants achieving a partial response (PR). 
In the Part 2B cohort, 34 participants with anti-PD-1/L1 naïve HNSCC received at least 
one cycle of 0.3 mg/kg GSK3359609 (feladilimab) in combination with 200 mg 
pembrolizumab. In the treated population (n=34), the median age was 62 years (range 37-
77 years); 85% were male and 53% received ≥1 prior line of systemic therapy in the 
advanced/metastatic setting. All 34 dosed participants were considered evaluable for 
efficacy analyses. The ORR in the evaluable population (n=34) was 24% (95% CI: 
10.7%, 41.2%) with 8 of the 34 participants achieving a complete response (n=3) or PR 
(n=5); disease control rate (DCR) was 65% (n=22; 95% CI: 46.5, 80.3). In addition, the 
majority of participants that achieved a response or stable disease had PD-L1 CPS status 
<20 (10/14 participants with CPS1 and <20, and 1 participant with CPS <1).The median 
progression-free survival (PFS) was 5.6 months (95% CI: 2.4, 7.4) [Rischin, 2019]. 


 
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2.3.5.3. 
GSK3359609 (feladilimab) Combination with Chemotherapy 
 Pembrolizumab 
In Part 2 combination with chemotherapy ± pembrolizumab, 69 of 69 participants (100%) 
experienced at least 1 AE. The most common AEs (occurring in 20% of participants 
overall for GSK3359609 (feladilimab) in combination with chemotherapy 
± pembrolizumab regardless of relationship) were nausea in 36 of 69 participants (52%), 
anemia in 25 of 69 participants (36%), neutropenia in 22 of 69 participants (32%), 
diarrhea in 21 of 69 participants (30%), and fatigue in 18 of 69 participants (26%). 
Overall, in Part 2 combination with chemotherapy ± pembrolizumab, 55 of 
69 participants (80%) experienced at least 1 AE of maximum Grade 3; Grade 3 
(39 participants, 57%), Grade 4 (13 participants, 19%), or Grade 5 (3 participants, 4%). 
Grade 5 AEs were considered by the investigator as not related to study treatment. 
In Part 2 combination with chemotherapy ± pembrolizumab, treatment-related AEs were 
experienced by 68 of 69 participants (99%) in the overall Part 2 combination with 
chemotherapy ± pembrolizumab. The most common treatment-related AE was nausea 
(45%). Most treatment-related AEs were Grade 3 and Grade 4 (45 participants, 65%). No 
participant experienced at least 1 treatment-related AE of maximum Grade 5.  
Of the 69 participants treated in Part 2 combination with chemotherapy 
± pembrolizumab, 30 participants (43%) experienced at least 1 SAE of which 
13 participants (19%) experienced at least 1 SAE considered by the investigator as 
related to study treatment. SAEs reported in >1 participant were febrile neutropenia, 
dyspnea, colitis, diarrhea, fatigue, pneumonia, pneumonia aspiration, syncope, and tumor 
hemorrhage. The most common SAE, in 5 of 69 participants (7%), was febrile 
neutropenia. Overall, 29 participants (42%) experienced at least 1 SAE of maximum 
Grade 3. Grade 3 (22 participants, 32%); Grade 4 (4 participants, 6%); Grade 5 
(3 participants, 4%). 
In the GSK3359609 (feladilimab)/docetaxel safety cohort (n=10) 1 participant (10%) 
experienced at least 1 treatment-related SAE of maximum Grade 3: Grade 3: fatigue. In 
the GSK3359609 (feladilimab)/5FU/cisplatin safety cohort (n=5) 3 participants (60%) 
experienced at least 1 treatment-related SAE of maximum Grade 3: 
Grade 3: pancytopenia, stomatitis, intestinal ischemia, blood creatinine increased, and 
neutrophil count decreased. Grade 4: mucosal inflammation, hypernatremia, and sepsis. 
In the GSK3359609 (feladilimab)/pemetrexed/carboplatin/pembrolizumab safety cohort 
(n=4) 1 participant (25%) experienced at least 1 treatment-related SAE of maximum 
Grade 3: Grade 3: myocarditis. In the GSK3359609 
(feladilimab)/paclitaxel/carboplatin/pembrolizumab safety cohort (n=3) 2 participants 
(67%) experienced at least 1 treatment-related SAE of maximum Grade 3: Grade 3: rash 
maculo-papular, febrile neutropenia. In the GSK3359609 
(feladilimab)/5FU/cisplatin/pembrolizumab safety cohort (n=8) 4 participants (50%) 
experienced at least 1 treatment-related SAE of maximum Grade 3: Grade 3: febrile 
neutropenia, diarrhea. Grade 4: febrile neutropenia. In the GSK3359609 
(feladilimab)/5FU/carboplatin/pembrolizumab safety cohort (n=11), 2 participants (18%) 
experienced at least 1 treatment-related SAE of maximum Grade 3. Grade 3: colitis, 
febrile neutropenia, pneumonia, dyspnea. 


 
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Thirteen participants experienced a least 1 AE leading to permanent discontinuation of 
study treatment in the Part 2 combination with chemotherapy ± pembrolizumab. Events 
of pneumonia aspiration and an event of lower respiratory infection in 1 participant each 
had a fatal outcome; neither event was considered by the investigator as related to study 
treatment. All remaining events leading to permanent discontinuation of study treatment 
were considered by the investigator as related to study treatment. 
Refer to GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline Document 
Number RPS-CLIN-015202, 2021]. 
2.4. 
Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) mAb with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development 
as an IV immunotherapy for advanced malignancies. Keytruda (pembrolizumab) is 
indicated for the treatment of patients across a number of indications. For more details on 
specific indications refer to pembrolizumab IB [Merck Sharp & Dohme Corp, 
Pembrolizumab IB, 2021] and approved labelling. 
The most common reported AEs (20% of patients) with pembrolizumab single agent 
include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, 
pyrexia, cough, dyspnea, constipation, pain and abdominal pain [KEYTRUDA FDA 
Pharmacology Toxicology Review, 2014]. Serious and fatal AEs associated with 
treatment include immune-mediated adverse reactions, which consisted of pneumonitis, 
colitis, endocrinopathies (i.e., hypophysitis, thyroid disorders, and Type1 diabetes 
mellitus), hepatitis, nephritis, infusion reactions, and skin reactions including Stevens-
Johnson syndrome and toxic epidermal necrolysis. 
2.5. 
GSK3174998 (Anti-OX40 Agonist) 
GSK3174998 is a humanized wild-type, IgG1 anti-OX40 agonist mAb. GSK3174998 
possesses mechanisms of action specific to the established functions of OX40 on T cells 
which include: 
• Transduction of a costimulatory signal following T cell priming and activation thus 
augmenting T cell activation, proliferation and survival through direct and indirect 
(e.g., cytokine release) mechanisms. 
• Inhibition of regulatory T cell (Treg) activity by blocking the release of the inhibitory 
cytokine IL-10 and the suppressive function of natural Tregs (nTregs); thereby further 
stimulating the nascent immune response. 
Additionally, as GSK3174998 is a wild-type, IgG1 mAb, its fragment crystallizable (Fc) 
domain binds to the Fc receptor (FcR) on innate immune cell populations which is 
anticipated to augment OX40 signaling via this cross-linking. GSK3174998 has the 


 
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potential to possess an antibody dependent cell- mediated cytotoxicity mechanism based 
on its inherent structure. 
Detailed information on the biology, pharmacology, pharmacokinetic, and nonclinical 
safety characteristics can be found in the GSK3174998 IB [GlaxoSmithKline Document 
Number 2014N212091_06, 2020 refer to Section 2.3.3.2.2 for summary of nonclinical 
safety]. 
2.5.1. 
GSK3174998 (Anti-OX40) Clinical Experience 
Details on the preliminary clinical findings and information regarding warnings, 
precautions, contraindications, warnings and other pertinent information can be found in 
GSK3174998 IB [GlaxoSmithKline Document Number 2014N212091_06, 2020]. 
Overall in Study 204691, in Part 2 combination with GSK3174998, (regardless of 
GSK3359609 (feladilimab) dose level in combination with GSK3174988), 4 of 19 
participants (21%) experienced at least 1 treatment-related AE. No participant 
experienced at least 1 treatment-related AE of maximum Grade 3. Three of 19 
participants (16%) experienced at least 1 treatment -related AE of maximum Grade 1 
(fatigue [2 events], decreased appetite, and neutrophil count increased). One participant 
(5%) experienced at least 1 treatment related AE of maximum Grade 2 (infusion-related 
reaction). Participants who received GSK3359609 (feladilimab) 8 mg + GSK3174998 24 
mg: 1 event each (25%) of decreased appetite and fatigue; GSK3359609 (feladilimab) 24 
mg + GSK3174998 24 mg: 1 event (10%) of infusion-related reaction of Grade 2; 
GSK3359609 (feladilimab) 80 mg + GSK3174998 24 mg: 1 event (25%) of neutrophil 
count increased and 1 event (25%) of fatigue.  
Of the 19 participants treated in Part 2 combination with GSK3174998, 7 participants 
(37%) experienced at least 1 SAE. SAEs reported in 3 participants (16%) were dyspnea, 
and in 1 participant (5%) each of abdominal pain, bronchitis, confusional state, 
dysphagia, hypotension, infusion related reaction, metapneumovirus infection, and 
metastases to central nervous system. Six participants experienced at least 1 SAE of 
maximum Grade 3. SAEs of maximum Grade 3 (dyspnea, abdominal pain, bronchitis, 
confusional state, dysphagia, hypotension, metapneumovirus infection), Grade 4 
(dyspnea), or Grade 5 (dyspnea) were experienced by 4 (21%), and 1 (5%), and 1 (5%) of 
19 participants, respectively. 
No participant in Part 2 combination with GSK3174998 experienced at least 1 SAE of 
maximum Grade 3 considered by the investigator as related to treatment.  
No participant in Part 2 combination with GSK3174998 experienced an AE leading to 
permanent discontinuation of study treatment. 
Refer to GSK3359609 (feladilimab) IB for further details [GlaxoSmithKline Document 
Number RPS-CLIN-015202, 2021]. 


 
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3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Part 1 GSK3359609 (feladilimab) Monotherapy 
Primary 
• 
To determine the safety, tolerability, MTD or 
the MAD of GSK3359609 (feladilimab) 
• 
AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, dose 
modifications 
Secondary 
• 
To determine the recommended dose of 
GSK3359609 (feladilimab) for further 
exploration 
• 
AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, dose 
modifications, PK, pharmacodynamic activity, 
antitumor activity 
• 
To evaluate the antitumor activity of 
GSK3359609 (feladilimab)  
• 
To characterize the PK properties of 
GSK3359609 (feladilimab) 
• 
ORR1, DCR1, PFS1, OS, TTR1, 2, DoR1,2 
• 
Plasma PK parameters such as Cmax, Ctau, 
AUC (0-) as data permit 
• 
To determine immunogenicity 
• 
ADA incidence by dose level/dose 
Exploratory  
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Objectives 
Endpoints 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; Cmax= 
maximum observed concentration; Ctau=minimum observed concentration; DCR=disease control rate; 
DLT=dose limiting toxicity; DNA=deoxyribonucleic acid; DoR=duration of response; 
 
 
 
IHC=immunohistochemistry; irRECIST=immune-related RECIST; MAD=maximum administered dose; 
MTD=maximum tolerated dose; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PK; pharmacokinetic; ; 
 
 RECIST=Response Evaluation Criteria in Solid Tumors; 
RNA=ribonucleic acid; SAE; serious adverse events; TTR=time to response 
1. irRECIST is the primary measure of clinical activity for response endpoints and PFS; RECISTv1.1 
guidelines are used for disease assessments.  
2. TTR and DoR will be evaluated if data permit; refer to Section 10.7.2.1 for further details on the 
possible analysis of antitumor activity in the dose escalation cohorts. 
Objectives 
Endpoints 
Part 2 GSK3359609 (feladilimab) (ICOS) in Combination with Pembrolizumab or 
GSK3174998 (anti-OX40)  
• 
Primary 
• 
To determine the safety, tolerability, 
MTD or the MAD of GSK3359609 
(feladilimab) in combination with 
pembrolizumab or GSK3174998 (anti-
OX40) 
• 
AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, 
dose modifications 
CCI
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Objectives 
Endpoints 
• 
Secondary 
• 
To determine the recommended dose(s) 
and schedule of GSK3359609 
(feladilimab) in combination with 
pembrolizumab or GSK3174998 for 
further exploration 
• 
To determine the recommended dose(s) 
of GSK3359609 (feladilimab) and 
GSK3174998 in combination 
 
• 
AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, 
dose modifications, PK, 
pharmacodynamic activity, antitumor 
activity 
• 
To evaluate the antitumor activity of 
GSK3359609 (feladilimab) in 
combination with pembrolizumab or 
GSK3174998  
• 
ORR1, DCR1, PFS1, OS, TTR1, 2, DoR1 
• 
To characterize the PK properties of 
GSK3359609 (feladilimab), 
pembrolizumab, and GSK3174998 when 
administered in combination 
• 
GSK3359609 (feladilimab), 
GSK3174998, and pembrolizumab PK 
parameters such as Cmax, Ctau, AUC (0-
) as data permit 
• 
To determine immunogenicity of 
GSK3359609 (feladilimab), 
pembrolizumab, orGSK3174998, when 
administered in combination 
• 
ADA incidence of each drug by dose 
level/ dose 
• 
Exploratory  
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Objectives 
Endpoints 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; Cmax= 
maximum observed concentration; Ctau=minimum observed concentration; CPS=combined positive score; 
DCR=disease control rate; DLT=dose limiting toxicity; DNA=deoxyribonucleic acid; DoR=duration of 
response; 
 
 
 HNSCC=head and neck squamous cell carcinoma; IHC=immunohistochemistry; 
irRECIST=immune –related RECIST; MAD=maximum administered dose; MTD=maximum tolerated 
dose; ORR=overall response rate; OS=overall survival; PD-L1= programmed cell death receptor 
1-ligand 1;  PFS=progression-free survival; PK; pharmacokinetic; 
 
 RECIST=Response Evaluation 
Criteria in Solid Tumors; RNA=ribonucleic acid; SAE; serious adverse events; TTR=time to response 
1. irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, 
DCR);RECISTv1.1 guidelines are used for PFS, DoR, TTR and disease assessments. 
2. 
 
 
CCI
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Objectives 
Endpoints 
Part 2A GSK3359609 (feladilimab) Combination with Chemotherapies (+Pembrolizumab) 
Primary 
• 
To determine the safety, tolerability, of 
GSK3359609 (feladilimab) in combination 
with standard of care chemotherapies  
pembrolizumab 
• 
AEs, SAEs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
• 
To determine the recommended dose of 
GSK3359609 (feladilimab) for further 
exploration 
• 
To characterize the PK properties of 
GSK3359609 (feladilimab), chemotherapies, 
and pembrolizumab 
• 
To determine immunogenicity of 
GSK3359609 (feladilimab) and 
pembrolizumab 
• 
AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, dose 
modifications, PK, pharmacodynamic activity, 
antitumor activity 
• 
Plasma PK parameters such as Cmax, and 
Ctau as data permit 
• 
ADA incidence by dose level/dose 
• 
Exploratory  
Abbreviations: ADA=anti-drug antibody; AE=adverse events; Cmax= maximum observed concentration; 
Ctau=minimum observed concentration; DCR=disease control rate; DLT=dose limiting toxicity; 
DNA=deoxyribonucleic acid; DoR=duration of response; irRECIST=immune –related RECIST; 
ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PK; pharmacokinetic;; 
RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE; serious adverse 
events; TTR=time to response 
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1. irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, 
DCR);RECISTv1.1 guidelines are used for PFS, DoR, TTR and disease assessments  
2. TTR and DoR will be evaluated if data permit; refer to Section 10.7.2.1 for further details. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a FTIH, open-label, multicenter study designed to investigate the safety, 
tolerability, pharmacology, PK, preliminary clinical activity, and establish a 
recommended dose of GSK3359609 (feladilimab) for further exploration. 
As illustrated in Figure 1, the study will be conducted in two parts (Part 1 GSK3359609 
(feladilimab) monotherapy and Part 2 GSK3359609 (feladilimab) combination therapy) 
whereby each part consists of a dose escalation/safety run-in phase followed by a cohort 
expansion phase. GSK3359609 (feladilimab) combinations with chemotherapy with or 
without pembrolizumab will only consist of safety run-in cohorts (Part 2A only). 
Part 1A dose escalation phase will evaluate escalating weight-based dose levels of 
monotherapy GSK33596069 administered intravenously once every three weeks (Q3W) 
to participants with selected relapsed and/or refractory solid tumors. Based on safety and 
tolerability, and the pharmacokinetic/pharmacodynamic characteristics of the molecule, 
recommended monotherapy dose level or dose levels may be further investigated in 
expansion cohorts (Part 1B). 
Part 2A pembrolizumab combination dose escalation phase will be initiated when a 
monotherapy dose level of GSK3359609 (feladilimab) has been deemed safe and has 
demonstrated consistent, dose-responsive pharmacodynamic activity; two dose levels 
below this dose level will become the starting dose investigated in combination with a 
200 mg fixed dose of pembrolizumab (refer to Section 4.5.7 for dose rationale). 
GSK3359609 (feladilimab) dosage will be investigated at fixed doses with GSK3174998 
and the chemotherapy combinations in Part 2A (Refer to Section 4.5.9 for the fixed-dose 
rationale). 
Part 2A GSK3174998 combination dose escalation phase will initiate at starting doses of 
8 mg for GSK3359609 (feladilimab) and GSK3174998 (refer to Table 2). RP2 
combination doses selected will consider safety and tolerability, clinical activity, and the 
PK/pharmacodynamic characteristics. 
The starting GSK3359609 (feladilimab) dose of 24 mg or 80 mg will be combined with 
standard doses of chemotherapy (refer to Section 4.5.3 and Section 4.5.8 for dose 
rationales) and pembrolizumab (200 mg); lower doses of GSK3359609 (feladilimab) that 
have been investigated in other cohorts may also be evaluated in combination with 
chemotherapy. 
As depicted in Figure 2, seamless design will be implemented to combine dose escalation 
with dose expansion, based on toxicity and efficacy [Pan, 2013]. In both Part 1 and Part 
2, the dose expansion phase may start before the dose escalation phase is completed. All 


 
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available safety and tolerability data from participants in dose expansion will be 
incorporated into dose escalation decision making. The basis of the decision to initiate 
expansion of a dose level/dose will consider the following graduation rules: 
1. Established safety and tolerability;  
2. Preliminary PK/pharmacodynamic characteristics (i.e., measures of target 
engagement and functional effects 
 
) and/or 
3. Preliminary antitumor activity. 
Once a dose level(s) passes the graduation rules (refer to Figure 2) the selected dose(s) 
may enter into the expansion phase for further investigation following approval by active 
study investigators. Alternate GSK3359609 (feladilimab) schedules are being 
investigated (GSK3359609 (feladilimab) Q6W in combination with pembrolizumab 
Q6W); drug sequencing may be investigated in the expansion phase. In addition, dose 
levels under investigation in the ongoing monotherapy dose escalation phase may 
incorporate information, such as safety data, from participants who were accrued to the 
expansion phase. Randomization and/or futility rules may be incorporated if appropriate 
in expansion phase to optimize the dose allocation based on evaluations of safety and 
antitumor activity. The details of randomization schema for expansion cohorts will be 
documented before the initiation of expansion cohort; details of the futility rules will be 
documented in the reporting and analysis plan (RAP)before initiation of interim analyses 
[Pan, 2013]. 
The overall study will enroll approximately 867 participants diagnosed with solid tumor 
malignancies. 
• In the dose escalation phases of the study, and in the PK/pharmacodynamic, and 
ADA expansion cohorts the solid tumor types selected for inclusion include 
bladder/urothelial cancer, cervical cancer, colorectal cancer (CRC), esophageal 
cancer with squamous cell histology, head and neck (HN) cancer, melanoma, 
malignant pleural mesothelioma (MPM), non-small-cell lung cancer (NSCLC), 
and prostate cancer. 
o PK/Pharmacodynamic expansion cohorts (Part 1C, Part 2C, and Part 
1D) are restricted to enrollment from sites located in Japan and China; 
these cohorts are active by country-specific amendments to the 204691 
protocol. 
• In the cohort expansion phases of the study (Part 1B and Part 2B), several 
expansion cohorts have been defined by tumor histology or by a specific 
characteristic such as tumors exhibiting high microsatellite instability (MSI-H), 
deficiency in DNA mismatch repair (dMMR) processes, or viral-mediated 
pathology; enrollment in these cohorts is not limited to the tumor 
types/histologies in the aforementioned list (defined as tumor agnostic). A Part 
2B HNSCC cohort will investigate GSK3359609 (feladilimab) at an alternative 
dosing schedule of once every 6 weeks (Q6W); participants will be randomly 
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assigned to GSK3359609 (feladilimab) doses of 48 mg or 160 mg Q6W in 
combination with pembrolizumab 400 mg administered at the schedule of Q6W. 
o A Part 2B expansion cohort will enroll approximately 30 participants with 
PD-1/L1 treatment naïve HNSCC that is PD-L1 CPS <1 
• Additional expansion cohorts may enroll participants with a specific tumor type 
selected from the aforementioned list or from a tumor type/histology not 
protocol-defined; the basis for the selection will be evidence-based and by an 
amendment to the protocol to define the cohorts. 
GSK3359609 (feladilimab) monotherapy and in combination with pembrolizumab or 
other anti-cancer agents may be investigated in biomarker defined cohorts to evaluate the 
effect/interaction of the status of the biomarker on the activity of the regimens. 
Additionally, cohorts may be defined based on other features such as prior response with 
an immune checkpoint inhibitor, disease characteristic, molecular/genetic alterations or 
pathology.  
The overall study size may extend beyond 867 by a protocol amendment if data from 
expansion phases support extended enrollment or additional combinations are 
investigated. 
Assessment of disease status will be performed by the Investigator in accordance with 
Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and Immune Related (ir) 
RECIST. A decision to discontinue treatment due to disease progression will be based 
upon irRECIST; primary efficacy response endpoint analysis will use irRECIST. Scans 
will be collected centrally and stored to allow for the option of central review. 


 
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Figure 1 
Study Design 
 
 
 
Abbreviations:  5-FU=fluorouracil; Cis=cisplatin; dMMR= deficient mismatch repair; Gem=gemcitabine; 
IHC=immunohistochemistry; MSI-H= microsatellite instability-high; NSCLC=non-small cell lung 
cancer; Pac=paclitaxel; PD-L1=programmed death; HNSCC= head and neck squamous cell cancer  
#: a subset of HNSCC participants will be randomly assigned to one of 3 doses of GSK3359609 
(feladilimab) (refer to Table 6) in combination with 200mg of pembrolizumab 
*Participants enrolled in the Part 2B cohorts (GSK3359609 (feladilimab)/pembrolizumab combination) may be 
stratified by PD-L1 IHC status and prior PD-1/L1 treatment 
1. The number of participants allocated to any Part is an estimate. 


 
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2. The number of cohorts indicated in any Part is an estimate. 
3. Expansion cohorts may increase enrollment following outcome of interim analyses (refer to Section 10.6 
for details); enrollment in the overall population will not exceed the approximate number of 867 
participants except by an amendment. 
4. Participants enrolled in Part 1 (GSK3359609 (feladilimab) monotherapy) upon disease progression may be 
permitted to receive GSK3359609 (feladilimab) in combination with pembrolizumab (defined as 
crossover); refer to Section 5.4 for further details. 
 
Figure 2 
Study Phase Progression Chart 
 
1. Figure 2 illustrates an example scenario; exact dose graduation will depend on data emerging from 
dose escalation 
2. Graduation rule for monotherapy and combination therapy may be different; graduation rules will 
be based on safety and efficacy in combination with exploratory PK/pharmacodynamic modeling 
3. Multiple tumor types may be enrolled in dose expansion phases 
4.1.1. 
Dose Escalation Phase 
Decisions to escalate to subsequent dose levels in Part 1A monotherapy and Part 2A 
combination therapy will be according to the dose selection design put into practice. The 
underlying principle behind dose selection designs used in this study is that selection of 
each subsequent dose level/dose considers the number of participants presenting with a 
dose limiting toxicity (DLT) event relative to the number of participants enrolled at the 
corresponding dose level/dose under evaluation. 
Additionally, the decision to escalate to the next dose level/dose will take into account 
the cumulative safety, available PK, and pharmacodynamic data from all participants in 
the current dose level as well as those from prior dose levels. 
Dose Escalation 
Mono:  Accelerated Titration
mTPI
Part 1A/2A
D1
D2
D3
Part 1B/2B
Graduation Rule in 
consult with Steering 
Committee
C1
C2
C3
C4
Dose Expansion 
Combo:     mTPI or Other
D6
D
4
D
5
D
6
D
7
D
8
D8
C4
C3
Recommended Dose(s) 
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Dose escalation may proceed until the maximum tolerated dose (MTD) or maximum 
administered dose (MAD), otherwise defined as the highest dose administered in the 
absence of reaching MTD, of the monotherapy and individual combination regimens are 
identified. 
4.1.1.1. 
Part 1A Monotherapy Dose Escalation 
In the monotherapy dose escalation phase of the study, two rule-based designs will be in 
use. For the first three dose levels (refer to Table 1), an accelerated titration design is 
planned with one participant enrolled at each of these dose levels. Each participant must 
receive at least one dose of GSK3359609 (feladilimab), complete the 28-day DLT 
evaluation period and the available safety data must be reviewed before a decision to 
escalate to the next dose level is made (i.e., the dose level is cleared). If the single 
participant experiences DLT or drug-related Grade 2 toxicity, this event will trigger the 
implementation of the modified Toxicity Probability Interval (mTPI) design [Ji, 2010] at 
that dose level and at subsequent dose levels as shown in Figure 3. If a participant 
withdraws from the study before the completion of the 28-day DLT evaluation period for 
reasons other than DLT, then the participant may be replaced to achieve the three-
participant required minimum. 
In the dose levels under evaluation by the mTPI design, a minimum of three participants 
will be accrued to each dose level. In the first dose level fully accrued under the mTPI 
design and in all subsequent dose levels, treatment will be administered at least one week 
apart between the first two participants enrolled; the third and any subsequent participants 
will be administered treatment at a minimum of one day apart. This staggered approach 
allows for an initial assessment of safety in a participant accrued to a dose level before 
initiating the next participant’s treatment. Evaluation of the available safety data over the 
first 28 days of treatment for each participant enrolled in that dose level is required from 
at least 3 participants before a decision is made to enroll participants at the next higher 
dose level. The maximum number of participants assigned to any single dose level will 
be at the discretion of the Sponsor in consultation with the investigators. 
Dose escalation for GSK3359609 (feladilimab) monotherapy will begin with a starting 
dose of 0.001 mg/kg administered Q3W; refer to Section 4.5 for justification of starting 
dose and schedule. Table 1 presents the maximum dose that may be selected for each 
dose level increase based on a maximum fold increase of 3.3. The predetermined 
maximum dose level of GSK3359609 (feladilimab) to be evaluated is 3.0 mg/kg 
administrated Q3W; if subsequent analyses of PK and pharmacodynamic properties and 
emerging clinical safety profile support the exploration of higher dose levels, escalations 
to dose levels greater than 3.0 mg/kg will follow the same deciding principles applied to 
the preceding dose levels. Dose levels intermediate to those presented in Table 1 or 
schedules other than once every three weeks may be explored if exposure is significantly 
higher than predicted, excessive toxicity is observed, or if further evaluation of PK and 
pharmacodynamic markers to inform on dose selection is warranted. 
4.1.1.2. 
Japan PK/pharmacodynamic Cohort (Part 1C and Part 2C, Japan only) 
In order to evaluate safety, tolerability, PK/pharmacodynamic and preliminary anti-
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+ pembrolizumab in Japanese participants with selected advanced solid tumors, the Part 
C (Japan PK/pharmacodynamic Cohort) was added in a country specific amendment. 
Briefly, a total of up to 20 Japanese participants in each cohort will be enrolled with at 
least 3 participants at each dose level based on the mTPI design rule (Section 4.1.1.2.1). 
Based on the mTPI design rule, a lower dose level of 0.1 mg/kg may be added, and 
additional participants may be added to further evaluate PK/pharmacodynamic and safety 
of GSK3359609 (feladilimab) as a monotherapy or combination with pembrolizumab at 
the optimized dose range in the main study (0.3mg/kg ~ 3.0mg/kg). All study related 
information such as study design, study assessments and data analyses are described in 
the Japan country specific protocol amendment 5. 
Participants enrolled in Part 1C will not be tolerated for transition to GSK3359609 
(feladilimab) and pembrolizumab combination therapy. Japan can also participate in any 
other enrolling cohorts for Part 2A and Part 2B after completing the evaluation of the 
GSK3359609 (feladilimab) dose/dose level under investigation in Part 2A and Part 2B as 
a monotherapy (Part 1C) and/or in combination with pembrolizumab (Part 2C). 
Table 1 
Part 1A Maximum Dose Levels 
Dose Level 
GSK3359609 (feladilimab) 
(mg/kg) 
Dose Selection Design 
1 
0.001 
Accelerated Titration 
2  
0.003 
Accelerated Titration 
3 
0.01 
Accelerated Titration 
4 
0.03 
mTPI 
5 
0.1 
mTPI 
6 
0.3 
mTPI 
7 
1.0 
mTPI 
8 
3.0 
mTPI 
9 
10.0 
mTPI 
4.1.1.2.1. Modified Toxicity Probability Interval 
The mTPI design assumptions include the following: 
(i) 
A maximum of 30 participants will complete the DLT evaluation period at any 
given dose; 
(ii) 
The true underlying toxicity rate for GSK3359609 (feladilimab) falls within the 
range from 25% to 35% and centers at 30%. 
The monitoring rules guiding dose escalation are provided in Figure 3. Columns provide 
the numbers of participants treated at a dose level, and rows provide the corresponding 
numbers of participants experiencing DLT. The entries in the table are dose-finding 
decisions (i.e., E, S, and D) representing escalating the dose, staying at the same dose, 
and de-escalating the dose, respectively. In addition, decision U indicates that the current 
dose level is unacceptable because of high toxicity and should be excluded from further 
investigation in the study. As an example, if one of three participants experience a DLT, 
the decision is located in row 1 and column 3, which indicates S, that is to stay at the 
current dose level. Consequently, an additional three participants will be treated at the 


 
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same dose level currently being investigated. If none of these three participants 
experience DLT, the decision is at row 1 and column 6, which is E, that is to escalate to 
the next dose level.  Thus, the next cohort of participants will be treated at the next-higher 
dose level.  If at this dose level three of three participants experience DLTs, the decision 
is DU, that is to dose de-escalate to the preceding lower dose level and subsequently 
exclude the current dose from the study because of unacceptable toxicity. 
Figure 3 
Modified TPI Dose Decision Rules 
 
As presented in Figure 3, the dose-finding decisions using the mTPI method were 
generated based on a beta/binomial model and pre-calculated before study initiation. The 
letters in different colors are computed based on the decision rules under the mTPI 
method and represent different dose-finding actions. In addition to actions that include 
de-escalate the dose (D), stay at the same dose (S), and escalate the dose (E), the table 
includes action unacceptable toxicity (U), which is defined as the execution of the dose-
exclusion rule in mTPI. 


 
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4.1.1.3. 
Part 2A Combination Therapy Dose Escalation/Safety Run-in 
4.1.1.3.1. GSK3359609 (feladilimab) Combination with Pembrolizumab 
Dose escalation for GSK3359609 (feladilimab) plus  
• pembrolizumab combination therapy will begin with a fixed dose of 200 mg 
pembrolizumab administered intravenously Q3W 
A starting dose level of GSK3359609 (feladilimab) in combination with pembrolizumab 
will be two dose levels below the Part 1A monotherapy dose that was deemed safe and 
had demonstrated pharmacodynamic activity. Dose decision rules will follow the mTPI 
method with Figure 3 depicting the dose-finding actions escalation decisions based on 
DLT observed within a cohort. Safety, tolerability, PK, pharmacodynamic measures, and 
antitumor activity will be considered in determining recommended phase 2 dose (RP2D) 
of GSK3359609 (feladilimab) in combination. If the combination doses in the starting 
dose cohort of Part 2A are not tolerable, lower doses of GSK3359609 (feladilimab) may 
be evaluated.  
4.1.1.3.2. GSK3359609 (feladilimab) Combination with Chemotherapy 
( pembrolizumab) 
The dose of GSK3359609 (feladilimab) in each chemotherapy combination will be 24 mg 
based upon current evidence of activity in other cohorts at 0.3 mg/kg and comparability 
of exposure at 24 mg. The passage below describes the initial dose escalation design: 
GSK3359609 (feladilimab) in combination with docetaxel or platinum-based 
chemotherapy doublets ( 200 mg pembrolizumab) consist of safety run-in cohorts only 
(refer to Figure 1). The mTPI design will guide dose escalation/de-escalation decisions to 
support determining the GSK3359609 (feladilimab) RP2 dose in combination with 
standard doses of chemotherapy (refer to Section 4.1.1.2.1 for mTPI details). An initial 
three participants will receive 80 mg of GSK3359609 (feladilimab) in combination with 
chemotherapy; if no DLTs are observed (refer to Section 4.1.1.4), an additional 6 to 9 
participants may receive this dose or de-escalate/escalate to a lower/higher dose in 
combination with chemotherapy ( pembrolizumab).  
A minimum of nine participants will receive GSK3359609 (feladilimab) at the dose 
recommended in combination with each chemotherapy regimen ( pembrolizumab). 
Safety, tolerability, PK, pharmacodynamic measures, and antitumor activity will be 
considered in determining RP2D of GSK3359609 (feladilimab) for each chemotherapy 
combination.  
4.1.1.3.3. GSK3359609 (feladilimab) Combination with GSK3174998 (Anti-OX40) 
GSK3174998 (anti-OX40) 
As presented in Table 2, dose escalation will initiate with 8 mg of GSK3359609 
(feladilimab) in combination with 8 mg of GSK3174998 with one participant enrolled in 
this combination dose cohort (Dose Cohort 1). This single participant will be evaluated 
for DLT. If the first participant becomes unevaluable for DLT due to reasons other than 
toxicity, another participant will be enrolled Cohort 1. If the single participant in Dose 


 
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Cohort 1 experiences a DLT or treatment-related  Grade 2 AE during the 28-day DLT 
observation period, then additional participants will enroll in Dose Cohort 1 and the two-
dimensional continual reassessment method (2D-CRM) will guide dose escalation 
decisions [Neuenschwander, 2014]. 
Starting with Dose Cohort 2 (if no occurrence of DLTs or ,Grade 2 treatment-related 
AEs) at least three participants will be enrolled and the two-dimensional continual 
reassessment method (2D-CRM) [Neuenschwander, 2014] will guide dose escalation 
decisions according to dose combinations presented in Table 2.  
In the first dose level fully accrued under the 2D-CRM design and in all subsequent dose 
levels, treatment will be administered at least 3 days apart between the first two 
participants enrolled; the third and any subsequent participants will be administered 
treatment at a minimum of one day apart (Refer to Section 4.1.1.1 for rationale of the 
staggered approach). Evaluation of the available safety data over the first 28 days of 
treatment for each participant enrolled in that dose level is required from at least 3 
participants before a decision is made to enroll additional participants at the next higher 
dose level. The maximum number of participants assigned to any single dose level will 
be at the discretion of the Sponsor in consultation with the investigators. 
Additional dose combinations (doses that have been evaluated as monotherapies; refer to 
GSK3359609 (feladilimab) IB [GlaxoSmithKline Document Number RPS-CLIN-
015202, 2021] and GSK3174998 IB [GlaxoSmithKline Document Number 
2014N212091_06, 2020]) and schedules may be explored based on emerging data (i.e., 
safety, PK, and PD). 
Table 2 
Planned Dose Escalation Levels for GSK3359609 (feladilimab) and 
GSK3174998  
Dose Combination 
Level Cohort 
GSK3359609 
(feladilimab) 
(mg) 
GSk3174998 
(mg) 
Dose Escalation Design 
1 
8 
8 
Run-in: if no occurrence of a DLT or drug-
related  Grade 2 AE in the DLT 
observation period 
Run-in and implement 2D-CRM: if 
occurrence of a DLT or drug-related  
Grade 2 AE in the DLT observation period 
2 
8 
24 
2D-CRM 
3 
24 
24 
2D-CRM 
4 
80 
24 
2D-CRM 
5 
80 
80 
2D-CRM 
If the starting dose combination level of GSK3359609 (feladilimab) in combination of 
GSK3174998 is not tolerable, lower doses of GSK3359609 (feladilimab) and/or 
GSK3174998 may be evaluated. 


 
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Safety, tolerability, PK, pharmacodynamic measures, and antitumor activity will be 
considered in determining RP2D of GSK3359609 (feladilimab) in combination with 
GSK3174998. A minimum of 10 additional participants may be enrolled at RP2D to 
further explore GSK3359609 (feladilimab) in combination with GSK3174998; in these 
participants, tumor biopsy at Screening will be required (refer to Table 28 for further 
details). Initially 4 participants will be enrolled to obtain further safety information; if no 
DLTs arise that prohibit further enrollment at the RP2D, an additional 6 participants will 
be enrolled at the RP2D.  
Description of the Two-Dimensional Continual Reassessment Method 
For each cohort under the 2D-CRM design, a dosing recommendation to the next dose 
level will be made using the 2D-CRM method. The 2D-CRM design makes use of a 5-
parameter Bayesian logistic regression model relating dose and dose limiting toxicity. 
The model is expected to locate the MTD efficiently while minimizing the number of 
participants exposed to pharmacologically inactive or unsafe dose combination levels. 
Further details on the model are provided in Section 10.2.2. 
All available data, including safety, PK and PD data from current and prior cohorts will 
be reviewed at the dose escalation meeting. Although the 2D-CRM will be used to 
recommend the next dosing level, clinical judgment by the Medical Monitor, internal 
dose-escalation committee and in consultation with the investigators can halt dose 
escalation or reduce the recommended dose of each agent in the combination as deemed 
appropriate at any time during the trial.  
The MTD will be defined as that dose combination that has the highest posterior 
probability of having a DLT rate within the Target Toxicity range and for which the 
posterior probability that the DLT rate lies within the Excessive Toxicity or the 
Unacceptable Toxicity range is less than 25%. 
The 2D-CRM estimates for each potential dose combination and the posterior 
probabilities that the DLT rate lies in each of four toxicity ranges are provided below:  
• 
A dose falls in the Underdosing range if the probability of a DLT at the dose is 
[0%, 16%) 
• 
A dose falls in the Target Toxicity range if the probability of a DLT at the dose 
is [16%, 33%)  
• 
A dose falls in the Excessive Toxicity range if the probability of a DLT at the 
dose is [33%, 60%)  
• 
A dose falls in the Unacceptable Toxicity range if the probability of a DLT at 
the dose is [60%, 100%] 
At the time of each dose-escalation decision, the dose combination with the highest 
posterior probability of lying in the Target Toxicity range will be the model-
recommended dose combination level for the next cohort. Additionally, the following 
constraints for the recommended dose combination level will be maintained:  


 
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• 
The posterior probability of the DLT rate lying in the Excessive Toxicity or 
Unacceptable Toxicity range is less than 25%.   
• 
The recommended dose is no more than 3.4 times that of the previous dose.  
Note that de-escalation as well as escalation is possible using this method. 
An updated posterior estimate of the dose-toxicity curve will also be provided at the time 
of the dose-escalation meeting. 
Dose escalation will continue until: 
i. An MTD is found: 
At least 9 participants (only applicable to combination treatment with 
GSK3174998) have been treated at the current target dose combination  
AND 
The posterior probability that the DLT rate for the current dose combination lies 
in either the excessive toxicity or unacceptable toxicity range is less than 25% 
AND 
The posterior probability that the DLT rate for the next higher dose lies in either 
the excessive toxicity or unacceptable toxicity range is greater than or equal to 
25%.  
OR 
ii. All dose combination levels are cleared: The MAD has been reached and at least 
9 participants (only applicable to combination treatment with GSK3174998) have 
been dosed at that dose combination level.  
OR 
iii. No dose combination level is cleared (i.e. all doses have a posterior probability of 
lying in either the excessive toxicity or unacceptable toxicity range of greater 
than or equal to 25%)  
AND 
At least two DLTs have been observed.  
Bayesian Prior 
The 2D-CRM methodology requires that a Bayesian prior distribution for the dose-
toxicity curve be pre-specified. A bivariate normal distribution for the prior of each pair 
of single-agent parameters (𝑙𝑛(𝛼), 𝑙𝑛(𝛽))𝑇 and a normal distribution for the prior of the 
interaction log-odds multiplier 𝜂 are assumed. Table 3 shows the parameters of prior 
distributions with reference dose levels 𝑑1
∗= 80 mg for GSK3359609 (feladilimab), and 
𝑑2
∗=24 mg (GSK3174998). The prior and reference dose levels may be updated based on 
the emerging data in which case details will be documented in the reporting and analysis 
plan (RAP). 


 
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Table 3 
Parameters of Prior Distributions 
Treatment/Term 
Parameter 
Mean 
Standard 
Deviation 
Correlation 
GSK3359609 
(feladilimab) 
𝑙𝑛(𝛼1), 𝑙𝑛(𝛽1) 
-3.5, -1 
5, 1 
0 
GSK3174998 
𝑙𝑛(𝛼2), 𝑙𝑛(𝛽2) 
-3, -1 
5, 1 
0 
Interaction 
𝜂 
0 
1.121 
N/A 
The DLT information based on available monotherapy data from GSK3359609 
(feladilimab) in study 204691 and GSK3174998 in study 202102 are incorporated into 
the DLT prior distribution calculation. Table 4 shows the DLT profile 𝑟/𝑛 at each dose 
combination for GSK3174998, where 𝑟 is the number of DLTs and 𝑛 is the number of 
participants of a given dose combination; these table present possible dose combinations 
based on the monotherapy doses evaluated for each single agent however it does not 
imply that all dose combinations will be studied. 
Table 4 
Prior Monotherapy DLT Profile for GSK3359609 (feladilimab) and 
GSK3174998 
 
GSK3359609 (feladilimab) Dose Level (mg) 
0 
0.08 
0.24 
0.8 
2.4 
8 
24 
80 
240 
GSK3174998 Dose 
Level (mg) 
800 
0/4 
 
 
 
 
 
 
 
 
240 
0/7 
 
 
 
 
 
 
 
 
80 
0/4 
 
 
 
 
 
 
 
 
24 
0/10 
 
 
 
 
 
 
 
 
8 
0/10 
 
 
 
 
 
 
 
 
2.4 
0/8 
 
 
 
 
 
 
 
 
0.8 
0/1 
 
 
 
 
 
 
 
 
0.24 
0/1 
 
 
 
 
 
 
 
 
0 
 
0/1 
0/1 
0/2 
0/8 
0/15 
0/17 
0/24 
1/11 
* No a priori (i.e. 0/0) in shaded area. 
 
4.1.1.4. 
Dose Limiting Toxicity 
The severity of all toxicities will be graded using National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.0) [NCI, 2010]. The 
DLT observation period is 28 days in length and begins on the day GSK3359609 
(feladilimab) is first administrated to the participant. 
A DLT is defined as an AE that meets at least one of the criteria listed in Table 5 and is 
considered by the investigator to be clinically relevant and attributed (probably, or 
possibly) to the study treatment during the 28-day DLT observation period. An AE 
considered related to the underlying disease under study it is not defined as a DLT. 
For Part 2 pembrolizumab combination, Grade 3 or Grade 4 toxicities that are known to 
occur with pembrolizumab therapy and are controlled within two weeks using the 
recommended supportive measures (refer to Section 7) may not be considered dose-


 
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limiting (refer to Table 5 for DLT definitions). These known toxicities will be evaluated 
during dose escalation decisions to assess for parameters that include increases in 
frequency or severity. 
Table 5 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition 
Hematologic 
• Febrile neutropenia as defined by CTCAE v4 
• Grade 4 neutropenia of >7 days in duration or requiring G-CSF 
• Grade 4 anemia of any duration 
• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia 
with bleeding 
Non-
hematologic 
• Grade 4 toxicity 
• Grade 3 pneumonitis of any duration 
• Grade 3 toxicity that does not resolve to Grade 1 or baseline within 3 days 
despite optimal supportive carea 
• Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 
ocular toxicity 
• Following events are not considered DLTs 
o  Grade 3 and Grade 4 asymptomatic electrolyte abnormalities that are 
corrected within 24 hours without clinical sequelae 
O Grade 3 nausea, vomiting, or fatigue that resolves to Grade 1 within 7 
days with optimal supportive care 
O Grade 3 and Grade 4 infusion reactions in participants not receiving 
prophylaxis for IRRs (refer to Section 7.12.3 for details on IRR 
management) 
Other 
• Toxicity that results in permanent discontinuation of GSK3359609 
(feladilimab) monotherapy or GSK3359609 (feladilimab) and agent in 
combination during the first four weeks of treatment 
• Grade 3/Grade 4 toxicity that results in a participant not receiving the 
expected doses of a regimen in Cycle 1, defined by 21 days 
• Any other toxicity considered to be dose-limiting that occurs beyond four 
weeks will be considered in the selection of the dose to recommend for 
expansion cohorts 
• Any other event which in the judgment of the investigator and GSK Medical 
Monitor is considered to be a DLT 
a. 
Abbreviations:  CTCAE=Common Toxicity Criteria for Adverse Events; DLT = Dose-limiting toxicity; G-CSF 
=Granulocyte colony-stimulating factor; GSK =GlaxoSmithKline; IRR=infusion related reaction 
b. Suggested toxicity management guidelines as described in Section 7 may include systemic corticosteroids for 
immune-related toxicities; if systemic corticosteroids use delays administration of the second dose of study 
treatment and the event does not otherwise meet the DLT criteria for non-hematologic toxicity, the dose delay 
will not be considered a DLT.  
If a participant experiences a DLT during the DLT observation period, the participant 
may resume dosing at the same or lower dose provided the toxicity did not meet study 
treatment discontinuation criteria and following approval by the Sponsor. 


