Clinical trial NCT04128696
Conditions: Neoplasms, Head and Neck
Keywords: GSK3359609 Pembrolizumab Programmed death receptor 1-ligand 1 Head and neck squamous cell carcinoma/cancer Inducible T cell co-stimulatory receptor Keynote-A01 Head & neck Phase III
Sponsor: GlaxoSmithKline
Start date: 2019-11-21; Completion date: 2023-06-20
Enrollment: 315 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of study is to evaluate if the addition of GSK3359609 to pembrolizumab as first-line treatment improves the efficacy of pembrolizumab in participants with recurrent or metastatic (R/M) head and neck squamous cell carcinoma/cancer (HNSCC).This is a randomized, double-blind, adaptive Phase II/III study comparing a combination of GSK3359609 inducible T cell co-stimulatory receptor (ICOS) agonist and pembrolizumab to pembrolizumab plus placebo in participants with programmed death receptor 1-ligand 1 (PD-L1) combined positive score (CPS) \>=1 R/M HNSCC.

Detailed description:

Arms: arm 1: Participants were administered feladilimab (humanized anti-ICOS immunoglobulin G4 \[IgG4\] monoclonal antibody \[mAb\]) and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an intravenous (IV) infusion once every three weeks. arm 2: Participants were administered placebo and pembrolizumab (humanized anti-PD-1 IgG4 mAb) as an IV infusion once every three weeks.
Interventions: intervention 1: feladilimab intervention 2: Pembrolizumab intervention 3: Placebo
Intervention descriptions: intervention 1: feladilimab is available as an intravenous infusion. intervention 2: Pembrolizumab is available as an intravenous infusion. intervention 3: Placebo is available as an intravenous infusion.

Protocol documents:
Prot_000.pdf: 
0 
 
 
 
Protocol Amendment 03 
Study ID:  209229 
Official Title of Study:  A Randomized, Double-blind, Adaptive, Phase II/III Study of 
GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment 
of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
NCT ID: NCT04128696 
Date of Document: 29-JUN-2021 


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TITLE PAGE 
Protocol Title: A Randomized, Double-blind, Adaptive, Phase II/III Study of 
GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment 
of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
Protocol Number: 209229 
Compound Number: 
GSK3359609 
Study Phase: Phase III 
Short Title: A Phase II/III study of GSK3359609 in combination with pembrolizumab 
compared with pembrolizumab plus placebo in participants with PD-L1 positive recurrent 
or metastatic HNSCC 
INDUCE-3 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information: refer to the 209229-study reference 
manual for contact details 
Regulatory Agency Identifying Number(s):  
IND: 143221 
EudraCT: 2019-002263-99 
Approval Date: 29-JUN-2021 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 


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SPONSOR SIGNATORY: 
Protocol Title: A Randomized, Double-blind, Adaptive, Phase II/III Study of 
GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment 
of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
Protocol Number: 209229 / Amendment 03 
 
Compound Number 
or Name: 
GSK3359609  
 
 
 
Sumita Roy-Ghanta, MD 
Clinical Development Lead,  
Oncology Research & Development 
GlaxoSmithKline 
 
Date 
 
The signed page is a separate document. 
 
 
 
 
Medical Monitor Name and Contact Information [will be provided separately OR can 
be found in the Study Reference Manual] 
 
 
 
 
 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Number 
Amendment 3 
29-JUN-2021 
TMF-13842230 
Amendment 2 
19-MAY-2020 
2019N403389_03 
Amendment 1-UK1 
10-FEB-2020 
2019N403389_02 
Amendment 1 
24-OCT-2019 
2019N403389_01 
Original Protocol 
20-AUG-2019 
2019N403389_00 
 
Amendment 3: 29-JUN-2021 
Overall Rationale for the Amendment: A Dear Investigator Letter (DIL) dated 13-
April-2021 was issued requiring the stopping of further screening and the discontinuation 
of the administration of GSK3359609 (feladilimab) or placebo for all participants on 
INDUCE-3, effective immediately. Further to the DIL, since all participants have the 
option to remain on pembrolizumab alone as study therapy, GSK issued a Protocol 
Clarification Letter (PCL) dated 28-April-2021 to reduce any unnecessary burden of on 
treatment and follow up assessments (the PCL did not alter any screening assessments). 
This protocol amendment is a follow up to the PCL, with a primary intent to only update 
the SoA; other impacted, relevant sections were also updated accordingly. Additionally, 
updates were made to management guidelines to align with pembrolizumab IB update.  