 
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Toxicity management and dose modification guidelines provided in sub-Sections of 
Section 7 are directed for those AEs of special interest that, although not observed in 
nonclinical studies, may be expected with the administration of immune directed 
therapies such as GSK3359609 (feladilimab). Additionally, Table 13 provides general 
guidance for the management of non-hematologic AEs. 
Guidance for the identification, evaluation, and the established algorithms for the 
treatment management of immune-related adverse events (irAEs) including dose 
modification algorithms are provided in Section 7.1 and Section 7.2. These guidelines are 
based on the experience of irAE management following the development of immune 
check-point inhibitors such pembrolizumab. Guidelines are also provided for 
hepatotoxicity (Section 7.4); gastrointestinal events (Section 7.5); renal toxicity (Section 
7.6); skin toxicity (Section 7.7); endocrine events (Section 7.8); pneumonitis (Section 
7.9); hematologic events (Section 7.10); uveitis/iritis (Section 7.11), and infusion 
reactions or severe cytokine release (Section 7.12). 
If there is a delay in administration of study treatment, refer to Section 7.18 for guidance 
on planning of subsequent study visits. 
4.1.1.5. 
Intra-Participant Dose Escalation 
For Part 1A, Part 2A, and expansion phases (i.e., PK/pharmacodynamic Cohort), intra-
participant dose escalations may be considered on a case-by-case basis provided the 
participant has completed at least one treatment cycle without the occurrence of drug-
related ≥Grade 2 AE or SAEs of any severity Grade in the first 28 days of treatment. For 
the expansion phases in which Week 6 on-treatment biopsy was mandatory, approval for 
intra-participant escalation also requires acquisition of this biopsy. Approval for intra-
participant dose escalations requires the approval of the GSK Medical Monitor. 
Additionally, all participants at the next higher dose level/levels must have completed the 
DLT observation period with MTD not reached. Participants may dose-escalate to the 
highest cleared dose. Individual participants may dose-escalate multiple times provided 
that the above criteria are met at each intra-participant dose escalation step. Cumulative 
safety data from these participants will be included in the overall determination of MTD 
and RP2D. 
Additional safety assessments or PK sampling may be specified at the time of dose 
escalation or schedule modification based on the safety profile in previous participants at 
the higher dose level. Intra-participant dose escalations or schedule modification will be 
discussed with investigators and approved by the GSK Medical Monitor and safety 
monitoring required will be specified in writing. 
4.1.1.6. 
Determination of RP2D 
A GSK3359609 (feladilimab) RP2D/doses will be determined from Part 1A and Part 2A 
combination with 200 mg pembrolizumab and may be further refined in Part 1B and Part 
2B; the RP2 doses of GSK3359609 (feladilimab) and GSK3174998 in combination will 
be determined from Part 2A. Dose escalation in Part 1A GSK3359609 (feladilimab) 
monotherapy is expected to be completed when approximately 22 participants are 
enrolled and complete the DLT observation period. For Part 2A combination studies the 


 
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target enrolment varies for each cohort, depending upon the number of dose levels being 
tested. For the cohorts with pembrolizumab and GSK3174998, enrolment is expected to 
be completed when approximately 36 and 35 participants, respectively, are enrolled in the 
dose determination stage have completed the DLT evaluation period. In both dose 
escalation phases of study, the RP2D may be the MTD, the MAD, or a lower dose that 
provides adequate PK properties and clinical activity with acceptable tolerability. The 
identification of MTD may not occur if a RP2D is established prior to reaching the MTD.  
More than one dose of GSK3359609 (feladilimab) may be recommended for further 
exploration in Part 1B and Part 2B or other studies. A final determination of RP2D(s) will 
consider the mTPI suggested dose level(s) (Part 1A/Part 2A pembrolizumab 
combination) and the 2D-CRM suggested dose level(s) (Part 2A GSK3359609 
(feladilimab) in combination with GSK3174998); available data from expansion cohorts, 
a clinically active dose (e.g., tumor response), the safety profile, and available PK and 
pharmacodynamic data generated from all enrolled participants. 
A GSK3359609 (feladilimab) RP2D in combination with standard doses of 
chemotherapy ( pembrolizumab) will be determined using mTPI for dose decision in 
Part 2A only.  
Alternate schedules or dose levels may be explored if data emerge supporting their 
investigation even after a RP2D is defined. Moreover, GSK3359609 (feladilimab) fixed 
doses may be investigated in the expansion phases of Part 1 and Part 2 and will be used in 
Part 2 combinations with chemotherapy ( pembrolizumab) and GSK3174998.  
4.1.2. 
Dose Expansion Phase 
Any dose level(s)/doses in the dose escalation phases (Part1A and Part 2A) may be 
selected for expansion in Part 1B and Part 2B of the study in order to collect additional 
data on safety, PK, pharmacodynamic activity, and preliminary clinical activity. 
Each expansion cohort will include participants defined by a single tumor type as 
indicated in Figure 1 or characterized by other features such as prior treatment with an 
immune checkpoint inhibitor, a molecular/genetic alteration (MSI-H/dMMR), or 
pathology. Participants enrolled in Part 1B and Part 2B, may be stratified by prior PD-
1/L1 treatment history (i.e., naïve or experienced; best response). The details of these 
subgroups will be presented in the reporting and analysis plan (RAP). 
In addition, participants enrolled to the Part 2B (GSK3359609 
(feladilimab)/pembrolizumab combination) NSCLC cohort may be grouped by PD-L1 
expression status (Tumor Proportion Score [TPS] ≥50% versus TPS <1-49%) as 
determined by IHC thus approximately 40 participants were allocated to this cohort to 
ensure sufficient representation of PD-L1 expression categories reported in a case series 
of 2222 patients [Herbst, 2016]; enrollment to this cohort may require further enrichment 
of participants based on PD-L1 status. Participants enrolled in Part 2B HNSCC may be 
grouped by PD-L1 expression status, by other features such as HPV status and prior 
treatment history. In the Part 2B HNSCC Randomization Cohort and Part 2B HNSCC 
Every 6 Week (Q6W) Cohort, participants will be randomly assigned to one dose level of 
GSK3359609 (feladilimab) in combination with either pembrolizumab 200 mg (Table 6) 


 
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or pembrolizumab 400 mg (Table 7), respectively. The Part 2B HNSCC cohort may 
target approximately 20 participants per dose level. Based on the interim analysis, a dose 
level in the randomized cohort(s) may be dropped and the randomization ratio may be 
changed. 
Table 6 
GSK3359609 (feladilimab) Dose Levels for HNSCC Randomization 
Cohort 
Randomization Cohort 
GSK3359609 (feladilimab) 
(mg/kg) 
Pembrolizumab (mg) 
1 
0.1 Q3W 
200 Q3W 
2 
1.0 Q3W 
200 Q3W 
3 
3.0 Q3W 
200 Q3W 
Table 7 
GSK3359609 (feladilimab) Dose for HNSCC Every 6 Week (Q6W) 
Schedule Cohort 
Randomization Cohort 
GSK3359609 (feladilimab) 
(mg) 
Pembrolizumab (mg) 
1 
48 Q6W 
400 Q6W 
2 
160 Q6W 
400 Q6W 
Other Part 2B cohorts may also group participants by PD-L1 IHC status using an 
expression scoring system and interpretation of score according to the 22C3 pharmDx 
package insert. Participants enrolled in Part 2B will also be grouped by prior PD-1/L1 
treatment history (i.e., naïve or experienced) or other features that emerge as relevant to 
evaluation of study treatment activity. A minimum of 10 participants per subgroup will 
be required to be enrolled, receive treatment and be evaluable for response for the interim 
analysis. 
GSK3359609 (feladilimab) as a monotherapy or in combination with pembrolizumab 
may be evaluated in biomarker defined cohorts in which participants may be selected 
based on ICOS expression on specific T cell populations or by some other biomarker; 
approximately 20 participants initially may be enrolled in each of those cohorts. In both 
Part 1B and Part 2B, the selection of indications will be evidence based either in part on 
data generated in Part 1A and Part 2A, respectively, as well as emerging nonclinical data 
or external clinical data. Appropriate adaptive randomization and futility rules may be 
incorporated in the expansion phase to optimize the dose allocation based on evaluations 
of safety and antitumor activities; an alternative GSK3359609 (feladilimab) schedule or 
drug sequencing approach may be investigated in the expansion phase. If any expansion 
cohort would support a single arm strategy, the expansion cohort could be further 


 
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increased in size to enable a pivotal study which would be the participant of a protocol 
amendment. 
As indicated in Section 11.7, the Steering Committee will review the totality of data 
available for Study 204691 to inform on the dose level indications for any of the 
expansion cohorts. Criteria that may be considered in the determination of which dose 
level(s) to expand and which tumor types to select for cohort expansion may include: 
• Safety and Tolerability parameters such as frequency of DLT, AEs of special interest 
(AESI), and the extent of dose modifications for either GSK3359609 (feladilimab) or 
pembrolizumab. 
• Target engagement and/or pharmacodynamic activity measures 
 
 
 
• Clinical activity parameters such as tumor response (i.e., complete response [CR], 
partial response [PR]) and stable disease (SD) with duration of 18 weeks allowing for 
a one-week window per Table 27. 
After approximately10 participants at any dose level have been enrolled in a given 
monotherapy expansion cohort with available unconfirmed overall response data, an 
analysis for futility may be conducted using a Bayesian model approach (refer to Section 
10.3). Based on the output from the model, the Steering Committee may recommend 
continued accrual to that expansion cohort or to the other expansion cohorts, or 
termination of accrual to any or all the cohorts. The Steering Committee could also 
recommend exploration of a different dose level on the basis of emerging data. The 
interim analysis based on the initial 10 participants may trigger an increase in sample size 
to approximately 30 participants for defined population that may be enriched by dose or 
another characteristic. These futility rules serve as guidance for further expansion; with 
expansion decisions informed by all available clinical data. 
For any of the expansion cohorts tested, if observed clinical benefit appears to be 
associated with specific disease characteristics and/or biomarkers, a new cohort may be 
opened for further investigation with participants enriched with these specific 
characteristics and/or biomarkers. 
The selection of dose level(s)/doses and tumor types/characteristics selected for cohort 
expansion will be communicated to the sites in writing. 
4.1.2.1. 
PK/Pharmacodynamic Dose Expansion Cohorts 
Any dose level or levels may be expanded beyond the expected 3 participants enrolled in 
dose escalation phase in order to collect additional data on safety, PK, pharmacodynamic 
activity, and preliminary efficacy. Participants can only be enrolled at previously cleared 
dose levels. Participants enrolled in PK/pharmacodynamic cohorts may have the dose 
escalated to a higher cleared dose level (i.e., not exceeding the MTD) once the necessary 
PK/pharmacodynamic procedures have been completed. Model-based designs may be 
employed for each PK/pharmacodynamic dose expansion cohort in order to sufficiently 
explore parameters critical (i.e., safety, tolerability, and efficacy) in establishing the 
CCI


 
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biologically optimal GSK 3359609 monotherapy dose and the biologically optimal doses 
of the two agents in combination. 
4.2. 
Study Treatment and Duration 
The study is comprised of two primary parts, each composed of two phases: 
1. Part 1: GSK3359609 (feladilimab) monotherapy 
a. Part 1A: dose escalation 
b. Part 1B: dose expansion 
 
 
2. Part 2: GSK3359609 (feladilimab) combination therapy 
a. Part 2A: dose escalation/safety run-in 
b. Part 2B: dose expansion 
 
Each part and phase of the study includes a screening period, a treatment period, and a 
follow-up period. For participants who meet all eligibility criteria and register into the 
study, the maximum duration of treatment with GSK3359609 (feladilimab) is expected to 
be approximately two years, up to 35 cycles; in those participants who receive 
combination therapy Q3W, the maximum duration of treatment with GSK3359609 
(feladilimab) in combination with pembrolizumab ( chemotherapy) or GSK3174998 is 
expected to be two years, up to 35 cycles. The maximum treatment duration for 
participants enrolled in HNSCC Q6W dosing cohort is expected to be approximately 2 
years, up to 18 cycles for both GSK3359609 (feladilimab) and pembrolizumab. The 
duration of chemotherapy treatment will be according to institutional practice but should 
be a minimum of 4 cycles (cycle=21 days); the maximum duration of GSK3359609 
(feladilimab) and pembrolizumab treatment is expected to be two years; thus, if the 
course of chemotherapy treatment is completed after a minimum of four cycles or 
discontinued prior to completion of a minimum of 4 cycles, GSK3359609 (feladilimab) 
and pembrolizumab treatment may continue. The maximum duration of other agents in 
combination with GSK3359609 (feladilimab) will be up to 35 cycles, in which 1 cycle is 
defined as 21 days, or approximately 2 years. The maximum follow-up period for safety 
assessments will be 90 days from the date of the last dose of study treatment. The 
expected maximum follow-up period for survival and subsequent anti-cancer therapy will 
be two years from the date of the last dose of study treatment. Participants who 
discontinue study treatment due to achieving confirmed CR (refer to Section 5.4 for 
additional requirements) will be followed for progression (refer to Section 5.4 for details 
on the frequency of these assessments). 
Participants participating in Part 1A or Part 1B will receive GSK3359609 (feladilimab) as 
an IV infusion administered once every three weeks at a dose level dependent on to 
which dose level the participant is accrued (Part 1A) or what dose level(s) was chosen for 
further exploration in dose expansion cohorts (Part 1B). 
Participants participating in Part 2A (pembrolizumab or GSK3174998 combination will 
receive GSK3359609 (feladilimab) as an IV infusion administered once every three 
weeks (refer to Table 1 and Table 2) in combination with 200 mg of pembrolizumab as 


 
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an IV infusion administered once Q3W for part 2A1 or with GSK3174998 as an IV 
infusion administered once every three weeks at doses ranging from 8 mg to 80 mg (refer 
to Table 2) for Part 2A2. The dose/doses of GSK3359609 (feladilimab) in Part 2B 
(pembrolizumab combination) will be defined based on the review of the outcome 
measures for Part 1A and Part 2A. 
Participants participating in Part 2A3 chemotherapy combination cohorts will receive 
GSK3359609 (feladilimab) 24 mg or 80 mg dose (refer to Table 8 for fixed doses) in 
combination with chemotherapy at doses and schedules based on standard of care 
practice (refer to Table 12); pembrolizumab 200 mg dose will be administered as an IV 
infusion administered once Q3W. 
4.3. 
Study Population 
The number of dose levels and the level at which the MTD or MAD is reached in Part 1A 
and Part 2A cannot be predetermined. An adequate number of participants will be 
enrolled into the study to establish the recommended dose(s) for further investigation. 
Overall it is estimated that a total of approximately 867 participants may be enrolled in 
this two-part study (approximately 166 participants in Parts 1A and 2A [dose 
escalation/safety run-in],approximately 40 participants in the Part 1C and Part 2C 
PK/pharmacodynamic cohorts (Japan only) in a Japan country specific amendment and 
20 participants in the Part1D PK/pharmacodynamic cohort (China only) in a China 
country specific amendment; approximately 641 participants in Parts 1B and 2B [cohort 
expansion]). The study population in Part 1A/Part 1B and Part 2A (dose escalation and 
GSK3359609 (feladilimab) plus chemotherapy safety cohorts) will be adults with 
advanced/recurrent solid tumor malignancies, who either: 
• have disease that has progressed on prior systemic therapy 
• are not candidates for standard of care therapy, or 
• have disease for which no further standard of care therapy exists. 
In the Part 2A GSK3359609 (feladilimab)/pembrolizumab plus chemotherapy safety 
cohorts and Part 2B combination with pembrolizumab the expansion cohort populations 
may be comprised of participants with advanced/recurrent solid tumors who have not 
received treatment for advanced disease.  
In Part 1A and Part 2A, if at any dose level a participant prematurely discontinues study 
treatment before the completion of the 28-day DLT observation period for reasons other 
than a DLT, a replacement participant may be enrolled and assigned to the same dose 
level if <3 participants complete the DLT observation period at that dose level. 
In those Part 1A dose levels that have a single participant enrolled, a replacement 
participant will be enrolled if <1 participant prematurely discontinues study treatment 
before the completion of the 28-day DLT period. 
Participants will not be replaced in Parts 1B and 2B of the study. 


 
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4.4. 
Design Justification 
In the GSK3359609 (feladilimab) monotherapy and combination dose escalation phases 
of the study, safety, tolerability, pharmacology, and preliminary efficacy will be 
evaluated utilizing designs that account for the starting dose level, greater precision 
around the true toxicity rate, and for Part 2A, the agents under investigation as 
combination therapy. 
Part 1A includes an accelerated titration design planned for the first three dose levels in 
order to minimize the number of participants enrolled at sub-optimal doses followed by 
the mTPI approach, a well-validated method to identify the MTD/RP2D of a given agent. 
Part 2A combinations of GSK3359609 (feladilimab) and pembrolizumab, or 
chemotherapy ( pembrolizumab) will employ the mTPI method where the dose of 
GSK3359609 (feladilimab) may be adjusted based on the DLT rate observed or by 
emerging evidence supporting a selected dose while in combination with a standard of 
care dose of pembrolizumab fixed at 200 mg and standard of care doses of 
chemotherapies (refer to Table 12). The Part 2A combination of GSK3359609 
(feladilimab) and GSK3174998 will employ a run-in design for the starting combination 
dose level (Dose Cohort 1) as the 2 lowest doses of both agents were selected based on 
the findings from a cytokine release assay (refer to Section 2.3.3.2.2 for details). The use 
of the 2D-CRM design for combination with GSK3174998 provides estimations of the 
target probability of dose-limiting toxicity at the recommended combination doses for 
phase II trials without treating too many participants at suboptimal doses.  
The solid tumor types selected for dose escalation include bladder/urothelial carcinoma, 
carcinoma of HN, cervical carcinoma, CRC, esophageal carcinoma of squamous 
histology, prostate carcinoma, melanoma, MPM and NSCLC. The selection of these solid 
tumors was based on evidence of prior response to immune checkpoint therapies 
[Swaika, 2015; Zamarin, 2015] and/or exhibiting features indicating a greater likelihood 
of susceptibility to immune directed therapies, such as tumor mutation load or 
number/phenotype of tumor infiltrating lymphocytes [Powles, 2014; Goodman, 2017; 
Hellmann, 2018]. 
The dose expansion phases of the study may commence while dose escalation phases are 
ongoing. GSK3359609 (feladilimab) dose levels cleared for safety (refer to Section 
4.1.1.1) may be investigated as expansion cohorts defined by specific solid tumor 
histology or perhaps by a specific characteristic, agnostic of tumor type, such as prior 
response to immunotherapy, biomarker phenotype that is evidenced-based (i.e., optimal 
immune features such as tumor mutation burden, and/or ICOS expression), or other 
features such as mismatch repair deficiencies which is suggestive of a greater likelihood 
to respond to anti-ICOS agonist monotherapy or as combination therapy with 
pembrolizumab [Le, 2017]. An alternate dosing schedule of GSK3359609 (feladilimab) 
Q6W will be explored in combination with pembrolizumab 400 mg Q6W in participants 
with HNSCC to evaluate safety, pharmacodynamic, PK and preliminary clinical activity 
(refer to Section 4.5.5). 
The inclusion of GSK3359609 (feladilimab) combinations with pembrolizumab, 
GSK3174998, and chemotherapy ( pembrolizumab) in the FTIH study setting is based 
on the rationale that targeting more than one axis in the cancer immunity cycle or 
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which potentially may be identified early in development. Although GSK3359609 
(feladilimab) is expected to have meaningful clinical activity as a monotherapy, the full 
potential of the molecule in certain indications is likely to be discovered in combination 
with other agents, particularly other immune checkpoint modulators. 
Clinical evidence from immune checkpoint modulators indicates the emergence of 
objective responses to these agents that activate antitumor immune responses may follow 
delayed kinetics of weeks or months [Wolchok, 2009]. The potential delay in tumor 
regression can be preceded by an initial apparent progression with the appearance of new 
lesions or increase in some lesions while certain lesions are regressing thereby producing 
an overall “mixed response”. While overall disease assessment of disease status will be in 
accordance with RECIST v1.1 and irRECIST, the decision to discontinue treatment due 
to disease progression will be based upon irRECIST to account for the unique biological 
mechanisms of immunotherapies. 
4.5. 
Dose Justification 
4.5.1. 
Part 1A: GSK3359609 (feladilimab) (ICOS) Monotherapy Dose 
Rationale 
The minimally anticipated biologic effect level (MABEL) approach was used as the basis 
for the 0.001 mg/kg starting dose of GSK3359609 (feladilimab) monotherapy in the dose 
escalation phase of the study. The basis of the approach is in consideration of the 
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) S9 guidance on selection of starting dose for a 
biopharmaceutical with immune agonistic properties. The projected human GSK3359609 
(feladilimab) exposure predicted by cynomolgus monkey PK and GSK3359609 
(feladilimab) pharmacology factored into the selection of the starting dose implemented 
in study 204691. 
The PK of GSK3359609 (feladilimab) was assessed in two cynomolgus monkey studies, 
with single and repeat doses ranging from 0.3 mg/kg to 100 mg/kg; GSK3359609 
(feladilimab) exposure was approximately dose-proportional (refer to Section 2.3.2). 
Across the dose levels tested, PK profiles did not demonstrate any evidence of target-
mediated disposition. These results suggest that allometric methods are appropriate to 
predict human PK; furthermore, human PK of GSK3359609 (feladilimab) is expected to 
be similar to the PK of mAbs of the same isotype (IgG4). Allometric scaling predicted a 
Cmax value of 0.028 g/mL at 0.001 mg/kg. 
The MABEL assessment was based on measures of 
 and 
functional effects (such as cytokine production and activation/ proliferation of T cell 
populations) as characterized by in vitro binding experiments using ex vivo CD3/CD28 
stimulated primary human peripheral blood mononuclear cells from healthy donors. The 
use of RO as a surrogate for biological activity was deemed appropriate as RO provides a 
general characterization of GSK3359609 (feladilimab) signaling in target cells and since 
individual biological effects of GSK3359609 (feladilimab) are not yet prioritized in terms 
of their impact on participant safety. The functional effect of GSK3359609 (feladilimab) 
was also characterized in several experiments yielding different activity coefficients 
depending on cell type, co-stimulation status, and cytokines analyzed. 
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A RO of 10% or binding effective concentration (EC)10 based on predicted Cmax was 
evaluated to guide selection of the starting dose. The binding EC10 (g/mL) of 
GSK3359609 (feladilimab) in CD4+ T cells ranged from 0.059 – 0.666 with a median 
value of 0.154; in CD8+ T cells the binding EC10 ranged from 0.055 - 0.842 with a 
median value of 0.144. The calculated starting dose based on the median EC10 values 
projected a starting dose of 0.005 mg/kg. Of note, RO calculations assumed that the 
difference between GSK3359609 (feladilimab) bound to protein and free GSK3359609 
(feladilimab) is negligible (RO = Cmax/ (EC50 + Cmax)). This approach will yield 
higher RO and as such more conservative dose estimates than the approach which 
assumes a specific level of target expression. In addition, using activated T cells, as was 
applied in the binding experiments summarized above, would produce a greater response 
than without T cell activation, in which case ICOS receptors are detectable in a small 
percentage of T cells (<5%). 
An EC10 threshold for the functional assays was also evaluated to guide starting dose 
selection. In the cytokine release immunoassay, TNF was the most sensitive of the five 
cytokines analyzed, the EC10 (g/mL) values of GSK3359609 (feladilimab) at the 24-
hour time-point were 0.006 and 0.028 with a median of 0.017. Percent increase in 
OX40+CD4+ T cells was the most sensitive measure of T cell activation status as 
measured by flow cytometry, the EC10 (g/mL) of GSK3359609 (feladilimab) at the 48-
hour time-point ranged from 0.002 to 0.186, with a median value of 0.029. The calculated 
starting dose based on the median EC10 values from both measures of functional effect 
projected a starting dose of 0.001 mg/kg; at the starting dose of 0.001 mg/kg, the RO as 
estimated from the binding assay would be 3%. 
The EC50 values of IFN as the cytokine purported to be relevant for immune antitumor 
activity [Ikeda, 2002] were analyzed to project a GSK3359609 (feladilimab) dose that 
may achieve relevant pharmacology. The projected 0.01 mg/kg dose of GSK3359609 
(feladilimab) would result in Cmax concentrations near the EC50 value of IFN. A dose 
of 0.05 mg/kg would result in Cmax concentrations near the EC50 value for binding of 
activated T cells. 
Refer to GSK3359609 (feladilimab) IB [GlaxoSmithKline Document Number RPS-
CLIN-015202, 2021] and Section 2.3.4 for further details. 
4.5.2. 
Part 2A: GSK3359609 (feladilimab) (ICOS) Starting Dose in 
Combination with Pembrolizumab 
No drug-drug interaction affecting the PK for the combination of GSK3359609 
(feladilimab) and pembrolizumab is expected. As a checkpoint inhibitor, rather than a 
direct immune-stimulator, pembrolizumab is not expected to substantially increase the 
potential for excessive cytokine release in response to GSK3359609 (feladilimab), but 
specific synergies cannot be excluded a priori. The starting dose of GSK3359609 
(feladilimab) for Part 2A (combination dose escalation phase) will be two dose levels 
below a dose that was shown to be tolerated and at which a pharmacodynamic effect was 
observed during the monotherapy dose escalation. 


 
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Refer to GSK3359609 (feladilimab) IB [GlaxoSmithKline Document Number RPS-
CLIN-015202, 2021] and Section 2.3.4 for further details.  
4.5.3. 
Part 2A:  GSK3359609 (feladilimab) (ICOS) Starting Dose in 
Combination with Chemotherapy Pembrolizumab 
No drug-drug interaction affecting the PK profiles is expected for the combinations of 
GSK3359609 (feladilimab) and docetaxel or carboplatin/cisplatin-based chemotherapies; 
including when GSK3359609 (feladilimab) and chemotherapies are in combination with 
pembrolizumab. The safety profiles of the defined chemotherapies are well established 
and expected to be unique to the potential immune-mediated toxicities identified as risks 
for GSK3359609 (feladilimab) (refer to Section 4.6.2) and known for pembrolizumab 
(refer to the pembrolizumab IB [Merck Sharp & Dohme Corp, Pembrolizumab IB, 2021]) 
except for infusion related reactions which can occur with specific chemotherapies. Refer 
to infusion related reaction management guidelines in Section 7.12.3. 
The starting dose of GSK3359609 (feladilimab) in the chemotherapy safety run-in 
cohorts will be 80 mg, as the dose level equivalent of 1mg/kg is one of the dose levels 
under investigation in the PK/PD cohorts and a dose level to be investigated in other 
expansion cohorts. The fixed dose of GSK3359609 (feladilimab) is expected to provide 
similar and adequate control of exposure variability compared to body-weight based 
dosing (refer to Section 4.5.6 for details on fixed dose justification). 
4.5.4. 
Part 2A: GSK3359609 (feladilimab) (ICOS) Starting Doses in 
Combination with GSK3174998 (OX40) 
Based on the preliminary data from this FTIH study, 204691, no dose-limiting toxicities 
were observed in the dose escalation cohorts over the range of GSK3359609 
(feladilimab) dose levels (0.001 mg/kg [~0.08 mg] to 3 mg/kg [~240 mg]) evaluated in 
advanced cancer participants receiving GSK3359609 (feladilimab) as a monotherapy; 
one participant in the PK/pharmacodynamic cohort receivingGSK3359609 (feladilimab) 
at 3 mg/kg experienced liver function test elevations that were considered DLTs. 
Additionally, there were no cases of cytokine release syndrome reported. Refer to 
GSK3359609 (feladilimab) IB for further details on the preliminary safety and PK results 
reported from the 204691 study [GlaxoSmithKline Document Number RPS-CLIN-
015202, 2021]. 
The lower starting dose of 8 mg (~0.1 mg/kg) is 1/30 of the top dose of GSK3359609 
(feladilimab) that was evaluated and was chosen based on the findings from the CRA that 
showed under specific experimental conditions increases in IFN or TNF responses 
(refer to Section 2.3.3.2.2 for further details). The GSK3359609 (feladilimab) doses of 
24mg and 80mg were selected based on the preliminary ICOS 
 
pharmacodynamic analysis in the periphery which showed high 
 
levels on CD4 and CD8 T cells over the 21-day dosing cycle starting at 0.3 m/kg (~24 
mg); close to total receptor saturation was observed at 1mg/kg (~80 mg) dose level. 
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4.5.5. 
GSK3359609 (feladilimab) Dosing Frequency 
Guided by GSK3359609 (feladilimab) pharmacodynamic activity and the expectation of 
standard IgG4 mAb PK terminal elimination half-life longer than 2 weeks, a dosing 
frequency of Q3W was initially selected for GSK3359609 (feladilimab), which is 
consistent with the population PK estimated median disposition half-life of ~3 weeks. 
Also, this dosing frequency schedule increases participant convenience for administration 
with planned combination partners also dosed Q3W (e.g. pembrolizumab). 
Since select partner agents may be dosed less frequently than every three weeks, 
alternative extended dosing schedules would provide additional convenience and 
flexibility to participants and clinicians beyond a Q3W option. Hence, a six-weekly 
(Q6W) dosing schedule for GSK3359609 (feladilimab) will be explored, specifically in 
randomized schedule optimization cohorts for participants with PD-1/L1 Naive HNSCC. 
Two doses for initial Q6W schedule exploration, 48 and 160 mg, are selected to provide 
matching cumulative exposures corresponding to respective Q3W regimens in the Q3W 
HNSCC dose-randomized cohorts (0.3 and 1 mg/kg). Preliminary PK simulations suggest 
a doubling of dose and interval for GSK3359609 (feladilimab) (e.g. 0.3 mg/kg Q3W to 
48 mg Q6W) is expected to provide similar cumulative AUC with an approximate 
doubling of end-of-infusion Cmax and marginally lower end-of-cycle trough 
concentrations (~43% at steady-state). The typical Cmax for 160 mg Q6W will be 
maintained below thresholds established with the Q3W regimens. 
4.5.6. 
GSK3359609 (feladilimab) Fixed Dose Rationale 
In Part 1A (monotherapy) and Part 2A (combination with pembrolizumab) GSK3359609 
(feladilimab) was administered on body weight-based dosing. Fixed doses may be tested 
in the expansion cohorts, in the safety run-in phase with chemotherapy combinations, 
assuming a typical median weight of 80 kg.  
Therapeutic monoclonal antibodies are often dosed based on body-size due to the concept 
that this reduces inter-participant variability in drug exposure. However, body-weight 
dependency of PK parameters does not always explain the observed variability in the 
exposure of monoclonal antibodies [Zhao, 2017]. The advantage of body-weight based 
versus fixed dosing in this study was evaluated through population PK modelling and 
simulation efforts. A preliminary population PK model was developed from monotherapy 
dose escalation (data up to doses of 1 mg/kg; n=19 participants).  
Simulations were performed by considering body weight distribution in the simulations 
were based on the observed distribution in the preliminary dataset. At the 5th percentile 
of body weight (40–47 kg), there was a 70-100% increase in median steady-state AUC(0-
); GSK3359609 (feladilimab) exposures higher than these increases have been evaluated 
in the current Phase 1 study with the 3 mg/kg dose regimen. At the 95th percentile of 
body weight (107–118 kg), there was a 23-32% decrease in median steady-state AUC(0-
) as compared to the median 80 kg exposure providing adequate RO with the minimal 
lowering of exposure. A similar outcome is expected for steady-state Cmax and trough 
concentrations between body weight-based and fixed dosing.  


 
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Overall, these preliminary population PK simulations indicate that using fixed dosing 
would result in a similar range of exposures as that of body weight-based dosing. Also, 
fixed dosing offers the advantage of reduced dosing errors, reduced drug wastage, shorten 
preparation time, and improve ease of administration. Thus, switching to a fixed dose 
based on a reference body weight of 80 kg is reasonable and appropriate. 
The fixed dose equivalents of the weight-based GSK3359609 (feladilimab) dose levels 
using 80 kg weight are presented in Table 8. 
Table 8 
GSK3359609 (feladilimab) Fixed Dose Calculations 
Dose Level 
GSK3359609 (feladilimab) 
mg/kg 
GSK3359609 (feladilimab) 
mg 
1 
0.001 
0.08 
2 
0.003 
0.24 
3 
0.01 
0.8 
4 
0,03 
2.4 
5 
0.1 
8.0 
6 
0.3 
24.0 
7 
0.6 
48.0 
8 
1.0 
80.0 
9 
2.0 
160.0 
10 
3.0 
240.0 
4.5.7. 
Part 2: Pembrolizumab Dose Rationale 
The dose of pembrolizumab planned is 200 mg Q3W. The dose recently approved in the 
United States and several other countries for treatment of melanoma participants is 
2 mg/kg Q3W. The rationale for selecting 200 mg Q3W is summarized below. 
In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of pembrolizumab when 
administered as monotherapy. The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and 
dose expansion cohorts evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in participants with 
advanced solid tumors.  All dose levels were well tolerated and no dose-limiting 
toxicities were observed.  This first-in-human study of pembrolizumab showed evidence 
of target engagement and objective evidence of tumor size reduction at all dose levels.  
No MTD had been identified. In addition, two randomized cohort evaluations of 
melanoma participants receiving pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg 
Q3W have been completed, and one randomized cohort evaluating 10 mg/kg Q3W versus 
10 mg/kg Q2W has also been completed. The clinical efficacy and safety data 
demonstrate a lack of important differences in efficacy or safety profile across doses 
[Merck Sharp & Dohme Corp, Pembrolizumab IB, 2021].  
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W.  Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety was found in 
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Exposures for 200 mg Q3W are expected to lie within this range and will be close to 
those obtained with 2 mg/kg Q3W dose. 
A population PK model, which characterized the influence of body weight and other 
participant covariates on exposure, has been developed. The PK profile of 
pembrolizumab is consistent with that of other humanized monoclonal antibodies, which 
typically have a low clearance and a limited volume of distribution. The distribution of 
exposures from the 200-mg fixed dose are predicted to considerably overlap those 
obtained with the 2 mg/kg dose and importantly will maintain individual participant 
exposures within the exposure range established in melanoma as associated with maximal 
clinical response.  PK properties of pembrolizumab, and specifically the weight-
dependency in clearance and volume of distribution are consistent with the conclusion 
there is no meaningful advantage to weight-based dosing relative to fixed dosing [Merck 
Sharp & Dohme Corp, Pembrolizumab IB, 2021]. 
In translating to other tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in participants with melanoma can be expected, as the 
anti-tumor effect of pembrolizumab is driven through immune system activation rather 
than through a direct interaction with tumor cells, rendering it independent of the specific 
tumor type. In addition, available PK results in participants with melanoma, NSCLC, and 
other tumor types support a lack of meaningful difference in PK exposures obtained from 
the doses tested among the various tumor types. Thus the 200 mg Q3W fixed-dose 
regimen is considered an appropriate fixed dose for other tumor indications. 
Moreover, a fixed dose regimen will simplify the dosing regimen to be more convenient 
for physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. The 
existing data suggest 200 mg Q3W as the appropriate dose for pembrolizumab. 
For the 2B HNSCC dose optimization cohort, the planned dose of pembrolizumab is 400 
mg every 6 weeks (Q6W). A 400 mg Q6W dosing regimen of pembrolizumab is 
expected to have a similar benefit-risk profile as 200 mg Q3W, in all treatment setting in 
which 200 mg Q3W pembrolizumab is currently approved [Lala, 2018; Geiger, 2019]. 
Specifically, the dosing regimen of 400 mg Q6W for pembrolizumab is considered 
adequate based on modelling and simulation (M&S) analyses, given the following 
rationale:  
• The proposed schedule is intended solely for an investigational study 
• Pharmacokinetic (PK) simulation demonstrating that in terms of pembrolizumab 
exposures- 
o Average concentration over the dosing interval (Cavg) (or area under the 
curve [AUC]) at 400 mg Q6W is similar to that at the approved 200 mg 
Q3W dose, thus bridging efficacy between dosing regimens. 
o Trough concentrations (Ctau) at 400 mg Q6W are generally within the range 
of those achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of 
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o Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the 
highest clinically tested dose of 10 mg/kg Q2W, supporting that the safety 
profile for 400 mg Q6W should be comparable to the established safety 
profile of pembrolizumab. 
• Exposure-response (E-R) for pembrolizumab has been demonstrated to be flat 
across indications, and OS predictions in melanoma and NSCLC demonstrate that 
efficacy at 400 mg Q6W is expected to be similar to that at 200 mg or 2 mg/kg 
Q3W, given the similar exposures; thus 400 mg Q6W is expected to be efficacious 
across indications. 
4.5.8. 
Part 2: Chemotherapy Dose Rationale 
Docetaxel is a semisynthetic taxane approved in different tumor indications. The dosage 
of docetaxel as a single-agent and in combination for several tumor indications, including 
NSCLC and HNSCC, is 75mg/m2, every three weeks; thus, this dose and schedule was 
selected in combination with GSK3359609 (feladilimab). 
The carboplatin chemotherapy doublets will calculate the dose of carboplatin according 
to Calvert formula using the target AUC of 4-6 mg/ml per min as per local standard of 
care in combination with: 
1. Pemetrexed at 500 mg/m2 
2. Gemcitabine at 1250 mg/m2 
3. Paclitaxel at 200 mg/m2 
The doses selected in combination are according to Category 1 recommendations in 
National Comprehensive Cancer Network treatment guidelines. 
Carboplatin (AUC 5) or cisplatin at 100 mg/m2 (per GSK assignment) will be combined 
with 5-FU at 1000 mg/m2 (Refer to Table 12 further details). The doses selected were in 
accordance with standard doses given for first-line treatment of recurrent or metastatic 
HNSCC [Vermorken, 2008]. 
4.5.9. 
Part 2: GSK3174998 (OX40) Dose Rationale 
In the GSK3174998 FTIH study, 201212, no DLTs or cases of CRS were observed over 
the GSK3174998 dose range evaluated (0.003 mg/kg [~0.24 mg] to 10 mg/kg [~800 mg]) 
in participants with advanced cancer. The OX40 
 pharmacodynamic 
analysis in the periphery showed high 
 levels on T cells over the 21-
day dosing cycle starting with the 0.3 m/kg (~24 mg) dose of GSK3174998 
[GlaxoSmithKline Document Number 2014N212091_06, 2020]. 
The lower starting dose of 8 mg (~0.1 mg/kg) is 1/100 of the top dose of GSK3174998 
evaluated and was chosen based on the findings from the CRA that showed, under 
specific experimental conditions, increases in IFN or TNF responses (refer to Section 
2.3.3.2.2 for further details). Nevertheless, the potential for CRS is expected to be low 
based on the ICOS and OX40 co-stimulatory receptor biology. Based on the totality of 
data, including 
, clinical activity, and safety, doses of 8 mg, 24 mg 
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and 80 mg GSK3174998 were selected for testing in the combination with GSK3359609 
(feladilimab). 
4.6. 
Benefit:Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK3359609 (feladilimab) [GlaxoSmithKline Document Number RPS-CLIN-015202, 
2021], pembrolizumab [Merck Sharp & Dohme Corp, Pembrolizumab IB, 2021], and 
GSK3174998 [GlaxoSmithKline Document Number 2014N212091_06, 2020] can be 
found in the respective IBs. Refer to the chemotherapy approved product labels for 
information on contraindications, warnings and precautions. 
The following sub sections outline the risk assessment and mitigation strategy for 
GSK3359609 (feladilimab) in this protocol. 
This is an open-label, first time in human study of this agent to be conducted in 
participants with select advanced solid tumors that are relapsed/refractory to standard 
therapies. GSK3359609 (feladilimab) has preclinical activity; preliminary clinical 
activity has been reported with GSK3359609 (feladilimab) as a monotherapy in 
metastatic melanoma and in HNSCC as well as GSK3359609 (feladilimab)  in 
combination with pembrolizumab in HNSCC (refer to Section 2.3.5.1 and Section 
2.3.5.2.1). Furthermore, there is evidence of durable tumor response or a prolongation of 
tumor control rate relative to historic expectations in  urothelial cancer, NSCLC, and 
cervical cancer. However, Study 204691 is non-randomized; moreover, it is unknown 
whether GSK3359609 (feladilimab) will have clinical activity as a monotherapy or in 
combination with pembrolizumab, GSK3174998, or chemotherapy across the other tumor 
types under investigation. Thus, any potential beneficial effect for an individual 
participant attributable to GSK3359609 (feladilimab) as a monotherapy or as part of 
combination therapy is possible using the basis of the preliminary clinical activity 
observed in Study 204691. For other tumor types there is insufficient experience to come 
to any conclusions. Furthermore, MTD was not reached and the dose ranges proposed in 
the combination studies are documented to result in meaningful 
 that 
correlates with durable clinical responses in several tumor types. Data obtained in this 
study may help identify individuals more likely to benefit or have side-effects from 
GSK3359609 (feladilimab). Study participants may benefit from the medical tests and 
screening performed during the study. 
The doses or dose ranges selected for the other compounds used in the combinations are 
all associated with tumor responses in several types of advanced solid malignancies as 
documented in the respective product package insert or Investigator’s Brochure.  
Finally, preliminary experience to date with pembrolizumab and conventional 
chemotherapy combinations shows no added toxicity by adding GSK3359609 
(feladilimab) to any of these agents. The observed toxicities are those previously 
documented with the respective agent qualitatively and quantitatively. 
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4.6.1. 
Risk Assessment 
The following sub sections outline the risk assessment and mitigation strategy for this 
protocol. Refer to the individual chemotherapy agent’s approved product label for the 
information on contraindications, warnings, and precautions. 
Table 9 
Risk Assessment and Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Immune-related AEs 
• Inflammatory AEs such as 
diarrhea/colitis, pneumonitis, 
nephritis, and hepatotoxicity 
are well established as 
treatment emergent AEs with 
immune-modulating agents 
and are consistent with the 
immune-stimulatory 
mechanism of action of these 
agents.  
 
• Participants with the following 
medical history are ineligible for 
this study 
o Toxicity (Grade 3) related to 
prior immunotherapy leading 
to study treatment 
discontinuation  
o Active autoimmune disease 
(refer to Section 5.2 
exclusion criterion 8) 
o Severe hypersensitivity to 
another mAb 
• Established management 
algorithms for irAEs 
• Refer to Section 7 for further 
details on the identification, 
evaluation, and management of 
toxicities with a potential 
immune etiology. 
Infusion and 
hypersensitivity reactions 
and potential severe 
Cytokine Release 
Syndrome (CRS) 
• Risk for infusion reactions and 
hypersensitivity is inherent to 
many mAbs [Brennan, 2010] 
• The overall rate of IRRs with 
ICOS is low and there have 
been no cases of CRS 
observed across the clinical 
program of GSK3359609 
(feladilimab) [GlaxoSmithKline 
Document RPS-CLIN-015202, 
2021]. 
 
• Participants with history of 
severe hypersensitivity to 
another mAb or to the 
chemotherapies under 
investigation including any 
ingredient used in the 
formulation are ineligible for this 
study  
• Refer to Section 7.12.3 for 
further details on management 
of infusion reactions and details 
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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Immune complex disease 
• Immune complex formation 
and deposition findings in 
nonclinical safety studies (refer 
to Section 2.3.3.1 and the 
GSK3359609 (feladilimab) IB) 
• Clinical laboratory safety 
assessments and 
immunogenicity testing 
Abbreviations: AE= adverse event; CRS=cytokine release syndrome; ICOS=inducible T cell co-stimulator; 
IB=investigator’s brochure; mAb=monoclonal antibody; TCR=T cell receptor 
 
4.6.2. 
Overall Benefit:Risk Conclusion 
Current data from GSK3359609 (feladilimab) preclinical studies indicate a potential for 
anti-tumor activity through effects resulting from stimulation of ICOS. Current 
preliminary clinical data using GSK3359609 (feladilimab) as monotherapy or in 
combination demonstrate benefit in several advanced solid tumor malignancies. 
Considering the measures taken to minimize risks to participants participating in the 
Phase I clinical trial, the potential risks identified in association with GSK3359609 
(feladilimab) as a monotherapy or combination therapy are justified by the anticipated 
benefits that may be afforded to participants with relapsed/refractory solid tumors. In 
particular, in the setting of previously treated metastatic melanoma. 
 
5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact participant eligibility is provided in the IB/IB supplements. 
Deviations from inclusion and exclusion criteria are not allowed as they may 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. 
5.1. 
Inclusion Criteria 
For a participant to be eligible for inclusion in this study all the following criteria must be 
fulfilled: 
1. Capable of giving signed, written informed consent 
2. Male or female, age 18 years (at the time consent is obtained). 


 
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3. Histological or cytological documentation of an invasive malignancy that was 
diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the 
following tumor types:  
• Bladder/urothelial cancer of the upper and lower urinary tract 
• Cervical 
• Colorectal (includes appendix) 
• Esophagus, squamous cell 
• Head and Neck Carcinoma  
• Melanoma/Cutaneous Melanoma (non-uveal) required in Part 1B Melanoma 
Biomarker Cohort 
• MPM 
• NSCLC 
• Prostate 
• MSI-H/dMMR tumor (Part 1B and Part 2B) 
• HPV-positive or EBV-positive tumor (Part 1B and Part 2B) 
Note: 
In Part 2A chemotherapy safety cohort for 5-FU/platinum combination with 
GSK3359609 (feladilimab) and pembrolizumab, only participants with HNSCC that was 
diagnosed as recurrent or metastatic and considered incurable by local therapies, are 
eligible.    
4. Disease that has progressed after standard therapy for the specific tumor type, or for 
which standard therapy has proven to be ineffective, intolerable, or is considered 
inappropriate, or if no further standard therapy exists; exceptions are in these tumor 
types in which pembrolizumab single agent may be a standard: NSCLC, HN 
squamous cell cancer (HNSCC), bladder/urothelial cancer, MSI-H/dMMR cancers, 
melanoma and cervical cancer (refer to the country-specific pembrolizumab/anti-
PD-1/L1 package inserts for the indications). In these Part 2B pembrolizumab 
combination expansion cohorts, prior treatment with anti-PD-1/L1 may not be 
required. 
• Participants must not have received more than 5 prior lines of therapy for 
advanced disease including both standards of care and investigational therapies. 
o Participants in the biomarker cohort are required to have received prior 
anti-PD-1/L1 and anti-CTLA-4 therapy (either concurrently or 
sequentially) 
o Participants with BRAF mutation positive melanoma are required to have 
received  prior BRAF targeted therapy; as well as prior anti-PD-1/L1 and 
anti-CTLA-4 therapy (either concurrently or sequentially) 
• Participants who received prior anti-PD-1/L1 therapy must fulfill the following 
requirements (Part 1B [except PK/PD cohort)/ Part 2B):  
o Have achieved a CR, PR or SD and subsequently had disease progression 
while still on PD 1/L1 therapy 
o Have received at least 2 doses of an approved PD-1/L1 inhibitor (by any 
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o Have demonstrated disease progression as defined by RECIST v1.1 
within 18 weeks from the last dose of the PD-1/L1 inhibitor. The initial 
evidence of disease progression is to be confirmed by a second 
assessment no less than four weeks from the date of the first documented 
PD (the confirmatory scan could be the baseline eligibility scan for this 
study) 
• 
In Part 2A 5-FU/platinum combination with GSK3359609 (feladilimab) and 
pembrolizumab cohort, participants must not have received prior systemic 
therapy administered in the recurrent or metastatic setting (with the exception of 
systemic therapy given as part of multimodal treatment for locally advanced 
disease). 
5. Archival tumor tissue obtained at any time from the initial diagnosis to study entry; a 
fresh tumor biopsy using a procedure that is safe for the participant on a lesion not 
previously irradiated unless lesion progressed will be required if archival tissue is 
unavailable (refer to Table 28). 
6. Agree to undergo a pre-treatment and on-treatment biopsy and have disease 
amenable to biopsy required in PK/pharmacodynamic Cohort (Part 1B), dose 
randomized HNSCC, HNSCC CPS<1, Melanoma dose expansion cohorts, 
Biomarker cohort, and PK/PD phase of Part 2A combination cohorts. 
7. Measurable disease per RECIST version 1.1 (refer to Appendix 6). Palpable lesions 
that are not measurable by radiographic or photographic evaluations may not be 
utilized as the only measurable lesion. Any measurable lesion biopsied at Screening 
cannot be followed as a target/index lesion unless agreed upon by GSK. 
8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (refer to 
Appendix 7). 
9. Life expectancy of at least 12 weeks. 
10. Adequate organ function as defined in Table 10: 


 
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Table 10 
Definitions for Adequate Organ Function 
Systema 
Laboratory Values 
Hematologicb 
ANC 
≥1.5x109/L 
Hemoglobin 
≥9 g/dL 
Platelets 
≥100x109/L 
Hepatic 
Total bilirubin 
For participants with Gilbert’s Syndrome (only if direct bilirubin 
≤35%) 
≤1.5xULN 
≤3.0xULN 
ALT 
≤2.5xULN;  
or ≤5xULN for participants 
with documented liver 
metastases  
Renal 
Calculated CrClc 
30 mL/min 
Cardiac 
Ejection fraction 
≥ 50% by 
echocardiogramd 
Abbreviations: ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; TSH 
= thyroid-stimulating hormone; ULN = upper limit of normal; WNL = within normal limits 
a. 
Participant eligibility for the GSK3359609 (feladilimab) chemotherapy combinations requires laboratory 
values fulfilling the warnings/precautions requirements indicated in the approved product label (i.e., CrCl 
requirements for cisplatin) 
b. 
Absolute Lymphocyte Count will be included in the baseline assessment, but no range limit requirement 
for the eligibility. 
c. 
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) formula (refer to Appendix 10) 
d. 
Multigated acquisition scan (MUGA) is acceptable if ECHO is not available (refer to Section 8.4.7) 
 
11. QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
<450 milliseconds (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. 
12. A female participant is eligible to participate if she is not pregnant (as confirmed by 
a negative serum beta-human chorionic gonadotrophin [-hCG] test in females of 
reproductive potential) and not lactating, or at least one of the following conditions 
applies: 
• Non-reproductive potential defined as: 
• 
Pre-menopausal females with one of the following: 
• 
Documented tubal ligation 
• 
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion  
• 
Hysterectomy 


 
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• 
Documented Bilateral Oophorectomy 
• 
Postmenopausal defined as 12 months of spontaneous amenorrhea. 
Females on hormone replacement therapy (HRT) and whose menopausal 
status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the 
study.  Otherwise, they must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrolment. 
a. Reproductive potential and agrees to follow one of the options listed in 
Appendix 3 from 30 days prior to the first dose of study medication and until 
120 days after the last dose of study treatment. 
13. Male participants with female partners of child bearing potential must agree to use 
one of the methods of contraception specified in Appendix 3 from time of first dose 
of study treatment until 120 days after the last dose of study treatment.  
14. 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. 
15. Documented Human Papilloma Virus (HPV)/ Epstein-Barr (EBV)-positive tumor as 
determined by a local laboratory for Part 1B and Part 2B pembrolizumab 
combination viral-positive expansion cohorts only 
16. Documented MSI-H or dMMR-positive tumor as determined by local laboratory for 
Part 1B and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts 
only. 
17. ICOS expression result using an analytically validated IHC assay by central 
laboratory for Part 1B Biomarker Cohort only. Participants may be required to have 
a defined ICOS expression score for eligibility; refer to Section 8.2 for details.  
18. Gene expression (GEX) result using an analytically validated method by central 
laboratory may also be required for Part 1B Biomarker Cohort only. Participants may 
be required to have a defined GEX result for eligibility; refer to Section 8.2 for 
details.  
19. PD-L1 CPS <1 using the FDA approved PD-L1 IHC 22C3 pharmDx assay by central 
laboratory testing for Part 2B HNSCC PD-L1 CPS <1 Cohort.  Documented test 
result of CPS<1 from FDA approved PD-L1 IHC 22C3 pharmDx assay in local 
laboratory, if available, may be accepted in lieu of the central laboratory test result.  
 
5.2. 
Exclusion Criteria 
A participant will not be eligible for inclusion in this study if any of the following criteria 
apply: 
1. Prior treatment with the following therapies: 
• 
Anticancer therapy within 30 days or 5 half-lives of the drug, whichever is 
shorter. At least 14 days must have elapsed between the last dose of prior 
anticancer agent and the first dose of study drug is administered. 


 
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• Part 2B (GSK3359609 (feladilimab)/pembrolizumab combination): prior 
pembrolizumab washout is not required 
• 
Prior radiation therapy:  permissible if at least one 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 two weeks before start of study drug for radiation of any 
intended use to the extremities for bone metastases and 4 weeks for radiation to 
the chest, brain, or visceral organs is required. 
• 
Radiation therapy to the lung that is >30 Gy requires a greater than 6 month 
washout from first dose of study treatment. 
• 
Investigational therapy within 30 days or 5 half-lives of the investigational 
product (whichever is shorter). At least 14 days must have elapsed between the 
last dose of investigational agent and the first dose of study drug is administered. 
2. Prior allogeneic tissue or other solid organ transplantation. 
3. Toxicity from previous anticancer treatment that includes: 
• 
≥Grade 3 toxicity considered related to prior immunotherapy and that led to 
treatment discontinuation. 
• 
Toxicity related to prior treatment that has not resolved to Grade 1 (except 
alopecia, endocrinopathy managed with replacement therapy, and peripheral 
neuropathy which must be Grade 2). 
4. Invasive malignancy or history of invasive malignancy other than disease under 
study within the last two years, except as noted below: 
• 
Any other invasive malignancy for which the participant was definitively 
treated, has been disease-free for 2 years and in the opinion of the principal 
investigator and GSK Medical Monitor will not affect the evaluation of the 
effects of the study treatment on the currently targeted malignancy, may be 
included in this clinical trial.  
• 
Curatively treated non-melanoma skin cancer  
5. Central nervous system (CNS) metastases, with the following exception: 
• 
Participants who have previously-treated CNS metastases, are asymptomatic, 
and have no requirement for steroids at least 14 days prior to first dose of study 
drug. 
Note: Participants with carcinomatous meningitis or leptomeningeal spread are 
excluded regardless of clinical stability. 
6. Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including granulocyte colony-
stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, 
recombinant erythropoietin) within 14 days prior to the first dose of GSK3359609 
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7. 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. 
8. Active autoimmune disease (refer to Appendix 2) that has required systemic 
treatment within the last two years (i.e., with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). 
a. 
Note: Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment. 
9. Concurrent medical condition requiring the use of systemic immunosuppressive 
medications within 7 days before the first dose of study treatment. Physiologic doses 
of corticosteroids for treatment of endocrinopathies or steroids with minimal 
systemic absorption, including topical, inhaled, or intranasal corticosteroids may be 
continued if the participant is on a stable dose.  
10. Condition requiring treatment with strong inhibitors/inducers of cytochrome p450 
(CYP) 3A4 within 7 days prior to first dose of chemotherapy (Note: requirement 
applies to participants enrolled to Part 2 chemotherapy combination with docetaxel) 
11. Active infection requiring systemic therapy, known human immunodeficiency virus 
infection, or positive test for hepatitis B active infection or hepatitis C active 
infection (refer to Table 27 for details). 
12. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease 
per investigator assessment). 
NOTE: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, persistent jaundice, or cirrhosis. 
13. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel 
disease, intra-abdominal abscess, or gastrointestinal obstruction that required surgery 
14. Receipt of any live vaccine within 4 weeks prior to first dose of study treatment. 
15. Recent history of allergen desensitization therapy within 4 weeks of starting study 
treatment. 
16. History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies 
under investigation including any ingredient used in the formulation. 
17. History or evidence of cardiac abnormalities including any of the following: 
• 
Recent (within the past 6 months) history of serious uncontrolled cardiac 
arrhythmia or clinically significant electrocardiogram 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. 


 
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• 
Congestive heart failure (Class II, III, or IV) as defined by the New York Heart 
Association functional classification system (Refer to Appendix 5). 
• 
Recent (within the past 6 months) history of symptomatic pericarditis. 
18. History (current and past) of idiopathic pulmonary fibrosis, pneumonitis (for past 
pneumonitis exclusion only if steroids were required for treatment), interstitial lung 
disease, or organizing pneumonia. Note: post-radiation changes in the lung related to 
prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring 
treatment may be permitted if agreed by the investigator and Medical Monitor. 
19. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural 
effusions. 
20. 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. 
21. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception 
to this criterion for a specific participant. 
5.3. 
Screening/Baseline/Run-in Failures 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are never subsequently assigned a randomization number.  To ensure transparent 
reporting of screen failure participants, meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of information on screen failure participants is required 
including Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse 
Events. 
5.4. 
Withdrawal/Stopping Criteria 
Participants will receive study treatment for the scheduled time period, if applicable, 
unless one of the following events occurs earlier: disease progression (as determined by 
irRECIST), death, or unacceptable toxicity, including meeting stopping criteria for liver 
chemistry (refer to Section 5.4.1), or other criteria are met as defined in Section 5.4.2 and 
in Section 7, and all subsections. Participants with infusion delays >21 days due to 
toxicity should consider discontinuing study drug(s) unless the treating investigator and 
Sponsor/Medical Monitor agree there is strong evidence supporting continued treatment. 
Participants enrolled in Part 2 combination with pembrolizumab or GSK3174998 who 
require permanent discontinuation of one of the study agents in a given treatment 
combination due to toxicity must permanently discontinue both agents in that 
combination, unless continued treatment with the remaining agent is agreed upon by the 
treating investigator and Sponsor/Medical Monitor. Participants enrolled in Part 2 
combination with chemotherapy who require permanent discontinuation of chemotherapy 
should continue treatment with GSK3359609 (feladilimab) and/or pembrolizumab unless 
toxicity ensues or otherwise indicated in Section 7 and associated subsections; if 


 
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GSK3359609 (feladilimab) and/or pembrolizumab is required to be permanently 
discontinued, then chemotherapy will be discontinued. 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
a. Deviation(s) from the protocol 
b. Request of the participant or proxy 
c. Discretion of the investigator  
d. Participant is lost to follow-up 
e. Closure or termination of the study  
The primary reason for discontinuation must be recorded in the participant’s medical 
records and electronic case report form (eCRF). 
If the participant voluntarily discontinues from treatment due to toxicity, ‘adverse event’ 
will be recorded as the primary reason for permanent discontinuation on the eCRF. 
Once a participant has permanently discontinued from study treatment, the participant 
will not be allowed to be retreated  
The assessments required at the treatment discontinuation visit (TDV) must be completed 
within 30 days of the decision to permanently discontinue study drug(s) and prior to the 
start of subsequent anti-cancer therapy. 
All participants who discontinue from study treatment (early or permanent) for any 
reason will have safety assessments at the time of discontinuation and during post study 
treatment follow-up as specified in Time and Events Tables (refer to Section 8.1). 
Participants with a CR or PR require confirmation of response via imaging at least 4 
weeks after the first imaging showed a CR or PR.  
Early discontinuation of GSK3359609 (feladilimab) and/or pembrolizumab or 
chemotherapy (early discontinuation of study treatment will not per se constitute 
permanent discontinuation) was considered for participants who have attained a 
confirmed complete response per RECIST 1.1 and who received study treatment for at 
least 24 weeks and had at least two treatments beyond the date when the initial CR was 
declared; these participants will undergo disease assessments at a frequency of 12 weeks 
(refer to Table 27 for details). These participants were permitted to resume study 
treatment upon disease progression; this retreatment was defined as a Second Course. In 
addition, participants with RECISTv1.1 confirmed SD, PR, or CR who complete the 35 
cycles of study treatment and study treatment is discontinued for this reason and not for 
other reasons such as disease progression or intolerability will undergo disease 
assessments at a frequency of 12 weeks (refer to Table 27); these participants were able 
to receive a second course of study treatment upon disease progression. For those 
participants to be eligible for a second course of study treatment, all following 
requirements were met: 


 
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• 
Experienced an investigator-determined radiographic disease progression by 
RECIST 1.1 after discontinuing the initial course of study treatment 
• 
No subsequent/ new anticancer treatment was administered after the last dose of 
study treatment 
• 
Fulfilled all of the safety parameters listed in the inclusion criteria and none of 
the safety parameters listed in the exclusion criteria 
• 
Study 204691 is ongoing 
If study treatment was restarted, participants were required to resume assessments 
outlined in Table 27; in addition, limited PK and immunogenicity sampling is required.  
Participants receiving GSK3359609 (feladilimab) monotherapy administered Q3W 
(Part 1) were allowed to crossover to receive GSK3359609 (feladilimab) in combination 
with pembrolizumab Q3W provided the participant has documented objective 
progression (i.e., radiologic and not clinical deterioration only) and has not experienced 
any drug-related AEs Grade 3 or SAEs of any Grade; additionally, the GSK medical 
monitor must be consulted and approve the decision before crossover is permitted. 
All participants who permanently discontinue study treatment for any reason will be 
followed for survival a every 12 weeks until death or until the last participant 
discontinues treatment and has had their last follow up for safety. If participants are 
unable or unwilling to attend clinic visits during follow-up, contact to assess survival may 
be made via another form of communication (e.g., telephone, email, etc.). 
All participants who permanently discontinue study treatment for reasons other than 
disease progression or consent withdrawal will be followed for progression or until the 
start of anti-cancer therapy whichever comes first. Refer to Table 27 for the frequency of 
assessments.  
5.4.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration (FDA) premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
If any of the following criteria are met, all study drugs must be discontinued and 
hepatotoxicity events must be reported to GSK within 24 hours. Complete liver event 
eCRF forms and SAE forms if the event also meets the criteria for SAE reporting. The 
eCRF liver event form does not appear automatically, but must be manually activated. 
If treatment is held or discontinued do not restart/rechallenge the participant with study 
treatment unless all the requirements described in this section have been met, including 
clearance from the sponsor. Liver chemistry stopping criteria are provided below. 
: 


 
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Liver Chemistry Stopping Criteria –Liver Stopping Event for the participants with ALT  
2.5 ULN at the baseline value 
ALT-Increase 
ALT  5xULN 
ALT Increase 
ALT  3xULN but <5xULN persists for 4 weeks 
Bilirubina, b 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INRb  
ALT  3xULN and INR>1.5 
Cannot Monitor 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomaticc 
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Abbreviations: ALT= alanine aminotransferase; INR=international normalized ratio; ULN=upper limit of normal 
a. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment if ALT 3xULN and bilirubin  2xULN. Additionally, if serum 
bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury.  
b. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, 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. 
c. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia). 
Liver Chemistry Stopping Criteria –Liver Stopping Event for Participants with ALT >2.5 or  5 x ULN at 
Baseline Value 
ALT absolute 
Both ALT  5xULN and 2x baseline value 
ALT Increase 
Both ALT  3xULN and ≥ 1.5x baseline value that persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot Monitor 
Both ALT  3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 weeks 
Symptomatic3 
 
Both ALT  3xULN and ≥ 1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention 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, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR 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). 
 


 
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Refer to Section 7.4 for additional guidance on the management of hepatotoxicity.  
5.4.1.1. 
Study Treatment Restart/Rechallenge 
If participant meets liver chemistry stopping criteria do not restart/rechallenge 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 4 for full guidance. 
5.4.2. 
Stopping Rules for Clinical Deterioration 
As indicated in Section 4.4, to adequately assess the antitumor effect of 
immunotherapeutic agents it is reasonable to allow participants experiencing apparent 
progression as defined by RECIST 1.1 guidelines to continue to receive treatment until 
progression is confirmed at the next imaging assessment at least 4 weeks later as 
indicated by irRECIST guidelines. Nevertheless, these considerations should be balanced 
by clinical judgment as to whether the participant is clinically deteriorating and unlikely 
to receive any benefit from continued study treatment. 
In cases where deterioration was assessed to have occurred after a clinical event that, in 
the investigator’s opinion, is attributable to disease progression and 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. In these cases, the decision to 
continue treatment must 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 worsening of at least 2 points from baseline 
• 
Skeletal related events defined by the following: 
• 
pathologic bone fracture in the region of cancer involvement 
• 
cancer related surgery to bone, and/or 
• 
spinal cord or nerve root compression 
• 
Development of new CNS metastases 
• 
Any setting where the initiation of new antineoplastic therapy has been deemed 
beneficial to the participant even in the absence of any such documented clinical 
event. 


 
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5.5. 
Participant and Study Completion 
For Part 1A and Part 2A combinations with pembrolizumab or GSK3174998 the dose 
escalation phases of the study, participants will be considered as completing the study if 
they complete screening assessments, receive at least two doses of study treatment or 
receive one dose but experience a DLT, are observed during the 28 day DLT observation 
period, and complete the treatment discontinuation visit and the follow-up visit for safety 
or have died while receiving study treatment or during post-study treatment follow-up 
period for safety. 
For Part 2A combinations with chemotherapy ( pembrolizumab), participants will be 
considered as completing the study if they complete the screening assessments, receive at 
least two doses of study treatment or receive one dose but experience a DLT that leads to 
study treatment discontinuation, are observed during the 28 day DLT observation period, 
and complete the treatment discontinuation visit and the safety follow-up visit or have 
died while receiving study treatment or during the post-study treatment safety follow-up 
period.  
For Part 1B and 2B, the expansion phases of the study, participants will be considered as 
completing the study if they complete screening assessments, receive at least one dose of 
study treatment, discontinue study treatment for reasons other than lost to follow-up or 
non-compliance, and complete the study treatment discontinuation visit and safety 
follow-up visits or have died while receiving study treatment or during post-treatment 
follow-up period. 
In the event the Sponsor decides to close the study, participants receiving ongoing study 
treatment will be considered as completing the study. 
The end of the study is defined as the completion of the last participant’s required visits 
post study treatment discontinuation. 
6. 
STUDY TREATMENT 
6.1. 
Investigational Product and Other Study Treatment 
The term ‘study treatment’ is used throughout the protocol to describe GSK3359609 
(feladilimab) administered as a monotherapy or as combination therapy to participants as 
per the protocol design. Study treatment may therefore refer to the individual study 
treatments or the combination of those study treatments. 
GSK3359609 (feladilimab) will be administered intravenously to participants at each 
study site under medical supervision of an investigator or designee. When administered 
in combination in Part 2 of the study, GSK3359609 (feladilimab) will be administered 
first. The date and time of administration will be documented in the source documents 
and reported in the eCRF. 
In Part 2, pembrolizumab and GSK3174998 (refer to Table 11) will be administered 
intravenously to participants starting at least 30 minutes and no more than one hour 
following the end of the GSK3359609 (feladilimab) infusion under medical supervision 


 
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of an investigator or designee. The date and time of administration will be documented in 
the source documents and reported in the eCRF. 
In Part 2 combinations with chemotherapy (refer to Figure 1), chemotherapy regimens 
will be administered to participants starting at least 30 minutes and no more than one 
hour following the end of the GSK3359609 (feladilimab) infusion. For the combinations 
of GSK3359609 (feladilimab) with chemotherapy and pembrolizumab, pembrolizumab 
will be administered intravenously to participants starting at least 30 minutes and no 
more than one hour following the end of the GSK3359609 (feladilimab) infusion then 
chemotherapy will be administered at least 30 minutes to one hour following the end of 
the pembrolizumab infusion under medical supervision of an investigator or designee. 
The sequence in which chemotherapy doublets are administered is per standard practice. 
The date and time of administration will be documented in the source documents and 
reported in the eCRF. Participants should receive the indicated premedication regimens 
and supplementation according to the approved product label or standard practice (i.e., 
corticosteroids, folic acid, vitamin B12, and diphenhydramine). Chemotherapy 
premedication indicated on the day of dosing should be administered after GSK3359609 
(feladilimab) EOI. 
All participants are required to remain under observation at the study site for at least 1.5 
hours post-infusion of the last study drug administered for the first two study treatment 
dosing visits. At subsequent study treatment dosing visits, for participants who 
experience infusion-related reactions, the post-infusion observation time should remain as 
at least 1.5 hours; for participants who do not experience infusion reactions, these 
participants should remain under observation at the study site post-study treatment 
infusion for at least 30 minutes or as per the judgement of the investigator or as per 
institutional guidelines. Refer to Section 7.12.3 for details on the management of 
participants experiencing infusion reactions. 
For drug administered by an investigator or designee, the dose of study treatment and 
study participant identification will be confirmed at the time of dosing by a member of 
the study site staff other than the person administering the study treatment. The specific 
time of study treatment administration (e.g., time of the week for first administration; 
time of the day for each administration) should take into consideration PK sampling time 
points, study visit procedures, and the post-infusion observation time interval. Infusions 
may be administered up to 72 hours before or after the planned date of treatment for 
administrative reasons only (e.g., scheduling an infusion around a holiday). 
The study reference manual (SRM) contains details on product administration and 
specific instructions for the calculation of GSK3359609 (feladilimab) dose, and for the 
preparation of GSK3359609 (feladilimab) and pembrolizumab and administration of 
these infusions. 
The details on the chemotherapy product characteristics and instructions for preparation 
and administration are according to the individual package inserts.  
Refer to Section 4.2 for information on the duration of study treatment. 


 
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Table 11 
GSK3359609 (feladilimab) and Combination Study Products 
Description and Administration 
 
Study Treatment 
Product Name: 
GSK3359609 
(feladilimab) 
Pembrolizumab 
GSK3174998 
Product 
Description 
Humanized anti-
ICOS IgG4 mAb 
Humanized anti-PD-1 
IgG4 mAb 
Humanized anti-OX40 
IgG1 mAb 
Dosage form 
/strength: 
10 mg/mL solution 
100 mg/4 mL 
solution/25 mg/mL 
Lyophilized powder for 
reconstitution 
Planned 
dosage level(s): 
Refer to Table 1 
(0.001 to 3 mg/kg)  
200 mg 
8 mg, 24 mg, 80 mg 
Route of 
Administration  
IV infusion 
IV infusion 
IV Infusion 
Dosing 
instructions/ 
Frequency: 
 
Administer diluted 
product /once 
Q3W or Q6W 
(refer to SRM for 
infusion time) 
Administer diluted 
product /once Q3W or 
Q6W (refer to SRM for 
infusion time) 
Administer diluted 
product/once Q3W 
(refer to SRM for 
infusion time) 
Part of Study 
1 and 2 
2 
2 
Manufacturer 
GSK 
Merck 
GSK 
 


 
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Table 12 
Chemotherapy Description and Administration 
Chemotherapy1 
Name 
Docetaxe
l 
Carboplati
n 
Pemetrexe
d 
Paclitaxel 
Gemcitabi
ne 
Cisplatin 
5-FU 
Description 
Microtub
ule 
stabilizer/ 
small 
molecule 
DNA 
cross-
linker/smal
l molecule 
Folate 
analog/ 
small 
molecule  
Microtubul
e 
stabilizer/ 
small 
molecule 
Nucleosid
e analog/ 
small 
molecule  
DNA 
cross-
linker/smal
l molecule 
Nucleosi
de 
analog/ 
small 
molecule 
Dosage 
form/streng
th 
Refer to 
package 
insert 
Refer to 
package 
insert 
Refer to 
package 
insert 
Refer to 
package 
insert 
Refer to 
package 
insert 
Refer to 
package 
insert 
Refer to 
package 
insert 
Dosage 
75mg/m2 
AUC 4-6 
mg/ml per 
min 
500 mg/m2 
200 mg/m2 
1250 
mg/m2 
100 mg/m2 
1000 
mg/m2/d
ay 
Route of 
administrati
on 
IV 
infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV 
infusion 
Dosing 
instructions
/ frequency 
Administ
er diluted 
product/ 
once 
Q3W 
Administer 
diluted 
product/on
ce Q3W 
Administer 
diluted 
product/on
ce Q3W 
Administer 
diluted 
product/on
ce Q3W 
Administer 
diluted 
product on 
Day 1 and 
Day 8 of 
every 21-
day cycle 
(Q3W) 
Administer 
diluted 
product/on
ce Q3W 
Administ
er diluted 
product 
continuo
us on 
Day 1 
through 
Day 4 of 
every 21-
day cycle 
(Q3W) 
Abbreviations: AUC=area under the curve; FU= Fluorouracil; IV=intravenous; Q3W= every three weeks 
1. 
Chemotherapies will be sourced locally from commercial stock, except in countries where Regulatory Authorities 
mandate that the sponsor supply all study treatment(s) required for the conduct of a clinical trial. 
6.2. 
Treatment Assignment 
Participants enrolled in Part 1 of the study will be assigned to receive GSK3359609 
(feladilimab) monotherapy in an open-label fashion; in the Part 1B melanoma cohort, 
participants will be randomly assigned to a GSK3359609 (feladilimab) dose level of 0.3 
mg/kg or 1.0 mg/kg in a 1:1 allocation ratio. Participants enrolled in Part 2 of the study 
will be assigned to a combination treatment in an open-label fashion and according to the 
combination treatment cohorts open for accrual. In the Part 2B melanoma cohort, 
participants will be randomly assigned to a GSK3359609 (feladilimab) dose level of 0.3 
mg/kg or 1.0 mg/kg in combination with 200 mg of pembrolizumab in a 1:1 allocation 
ratio. In the Part 2B HNSCC randomization cohort, participants will be randomly 
assigned to a GSK3359609 (feladilimab) dose level of 0.1 mg/kg or 1 mg/kg or 3.0 
mg/kg in combination with 200 mg of pembrolizumab in a 1:1:1 ratio (refer to Table 6). 
Other expansion cohorts may investigate more than one dose level of GSK3359609 
(feladilimab); if implemented, participants in this cohort will be randomly assigned to the 
selected dose levels.  


 
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6.3. 
Blinding 
This is an open-label study. 
6.4. 
Packaging and Labeling 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
6.5. 
Preparation/Handling/Storage/Accountability 
6.5.1. 
Preparation 
Refer to the SRM for instructions on the preparation of GSK3359609 (feladilimab), 
pembrolizumab, and GSK3174998. Refer to chemotherapy package inserts for 
preparation instructions. 
6.5.2. 
Handling 
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. 
Material Safety Data Sheets (MSDS)/equivalent documents describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK. 
6.5.3. 
Storage 
All study treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the investigator and authorized site staff. 
Refer to the SRM for storage condition specifications and temperature monitoring 
requirements. 
6.5.4. 
Accountability 
• 
Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.   
• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).   
• 
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 


 
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6.6. 
Compliance with Study Treatment Administration 
All study treatments will be intravenously administered to participants at the site. 
Administration will be documented in the source documents and reported in the eCRF. 
6.7. 
Treatment of Study Treatment Overdose 
6.7.1. 
GSK3359609 (feladilimab) (ICOS) or GSK3174998 (OX40) 
Overdose 
An overdose is defined as administration of a dose that is at least 50% greater than the 
intended dose. In the event of an overdose the investigator must: 
1. Contact the Medical Monitor immediately 
2. Closely monitor the participant for adverse events (AEs)/serious adverse events 
(SAEs) 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. 
An overdose event that is not associated with clinical symptoms or abnormal laboratory 
results is defined as an event of clinical interest (ECI); refer to Appendix 8 for details on 
the expedited reporting requirements for ECI. 
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. 
There is no specific antidote for overdose with GSK3359609 (feladilimab). In the event 
of a suspected overdose, it is recommended that the appropriate supportive clinical care 
be instituted as dictated by the participant’s clinical status. 
6.7.2. 
Pembrolizumab Overdose 
An overdose of pembrolizumab will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the participant must be observed closely for 
signs of toxicity. Contact the Medical Monitor immediately and closely monitor the 
participant for AEs/SAEs and laboratory abnormalities. Appropriate supportive treatment 
should be provided if clinically indicated. An overdose event that is not associated with 
clinical symptoms or abnormal laboratory results is defined as an ECI; refer to Appendix 
8 for details on the expedited reporting requirements for ECI. 


 
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6.7.3. 
Chemotherapy Overdose 
Refer to the instructions in the approved product labels in the event of an overdose of 
docetaxel; carboplatin; pemetrexed; paclitaxel, gemcitabine, cisplatin, or 5-FU. Contact 
the Medical Monitor immediately and closely monitor the participant for AEs/SAEs.  
6.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after permanent 
discontinuation of study treatment. The investigator is responsible for ensuring that 
consideration has been given to the post-study care of the participant’s medical condition. 
Refer to Section 5.4 and Section 8.1 for details on the follow-up assessments required for 
participants who have permanently discontinued study treatment. 
6.9. 
Concomitant Medications and Non-Drug Therapies 
Participants will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until discontinuation of study 
treatment. Any permitted concomitant medication(s), including non-prescription 
medication(s) and herbal product(s), taken during the study will be recorded in the eCRF. 
The minimum requirement for reporting is drug name, dose, dates of administration, and 
the reason for medication. 
Questions regarding concomitant medications must be directed to the GSK for 
clarification. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. Refer to the drug 
interaction information in the chemotherapy product package inserts for precautions and 
prohibited concomitant medications. 
6.9.1. 
Permitted Medications and Non-Drug Therapies 
Participants enrolled in chemotherapy-containing cohorts (Part 2A) should receive 
premedication/supplementation regimens according to the approved product label or 
standard practice. All participants should receive full supportive care during the treatment 
course of the study, including transfusion of blood and blood products, and treatment 
with antibiotics, antiemetics, antidiarrheals, and analgesics, as appropriate. Seasonal flu 
vaccine is permitted as an injection only, that is, intra-nasal flu vaccine is not permitted. 
Elective palliative surgery or radiation may be permitted on a case-by-case basis in 
consultation with GSK Medical Monitor. 
The following medications are permitted as indicated: 
a. Bisphosphonates and receptor activator of nuclear factor-kappaB ligand 
(RANKL) inhibitors (e.g., denosumab): participants are required to have been 
on a stable dose for at least 4 weeks prior to receiving first dose of 
GSK3359609 (feladilimab). Prophylactic use in participants without evidence 


 
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or history of bone metastasis is not permitted, except for the treatment of 
osteoporosis. 
b. Growth factors: initiation of growth factors is not permitted during the first 4 
weeks of study treatment, unless clinically indicated for toxicity management 
and agreed upon by the investigator and the GSK Medical Monitor. 
c. Steroids: refer to Section 7 and the associated sub-sections for acceptable use 
while participant in on study treatment. Participants with pre-existing 
conditions requiring steroids are permitted to continue taking up to a 
maximum of 10 mg of prednisone or equivalent provided the participant has 
been on a stable dose for at least 28 days before first dose of GSK3359609 
(feladilimab); refer to exclusion criterion 9 in Section 5.2 for further 
requirements. Steroids used for chemotherapy premedication are permitted. 
6.9.2. 
Prohibited Medications and Non-Drug Therapies 
The following medications are prohibited before the first dose of study treatment (refer to 
Section 5.2 for specific time requirements) and while on treatment in this study: 
a. Anticancer therapies other than those referred to as Study Treatment that include 
but are not limited to chemotherapy, immunotherapy, biologic therapy, hormonal 
therapy (other than physiologic replacement), surgery, and radiation therapy 
(other than palliative intervention as described in Section 6.9.1) 
b. Any investigational drug (s) other than those referred to as Study Treatment 
c. Live vaccines such as intra-nasal flu vaccine 
d. Strong CYP3A4 inhibitors and inducers in participants enrolled in the docetaxel-
containing cohorts (use as premedication is permitted)  
7. 
DOSE AND SAFETY MANAGEMENT GUIDELINES 
Distinct safety management guidelines, including dose modification algorithms, are 
provided in this section for participants treated with: 
• 
GSK3359609 (feladilimab) 
• 
Pembrolizumab 
• 
GSK3174998 
• 
Chemotherapies 
Please note: In instances where the investigator is directed to permanently discontinue 
study treatment, the instructions are mandatory as described in Section 5.4. 
An overview of general dose modification guidelines for GSK3359609 (feladilimab) and 
pembrolizumab is presented in Table 13.  
All AEs are to be graded according to NCI-CTCAE (version 4.0) [NCI, 2010]. All dose 
modifications and the reason(s) for the dose modification must be documented in the 
eCRF. 


 
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Table 13 
General Dose Modification and Management Guidelines for Drug-
related or Immune-Related Non-Hematologic Adverse Events Not 
Otherwise Specified 
Severity 
Management 
Follow-up 
Grade 1 
• 
Continue study drug(s)a 
• 
Administer 
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 
• 
Continue study drug(s)a 
• 
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 holding study drug(s)a 
• 
Consider starting moderate dose systemic 
corticosteroids (e.g., 0.5 mg/kg/day of 
prednisone or equivalent) if considered 
GSK3359609 (feladilimab), pembrolizumab 
and/or GSK3174998- related 
o Continue steroids until improvement to 
Grade 1 or resolution; taper steroids as 
medically appropriate 
• 
Resume study drug(s) at the same dose if 
symptoms have improved to Grade 1 and if 
applicable steroid dose is 10 mg prednisone/day 
or less 
• 
If symptoms continue or worsen to Grade 3 to 
Grade 4, see below 
Grade 3/Grade 4 • 
Hold study drug(s)a 
• 
Note: events that 
require 
discontinuation of 
study drug(s)a include 
Guillain-Barre 
Syndrome, 
encephalitis 
• 
Consult subspecialist 
• 
Administer 1-
2 mg/kg/day IV 
methylprednisolone if 
considered 
GSK3359609 
(feladilimab) 
pembrolizumab and/or 
GSK3174998 related 
• 
Discuss with 
Sponsor/Medical 
Monitor 
Symptoms improve to  Grade 2: 
• 
Continue steroids until improvement to ≤Grade 
1 or baseline; taper steroids over at least 1 
month, then if symptoms have improved to 
Grade 1 within 12 weeks of last dose and 
steroid dose is 10 mg prednisone or equivalent 
per day within 12 weeks, consider resuming 
study drug(s)  
Symptoms ongoing: 
• 
Discuss further management with consultant 
and Sponsor/Medical Monitor 
• 
Consider alternative immunosuppressive 
therapy 


 
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Severity 
Management 
Follow-up 
Grade 4 or 
recurrent 
Grade 3 
• 
Permanently 
discontinue study 
drug(s)a 
• 
Consult subspecialists 
• 
•Administer 1-2 
mg/kg/day IV 
methylprednisolone 
• 
Discuss with 
Sponsor/Medical 
Monitor 
 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy) guidance applies to all study drugs; discuss 
management on a case-by-case basis with the Sponsor/Medical Monitor. Refer to Section 7.18 for 
guidance on chemotherapy dose modifications. In cases where treatment with study drug(s) was held for 
Grade 2 AEs, permanently discontinue study drug(s) if Grade 2 AE does not resolve to Grade 1 within 
12 weeks of the last dose.  
7.1. 
General Guidelines for Immune-Related Adverse Events 
An irAE is defined as a clinically significant AE of any organ that is associated with 
study treatment exposure to GSK3359609 (feladilimab) or pembrolizumab is of unknown 
etiology and is consistent with an immune-related mechanism. 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 
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 holding 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. 
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 Time and 
Events Table (Section 8.1, Table 27) to monitor for new or worsening irAEs and ensure 
continued dosing is appropriate. 
AESI are defined as events of potential immunologic etiology. Such events recently 
reported after treatment with other immune modulatory therapy include colitis, uveitis, 
hepatitis, pneumonitis, diarrhea, endocrine disorders, and specific cutaneous toxicities, as 
well as other events that may be immune mediated. 
7.3. 
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.  
Investigators must contact the GSK Medical Monitor for all Grade 3 or greater clinically 
significant non-hematological drug-related toxicities where permanent discontinuation of 
study treatment may be warranted according to the guidelines provided in Section 7. 
Otherwise, investigators are encouraged to contact the GSK Medical Monitor as needed 
to discuss any case that warrants separate discussion outside of the scope of current 
guidelines. 
In the event the toxicity does not resolve to Grade 1 or baseline within 12 weeks after 
the last infusion, 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 GSK Medical 
Monitor and investigator must 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. 
7.4. 
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, aspartate aminotransferase (AST) or alanine 


 
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aminotransferase (ALT) >3 x upper limit of normal (ULN) and concomitant bilirubin 
≥2.0 x ULN (>35% direct bilirubin), in the absence of elevated alkaline phosphatase or 
biliary injury, suggests significant liver injury and which constitutes an ECI (refer to 
Appendix 8). 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 Table 14. 
Hepatotoxicity events must be reported to GSK within 24 hours. Complete liver event 
eCRF forms and SAE forms if the event also meets the criteria for SAE reporting. The 
eCRF liver event form does not appear automatically, but must be manually activated. 
If treatment is held or discontinued do not restart/rechallenge the participant with study 
treatment unless all the requirements described in Section 5.4.1.1 have been met, 
including clearance from the sponsor. Liver chemistry stopping criteria are provided in 
Section 5.4.1. 
Table 14 
Guidelines for Dose Modification and Management of Drug-related 
Hepatotoxicity 
Severity 
Management 
Follow-up 
Grade1 
ALT > ULN to 3x ULN 
OR 
Total bilirubin  
> ULN to 1.5x ULN 
MONITOR 
• Assess liver function at 
least weekly 
Monitor the participant at least weekly until liver 
chemistries resolve, stabilize, or return to within 
baseline 
Hepatotoxicity improves to ≤ Grade 1 or 
baseline or remains stable:  
• Provide close follow-up to evaluate for 
increased severity. 
Hepatotoxicity worsens to ≥ Grade 2: 
• See below 
Grade 2 
 
ALT >3-5x ULN  
OR 
Total bilirubin >1.5-
3xULN 
• Hold study drug(s)a  
• Assess for infection and 
liver metastases 
• Repeat liver chemistries 
(include ALT, AST, 
alkaline phosphatase, 
bilirubin) and perform 
liver event follow-up 
assessments within 24-
72 hours (see below) 
• Assess liver function at 
least twice weekly 
• Discuss with 
Sponsor/Medical 
Monitor  
• Consider consultation 
with a hepatologist 
Monitor the participant at least twice weekly until 
liver chemistries resolve, stabilize, or return to 
within baseline 
Hepatotoxicity improves to ≤ Grade 1 or 
baseline within 7 days:  
• Resume study drug(s) (note: requirements 
specified in Section 5.4.1.1 must be met before 
treatment can restart) 
• Provide close follow-up to evaluate for 
recurrence 
Hepatotoxicity ongoing > 7 days: 
• Start systemic steroids (e.g., 0.5 mg/kg/day 
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Severity 
Management 
Follow-up 
GSK3359609 (feladilimab) and/or 
pembrolizumab related 
• Continue steroids until improvement to 
≤ Grade 1; taper steroids over at least one 
month 
• Resume study drug(s) if hepatotoxicity resolves 
to ≤ Grade 1, and if applicable, steroid dose is 
10 mg prednisone or equivalent per day within 
12 weeks of last dose. (note: requirements 
specified in Section 5.4.1.1 must be met before 
treatment can restart) 
• Provide close follow-up to evaluate for 
recurrence 
Discontinue study treatment if: 
• Hepatotoxicity continues or worsens to ALT >5x 
ULN or total bilirubin to >3x ULN (follow 
instructions below) 
• ALT  3xULN but <5xULN persists for 4 
weeks 
• ALT  3xULN but <5xULN and cannot be 
monitored weekly for 4 weeks 
• Unable to reduce steroid dose to 10 mg 
prednisone or equivalent per day within 12 
weeks, if applicable 
Recurrence after rechallenge: 
• Discontinue study drug(s) permanently 
• Monitor participant closely for clinical signs and 
symptoms 
• Perform full panel LFTs a weekly or more 
frequently if clinically indicated until ALT 
decreases to  Grade 1 
• At the time of the recurrence, complete the 
eCRF liver event forms. 


 
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Severity 
Management 
Follow-up 
Grade 3 
ALT >5 x ULN-20 x 
ULN 
OR 
Total bilirubin >3x 
ULN-10 x ULN 
• Immediately discontinue 
study drug(s)a 
• Assess for infection and 
liver metastases 
• Repeat liver chemistries 
(include ALT, AST, 
alkaline phosphatase, 
bilirubin) and perform 
liver event follow-up 
assessment within 24 
hours (see below) 
• Assess liver function at 
least twice weekly 
• Consider administration 
of 1-2 mg/kg/day IV 
methylprednisolone, if 
considered 
GSK3359609 
(feladilimab) and/or 
pembrolizumab related 
• Discuss with 
Sponsor/Medical 
Monitor within 24 hours 
• Consider consultation 
with a hepatologist 
Monitor the participant at least twice weekly until 
liver chemistries resolve, stabilize, or return to 
within baseline 
 
• If ALT or bilirubin have not decreased within 72 
hours in the absence of other etiologies, and if 
applicable, steroid treatment has not been 
administered, initiate treatment with 1-
2 mg/kg/day IV methylprednisolone: 
• Continue steroids until improvement to 
≤ Grade 1 or baseline or resolution; taper 
steroids over at least one month 
• If serum transaminase levels do not 
decrease 48 hours after initiation of 
systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be 
given. Infliximab is not recommended due to 
its potential for hepatotoxicity. 
 


 
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Severity 
Management 
Follow-up 
Grade 4 
ALT >20 x ULN 
OR 
Total bilirubin >10x 
ULN 
Additional Stopping 
Criteria: ALT 3x 
ULN AND Total 
bilirubin 2x ULN 
(>35% direct bilirubin)b 
ALT3xULN and 
INR>1.5, if INR 
measuredc 
ALT  3xULN 
associated with 
symptoms (new or 
worsening) believed to 
be related to liver 
injury or 
hypersensitivityd 
• Immediately discontinue 
study drug(s)a 
• Assess for infection and 
liver metastases 
• Repeat liver chemistries 
(include ALT, AST, 
alkaline phosphatase, 
bilirubin) and perform 
liver event follow-up 
assessment within 24 
hours (see below) 
• Assess liver function at 
least twice weekly 
• Administer 1-
2 mg/kg/day IV 
methylprednisolone, if 
considered 
GSK3359609 
(feladilimab) 
pembrolizumab and/or 
GSK3174997 related 
• Discuss with 
Sponsor/Medical 
Monitor within 24 hours 
• Consider consultation 
with a hepatologist 
Monitor the participant at least twice weekly until 
liver chemistries resolve, stabilize, or return to 
within baseline 
 
• Continue steroids, if applicable, until 
improvement to ≤ Grade 1 or baseline or 
resolution; taper steroids over at least one 
month 
• If serum transaminase levels do not 
decrease 48 hours after initiation of 
systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be 
given. Infliximab is not recommended due to 
its potential for hepatotoxicity. 
 
Abbreviations: ALT = Alanine aminotransferase; ULN = Upper limit of normal; AST = Aspartate aminotransferase; IV = 
Intravenous LFT = liver function tests; INR = International Normalized Ratio 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with pembrolizumab, 
GSK3174998, or chemotherapy), guidance applies to all study drugs; discuss management on a case-by-case 
basis with the Sponsor/Medical Monitor. Refer to Section 7.18 for guidance on chemotherapy dose modifications.  
b. 
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.  
c. 
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. 
d. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia 
Liver Event Follow-up Assessments 
• 
Viral hepatitis serology: Hepatitis A IgM antibody; Hepatitis B surface antigen 
and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM 
antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
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• 
Blood sample for PK analysis, obtained within 28 days after last dose of study 
drug: Record the date/time of the PK blood sample draw and the date/time of the 
last dose of study treatment prior to blood sample draw on the eCRF. If the date or 
time of the last dose is unclear, provide the participant’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample 
• 
Serum creatine phosphokinase and lactate dehydrogenase  
• 
Fractionate bilirubin, if total bilirubin 2 x ULN 
• 
Obtain complete blood count with differential to assess eosinophilia 
• 
Record the appearance or worsening of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• 
Record use of concomitant medications on the concomitant medications report 
form including acetaminophen, herbal remedies, other over the counter 
medications 
• 
Record alcohol use on the liver event alcohol intake case report form 
• 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total IgG (or gamma globulins). 
• Serum acetaminophen adduct high-performance liquid chromatography assay 
(quantifies potential acetaminophen contribution to liver injury in participants 
with definite or likely acetaminophen use in the preceding week [James, 
2009]). 
• 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver disease; complete Liver Imaging and/or Liver 
Biopsy eCRF forms. 
7.5. 
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 15. 


 
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Table 15 
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 
• 
Hold study drug(s)a 
• 
Administer antidiarrheal 
and symptomatic 
treatment 
• 
Discuss with 
Sponsor/Medical Monitor 
Symptoms resolve to ≤ Grade 1 or baseline within 3 
days:  
• 
Resume study drug(s) 
Symptoms ongoing >3 days, blood or mucus in stool, 
or ulceration/bleeding on endoscopy: 
• 
Consider GI consultation and endoscopy to confirm 
or rule out colitis  
• 
Start systemic corticosteroids (initial dose of 1-2 
mg/kg prednisone or equivalent) 
• 
Continue steroids until improvement to Grade 1 
or resolution; taper steroids as medically 
appropriate 
• 
Resume study drug(s) if toxicity has resolved to 
Grade 1 and, if applicable, 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 drug(s) must be permanently 
discontinued. 
• 
If symptoms continue or worsen to Grade 3-4, see 
below 
Grade 3 
• 
Hold study drug(s)a 
• 
Assess for bowel 
perforation; do not 
administer corticosteroids 
if present 
• 
Consult gastrointestinal 
(GI) service, perform 
endoscopy with biopsy 
• 
Administer 1-2 mg/kg/day 
IV methylprednisolone, if 
considered GSK3359609 
(feladilimab) 
pembrolizumab and/or 
GSK3174998 related 
• 
Discuss with 
Sponsor/Medical Monitor 
• 
Resume study drug(s) if toxicity resolved to Grade 
1 
If steroids are indicated: 
• 
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, re-taper 
starting at a higher dose followed by a more 
prolonged taper. 
• 
Resume study drug(s) if toxicity 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 
drug(s) must be permanently discontinued. 
 


 
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Severity 
Management 
Follow-up 
Recurrent 
Grade 3/ 
Grade 4 
• 
Permanently discontinue 
study drug(s) 
• 
Immediately inform 
Sponsor/Medical Monitor 
• 
Management as per Grade 3 
Abbreviations: GI=gastrointestinal; IV=intravenous 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to both study drugs; discuss management 
on a case-by-case basis with the Sponsor/Medical Monitor.  Refer to Section 7.18 for guidance on 
chemotherapy dose modifications. 
7.6. 
Management of Renal Toxicity 
Differential diagnosis: all attempts should be made to rule out other causes such as 
metastatic disease or infection. Dose modification guidelines for renal toxicity are 
provided in Table 16. 


 
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Table 16 
Guidelines for Dose Modification and Management of Renal Events 
Severity 
Management 
Follow-up 
Grade 1 
• 
Administer 
symptomatic treatment 
as appropriate 
• 
Continue study 
drug(s)a 
Symptoms resolve to baseline within 7 days: 
• 
Provide close follow-up to evaluate for 
increased severity 
Symptoms ongoing >7 days: 
• 
Consider following algorithm for Grade 2 events 
Grade 2 
• 
Hold study drug(s)a 
• 
Investigate etiology 
• 
Consider consulting 
nephrologist, biopsy, 
and/or diagnostic 
procedure 
• 
Discuss with 
Sponsor/Medical 
Monitor 
• 
Monitor changes of 
renal function 
• 
Resume study drug(s) if toxicity resolved to 
Grade 1 
• 
If symptoms continue or worsen to Grade 3 or 
Grade 4, refer to Grade 3/Grade4 guidance 
If steroids are indicated: 
• 
Start systemic steroids (e.g. 0.5 mg/kg/day of 
prednisone or equivalent) 
• 
Continue steroids until toxicity resolves to Grade 
1; taper steroids as medically appropriate 
• 
Resume study drug(s) if toxicity has resolved to 
Grade 1 within 12 weeks of last dose and 
steroid dose is 10 mg prednisone or equivalent 
per day within 12 weeks  
Grade 3/Grade 4 
• 
Permanently 
discontinue study 
drug(s)a 
• 
Consult subspecialist 
• 
Administer 1-
2 mg/kg/day IV 
methylprednisolone, if 
considered 
GSK3359609 
(feladilimab) 
pembrolizumab and/or 
GSK3174998 related  
• 
Discuss with 
Sponsor/Medical 
Monitor 
• 
Monitor changes of 
renal function 
Symptoms improve to Grade 2:  
• 
If applicable, continue steroids until 
improvement to ≤Grade 1 or baseline; taper 
steroids over at least 1 month, then if symptoms 
have improved to Grade 1 and steroid dose is 
10 mg prednisone/day or less, consider 
resumption of study drug(s) at the next lower 
dose level following consultation with medical 
monitor 
Symptoms ongoing:  
• 
Discuss further management with consultant 
and Sponsor/Medical Monitor 
• 
Consider alternative immunosuppressive 
therapy 
Abbreviations: intravenous 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to all study drugs; discuss management on 
a case-by-case basis with the Sponsor/Medical Monitor. Refer to Section 7.18 for guidance on chemotherapy 
dose modifications. 


 
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7.7. 
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 17.  
Table 17 
Guidelines for Dose Modification and Management of Skin Toxicity 
Severity 
Management 
Follow-up 
Localized rash 
• 
Symptomatic 
management 
Provide close follow-up 
Non-localized rash 
(diffuse, ≤50% of 
skin) 
• 
Hold study drug(s)a 
• 
Discuss with 
Sponsor/Medical 
Monitor 
• 
Consider dermatology 
consultation and 
biopsy 
Symptoms resolve to baseline within 7 days:  
• 
Resume study drug(s) 
Symptoms ongoing > 7 days: 
• 
Start topical or systemic corticosteroids (e.g. 0.5-
1 mg/kg/day of prednisone or equivalent), if 
considered GSK3359609 (feladilimab), 
pembrolizumab, and/or GSK3174998 related 
• 
Continue steroids until improvement to Grade 
1 or resolution; taper steroids as medically 
appropriate 
• 
Resume study drug(s) if symptoms have 
improved to Grade 1 within 12 weeks of last 
dose and, if applicable, steroid dose is 10 mg 
prednisone or equivalent per day within 12 weeks 
• 
If symptoms continue or worsen, see below 
Rash complicated 
by full thickness 
dermal ulceration, 
or necrotic, 
bullous, or 
hemorrhagic 
manifestations 
• 
Permanently 
discontinue study 
drug(s)a 
• 
Administer 1-2 
mg/kg/day IV 
methylprednisolone, if 
considered study 
treatment related 
• 
Discuss with 
Sponsor/Medical 
Monitor 
• 
Consider dermatology 
consultation and 
biopsy 
• 
When dermatitis is controlled, if applicable, 
taper steroids over at least one month period 
Stevens-Johnson 
syndrome (SJS), 
toxic epidermal 
necrolysis (TEN), 
or Drug reaction 
with eosinophilia 
and systemic 
symptoms 
(DRESS) 
• 
Suspected SJS, TEN, 
or DRESS 
o Hold study drugsa 
• 
Confirmed SJS, TEN, 
DRESS 
o Permanently 
discontinue study 
drugsa 
Ensure adequate 
• 
• When event is controlled, taper steroids over 
at least one month period, d, if applicable  


 
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Severity 
Management 
Follow-up 
evaluation to confirm 
etiology or exclude other 
causes 
Based on severity of AE 
administer corticosteroids 
Abbreviations: IV = Intravenous 
a. If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to all study drugs; discuss management on 
a case-by-case basis with the Sponsor/Medical Monitor.  Refer to Section 7.18 for guidance on chemotherapy 
dose modifications. 
7.8. 
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, 
hyperglycemia, hyperthyroidism, hypophysitis, hypopituitarism, hypothyroidism, thyroid 
disorder, and thyroiditis.  
Dose modification guidelines for endocrine events are provided in Table 18.  
Table 18 
Guidelines for Dose Modification and Management of Endocrine 
Events 
Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and/or electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes an adrenal crisis and must be considered a medical emergency. 
Severity/Toxicity 
Management 
Follow-upa 
Grade 2 
 
• 
Signs and/or 
symptoms of 
dysfunction 
• 
Endocrinopathies 
requiring hormone 
replacement or 
medical intervention 
• 
Consider holding study 
drug(s)b 
• 
Grade 2 hypophysitis 
hold study drug(s) 
• 
Assess endocrine function 
• 
Consider pituitary imaging 
• 
Administer up to 1-2 
mg/kg/day IV 
methylprednisolone if 
clinically indicated 
• 
Initiate appropriate 
hormone-replacement 
Consider resuming study drug(s) 
when: 
• 
Participant is stable (on 
hormone-replacement therapy if 
indicated) and symptoms have 
resolved to Grade 1 within 12 
weeks of last dose 
• 
If participant is receiving ≤10 
mg prednisone or equivalent 
per day; reduction of 
corticosteroid must have 
occurred within 12 weeks. 