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Section # and 
Name 
Description of Change Brief Rationale 
1.4 Schedule of 
Activities (SoA) 
Assessments related to 
GSK3359609 
(feladilimab) were 
removed. These 
include 
feladilimab/placebo 
infusions; feladilimab 
PK collections, 
immunogenicity, IRR 
lab panel, plasma 
collections, PBMC 
collections, optional 
biopsy, Patient 
Reported Outcomes 
(PROs), Healthcare 
Resource Utilization 
(HCRU), prior protocol 
required disease 
assessments, follow-up 
subsequent anticancer 
therapy and disease 
assessments, and 
pembrolizumab second 
course. 
Since there will be no further 
screening into the study and no 
further dosing of GSK3359609 or 
placebo, there is no need to collect 
samples, PROs or efficacy 
assessments to determine the effect of 
GSK3359609. 
6 Study Intervention 
Line added to refer to 
SoA 
Alignment with updated SoA 
6.1.1 Duration of 
Second Course 
Section deleted 
2nd Course will not be administered 
as subsequent anti-cancer therapy 
will not be followed and PFS2 will 
not be analysed as the study is 
terminated with no further screening. 
6.6.1. General 
Guidelines for 
Immune-Related 
Adverse Events 
Table 5 was updated 
for irAEs including 
neurological toxicities 
and exfoliative 
dermatologic 
conditions 
To align with pembrolizumab IB 
update (Edition 20-Mar-2021) 


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Section # and 
Name 
Description of Change Brief Rationale 
7.1 Discontinuation 
of Study 
Intervention 
Removed wording 
around 2nd Course. 
Added timeframe for 
completion of survival 
follow-up. 
2nd Course will not be administered 
as subsequent anti-cancer therapy 
will not be followed and PFS2 will 
not be analysed as the study is 
terminated with no further screening. 
A timeframe for completion of 
survival follow-up is added as study 
is terminated. 
8.1. Efficacy 
Assessments 
Removed requirement 
for confirmatory scan 
per iRECIST 
iRECIST may be followed at 
Investigator discretion once 
progression is determined by 
RECIST 1.1 up to a maximum of 35 
cycles 
8.1.1. Disease 
Assessments 
Removed wording 
around 2nd Course 
2nd Course will not be administered 
as subsequent anti-cancer therapy 
will not be followed and PFS2 will 
not be analysed as the study is 
terminated with no further screening 
9.4 Statistical 
Analyses 
Added that primary and 
secondary endpoints 
would be included in 
main CSR. A separate 
final CSR will report 
updated key safety 
analyses at end of 
study. 
Clarifies reporting as the study is 
terminated with no further screening 
10.14. Appendix 14: 
Second Treatment 
Course 
Removed wording 
around 2nd Course 
2nd Course will not be administered 
as subsequent anti-cancer therapy 
will not be followed and PFS2 will 
not be analysed as the study is 
terminated with no further screening 
10.3.5. Reporting of 
SAE to GSK 
Removed requirement 
for investigator to show 
evidence of SAE 
causality in the eCRF 
within 72 hours 
Change to GSK standard procedure 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
PROTOCOL SUMMARY ........................................................................................ 10 
1.1. 
Background ................................................................................................ 10 
1.1.1. 
Inducible T Cell Costimulatory Receptor and GSK3359609 ......... 10 
1.1.1.1. 
GSK3359609 Clinical Experience ............................... 11 
1.1.2. 
Pembrolizumab ............................................................................ 11 
1.1.2.1. 
Pharmaceutical and Therapeutic Background ............ 12 
1.1.2.2. 
Non-clinical and Clinical Studies ................................. 12 
1.1.3. 
GSK3359609 Monotherapy and in Combination with 
Pembrolizumab in HNSCC .......................................................... 13 
1.2. 
Synopsis ..................................................................................................... 13 
1.3. 
Schema ...................................................................................................... 19 
1.4. 
Schedule of Activities (SoA) ........................................................................ 20 
2. 
INTRODUCTION .................................................................................................... 31 
2.1. 
Study Rationale .......................................................................................... 31 
2.2. 
Benefit/Risk Assessment ............................................................................ 33 
2.2.1. 
Risk Assessment ......................................................................... 33 
2.2.2. 
Overall Benefit: Risk Conclusion .................................................. 36 
3. 
OBJECTIVES AND ENDPOINTS ........................................................................... 36 
4. 
STUDY DESIGN .................................................................................................... 38 
4.1. 
Overall Design ............................................................................................ 38 
4.2. 
Scientific Rationale for Study Design .......................................................... 39 
4.3. 
Justification for Dose .................................................................................. 40 
4.3.1. 
GSK3359609 Dose Justification .................................................. 40 
4.3.2. 
Pembrolizumab Dose Justification ............................................... 41 
4.4. 
End of Study Definition ............................................................................... 42 
5. 
STUDY POPULATION ........................................................................................... 42 
5.1. 
Inclusion Criteria ......................................................................................... 42 
5.2. 
Exclusion Criteria ........................................................................................ 46 
5.3. 
Lifestyle Considerations .............................................................................. 49 
5.4. 
Screen Failures........................................................................................... 49 
6. 
STUDY INTERVENTION ........................................................................................ 49 
6.1. 
Study Intervention(s) Administered ............................................................. 49 
6.2. 
Preparation/Handling/Storage/Accountability .............................................. 51 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................... 51 
6.4. 
Study Intervention Compliance ................................................................... 52 
6.5. 
Concomitant Therapy.................................................................................. 52 
6.5.1. 
Permitted Medications and Non-drug Therapies .......................... 52 
6.5.2. 
Prohibited Medications and Non-drug Therapies ......................... 53 
6.5.2.1. 
Anti-cancer Therapy After Study Intervention 
Discontinuation ........................................................... 53 
6.6. 
Dose Modification ....................................................................................... 53 
6.6.1. 
General Guidelines for Immune-Related Adverse Events ............ 54 