 
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Severity/Toxicity 
Management 
Follow-upa 
therapy 
(e.g., hypothyroidism) 
• 
Consider consultation with 
endocrinology 
• 
Non-selective beta-
blockers are suggested for 
hyperthyroidism 
• 
Discuss with 
Sponsor/Medical Monitor 
Grade 3/ Grade 4 
 
• 
Adrenal crisis or other 
adverse reactions 
requiring 
hospitalization, urgent 
medical intervention. 
• 
Hyper/Hypothyroidism 
• 
Hypophysitis 
• 
Hold study drug(s)b 
• 
Hypothyroidism: may 
continue study treatmentc 
• 
Permanently discontinue 
study drugs for Grade 4 
hyperthyroidism 
• 
Discuss with 
Sponsor/Medical Monitor 
• 
Consider immediate 
initiation of 1-2 mg/kg/day 
IV methylprednisolone, if 
considered GSK3359609 
(feladilimab), 
pembrolizumab, and/or 
GSK3174998 related 
• 
Consult endocrinology 
• 
Other management as 
above 
Consider resuming study drug(s) 
when: 
• 
Participant is stable (on 
hormone-replacement therapy if 
indicated) and symptoms have 
resolved to Grade 1 within 12 
weeks of last dose of study 
treatment 
• 
If participant is receiving 
≤10 mg prednisone or 
equivalent per day; reduction of 
corticosteroid must have 
occurred within 12 weeks. 


 
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Severity/Toxicity 
Management 
Follow-upa 
• 
New onset Type I 
diabetes mellitus 
including diabetic 
ketoacidosis 
• 
Grade3/Grade 4 
hyperglycemia 
associated with 
evidence of beta cell 
failure 
• 
Hold study drugs(s)a 
• 
Recommend insulin 
replacement therapy for 
Type I diabetes 
mellitus/Grade 3 and 
Grade 4 hyperglycemia 
associated with 
metabolic acidosis or 
ketonuria 
• 
Administer 
antihyperglycemic in 
participants with 
hyperglycemia 
• 
Evaluate serum glucose 
and a metabolic panel, 
urine ketones, 
glycosylated hemoglobin, 
and C-peptide 
Consider resuming study drug(s) 
when: 
• 
Participant is clinically and 
metabolically stable. 
Abbreviations: IV = Intravenous 
a. 
Permanently discontinue study drug(s) if hypophysitis of severity Grade 2 or Grade 3 hyperthyroidism does 
not resolve to Grade 1 or baseline within 12 weeks of last dose or there is an inability to reduce prednisone to 
10 mg or equivalent per day within 12 weeks. 
b. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance may apply to all study drugs discuss management 
on a case-by-case basis with the Sponsor/Medical Monitor.  
c. 
Study treatment may continue while thyroid replacement therapy is instituted. 
7.9. 
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. 
Differential diagnosis: All attempts should be made to rule out other causes such as 
metastatic disease, and bacterial or viral infection. 
NOTE: 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 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 must 
be reported regardless of etiology. Dose modification guidelines for pneumonitis are 
provided in Table 19. 


 
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Table 19 
Guidelines for Dose Modification and Management of Pneumonitis 
Severity 
Management 
Follow-up 
Grade 1 
(asymptomatic with 
radiographic findings 
only) 
• 
Discuss continued treatment 
with study drug(s) with 
Sponsor/Medical Monitor 
• 
Consider pulmonary 
consultation and/or 
bronchoscopy if clinically 
indicated 
• 
Serial imaging 
Grade 2 
• 
Hold study drugs(s)a 
• 
Consider pulmonary 
consultation with 
bronchoscopy and 
bronchoalveolar lavage 
(BAL)  
• 
Administer 1-2 mg/kg per 
day IV methylprednisolone, 
if considered GSK3359609 
(feladilimab), 
pembrolizumab, and/or 
GSK3174998 related  
• 
Discuss with 
Sponsor/Medical Monitor 
If steroids indicated: 
• 
If toxicity resolves to ≤ Grade 1, taper 
steroids over at least 1 month. 
Permanently discontinue study 
drugs(s) if unable to reduce steroid 
dose to ≤10 mg prednisone or 
equivalent per day within 12 weeks.   
• 
Rechallenge with study drug(s) at the 
same dose(s) may be considered if a 
first event resolves to Grade 1 within 
12 weeks of last dose.  
• 
Repeat chest imaging monthly as 
clinically indicated.  
Grade 3 and 4 or 
Recurrent Grade 2 
• 
Permanently discontinue 
study drug(s)a 
• 
Bronchoscopy with biopsy 
and BAL is recommended 
• 
Administer 1-2 mg/kg per 
day IV methylprednisolone, 
if considered GSK3359609 
(feladilimab) pembrolizumab 
and/or GSK3174998 related  
• 
Discuss with 
Sponsor/Medical Monitor 
If steroids indicated: 
• 
When symptoms resolve 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, re-taper starting at a higher dose 
followed by a more prolonged taper. 
• 
Add anti-infective prophylaxis as 
appropriate. 
Abbreviations: IV = Intravenous 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to all study drugs; discuss management on 
a case-by-case basis with the Sponsor/Medical Monitor.  


 
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7.10. 
Management of Hematologic Events 
Dose modification guidelines for hematologic events are provided in Table 20. 
Table 20 
Guidelines for Dose Modification and Management of Hematologic 
Events 
Severity 
Management 
Follow-up 
Grade 1/ 
Grade 2 
• 
As clinically indicated 
• 
Provide close follow-up to evaluate for increased 
severity 
Grade 3 
• 
Consider holding study 
drug(s)a 
• 
Discuss with Medical 
Monitor 
• 
Obtain flow cytometry study 
of T and B lymphocytes 
• 
Consult hematology 
• 
Further management as 
clinically indicated 
• 
As clinically indicated 
• 
Retreatment with study drug(s) may be considered 
on a case-by-case basis if agreed upon by 
investigator and Sponsor/Medical Monitor. 
Grade 4 
• 
Consider discontinuation of 
study drug(s) for any 
severe or life threatening 
event a 
• 
Consult hematology 
• 
Obtain flow cytometry study 
of T and B lymphocytes. 
• 
Discuss with 
Sponsor/Medical Monitor 
• 
As clinically indicated 
• 
Retreatment with study drug(s) may be considered 
on a case-by-case basis if agreed upon by 
investigator and Sponsor/Medical Monitor. 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab or GSK3174998) guidance applies to both study drugs; discuss management on a case-by-
case basis with the Sponsor/Medical Monitor; refer to Section 7.18 for guidance on chemotherapy dose 
modifications for hematologic events. 
7.11. 
Management of 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 must be reported 
regardless of etiology. Dose modification guidelines for uveitis/iritis are provided in 
Table 21. 


 
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Table 21 
Guidelines for Dose Modification and Management of Uveitis/Iritis 
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 
• 
Hold study drug(s)a 
• 
Consultation with 
ophthalmologist is strongly 
recommended 
• 
Treat with topical steroids such 
as 1% prednisolone acetate 
suspension and iridocyclitics, if 
considered GSK3359609 
(feladilimab) pembrolizumab 
and/or GSK3174998 related 
• 
Discuss with Sponsor/Medical 
Monitor 
Symptoms resolve to baseline within 7 days:  
• 
Resume study drug(s) 
Symptoms ongoing > 7 days: 
• 
Discontinue study drug(s) 
• 
If symptoms continue or worsen to Grade 3 or 
Grade 4, see below 
Grade 3 
• 
Permanently discontinue study 
drug(s) a 
• 
Administer 1-2 mg/kg per day IV 
methylprednisolone, if 
considered GSK3359609 
(feladilimab) pembrolizumab 
and/or GSK3174998 related 
(local administration of 
corticosteroids may be 
considered after consultation 
with an ophthalmologist) 
• 
Consultation with 
ophthalmologist is strongly 
recommended 
• 
Discuss with Sponsor/Medical 
Monitor 
• 
If applicable, continue steroids until 
improvement to ≤ Grade 1; taper steroids over 
at least one month 
Grade 4 
• 
Permanently discontinue study 
drug(s) 
• 
Immediately inform 
Sponsor/Medical Monitor 
• 
Management as per Grade 3 
Abbreviations: IV = Intravenous 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to all study drugs; discuss management on 
a case-by-case basis with the Sponsor/Medical Monitor. 


 
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7.12. 
Management of Infusion Reactions or Severe Cytokine 
Release Syndrome (sCRS) 
Infusion reactions are a well-documented AE associated with the administration of mAbs, 
and are known to occur with specific chemotherapies. Infusion reactions typically 
develop within 30 minutes to two hours after initiation of drug infusion, although 
symptoms may be delayed for up to 48 hours. The incidence of infusion reactions varies 
by mAb and chemotherapeutic agent, and there are multiple mechanisms known to lead 
to infusion-related reactions including both IgE-dependent anaphylactic and non-IgE 
dependent anaphylactoid hypersensitivities. Cytokine release syndrome, and when 
severe, cytokine “storm”, has been identified as a sequelae of immune system activation 
associated with infusion reactions. As of March 2021, there have been no reported cases 
of cytokine release syndrome associated with GSK3359609 (feladilimab) infusions.  
7.12.1. 
Infusion Reaction 
Infusion reactions may affect any organ system in the body. Most are mild in severity, 
although severe and fatal reactions can occur. As a group, infusion reactions (including 
both cytokine mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur one to two days after administration. The 
NCI-CTCAE (version 4.0) [NCI, 2010] for grading adverse reactions during the infusion 
of a pharmacological or biological substance has a term for grading the severity of 
infusion reactions and separate terms for grading allergic reactions, anaphylaxis, and 
cytokine release syndrome. The use of these separate terms in grading severity of the 
event may be useful for classifying the nature of an infusion reaction for research 
purposes; they are less useful for clinical care, since it may not be obvious if the 
participant is having an allergic infusion reaction or a non-allergic infusion reaction. 
Clinically, infusion reactions may present with fever, chills, 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. 
7.12.2. 
Cytokine Release Syndrome 
Cytokine-associated toxicity, also known as CRS, is a non–antigen-specific toxicity that 
occurs as a result of strong immune activation. The magnitude of immune activation 
typically required to mediate clinical benefit using modern immunotherapies exceeds 
levels of immune activation that occurs in more natural settings. As immune-based 
therapies have become more potent, CRS is becoming increasingly recognized. 
Symptomatology associated with CRS and the severity of symptoms varies greatly, and 
management can be complicated by inter-current conditions in these participants. Fever is 
a hallmark, and many features of CRS mimic infection. It is not uncommon for 
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Potentially life-threatening complications of CRS include cardiac dysfunction, adult 
respiratory distress syndrome, neurologic toxicity, renal and/or hepatic failure, and 
disseminated intravascular coagulation. Of concern is cardiac dysfunction, which can be 
rapid onset and severe, but is typically reversible.  
It is difficult to determine the exact etiology of this AE in the clinical setting proximate to 
its occurrence, which makes it difficult to differentiate between a typical infusion 
reaction and CRS. Since there is a wide commonality in the clinical presentation of these 
events, the immediate treatment (refer to Section 7.12.3) does not vary with respect to the 
etiology. 
To better understand the underlying etiology of these events, serum tryptase, C-reactive 
protein (CRP), ferritin, and a cytokine panel must be drawn during the occurrence of an 
infusion reaction/CRS of any grade as outlined in Table 22. The serum tryptase, CRP and 
ferritin panels must be performed. The serum cytokine panel will be performed at a GSK 
designated laboratory. These data will aid in the classifying (albeit retrospectively) the 
etiology of the AE.  
 
Table 22 
Infusion-Related Reaction Laboratory Panel 
Biomarker 
Relationship to Adverse Event 
Serum tryptasea 
IgE-related infusion reaction (Allergic/anaphylaxis) [Schwartz, 
2006] 
Serum CRPa 
Elevated in CRS [Lee, 2014] 
Serum ferritina 
Elevated in CRS [Lee, 2014] 
Serum cytokine panelb 
(IFNγ*^, TNFα*^, IL-2*, IL-4, IL-
6*^, IL-8*, IL-10*, IL-12p70, and 
IL-13) 
* Reported to be elevated in CRS [Lee, 2014] 
^ Consistently reported as elevated in CRS [Lee, 2014] 
Abbreviations: CRP=C-reactive protein; CRS= Cytokine Release Syndrome; IFN = Interferon gamma; TNF = 
Tumor necrosis factor alfa; IgE: immunoglobulin E; IL = Interleukin 
a. 
Performed by investigator designated local laboratory if available; otherwise performed by GSK designated 
laboratory 
b. 
Performed by GSK designated laboratory 
7.12.3. 
Guidelines for Management of Infusion Reactions/CRS 
Prophylactic pre-infusion medications/premedications are not permitted prior to the first 
infusion except in combinations with chemotherapy/chemotherapies where premedication 
is required/recommended per approved product label or standard practice. In the 
combinations of GSK3359609 (feladilimab) with pembrolizumab or GSK3174998, 
prophylactic premedication may be permitted if deemed medically appropriate by the 
GSK Medical Monitor in consultation with investigators following IRR across cohorts.  
If multiple participants experience clinically significant infusion reactions, the infusion 
rate may be slowed for all future administrations of study drug(s) for all participants; this 
will be communicated to the sites in writing. 


 
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For Grade 1 symptoms (Mild reaction [e.g., localized cutaneous reactions including 
mild pruritus, flushing, rash] requires infusion rate to be decreased; intervention may be 
indicated): 
• 
Decrease the rate of the study drug infusion by at least 25% of the original rate  
• 
The participant must be closely monitored until resolution of symptoms. 
• 
Diphenhydramine 50 mg may be administered at the discretion of the treating 
physician. 
• 
If symptoms resolve, the infusion rate may be increased to the original infusion 
rate; if no further complications ensue, the rate of subsequent infusions may be 
increased to the original infusion rate. 
• 
If a participant has a Grade 1 infusion reaction with study drug(s), subsequent 
infusions can be given without prophylactic medications if the infusion reaction 
resolves within 3 hours. Prophylactic pre-infusion medications must be given 
before all subsequent infusions of study drug(s) if symptoms resolve >3 hours. 
• 
The following prophylactic pre-infusion medications are recommended before 
future infusions of study drug(s): diphenhydramine 50 mg (or equivalent) and/or 
paracetamol (acetaminophen) 500 mg to 1000 mg should be administered at least 
30 minutes before additional study drug administrations. 
• 
Obtain serum for CRP, tryptase, ferritin, and cytokine panel (refer to Table 22, 
and SRM). 
For Grade 2 symptoms (Moderate reaction [i.e., any symptom not listed above (mild 
symptoms) or below (severe symptoms) such as generalized pruritus, flushing, rash, 
dyspnea, or hypotension with systolic blood pressure > 80 mmHg]): 
• 
Discontinue the study drug infusion. 
• 
Consider treatment with IV infusion of normal saline, histamine 1 and/or 
histamine 2 blockers, acetaminophen, or NSAIDs as appropriate. Corticosteroid 
therapy may be administered at the discretion of the treating physician.  
• 
Obtain serum for CRP, tryptase, ferritin, and cytokine panel (see Table 22 and 
SRM). 
• 
Participant must be closely monitored until resolution of symptoms. 
• 
If symptoms resolve to baseline within one hour of stopping drug infusion, restart 
the infusion at 50% of the original infusion rate; monitor the participant closely. 
• 
For scheduling purposes, the study drug(s) may be administered the following 
day if the infusion cannot be continued the same day. 
• 
If no further complications ensue, the rate at subsequent infusions may be 
increased to 100% of the original infusion rate. 
• 
If symptoms recur, immediately discontinue the infusion; administer 
diphenhydramine 50 mg IV and continue to monitor the participant closely until 


 
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resolution of symptoms to Grade 1. No further study drug will be administered at 
that visit. 
• 
If symptoms resolve later than one hour, then the infusion should not be restarted. 
Prophylactic pre-infusion medications must be considered before all subsequent 
infusions of study drug(s). 
• 
Participant may be premedicated prior to infusion with diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 500 mg to 1000 mg (acetaminophen) at least 
30 minutes before additional study drug administrations. Participants who develop 
Grade 2 infusion reactions despite adequate premedication should be permanently 
discontinued from further trial treatment administration. 
For Grade 3 or Grade 4 symptoms (Severe reaction [e.g., bronchospasm, generalized 
urticaria, systolic blood pressure < 80 mmHg, 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 study drug infusion. No further study drug 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, no effective alternative therapy is available, 
participants who did not receive prophylactic treatment for infusion reactions). 
Participants who have develop severe hypersensitivity reactions related to paclitaxel 
should not be rechallenged with paclitaxel. 
• 
Any participant rechallenged with study drug(s) must receive 
prophylaxis/premedication, as per institutional guidelines, prior to subsequent 
administration of study drug(s). In these participants, the infusion rate must 
be reduced by 50% of the original infusion rate and the participant must 
remain under observation a minimum of three hours, post-administration of 
study drug(s). 
• 
Begin an IV infusion of normal saline, and treat the participant as follows: 
Recommend bronchodilators, 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 per institutional 
guidelines. 
• 
Consider administering etanercept or tocilizumab 
• 
Consider additional intervention in consultation with the investigator and the 
Sponsor/Medical Monitor. 
• 
Obtain serum for CRP, tryptase, ferritin, and cytokine panel (refer to Table 22, 
and SRM for further details). 
• 
Participant must be closely monitored until resolution of symptoms. 


 
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7.13. 
Management of Myocarditis 
Dose modification and management guidelines for myocarditis are provided in Table 23. 
Table 23 
Guidelines for Dose Modification and Management of Myocarditis 
Severity 
Management 
Follow-up 
Grade 1/ 
• Hold study drug(s)a 
• Based on severity of 
administer corticosteroids 
• Consider cardiology 
consultation 
• Evaluate to confirm 
etiology and/or exclude 
other causes 
• Continue steroids until 
toxicity resolves to 
Grade 1; taper steroids 
as medically appropriate 
• Resume study drug(s) if 
toxicity has resolved to 
Grade 1 within 12 weeks 
of last dose and if 
applicable steroid dose is 
10 mg prednisone or 
equivalent per day within 
12 weeks  
Grade 2/Grade 3/Grade 4 
• Permanently discontinue 
study drug(s)a 
• Immediately inform 
Medical Monitor 
• Administer corticosteroids 
• Consider cardiology 
consultation 
• Evaluate to confirm 
etiology and/or exclude 
other causes 
• Continue steroids until 
toxicity resolves to Grade 
1; taper steroids as 
medically appropriate 
a. 
If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in combination with 
pembrolizumab, GSK3174998, or chemotherapy), guidance applies to both all study drugs; discuss management on a 
case-by-case basis with the Sponsor/Medical Monitor. 


 
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7.14. 
Management of Neurotoxicity 
Dose modification and management guidelines for neurological toxicities are provided in 
Table 24. 
Table 24 
Guidelines for Dose Modification and Management of Neurological 
Toxicities 
Severity 
Management 
Follow-up 
Grade 2 
• Hold study drug(s)a 
• Based on severity 
administer corticosteroids 
• Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
• Continue steroids until 
toxicity resolves to 
Grade 1; taper steroids 
as medically appropriate 
• Resume study drug(s) if 
toxicity has resolved to 
Grade 1 within 12 weeks 
of last dose and if 
applicable steroid dose is 
10 mg prednisone or 
equivalent per day within 
12 weeks 
Grade 3/Grade 4 
• Permanently discontinue 
study drug(s)a 
• Immediately inform 
Medical Monitor 
• Administer corticosteroids 
• Evaluate to confirm 
etiology and/or exclude 
other causes 
• Continue steroids until 
toxicity resolves to 
Grade 1; taper steroids as 
medically appropriate 
a. If >1 study drug is administered per protocol (e.g. GSK3359609 (feladilimab) in 
combination with pembrolizumab, GSK3174998, or chemotherapy), guidance 
applies all study drugs; discuss management on a case-by-case basis with the 
Sponsor/Medical Monitor. 
7.15. 
Management of QTc Events 
• 
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. The QTcF should be based on single or at time-points where 
triplicate electrocardiograms (ECGs) obtained over a brief (e.g., 5-10 minute) 
recording period (refer to Time and Events Table 27) are required, averaged QTc 
values. 
If a participant meets the following criteria, the participant must discontinue study 
treatment: 
• 
QTcF >500 msec 
OR 


 
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• 
Change from baseline of QTcF >60 msec 
For participants with underlying bundle branch block, follow the discontinuation 
criteria listed below: 
Baseline QTcF with Bundle Branch Block 
Discontinuation QTcF with Bundle Branch 
Block 
<450 msec 
500 msec 
450 – <480 msec 
530 msec 
1. QTcF = QT duration corrected for heart rate by Fridericia’s formula 
7.16. 
Management of Left Ventricular Dysfunction 
Echocardiography (ECHO), or Multigated Acquisition Scan (MUGA) in lieu of ECHOs 
(if not available), must be performed at Screening, and if clinically indicated as outlined 
in the Time and Events Table 27. The same modality used at Screening must be used in 
any subsequent assessments; contact GSK if same modality is no longer feasible. 
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 must temporarily discontinue study treatment and have repeat 
echocardiogram performed. LVEF must 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 GSK Medical Monitor. 
Participants with symptoms of LV systolic dysfunction without an accompanying 
decrease in LVEF by echocardiogram must have a full evaluation performed as 
appropriate (e.g., cardiology consult, additional workup for swelling/shortness of breath) 
and symptoms must resolve to <Grade 2 prior to discussion of restarting study treatment 
at the same or reduced dose with the GSK Medical Monitor. 
7.17. 
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 
discontinue study treatment. Valvular toxicity must 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 GSK Medical Monitor. 
7.18. 
Management Guidance of Chemotherapy-related Toxicities 
Refer to Table 25 and Table 26 for guidance on specific chemotherapy-related AEs; as 
these tables are guidance only, refer to chemotherapy prescribing information or standard 
practice guidelines for the management of these AEs, other AEs or potential safety-
related issues. 


 
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Table 25 
Dose Reductions for Chemotherapy-related Hematologic Events 
Chemotherapy Regimen 
Toxicity 
Actiona 
Docetaxel 
• ANC <1.5x109/L, 
platelets <75x109/L, or 
hemoglobin <9g/dL (after 
transfusion if needed) 
• Febrile neutropenia 
• Hold docetaxel until 
recovery: ANC 
1.5x109/L, platelets 
100x109/L  
o Recovery within 7 
days, resume 100% 
of previous dose; 
>7 days, resume 
80% of previous 
dose 
• Hold docetaxel; upon 
recovery, if ANC < 
500/mm3 for more 
than 7 days, resume 
at 55mg/m2 
Pemetrexed/Carboplatin 
ANC <1.5x109/L, platelets 
<75x109/L, or hemoglobin 
<9g/dL (after transfusion if 
needed) 
 
Hold both drugs until 
recovery: ANC 
1.5x109/L, platelets 
100x109/L.  
Administer 75% of 
previous pemetrexed 
dose if: 
• ANC were 
<0.5x109/L and 
platelets were 
50x109/L 
• Platelets were 
<50x109/L without 
bleeding 
Administer 50% of 
pemetrexed previous 
dose if: 
• Platelets were 
<50x109/L with 
bleeding 
Paclitaxel/Carboplatin 
ANC <1.5x109/L, platelets 
<75x109/L, or hemoglobin 
<9g/dL (after transfusion if 
needed) 
 
Hold both drugs until 
recovery: ANC 
1.5x109/L, platelets 
100x109/L.  
Administer 80% of 
previous dose if: 
• ANC were 
<0.5x109/L for >7 
days 


 
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Chemotherapy Regimen 
Toxicity 
Actiona 
Gemcitabine/Carboplatin ANC <1.5x109/L, platelets 
<75x109/L, or hemoglobin 
<9g/dL (after transfusion if 
needed) 
Hold both drugs until 
recovery: ANC 
1.5x109/L, platelets 
100x109/L.  
Administer 80% of 
previous dose if: 
• Refer to approved 
product label for 
dose adjustments  
a. 
Resume treatment with chemotherapy after resolution as indicated; treatment with GSK3359609 
(feladilimab) and pembrolizumab may continue unless otherwise instructed (refer to Section 7.10) 
Table 26 
Dose Reductions for Chemotherapy-related Non-Hematologic 
Events 
Chemotherapy Regimen 
Toxicity 
Actiona 
Docetaxel 
• Grade 3/Grade 4 event, 
except peripheral 
neuropathy 
• Grade 3/Grade 4 
peripheral neuropathies 
 
• Hold docetaxel upon 
recovery to 
Grade 1/baseline, 
resume treatment at 
55mg/m2 
• Consider permanent 
discontinuation; 
discuss with medical 
monitor  
Pemetrexed/Carboplatin • Grade 3/Grade 4 event, or 
Grade 1/ Grade 2 diarrhea 
requiring hospitalization, 
except mucositis or 
neurological toxicities 
• Grade 3/Grade 4 
mucositis 
• Grade 3/Grade 4 
neurological toxicities or 
recurrent Grade 3/Grade 4 
toxicity resulting in 2 dose 
reductions 
• Hold until recover to 
Grade 1/baseline, 
resume treatment at 
75% of previous dose 
• Hold until recover to 
Grade 1/baseline, 
resume treatment, 
except pemetrexed at 
50% of previous dose 
• Consider permanent 
discontinuation; 
discuss with medical 
monitor 
a. 
Resume treatment with chemotherapy after resolution as indicated; treatment with GSK3359609 
(feladilimab) and pembrolizumab may continue unless otherwise instructed (refer to Section 7.1- 
Section 7.19 for further management guidelines) 
 


 
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7.19. 
Dose Delay 
If there is a dose delay between one and 7 days, the procedures at the original scheduled 
visit (including dosing) should be performed as soon as possible. If the delay is 8 days, 
the visit and dose(s) will be considered missed. The procedures at the next scheduled visit 
should be performed, and subsequent visits will follow Q3W. Participants with infusion 
delays greater than three weeks due to toxicity should discontinue study drug(s) unless 
the treating investigator and Sponsor/Medical Monitor agree there is strong evidence 
supporting continued treatment. For participants requiring elective surgery or radiation 
therapy, consult the GSK Medical Monitor for study treatment management. (refer to 
Section 6.9.1 for details on permitted medications and non-drug therapies). 
 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed except for immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the 
Time and Events Table, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table Section 8.1. 
The following points must be noted: 
• 
If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order: 
1. 12-lead ECG 
2. Vital signs 
3. Blood draws (e.g. PK blood draws) 
Note: 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, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other assessments may be 
altered during the course of the study based on emerging data (e.g., to obtain 
data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 
• 
If a change in timing or addition of time points for any planned study 
assessments occurs, the change will be documented in a Note to File; this will 
not constitute a protocol amendment. 
• 
The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 
• 
No more than 500 mL of blood will be collected over the first four doses of 
study treatment. 


 
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8.1. 
Time and Events Tables 
This section presents the Time and Events sections with supplemental footnotes to 
describe assessments windows and sequencing of assessments and procedures, if 
applicable. 
Informed consent must be signed by a participant before any study required procedures 
are performed. However, procedures conducted as part of the participant’s routine 
clinical management or as part of another clinical trial within the screening window (e.g., 
imaging studies) and obtained prior to signing of the study informed consent may be used 
for screening/baseline assessments provided the procedure fulfils the protocol defined 
specifications and has been performed within the protocol indicated timeframe. 
 


 
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Table 27 
Time and Events: Safety, Laboratory, Efficacy, Study Treatment Procedures 
Study Procedure1 
Screening2 
Treatment Period3 
Weeks 
Treatment 
Discontinuation4 
Follow-up 
Notes 
0 
1 2 3 4 
5 6 
9 
12 
>12 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
(past and current) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PD-L1 IHC by 22C3 PharmDx 
Assay Result (Part 2B HNSCC PD-
L1 CPS <1 cohort only)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICOS IHC assay2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Required for Biomarker cohort only 
Gene Expression assay 
X 
 
 
 
 
 
 
 
 
 
 
 
 
May be required at Screening for 
biomarker cohort only 
Anticancer Therapy 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Screening=prior anticancer therapy 
Follow-up= subsequent anticancer 
therapy 
Participant Registration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Participant registration will occur 
after all screening assessments 
have been performed and the 
participant has met all eligibility 
requirements 
Safety Assessments 
 
ECOG PS 
X 
X 
X X X X X X 
X 
X 
Q3W 
X 
 
 
Vital signs, height and weight 
X 
X 
X X X X X X 
X 
X 
Q3W 
X 
 
Height measured and recorded at 
screening only 


 
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Study Procedure1 
Screening2 
Treatment Period3 
Weeks 
Treatment 
Discontinuation4 
Follow-up 
Notes 
0 
1 2 3 4 
5 6 
9 
12 
>12 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO required at Screening visit 
within 28 days prior to first dose of 
study treatment and during 
treatment phase, if clinically 
indicated. MUGA can be used if not 
available 
12-lead ECG5 
X 
X 
 
 
X 
 
 
X 
X 
X 
Q12W 
X 
 
 
AE/SAE review6 
 
Continuous: assess at each visit from signing of ICF 
X 
X 
 
Concomitant medication review 
 
Continuous: assess at each visit from first dose of study 
treatment 
X 
Q12W 
 
Safety Laboratory Assessments 
Hepatitis B and C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum -hCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Required for females of child 
bearing potential. Serum pregnancy 
test must be performed within 7 
days prior to first dose of 
GSK3359609 (feladilimab) 
Hematology/Clinical Chemistry 
(Refer to Table 29) 
X 
X 
X X X X X X 
X 
X 
Q3W 
X 
 
Must be drawn pre-dose or within 
72 h prior to dosing 
Thyroid function 
(Refer to Table 29) 
X 
 
 
 
 
 
 
X 
 
X 
Q6W 
X 
 
Must be drawn pre-dose or within 
72 h prior to dosing 
Troponin 
 
X 
 
 
X 
 
 
X 
X 
X 
Q3W 
X 
 
Troponin I or Troponin T. 
Must be drawn pre-dose or within 
72 h prior to dosing 
Urinalysis 
X 
 
X X X X X X 
X 
X 
Q3W 
X 
 
Must be drawn pre-dose or within 
72 h prior to dosing 
Part 1 Monotherapy Study Treatment7 
Administer GSK3359609 
(feladilimab) 
 
X 
 
 
X 
 
 
X 
X 
X 
Q3W 
 
 
 


 
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Study Procedure1 
Screening2 
Treatment Period3 
Weeks 
Treatment 
Discontinuation4 
Follow-up 
Notes 
0 
1 2 3 4 
5 6 
9 
12 
>12 
Part 2 Combination Study Treatment7 
Administer GSK3359609 
(feladilimab) (Q3W) 
 
X 
 
 
X 
 
 
X 
X 
X 
Q3W 
 
 
 
Administer GSK3359609 
(feladilimab) (Q6W) 
 
X 
 
 
 
 
 
X 
 
X 
Q6W 
 
 
 


 
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Study Procedure1 
Screening2 
Treatment Period3 
Weeks 
Treatment 
Discontinuation4 
Follow-up 
Notes 
0 
1 2 3 4 
5 6 
9 
12 
>12 
Administer Pembrolizumab8 (Q3W) 
 
X 
 
 
X 
 
 
X 
X 
X 
Q3W 
 
 
 
Administer Pembrolizumab8 (Q6W) 
 
X 
 
 
 
 
 
X 
 
X 
Q6W 
 
 
 
Administer GSK31749988 
 
X 
 
 
X 
 
 
X 
X 
X 
Q3W 
 
 
 
Administer Docetaxel9 
 
X 
 
 
X 
 
 
X 
X 
X 
X^9 
 
 
^Treatment with docetaxel may 
continue beyond 6 cycles according 
to standard practice 
Administer 
Pemetrexed9/Carboplatin9 
 
X 
 
 
X 
 
 
X 
X 
X 
X^9 
 
 
^Treatment with pemetrexed may 
continue beyond 6 cycles according 
to standard practice 
Administer Paclitaxel9/Carboplatin9 
 
X 
 
 
X 
 
 
X 
X 
X 
X9 
 
 
 
Administer 
Gemcitabine^9/Carboplatin9 
 
X 
 
 
X 
 
 
X 
X 
X 
X9 
 
 
^Gemcitabine will be administered 
on Day 1 and Day 8 of every 3-
week/21-day cycle 
Administer 5-FU^/Cisplatin9 or 
Carboplatin9 
 
X 
 
 
X 
 
 
X 
X 
X 
X9 
 
 
^Fluorouracil (5-FU) will be 
administered continuous on Day 1 
through Day 4 of every 3-week/21-
day cycle 
Efficacy Assessments 
Tumor imaging/clinical exam10 
X 
 
 
 
 
 
 
 
X 
 
Q9W10 
 
 
Up to WK 27 then per institutional 
guidelines 
Tumor imaging/clinical exam for 5-
FU Platinum chemotherapy 
combination cohort10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Follow institutional guidelines for 
imaging after screening 


 
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Study Procedure1 
Screening2 
Treatment Period3 
Weeks 
Treatment 
Discontinuation4 
Follow-up 
Notes 
0 
1 2 3 4 
5 6 
9 
12 
>12 
Follow-up for Survival 
 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Participants will be followed every 
12 weeks for survival and 
subsequent anti-cancer therapy, 
the window for this visit is ±10 
days. The survival follow-up visit 
will commence after discontinuation 
of study treatment. Follow-up for 
survival may not be required when 
75% of events have been reached 
in the last cohort opened; 
investigators will be notified in 
writing when survival follow-up is 
no longer required. 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; -hCG = Beta-human chorionic gonadotropin; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; EOI=end of infusion; ICF=informed consent form; irRECIST=immune-related RECIST; MUGA=multigated acquisition 
scan; RECIST=response evaluation criteria in solid tumors; SAE=serious adverse event; W=week 
1. 
Procedures scheduled on study treatment administration days should be done prior to dosing, unless otherwise specified; these assessments can be performed 3 days prior to 
dosing day. Assessments performed 3 weeks can be done 3 days of scheduled occurrence, those performed >3 weeks can be done 7 days of scheduled occurrence unless 
otherwise specified. A participant in Part 1 who upon disease progression is permitted to receive GSK3359609 (feladilimab) in combination with pembrolizumab (crossover) will 
continue to follow the Part 1 visit assessment schedule to which the participant started. 
2. 
All assessments performed at Screening must be performed within 14 days prior to first dose unless otherwise specified. Informed consent can be signed within 45 days prior to 
first dose. For participants in the Biomarker cohort (Part 1B), archival tumor tissue OR fresh biopsy obtained at screening is mandatory. NOTE: An evaluable ICOS expression at 
baseline on either archival or fresh tissue using a validated IHC assay by central laboratory testing is required for eligibility to enroll. In Part 1B biomarker cohort, participants may 
also require gene expression signature analysis at baseline (NOTE: testing will be retrospective initially but may switch to prospective testing for enrollment depending on 
prevalence): submitting tumor tissue (archival OR fresh biopsy) at screening for testing can occur after signing of informed consent and within 45 days prior to first dose (Day 1). 
For participants in Part 2B HNSCC PD-L1 CPS < 1 cohort, a documented CPS score of <1 from FDA approved PD-L1 IHC 22C3 PharmDx assay is required for eligibility; 
documented test results from local laboratory, if available, may be accepted in lieu of the central test result. For participants requiring central laboratory testing by the PD-L1 IHC 
22C3 pharmDx assay: submitting tumor tissue (archival or fresh biopsy) for this testing can occur after signing of informed consent and within 45 days prior to first dose (Day 1). 
3. 
In participants who attain a CR and study treatment is discontinued (early) or in those who complete 35 cycles of study treatment, second course treatment was an option and has 
been removed. 
4. 
The assessments required at the study treatment discontinuation visit (permanent discontinuation) must be completed within 30 days from the date study treatment was 
discontinued and must occur prior to the start of subsequent anti-cancer therapy; the window for this visit is +10 days. If tumor imaging/clinical examination assessment occurred 
within less than the indicated time period, these assessments do not need to be repeated for this visit unless required to confirm disease progression by irRECIST.  


 
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5. 
For Part 1 only: On Day 1 ECG measurements will be performed in triplicate at pre-dose (within 60 minutes prior to start of GSK3359609 (feladilimab) infusion) and at the following 
times after the infusion: EOI + 30m, EOI + 4h, EOI + 24h, on Day 22 ECG measurements will be performed in triplicate at pre-dose and on Day 85 ECG measurements will be 
performed in triplicate at pre-dose and at the following times after the infusion: EOI+30m. All other ECG measurements in Part 1 and all ECG measurements in Part 2 are 
performed as single ECG measurements. For Part 2, ECGs are performed at pre-dose only.  
6. 
AEs and concurrent medications will be collected until at least 30 days after the last dose of study treatment. All AESIs and SAEs, and any concurrent medications relevant to the 
reported AESIs and SAEs, will be collected until at least 90 days after the last dose of study treatment or until the start of new anticancer therapy, whichever occurs first. Any drug-
related or study-related SAEs occurring after 90 days will be reported according to the instructions in Section 8.4.1.1. 
7. 
Study treatment must be administered within 3 days of scheduled visit unless otherwise indicated. Refer to Section 4.2 for maximum duration of study treatment. 
8. 
GSK3359609 (feladilimab) will be administered first; pembrolizumab or GSK3174998 will be administered at least 30 minutes and no longer than one hour following GSK3359609 
(feladilimab) EOI. Refer to Section 4.2 for maximum duration of study treatment.  
9. 
GSK3359609 (feladilimab) will be administered first; chemotherapies will be administered at least 30 minutes and no longer than one hour following GSK3359609 (feladilimab) 
EOI. Chemotherapy premedication indicated on day of dosing should be administered after GSK3359609 (feladilimab) infusion. Chemotherapies should be administered for a 
minimum of 4 and maximum of 6 cycles according to standard practice.  
10. Disease assessments which include tumor imaging and clinical exams, if indicated, must be performed within 30 days prior to first dose of study treatment and will be performed 
every 9 weeks until Week 54 then every 12 weeks thereafter until disease progression; participants who discontinue for reasons other than progression will be followed for 
progression until the start of subsequent anticancer therapy every 9 weeks until Week 54 then every 12 weeks thereafter. Participants who attain a CR and met the requirements 
defined in Section 5.4 for early discontinuation of study treatment and discontinue study treatment will undergo disease assessments every 12 weeks until progression. Refer to 
Section 8.3.1 for further details on the use of RECIST 1.1 and irRECIST guidelines in assessing overall tumor burden at Screening and tumor response. 
 
 
 


 
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Table 28 
Time and Events: Pharmacokinetics, Immunogenicity, Biomarker Assessments (Part 1 and Part 2) 
Study Procedure 
Screening 
Treatment Period 
Week 
Day 
30 d 
post-
last 
dose1,4 
12 w 
post 
last 
dose
1 
Notes 
0 
1 
2 
3 
4 
5 
6 
9 
12 
15 
 
1*# 
2 
8 
15 
22* 
29 
36 
43
*# 
64
* 
85
*# 
106* 
127*
# 
Tumor Specimens 
Archival tumor 
tissue2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fresh tumor 
biopsy3^ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
^Week 6 and 30 
d post-last dose 
biopsy are no 
longer required/ 
optional 
*Indicates dosing day for Q3W schedule; # indicates dosing day for Q6W schedule 
Abbreviations: EOI = end of infusion; d = day; h = hour; min = minute; PBMC = peripheral blood mononuclear cells; PK=pharmacokinetics; w = week 
Time-point definitions: X = any time at that visit; pre = collect prior to dosing per institutional guidance, as long as it is collected prior to dosing of the corresponding agent, unless 
otherwise specified; EOI= within 1 minute of the end of study treatment infusion; EOI+30 minutes = within 1 minute; EOI+1 hour= within 5 minutes; EOI+2 hours= within 5 
minutes; EOI+4 hours = within 5 minutes; EOI+24 hours = within 60 minutes of the end of study treatment infusion. Assessments performed 3 weeks can be done 3 days of 
scheduled occurrence, those performed >3 weeks can be done 7 days of scheduled occurrence unless otherwise specified. For Part 2: pre = reference is GSK3359609 (feladilimab) 
infusion time; EOI time-point for biomarker assessments is in reference to EOI of second agent or third agent, if applicable (except for chemotherapy); for chemotherapy combinations, 
EOI time-points for biomarker assessments is in reference to EOI of GSK3359609 (feladilimab). Refer to the SRM for further details on PK time-points and references. 
1. 
Procedures required at this visit can be performed 7days, unless otherwise indicated (refer to footnote 4 for biomarker samples taken at 30 days post study treatment visit). If the 
decision to discontinue study treatment was after 30 days from last dose, then assessments required at this visit should be completed within 10 days from date decision was made 
to discontinue study treatment. 
2. 
Archival specimen should only be submitted to central laboratory in those participants fulfilling all eligibility criteria. For participants screening for enrollment to Part 2B HNSCC 
PD-L1 CPS <1 cohort, if PD-L1 IHC testing by 22C3 pharmDx assay by central laboratory is needed, archival tumor tissue can be submitted after signing of consent (within 45 
days from Day 1). If archival specimen is not available, a fresh tumor biopsy is required (Note: this procedure can be performed after signing consent and within 45 days from Day 
1 for Part 2B HNSCC PD-L1 CPS <1 cohort). In the participants enrolled in the part 1B biomarker cohort, an evaluable result for ICOS expression from central lab testing using 
archival tissue is acceptable for eligibility although both archival and fresh biopsy at baseline are required; these specimens will be used for assessment of the biomarker status. 
3. 
Screening and on-treatment fresh tumor biopsies are required for monotherapy dose expansion cohorts in Part 1B. Note that both fresh and archival biopsies at screening are 
required for the biomarker cohort in Part 1B. For Part 2B, fresh screening and on-treatment biopsies are required in HNSCC dose randomized cohort, HNSCC PD-L1 CPS <1 
cohort, HNSCC Q6W cohort and melanoma expansion cohort. Also, in Parts 1B and 2B, fresh tumor biopsy should be attempted at screening (any time before first dose) and at 


 
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Week 6 (after the 3rd dose of study treatment +7 days). Once evaluable paired tumor biopsies are collected for up to 10 participants per expansion cohort, this requirement may 
be waived. Fresh screening and on-treatment biopsies are optional in Part 1A. For Part 2A, fresh screening and on-treatment biopsies are required for participants treated at the 
GSK3359609 (feladilimab)/GSK3174998 combination RP2 doses. Fresh screening and on-treatment biopsies are optional for participants enrolled during the safety/dose 
escalation phase of these cohorts in Part 2A. Tumor lesions planned for biopsy must not be followed as target lesions for disease assessment unless agreed upon by GSK. 
Unscheduled tumor biopsies may be performed any time during the treatment period upon participant consent for this optional procedure. Japan Part 1C and Part 2C PK/PD 
cohort, biopsies are not required. 
 
 
 


 
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8.2. 
Screening and Critical Baseline Assessments 
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity. 
• Medical history including cardiovascular medical history/risk factors will be 
assessed as related to the inclusion/exclusion criteria listed in Section 5.1 and 
Section 5.2. 
• Disease characteristics including medical, surgical, and treatment history 
including radiotherapy, date of initial diagnosis, stage at initial diagnosis, 
histology, tumor genetic/genomic features, tumor viral status and current sites of 
disease will be taken as part of the medical history and disease status; scans from 
imaging studies performed prior to screening scans required for baseline lesion 
assessments may be requested (refer to Section 10.7.6.2). Details concerning prior 
anti-cancer therapy (e.g., systemic and radiation therapy) including best response 
to prior systemic therapy will be recorded for at least two prior lines of therapy (if 
available). 
• For participants with PD-1/L1 treatment naïve HNSCC screening for enrollment 
to the Part 2B HNSCC PD-L1 CPS <1 cohort only: An evaluable CPS score of <1 
using the PD-L1 IHC 22C3 PharmDx assay for PD-L1 protein expression is 
required for eligibility. Documented test result of CPS<1 from local laboratory 
using the PD-L1 IHC 22C3 PharmDx assay and testing conducted as per the 
guidelines in the assay IFU , if available, may be accepted in lieu of the central 
laboratory test result; refer to Section 5.1 inclusion criterion 19 for CPS eligibility 
requirements. 
• For participants in the Biomarker cohort (Part 1B), an evaluable result for ICOS 
expression using a validated IHC assay by central laboratory testing is required; 
and could be used to enrich for ICOS high expression if prevalence of ICOS 
expression is low in the initial 15 participants enrolled. Refer to Section 5.1 
inclusion criterion 17.  
• For participants in  the Biomarker Cohort  (Part 1B), gene expression using a 
validated Nanostring gene expression CounterFLEX system assay by central lab; 
there may be a requirement  for gene expression signature result for participant 
eligibility in the biomarker cohort, and could be used to enrich for signature high 
if the prevalence of gene expression signature positive participants is low in the 
initial 15 enrolled participants. Refer to Section 5.1 inclusion criterion 18. 
Baseline lesion assessments required within 30 days prior to the first dose of 
GSK3359609 (feladilimab) include: 
• Computed Tomography (CT) scan with contrast of the chest, abdomen, and pelvis 
• For participants with head and neck cancer, a CT/Magnetic Resonance 
Imaging (MRI) of the head and neck area is required 
• Clinical disease assessment for palpable/visible lesions 
• Other areas as indicated by the participant’s underlying disease present prior to 
screening 


 
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• 
NOTE: 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. Refer to RECIST version 1.1 guidelines for use of fluorodeoxyglucose-
positron emission tomography (FDG-PET)/CT [Eisenhauer, 2009]. 
• 
Refer to Section 8.3.1 for baseline documentation of target and non-target lesions.  
Safety and laboratory assessments required at baseline include: 
• Physical examination 
• Performance Status 
• Vital Signs 
• Concomitant medication 
o  Recorded starting from screening through post-study follow-up.  
o At a minimum, the drug name, route of administration, dose and frequency 
of dosing, along with start and stop dates should be recorded. 
• Electrocardiogram 
• Echocardiogram or MUGA 
• Laboratory assessments (refer to Section 8.4.8) 
Refer to Time and Events Table 27, and Table 28 for additional details on assessments 
required at Screening and prior to start of study treatment. 
8.3. 
Efficacy 
8.3.1. 
Evaluation of Anti-Cancer Activity 
• 
RECIST version 1.1 guidelines will be used to determine the overall tumor burden at 
screening, select target and non-target lesions, and in the disease assessments 
through the duration of the study [Eisenhauer, 2009]. 
• 
As indicated in RECIST version 1.1 guidelines: 
• 
Lymph nodes that have a short axis of <10 mm are considered non-pathological 
and must not be recorded or followed. 
• 
Pathological lymph nodes with <15 mm, but 10 mm short axis are considered 
non-measurable. 
• 
Pathological lymph nodes with 15 mm short axis are considered measurable and 
can be selected as target lesions; however, lymph nodes should not be selected as 
target lesions when other suitable target lesions are available. 
• 
Measurable lesions up to a maximum of two lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions, 
and recorded and measured at baseline. These lesions should be selected based on 
their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 


 
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Note: Cystic lesions thought to represent cystic metastases must 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 must 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, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions. 
• 
All other lesions (or sites of disease) must be identified as non-target and must 
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 must be noted throughout follow-up. 
• 
Disease assessment modalities may include imaging (e.g., CT scan, MRI, bone scan) 
and physical examination (as indicated for palpable/superficial lesions). 
• 
As indicated in Section 8.2, baseline disease assessment must be completed within 
30 days prior to the first dose of GSK3359609 (feladilimab). On-treatment disease 
assessments occur according to standard practice. At each post-baseline assessment, 
evaluation of the sites of disease (all target and non-target lesions) identified by the 
baseline scans is required. CT scans with contrast are required at each post-baseline 
assessment. To ensure comparability between the baseline and subsequent 
assessments, the same method of assessment and the same technique will be used 
when assessing response. 
• 
Refer to the Time and Events Table 27 for the schedule of assessments of anticancer 
activity. Assessments must be performed on a calendar schedule and should not be 
affected by dose interruptions/delays. 
• 
For post-baseline assessments, a window of 7 days is permitted to allow for flexible 
scheduling. If the last radiographic assessment was more than 9 weeks prior to the 
participant’s discontinuation from study treatment, or >12 weeks if after Week 54, a 
disease assessment should be obtained. 
• 
Participants with disease progression by RECIST version 1.1 guidelines are required 
to have a confirmatory disease assessment at least 4 weeks after the date disease 
progression was declared in order to confirm disease progression by irRECIST 
guidelines.  
• 
Participants whose disease responds (either CR or PR) must have a confirmatory 
disease assessment performed at least 4 weeks after the date of assessment during 
which the response was demonstrated. More frequent disease assessments may be 
performed at the discretion of the investigator. In the participants who attain a 
confirmed CR and fulfill the requirement for early discontinuation of study treatment 
(refer to Section 5.4), disease assessments at a frequency of will be performed per 
standard of care. 
• 
The visit level responses and treatment-based decisions will incorporate irRECIST 
guidelines as described in Appendix 6. 


 
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8.4. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 8.1). Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring. 
8.4.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Appendix 9. 
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  
8.4.1.1. 
Time and Frequency for collecting AE and SAE information 
• 
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 provides consent to 
participate in the study up to 90 days after the last dose of study treatment. If 
subsequent anti-cancer treatment is initiated during the 90-day follow-up period yet 
<30 days after the date study treatment was discontinued, AESI and SAEs must 
continue to be followed until 30 days after last dose of study treatment. 
• 
AEs will be collected from the start of Study Treatment until the follow-up contact 
(see Section 8.4.1.2), at the time-points specified in the Time and Events Table 
(Section 8.1). 
• 
Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF. 
• 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 13.9.6. 
• 
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 reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK. 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 9. 
8.4.1.2. 
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 AEs of special 
interest (as defined in Appendix 8) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the participant is lost to follow-


 
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up (as defined in Section 5.4. Further information on follow-up procedures is given in 
Appendix 9. 
8.4.1.3. 
Cardiovascular and Death Events 
All cardiovascular (CV) events (as defined in Section 8.4.1.3.1) and deaths, whether or 
not considered SAEs, require specific CV and Death sections of the eCRF to be 
completed.  These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information must be 
recorded in the specific CV section of the eCRF within one week of receipt of a CV 
Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.4.1.3.1.  Definition of Cardiovascular Events 
A cardiovascular 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 
8.4.1.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of participants and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and investigators. 


 
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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.2. 
Pregnancy 
• 
Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of dosing and until 120 days after date of 
last dose of study treatment. 
• 
If a pregnancy is reported then the investigator must inform GSK within 24 hours of 
learning of the pregnancy and must follow the procedures outlined in Section 13.9.7. 
8.4.3. 
Physical Examinations 
• 
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height (at 
Screening only) and weight will also be measured and recorded. 
• 
A brief physical examination will include at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.4.4. 
Performance Status 
Performance status will be assessed using the ECOG scale as described in Appendix 7. 
8.4.5. 
Vital Signs 
• Vital signs will be measured in semi-supine position after 5 minutes of rest and 
will include temperature, systolic and diastolic blood pressure and pulse rate. 
• In the case of an abnormal first reading, three readings of blood pressure 
and/or pulse rate must be taken, whereby the first reading should be 
rejected and the second and third averaged to give the measurement to be 
recorded in the eCRF. 
• 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 fever, refer to Section 7.12.3 for fever management 
guidelines. 


 
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8.4.6. 
Electrocardiogram 
12-lead electrocardiograms will be obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals; manual 
calculation of QTcF is permitted. Refer to Section 7.14 for QTcF withdrawal criteria and 
additional QTcF measurements that may be necessary. Refer to Time and Events Table 
27 for details on ECG assessment time-points and requirements for triplicate or single 
ECG measurements. 
8.4.7. 
Echocardiograms 
Echocardiograms will be performed at baseline to assess cardiac ejection fraction and 
cardiac valve morphology for the purpose of study eligibility, as specified in the Time 
and Events Table 27. Additional ECHO assessments may be performed if clinically 
warranted. The evaluation of the echocardiography must include an evaluation for LVEF 
and both right and left-sided valvular lesions. MUGA can be used in lieu of ECHO (if not 
available) in the assessment of LVEF; the same modality should be used in any 
subsequent assessments. 
Refer to Section 7.15 and Section 7.16 for withdrawal criteria and follow-up assessments 
in the event of LV dysfunction or valvular toxicity, respectively. 
8.4.8. 
Clinical Safety Laboratory Assessments 
All protocol required laboratory assessments, as defined in Table 29 must be conducted 
in accordance with the Protocol Time and Events Schedule.  Reference ranges for all 
safety parameters must be provided to the site by the laboratory responsible for the 
assessments. 
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date.  Details for 
the preparation and shipment of samples that are required to be tested by a central 
laboratory will be provided by the laboratory and are detailed in the laboratory manual. 
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 also recorded in the CRF. 
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws. 
The study-required laboratory assessments indicated in Table 29 will be performed by a 
local laboratory unless otherwise indicated. The results of each test must be entered into 
the CRF. 


 
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Table 29 
Protocol Required Safety Laboratory Assessments 
Laboratory Assessments 
Parameters 
Hematology 
RBC Indices 
WBC count with Differential 
Platelets 
Hemoglobin 
Neutrophils 
 
Hematocrit 
Lymphocytes 
 
RBC count 
Monocytes 
 
 
Eosinophils 
 
 
Basophils 
 
Clinical Chemistry 
BUNa 
Potassium 
Bilirubin 
AST (SGOT) 
Creatinineb 
Sodium 
Total protein 
ALT (SGPT) 
Glucose 
Calcium 
Albumin 
Alkaline phosphatase 
Cardiac Function 
• 
Troponin I or Troponin T 
Thyroid Function 
• 
Thyroid stimulating hormone 
• 
Free T4 
• 
Free T3 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood and ketones by dipstick 
Other Screening Tests 
• 
Hepatitis B (HBsAg) 
• 
Hepatitis C (Hep C antibody)c 
• 
Serum -hCG Pregnancy test (as needed for women of childbearing 
potential) 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; -hCG=beta-human chorionic 
gonadotropin; BUN=blood urea nitrogen; HBsAg=Hepatitis B surface antigen; RBC=red blood cells; SGOT=serum 
glutamic oxaloacetic transaminase; SGPT= serum glutamic pyruvic transaminase; T3= triiodothyronineT4= thyroxine; 
WBC = white blood cells 
a. 
Required if local laboratory testing is available 
b. 
Creatinine clearance is also required to be calculated using the formula provided in Appendix 10. 
c. 
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. Hepatitis C RNA Test is optional with negative Hepatitis C antibody 
test. 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study treatment 
must be repeated until the values return to normal or baseline. If such values do not return 
to normal within a period judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified. 
8.4.9. 
Patient Reported Outcomes 
8.5. 
Pharmacokinetics 
As per this amendment, these samples will no longer be collected. 
 
CCI


 
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8.6. 
Immunogenicity 
As per this amendment, these samples will no longer be collected. 
8.7. 
Biomarkers/Pharmacodynamic Markers 
CCI


 
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8.8. 
Genetics 
Information regarding genetic research is included in Appendix 11. 
CCI


 
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9. 
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. 
• 
eCRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy. Participant initials 
will not be collected or transmitted to GSK according to GSK policy. 
10. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
10.1. 
Hypotheses 
10.1.1. 
Part 1A and Part 2A Dose Escalation/Safety Run-in 
In Part 1A and Part 2A, the primary aims are determining the recommended dose or 
doses for further exploration, the safety profile, and the pharmacology of GSK3359609 
(feladilimab) monotherapy and in combination with pembrolizumab, chemotherapy 
( pembrolizumab), or GSK3174998 in participants with advanced solid malignancies. 
Descriptive methods will be used in analyses of the data obtained from this study. No 
formal statistical hypotheses are being tested. 
10.1.2. 
Part 1B GSK3359609 (feladilimab) Monotherapy Expansion/ Part 
2B GSK3359609 (feladilimab) Combination with Pembrolizumab 
Expansion of PD-1/L1 Experienced Participants  
The assumptions for the secondary endpoint of overall response rate (ORR) underlying 
the design are detailed below: 
The null hypothesis for the secondary endpoint of ORR is: 
H0: p=10%. 
The alternative hypothesis is: 
HA: p=30%. 
In the Part 1B Biomarker Cohort, the null hypothesis for the difference in ORR of 
GSK3359609 (feladilimab) in the biomarker positive population (i.e., ICOS high) and  
biomarker negative population (i.e., ICOS low) is given below: 
The null hypothesis is: 
H0: pH – pL ≤ 0% 


 
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The alternative hypothesis is: 
HA: pH – pL > 0%, 
where pH represents ORR in the ICOS high population and pL represents ORR in the 
ICOS low population. 
 
10.1.3. 
Part 2B GSK3359609 (feladilimab) Combination with 
Pembrolizumab Expansion of PD-1/L1 Naïve Participants 
For each cohort, the aim is to test the null hypothesis that the ORR for the combination is 
equal to the historical response rate of monotherapy pembrolizumab which is expected to 
be between 15% to 40% according to tumor types selected for the study. In the 
KEYNOTE-001 trial, the reported pembrolizumab monotherapy ORR was 19.4% in 495 
NSCLC participants across different histologies and PD-L1 status [Garon, 2015].  
Overall, the aim of each expansion cohort is to detect an improvement in the ORR of the 
combination therapy compared with pembrolizumab monotherapy in the range of 20% 
over the null, with power of at least 80% and no more than a 10% type 1 error rate.   
• PD-1/L1 naïve Expansion Cohorts (HNSCC, NSCLC PD-L1 <50%, 
Bladder/Urothelial and Viral-positive Cancers) 
The null hypothesis for ORR is: 
H0: p=20% 
The alternative hypothesis is: 
HA:p=40% 
• PD-1/L1 Treatment-Naïve HNSCC PD-L1 CPS <1 Cohort 
The null hypothesis for proportion of participants with a change in PD-L1 CPS status 
from <1 to ≥1 is: 
H0: p=10% 
The alternative hypothesis is: 
HA: p=40% 
• PD-1/L1 naïve Expansion Cohort (NSCLC PD-L1 50% and MSI-H/dMMR 
Cancers) 
The null hypothesis for ORR is: 
H0: p=30% 
The alternative hypothesis is: 
HA: p=50% 


 
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10.2. 
Dose Escalation 
10.2.1. 
Modified Toxicity Probability Interval  (mTPI) 
Safety and tolerability of GSK3359609 (feladilimab) administered alone and in 
combination with a 200-mg fixed dose of pembrolizumab or chemotherapy 
( pembrolizumab) will be evaluated using an adaptive mTPI approach. The mTPI design 
is an extension of the toxicity probability interval method and employs a simple beta-
binomial hierarchic model [Ji, 2010]. Decision rules are based on calculating the unit 
probability mass (UPM) of three intervals corresponding to under dosing, proper dosing, 
and overdosing in terms of toxicity. Specifically, the under-dosing interval is defined as 
(0, pT – ε1), the overdosing interval as (pT + ε2, 1), and the proper dosing interval as (pT – 
ε1, pT + ε2), where ε1 and ε2 are small fractions, such as 0.05, to account for the 
uncertainty around the true target toxicity. A sensitivity analysis showed that the mTPI 
design is robust to the specification of ε values [Ji, 2010]. In addition, ε1 and ε2 could take 
different values to reflect physician preference and the nature of the disease. For 
advanced diseases with few treatment options, higher toxicity rates might be considered 
acceptable, implying a specification of ε2 > ε1. For less-advanced diseases, the two ε 
values could be identical or ε1 > ε2. The three dosing intervals are associated with three 
different dose-escalation decisions. The under-dosing interval corresponds to a dose 
escalation (E), overdosing corresponds to a dose de-escalation (D), and proper dosing 
corresponds to staying at the current dose (S). Given an interval and a probability 
distribution, the UPM of that interval is defined as the probability of the interval divided 
by the length of the interval. The mTPI design calculates the UPMs for the three dosing 
intervals, and the one with the largest UPM implies the corresponding dose-finding 
decision. That decision provides the dose level to be used for future participants. For 
example, if the under-dosing interval has the largest UPM, decision E, to escalate, will be 
executed, and the next cohort of participants will be treated at the next higher dose level. 
Analyses showed that the decision based on the UPM is optimal in that it minimized a 
subsequent expected loss [Ji, 2010]. Under the mTPI design, a trial is terminated when 
either the lowest dose is above the MTD or a pre-specified maximum sample size is 
reached. 
10.2.2. 
2D-CRM 
Dose escalation of GSK3359609 (feladilimab) in combination with GSK3174998 will be 
guided by the 2D-CRM method with a 5-parameter logistic model [Neuenschwander, 
2014]. This model will estimate the probability of observing a DLT at each dose 
combination in the study as DLT information becomes available.  
Let 𝑝1𝑖 and 𝑝2𝑗 denote the single-agent DLT rate of treatment 1 at dose 𝑑1𝑖 (𝑖= 1,…, 𝐼) 
and treatment 2 at dose at dose 𝑑2𝑗 (𝑗= 1,…, 𝐽), respectively, where 𝐼 and 𝐽 represent the 
total number of dose levels for treatment 1 and 2. Similarly, let 𝑝𝑖𝑗 present the DLT rate 
for treatment 1 at dose 𝑑1𝑖 in combination with treatment 2 at dose 𝑑2𝑗. The 5-parameter 
logistic model composes of three components, including two independent single-agent 
logistic model 


 
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and a model introducing the interaction coefficient 𝑒𝜂 in the overall odds of the DLT rate, 
 
where 𝑙𝑛(⋅) is the natural logarithm,  𝑑1
∗ and 𝑑2
∗ are the reference dose for treatment 1 and 
treatment 2. 
The 2D-CRM model implementation will be performed using the Fixed and Adaptive 
Clinical Trial Simulator (FACTS) (Version 6.1 or higher) software from Tessella. 
10.3. 
Dose Expansion 
The expansion phases of GSK3359609 (feladilimab) alone and in combination with 
pembrolizumab are designed to evaluate preliminary clinical activity. Futility 
assessments will be conducted (in select cohorts) to evaluate accumulating data including 
safety, responses, PK and pharmacodynamics. The methodology is based on the 
predictive probability of success if enrollment continues until all planned participants are 
recruited [Lee, 2008].  
In the expansion cohorts, after a minimum of 10 participants have been enrolled in one 
dose/dose level in a cohort, the number of observed responses as well as other available 
date will be used for futility analysis according to the rules summarized in Section 10.6. 
 
 
 
 
10.4. 
Sample Size Considerations 
10.4.1. 
Sample Size Assumptions 
The sample size for each part of the trial was chosen to adequately characterize the 
safety, preliminary clinical activity, PK, and pharmacodynamic marker data according to 
the objectives of each part of the study. 
10.4.2. 
Dose Escalation 
Approximately 166 participants are planned to be enrolled in Parts 1A and 2A. The actual 
total number of participants to be enrolled into Part 1A and Part 2A will depend on the 
number of dose escalations required to establish the MTD/MAD of GSK3359609 
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(feladilimab) alone or in combination with pembrolizumab, chemotherapy 
( pembrolizumab), and GSK3174998. 
To complete dose escalation/safety run-ins in Part 1A and Part 2A GSK3359609 
(feladilimab) in combination with pembrolizumab, or chemotherapy (pembrolizumab) 
(refer to Figure 1), it is estimated that approximately 131 participants will be enrolled. 
Doses of GSK3359609 (feladilimab) to be studied in Part 1A and Part 2A GSK3359609 
(feladilimab) in combination with pembrolizumab or chemotherapy (pembrolizumab) 
will be guided by the mTPI design. Doses of GSK3359609 (feladilimab) in combination 
with GSK3174998 will be guided by the 2D-CRM design (see Section 4.1.1).  
Dose combinations of GSK3359609 (feladilimab) in combination with GSK3174998 will 
be guided by the 2D-CRM design. It is estimated that approximately 35 participants will 
be enrolled in Part 2A GSK3359609 (feladilimab) in combination with GSK3174998, 
including approximately 25 participants completing the DLT evaluation period and an 
additional ~10 participants enrolled at RP2D of GSK3359609 (feladilimab) in 
combination with GSK3174998 for further exploration.  
Details of the scenarios are provided in Table 30. The dose combinations in the table are 
the pre-selected dose combinations that are projected to be used in the trial. The actual 
doses combinations used during the conduct of the trial may be different. 
For the 2D-CRM simulations, the selected reference dose was 80 mg for GSK3359609 
(feladilimab) and 24 mg for GSK3174998.  The prior distributions of each pair of single-
agent parameters (𝑙𝑛(𝛼), 𝑙𝑛(𝛽))𝑇 and the interaction log-odds multiplier 𝜂 as well as the 
prior DLT information described in Section 4.1.1.3.3 were used. The simulation results 
for dose selection under various scenarios are shown in Table 30. Note that GSK3359609 
(feladilimab) in combination with GSK3174998 assumes the single run-in participant 
experiences neither DLT nor drug-related  Grade 2 AE in the DLT observation period 
(i.e. 0/1 in the (8 mg, 8 mg) dose combination). 


 
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Table 30 
Results Under Various Scenarios: GSK3359609 (feladilimab) in 
Combination with GSK3174998 (2DCRM method 
 
GSK3359609 
(feladilimab) 
(mg) 
 
GSK3174998 
(mg) 
Scenario 1: 
Low Toxicity 
Scenario 2: 
Moderate Toxicity 
Scenario 3: 
High Toxicity 
True 
DLT 
Rate 
Percent of 
Trials 
Selecting 
Dose as MTD 
(%) 
True 
DLT 
Rate 
Percent of 
Trials 
Selecting Dose 
as MTD (%) 
True DLT 
Rate 
Percent of 
Trials 
Selecting 
Dose as MTD 
(%) 
8 
8 
0 
0.0 
0 
0.0 
0.05 
0.0 
8 
24 
0.01 
0.0 
0.05 
0.0 
0.1 
0.0 
24 
24 
0.02 
0.1 
0.1 
14.3 
0.25 
61.1 
80 
24 
0.05 
37.9 
0.25 
82.2 
0.45 
38.7 
80 
80 
0.1 
62.0 
0.4 
3.5 
0.55 
0.2 
Note: For each scenario, entries are shaded for optimal choice of dose combination; i.e., a dose with a DLT rate in the 
target toxicity interval [0.16, 0.33) or the highest dose when all dose combinations are under-dosing. 
 
10.4.3. 
Dose Expansion 
Approximately 641 participants will be enrolled in Parts 1B and 2B, including 
approximately 52 participants in Part 1B PK/PD, an average of 210 participants in the 
Part 1B non-PK/PD expansion cohorts (to include 60 participants in the ICOS biomarker 
cohort), and an average of 379 participants in the Part 2B expansion cohorts. In the 
expansion phases of Part 1 and Part 2, the sample size of a cohort or cohorts may target 
approximately 30 participants per cohort. The condition by which the sample size will 
increase depends on the outcome from interim analysis of the null/alternative hypotheses 
that was determined for a tumor type.  
For each tumor indication expansion cohort, an interim analysis will be conducted after 
efficacy data at any dose level are available on a minimum of participants (refer to 
Section 10.6); a separate decision will be made for each disease cohort and dose. The trial 
may continue to enroll the maximum planned sample size to provide a better estimate on 
the distribution of the response rate in the different doses and target populations. 
The trial is not designed to stop early for efficacy but is designed to assess futility if the 
predictive probability of success is 10% or less. The type I error rate, power, and 
predictive probability for assessing futility were determined from stating the minimum 
and maximum sample size, futility stopping rate, and the optimizing criterion as 
minimizing the sample size under null hypothesis.  A very weak informative prior 
distribution with a mean response rate equal to the target response rate is assumed. Thus, 


 
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the predictive probability for the response rate will be primarily driven by the data. The 
detailed decision criteria for all cohorts are documented in Section 10.6. 
For monotherapy therapy expansion cohorts and any PD-1/L1 experienced combination 
therapy expansion cohorts starting with 10 participants in each cohort and allowing for a 
maximum sample size of 30 for each cohort, this design will have an overall type I error 
rate (α) 5%. Under null hypotheses with 10% ORR, the expected sample size of the 
design is 15 participants per cohort; and probability of early termination (PET) is 35% by 
10 participants evaluated and 80% by 20 participants evaluated. Under the alternative 
hypothesis, if the true response rate is 30%, the probability of success is 83%; the 
expected sample size of the design is 28 participants in total and PET is 3% by 10 
participants and 13% by 20 participants. 
For the PD-1/L1 naïve combination expansion cohorts including HNSCC, NSCLC with 
PD-L1 <50%, bladder/urothelial cancer, cervical, and viral-positive cancers, starting with 
10 participants in each cohort and allowing for a maximum sample size of 30 for each 
cohort, this design will have an overall type I error rate (α) 9.8%. Under null hypotheses 
with 20% ORR, the expected sample size of the design is 16 participants per cohort; and 
probability of early termination (PET) is 38% by 10 participants evaluated and 72% by 
20 participants evaluated. Under the alternative hypothesis, if the true response rate is 
40%, the probability of success is 83%; the expected sample size of the design is 28 
participants in total and PET is 5% by 10 participants evaluated and 12% by 20 
participants evaluated. 
For the HNSCC PD-l/L1 treatment naïve pembrolizumab combination expansion cohort 
with PD-L1 CPS <1, a sample size of 30 participants will have at least 90% power to 
detect a difference (P1-P0) of 30% or 40% for the test of hypothesis in the proportion of 
participants with a change in PD-L1 status from CPS <1 to CPS ≥1 with an overall type I 
error rate (α) of 2.5% (Refer to Table 31). Assuming a null proportion (P0) of 10% in the 
number of participants with a change in PD-L1 CPS status, a minimum of 8 participants 
must be observed to conclude a proportion increase of 30% or 40%. 
Table 31 
Sample Size and Power Analysis for HNSCC PD-L1 CPS <1 Cohort 
Null 
proportion 
(P0) 
Alternative 
proportion 
(P1) 
Effect Size 
(H1-H0) 
Power (%) 
Minimum # 
of Converting 
Participants 
Needed for 
Concluding 
an Effect  
0.1 
0.4 
0.3 
95.7 
8 
0.1 
0.5 
0.4 
99.7 
8 
 
In the combined biomarker cohort, a total sample size of 93, which is comprised of 33 
participants from the Part 1B melanoma randomized cohort (with known biomarker 


 
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groups of 7 ICOS high and 26 ICOS low) and 60 participants from the biomarker cohort 
(to target approximately 20 ICOS high participants 40 ICOS low participants under a 
30% prevalence rate assumption) is sufficient to detect a clinically important difference 
of 15% between groups in overall response rate (ORR) using a one-tailed z-test of 
proportions between two groups with 62% power and 10% level of significance. The 
15% difference represents a 25% overall response rate in ICOS high participants and a 
10% response rate in ICOS low participants.  
Sample Size Sensitivity  
For the PD-1/L1 naïve combination expansion cohorts including NSCLC with PD-
L1≥50% and MSI-H/dMMR cancers, starting with 10 participants in each cohort and 
allowing for a maximum sample size of 30 for each cohort, this design will have an 
overall type I error rate (α) 7.9%. Under null hypotheses with 30% ORR, the expected 
sample size of the design is 19 participants per cohort; and probability of early 
termination (PET) is 15% by 10 participants evaluated and 55% by 20 participants 
evaluated. Under the alternative hypothesis, if the true response rate is 50%, the 
probability of success is 80%; the expected sample size of the design is 29 participants in 
total and PET is 1.0% by 10 participants evaluated and 6.2% by 20 participants 
evaluated. 
Randomized Expansion Cohorts 
In the Part 1B and Part 2B melanoma cohorts, participants will be randomly assigned to a 
GSK3359609 (feladilimab) dose level of 0.3 mg/kg or 1.0 mg/kg in combination with 
200 mg of pembrolizumab in a 1:1 allocation ratio with approximately 10 participants per 
dose level. In the Part 2B HNSCC randomization cohort, PD-1/L1 Naive participants will 
be randomly assigned to a GSK3359609 (feladilimab) dose level of 0.1 mg/kg or 1 mg/kg 
or 3.0 mg/kg in combination with 200 mg of pembrolizumab in a 1:1:1 ratio. The Part 2B 
HNSCC randomization cohort may target approximately 20 participants per dose level. 
As in the Part 2B HNSCC randomized cohorts, the Part 2B HNSCC Q6W Cohort 
(Schedule Optimization Cohort) will enroll participants with PD-1/L1 treatment naive 
HNSCC. Participants will be assigned to one dose level of GSK3359609 (feladilimab) 
dosed Q6W in combination with pembrolizumab 400 mg dosed Q6W. Participants will 
be randomized to a GSK3359609 (feladilimab) fixed dose level of 48 mg Q6W or 
160 mg Q6W in combination with pembrolizumab 400 mg in a 1:1 ratio. Similar to the 
HNSCC dose-randomized cohorts, the Part 2B HNSCC Q6W cohort may target 
approximately 20 participants per dose level and based on interim analysis, a dose level 
may be dropped or randomization ratio changed. 
The melanoma randomization cohorts and the HNSCC randomization cohort are 
designed to provide supportive data for the dose selection, primarily on the basis of 
antitumor activity, tolerability, safety and PK/PD measures. It is not designed to evaluate 
formal statistical hypotheses. The dose/exposure response relationship may be explored 
further in the HNSCC population. 
Assuming an ORR of 30% at 0.3 mg/kg and 45% at 1 mg/kg in melanoma randomization 
cohorts, the sample size of ~10 participants per melanoma randomized arm provides a 
probability of 68.3% that a dosage regimen with truly poorer ORR will not be selected 


 
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for further investigation. For the sample size justification purpose, it is assumed that the 
dose regimen with the larger test statistic compared with a 10% ORR in the historical 
control will be selected in melanoma cohorts. 
Assuming an ORR of 16% at 0.1 mg/kg, 30% at 0.3 mg/kg with 30 participants, 30% at 1 
mg/kg and 3 mg/kg in the HNSCC randomization cohort, the sample size of ~20 
participants at randomized arm dose levels provides a probability of 98% that a dosage 
regimen(s) with truly poorer ORR will not be selected for further investigation in 
HNSCC. For the sample size justification purpose, it is assumed that the dose regimen 
with the largest test statistic compared with a 16% ORR in the historical control will be 
selected in the HNSCC cohort.  
Interim analyses may be performed with at least ~15 participants evaluable for ORR, PK 
or PD at HNSCC randomized dose levels to estimate the dose response relationship and 
to ensure that a dosage regimen with truly poorest ORR will not be selected for further 
investigation. A sample size of 15 participants across HNSCC randomized dose levels 
provides a probability of 97% that a dosage regimen with truly poorer ORR will not be 
selected in the case of true ORR of (16%, 30%, 30%, 30%) at dose levels (0.1 mg/kg, 0.3 
mg/kg, 1 mg/kg, 3 mg/kg); please refer to Section 10.4.4 for details. Based on the interim 
analysis, a dose level in the HNSCC randomized cohort may be dropped and/or the 
randomization ratio may be changed. 
For the Schedule Optimization Cohort (Part 2B HNSCC Q6W), an equivalence test 
method was used for comparing the AUC under the Q3W and Q6W dosing schedule, 
where dose 24 mg (Q3W) is compared to dose 48 mg (Q6W) and dose 80 mg (Q3W) is 
compared to dose 160 mg (Q6W). Absence of effect of Q6W on the PK of study 
compound (GSK3359609 (feladilimab) 48 mg/160mg) in combination with 
pembrolizumab (200 mg Q3W or Q6W) will be concluded if the 90% confidence 
intervals for the ratios of geometric means, under Q3W and Q6W, are contained within 
the equivalence interval from 80% to 125% for AUC of the study compound in 
combination with pembrolizumab. If Q6W has no effect on the PK of study compound in 
combination with pembrolizumab (vs. Q3W), data from 20 participants will provide at 
least 90% power with respect to AUC of study compound in combination with 
pembrolizumab, to conclude that Q6W has no effect on the PK. These calculations use 
the approach that assumes the log(AUC) of study compound in combination with 
pembrolizumab are normally distributed with intra-participant coefficients of variation 
(CV) equal to 50%, as estimated from historical data (CV for AUC under Q3W), and that 
the no-effect level is defined as 80% to 125% [Hauschke, 1992]. 
The average sample size in Part 1B is approximately 223 participants in all cohorts under 
the null hypothesis, including approximately 52 participants in the PK/PD cohort, 
approximately 20 participants in the randomized cohort, and approximately 151 
participants in non-randomized cohorts (to include approximately 60 participants in the 
biomarker cohort). 
 
The average sample size in Part 2B is 343 in all cohorts under the null hypothesis, 
including 75 participants in 5 non-randomized PD-1/L1 experienced cohorts, 118 


 
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participants in 7 non-randomized PD-1/L1 naïve cohorts, 30 participants in HNSCC 
CPS<1 cohorts, and 120 participants in randomized cohorts. Similarly, the average 
sample size in Part 1B is 190 participants if two cohorts (non-biomarker) are under the 
alternative hypothesis and the biomarker cohort is under the alternative hypothesis. The 
average sample size in Part 2B is 379 participants if three PD-1/L1 naïve cohorts out of 
HNSCC, NSCLC with PD-L1<50%, bladder/urothelial cancer, cervical, and viral-
positive cancers are under the alternative hypothesis. Note that average sample size under 
the null and alternative hypothesis is only defined for those cohorts assessing the 
predictive probability of success (i.e. futility); refer to Section 10.6. All other cohorts use 
the planned (maximum) sample size. 
10.4.4. 
Sample Size Sensitivity 
Table 32 shows the probability of not selecting a dosage regimen(s) with truly worst 
ORR in the HNSCC cohort based on 10,000 simulations. The calculations are based on 
the following assumptions: 
• An allocation ratio of 1:1:1 among randomized dosage regimens 0.1 mg/kg, 1 
mg/kg, 3 mg/kg 
• The dosage regimen 0.3 mg/kg has 30 participants. 
• The dose regimen with the largest test statistic will be selected in the HNSCC 
cohort; the test statistics are calculated based on the exact test of the superiority 
over a 16% historical ORR. 
Table 32 
Sample Size Sensitivity in the HNSCC Randomized Cohort 
ORR at (0.1, 0.3, 1, 3) mg/kg* 
Sample Size 
per randomized arm 
Prob(Identify a dose with truly 
best ORR) 
(16%, 30%, 30%, 30%) 
5 
97.0% 
10 
98.8% 
20 
98.0% 
30 
98.2% 
(16%, 30%, 30%, 16%) 
5 
94.6% 
10 
97.9% 
20 
96.0% 
30 
96.6% 
(16%, 30%, 45%, 45%) 
5 
63.0% 
10 
74.2% 
20 
98.3% 
30 
99.5% 
* The dose level of 0.3 mg/kg is not a randomized HNSCC dosage regimen and it is estimated that ~30 
participants will be enrolled. 
10.4.5. 
Sample Size Re-estimation or Adjustment 
Sample size re-estimation is not planned for this study. 


 
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10.5. 
Data Analysis Considerations 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the 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. 
In the dose escalation cohorts, the dose will be escalated based on all available data, 
including pharmacodynamic and PK data and the safety profile of prior cohorts. The DLT 
information on all participants enrolled in the trial are used to update the estimated dose-
toxicity relationship and provide supportive information in addition to the inference 
stemming from the adaptive dose finding design in the next escalation/de-escalation 
decision. 
The expansion phases are designed to evaluate preliminary clinical activity. A futility 
assessment will be conducted and enrollment into a disease-specific cohort may be 
paused in order to evaluate accumulating data including safety, clinical responses, and 
pharmacokinetic and pharmacodynamic data. 
10.5.1. 
Analysis Populations 
All Treated Population: defined as all participants who receive at least one dose of 
GSK3359609 (feladilimab). Safety and anti-cancer activity will be evaluated based on 
this analysis population. 
Pharmacokinetic Population: defined as all participants from the All Treated 
Population for whom a PK sample is obtained and analyzed. 
Pharmacodynamic Population: defined as participants in the All Treated Participants 
Population for whom pre- and on-treatment paired and evaluable tumor biopsies or pre- 
and on-treatment blood samples were obtained and analyzed for biomarkers. 
Additional analysis populations may be defined in the RAP. 
10.6. 
Interim Analysis 
No formal interim analyses will be performed using the data generated during the dose 
escalation phases of the study. Available safety and PK/pharmacodynamic data will be 
reviewed after completion of each dose level, refer to Section 4.1.1 for further details. 
This review will support the decision to escalate to the dose level using the rules as 
described in Section 4.1.1 and Section 10.2. The Steering Committee will guide the 
transition of the study from dose escalation to cohort expansion for both monotherapy 
and combination therapy, refer to Section 4.1.1.5 for further details. Analyses may be 
performed at the end of dose escalation to support choice of the RP2D.  
For dose expansion cohorts, continuous assessment of efficacy and safety will be 
performed after first interim analysis based upon a minimum of 10 participants in at least 
one of the expansion cohort with available unconfirmed overall response data.  


 
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Presented in Table 33, Table 34, and Table 35 are the futility interim analysis decision 
rules for the 10th to 30th evaluable participants by specifying the number of participants 
with an unconfirmed ORR for continuing enrollment or stopping for futility when total 
sample size is up to 30. Additional futility looks may be performed, if necessary. These 
rules are intended as a guideline only; the basis of the rules for the Part 2B 
pembrolizumab combination was guided by the response rates reported in 
pembrolizumab approved product label [KEYTRUDA FDA Pharmacology Toxicology 
Review, 2014; KEYTRUDA SPC, 2017]. 
For MSI high or virally mediated cohorts, the assumption and futility assessment may be 
updated based on emerging information. Participants enrolled in Part 1B and Part 2B will 
be stratified by prior PD-1/L1 treatment history (i.e., naïve or experienced; best 
response). The details of these subgroups will be presented in the reporting and analysis 
plan (RAP). 
Actual decisions will depend on the totality of the data and any emerging pembrolizumab 
clinical trial data. Any additional decision rules will be documented in RAP before the 
interim analysis. Should the recommendation to stop for futility be disregarded in favor 
of a decision to continue the trial based on the totality of the data, the overall type I error 
rate of the expansion phase will be inflated. 
Table 33 
Futility Boundary for Monotherapy Expansion Cohorts and PD-1/L1 
Experienced Pembrolizumab Combination Therapy Expansion 
Cohorts 
Number of 
Participantsa 
Number of Responders 
0 
1 
2 
3 
4 
5 
10   
  
  
  
  
  
11   
  
  
  
  
  
12   
  
  
  
  
  
13   
  
  
  
  
  
14   
  
  
  
  
  
15   
  
  
  
  
  
16   
  
  
  
  
  
17   
  
  
  
  
  
18   
  
  
  
  
  
19   
  
  
  
  
  
20   
  
  
  
  
  
21   
  
  
  
  
  
22   
  
  
  
  
  
23   
  
  
  
  
  
24   
  
  
  
  
  
25   
  
  
  
  
  
26   
  
  
  
  
  
27  
 
 
 
 
 
28  
 
 
 
 
 


 
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Number of 
Participantsa 
Number of Responders 
0 
1 
2 
3 
4 
5 
29  
 
 
 
 
 
30  
 
 
 
 
 
a. 
Shaded regions indicate enrollment pause based on meeting futility 
Table 34 
Futility Boundary for PD-1/L1 Naïve Pembrolizumab Combination 
Therapy Expansion Cohorts (HNSCC, NSCLC PD-L1 <50%, 
Bladder/Urothelial Cancer and Viral-positive Cancer) 
Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
10   
  
  
  
  
  
  
  
11   
  
  
  
  
  
  
  
12   
  
  
  
  
  
  
  
13   
  
  
  
  
  
  
  
14   
  
  
  
  
  
  
  
15   
  
  
  
  
  
  
  
16   
  
  
  
  
  
  
  
17   
  
  
  
  
  
  
  
18   
  
  
  
  
  
  
  
19   
  
  
  
  
  
  
  
20   
  
  
  
  
  
  
  
21   
  
  
  
  
  
  
  
22   
  
  
  
  
  
  
  
23   
  
  
  
  
  
  
  
24   
  
  
  
  
  
  
  
25   
  
  
  
  
  
  
  
26   
  
  
  
  
  
  
  
27   
  
  
  
  
  
  
  
28   
  
  
  
  
  
  
  
29   
  
  
  
  
  
  
  
30   
  
  
  
  
  
  
  
a. 
Shaded regions indicate enrollment pause based on meeting futility 
Table 35 
Futility Boundary for PD-1/L1 Naïve Pembrolizumab Combination 
Therapy Expansion Cohort (NSCLC with PD-L150% and MSI-H/ 
dMMR Cancers) 
Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
10 
11 
12 
13 


 
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Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
a. 
Shaded regions indicate enrollment pause based on meeting futility 
The mTPI or 2D-CRM recommended dose-escalation levels, futility assessment rules, 
and posterior probabilities are only guidelines and the totality of the data across all tumor 
types will be considered by the team in decision making.  
Interim analyses of the HNSCC cohort may be performed with at least ~15 participants 
evaluable for ORR, PK or PD at HNSCC randomized dose levels to provide supportive 
data for the dose selection. Dose/Exposure response relationship may be explored. 
10.7. 
Key Elements of the Analysis Plan 
10.7.1. 
Primary Analyses 
As the primary endpoints of Part 1A/B and Part 2A/B include safety and tolerability, the 
primary analyses will be descriptive in nature. 
The All Treated Population will consist of all participants receiving at least one dose of 
study drug and will be used for the analysis of safety and efficacy data. Complete details 
of the analyses will be provided in the RAP. 
10.7.1.1. 
Safety Analyses 
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP. 


 
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10.7.1.2. 
Extent of Exposure 
The number of participants administered study treatment will be summarized according 
to the duration of therapy. 
10.7.1.3. 
Adverse Events 
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE v4 [NCI, 2010]. 
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. AEs, if listed 
in the NCI-CTCAE v 4 [NCI, 2010], will be summarized by the maximum severity 
Grade. Otherwise, the AEs will be summarized by maximum intensity. 
DLTs will be listed for each participant and summarized by dose cohort. 
AEs of special interest will be outlined in the RAP. 
The incidence of deaths and the primary cause of death will be summarized. 
10.7.1.4. 
Clinical Laboratory Evaluations 
Clinical laboratory testing data will be summarized using frequencies and proportions 
according to NCI-CTCAE v4 [NCI, 2010]. Laboratory test results outside the reference 
ranges that do not have an associated NCI-CTCAE criterion will be summarized using 
proportions. Further details will be provided in the RAP. 
10.7.2. 
Secondary Analyses 
A key aim of Part 1B and Part 2B is to demonstrate clinically meaningful response rates 
in each of the disease cohorts using Bayesian-based independent tumor type modeling or 
hierarchical modeling, as described in Section 10.3 [Berry, 2013]. 
10.7.2.1. 
Clinical Activity 
irRECIST is the primary measure of clinical activity for response endpoints; RECISTv1.1 
guidelines are used for disease assessments and PFS. The number and types of responses, 
as outlined in RECIST 1.1 and irRECIST will be listed and summarized separately, as 
appropriate. 
ORR is defined as the percentage of participants with a best overall confirmed CR or a 
PR at any time as per disease-specific criteria (refer to Section 8.3.1 and Appendix 6). 
Disease control rate (DCR) is defined as the percentage of participants with a confirmed 
CR+ PR at any time, plus SD ≥18 weeks allowing for a one-week window per Table 27, 
participants with unknown or missing response will be treated as non-responders that is 
these participants will be included in the denominator when calculating the percentage of 
ORR and DCR. Exact methods for calculated confidence intervals will be given in the 
RAP. 


 
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Duration of response (DOR) will be summarized for participants with a confirmed CR or 
PR and is defined as the time from date of initial confirmed response to the date of 
disease progression or death due to any cause. Censoring rules will follow those of the 
PFS analysis. Time to overall response (TTR) will be summarized for participants with a 
confirmed CR or PR and is defined as the time from date of first dose of study treatment 
to date of first documented confirmed CR or PR. DOR and TTR will be summarized 
using descriptive statistics if data permit. 
PFS is defined as time from the date of first dose of study treatment to the date of disease 
progression according to clinical or radiographic assessment or death due to any cause, 
whichever occurs earliest. For the analysis of PFS, if the participant received subsequent 
anti-cancer therapy prior to the date of documented events, PFS will be censored at the 
last adequate assessment (e.g. assessment where visit level response is CR, PR, or stable 
disease [SD]) prior to the initiation of therapy. Progressive disease (PD) will also be 
defined per standard criteria. Otherwise, if the participant does not have a documented 
date of events, PFS will be censored at the date of the last adequate assessment. Further 
details on rules for censoring will be provided in the RAP.  
OS is defined as time from the date of first dose of study treatment to the date of death 
due to any cause. If a participant does not have a documented date of death, time of death 
will be censored at the date of last contact. 
PFS and OS may be summarized using Kaplan-Meier methods if data permit. 
In the dose escalation phases, best overall response may be evaluated to explore 
preliminary antitumor activity.  
In addition, participants enrolled in the dose escalation and the PK/PD cohorts with the 
same tumor histology/characteristic, prior PD-1/L1 treatment history and treated with the 
same dose regimen may be included in the assessment of futility and final efficacy 
analysis in the expansion cohorts. 
Further details on analysis of clinical activity will be provided in the RAP.  
10.7.3. 
Pharmacokinetic Analyses 
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10.7.5. 
Immunogenicity 
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3359609 (feladilimab) (Part 1 and 2), pembrolizumab, (Part 2 only), GSK3174998 
(Part 2 only), refer to Table 28. These samples may also be tested for presence of 
antibodies that bind to Chinese Hamster Ovary (CHO) host cell proteins such as 
phospholipase B- like 2 (PLBL2). Immunogenicity testing will occur in dosed 
participants then analyzed, summarized descriptively and/or presented graphically. The 
cumulative incidence of ADA, i.e. % of participants that develop ADA, magnitude of the 
response (titers), and duration of the ADA response (transient vs. persistent) may be 
reported. Data permitting, impact of ADA on safety, efficacy, or PK/PD relationships 
may be considered.  
10.7.6. 
Other Analyses 
10.7.6.1. 
Translational Research Analysis 
 
 
 
 
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. 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. 
10.7.6.2. 
Tumor Kinetic Analysis 
 
 
 
 
 
10.7.6.3. 
Patient Reported Outcome 
 
 
 Refer to the RAP for further details. 
11. 
STUDY GOVERNANCE CONSIDERATIONS 
11.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of participants begins. 
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11.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
The study will also be conducted in accordance with ICH GCP, all applicable participant 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki. This includes, but is not limited to, the following: 
• IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable 
o The IEC/IRB, and where applicable the regulatory authority, approve the 
clinical protocol and all optional assessments, including genetic research 
• Obtaining signed informed consent 
o Signed informed consent must be obtained for each participant prior to 
participation in the study. 
• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC) 
• 
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission. 
• 
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, except for the optional assessments, can be initiated. 
• 
GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 
11.3. 
Quality Assurance 
• 
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
• 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified. 


 
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11.4. 
Study and Site Closure 
• 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
• 
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites. 
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action. 
• 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 
• 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 
11.5. 
Records Retention 
• 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location. 
• 
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff. 
• 
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken. 
• 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
• 
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 


 
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institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 
• 
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site. 
11.6. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, 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. 
11.7. 
Steering Committee 
A Steering Committee will be established to review safety, PK, and other clinical data 
during the course of the study to provide an objective interpretation of study results and 
guidance for key decisions. The remit of the Steering Committee will include but not be 
limited to guidance for the transition of the study from dose escalation to cohort 
expansion, the initial starting dose of GSK3359609 (feladilimab) for each combination 
evaluated in Part 2A, the dose of the combination partner if not standard of care, the dose 
escalation design to implement in Part 2A, the selection of specific tumor types or 
features to include in the expansion cohorts, and the selection of the RP2D. In the final 
determination of the MTD and RP2D, all available safety and tolerability data will be 
considered. Pending review of emerging data from this study and under the guidance of 
the Steering Committee, the protocol may be subsequently amended to include 
investigation of additional immune therapy combinations with GSK3359609 
(feladilimab). The remit, membership, roles and responsibilities of the Steering 
Committee are described in a Steering Committee Charter. 


 
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12. 
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13. 
APPENDICES 
13.1. 
Appendix 1:  Abbreviations and Trademarks 
Abbreviations 
2D-CRM 
Two-Dimensional Continual Reassessment Method 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AKT 
v-AKT Murine Thymoma Viral Oncogene 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC(0-t) 
Area under the plasma concentration-time curve from time 
0 to the time of the last quantifiable concentration) 
AUC(0-) 
Area under the concentration-time curve over the dosing 
interval 
-hCG 
Beta-human chorionic gonadotropin 
BAL 
Bronchoalveolar Lavage 
cfDNA 
cell-free DNA 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum observed concentration 
Ctau 
Minimum Observed Concentration; 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CrCl 
Creatinine Clearance 
CRP 
C Reactive Protein 
CRS 
Cytokine Release Syndrome 
CT 
Computed Tomography 
CTC-AE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4  
CV 
Cardiovascular 
DCR 
Disease Control Rate 
DILI 
Drug-induced Liver Injury 
DLT 
Dose Limiting Toxicity 
dMMR 
Deficient mismatch repair 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
EC 
Effective Concentration 
ECHO 
Echocardiography 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 


 
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FDA 
Food and Drug Administration 
eCRF 
Electronic Case Report Form 
G-CSF 
Granulocyte Colony-stimulating Factor 
GCP 
Good Clinical Practice 
GSK3 
Glycogen Synthase Kinase-3 beta 
GSK 
GlaxoSmithKline 
Fc 
Fragment Crystallizable 
FcR 
FC-gamma Receptor 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FTIH 
First-time-in-human 
HNSCC 
Head and Neck Squamous Cell Carcinoma/Cancer 
HPV 
Human Papilloma Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ICOS 
Inducible T Cell Co-Stimulator 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IFN 
Interferon, gamma 
Ig 
Immunoglobulin 
IEC 
Independent Ethics Committees 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
IRR 
Infusion-related Reactions 
irRECIST 
Immune-related RECIST 
IV 
Intravenous 
Kg 
Kilogram(s) 
LVEF 
Left Ventricular Ejection Fraction 
mAb 
Monoclonal Antibody 
MABEL 
Minimum Anticipated Biological Effect Level 
MAD 
Maximum Administered Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
g 
Microgram(s) 
Mg 
Milligram(s) 
mmHg 
Millimeters of Mercury 
mL 
Milliliter(s) 
MPM 
Malignant Pleural Mesothelioma 
MRI 
Magnetic Resonance Imaging 
MSDS 
Material Safety Data Sheet 
CCI


 
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MSEC 
Millisecond(s) 
MSI-H 
Microsatellite Instability-High 
MTD 
Maximum Tolerated Dose 
mTPI 
Modified Toxicity Probability Interval 
MUGA 
Multigated Acquisition Scan 
NCI-CTCAE 
National Cancer Institute - Common Toxicity Criteria for 
Adverse Events  
NK 
Natural Killer 
nM 
Nanomolar(s) 
NOAEL 
No Observed Adverse Effect Level 
NSCLC 
Non-small-cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PD-1 
Programmed Death Receptor Protein 1 
PD-L 
PD Ligand 
PFS 
Progression-free Survival 
PI 
Principal Investigators 
PI3K 
Phosphatidylinositol 3-kinase 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance Status 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
QTc 
Corrected QT interval duration, corrected 
RANKL 
Receptor Activator of Nuclear Factor-kappa B Ligand 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SRM 
Study Reference Manual 
STING 
Stimulator of interferon genes 
TCR 
T Cell Receptor 
TDV 
Treatment Discontinuation Visit 
TIL 
Tumor Infiltrating Lymphocytes 
TNF 
Tumor Necrosis Factor, alpha 
TGFβ 
Tumor Growth Factor, beta 
Treg 
T Regulatory Cells 
TSH 
Thyroid Stimulating Hormone 
TTR 
Time to Response 
CCI
CCI


 
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ULN 
Upper Limit of Normal 
UPM 
Unit Probability Mass 
WNL 
With Normal Limits 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Keytruda 
 


 
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13.2. 
Appendix 2: Immune-related Diseases 
Table 36 
Potential Immune-mediated Diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including 
paralyses/paresis (e.g. 
Bell’s palsy) 
• 
Optic neuritis 
• 
Multiple sclerosis  
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis 
• 
Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome  
• 
Immune-mediated 
peripheral neuropathies 
and plexopathies, 
(including chronic 
inflammatory 
demyelinating 
polyneuropathy, 
multifocal motor 
neuropathy and 
polyneuropathies 
associated with 
monoclonal 
gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic Scleroderma 
(Systemic sclerosis), 
including diffuse 
systemic form and 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
Dermatomyositis, 
Polymyositis, 
• 
Antisynthetase 
syndrome 
• 
Rheumatoid arthritis and 
associated conditions 
including Juvenile 
chronic arthritis and 
Still’s disease) 
• 
Polymyalgia rheumatica  
• 
Spondyloarthritis, 
including ankylosing 
spondylitis, reactive 
arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localized Scleroderma 
(Morphoea) 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel 
disease, including 
Crohn’s disease, 
ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis 
• 
Celiac disease 
• 
Autoimmune pancreatitis 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s 
disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular autoimmune 
syndrome 
• 
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Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including: giant cell 
arteritis such as 
Takayasu's arteritis and 
temporal arteritis.  
• 
Medium sized and/or 
small vessels vasculitis 
including: polyarteritis 
nodosa, Kawasaki's 
disease, microscopic 
polyangiitis, Wegener's 
granulomatosis, Churg–
Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s 
disease (thromboangiitis 
obliterans), necrotizing 
vasculitis and anti-
neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type 
unspecified), Henoch-
Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic 
vasculitis. 
• 
Autoimmune hemolytic 
anemia 
• 
Autoimmune 
thrombocytopenia 
• 
Antiphospholipid 
syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic 
anemia 
• 
Autoimmune 
neutropenia  
• 
Autoimmune 
pancytopenia 
• 
Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune 
diseases (including 
autoimmune uveitis and 
autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
 


 
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13.3. 
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) 
Female participants of reproductive potential must use one of the following highly 
effective contraceptive methods as indicated in Section 5.1 [Hatcher, 2007]: 
• Contraceptive subdermal implant with a <1% rate of failure per year as stated in 
the product label 
• Intrauterine device or intrauterine system that meets the <1% failure rate as stated 
in the product label 
• Oral Contraceptive, combined estrogen and progestogen  
• Injectable progestogen  
• Contraceptive vaginal ring  
• Percutaneous contraceptive patches  
• Male partner sterilization with documentation of azoospermia prior to the female 
participant's entry into the study; this male must be the sole partner for that 
participant.  
o For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the participant or review 
of the participant's medical history for study eligibility, as obtained via a 
verbal interview with the participant or from the participant’s medical 
records. 
For male participants with female partners of child-bearing potential the use of one of 
the following contraceptive methods is required as indicated in Section 5.1: 
Vasectomy with documentation of azoospermia 
• Male condom plus partner use of one of the contraceptive options below:  
o Contraceptive subdermal implant  
o Intrauterine device or intrauterine system  
o Oral Contraceptive, combined estrogen and progestogen  
o Injectable progestogen  
o Contraceptive vaginal ring 
o Percutaneous contraceptive patches 
These lists do not apply to FRP 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. This is an all-inclusive list of 
those methods that meet the GSK definition of highly effective: having a failure rate of 
less than 1% per year when used consistently and, correctly and, when applicable, in 
accordance with the product label. For non-product methods (e.g., male sterility), the 
investigator determines what is consistent and correct use. The investigator is responsible 


 
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for ensuring that participants understand how to properly use these methods of 
contraception. 