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6.6.2. 
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Immunotherapy Treatment ......................... 58 
6.7. 
Intervention after the End of the Study ........................................................ 60 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 61 
7.1. 
Discontinuation of Study Intervention .......................................................... 61 
7.1.1. 
Liver Chemistry Stopping Criteria ................................................ 62 
7.1.1.1. 
Study Intervention Restart or Rechallenge after 
liver stopping criteria met ............................................ 62 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................... 63 
7.3. 
Lost to Follow Up ........................................................................................ 63 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 64 
8.1. 
Efficacy Assessments ................................................................................. 66 
8.1.1. 
Disease Assessments.................................................................. 67 
8.2. 
Safety Assessments ................................................................................... 68 
8.2.1. 
Physical Examinations ................................................................. 68 
8.2.2. 
Performance Status ..................................................................... 68 
8.2.3. 
Vital Signs .................................................................................... 68 
8.2.4. 
Electrocardiograms ...................................................................... 69 
8.2.5. 
Echocardiograms ......................................................................... 69 
8.2.6. 
Clinical Safety Laboratory Assessments ...................................... 69 
8.3. 
Adverse Events and Serious Adverse Events ............................................. 69 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 70 
8.3.2. 
Method of Detecting AEs and SAEs ............................................. 70 
8.3.3. 
Follow-up of AEs and SAEs ......................................................... 70 
8.3.4. 
Regulatory Reporting Requirements for SAEs ............................. 71 
8.3.5. 
Pregnancy ................................................................................... 71 
8.3.6. 
Cardiovascular and Death Events ................................................ 71 
8.3.7. 
Events of Clinical Interest ............................................................ 72 
8.4. 
Treatment of Overdose ............................................................................... 72 
8.4.1. 
GSK3359609 ............................................................................... 73 
8.4.2. 
Pembrolizumab ............................................................................ 73 
8.5. 
Pharmacokinetics ....................................................................................... 73 
8.6. 
Pharmacodynamics .................................................................................... 73 
8.7. 
Genetics ..................................................................................................... 73 
8.8. 
Biomarkers ................................................................................................. 74 
8.8.1. 
RNA Research ............................................................................. 75 
8.8.2. 
DNA Research ............................................................................. 75 
8.8.3. 
Tumor Tissue ............................................................................... 75 
8.8.4. 
Blood Samples ............................................................................ 76 
8.9. 
Immunogenicity........................................................................................... 76 
8.10. 
Medical Resource Utilization and Health Economics .................................. 76 
8.11. 
Patient Reported Outcomes ........................................................................ 77 
8.11.1. 
EORTC Item Library 50 and 51: Select Domains from the 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire 30-item Core module 
(EORTC QLQ-C30) and 35-Item Head and Neck Module 
(EORTC QLQ-H&N35) ................................................................. 77 
8.11.2. 
Brief Pain Inventory Short-Form- Item 3 (BPI-I3) .......................... 77 