 
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13.4. 
Appendix 4: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines 
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. 
Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment 
Following drug-induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. 
Clinical outcomes vary by drug, with nearly 50% fatality with halothane re-administered 
within one month of initial injury. However, some drugs seldom result in recurrent liver 
injury or fatality.   
Risk factors for a fatal drug rechallenge outcome include: 
• 
Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia) 
• 
jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total) 
• 
participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR 1.5 
• 
SAE or fatality has earlier been observed with drug rechallenges [Papay, 2009; 
Hunt, 2010] 
• 
evidence of drug-related nonclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010]. 
Rechallenge refers to resuming study treatment following drug-induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a 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 favorable.   
Approval by GSK for rechallenge with study treatment can be considered where: 


 
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• 
Investigator requests consideration of rechallenge with study treatment for a 
participant who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available.   
• 
Ethics Committee or IRB approval for rechallenge with study treatment must be 
obtained, as required. 
• 
If the rechallenge is approved by GSK Medical Governance in writing, the 
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. 
• 
If after study treatment rechallenge, participant meets protocol-defined liver 
chemistry stopping criteria, study treatment must be permanently discontinued.  
• 
GSK Medical Monitor, and the Ethics Committee or IRB as required, must be 
informed of the participant’s outcome following study treatment rechallenge.  
• 
GSK to be notified of any AEs, as per Section 8.4.1. 
AND/OR 
Restart Following Transient Resolving Liver Stopping Events NOT Related 
to Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, and acute viral hepatitis).  Furthermore, there should be 
no evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not 
be associated with HLA markers of liver injury. 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• 
Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has a 


 
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human leukocyte antigen (HLA) genetic marker associated with liver injury (e.g., 
lapatinib, abacavir, amoxicillin/clavulanate) are reviewed and excluded. 
• 
Ethics Committee or IRB approval of study treatment restart must be obtained, as 
required. 
• 
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. 
• 
GSK Medical Monitor, and the Ethics Committee or IRB as required, must be 
informed of the participant’s outcome following study treatment restart. 
• 
GSK to be notified of any AEs, as per Section 8.4.1. 
 


 
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13.5. 
Appendix 5: NYHA Functional Classification System for 
Heart Failure 
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994] 
provides a simple way of classifying the extent of heart failure. It places participants in 
one of four categories based on the level of limitation experienced during physical 
activity: 
Class 
Symptoms 
Class I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath). 
Class II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased. 
 


 
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13.6. 
Appendix 6: 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 must 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 must be noted as CT on the eCRF. 
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required. 
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended. 
Minimum size of a measurable baseline lesion must 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 must be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible, the same 
scanner should be used. 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray. 
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 


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


 
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Immune-Related RECIST Response Criteria 
Evaluation of target lesions 
New, measurablea 
lesions  
Incorporated into tumor burden 
New, nonmeasurable 
lesions  
Do not define progression (but preclude CR) 
irCR 
Disappearance of all lesions in two consecutive observations not 
less than 4 weeks apart. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
irPR 
30% decrease in tumor burden compared with baseline in two 
observations at least 4 weeks apart 
irSD 
30% decrease in tumor burden compared with baseline cannot be 
established nor 20% increase compared with nadir 
irPDb 
At least 20% increase in tumor burden compared with nadir (at any 
single time point) in two consecutive observations at least 4 weeks 
apart. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.   
a. 
Measurable per RECIST v1.1. 
b. 
Treatment decisions will be based upon the immune-related RECIST guidelines. 
Antitumor response based on total measurable tumor burden 
For Modified RECIST based on RECIST v1.1 and Immune-Related RECIST [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 five lesions in total and a maximum of 
two 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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Evaluation of non-target lesions 
Definitions for assessment of response for non-target lesions are as follows: 
• 
Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. 
<10 mm short axis). 
• 
Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline 10 mm short axis. 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
• 
Not Applicable (NA): No non-target lesions at baseline. 
• 
Not Evaluable (NE): Cannot be classified by one of the four preceding definitions. 
Note: 
• 
In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. 
• 
Sites of non-target lesions, which are not assessed at a time point based on the 
assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable"). 
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 must 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 would be 
declared. 
Evaluation of overall response 
Table 37 presents the overall response at an individual disease assessment time-point 
accounting for all possible combinations of 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 37 
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 
Abbreviations: CR = Complete response, PR = Partial response, SD = Stable disease, PD = Progressive disease, 
NA = Not applicable, and NE = Not Evaluable 
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 investigator’s 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 days as 
defined in the RAP. 
• 
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 must be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.   
 


 
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13.7. 
Appendix 7: ECOG Performance Status 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled. Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
Dead. 
a. 
Oken, 1982. 
 


 
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13.8. 
Appendix 8: Events of Clinical Interest 
These are selected events considered of clinical interest; they may be non-serious AEs or 
SAEs. Events of Clinical Interest are different from Adverse Events of Special Interest 
(AESI) in that an AESI is defined as an adverse event of potential immunologic etiology. 
Such events recently reported after treatment with other immune modulatory therapy 
include colitis, uveitis, hepatitis, pneumonitis, diarrhea, endocrine disorders, and specific 
cutaneous toxicities, as well as other events that may be immune mediated. 
 For the time period beginning with the administration of the first dose of study treatment 
through 30 days following discontinuation of study treatment, any ECI, or follow up to an 
ECI, whether or not related to the study drug(s), must be reported to the Sponsor either by 
electronic media (eCRF [required for AE/SAE] or email) or phone call within the time 
frame indicated by event. ECI include: 
1. Overdose of study drug(s) (GSK3359609 (feladilimab) and pembrolizumab (Part 
2 only) that is not associated with clinical symptoms or abnormal laboratory 
results must be reported within 5 days. 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*This ECI must be reported within 24 hours. 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
Investigators/study coordinators/designated site personnel are required to record these 
experiences in the eCRF (as described in the eCRF completion guidance document) 
and to provide supplemental information (such as medical history, concomitant 
medications, investigations, etc.) about the event. 


 
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13.9. 
Appendix 9: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
13.9.1. 
Definition of Adverse Events 
Adverse Event Definition: 
• 
An AE is any untoward medical occurrence in a participant or clinical 
investigation participant, temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal product. 
 
Events meeting AE definition include: 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This must 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; progression of the cancer under study is not 
considered an adverse event unless it is considered to be drug-related by the 
investigator. However, the signs and symptoms and/or clinical sequelae resulting 
from lack of efficacy will be reported if they fulfill the definition of an AE or 
SAE.  
 
Events NOT meeting definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 


 
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• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
13.9.2. 
Definition of Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc.). 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE: 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
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 hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
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 out-patient setting. Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. If in doubt as to whether 
“hospitalization” occurred or was necessary, the AE must be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in disability/incapacity 
NOTE: 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 


 
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• 
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 or 
prevent everyday life functions but do not constitute a substantial disruption 
e. Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These should also 
be considered serious. 
• 
Examples of such events are invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse 
g. Is associated with liver injury and impaired liver function defined as: 
• 
ALT  3xULN and total bilirubin*  2xULN (>35% direct), or 
• 
ALT  3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and 
ALT  3xULN and total bilirubin  2xULN, then the event is still to be reported as an 
SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
participants receiving anticoagulants. If INR measurement is obtained, the value is to 
be recorded on the SAE form. 
• 
Refer to Section 7.4 for the required liver chemistry follow-up instructions 
13.9.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) 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 


 
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• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
13.9.4. 
Recording of AEs and SAEs 
AEs and SAE Recording: 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in 
the CRF 
• 
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 instance, all participant identifiers, with the exception 
of the subject number, will be blinded on the copies of the medical records prior to 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
13.9.5. 
Evaluating AEs and SAEs 
Assessment of Severity: 
• 
The investigator will make an assessment of severity for each AE and SAE 
reported during the study and will assign a grade according to the NCI-CTCAE 
v4.0 [NCI, 2010]. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment 
and the occurrence of each AE/SAE. 
• 
A "reasonable possibility" is meant to convey there is evidence, facts 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. 


 
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• 
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. 
• 
The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment. 
• 
For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations when an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event prior to the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist. This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator may be requested to provide GSK with a copy 
of any post-mortem findings, including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 
13.9.6. 
Reporting of SAEs to GSK 
SAE reporting to GSK via electronic data collection tool 
• 
Primary mechanism for reporting SAEs to GSK will be the electronic data 
collection tool 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool provided in the SRM. Refer to the SRM for 
details on submitting the paper SAE forms.  


 
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• 
If paper SAE forms are used to report a SAE, the site will need to enter the serious 
adverse event data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool 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 on a paper SAE form 
or to the Medical Monitor by telephone. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol and in the 
SRM on the Sponsor/Medical Monitor Contact Information page. 
 
13.9.7. 
Collection of Pregnancy Information 
Action to be taken if pregnancy occurs in a female participant 
• 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 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 as described in Section 13.9.6. 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. 
• Discontinue study treatment if applicable; participant may be withdrawn from the 
study. 


 
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Action to be taken if pregnancy occurs in a female partner of a male study 
participant 
• 
Investigator will attempt to collect pregnancy information on any female partner of a 
male study participant who becomes pregnant while participating in this study.  This 
applies only to participants who are randomized to receive study medication. 
• 
After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 24 hours of learning of the partner’s pregnancy. 
• 
Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 


 
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13.10. 
Appendix 10: CKD-EPI Formula 
CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3/4/5 
defined by eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula 
[Levey, 2009]. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
 


 
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13.11. 
Appendix 11: Genetic Research 
Genetics – Background 
Genetic Research Objectives and Analyses 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:  
• 
Response to medicine, including GSK3359609 (feladilimab), pembrolizumab, other 
immune therapy under investigation in this study, or any concomitant medicines; 
• 
Cancer susceptibility, severity, and progression and related conditions  
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate. 
Study Population 
Any participant who is enrolled in the study can participate in genetic research. Any 
participant who has received an allogeneic bone marrow transplant must be excluded 
from the genetic research. 
Study Assessments and Procedures 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  
• 
A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the participant has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory manual. 
The DNA from the blood sample may undergo quality control analyses to confirm 
the integrity of the sample. If there are concerns regarding the quality of the sample, 
then the sample may be destroyed. The blood sample is taken on a single occasion 
unless a duplicate sample is required due to an inability to utilize the original sample. 


 
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The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to the 
participant by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).  
Samples will be stored securely and may be kept for up to 15 years after the last 
participant completes the study, or GSK may destroy the samples sooner.  GSK or those 
working with GSK (for example, other researchers) will only use samples collected from 
the study for the purpose stated in this protocol and in the informed consent form.  
Samples may be used as part of the development of a companion diagnostic to support 
the GSK medicinal product. 
Participants can request their sample to be destroyed at any time. 
Informed Consent 
Participants who do not wish to participate in the genetic research may still participate in 
the study. Genetic informed consent must be obtained prior to any blood being taken. 
Participant Withdrawal from Study 
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant will be 
given a choice of one of the following options concerning the genetic sample, if already 
collected: 
• 
Continue to participate in the genetic research in which case the genetic DNA sample 
is retained 
• 
Discontinue participation in the genetic research and destroy the genetic DNA 
sample  
If a participant withdraws consent for genetic research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records.  
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.  
• 
If a participant withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.   
• 
Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate.  
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the 
participant does not meet the entry criteria for participation in the study, then the 
investigator must instruct the participant that their genetic sample will be destroyed. No 


 
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forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process. In this instance a sample destruction form will not be 
available to include in the site files. 
Provision of Study Results and Confidentiality of Participant’s Genetic Data 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’s medical care at the time of the study, 
unless required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 


 
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13.12. 
Appendix 12 - Country Specific Requirements 
13.12.1. 
COUNTRY SPECIFIC REQUIREMENTS (JAPAN) 
Effective Date: 
2020 
Version: 
JPN_01 
13.12.1.1. Study Conduct Considerations 
13.12.1.1.1. 
Regulatory and Ethical Considerations 
The study will be conducted in accordance with “the Ministerial Ordinance on the 
Standards for the Conduct of Clinical Trials of Medicinal Products (MHW Notification 
No.28 dated 27th March, 1997)” and Pharmaceuticals and Medical Devices Act. 
The statement “I acknowledge that I am responsible for overall the study conduct.” on the 
Investigator Protocol Agreement Page means the investigator’s responsibility defined by 
Japanese GCP. 
GSK will submit the Clinical Trial Notifications (CTN) to the regulatory authorities in 
accordance with Pharmaceuticals and Medical Devices Act before conclusion of any 
contract for the conduct of the study with study sites. 
13.12.1.1.2. 
Informed Consent 
Prior to participation in the study, the investigator should fully inform the potential 
participant (and/or the participant's legally acceptable representative) of the study 
including the written information. The investigator should provide the participant (and/or 
the participant's legally acceptable representative) ample time and opportunity to inquire 
about details of the study. The participant (and/or the participant’s legally acceptable 
representative) should sign and personally date the consent form. The participant may 
consider the content of the written information at home. The person, who conducted the 
informed consent discussion and the study collaborator giving supplementary 
explanation, where applicable, should sign and personally date the consent form. If an 
impartial witness is required, the witness should sign and personally date the consent 
form. The investigator should retain this signed and dated form (and other written 
information) together with the source medical records, such as clinical charts (in 
accordance with the rules for records retention, if any, at each medical institution) and 
give a copy to the participant (and/or the participant’s legally acceptable representative). 
13.12.1.2. Notes on "Permitted Medications and Non-Drug Therapies" 
Of "Permitted Medications and Non-Drug Therapies" accepted in this study (Section 
6.9.1), blood products and growth factors (e.g., granulocyte-macrophage colony-
stimulating factor, macrophage colony-stimulating factor, erythropoiesis-stimulating 
factor, platelet-stimulating agent) include drugs that are not approved for the treatment of 
events associated with cancer chemotherapy in Japan. 


 
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13.12.1.3. Considerations for Resuming Lactation After the Last Dose of Study 
Treatment 
If the participant who discontinues lactation and participates in the study strongly wishes 
to resume lactation after the last dose of study treatment, the investigator will decide to 
resume lactation after 125 days (5 times the elimination half-life of GSK3359609 
(feladilimab)) from the last dose of study treatment, taking into account the condition, 
circumstances and aftertreatment of the participant. 
13.12.1.4. Screening test for Hepatitis B for Japanese Participants Enrolled in 
Part 2A Chemotherapy Safety Run-in Cohorts 
In addition to HBsAg test, HBcAb and HBcAb tests are required at screening for 
Japanese participants who will be enrolled in the Part 2A chemotherapy safety run-in 
cohorts (refer to Section 8.4.8). 
For HBcAb and/or HBsAb positive Japanese participants, to monitor for hepatitis B 
reactivation it is required  to monitor liver function tests and HBV DNA levels in 
accordance with guidelines from the Japan Society of Hepatology (Japan Society of 
Hepatology, 2019).  
13.12.1.5. Genetics (Protocol Appendix 11) 
In this study, genetics may be evaluated after review by the ethical review committee 
established by GSK in accordance with Japanese ethical guidelines for human 
genome/gene analysis research, see Section 8.7 for further details on genetic research. 
Where local regulations and IRB/IEC allow, a 6 ml blood sample will be taken for 
Deoxyribonucleic acid (DNA) extraction. 
 


 
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13.13. 
Appendix 13 – Substantial Protocol Changes from Previous 
Amendment 
Substantial Amendment Changes with Rationale 
Table 28: Elimination of the collection of the following: 
-pembrolizumab pharmacokinetics and immunogenicity 
-Pharmacodynamic immunogenicity blood samples:  
- Pharmacokinetic Blood Specimens 
 
GSK3359609 (feladilimab) (Q3W & Q6W) 
 
GSK3174998 
 
Chemotherapy (excluding 5-FU) 
 
Fluorouracil (5-FU) 
-Removed Table 29 and renumbered tables accordingly 
-Updated tumor biopsy requirement 
Rationale: Assessments no longer required 
 
 
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Section 5.4.1: Clarification of processes for hepatoxicity. The following language was 
added: 
If any of the following criteria are met, all study drugs must be discontinued and 
hepatotoxicity events must be reported to GSK within 24 hours. Complete liver event 
eCRF forms and SAE forms if the event also meets the criteria for SAE reporting. The 
eCRF liver event form does not appear automatically, but must be manually activated. 
If treatment is held or discontinued do not restart/rechallenge the participant with study 
treatment unless all the requirements described in this section have been met, including 
clearance from the sponsor. Liver chemistry stopping criteria are provided 
below.Rationale: Reinforce alignment with GSK safety reporting standard operating 
procedures. 
 
Section 1 update, removal of section 4.3.0, and removal of Table 30 (renumbered 
accordingly): Elimination of Retreatment Option (Second Course) along with 
Clarification of End of Study and Off Study procedures 
Rationale: Alignment with programmatic changes 
Updated Table 27 Efficacy assessment and standarsRationale: Alignment with 
programmatic changes 
 
Updated Section 8.5 to remove requirements for sample collection, sample analysis, and 
immunogenicity requirements. 
Rationale: Alignment with programmatic changes 
 
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204691 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A Phase I Open Label Study 
of GSK3359609 Administered Alone and in Combination 
with Anticancer Agents in Participants with Selected 
Advanced Solid Tumors 
Compound Number  : GSK3359609 
Effective Date  
: 06 May 2022 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol TMF-11734800. 
• 
This RAP is intended to describe the requirements during the study that include 
support for dose escalation decisions to progress to the next dose level or transition 
to expansion phase, including determination of the MTD or MAD for GSK3359609 
or futility analysis for expansion phase of GSK3359609 delivered as monotherapy or 
in combination.  
• 
This RAP will be provided to the study team members to convey the content of the 
reporting efforts, specifically Statistical Analysis Complete (SAC) for the final 
analysis. 
 
RAP Author(s): 
 
Study Statistician, RD Clinical Statistics 
 
 
 
 
 
 
 
 
 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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RAP Team Approvals: 
Reviewer 
Date 
Approval Method 
 
  
25APR2022 
Email 
Principal Programmer  
RD Clinical Programming 
  
Clinical Pharmacology Manager 
RD CPMS 
25APR2022 
Email 
Value Evidence and Outcomes 
22APR2022 
Email 
RD Clinical Science 
22APR2022 
Email 
RD Clinical Safety 
25APR2022 
Email 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval Method 
 
06 May 2022 
eTMF 
Statistics Leader 
RD Clinical Statistics 
 
06 May 2022 
eTMF 
Programming Leader 
RD Clinical Programming 
PPD
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS 
PAGE 
TABLE OF CONTENTS .................................................................................................. 3 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
RAP Amendments ........................................................................................ 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design .............................................................................................. 14 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 17 
2.4.1. 
Part 1A and Part 2A Dose Escalation/Safety Run-in .................... 17 
2.4.2. 
Part 1B GSK3359609 Monotherapy Expansion/ Part 2B 
GSK3359609 Combination with Pembrolizumab 
Expansion of PD-1/L1 Experienced Participants .......................... 17 
2.4.3. 
Part 2B GSK3359609 Combination with Pembrolizumab 
Expansion of PD-1/L1 Naïve Participants .................................... 18 
3. 
PLANNED ANALYSES .......................................................................................... 19 
3.1. 
Interim Analyses ......................................................................................... 19 
3.2. 
Final Analyses ............................................................................................ 22 
4. 
ANALYSIS POPULATIONS ................................................................................... 22 
4.1. 
Protocol Deviations ..................................................................................... 23 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 23 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 23 
5.1.1. 
Study Population .......................................................................... 24 
5.1.2. 
Safety .......................................................................................... 26 
5.1.3. 
Efficacy ........................................................................................ 26 
5.1.4. 
PK................................................................................................ 26 
5.2. 
Baseline Definitions .................................................................................... 26 
5.3. 
Multicentre Studies ..................................................................................... 27 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 27 
5.4.1. 
Covariates and Other Strata ........................................................ 27 
5.4.2. 
Examination of Subgroups ........................................................... 27 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 28 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 28 
6. 
STUDY POPULATION ANALYSES ....................................................................... 29 
6.1. 
Overview of Planned Study Population Analyses ........................................ 29 
6.2. 
Disposition of Participants ........................................................................... 29 
6.3. 
Demographic and Baseline Characteristics ................................................. 30 
6.4. 
Concomitant Medications ............................................................................ 31 
6.5. 
Extent of Exposure ..................................................................................... 31 
6.6. 
Subsequent Anticancer Therapies .............................................................. 32 


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7. 
PRIMARY ENDPOINTS ANALYSES ...................................................................... 33 
7.1. 
Adverse Events Analyses ........................................................................... 33 
7.2. 
Adverse Events of Special Interest Analyses .............................................. 34 
7.3. 
Deaths and Serious Adverse Events ........................................................... 35 
7.4. 
Adverse Events Leading to Discontinuation of Administered 
Treatment ................................................................................................... 36 
7.5. 
Events of Clinical Interest Analyses ............................................................ 36 
7.6. 
Pregnancies ................................................................................................ 36 
7.7. 
Clinical Laboratory Analyses ....................................................................... 36 
7.7.1. 
Analyses of Liver Function Tests ................................................. 38 
7.8. 
Other Safety Analyses ................................................................................ 38 
7.8.1. 
ECG ............................................................................................. 38 
7.8.2. 
Vital Signs .................................................................................... 39 
7.8.3. 
LVEF ........................................................................................... 40 
7.8.4. 
Performance Status ..................................................................... 40 
8. 
SECONDARY ENDPOINTS ANALYSES ............................................................... 41 
8.1. 
Pharmacokinetic Analyses .......................................................................... 41 
8.1.1. 
Endpoint / Variables ..................................................................... 41 
8.1.2. 
Summary Measure ...................................................................... 42 
8.1.3. 
Population of Interest ................................................................... 43 
8.1.4. 
Statistical Analyses / Methods ..................................................... 43 
8.2. 
Population Pharmacokinetic Analyses ........................................................ 44 
8.3. 
Efficacy Analyses ........................................................................................ 44 
8.3.1. 
Endpoints / Variables ................................................................... 45 
8.3.2. 
Summary Measure ...................................................................... 45 
8.3.3. 
Population of Interest ................................................................... 53 
8.3.4. 
Statistical Analyses / Methods ..................................................... 53 
9. 
OTHER STATISTICAL ANALYSES ....................................................................... 54 
9.1. 
Pharmacodynamic and Biomarker Analyses ............................................... 54 
9.2. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................ 54 
9.3. 
Pharmacogenetic Analyses ........................................................................ 54 
9.4. 
Immunogenicity Analyses ........................................................................... 54 
9.6. 
Patient Reported Outcomes ........................................................................ 55 
10. REFERENCES ....................................................................................................... 56 
11. APPENDICES ........................................................................................................ 57 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 57 
11.1.1. 
Exclusions from Per Protocol Population ..................................... 57 
11.2. 
Appendix 2: Schedule of Activities .............................................................. 58 
11.2.1. 
Protocol Defined Schedule of Events ........................................... 58 
11.3. 
Appendix 3: Assessment Windows ............................................................. 59 
11.3.1. 
Definitions of Assessment Windows for Analyses ........................ 59 
11.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 60 
11.4.1. 
Study Phases .............................................................................. 60 
11.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 61 
11.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 62 
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11.5.1. 
Reporting Process ....................................................................... 62 
11.5.2. 
Reporting Standards .................................................................... 62 
11.5.3. 
Reporting Standards for Pharmacokinetic .................................... 63 
11.6. 
Appendix 6: Derived and Transformed Data ............................................... 64 
11.6.1. 
General ........................................................................................ 64 
11.6.2. 
Study Population .......................................................................... 65 
11.6.3. 
Efficacy ........................................................................................ 65 
11.6.4. 
Safety .......................................................................................... 66 
11.6.5. 
Pharmacokinetic .......................................................................... 67 
11.6.6. 
Population Pharmacokinetic (PopPK) .......................................... 67 
11.6.7. 
Pharmacodynamic and Biomarker ............................................... 68 
11.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 68 
11.7.1. 
Premature Withdrawals ................................................................ 68 
11.7.2. 
Handling of Missing Data ............................................................. 68 
11.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 72 
11.8.1. 
Laboratory Values ........................................................................ 72 
11.8.2. 
ECG ............................................................................................. 72 
11.8.3. 
Vital Signs .................................................................................... 72 
11.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 73 
11.9.1. 
Population Pharmacokinetic (PopPK) Dataset 
Specification ................................................................................ 73 
11.9.2. 
Population Pharmacokinetic (PopPK) Methodology ..................... 73 
11.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 75 
11.10.1. Pharmacokinetic / Pharmacodynamic Dataset 
Specification ................................................................................ 75 
11.10.2. Pharmacokinetic / Pharmacodynamic Methodology ..................... 75 
11.11. Appendix 11: Abbreviations & Trade Marks ................................................ 77 
11.11.1. Abbreviations ............................................................................... 77 
11.11.2. Trademarks ................................................................................. 79 
11.12. Appendix 12: List of Data Displays.............................................................. 80 
 


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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report (CSR) for Protocol: 
Revision Chronology: 
2015N238345_00 
26-JAN-2016 
Original 
2015N238345_01 
14-MAR-2016 
Amendment No. 1 
2015N238345_02 
14-NOV-2016 
Amendment No. 2 
2015N238345_03 
13-DEC-2017 
Amendment No. 3 
2015N238345_04 
30-OCT-2018 
Amendment No. 4 
2015N238345_06 
14-MAR-2019 
Amendment No. 5 
2015N238345_11 
27-FEB-2020 
Amendment No. 6 
2015N238345_13 
08-APR-2020 
Amendment No. 7 
2015N238345_15 
09-OCT-2020 
Amendment No. 8 
TMF-11734800 
20-AUG-2021 
Amendment No. 9 
Note: Country specific amendments are not listed here since all changes were later incorporated into the 
global protocol amendments. 
This RAP will cover all of the individual CSR cycles compiled throughout the study with 
the support of documents such as a list of TLFs and mock shells within each reporting 
effort (\arwork\gsk3359609\mid204691).  The cohorts included within each cycle are: 
CSR Cycle 
Study Cohort Numbers1  
CSR Cycle 1 
100, 300, 202, 401 
CSR Cycle 2 
201, 600 
CSR Cycle 3  
All remaining cohorts 
1. See Section 5.1.1 for description for each cohort number. 
CSR Cycles 2 and 3, following the decision to discontinue the asset, will be a reduced set 
of displays compared to the analysis described in this document, as indicated in the 
supporting mock shell document. 
The above table corresponds to data processing cycles. The actual organization of binders 
in the GSK archive and the themes of CSR’s will reflect the division of data into 
pharmacokinetics/pharmacodynamics, including safety and preliminary efficacy. The 
efficacy data is intended to be the output of all the expansion cohorts. In turn, the data 
dissemination plan includes 2 publications, the first based on dose escalation, 
pharmacokinetics, and safety and the second based on analysis of clinical efficacy. 
The mapping of cohorts in the CSR documents and the subsequent publications is 
summarized in the following table: 
Binder/ CSR Document 
Cohorts 
Dose Escalation- PK-PD-Safety 
100, 201, 300, 600, 500-510 
Dose Expansion – Preliminary Efficacy 
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1.1. 
RAP Amendments 
Revision chronology:  
RAP Section 
Amendment Details 
Reporting and Analysis Plan_Study204691_Final_Vn 07APR2020 
Reporting and Analysis Plan_Study204691_Amendment1_Final_V1 [18OCT2020]  
5.1 
• 
Refined definition and scope of analyses for efficacy analysis cohort 
9.5 
• 
Updated PRO section for future analyses 
Multiple sections 
• 
Updates to output descriptions based on new IDSL standards  
Multiple sections 
• 
Additions of text clarity  
Reporting and Analysis Plan_Study204691_Amendment2_Final_V1 [TBC]  
Multiple sections 
• 
Updates in line with Protocol Amendment 9 
Multiple sections 
• 
Updates to cover differing display approaches across CSR cycles 
Multiple sections 
• 
Removal of individual crossover outputs. Addition of crossover/re-
treatment listing 
Section 5.4.2 
• 
Confirmation of subgroups and ranges 
Section 7.5 
• 
Addition of listings for impact of Covid-19 
Section 8.3.2.5 
• 
Update TTR to RECIST v1.1 (as per other time to event) 
Section 9.6 
• 
Removal of all PRO analyses except compliance 
Multiple sections 
• 
Additions of text clarity and corrections 
 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis 
specified in the current protocol. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Part 1 GSK3359609 (feladilimab) Monotherapy 
Primary 
• 
To determine the safety, tolerability, MTD or the 
MAD of GSK3359609 (feladilimab) 
• 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
• 
To determine the recommended dose of 
GSK3359609 (feladilimab) for further 
exploration 
 
• 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications, 
PK, pharmacodynamic activity, antitumor 
activity 
• 
To evaluate the antitumor activity of 
GSK3359609 (feladilimab) 
• 
ORR1, DCR1, PFS1, OS, TTR1,2, DoR1,2 
• 
To characterize the PK properties of 
GSK3359609 (feladilimab) 
• 
Plasma PK parameters such as Cmax, Ctau, 
AUC (0-) as data permit 
• 
To determine immunogenicity 
• 
ADA incidence by dose level/dose 
• 
Exploratory  
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Objectives 
Endpoints 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; Cmax= 
maximum observed concentration; Ctau=minimum observed concentration; DCR=disease control rate; 
DLT=dose limiting toxicity; DNA=deoxyribonucleic acid; DoR=duration of response; 
 
 
 
IHC=immunohistochemistry; irRECIST=immune-related RECIST; MAD=maximum administered dose; 
MTD=maximum tolerated dose; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PK=pharmacokinetic; 
 
 RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic 
acid; SAE=serious adverse events; TTR=time to response 
1. irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, DCR); 
RECISTv1.1 guidelines are used for PFS, DoR, TTR and disease assessments. 
2. TTR and DoR will be evaluated if data permit. Refer to Protocol Section 10.7.2.1 for further 
details on the possible analysis of antitumor activity in the dose escalation cohorts. 
 
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Objectives 
Endpoints 
Part 2 GSK3359609 (ICOS) in Combination with Pembrolizumab or GSK3174998 (anti-OX40) 
 
Primary 
• 
To determine the safety, tolerability, MTD or the 
MAD of GSK3359609 (feladilimab) in 
combination with pembrolizumab or 
GSK3174998 (anti-OX40) 
• 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
• 
To determine the recommended dose(s) and 
schedule of GSK3359609 (feladilimab) in 
combination with pembrolizumab or 
GSK3174998 for further exploration 
• 
To determine the recommended dose(s) of 
GSK3359609(feladilimab) and GSK3174998 in 
combination 
• 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications, 
PK, pharmacodynamic activity, antitumor 
activity 
 
• 
To evaluate the antitumor activity of 
GSK3359609 (feladilimab) in combination with 
pembrolizumab or GSK3174998 
• 
ORR1, DCR1, PFS1, OS, TTR1,2 DoR1,2 
• 
To characterize the PK properties of 
GSK3359609 (feladilimab), pembrolizumab or 
GSK3174998 when administered in 
combination 
• 
GSK3359609 (feladilimab), GSK3174998, and 
pembrolizumab PK parameters such as Cmax, 
Ctau, AUC (0-) as data permit 
• 
To determine immunogenicity of GSK3359609 
(feladilimab), pembrolizumab or GSK3174998 
when administered in combination 
• 
ADA incidence of each drug by dose level/dose 
• 
Exploratory  
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Objectives 
Endpoints 
Abbreviations: ADA=anti-drug antibody; AE=adverse events; AUC=area under the curve; Cmax= maximum observed 
concentration; Ctau=minimum observed concentration; CPS=combined positive score; DCR=disease control rate; 
DLT=dose limiting toxicity; DNA=deoxyribonucleic acid; DoR=duration of response; 
 
 
 HNSCC=head and neck squamous cell carcinoma; 
IHC=immunohistochemistry; irRECIST=immune –related RECIST; MAD=maximum administered dose; 
MTD=maximum tolerated dose; ORR=overall response rate; OS=overall survival; PD-L1= programmed cell death 
receptor 1-ligand 1; PFS=progression-free survival; PK=pharmacokinetic; 
 
 RECIST=Response Evaluation Criteria in Solid Tumors; 
RNA=ribonucleic acid; SAE=serious adverse events; TTR=time to response 
1. 
irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, DCR); RECISTv1.1 
guidelines are used for PFS, DoR, TTR and disease assessments. 
2. 
 
 
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Objectives 
Endpoints 
Part 2A GSK3359609 (feladilimab) Combination with Chemotherapies (Pembrolizumab) 
Primary 
• 
To determine the safety, tolerability, of 
GSK3359609 (feladilimab) in combination with 
standard of care chemotherapies  
pembrolizumab 
• 
AEs, SAEs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
• 
To determine the recommended dose of 
GSK3359609 (feladilimab) for further 
exploration 
• 
AEs, SAEs, DLTs, changes in safety/ laboratory 
assessment parameters, dose modifications, 
PK, pharmacodynamic activity, antitumor 
activity 
• 
To characterize the PK properties of 
GSK3359609 (feladilimab), chemotherapies and 
pembrolizumab 
• 
Plasma PK parameters such as Cmax, and 
Ctau as data permit 
• 
To determine immunogenicity of GSK3359609 
(feladilimab) and pembrolizumab 
• 
ADA incidence by dose level/dose 
• 
Exploratory  
Abbreviations: ADA=anti-drug antibody; AE=adverse events; Cmax= maximum observed concentration; 
Ctau=minimum observed concentration; DCR=disease control rate; DLT=dose limiting toxicity; DNA=deoxyribonucleic 
acid; DoR=duration of response; irRECIST=immune –related RECIST; ORR=overall response rate; OS=overall 
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survival; PFS=progression-free survival; PK; pharmacokinetic; RECIST=Response Evaluation Criteria in Solid Tumors; 
RNA=ribonucleic acid; SAE; serious adverse events; TTR=time to response 
1. 
irRECIST is the primary measure of clinical activity for response endpoints (i.e., ORR, DCR); RECISTv1.1 
guidelines are used for PFS, DoR, TTR and disease assessments. 
2. 
TTR and DoR will be evaluated if data permit; Refer to Protocol Section 10.7.2.1 for further details. 
 


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2.3. 
Study Design 
Figure 1 
Study Design 
Overview of Study Design and Key Features 
 
 
 
 
Abbreviations: 5-FU=fluorouracil; Cis=cisplatin; dMMR= deficient mismatch repair; Gem=gemcitabine; 
IHC = immunohistochemistry; MSI-H= microsatellite instability-high; NSCLC=non-small cell lung cancer; 
Pac=paclitaxel; PD-L1=programmed death; HNSCC= head and neck squamous cell cancer. 
#: a subset of HNSCC participants will be randomly assigned to one of 3 doses of GSK3359609 
(feladilimab) (refer to Table 6 of protocol) in combination with 200mg of pembrolizumab 
*Participants enrolled in the Part 2B cohorts (GSK3359609 (feladilimab)/pembrolizumab combination) 
may be stratified by PD-L1 IHC status and prior PD-1/L1 treatment 
1. The number of participants allocated to any Part is an estimate.  
2. The number of cohorts indicated in any Part is an estimate. 
3. Expansion cohorts may increase enrollment following outcome of interim analyses (refer to 


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Overview of Study Design and Key Features 
Protocol Section 10.6 for details); enrollment in the overall population will not exceed 867 
participants except by a Protocol amendment. 
4. Participants enrolled in Part 1 (GSK3359609 (feladilimab) monotherapy) upon disease 
progression may be permitted to receive GSK3359609 (feladilimab) in combination with 
pembrolizumab (defined as crossover). 
 
Note: Within Protocol Amendment 7, three additional combinations with GSK3359609 (feladilimab) were 
added: dostarlimab or dostarlimab plus cobolimab or bintrafusp alfa (M7824). These were removed within 
the current protocol and therefore will not be mentioned in further sections.  However, any data collected 
for the few participants enrolled into these cohorts will be listed as well as displaying the number of 
participants within each cohort in the summary of study populations table. 
 
GSK3359609 (feladilimab) will be written as GSK3359609 throughout the remainder of the document. 
 
Design 
Features 
• 
As illustrated in Figure 1, the study will be conducted in two parts (Part 1 
GSK3359609 monotherapy and Part 2 GSK3359609 combination therapy) whereby 
each part consists of a dose escalation phase (A) followed by a cohort expansion 
phase (B). 
• 
In Part 1 of the study, all participants will receive GSK3359609 monotherapy.  
• 
In Part 2, participants will be enrolled into expansion cohorts defined by tumor 
histology or by a specific characteristic. 
• 
In Part 2A of the study, participants will receive GSK3359609 in combination with: 
• 
Pembrolizumab  
• 
Standard of care chemotherapy regimens (Docetaxel, Pemetrexed/Carboplatin, 
Paclitaxel/Carboplatin, Gemcitabine/Carboplatin, Fluorouracil (5-
FU)/Carboplatin, Fluorouracil (5-FU)/Cisplatin) with and without pembrolizumab  
• 
GSK3174998 (OX40) 
• 
In Part 2B all participants will receive GSK3359609 in combination with 
pembrolizumab 
• 
In Part 2C (Japanese expansion cohort) participants will receive GSK3359609 at one 
of the three defined dose levels (0.3, 1, 3 mg/kg) in combination with 200mg of 
pembrolizumab. 
• 
Participants receiving GSK3359609 monotherapy (Part 1) except the Japan and 
China PK/pharmacodynamic cohorts (Part 1C and Part 1D) may be allowed to 
crossover to receive GSK3359609 in combination with pembrolizumab provided the 
participant has documented objective progression and should not have experienced 
any drug-related AEs ≥Grade 3 or SAEs of any Grade. 
• 
Each part and phase of the study includes a screening period, a treatment period, 
and a follow-up period.  For participants who meet all eligibility criteria and register 
into the study, the maximum duration of treatment with GSK3359609 is expected to 
be two years; in those participants who receive combination therapy, the maximum 
duration of treatment with GSK3359609 in combination with pembrolizumab 
(chemotherapy) or GSK3174998 is expected to be two years.  
• 
The duration of chemotherapy treatment will be according to institutional practice but 
should be a minimum of 4 cycles (cycle=21 days); the maximum duration of 
GSK3359609 and pembrolizumab treatment is expected to be 2 years; thus, if the 
course of chemotherapy treatment is completed after a minimum of four cycles or 
discontinued prior to completion of a minimum of 4 cycles, GSK3359609 and 
pembrolizumab treatment may continue. 
• 
The maximum follow-up period for safety assessments will be 90 days from the date 


CONFIDENTIAL 
 
 
 
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Overview of Study Design and Key Features 
of the last dose of study treatment. The expected maximum follow-up period for 
survival and subsequent anticancer therapy will be two years from the date of the last 
dose of study treatment. 
• 
All participants who permanently discontinue study treatment for any reason will be 
followed for survival and new anticancer therapy (including radiotherapy) every 12 
weeks until death, termination of the overall study or a cohort by the sponsor or until 
the participant has been followed for two years. 
• 
Participants who attain a CR and discontinue study treatment prior to completing 35 
cycles OR in participants with RECISTv1.1 confirmed SD, PR or CR who discontinue 
study treatment after completing 35 cycles of study treatment may be eligible to 
receive up to an additional 18 cycles (approximately 1 year) of study treatment upon 
disease progression within the initial treatment phase. Maximum treatment duration 
for participants participating in HNSCC Q6W Dosing cohort is 8 cycles 
(approximately 1 year) for both GSK3359609 and pembrolizumab. This is termed re-
treatment or second course treatment. 
 
Dosing 
• 
The weight-based dose levels of GSK3359609 monotherapy in Part 1A are displayed 
in Table 1 in protocol. Dose range in unit (mg/kg) starts from 0.001, then 0.003, 0.01, 
0.03, 0.1, 0.3, 1.0, 3.0 to 10.0 Q3W.  
• 
The starting dose of GSK3359609 in combination with pembrolizumab (fixed at 200 
mg) for Part 2A will be two dose levels below a dose that was shown to be tolerated 
and at which a pharmacodynamics effect was observed during monotherapy in Part 
1A. 
• 
The starting dose of 80 mg Q3W GSK3359609 will be combined with standard of 
care chemotherapy regimens in Part 2A. A reduced dose of GSK3359609 (24 mg) 
may also be used. Chemotherapy will only be provided for 4-6 cycles (according to 
standard practice). Treatment with docetaxel and pemetrexed may continue beyond 
6 cycles according to standard practice. Participants will be split into those receiving 
200mg pembrolizumab or not.  
• 
Part 2A GSK3174998 and GSK3359609 combination dose escalation phase will 
initiate at starting doses of 8 mg Q3W for GSK3359609 and GSK3174998 and 
increase up to 24 and 80 mg Q3W in a staggered approach across the two 
treatments.  
• 
Any dose level(s)/doses in the dose escalation phases (Part 1A and Part 2A) may be 
selected for expansion of the study in Part 1B (GSK3359609 monotherapy) and Part 
2B (GSK3359609 in combination with pembrolizumab fixed at 200 mg) with 3 weekly 
cycles. 
• 
The Part 1B Biomarker Cohort will have a fixed dose of 24mg Q3W. 
• 
The Part 2B HNSCC Q6W cohort will investigate GSK3359609 at an alternative 
dosing schedule of once every 6 weeks; participants will be randomly assigned to 
GSK3359609 doses of 48 mg or 160 mg Q6W in combination with pembrolizumab 
400 mg administered at the schedule of Q6W. 
• 
In Part 1C (Japanese PK/PD cohort) and Part 1D (Chinese PK/PD cohort) 
participants will receive GSK3359609 monotherapy at selected previously defined 
escalation dose levels Q3W. 
• 
In Part 2C (Japanese expansion cohort) participants will receive GSK3359609 at 
selected previously defined escalation dose levels in combination with 200mg of 
pembrolizumab Q3W. 
 
Time & 
• 
Refer to Appendix 2: Schedule of Activities 


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Overview of Study Design and Key Features 
Events 
Treatment 
Assignment 
• 
Participants enrolled in Part 1 of the study will be assigned to receive GSK3359609 
monotherapy in an open-label fashion. Participants enrolled in Part 2 of the study will 
be assigned to a combination treatment either in the order in which screening 
assessments are completed or in the order in which dose escalation phase for each 
combination agent has been initiated. 
Interim 
Analysis 
• 
The data collected on the study will be reviewed on a regular ongoing basis.  
Available safety and PK/pharmacodynamic data will be reviewed after completion of 
each dose level.  For dose expansion cohorts (aggregating dose escalation cohort 
and PK/PD cohort), continuous assessment of efficacy and safety data will be 
performed to ensure futility and safety across the cohorts.  Actual decisions will 
depend on the totality of the data and any emerging pembrolizumab clinical trial data.  
Full details will be provided in the documents area of each specific interim analysis 
study area. 
2.4. 
Statistical Hypotheses / Statistical Analyses 
2.4.1. 
Part 1A and Part 2A Dose Escalation/Safety Run-in 
In Part 1A and Part 2A, the primary aims are determining the recommended dose or 
doses for further exploration, the safety profile, and the pharmacology of GSK3359609 
monotherapy and in combination with pembrolizumab, chemotherapy (pembrolizumab), 
or GSK3174998 in participants with advanced solid malignancies. Descriptive methods 
will be used in analyses of the data obtained from this study. No formal statistical 
hypotheses are being tested. 
2.4.2. 
Part 1B GSK3359609 Monotherapy Expansion/ Part 2B 
GSK3359609 Combination with Pembrolizumab Expansion of PD-
1/L1 Experienced Participants 
The assumptions for the secondary endpoint of overall response rate (ORR) underlying 
the design are detailed below: 
The null hypothesis for the secondary endpoint ORR is: 
H0: p=10%. 
The alternative hypothesis is: 
HA: p=30%. 
In the Part 1B Biomarker Cohort, the null hypothesis for the difference in ORR of 
GSK3359609 in the biomarker positive population (i.e., ICOS high) and 
biomarker negative population (i.e., ICOS low) is given below: 
The null hypothesis is: 
H0: pH – pL ≤ 0% 
The alternative hypothesis is: 
HA: pH – pL > 0%, 
where pH represents ORR in the ICOS high population and pL represents ORR in the 
ICOS low population. 


CONFIDENTIAL 
 
 
 
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2.4.3. 
Part 2B GSK3359609 Combination with Pembrolizumab 
Expansion of PD-1/L1 Naïve Participants  
For each cohort, the aim is to test the null hypothesis that the ORR for the combination is 
equal to the historical response rate of monotherapy pembrolizumab which is expected to 
be between 15% to 40% according to tumor types selected for the study. In the 
KEYNOTE-001 trial, the reported pembrolizumab monotherapy ORR was 19.4% in 495 
NSCLC participants across different histologies and PD-L1 status [Garon, 2015].  
Overall, the aim of each expansion cohort is to detect an improvement in the ORR of the 
combination therapy compared with pembrolizumab monotherapy in the range of 20% 
over the null, with power of at least 80% and no more than a 10% type 1 error rate.   
• PD-1/L1 naïve Expansion Cohorts (HNSCC, NSCLC PD-L1 <50%, 
Bladder/Urothelial and Viral-positive Cancers) 
The null hypothesis for ORR is: 
H0: p=20% 
The alternative hypothesis is: 
 
HA: p=40% 
• PD-1/L1 Treatment-Naïve HNSCC PD-L1 CPS <1 Cohort 
The null hypothesis for proportion of participants with a change in PD-L1 CPS status 
from <1 to ≥1 is: 
H0: p=10% 
The alternative hypothesis is: 
HA: p=40% 
• PD-1/L1 naïve Expansion Cohort (NSCLC PD-L1 50% and MSI-H/dMMR 
Cancers) 
The null hypothesis for ORR is: 
H0: p=30% 
The alternative hypothesis is: 
HA: p=50% 


CONFIDENTIAL 
 
 
 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
During the dose escalation phases of the study, no formal interim analyses will be 
performed. Available safety and PK/pharmacodynamic data will be reviewed after 
completion of each dose level. This review will support the decision to escalate to the 
dose level using the corresponding dose-escalation guidelines based on Modified 
Toxicity Probability Interval (mTPI) or 2D-CRM design and totality of data across all 
tumor types will be considered in decision making. The Steering Committee will guide 
the transition of the study from dose escalation to cohort expansion for both monotherapy 
and combination therapy, refer to Section 4.1.1.5 in the protocol for further details. 
Within the dose expansion (DE) phase of the study,  
• after a minimum of 10 evaluable participants in one of the DE cohorts have been 
enrolled in one dose/dose level in a cohort, the number of observed best 
unconfirmed responses as well as other available data will be used for futility 
analysis according to the rules summarized in protocol Section 10.6. 
• continuous assessment of efficacy and safety will be performed after first interim 
analysis (based upon a minimum of 10 evaluable participants in at least one of the 
disease-specific cohorts with available unconfirmed overall response data). 
• administrative interim analysis (inflection point) will include: 
o safety data accumulated to the inflection point analysed by dose level.  
o efficacy data accumulated to the inflection point analysed by tumor type, 
PD-1/L1 treatment (naïve/experienced), and prior anti-cancer therapy 
status. 
o efficacy analysis summarized by sub-tumor type if data permit, such as (1) 
EGFR/ALK/ROS1 mutated patients in NSCLC; (2) Ocular in Melanoma 
patients; (3) Squamous in HNSCC patients. 
o efficacy analyses summarized within three different cohorts, (1) regimen 
cohort; (2) combined cohort; (3) analysis cohort as indicated in the 
specifications document (\arwork\gsk3359609\mid204691) provided for 
each reporting effort. 
Presented in Table 1, Table 2 and Table 3 are the futility interim analysis decision rules 
for the 10th to 30th evaluable participants by specifying the number of participants with 
an unconfirmed ORR per irRECIST for continuing enrollment or stopping for futility 
when total sample size is up to 30. The efficacy analysis cohort used for interim analysis 
is defined by using disease specific regimen cohort, in addition to pooling participants 
from DE and PK/PD regimen cohorts where primary tumor type and/or histology is the 
same at the recommended dose level (primarily 0.1 mg/kg for monotherapy and 0.3 
mg/kg for combination therapy). 
 


CONFIDENTIAL 
 
 
 
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Table 1 
Futility Boundary for Monotherapy Expansion Cohorts and PD-1/L1 
Experienced Pembrolizumab Combination Therapy Expansion 
Cohorts 
Number of 
Participantsa 
Number of Responders 
0 
1 
2 
3 
4 
5 
10 
  
  
  
  
  
  
11 
  
  
  
  
  
  
12 
  
  
  
  
  
  
13 
  
  
  
  
  
  
14 
  
  
  
  
  
  
15 
  
  
  
  
  
  
16 
  
  
  
  
  
  
17 
  
  
  
  
  
  
18 
  
  
  
  
  
  
19 
  
  
  
  
  
  
20 
  
  
  
  
  
  
21 
  
  
  
  
  
  
22 
  
  
  
  
  
  
23 
  
  
  
  
  
  
24 
  
  
  
  
  
  
25 
  
  
  
  
  
  
26 
  
  
  
  
  
  
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
 
a. 
Shaded regions indicate enrollment pause based on meeting futility 
Table 2 
Futility Boundary for PD-1/L1 Naïve Pembrolizumab Combination 
Therapy Expansion Cohorts (HNSCC, NSCLC PD-L1 <50%, 
Bladder/Urothelial Cancer and Viral-positive Cancer) 
Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
10 
  
  
  
  
  
  
  
  
11 
  
  
  
  
  
  
  
  
12 
  
  
  
  
  
  
  
  
13 
  
  
  
  
  
  
  
  
14 
  
  
  
  
  
  
  
  
15 
  
  
  
  
  
  
  
  
16 
  
  
  
  
  
  
  
  
17 
  
  
  
  
  
  
  
  
18 
  
  
  
  
  
  
  
  
19 
  
  
  
  
  
  
  
  
20 
  
  
  
  
  
  
  
  


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Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
21 
  
  
  
  
  
  
  
  
22 
  
  
  
  
  
  
  
  
23 
  
  
  
  
  
  
  
  
24 
  
  
  
  
  
  
  
  
25 
  
  
  
  
  
  
  
  
26 
  
  
  
  
  
  
  
  
27 
  
  
  
  
  
  
  
  
28 
  
  
  
  
  
  
  
  
29 
  
  
  
  
  
  
  
  
30 
  
  
  
  
  
  
  
  
a. 
Shaded regions indicate enrollment pause based on meeting futility 
Table 3 
Futility Boundary for PD-1/L1 Naïve Pembrolizumab Combination 
Therapy Expansion Cohort (NSCLC with PD-L150% and MSI-H/ 
dMMR Cancers) 
Number of 
Participantsa 
Number of Responders 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
a. 
Shaded regions indicate enrollment pause based on meeting futility 


CONFIDENTIAL 
 
 
 
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3.2. 
Final Analyses 
Final analyses will be performed on a selected group (i.e., subset) of cohorts and groups 
will be reported in CSR cycles on a rolling basis as outlined in Section 1.   
The planned analyses for primary, secondary, and key exploratory endpoints will be 
performed at each CSR cycle after the completion of the following sequential steps: 
1. All required database cleaning activities have been completed and final database 
release (DBR) have been declared by Data Management on the participant data 
within the selected cohorts. Note: Database freeze (DBF) will be declared at study 
conclusion for all cohorts  
2. Randomization codes (where applicable) have been distributed according to RandAll 
NG procedures.  
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• 
All participants who were screened for 
eligibility 
• 
Screening Status 
Enrolled 
• 
All participants who passed screening and 
entered the study.  
• 
Disposition 
• 
Demographics 
All Treated 
• 
All participants who received at least one 
dose of study treatment.  
• 
Study Population  
• 
Efficacy 
• 
Safety 
All Evaluable 
• 
Participants in All Treated who had at least 
one post baseline disease assessment or 
have progressed, died, or permanently 
discontinued from treatment. 
• 
Efficacy in interim analyses of 
efficacy cohorts (pooling of 
DE+PK/PD participants with 
similar histologies and same 
dose level). 
Crossover 
• 
Participants who were treated in 
monotherapy and then crossover to the 
combination therapy with pembrolizumab. 
• 
Study Population 
Re-treatment 
• 
Participants who responded on their 
original treatment and were re-treated 
following progression. 
• 
Study Population 
Pharmacokinetic 
• 
Participants in the All Treated Population 
for whom a PK sample is obtained and 
analysed. 
• 
PK 
Pharmacodynamic 
• 
Participants in the All Treated Population 
for whom pre- and on-treatment paired and 
evaluable tumor biopsies or pre- and on-
treatment blood samples were obtained 
and analyzed for biomarkers. 
• 
N/A: Will be determined and 
used by the EMU (biomarker) 
group only. Will not be part of 
the CSRs. 
DLT Evaluable 
• 
All Treated Population in the dose 
escalation phase or PK/PD cohorts, who 
completed the 28-day DLT observation 
period or experienced a DLT during the 
determinative period (28 days). 
• 
DLT (including Parts 1A, 2A, 
1C, 1D, 2C) 


CONFIDENTIAL 
 
 
 
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4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [14OCT2021 Version 7].  
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations are captured and categorized on the protocol deviations 
dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided for 
the All Treated Population. This will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
For participants who were treated in monotherapy and then crossed over to the 
combination therapy with pembrolizumab or those who responded to therapy on their 
original treatment and were re-treated following progression, only the data prior to 
crossover/re-treatment will be included throughout the analysis unless otherwise stated.   


CONFIDENTIAL 
 
 
 
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5.1.1. 
Study Population  
Study population will be displayed by study part and regimen cohort and will be labelled 
and separated as follows: 
 
Cohort Descriptions 
Cohort [RandAll NG] 
Data Displays for Reporting  
Regimen 
Code 
Description 
Study Part 
Description 
Order in 
TLF  
100 
Part 1A-Dose Escalation 0.001 
mg/kg 
Monotherapy  
Part 1 
DE 
1 
201 
Part 1B-Cohort Expansion 1 
PK/PD 
2 
204 
Part 1B-Cohort Expansion 4 
CERVICAL 1.000 mg/kg 
3 
202 
Part 1B-Cohort Expansion 2 
HNSCC 1.000 mg/kg 
4 
203 
Part 1B-Cohort Expansion 3 
NSCLC 0.300 mg/kg 
5 
203 
Part 1B-Cohort Expansion 3 
NSCLC 1.000 mg/kg 
6 
207 
Part 1B-Cohort Expansion 7 
MELANOMA 0.300 mg/kg 
7 
207 
Part 1B-Cohort Expansion 7 
MELANOMA 1.000 mg/kg 
8 
206 
Part 1B-Cohort Expansion 6 
MSI-H/DMMR 0.300 or 1.000 
mg/kg 
9 
208 
Part 1B-Cohort Expansion 8 
BLADDER/UROTHELIAL 
0.300 or 1.000 mg/kg 
10 
205 
Part 1B-Cohort Expansion 5 
VIRAL-POSITIVE 1.000 mg/kg 
11 
290 
Biomarker, Part 1 
BIOMARKER 24 mg 
12 
700 
Part 1C - GSK3359609 (Japan 
PK/PD cohort) 
GSK3359609 (JAPAN PK/PD 
COHORT) 
13 
800 
Part 1D-China PK/PD Cohort 
GSK3359609 (CHINA PK/PD 
COHORT) 
14 
300 
Part 2A-Dose Escalation: 
pembrolizumab 
Part 2 Combination 
with Pembrolizumab 
DE 
1 
407 
Part 2B-Cohort Expansion 7 
CERVICAL 0.300 mg/kg 
2 
408 
Part 2B-Cohort Expansion 8 
HNSCC 0.100 mg/kg 
3 
401 
Part 2B-Cohort Expansion 1 
HNSCC 0.300 mg/kg 
4 
408 
Part 2B-Cohort Expansion 8 
HNSCC 1.000 mg/kg 
5 
408 
Part 2B-Cohort Expansion 8 
HNSCC 3.000 mg/kg 
6 
402 
Part 2B-Cohort Expansion 2 
NSCLC 0.300 mg/kg 
7 
406 
Part 2B-Cohort Expansion 6 
MELANOMA 0.300 mg/kg 
8 
406 
Part 2B-Cohort Expansion 6 
MELANOMA 1.000 mg/kg 
9 
405 
Part 2B-Cohort Expansion 5 
MSI-H/DMMR 0.300 mg/kg 
10 


CONFIDENTIAL 
 
 
 
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Cohort Descriptions 
Cohort [RandAll NG] 
Data Displays for Reporting  
Regimen 
Code 
Description 
Study Part 
Description 
Order in 
TLF  
403 
Part 2B-Cohort Expansion 3 
BLADDER/UROTHELIAL 
0.300 mg/kg 
11 
404 
Part 2B-Cohort Expansion 4 
VIRAL-POSITIVE 0.300 mg/kg 
12 
409 
Part 2B-Cohort Expansion 9 
HNSCC_CPS<1 
13 
410 
Part 2B-Cohort Expansion 10 
HNSCC 48 mg 
14 
410 
Part 2B-Cohort Expansion 10 
HNSCC 160 mg 
15 
600 
Combination Dose Escalation - 
GSK3174998, all dose levels 
DE_OX40 
16 
701 
Part 2C - 
GSK3359609/Pembrolizumab 
(Japan PK/PD cohort) 
GSK3359609/ 
PEMBROLIZUMAB (JAPAN 
PK/PD COHORT) 
17 
500 
Chemotherapy: DOCETAXEL 
Part 2 
Combination with 
Chemotherapies 
(±Pembrolizumab) 
GSK3359609 + 
CHEMOTHERAPY 
1 
501 
Chemotherapy: 
PEMETREXED/CARBOPLATI
N 
502 
Chemotherapy: 
PACLITAXEL/CARBOPLATIN 
503 
Chemotherapy: 
GEMCITABINE/CARBOPLATI
N 
504 
Chemotherapy: Fluorouracil / 
Cisplatin 
505 
Chemotherapy: Fluorouracil / 
Carboplatin 
506 
Chemotherapy: Pemetrexed / 
Carboplatin / Pembrolizumab 
GSK3359609 + 
PEMBROLIZUMAB + 
CHEMOTHERAPY 
2 
507 
Chemotherapy: Paclitaxel / 
Carboplatin / Pembrolizumab 
508 
Chemotherapy: Gemcitabine / 
Carboplatin/ Pembrolizumab 
509 
Chemotherapy: Fluorouracil / 
Cisplatin / Pembrolizumab 
510 
Chemotherapy: Fluorouracil / 
Carboplatin / Pembrolizumab 
For chemotherapy, due to the low numbers of participants, cohorts will be grouped into 
chemotherapy cohorts with and without pembrolizumab.  The only table displayed by 
regimen cohort will be the summary of study populations. 


CONFIDENTIAL 
 
 
 
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5.1.2. 
Safety 
Safety tables and figures for CSR cycles 1 and 2 will be displayed by regimen cohort as 
indicated for Study Population in Section 5.1.1 as well as by dose level received.  For the 
CSR cycle 3, since little difference was seen between the dose levels in the first CSR 
cycles, Study Parts 1A, 1B, 2A and 2B will be displayed by regimen cohort or 
chemotherapy group only.  However, the data from the regional study parts 1C, 1D and 
2C will continue to be displayed by regimen cohort and dose level. 
 
Listings will display both regimen cohort and dose level throughout. 
 
5.1.3. 
Efficacy 
For CSR Cycle 1, efficacy will be presented by efficacy analysis cohorts.  Efficacy 
analysis cohorts are defined by tumor histology and/or by a specific tumor-agnostic 
characteristic. These cohorts are comprised of participants from the dose expansion phase 
(e.g., 1B, 2B) as well as participants from the dose escalation phase (e.g., 1A, 2A) if the 
cohort criteria are met.  Efficacy for dose escalation cohorts will not be presented 
separately.  Efficacy cohorts may be further classified according to prior PD-1/L1 therapy 
as detailed in Section 5.4.2. Differences between the regimen cohorts and the efficacy 
analysis cohorts will be provided in the footnotes of efficacy outputs at the CSR. 
 
For CSR Cycle 2 and 3, efficacy will be displayed by regimen cohort as indicated for 
Study Population in Section 5.1.1.  Study parts 1C, 1D and 2C will not be included and 
the Chemotherapy cohorts will only be displayed in the response listing.  For Part 2 
Combination with Pembrolizumab, the tumor types Bladder/Urothelial, Cervical, HNSCC, 
Melanoma and NSCLC will be further classified according to prior PD-1/L1 therapy.  
 
5.1.4. 
PK 
PK concentration and parameter summary tables and figures and 
 
tables will be displayed by study cohort and dose level. Study cohort is the same as 
regimen cohort described for Study Population in Section 5.1.1 but without the split by 
dose.  The PK parameter analyses tables will be pooled across appropriate study cohorts 
within dose level to increase the sample size.  The PK parameter summary tables may 
also pool across study cohorts. 
 
Listings will display both regimen cohort and dose level throughout. 
5.2. 
Baseline Definitions  
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. For laboratory data, baseline will be the latest non-missing 
pre-dose value from central lab. If no central lab value is available, the latest non-missing 
pre-dose value from local lab will be used.  
Unless otherwise stated, if baseline data are missing, no derivation will be performed, and 
baseline will be set to missing. 
CCI


CONFIDENTIAL 
 
 
 
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Parameter 
Study Assessments Considered as Baseline  
(Part 1 and Part 2) 
Baseline Used in 
Data Display 
Screening 
Day 1 (Pre-Dose) 
[Efficacy] 
Tumor imaging/Clinical 
exam 
X 
 
Screening 
[Safety] 
Hematology/Clinical 
Chemistry/Urinalysis 
X 
X 
Day 1 (if performed, 
otherwise Screening) 
Thyroid 
X 
 
Screening 
Troponin 
 
X 
Day 1 
Physical Exam 
X 
X 
Day 1 
ECOG PS 
X 
X 
Day 1 
Vital signs 
X 
X 
Day 1 
12-lead ECG 
X 
X 
Day 1 
[Other] 
PRO (patient reported 
outcome)   
 
X 
Day 1 
PK/Immunogenicity 
 
X 
Day 1 
Biomarker/PD 
X 
X 
Screening1 
1. Based on screening unless visit has been classified as tumor imagining /clinical exam, then Day 1. 
 
Only for Part 1, ECG is collected in triplicate at selected time points (see Table 25 in the 
protocol for details); in these cases, the mean of the available values will be used as 
baseline (even if less than 3).  All values collected need to be prior to treatment start.   
 
5.3. 
Multicentre Studies 
In this multicentre global study, enrollment will be presented by country and 
investigative site. Data from all study sites will be integrated and no controlling for 
center-effect will be considered in the statistical analyses. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
There are no planned covariates or strata considered for this study. 
5.4.2. 
Examination of Subgroups 
Efficacy for participants in combination with pembrolizumab (Part 2) will be summarized 
by prior PD-1/L1 treatment (Naïve, Experienced) for selected cohorts as detailed in 
Section 5.1.3. Efficacy for participants within selected cohorts will also be summarized 
by HPV status (HPV+, HPV-, Non-oropharynx, Unknown) if the sample size permits.  
Additionally, key efficacy tables will be repeated by PD-L1 IHC Status and ICOS IHC 
intra tumoral result status. The following cut offs will be used for PD-L1 IHC status: 


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Cohort 
CPS or TPS 
Reference line(s) 
Cut off 
Bladder/Urothelial 
CPS 
10 
<10 
>=10 
NSCLC 
TPS 
50 
<1 
1-49 
>=50 
HNSCC1 
CPS 
1 & 20 
<1 
1-19 
>=20 
Cervical 
CPS 
1  
<1 
>=1 
1. HNSCC includes all doses from the cohorts HNSCC 0.3 mg/kg, HNSCC Randomized and HNSCC 
Q6W.  HNSCC CPS<1 is not included since all participants fall into the <1 category.  
The following cut offs will be used for ICOS IHC status of ICOS-High and ICOS-
Low/Neg respectively: 
Cohort 
Part 1 
Part 2 
Bladder/Urothelial 
>=10, <10 
>=10, <10 
NSCLC 
>=10, <10 
>=5, <5 
HNSCC 
>=10, <10 
>=5, <5 
Cervical 
>=10, <10 
>=10, <10 
Melanoma1 
>=10, <10 
>=5, <5 
1. Includes the Melanoma Biomarker 24mg regimen cohort. 
5.5. 
Multiple Comparisons and Multiplicity 
There are no planned adjustments for multiple comparisons or multiplicity. 
 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
Section 11.3 
Appendix 3: Assessment Windows 
Section 11.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
Section 11.5 
Appendix 5: Data Display Standards & Handling Conventions 
Section 11.6 
Appendix 6: Derived and Transformed Data 
Section 11.7 
Appendix 7: Reporting Standards for Missing Data 
Section 11.8 
Appendix 8: Values of Potential Clinical Importance 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population displays will be based on the All Treated Population and displayed 
by regimen cohort as specified in Section 5.1.1, unless otherwise stated.  
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior therapy, medical condition, 
concomitant medications and exposure will be based on GSK Core Data Standards.  
6.2. 
Disposition of Participants 
A summary of the number of participants in each of the analysis populations, described in 
Section 4, will be provided using the Enrolled Population. A summary will also be 
provided for the number and percentage of participants in each of the subgroups defined 
in Section 5.4 for the All Treated Population. In addition, the number and percentage of 
participants treated by country and center will be summarized using the Enrolled 
Population and well as the All Treated Population if these populations are different.  A 
summary table and listing identifying reasons for screening failures will be presented 
based on the Screened Population. 
A summary of study treatment status will be provided. The display will show the number 
and percentage of participants who are ongoing or discontinued study treatment, with a 
summary of the primary reasons for discontinuation of study treatment. Participants in 
the crossover or retreatment phase will be included in an ongoing at crossover/re-
treatment row. For participants in Part 2, study treatment status for each additional 
treatment and primary reasons for discontinuation for each will also be displayed. 
Reasons for study treatment discontinuation will be presented in the order they are 
displayed in the eCRF. 
A listing of study treatment discontinuation for each treatment will be generated. The 
listing will include last dose date, date of decision to receive no future study treatment 
and additional specified reasons for study treatment discontinuation. 
A summary of study status and reason for study withdrawal will be provided. The study 
status display will show the number and percentage of participants who withdrew from 
the study without meeting the above criteria, including primary reasons for study 
withdrawal. The number and percentage of participants who died, completed the study 
and those ongoing on study treatment, at crossover/re-treatment or in follow up will also 
be presented. Reasons for study withdrawal will be presented in the order they are 
displayed in the eCRF.  A listing of reason for study withdrawal will also be provided. 
Using the All Treated population, listings will also be provided detailing planned and 
actual treatments, and participants excluded from any population.  Additionally, a listing 
with the participants who crossover to combination with pembrolizumab or are re-treated 
with their original treatment will be displayed with the start and end dates of each stage 
provided. 


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Duration of follow-up in months, defined as the time from randomization or treatment 
start to last contact or death, will be summarized by minimum, median, maximum and 
first and third quartiles.  This will include the time after crossover or re-treatment if 
applicable. 
6.3. 
Demographic and Baseline Characteristics 
The demographic characteristics age (years), race, ethnicity, sex, baseline height (cm), 
baseline body weight (kg) and body mass index (BMI; kg/m2) will be summarized and 
listed for the All Treated Population. As full date of birth is not provided, age will be 
derived at the time of screening using the year of birth imputed with 30th June. Age, 
height, weight and BMI will be summarized using the mean, standard deviation, 
minimum, median, and maximum. In addition, age will also be categorized and 
summarized by 18-64, 65-84, and ≥85 years for both the All Treated population as part of 
the demography summary table, and also separately for the All Enrolled Population for 
compliance with Regulatory requirements. The number and percentage of participants 
will be computed for sex and ethnicity. Race and racial combinations will be summarized 
and listed.  
Disease history and characteristics at initial diagnosis and at screening will be reported 
for the All Treated Population. It includes details of the tumor under study such as the 
primary tumor type and where applicable primary tumor location (e.g., oral cavity for 
HNSCC), the histology, the histologic grade, stage at initial diagnosis, presence of 
measurable disease at screening, presence of non-target lesions at screening, time since 
initial diagnosis in days, time from last progression in days, the number of prior 
anticancer therapy and radiotherapy regimens received and the intent of the anticancer 
therapy (i.e. adjuvant or metastatic). Durations will be derived with respect to the date of 
first dose. If the participant has metastatic disease at screening, then time from date of 
initial diagnosis to date of diagnosis of metastatic disease in days will also be derived. 
Disease burden at baseline, including number of organs involved, location of organs 
involved and the sum of measurable target lesions at baseline will be reported for the All 
Treated Population 
Indicators (yes/no) for the following, collected at screening, will also be summarized: 
Measurable disease, non-target lesions, prior adjuvant/neo-adjuvant, EGFR/ALK/ROS1 
mutation, BRAF mutation, MSI-H, HPV and metastatic disease as well as the number of 
prior advanced/metastatic anti-cancer therapies. Disease history and characteristics, 
including dates and additional specified text, will be presented in data listings. 
Predefined medical conditions (angina pectoris, diabetes, hypertension, hyperlipidemia, 
myocardial infarction, stroke) and other medical conditions will be collected at screening.  
These conditions will be summarized by whether they are past or current.  In addition, 
separate summaries will be provided for past and current cancer related medical 
conditions. All medical conditions will be listed. 
Prior anticancer therapies will be coded using GSK Drug coding dictionary version 1.4 or 
higher and summarized and listed for the All Treated Population. Therapies will be 
classified by general type (chemotherapy, immunotherapy, hormonal therapy, biologic 


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therapy, small molecule targeted therapy, bis-phosphate, vaccine, surgery, radiotherapy 
and unknown) as well as by immunotherapy type (CTLA-4, PD-1/L1, other 
immunotherapy) and the number and percentage of participants with each type will be 
displayed. A summary of the number of prior anticancer therapy regimens/lines by type, 
the intent of the therapy (e.g., neo-adjuvant, adjuvant etc) will also be provided.  
Prior anticancer radiotherapy will be listed as well as prior cancer related surgeries.  
Additional baseline listings and summaries will be provided for substance (tobacco and 
alcohol) use.  
6.4. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary version 1.4 or 
higher, summarized, and listed for the All Treated Population. The summary of 
concomitant medications will show the number and percentage of participants taking 
concomitant medications by ingredient. Multi-ingredient products will be summarized by 
their separate ingredients rather than as a combination of ingredients. The ingredients will 
be summarized by the base component, using CMBASECD and CMBASE. Anatomical 
Therapeutic Chemical (ATC) classification Level 1 (Body System) information will be 
included in the dataset created but will not appear on the listing or summary. 
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes Amoxicillin on two separate 
occasions, the participant is counted only once under the ingredient “Amoxicillin”. All 
medications, regardless of onset date will be included in the summary and listing.  
Blood products (including platelets or red blood cells) or blood supportive care products 
(growth factor support) with onset date after the start of study treatment will also be 
summarized if data permit. The number and percentage of participants receiving each 
type of blood product and blood supportive care products after the start of study treatment 
will be provided. Supporting listings will also be provided. 
6.5. 
Extent of Exposure 
Extent of exposure to GSK3359609 monotherapy, GSK3359609 in combination with 
pembrolizumab, GSK3359609 in combination with chemotherapy±pembrolizumab and 
GSK3359609 in combination with GSK3174998 will be displayed for each drug 
component separately for the All Treated Population.  
The duration of exposure to study treatment in weeks for each participant and treatment, 
is defined as treatment stop date – treatment start date + 1 /7.   For participants on a 
combination therapy this will considered the first and last treatment date across all 
treatments.  For a participant who moves to crossover treatment or re-treatment, the 
treatment stop date for the original treatment will be the last available treatment stop date 
prior to crossover/re-treatment.  
Duration of exposure to study treatment by dose level will be presented graphically (i.e., 
duration of treatment plots). A horizontal bar graph of duration of treatment will be 


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produced to display duration of treatment in weeks for each participant. Participants 
without a stop date will be indicated as ongoing.  
The number of infusions administered for each drug component (prior to any crossover 
therapy) will also be determined and summarized with mean, median, standard deviation, 
minimum, and maximum as well as the number and percentage of participants who 
received a given number of infusions for each drug component. This will be categorized 
into <4, 4 – 10, and >10 infusions and summarized.  
The infusion dose intensity (mg/cycle) will also be listed and summarized for each drug 
component within the original treatment using mean, median, standard deviation, 
minimum, and maximum. The dose intensity is calculated by 3-week period (cycles) as 
the cumulative dose divided by expected duration of exposure (last infusion date – first 
infusion date + 21)/21).  The cumulative dose (mg) is the sum of the actual dose 
administered during each infusion for a participant throughout the study. A listing of 
expected duration, dose intensity and a summary of dose modifications by participant 
will be provided. A listing will also be provided for dose scheduled and received as well 
as cumulative dose at each time point. 
Dose modifications will also be summarized.  Duration of dose delay is defined as period 
from the expected start date of dose to actual start date of current dose. Calculation: 
(actual start date of current dose - expected start date of dose). Expected start date of dose 
= actual start date of previous dose + 21.  Dose delays will be summarized by the number 
of participants with any delay, the total number of dose delays per category (0, 1, 2, ≥3 
and Not Evaluable) and the delay duration in intervals of 1-21, 22-42 and >42 days.  
For participants with dose modifications of reduction, missed dose or dose escalation 
separate summary tables will be produced for each category of modification and for each 
drug component showing the number of participants with any modifications, the number 
of dose modifications per category (0, 1, 2, ≥3 and Not Evaluable) and the reasons for the 
modifications.  A separate listing containing further details including primary reason for 
the modification, will be produced for each dose modification category.  
For participants with incomplete infusions or infusion interruptions separate summary 
tables will be produced for each of the two modification categories and for each drug 
component showing the number of participants with any modifications, the number of 
dose modifications per category (0, 1, 2, ≥3) and the reasons for the modifications. A 
listing containing further details including primary reason for the modification, will be 
produced for each of the two modification categories. 
6.6. 
Subsequent Anticancer Therapies 
Follow-up anticancer therapies will be coded using GSK Drug coding dictionary version 
1.4 or higher and summarized and listed for the All Treated Population. Therapies will be 
classified by general type (chemotherapy, immunotherapy, hormonal therapy, biologic 
therapy, surgery and radiotherapy) and the number and percentage of participants with 
each type will be displayed. Time from study treatment discontinuation to the first post-
study treatment anticancer therapy as determined for efficacy will also be included in this 
summary table.  


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7. 
PRIMARY ENDPOINTS ANALYSES 
The safety analyses will be based on the All Treated population. Data will be displayed as 
specified in Section 5.1.2. 
7.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. AEs will be coded 
to the preferred term (PT) level using the Medical Dictionary for Regulatory Affairs 
(MedDRA version 20.1 or higher) and grouped by system organ class (SOC).  AEs will 
be graded by the investigator according to the NCI-CTCAE version 4.0 or higher. 
An overview of the number and percentage of participants experiencing any AE, any AE 
leading to permanent discontinuation of study treatment and any AE leading to dose 
interruption/delay will be produced.  The reasons of infusion interrupted but completed 
and infusion stopped early and not completed will be combined into the dose 
interruption/delay category. Where multiple action taken options are selected for an AE, 
within and across drug components, all will be included in the summary to indicate how 
many participants experienced each.  The table will also include the number and 
percentage of participants experiencing any SAE, any SAE related to study treatment, 
any fatal SAE and any fatal SAE related to study treatment.  
A summary of the number and percentage of participants with any AE by maximum 
severity grade will be produced with an additional column grouping AEs of grade 3 to 5. 
The maximum grade throughout the duration of event rather than the severity grade at 
onset will be used to determine the severity grade recorded by a participant at each level 
of summarization. The summary will use the following algorithms for counting the 
participant: 
• 
Preferred term row: Participants experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum severity 
grade per dose level received.  
• 
System organ class (SOC) rows: Each participant is counted only once at the 
maximum severity grade at each SOC level per dose level received, although they 
may have several different preferred term events within the same SOC.  
• 
Any event row: Each participant with at least one AE will be counted only once at 
the maximum grade, for each dose level received, no matter how many events they 
have. 
The summary table will be displayed in descending frequency of total incidence by SOC 
and Preferred Term (PT), and by alphabetic order when PT with equal incidence within 
the SOC. An alternative option will be to display descending frequency of PT. If 
maximum severity grade is missing but the severity grade at onset is available, then this 
will be used instead. If both are missing and there are no other events with a severity 
grade for the participant, at each level of summarization, then this event will be displayed 
in an “unknown” row.  


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In addition, the number and percentage of participants with AEs (all grades) will be 
summarized and displayed in descending frequency of total incidence by PT and also by 
SOC and PT.  
A separate summary will be provided for study treatment related AEs. A study treatment 
related AE is defined as an AE for which the investigator classifies the relationship to any 
of the study treatments as “Yes” or as determined by the study team. A conservative 
(worst-case scenario) approach will be taken to handle missing relatedness data, i.e., the 
summary table will include events with the relationship to study treatment as ‘Yes’ if 
missing. The summary table will be displayed in descending frequency of total incidence 
by PT.  Additional summary tables for study treatment-related AEs will be provided of 
the number and percentage of participants for study treatment related AEs with an 
outcome of fatal by PT, for any study treatment related AE by PT and maximum severity 
grade and also by SOC, PT and maximum severity grade. 
A summary of non-serious AEs that occurred in strictly 5% of the participants or above 
in any dose level within the cohort and for the All Treated Population will be provided 
(no rounding for the percentage will be used in terms of 5% threshold, e.g., event with 
4.9% incidence rate should not be included in this table). The summary will be displayed 
in descending frequency of total incidence by SOC and PT and will show both the 
number of participants and occurrences.  The ‘ANY EVENT’ rows will include the 
number of participants meeting the 5% threshold. 
Additional tables for common AEs will be produced by PT, for all AEs experienced by 
5% or more of the total within a cohort and for the All Treated Population, grade 3-5 AEs 
experienced by 2% or more of the total within a cohort and for the All Treated Population 
and also for study treatment related grade 3-5 AEs experienced by 2% of more of the 
total within a cohort and for the All Treated Population.  The ‘ANY EVENT’ row of 
these tables will be based on the full set of participants meeting the AE rather than the 
subset of participants with “common” adverse events that meet the threshold.  Any 
percentage which rounds to the threshold (e.g., 4.99%) will be included.  
 
A plot of the percentage of participants experiencing the most common (>=5%) adverse 
events by maximum severity grade will be produced by regimen cohort. 
All AEs will be listed. Additionally, a listing of participant IDs for each individual AE 
will be produced as well as a listing showing the relationship between MedDRA SOC, 
PT, and Verbatim Text for each AE. Finally, a listing of adverse events recorded as DLTs 
will be provided for dose escalation cohorts only. 
7.2. 
Adverse Events of Special Interest Analyses 
Adverse events of special interest (AESI) include AEs of any grade that may have a 
potential immunologic aetiology. AESIs have been selected based on pre-clinical and 
clinical experience by the safety review team. AESIs for GSK3359609 are pneumonitis, 
colitis, hepatitis, endocrinopathies, nephritis and renal function, skin adverse reactions, 
myocarditis and other specified immune-mediated AEs, and infusion-related reactions.  


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Potential AESIs are selected using lists of terms of interest, determined by clinical/safety 
review to identify each type of event.  These are provided in Appendix 6 (Section 11.6.4) 
and the preferred terms within each AESI terms of interest list will be reviewed and 
updated on an ongoing basis based on MedDRA dictionary updates. 
Summaries of the number and percentage of participants with these events will be 
summarized by subclass of AESIs, preferred term and maximum severity grade in one 
table. A similar table will be produced for serious AESIs. The AESIs identified through 
this process will be listed. 
AESIs are also identified on the CRF by the investigator.  These will be listed separately. 
7.3. 
Deaths and Serious Adverse Events 
All deaths will be summarized based on the number and percentage of participants for the 
All Treated population. This summary will classify participants by time of death relative 
to the last dose of GSK3359609 (>30 days or 30 days) and by the primary cause of 
death in the order listed in the eCRF. Participants who either progressed on monotherapy 
and crossed over to combination therapy with Pembrolizumab or responded on their 
original treatment and were re-treated following progression will be classified as ‘Alive 
at crossover/re-treatment’ as applicable in the summary table. A supportive listing will 
also be generated to provide specific details for participants who died.  
 
All SAEs will be tabulated based on the number and percentage of participants who 
experienced the events. Additionally, separate summaries will be provided for study 
treatment related SAEs, fatal SAEs, study treatment related fatal and non-fatal SAEs and 
common (>=2 events) grade 3-5 SAEs. The summary tables will be displayed in 
descending frequency of total incidence by PT.  Additional tables will be produced 
displaying SAEs in descending frequency of total incidence by SOC and PT, using 
alphabetic order when PTs with equal incidence occur within the SOC as well as SAEs 
by maximum toxicity and descending frequency of PTs.  
Finally, a table will be provided summarizing the number of occurrences as well as the 
number of participants with SAEs, the number of treatment-related SAEs, fatal SAEs and 
treatment-related fatal SAEs.  In the table, this information will be provided for all event 
types and for each PT. A study treatment related SAE is defined as an SAE for which the 
investigator classifies the relationship to study treatment as “Yes” or determined by the 
study team. A worst-case scenario approach will be taken to handle missing data, i.e., the 
summary table will include events with the relationship to study treatment as ‘Yes’ if 
missing.  
SAEs are included in the listing of all AEs. Separate supportive listings with participant-
level details will be generated for non-fatal SAEs and the reasons for considering each 
SAE as serious. 


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7.4. 
Adverse Events Leading to Discontinuation of Administered 
Treatment  
AEs leading to discontinuation of study treatment will be summarized separately in 
descending frequency of total incidence by PT only.  In addition, AEs leading to 
discontinuation of study treatment will be listed. 
 
7.5. 
Events of Clinical Interest Analyses 
These are selected events considered of clinical interest recorded during the time period 
beginning with the administration of study treatment through to 30 days following 
discontinuation of study treatment. Events of clinical interest (ECI) include: 
1. Overdose of study drug(s) (GSK3359609 and pembrolizumab (Part 2 only)) that is 
not associated with clinical symptoms or abnormal laboratory results. 
2. An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
laboratory value that is greater than or equal to 3 times the upper limit of normal and 
an elevated total bilirubin laboratory value that is greater than or equal to 2 times the 
upper limit of normal and, at the same time, an alkaline phosphatase laboratory value 
that is less than 2 times the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing. 
3. Infection with COVID-19 coronavirus, whether suspected based on exposure history 
and clinical signs and symptoms or confirmed by laboratory test in the context of 
exposure history and clinical signs and symptoms. Reporting will follow WHO and 
GSK guidelines. 
 
The events will be determined from AE tables and liver result tables. Additionally, 
listings of the COVID-19 related PDs and assessments and symptoms of COVID-19 AEs 
will be provided. 
7.6. 
Pregnancies  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If participants become pregnant while on 
the study, the information will be included in the narratives and no separate table or 
listing will be produced. 
 
7.7. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of hematology, chemistry, cardiac 
function, thyroid function, and urinalysis tests will be based on GSK Core Data 
Standards. Displays will be based on the All Treated population and data will be 
displayed as specified in Section 5.1.2.   
The assessment of laboratory toxicities will examine the laboratory tests listed in protocol 
Table 28. For laboratory tests which are gradable, values will be graded and reported 


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using the Common Terminology Criteria for Adverse Events (CTCAE v4.0). In some 
cases, there will be two bi-directional parameters (hyper- and hypo-) created and the tests 
will be graded by CTCAE v4.0 in both directions. 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
laboratory tests that are gradable by CTCAE v4.0. These summaries will display the 
number and percentage of participants in each baseline grade category versus the number 
in each maximum grade category at each scheduled visit and for the worst-case post-
baseline.  The worst-case summary will use all available scheduled and unscheduled 
visits post-baseline.  Missing baseline grade will be assumed as grade 0. For laboratory 
tests that are graded for both low and high values, summaries will be displayed separately 
and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia. 
For laboratory tests that are not gradable by CTCAE v4.0, summaries of worst-case 
changes from baseline with respect to normal range will be generated. Decreases to low, 
changes to normal or no changes from baseline, and increases to high will be summarized 
at each scheduled visit as well as for the worst-case post-baseline. Participants with 
missing baseline value are assumed to have normal baseline value. If a participant has a 
decrease to low and an increase to high during the same scheduled visit or for worst-case, 
then the participant is counted in both the “Decrease to Low” categories and the “Increase 
to High” categories. The worst-case summary will use all available scheduled and 
unscheduled visits post-baseline to determine if the participant has at least one low and/or 
high value for each laboratory test. 
For the following laboratory parameters, every participant will be assessed separately for 
low and/or high values.  The following groups indicate whether laboratory severity 
grades are assessed according to a low value, high value, or separately for both low and 
high values. 
• 
Low Value: Maximum Severity (Grade 4) for the following laboratory tests: white 
blood cells (WBC), neutrophils, platelets, and albumin; Normal Range for the 
laboratory tests: RBC, haematocrit, total protein and basophils 
• 
High Value: Maximum Severity (Grade 4) for the following laboratory tests: alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline 
phosphatase and creatinine; Normal Range for the laboratory tests: blood urea 
nitrogen (BUN), and eosinophils. 
• 
Low and High Values: Potassium, sodium, glucose, and calcium, haemoglobin, 
lymphocytes will be assessed for the maximum severity grade for both low and high 
values. Monocytes will be assessed for the Normal Range for both low and high 
values. For these laboratory parameters, every participant will be assessed separately 
for high and low values (i.e., separate summary on severity grade/normal range will 
be produced for high glucose (hyperglycemia) and low glucose (hypoglycemia), high 
potassium (hyperkalemia) and low potassium (hypokalemia), high sodium 
(hypernatremia) and low sodium (hyponatremia), high calcium (hypercalcemia) and 
low calcium (hypocalcemia), high hemoglobin (hemoglobin increased) and low 
hemoglobin (anemia), high lymphocytes (lymphocyte count increased) and low 


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lymphocytes (lymphocyte count decreased) and high monocytes (monocytosis) and 
low monocytes (monocytopenia). 
Separate tables for hematology, and chemistry laboratory tests will be produced. Cardiac 
function tests will be included with hematology laboratory tests and thyroid function tests 
will be included with chemistry laboratory tests.  Unless otherwise specified, the 
denominator for calculating percentages at each scheduled visit will be based on the 
number of participants with a non-missing value at each visit. The denominator for worst-
case will be the number of participants with a non-missing post-baseline value.  
Additionally, summary tables for hematology (and cardiac function) and chemistry (and 
thyroid function) will summarize the change from baseline at each scheduled visit using 
mean, median, standard deviation, minimum and maximum.  
All laboratory data will be listed. A supporting listing of laboratory data for participants 
with any value outside the normal range or of potential clinical importance will also be 
provided. 
 
7.7.1. 
Analyses of Liver Function Tests 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to liver monitoring/stopping events, if data permits.  In addition, a 
listing of participants meeting hepatobiliary laboratory criteria post-baseline, a liver 
stopping event profile and a listing of liver monitoring/stopping event reporting will be 
provided. Finally, an e-DISH plot of maximum post baseline total bilirubin versus 
maximum post baseline ALT will be created. 
7.8. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. Displays will be based 
on the All Treated population and data will be displayed as specified in Section 5.1.2.   
Unless otherwise specified, the denominator for calculating percentages calculation at 
each scheduled visit will be based on the number of participants with non-missing value 
at each visit. 
7.8.1. 
ECG 
The key ECG measurement taken in this study will be the uncorrected QT interval 
(msec). The QT correction (QTc) will then either be calculated automatically or it will be 
calculated manually using the Fridericia formula (QTcF (msec)).  In the case QTcF is 
required to be calculated manually, RR interval (msec) will also be recorded on the 
eCRF. Additionally, an overall interpretation of the ECG reading will be provided 
(normal, abnormal not clinically significant, abnormal clinically significant, no result and 
unable to evaluate). 
For Part 1 only, on Day 1 the ECG measurements will be performed in triplicate at pre-
dose (within 60 minutes prior to start of GSK3359609 infusion) and at the following 


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times following the end of infusion: 30 minutes, 4 hours and 24 hours. On Day 22 
measurements will be performed in triplicate at pre-dose and on Day 85 measurements 
will be performed in triplicate at pre-dose and 30 minutes following the end of infusion. 
All other ECG measurements in Part 1 and all ECG measurements in Part 2 are 
performed as single measurements at pre-dose only.  
For the numeric results recorded in triplicate, the mean of the available values (even if 
less than 3 are available) will be taken and used throughout the table and figure 
summaries. All available values will be provided on listings.  For the overall 
interpretation, the worst of the recorded readings will be used in the order from worst to 
best to missing as: abnormal clinically significant, abnormal not clinically significant, 
normal, unable to evaluate, no result. 
A summary of the number and percentage of participants who had each of the ECG 
findings will be displayed for baseline and by each scheduled visit and assessment time 
as well as for the worst-case post-baseline. The worst-case summary will use all available 
scheduled and unscheduled visits post-baseline to determine the worst finding.  A 
summary of the change from baseline will also be provided at each scheduled visit and 
assessment time using mean, median, standard deviation, minimum and maximum.  
The QTc values based on Fridericia formula will be rounded to an integer and the values 
will be categorized into the following ranges: Grade 0 (<450), Grade 1 (450-480), Grade 
2 (481-500), and Grade 3 (≥501). Summaries of grade increases relative to baseline will 
be provided for the categories of ‘No Change or Decrease to <450’, ‘Any Increase ≥450’, 
‘Increase to ≥450 to ≤480’, ‘Increase to ≥481 to ≤500’ and ‘Increase to ≥501’.   
QTcF shifts from the baseline value to the worst-case post-baseline value will be plotted 
with the baseline value displayed on the x axis. The figure will have reference lines at 
480 and 500 msec on both axes.  The change from baseline in QTcF values will be 
categorized into the clinical concern ranges: 31-60 and >60 msec. A summary of change 
from baseline in QTcF value will display the number and percentage of participants with 
a change within each range for the worst-case post-baseline. Participants with missing 
baseline values will be excluded from all the QTcF summaries.  
Listings of abnormal ECG findings and a listing of ECG values will be provided. 
 
7.8.2. 
Vital Signs 
Change from baseline values of vital signs (Systolic and diastolic blood pressure (BP), 
pulse rate, temperature and weight) will be summarized by scheduled visit using mean, 
median, standard deviation, minimum and maximum. If more than one measurement is 
collected within a visit, then the mean will be taken and used in the summary.  Listings of 
all vital signs values by participant and visit will be provided. 
In addition, vital signs values will be categorized as follows: 
• 
Systolic BP (mmHg): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159) and 
Grade 3 (≥160) 


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• 
Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), and Grade 
3 (≥100) 
• 
Pulse rate (beats/min): Low (<60), Normal (60-100), and High (>100) 
Summaries of increase in systolic and diastolic blood pressure from baseline with respect 
to the categories defined above will be performed. These summaries will display the 
number and percentage of participants with any grade increase (i.e., increase of grade 1-
3), an increase of grade 2-3 and then separately, increases to grade 1, grade 2 and grade 3 
and for the worst-case post-baseline. 
Pulse rate is summarized for the worst-case pulse rate category experienced relative to 
the normal range post-baseline.  Participants are counted in the worst-case category that 
their value changes to (low, normal or high) unless there is no change in their category. 
Participants whose value category is unchanged (e.g., High to High), or whose value 
became normal, are recorded in the "To Normal or No Change" category.  Participants 
are counted twice if the participant has values that changed 'To Low' or ‘To High’, so the 
percentages may not add to 100%.  Participants with missing baseline data are assumed 
to have normal baseline values. 
 
7.8.3. 
LVEF 
ECHO/MUGA is only standardly collected at the screening visit (within 28 days prior to 
first dose of study treatment) and is only required during the treatment phase if clinically 
indicated. All values collected will be listed. 
 
7.8.4. 
Performance Status 
ECOG performance status will be summarized using the number and percentage of 
participants with each status at baseline and each post-baseline scheduled visit as well as 
the last assessment post baseline, best case post baseline and worst-case post baseline.  
Additionally, a summary of change from baseline, categorized into improved, no change, 
deteriorated (ordered best to worse), will be performed by scheduled visits, as well as the 
last assessment post baseline, best case post baseline and worst-case post baseline.   
The last assessment post baseline will be the grade recorded at the last visit after 
treatment start and prior to crossover (if applicable).  The best- and worst-case post 
baseline will be the minimum and maximum grade respectively, recorded after treatment 
start and prior to crossover (if applicable).  For the change from baseline table, the grade 
identified will be used to compare to baseline and determine the change category. 
A supporting listing will also be provided.  


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8. 
SECONDARY ENDPOINTS ANALYSES 
8.1. 
Pharmacokinetic Analyses 
Pharmacokinetic parameters will be calculated by, or under the auspices of, CPMS, 
Quantitative Science, GlaxoSmithKline. 
Statistical analysis of GSK3359609, pembrolizumab, chemotherapy and GSK3174998 
pharmacokinetic parameters, as data permits, will be performed by, or under the direct 
auspices of Oncology Statistics and Programming, GlaxoSmithKline. 
The pharmacokinetic (PK) analyses will be based on the PK Concentration, and PK 
Parameter populations, unless otherwise specified.  
Table 4 provides an overview of the planned Pharmacokinetic analyses. 
 
Table 4 
Overview of Planned Pharmacokinetic Analyses 
Endpoint / Parameter/ 
Display Type 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F L 
T 
F 
F 
L 
PK Concentrations 
Plasma GSK3359609 
Concentrations 
 
 
 
Y 
Y 
Y 
Y 
 
 
 
 
Y 
Y 
 
Plasma Pembrolizumab 
Concentrations 
 
 
 
Y 
Y 
 
Y 
 
 
 
 
Y 
 
 
Plasma GSK3174998 
Concentrations 
 
 
 
Y 
Y 
Y 
Y 
 
 
 
 
Y 
Y 
 
PK Parameters 
Plasma GSK3359609 
Parameters 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
Y 
Y 
 
Plasma Pembrolizumab 
Parameters  
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
 
 
 
Plasma GSK3174998 
Parameters 
 
 
 
Y 
 
 
Y 
Y 
 
 
Y 
Y 
Y 
 
NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual participant observed raw data.     
 
8.1.1. 
Endpoint / Variables 
8.1.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 11.5.3 
Reporting Standards for Pharmacokinetic). 


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Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by regimen cohort and dose level.  Additionally, 
individual, mean and median concentration plots will be provided for treatment Cycle 1 
data.  
8.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix WinNonlin 6.3 or higher (CERTARA, NJ). All calculations of non-
compartmental parameters will be based on actual sampling times. Pharmacokinetic 
parameters listed in Table 5 may be determined from the concentration-time data, as data 
permits. 
Table 5 
Pharmacokinetic Parameters 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctau 
Concentration at the end of dosing interval. 
AUC(0-t) 
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC(0-) 
Area under the concentration-time curve over the dosing interval. 
AUC(0-) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite 
time 
z 
apparent terminal phase elimination rate constant (single dose) 
t½ 
Apparent terminal phase half-life will be calculated as:  
t½ = ln2 / z 
CL 
systemic clearance of parent drug 
NOTES: 
• 
Additional parameters may be included as required. 
8.1.2. 
Summary Measure 
All derived PK parameters will be listed. 
For each of these parameters, except tmax, the following summary statistics will be 
calculated for each dose level: median, minimum, maximum, arithmetic mean, 95% 
confidence interval for the arithmetic mean, standard deviation (STD), coefficient of 
variation (%CV = 100*(sqrt (exp(STD2) – 1))) [NOTE: STD = STD of natural log (loge) 
transformed data]), geometric mean, 95% confidence interval for the geometric mean and 
standard deviation of natural logarithmically transformed data. 


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For tmax, median, maximum, minimum, arithmetic mean, 95% confidence interval, and 
standard deviation will be calculated. The first point, last point and number of points used 
in the determination of z will be included on the listing of the derived parameters. 
All PK parameters will be reported to at least 3 significant digits, but to no more 
significant digits than the precision of the original data. 
8.1.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic 
population, unless otherwise specified. 
8.1.4. 
Statistical Analyses / Methods 
Dose Proportionality:  
If more than two dose levels are required to reach RP2D within the dose escalation 
cohorts, dose proportionality of GSK3359609 AUC(0-), Ctau and Cmax will be 
evaluated at Cycle 1.  Regimen cohorts with the same dose levels may be combined to 
increase the number of participants included in the model. 
GSK3359609 and GSK3174998 AUC(0-), Ctau and Cmax will be assessed separately 
for dose proportionality using the power model as described below: 
y =  * dose 
where y denotes the pharmacokinetic parameter and α is an intercept term.  Dose 
proportionality in this model equates to β=1.  A point estimate and 90% confidence 
interval will be derived for β.  will be estimated by regressing the loge-transformed PK 
parameter on loge dose.   
Loge(PK parameter) =  +   loge(dose) 
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed. Both the intercept and slope will be fitted as random effects.  If the model 
with random intercept and slope fails to converge, the model will be refitted with slope as 
a fixed effect.  If the mixed effects model still does not converge then a fixed effects 
power model will be fitted.  The mean slope will be estimated from the power model and 
the corresponding 90% confidence interval calculated. 
Additionally, dose proportionality for GSK3359609 and GSK3174998 at Cycle 1 will be 
assessed using Analysis of Variance (ANOVA) models for loge-transformed, dose-
normalized AUC(0-), Ctau and Cmax with a fixed effect term for treatment group (dose 
level).  Differences in least squares means between each dose and the reference dose will 
be calculated.  These differences and the corresponding 90% CIs will be back-
transformed (exponentiated).  The reference dose will be chosen based on the lowest 
clinically relevant dose over which PK can be adequately described and all other doses 
will be test doses.  PK parameters will be dose-normalized prior to loge-transformation by 
multiplying by reference dose/dose. 
Accumulation 
To assess accumulation of GSK3359609, Pembrolizumab and GSK3174998, where data 
allow, ANOVA with a fixed effect term for day and a random effect term for participant 


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will be performed on loge-transformed Ctau for each treatment group (dose level) 
separately.  The observed accumulation ratio (Ro) will be estimated by exponentiating 
the difference in least squares means (e.g., end of cycle concentration Ctau after 6 cycles 
(Day 106) – Cycle 1 end of cycle Ctau) and the associated 90% confidence interval. 
8.2. 
Population Pharmacokinetic Analyses 
Population PK analyses may be conducted under the direction of CPMS, Quantitative 
Sciences, GSK.  The data from this study may be combined with the data from other 
studies for a population PK analysis, which may be reported separately. 
8.3. 
Efficacy Analyses 
The All Evaluable population will be used at the time of the interim analysis. For final 
analysis, the All Treated Population will be used. Data will be displayed as specified in 
Section 5.1.3. 
Table 6 provides an overview of the planned efficacy analyses. All efficacy data and 
calculated endpoints will be listed. 
Table 6 
Overview of Planned Efficacy Analyses 
Endpoint / Parameter  
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Tumor Measurement (CT or MRI Scan Assessments)  
Best tumor percentage change 
from baseline (irRECIST) 
 
 
 
 
Y 
 
 
Best tumor percentage change 
from baseline (RECIST1.1) 
 
 
 
 
Y 
 
 
Endpoints based on Best Overall Response (confirmed and unconfirmed) 
Overall Response Rate (ORR) 
(irRECIST) 
 
 
 
Y 
 
 
Y 
Overall Response Rate (ORR) 
(RECIST1.1) 
 
 
 
Y 
 
 
Y 
Disease Control Rate (DCR) 
(irRECIST) 
 
 
 
Y 
 
 
Y 
Disease Control Rate (DCR) 
(RECIST1.1) 
 
 
 
Y 
 
 
Y 
Survival  
Overall Survival (OS) 
Y 
Y 
 
 
 
Y 
Time to Event 
Progression Free Survival (PFS) 
(RECIST1.1) 
Y 
Y 
 
 
Y 
Time to Response (TTR) 
(RECIST 1.1) 
Y 
Y 
 
 
 
Duration of Response (DOR) 
(RECIST1.1) 
Y 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e., modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e., descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual participant observed raw data. 


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8.3.1. 
Endpoints / Variables 
Tumor response i.e., complete response (CR/irCR), partial response (PR/irPR), and stable 
disease (SD/irSD), and progressive disease (PD/irPD) will be based on the assessments 
from the investigators’ review of objective evidence (e.g., radiological scan). Overall 
responses were measured in accordance with the RECIST v1.1 and irRECIST.  
Assessments start at Week 9 for all but the 5-FU/Platinum chemotherapy combination 
cohort which start at Week 18.  Assessments will then be performed every 9 weeks from 
the start of treatment until Week 54 then every 12 weeks thereafter until disease 
progression; participants who discontinue for reasons other than progression will be 
followed for progression until the start of subsequent anticancer therapy every 9 weeks 
until Week 54 then every 12 weeks thereafter. Participants who attain a CR and met the 
requirements defined in Section 5.4 of the protocol for early discontinuation of study 
treatment and discontinue study treatment will undergo disease assessments every 12 
weeks until progression. 
 
Participants who crossover from monotherapy to the combination therapy, disease 
assessments subsequent to crossover will be disregarded in the summarization of 
monotherapy. 
The efficacy endpoint analysis will be based on ORR, DCR, PFS, OS, DOR and TTR.  
The response endpoints ORR and DCR will be primarily based on irRECIST but may be 
repeated by RECIST v1.1. The survival endpoints of PFS, TTR and DOR will be by 
RECIST v1.1 only. 
8.3.2. 
Summary Measure 
Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to RECIST (version 1.1) and irRECIST 
[Wolchok, 2009; Nishino, 2013] as outlined in Appendix 6 of the protocol. The 
irRECIST guidelines will be used to determine treatment decisions and will be used for 
the primary analysis of anticancer activity. 
Best Overall Response 
Best overall response (BOR) will be derived to calculate the efficacy endpoints.  Best 
overall response is defined as the best response recorded from enrollment/randomization 
into a cohort until the criteria for progression are met (taking into account any 
requirement for confirmation), the initiation of new anticancer therapy/crossover or 
death, whichever is earliest. The order from best to worst of the available responses is 
CR/irCR, PR/irPR, stable disease (SD/irSD), progressive disease (PD/irPD) and not 
evaluable (NE).  
• To be assigned a status of SD/irSD, follow-up disease assessment(s) must have met 
the SD/irSD criteria at a minimum of 8 weeks (56 days) from baseline. Note that 
duration of stable disease (SD for RECIST/irSD for irRECIST) is measured from the 
date of first dose in non-randomized cohorts or the date of randomization in 
randomized cohorts until the last adequate non-PD/irPD response. 


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• If the minimum of 8 weeks (56 days) for SD/irSD is not met, the best overall 
response will depend on the subsequent assessments. If an assessment of PD follows 
the assessment of SD and SD does not meet the minimum 8-week requirement the 
best response will be PD. Alternatively, participants with no further adequate 
assessments, after an SD assessment not meeting the minimum time criteria, will be 
considered not evaluable. 
• A participant without any adequate post-baseline assessments will have a BOR of 
NE. 
 
The number and percentage of participants for each available BOR will be provided, both 
with and without confirmation, and for RECIST v1.1 and irRECIST.  
RECIST (version 1.1) Criteria 
Best overall response will be derived for RECIST v1.1 with confirmation of CR/PR and 
without.  Best overall response without confirmation can be based on just one occurrence 
of the best available response available for the participant.  For the derivation with 
(consecutive) confirmation, these additional points need to be considered: 
• To be assigned a status of confirmed CR/PR, a confirmatory disease assessment 
should be performed no less than 4 weeks (28 days) after the criteria for response are 
first met. 
• Responses of CR/PR that do not meet the requirements of confirmed CR/PR are still 
eligible to be considered SD if it has met the SD duration criteria. 
• Assessments that are not done or are not evaluable can be disregarded when checking 
for confirmation. For example, a participant with PR-NE-PR is a confirmed response.   
 
Confirmed best overall response per RECIST v1.1 will be derived according to Table 7.  


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Table 7 
Best Overall Response per RECIST 1.1 
Overall Response 
First time point 
Overall Response 
Subsequent Time Point 
(minimum of 28 days later) 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR[1] 
CR 
SD 
 
SD provided minimum criteria for SD duration met[2], 
otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met[2], 
otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met[2], 
otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met[2], 
otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met[2], 
otherwise NE 
NE 
NE 
NE 
[1] If CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes CR may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the participant had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.  
[2] Minimum criteria for SD disease duration is at least 56 days to qualify as SD for BOR. 
Note: If Best Overall Response is CR or PR, the participant is classified as a responder for the ORR analysis. 
irRECIST Criteria 
The principle of deriving BOR, with and without confirmation, per irRECIST (irBOR) 
closely follows RECIST v1.1. The exception is that participants with disease progression 
by RECIST version 1.1 guidelines are required to have a confirmatory disease assessment 
at least 4 weeks after disease progression was declared in order to confirm disease 
progression by irRECIST guidelines. Additionally, unconfirmed irPD will not override a 
subsequent irBOR of irSD, irPR, or irCR, meaning that irPR or irSD can be assigned as 
irBOR, providing that the criteria for confirmation of irPD are not met. 
If irBOR is irPD and is confirmed consecutively, irBOR will be termed as irCPD even if 
there are subsequent irSD, irPR, or irCR after the confirmed irCPD. If irBOR is irPD but 
not confirmed, and there is no subsequent irSD, irPR, or irCR (e.g., NE or lost follow-
up), the irBOR will be termed as irUPD.  
If irBOR is irPD but not confirmed and there is no subsequent irSD, irPR, or irCR (e.g., 
NE or lost follow-up) due to study conclusion, the confirmed BOR will be termed as 
irCPD.  
Both irCPD and irUPD will be categorized as irPD in the summary of confirmed irBOR. 
 


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8.3.2.1. 
ORR and DCR  
Overall response rate (ORR) and disease control rate (DCR) per RECIST v1.1 criteria are 
defined below. ORR and DCR per irRECIST criteria are defined similarly. 
• ORR is defined as the percentage of participants achieving a (confirmed) CR/PR as 
BOR, as assessed by the investigator per RECIST 1.1 criteria. 
• DCR is defined as the percentage of participants achieving a (confirmed) CR/PR, or 
SD as BOR, as assessed by the investigator per RECIST 1.1 criteria. A status of SD 
will be assigned if the follow-up disease assessment has met the SD criteria at least 
once after the date of first dose/randomization at a minimum of 8 weeks (56 days; 
minimum of 9 weeks minus one-week visit window). 
• DCR with SD durability is defined as the percentage of participants achieving a 
(confirmed) CR/PR, or SD≥18 weeks. A status of SD≥18 weeks will be assigned if 
the follow-up disease assessment has met the SD criteria at least once after the date of 
first dose/randomization at a minimum of 17 weeks (119 days) considering a one-
week visit window. 
 
The number and percentage of participants achieving ORR and DCR (9 and 18 weeks) 
will be provided for both RECIST v1.1 and irRECIST.  Percentages will be calculated 
using the number of participants within each cohort. The 2-sided 95% exact (Clopper-
Pearson) confidence limits for the binomial proportion will also be included.  
8.3.2.2. 
Progression-Free Survival  
PFS is defined as the interval between the date of first dose of study treatment (or date of 
randomization for randomized cohorts) and the date of disease progression (taking into 
account any requirement for confirmation when needed) according to radiological 
response from investigator assessment, or death due to any cause, whichever occurs 
earlier. 
Participants whose disease progressed or who died after an extended period (two or more 
consecutive scheduled disease assessments) without adequate assessment will be 
censored at their date of last adequate assessment prior to progression or death even if 
subsequent information is available regarding progression or death. For this type of 
censoring due to extended time without an adequate assessment, the date of ‘last adequate 
disease assessment’ will be defined as the date of the last radiological assessment by 
investigator that shows no disease progression prior to the missing assessments, the start 
date of new anticancer therapy or crossover, the date of first progression, or the date of 
death, whichever is the earliest. 
Extended time without adequate assessment 
As the assessment schedule changes through the course of the study (i.e., every 9 weeks 
until Week 54 then every 12 weeks thereafter until disease progression). Specifically, 
participants who attain a CR and met the requirements defined in Section 5.4 in the 
protocol for early discontinuation of study treatment and discontinue study treatment will 
undergo disease assessments every 12 weeks until progression.  The following rules will 
be used for identifying the duration of extended time without adequate assessment. 


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• If PFS event is on or prior to Week 64, then a participant will be identified as an 
extended loss to follow up if the participant did not have an adequate disease 
assessment during the time period of 140 days (18 weeks + two one-week windows) 
prior to PFS event; 
• Else if PFS event is after Week 64 and on or prior to Week 67, then a participant will 
be identified as an extended loss to follow up if the participant did not have an 
adequate disease assessment during the time period of 154 days (20 weeks + two one-
week windows) prior to PFS event; 
• Else if PFS event is after Week 67 and on or prior to Week 77, then a participant will 
be identified as an extended loss to follow up if the participant did not have an 
adequate disease assessment during the time period of 168 days (22 weeks + two one-
week windows) prior to PFS event; 
• Else if PFS event is after Week 77, then a participant will be identified as an extended 
loss to follow up if the participant did not have an adequate disease assessment during 
the time period of 182 days (24 weeks + two one-week windows). 
Crossover/Anticancer Therapy 
For participants who receive subsequent anticancer therapy including radiotherapy and 
cancer-related surgery or crossover from monotherapy to combination therapy the 
following rules will apply: 
• If the start date of anticancer therapy/crossover is partial (i.e., either missing the day 
but has the month and year available or missing both day and month), the imputation 
rules described in Appendix 7 will be applied. No imputation will be made for 
completely missing dates. 
• If anticancer therapy/crossover is started without documented disease progression or 
is started prior to documented disease progression, then PFS will be censored at the 
date of the last adequate assessment (last assessment with any investigator 
radiological response excluding NE) that is on or before the date of initiation of 
anticancer therapy/crossover. The date of response at the last adequate assessment 
will be used as the censoring date. 
• If a participant has only a baseline visit or does not have an adequate assessment that 
is on or before the date of initiation of anticancer therapy/crossover, PFS will be 
censored at the date of first dose or randomization. 
If a participant has neither progressed nor died nor started new anticancer therapy nor 
crossed over, then PFS will be censored at the date of the last adequate assessment. 
If there is no adequate baseline assessment, the participants will be censored at their date 
of first dose for participants in non-randomized cohorts or at the date of randomization 
for participants in randomized cohorts. Participants without any adequate post-baseline 
tumor assessments will be censored at the date of first dose for participants in non-
randomized cohorts or at the date of randomization for participants in randomized 
cohorts. 
A summary of the assignments for progression and censoring dates for PFS per RECIST 
v1.1 criteria are specified in the following Table 8. 


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Table 8 
Assignments for Progression and Censoring Dates for PFS Analysis 
per RECIST v1.1 
Scenario 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event (Progression/Death) 
Or Censored 
No adequate1 baseline tumor 
assessments and the participant 
has not died  
First dose or randomization2
 
 
Censored 
No adequate1 post-baseline 
assessments and the participant 
has not died  
First dose or randomization2 
Censored 
Progression documented 
between scheduled visits 
Date of assessment of 
progression 
Event 
With post-baseline assessment 
but no progression (or death)  
Date of last adequate assessment 
of response1 
Censored 
No adequate post-baseline 
assessment before start of new 
anticancer therapy 
First dose or randomization2 
Censored 
With adequate1 post-baseline 
assessment and new anticancer 
therapy started (prior to 
documented disease progression 
or death)3  
Date of last adequate assessment 
of response1 (on or prior to 
starting anticancer therapy)  
Censored 
With adequate1 post-baseline 
assessment and crossover 
started (prior to documented 
disease progression or death)3  
Date of last adequate assessment 
of response1 (on or prior to 
starting crossover)  
Censored 
Death before first scheduled 
assessment  
Date of death  
Event 
 
Death between adequate 
assessment visits 
Date of death 
Event 
Death or progression after two or 
more missed scheduled 
assessment 
Date of first dose or 
randomization (if there is no 
adequate post-baseline 
assessments) or date of last 
adequate assessment of 
response (prior to missed 
assessments): If the time 
difference between PD/death and 
last adequate disease 
assessment/start date is more 
than the duration of extended 
time without adequate 
assessment, PFS will be 
censored at the last adequate 
Censored 


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Scenario 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event (Progression/Death) 
Or Censored 
disease assessment prior to 
PD/death/start date 
1. 
An adequate assessment is defined as an assessment where the Investigator determined response is CR, 
PR, or SD.  
2. 
The date of first dose of GSK3359609 or the randomization date.  
3. 
If PD and New anticancer therapy/crossover occur on the same day assume the progression was 
documented first. The outcome is progression (event) and the event date is the date of the assessment of 
progression. If anticancer therapy/crossover is started prior to any adequate assessments, censoring date 
should be the date of first dose or randomization.  
The non-parametric Kaplan-Meier method will be used to estimate the survival curves for 
PFS within the All Treated population for each cohort, as specified in Section 5.1.3. 
Kaplan-Meier plots of the PFS survival curves will be presented. Kaplan-Meier estimates 
for the median PFS, the first and third quartiles and the survival estimates at 6 months 
will be presented, along with 95% CIs. CIs for quartiles will be estimated using 
Brookmeyer-Crowley method [Brookmeyer, 1982] and based on the loglog 
transformation. 
8.3.2.3. 
Overall Survival (OS) 
OS is defined as the interval between the date of first assigned study 
therapy/randomization and date of death due to any cause. The length of this interval is 
calculated as the date of death minus date of first assigned study therapy/randomization 
plus 1 day. 
In the absence of confirmation of death or if the death date is partial, survival time will be 
censored at the last date the participant is known to be alive. Only participant contacts 
recorded in the eCRF can be used for the calculation of last date of contact. The date of 
censorship will be the latest from either the follow-up record or the last assessment. 
Participants lacking data beyond the day of first dose/randomization will have their 
survival time censored at the date of first dose/randomization. When calculating overall 
survival, all deaths following crossover or re-treatment will be included. 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves for 
OS within the All Treated population for each cohort, as specified in Section 5.1.3. 
Kaplan-Meier plots of the OS survival curves will be presented. Kaplan-Meier estimates 
for the median overall survival, the first and third quartiles and the survival estimates at 6 
months will be presented, along with 95% CIs. CIs for quartiles will be estimated using 
Brookmeyer-Crowley method [Brookmeyer, 1982] and based on the loglog 
transformation. 
 
8.3.2.4. 
Duration of response (DOR) per RECIST v1.1 
Duration of response (DOR) per RECIST v1.1 will be summarized for participants with a 
confirmed CR or PR. It is defined as the interval of time in months from the date of the 
first documented evidence of a response (confirmed CR or PR) to the date of first 
documented evidence of disease progression according to radiological response from 


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investigator assessment per RECIST v1.1, or date of last adequate assessment of response 
or the date of death due to any cause (whichever occurs earlier). Censoring rules will 
follow those of the PFS analysis per RECIST v1.1 where they apply.  
The non-parametric Kaplan-Meier method will be used to estimate the survival curves for 
DOR within the All Treated population for each cohort where data permits. Kaplan-
Meier plots of the DOR survival curves will be presented. Kaplan-Meier estimates for the 
median DOR, the first and third quartiles, along with 95% CIs. CIs for quartiles will be 
estimated using Brookmeyer-Crowley method [Brookmeyer, 1982] and the loglog 
transformation.  Only the subset of participants who show a response of CR or PR from 
All Treated population will be included in these analyses. 
 
8.3.2.5. 
Time to response (TTR) per RECIST v1.1 
Time to overall response (TTR) will be summarized at the final analysis for the All 
Treated Population with a confirmed CR or PR and is defined as the time from date of 
first dose of study treatment/randomization to the date of first documented confirmed (≥4 
weeks) CR or PR. Although only confirmed CR and PR will be included, the first date of 
the (at least) two occurrences of the response will be used. 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves for 
TTR within the All Treated population for each cohort where data permits. Kaplan-Meier 
plots of the TTR survival curves will be presented. Kaplan-Meier estimates for the 
median TTR, the first and third quartiles, along with 95% CIs. CIs for quartiles will be 
estimated using Brookmeyer-Crowley method [Brookmeyer, 1982] and the loglog 
transformation.  Only the subset of participants who show a confirmed CR or PR from 
All Treated population will be included in this analysis.  
 
8.3.2.6. 
Change of Tumor Measurement  
Best percentage change from baseline will be the minimum percentage change from 
baseline across visits on or prior to the first documented PD or crossover/new anticancer 
therapy. 
(1) If PD occurred, all disease assessments until the PD date will be considered. 
(2) If PD is unavailable, all disease assessments before crossover/new anticancer therapy, 
will be considered 
Waterfall plots will display the best percentage change in tumor measurement (the 
minimum value) for both irRECIST and RECIST v1.1 with the respective unconfirmed 
BOR included in the display. 
 


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8.3.3. 
Population of Interest 
The efficacy analyses will be based on the All Treated population for the final analyses.  
 
Table 9 
Population of interest for Efficacy Endpoints 
Endpoints 
IA / IPM 
SAC 
PFS/OS 
All Treated Population 
All Treated Population 
TTR/DOR 
All Evaluable Population 
All Treated Population 
ORR/DCR 
All Evaluable Population 
All Treated Population  
 
8.3.4. 
Statistical Analyses / Methods 
Planned displays will be based on GSK Data Standards and statistical principles. 
 
8.3.4.1. 
Statistical Methodology Specification 
PFS and OS will be summarized and plotted using the Kaplan-Meier method if the data 
warrant.  
Statistical Analyses 
Endpoint(s) 
• 
PFS 
• 
OS 
• 
DOR 
• 
TTR 
Method of Analysis 
• 
Kaplan-Meier (if data warrant) for PFS, OS, TTR and DOR 


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9. 
OTHER STATISTICAL ANALYSES 
9.1. 
Pharmacodynamic and Biomarker Analyses 
The pharmacodynamic and biomarker analysis for this study will be defined separately in 
an independent analysis plan.  All details of endpoints, populations, analyses and display 
of results will be provided.  
9.2. 
Pharmacokinetic/Pharmacodynamic Analyses 
9.3. 
Pharmacogenetic Analyses 
Further details on PGx analyses discussed in the protocol may be identified /addressed in 
a separate PGx RAP, if applicable. 
9.4. 
Immunogenicity Analyses 
Serum samples will be collected and tested for the presence of antibodies that bind to 
GSK3359609 and pembrolizumab, or GSK3359609 and GSK3174998, refer to Section 
10.7.5 in the protocol. These samples may also be tested for presence of antibodies that 
bind to Chinese Hamster Ovary (CHO) host cell proteins such as phospholipase B- like 2 
(PLBL2). 
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.  Binding assays will primarily be used. 
Participants who have been treated will be initially assessed for anti-drug antibodies 
(ADA) with a screening assay at each planned visit.  Where there is a positive screening 
assay result, a confirmatory assay will be performed.  Positive confirmatory results will 
be accompanied by a titer value indicating the level of ADA detected.  The results from 
the screening and confirmatory assay will be listed alongside the titer value. The 
incidence rates of positive immunogenicity via confirmatory assay will also be 
summarized, and ADA data may potentially be pooled with ADA data from the Phase I 
(204691) or other trials.   
CCI
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9.6. 
Patient Reported Outcomes 
  
 
 
 
CCI
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10. 
REFERENCES 
Brookmeyer, R. and Crowley, J. A confidence interval for the median survival time. 
Biometrics. 1982; 38:29-41. doi:10.2307/2530286 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the Treatment of Non–Small-Cell 
Lung Cancer. N Engl J Med. 2015; 372:2018-2028. 
Nishino M, Giobbie-Hurder A, Gargano M, et al. Developing a common language for 
tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Cancer Res. 2013; 19:3936-3943. 
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res 
2009;15(23): 7412-20. 
 
 
 


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11. 
APPENDICES 
11.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
11.1.1. 
Exclusions from Per Protocol Population 
Not applicable. 
 
 


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11.2. 
Appendix 2: Schedule of Activities 
11.2.1. 
Protocol Defined Schedule of Events 
See Protocol Section 8. 


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11.3. 
Appendix 3: Assessment Windows 
11.3.1. 
Definitions of Assessment Windows for Analyses 
Duration of SD for both RECIST v1.1 and irRECIST is calculated when SD is the 
unconfirmed best overall response. A one-week visit window was considered in the 
duration of SD, i.e., a minimum of 8 weeks for iSD (irSD≥9 weeks) and 17 weeks for 
SD≥18 weeks. This is a result of post-baseline assessments, a window of 7 days is 
permitted to allow for flexible scheduling. 


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11.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
11.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
Study Treatment Start Date. 
Study Phase 
Definition 
Pre-Treatment  
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 30  
Post-Treatment 
Date > Study Treatment Stop Date + 30  
 
11.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial 
dates for concomitant medication. Use the rules in this table if concomitant medication date is 
completely missing. 
 


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11.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after treatment start date or missing & on or before 
treatment stop date.  
o Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date + 
30. 
o AE Start Date is missing 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
 


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11.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
11.5.1. 
Reporting Process 
11.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings. 
• 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology. 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
• 
Summary Statistics: values will be reported relative to the precision on the eCRF. Min and max will 
be to the same as the raw data, mean and median to 1 extra decimal place, standard deviation to 2 
extra decimal places. 
• 
Listings: values will be displayed to the same precision on the eCRF. 
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
o Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
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o Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the participant’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and/or figures except for worst post – 
baseline analysis. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
11.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation (CPMS) function will be created according 
to SOP 00000314000: Non-Compartmental Analysis of Clinical Pharmacokinetic 
Data 
Note: Concentration values will be imputed as per GUI_51487 (v 4.0) 
 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487(v 4.0) for descriptive 
summary statistics/analysis and summarized graphical displays only.   
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
Not applicable 
Pharmacokinetic Parameter Derivation 
 PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived as data permits: Cmax, tmax, Ctau, 
AUC(0-t), AUC(0-), AUC(0-), z, t½, CL 
Pharmacokinetic Parameter Data 
 Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to GUI_51487(v 4.0) 
 Descriptive 
Summary Statistics, 
Graphical Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to Reporting Effort specific Mockup specifications.   
 


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11.6. 
Appendix 6: Derived and Transformed Data 
11.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date/Randomization Date: 
o Ref Date = Missing                                               → Study Day = Missing  
o Ref Date < First Dose Date/Randomization Date → Study Day = Ref Date – First Dose 
Date/Randomization Date 
o Ref Data ≥ First Dose Date/Randomization Date → Study Day = Ref Date – (First Dose 
Date/Randomization Date) + 1 
• 
For participants in non-randomized cohorts, First Dose Date will be used in study day for both safety 
and efficacy. 
• 
For participants in randomized cohorts, First Dose Date will be used in study day for safety and 
Randomization Date will be used in study day for efficacy. 
Change from Baseline 
• 
Change from Baseline = Post-Baseline Visit Value – Baseline 
• 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
• 
Maximum Increase/Decrease from Baseline = maximum (Increase/Decrease from Baseline) 
• 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change 
from Baseline is set to missing 
Date of Response 
• For post-baseline disease assessments, the date of response (PR or CR) is assigned to the latest date 
of disease assessments within a particular visit; for other response categories (SD [or Non-CR/Non-PD], 
NE, PD), the date of response is assigned to the earliest date of disease assessments within a 
particular visit. 
Date of New Anticancer Therapy/Crossover 
• Derived as the earliest date of new anticancer therapy, radiotherapy, cancer-related surgical procedure, 
or the first dosing date of the combination therapy after crossover. 
• Missing or partial dates will be imputed for derivation of date of new anticancer therapy following rules 
specified in Section 11.7.2. 
Duration and Elapsed Time 
• Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are calculated as the stop 
date minus the start date plus one. 
• For elapsed time (e.g., the time since initial diagnosis): 
o If the reference date is on or after the event date, then the elapsed time is the reference date minus 
the event date + 1 
o If the reference date is before the event date, then the elapsed time is the reference date minus the 
event date 
• 
For time to event (TTE) durations such as PFS  


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o To report in months, divide the number of days by 30.4375 
o To report in weeks, divide the number of days by 7 
o To report in years, divide the number of days by 365.25.  
These algorithms for time to event return decimal numbers and ignore the actual numbers of days in 
the months or years between start date and stop date. The “year” used in these algorithms is 365.25 
days long, and the “month” is one twelfth of that year. 
• 
For converting all other durations (e.g., duration of adverse events, duration of exposure, age) to 
weeks, months or years use the following: 
o To report the duration in weeks divide the number of days by 7 
o To report the duration in months use: (YEAR(stopdate + 1) – YEAR(startdate)) * 12 + 
(MONTH(stopdate + 1) – month(startdate) – 1) + (DAY(stopdate + 1) > = DAY(startdate)) 
o To report the duration in years use:intck(‘year’, startdate, stopdate + 1) – (month(stopdate + 1) < 
month(startdate) or (month(stopdate + 1) = month(startdate) and day(stopdate + 1) < 
day(startdate))) 
These algorithms return whole numbers for months and years, accurately accounting for the actual 
numbers of days in the months or years between the start date and the stop date. 
 
11.6.2. 
Study Population 
Extent of Exposure 
• 
Number of weeks of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Weeks = [Treatment Stop Date – Treatment Start Date + 1] /7  
• 
The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (the actual dose administered during each infusion) 
• 
The infusion dose intensity is the cumulative dose divided by the number of 3 weeks periods (cycles) 
across the entire treatment period: 
Dose intensity = Cumulative Dose/((last infusion date – first infusion date + 21)/21) 
 
Refer to Section 6.5 for further details. 
11.6.3. 
Efficacy 
Efficacy Endpoints  
Overall Response Rate (ORR) (irRECIST and RECIST v1.1) 
• 
ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of CR 
or PR from the start of treatment until disease progression or death due to any cause or the start of new 
anticancer therapy/crossover. 
• 
ORR per irRECIST is defined as the percentage of participants with a best overall response of irCR or 
irPR from the start of treatment until confirmed disease progression or death due to any cause or the 
start of new anticancer therapy/crossover. 
• 
This will be based on overall responses from the Investigator assessment. 
• 
The overall response observed for the participant will be used to derive best overall response. 
Refer to Section 8.3.2.1 for details 
Disease Control Rate (DCR) (irRECIST and RECIST v1.1) 
• 
DCR per RECIST v1.1 is defined as the percentage of participants with a best overall response of CR 
or PR at any time plus SD meeting the minimum time criteria from the start of treatment until disease 
progression or death due to any cause or the start of new anticancer therapy/crossover 
• 
DCR per irRECIST is defined as the percentage of participants with a best overall response of irCR or 
irPR at any time plus irSD meeting the minimum time criteria from the start of treatment until confirmed 


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Efficacy Endpoints  
disease progression or death due to any cause or the start of new anticancer therapy/crossover 
Refer to Section 8.3.2.1 for details 
Progression Free Survival (PFS) (RECIST v1.1) 
• 
Progression-Free survival (PFS) per RECIST v1.1 is defined as the interval of time from randomization 
date (or first dose date if not randomized); to the earlier date of first assessment of disease progression, 
or death due to any cause. Disease progression will be based on the assessments by the Investigator. 
Refer to Section 8.3.2.2 for details 
Overall Survival (OS) 
• 
OS is defined as the interval of time (in weeks) between from randomization date (or first dose date if 
not randomized) and the date of death due to any cause. 
Refer to Section 8.3.2.3 for details 
Duration of Response (DOR) (RECIST v1.1) 
• 
DOR per RECIST v1.1 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 a response (confirmed CR or 
PR) 
Refer to Section 8.3.2.4 for details 
Time to Response (TTR) (RECIST v1.1) 
• 
TTR per RECIST v1.1 is defined for participants with a confirmed CR or PR, as the time from first dose 
to the first documented evidence of CR or PR 
Refer to Section 8.3.2.5 for details 
11.6.4. 
Safety 
Adverse Events 
Adverse Events of Special Interest (AESI) 
TOI List Name 
Dictionary 
Code  
Dictionary 
Version 
Status 
Type 
ICOS Colitis 
MedDRA 
319004 
23.0 
Active 
Study Specific 
TOI 
ICOS 
Endocrinopathies 
MedDRA 
319007 
23.0 
Active 
Study Specific 
TOI 
ICOS Hepatitis 
MedDRA 
319005 
23.0 
Active 
Study Specific 
TOI 
ICOS Infusion 
Related Reactions 
MedDRA 
319013 
23.0 
Active 
Study Specific 
TOI 
ICOS Myocarditis 
MedDRA 
319011 
23.0 
Active 
Study Specific 
TOI 
ICOS Nephritis and 
Renal Function 
MedDRA 
319009 
23.0 
Active 
Study Specific 
TOI 
ICOS Other 
Immune Mediated 
Adverse Events 
MedDRA 
319012 
23.0 
Active 
Study Specific 
TOI 
ICOS Pneumonitis 
MedDRA 
319003 
23.0 
Active 
Study Specific 
TOI 
ICOS Skin Adverse 
Reactions 
MedDRA 
319010 
23.0 
Active 
Study Specific 
TOI 
 
 


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ECG Parameters 
Corrected QT Intervals 
• 
When not entered directly in the eCRF, corrected QT intervals using Fredericia’s (QTcF) formula will be 
calculated, in msec, using QT and the RR interval:  
 
 
 
11.6.5. 
Pharmacokinetic 
PK Parameters 
Cmax 
• 
Maximum observed concentration, determined directly from the concentration-time data. 
Tmax 
• 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctau 
• 
Concentration at the end of dosing interval. 
AUC(0-t) 
• 
Area under the concentration-time curve from time zero to the time of the last quantifiable concentration 
(C(t)) will be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
AUC(0-) 
• 
Area under the concentration-time curve over the dosing interval. 
AUC(0-) 
• 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time. 
z 
• 
Apparent terminal phase elimination rate constant. 
T½ 
• 
Apparent terminal phase half-life will be calculated as:  
                                                                    t½ = ln2 / z                           
NOTES: 
• 
Additional parameters may be included as required. 
 
11.6.6. 
Population Pharmacokinetic (PopPK) 
Parameters 
CL 
Systemic clearance of parent drug. 
Vc 
Apparent volume of distribution of parent drug. 
 


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11.6.7. 
Pharmacodynamic and Biomarker 
The pharmacodynamic and biomarker endpoints for this study will be defined separately 
in an independent analysis plan.   
11.7. 
Appendix 7: Reporting Standards for Missing Data 
11.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
For Part 1A and Part 2A combination with pembrolizumab, the dose escalation phases 
of the study, participants will be considered as completing the study if they complete 
screening assessments, receive at least one dose of study treatment, are observed 
during the 28 day DLT observation period, and complete the treatment discontinuation 
visit and the follow-up visit for safety or have died while receiving study treatment or 
during post-study treatment follow-up period for safety.  
• 
For Part 1A, if a participant withdraws from the study before the completion of the 28 
day DLT evaluation period for reasons other than DLT, then the participant may be 
replaced to achieve the three-participant required minimum. 
• 
For Part 2A combinations with chemotherapy, participants will be considered as 
completing the study if they complete the screening assessments, receive at least one 
dose of study treatment, are observed during the 28 day DLT observation period, and 
complete the treatment discontinuation visit and the safety follow-up visit or have died 
while receiving study treatment or during the post-study treatment safety follow-up 
period. 
• 
For Part 1B and 2B, the expansion phases of the study, participants will be considered 
as completing the study if they complete screening assessments, receive at least one 
dose of study treatment, discontinue study treatment for reasons other than lost to 
follow-up or non-compliance, and complete the study treatment discontinuation visit 
and follow-up visits or have died while receiving study treatment or during post-
treatment follow-up period. 
• 
In the event the Sponsor decides to close the study, participants receiving ongoing 
study treatment will be considered as completing the study. 
• 
The end of the study is defined as the completion of the last participant’s required visits 
post study treatment discontinuation. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be summarized as withdrawal visits. 
11.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 


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Element 
Reporting Detail 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
11.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
• 
Imputed partial dates will not be used to derive study day, duration (e.g., 
duration of adverse events), or elapsed time variables (e.g., time since 
diagnosis). In addition, imputed dates are not used for deriving the last contact 
date in overall survival analysis dataset. 
Birth Date 
• 
As only the year of birth is being collected within the EDC system, participant 
birth date and month will be defaulted to ‘30/JUN’. For example, if birth year is 
1989 then birthdate will be 30/Jun/1989. 
Adverse Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = 1st of month. 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year 
of study treatment start date then 
▪ 
If stop date contains a full date and 
stop date is earlier than study treatment start date 
then set start date= 1st of month. 
▪ 
Else set start date = study treatment 
start date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment 
start date then 
▪ 
If stop date contains a full date and 
stop date is earlier than study treatment start date 
then set start date = January 1. 
▪ 
Else set start date = study treatment 
start date.       
o 
Else set start date = January 1. 
Missing stop day  
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
Concomitant 
Medications/Medica
l History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start day 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = 1st of month. 


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Element 
Reporting Detail 
• 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year 
of study treatment start date then 
▪ 
If stop date contains a full date and 
stop date is earlier than study treatment start date then 
set start date= 1st of month. 
▪ 
Else set start date = study treatment 
start date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
• 
If study treatment start date is missing (i.e. participant did 
not start study treatment), then set start date = January 1. 
• 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment 
start date then 
▪ 
If stop date contains a full date and 
stop date is earlier than study treatment start date then 
set start date = January 1. 
▪ 
Else set start date = study treatment 
start date.       
• 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year)  
Missing end day and 
month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
•
Prior Anticancer 
Therapy/Radiothera
py/Surgical 
Procedures 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. 
• 
If partial start date contains a year only set to January 1st. 
• 
If partial start date contains a month and year set to the 1st of the month. 
• 
No imputation for partial end dates will be performed. 
New Anticancer 
Therapy/ 
Radiotherapy/ 
Surgical 
Procedures/Crosso
ver for Efficacy 
Evaluation (e.g., 
response rate, time 
to event) 
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be imputed in order to define event and 
censoring rules for progression-free survival, response rate, or duration of response 
(i.e. start date for new anti-cancer therapy). Dates will only be imputed when a month 
and year are available, but the day is missing. The following rules will be used to 
impute the date when partial start dates are present on anti-cancer therapy, 
radiotherapy, and/or surgical procedures dataset[s]: 
• 
Completely missing start dates will remain missing, with no imputation applied; 
• 
Partial start dates will be imputed using the following convention: 
• 
If both month and day are missing, no imputation will be applied; 
• 
If only day is missing:  
o If the month of partial date is the same as the month of last dosing 
date, minimum of (last dosing date + 1, last day of the month) will be 
used for the day; 
o If the month of partial date is the same as the month of last disease 
assessment and the last disease assessment is PD, minimum of (last 
date of disease assessment + 1, last day of the month) will be used for 
the day; 
o If both conditions above are met, the later date will be used for the day; 
o Otherwise, a ‘01’ will be used for the day; 


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Element 
Reporting Detail 
• 
Completely or partial missing end dates will remain missing, with no imputation 
applied; 
Exposure End 
Dates 
• 
If treatment end date is missing for a cycle, treatment start date for the cycle will 
be used. 
• 
If there is more than one study treatment, imputation of missing treatment end 
date will be applied to all applicable treatments following rules below and 
treatment end date is the latest treatment end date across all study treatments. 
• 
Only treatment cycles prior to crossover or re-treatment (if applicable) will be 
considered for exposure end date.  
 


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11.8. 
Appendix 8: Values of Potential Clinical Importance 
11.8.1. 
Laboratory Values 
To identify laboratory values of potential clinical importance (PCI), National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be 
used to assign grades to the relevant laboratory parameters and results categorized as 
Grade 1 and above will be considered as a PCI. 
For laboratory data which are not listed in the NCI CTCAE (v4.0 and v4.03), a summary 
of values outside the normal range will be provided. 
 
11.8.2. 
ECG 
ECG Parameter 
Units 
 
Clinical Concern Range 
 
Lower 
Upper 
 
Absolute 
Absolute QTcF Interval 
msec 
Grade 1 
≥ 450 
< 481  
Grade 2 
≥ 481  
< 501 
Grade 3 
≥ 501  
 
 
Change from Baseline 
Increase from Baseline QTcF 
msec 
 
> 30   
≤ 60   
msec 
 
> 60   
 
 
11.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
 
Clinical Concern Range 
 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
Grade 1 
≥120   
<140 
 
mmHg 
Grade 2 
≥140   
<160 
 
mmHg 
Grade 3 
≥160  
 
Diastolic Blood Pressure 
mmHg 
Grade 1 
≥ 80   
< 90 
 
mmHg 
Grade 2 
≥ 90  
< 100 
 
mmHg 
Grade 3 
≥ 100  
 
Pulse Rate 
bpm 
L/H 
< 60 
> 100 
Temperature 
Degrees C 
L/H 
≤ 35 
≥ 38 
 
 
 
 
 


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11.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
11.9.1. 
Population Pharmacokinetic (PopPK) Dataset Specification 
The PopPK dataset specification will be developed according to current CPMS SOPs and 
best practices to capture relevant information for analyses. 
11.9.2. 
Population Pharmacokinetic (PopPK) Methodology 
Population PK analysis may be performed in the following sequence of steps: 
2. Base structural model development 
• 
Plasma concentration-time data may be analysed with nonlinear mixed 
effects modelling using appropriate validated software to develop a base 
population PK model 
• 
Based on the preliminary analysis, drug concentration data of GSK3359609 
may be analysed using a two-compartment IV infusion model parameterized 
using either clearances and distribution volumes or using macro rate 
constants (A, B, ALPHA and BETA), depending on parameters to be 
estimated 
• 
Inter-individual or between-participant variability (IIV or BSV) may be 
initially modelled using an exponential random effects model. Random 
effects for clearances and volumes or A and B and BETA may be 
incorporated, depending on model parameterization used. If the goodness-of-
fit plots reveal potential biases in the random effects model, alternative 
random effects models may be considered 
• 
A proportional error model may initially be used to describe the residual 
variability. If the goodness-of-fit plots reveal potential biases in the residual 
variability model, other residual error models will be considered as 
appropriate  
3. Covariate analysis 
• 
Covariate analysis may be performed to explore measurable sources of 
PK variability. Different approaches may be evaluated for covariate model 
building including a step-wise process consisting of a forward and a 
backward selection procedure and/or a full-model approach. Some of the 
prospectively identified covariates are listed below:  
• 
Continuous covariates such as age, albumin, measures of body size 
(e.g., body weight, body mass index,);  
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• 
Categorical covariates such as gender, race, ethnicity, tumor type, 
disease status, prior treatment status 
4. Model refinement 
• 
Model refinement steps may be performed, including, where appropriate, 
exploration of model improvement through reparameterization or the 
estimation of off-diagonal random effects, interpretation of magnitude of the 
variability, interpretation of standard errors of the fixed and random effects 
parameters, and simplification of covariate models. 
5. Model evaluation 
• 
Non-parametric bootstrapping may be performed to test model robustness.  
• 
The model performance may be evaluated by performing predictive check 
• 
Individual post hoc estimated PK parameters may be summarized 
descriptively   
• 
Individual participant PK parameters and exposure measures for Cycle 1 may 
be estimated and documented for the purposes of any subsequent 
exposure-response (PK/PD) analyses 
 
Any population PK analyses not described a priori but undertaken based on emerging 
data will be described in detail in the report. 


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11.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
11.10.1. 
Pharmacokinetic / Pharmacodynamic Dataset Specification 
The PK/PD dataset specification(s) will be developed according to current CPMS SOPs 
and best practices to capture relevant information for analyses. 
11.10.2. 
Pharmacokinetic / Pharmacodynamic Methodology 
The primary goal of PK/PD analyses is to characterize the exposure-response 
relationships for GSK3359609. The exposure-response analyses may focus on SAEs 
(Grade 3) as well as efficacy endpoints and may also include an investigation to assess 
the impact of different exposure estimates. Where appropriate, drug plasma concentration 
(or pharmacokinetic parameter) data and pharmacodynamic data may be combined and 
analysed with nonlinear mixed effects modelling using suitable software.  The influence 
of participant demographics and baseline characteristics, including disease activity, in 
this population may also be investigated.  All participants included in the 
pharmacokinetic analysis set with at least one follow-up scan will be included in 
exposure-efficacy assessments.  
11.10.2.1. Exposure Metrics for Exposure – Response 
Exposure measures may be derived from observed peak or trough concentrations or using the 
individual post hoc estimates obtained from the population PK analysis. Example exposure 
measures are as follows: peak concentration (Cmax) after first dose, trough concentration 
(Cmin), or model-derived AUC0-t, where t represents the planned cycle time in days 
11.10.2.2. Exposure – Response Assessments for Clinical Endpoints 
Exposure – Adverse Events 
Data permitting and as deemed relevant, presence or absence of adverse events may be 
described using a conventional logistic regression model for  Grade 3 AE. Severity of 
AE may also be analyzed using an ordered logistic regression model assuming Grades 0 
(no toxicity), 1, 2 and 3, with exposure subdivided into quartiles/quintiles.   
Time-to-event analysis may also be applied to assess exposure-safety relationships.  In 
this case, non-parametric Kaplan-Meier method may be used to estimate survival curves, 
with Kaplan-Meier plots of SAE event-free survival presented by binned exposure 
estimates (e.g. quartiles of exposure).  The Kaplan-Meier estimates for the median SAE 
event-free survival may be presented, along with 95% CIs. The treatment difference in 
survival may then be assessed by the stratified log-rank test. A hazard ratio and its 95% 
confidence interval from a Cox model may also be reported separately. 
 
 
 


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Exposure – Efficacy 
Exposure – Clinical Response Relationship 
Data permitting and as deemed relevant, ORR per RECIST v1.1, defined as the 
proportion of the participants in the analysis population who have a CR or PR based upon 
investigator assessment may be summarized by binned exposure estimates.  Presence or 
absence of clinical response may be described using a conventional logistic regression 
model. Time-to-response may be explored using Kaplan-Meier survival curves.  Best 
clinical response may also be analyzed using an ordered logistic regression, with 
response categorized from 0 (progressive disease) to 3 (complete response). Exposure 
will be treated as a categorical variable, subdivided into quartiles and quintiles.   
Exposure-Progression Free Survival Relationship 
Data permitting and as deemed relevant, PFS may be explored using Kaplan Meier plots 
with exposure subdivided into quartiles and quintiles, and occurrence of progression may 
also be described using a conventional logistic regression model.   
Exposure-Longitudinal Tumor Size Modeling 
Data permitting and as deemed relevant, tumor size will be recorded as the sum of 
longest dimensions (SLD) of target lesions, using RECIST version 1.1.  If data permits, 
tumor size modeling may be pursued to quantify exposure-response relationships for 
efficacy. Longitudinal tumor kinetics may be described via a nonlinear mixed‐effects 
framework. Exposure may be assessed as a covariate on tumor growth/ shrinkage 
parameters.  Other prognostic covariates may be explored to normalize for potential 
imbalances in exposure.  
 
 
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11.11. 
Appendix 11: Abbreviations & Trade Marks 
11.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
AUC(0-) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated to 
infinite time 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to last time of 
quantifiable concentration within a participant across all treatments 
AUC(0-) 
Area under the concentration-time curve over the dosing interval 
BMI 
Body mass index 
BOR 
Best Overall Response 
BSV 
Between-subject variability 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CL 
Clearance 
Cmax 
Maximum observed concentration  
CPMS 
Clinical Pharmacology Modelling & Simulation 
CPS 
Combined Positive Score 
CR 
Complete Response 
CSR 
Clinical Study Report 
Ctau 
Concentration at the end of dosing interval 
DCR 
Disease Control Rate 
DE 
Dose Expansion 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
DP 
Decimal Places 
dMMR 
Deficient Mismatch Repair 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
GSK 
GlaxoSmithKline 
HNSCC 
Head and Neck Squamous Cell Cancer 
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Abbreviation 
Description 
HPV 
Human Papillomavirus 
HR 
Hazard Ratio 
HRQoL 
Health Related Quality of Life 
IA 
Interim Analysis 
ICOS 
anti-Inducible T cell Co-Stimulator 
IDSL 
Integrated Data Standards Library 
IHC 
Immunohistochemistry 
IIV 
Inter-individual variability 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
irBOR 
Immune-related Best Overall Response 
irCR 
Immune-related Complete Response 
irSD 
Immune-related Stable Disease 
irPD 
Immune-related Progressive Disease 
irPR 
Immune-related Partial Response 
irRECIST 
Immune-related RECIST 
kg 
Kilogram(s) 
LFT 
Liver Function Test 
LVEF 
Left Ventricular Ejection Fraction 
MAD 
Maximum Administered Dose 
MSI-H 
Microsatellite Instability-high 
MTD 
Maximum Tolerated Dose  
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
mmHg 
Millimeters of Mercury 
msec 
Milliseconds 
MUGA 
Multigated Acquisition Scan 
NA 
Not Applicable 
NCI-CTCAE 
National Cancer Institute - Common Toxicity Criteria for Adverse Events  
NE 
Not Evaluable 
NSCLC 
Non-small Cell Lung Cancer 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-L1 
Programmed Death 
PFS 
Progression-free Survival 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient Reported Outcome 
PS 
Performance Status 
PT 
Preferred Term 
Q3W 
Every 3 Weeks 
Q6W 
Every 6 Weeks 
QTc 
Corrected QT interval duration, corrected 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QoL 
Quality of Life 
RAP 
Reporting and Analysis Plan 
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Abbreviation 
Description 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria in Solid Tumors 
REML 
Restricted Maximum Likelihood 
RNA 
Ribonucleic acid 
ROS1 
c-ros oncogene 1 
RP2D 
Recommended Phase 2 Dose 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event(s) 
SAS 
Statistical Analysis Software 
SD 
Stable Disease 
SLD 
Sum of longest dimensions 
STD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
t½ 
Terminal half-life 
tmax 
Time of maximum observed concentration 
TTR 
Time to Response 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
 
11.11.2. Trademarks 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 


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11.12. 
Appendix 12: List of Data Displays 
The list of data displays for each of the individual rolling CSRs compiled throughout the 
study will be provided within each individual reporting effort alongside other supporting 
documents such as a list of TLFs and mock shells within the relevant reporting effort 
(\arwork\gsk3359609\mid204691).