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8.11.3. 
The Patient-Reported Outcomes Measurement 
Information System- Short Form Physical Function- 8 item 
(PROMIS SF PF 8c) .................................................................... 77 
8.11.4. 
Patient Global Impression Items (PGIS and PGIC) ...................... 79 
8.11.5. 
Europol Questionnaire (EQ-5D-3L) .............................................. 79 
8.11.6. 
Functional Assessment of Cancer Therapy – General 
Population (FACT-GP5) ............................................................... 79 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 80 
9.1. 
Statistical Hypotheses................................................................................. 80 
9.1.1. 
Primary Hypotheses .................................................................... 80 
9.1.2. 
Key Secondary Hypotheses ......................................................... 80 
9.2. 
Sample Size Determination ........................................................................ 81 
9.2.1. 
Remain as a Phase II Study ........................................................ 82 
9.2.2. 
Expand to a Phase III Study ........................................................ 83 
9.2.3. 
Sample Size Sensitivity ................................................................ 84 
9.3. 
Populations for Analyses ............................................................................ 84 
9.4. 
Statistical Analyses ..................................................................................... 86 
9.4.1. 
Efficacy Analyses ......................................................................... 86 
9.4.1.1. 
Primary Analyses ....................................................... 87 
9.4.1.2. 
Secondary Analyses ................................................... 89 
9.4.1.3. 
Exploratory Analyses .................................................. 91 
9.4.2. 
Safety Analyses ........................................................................... 91 
9.4.3. 
Patient Reported Outcomes ......................................................... 92 
9.4.4. 
Other Exploratory Analyses ......................................................... 93 
9.5. 
Interim Analyses ......................................................................................... 93 
9.6. 
Independent Data Monitoring Committee .................................................... 97 
9.7. 
Blinded Independent Central Review Auditing ............................................ 97 
9.8. 
Multiplicity ................................................................................................... 98 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 101 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 101 
10.1.1. 
Regulatory and Ethical Considerations ...................................... 101 
10.1.2. 
Informed Consent Process ........................................................ 101 
10.1.3. 
Data Protection .......................................................................... 102 
10.1.4. 
Dissemination of Clinical Study Data ......................................... 102 
10.1.5. 
Data Quality Assurance ............................................................. 102 
10.1.6. 
Source Data ............................................................................... 103 
10.1.7. 
Study and Site Closure .............................................................. 103 
10.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 105 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 107 
10.3.1. 
Definition of AE .......................................................................... 107 
10.3.2. 
Definition of SAE ........................................................................ 108 
10.3.3. 
Definition of Cardiovascular Events ........................................... 109 
10.3.4. 
Recording and Follow-Up of AE and SAE .................................. 109 
10.3.5. 
Reporting of SAE to GSK ........................................................... 111 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 112 
10.4.1. 
Definitions: ................................................................................. 112 


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10.4.2. 
Contraception Guidance: ........................................................... 113 
10.4.3. 
Collection of Pregnancy Information: ......................................... 114 
10.5. 
Appendix 5: ECOG Performance Status ................................................... 116 
10.6. 
Appendix 6: Renal Function Measures ..................................................... 117 
10.7. 
Appendix 7: Genetics ................................................................................ 119 
10.8. 
Appendix 8: Liver Safety: Required Actions, Follow-up Assessments 
and Study Intervention Rechallenge Guidelines ........................................ 120 
10.8.1. 
Study Intervention Rechallenge Guidelines ................................ 123 
10.8.1.1. Rechallenge Following Liver Stopping Events 
that are Possibly Related to Study Treatment ........... 123 
10.8.1.2. Restart Following Transient Resolving Liver 
Stopping Events NOT Related to Study 
Treatment ................................................................. 124 
10.9. 
Appendix 9: Country-specific Requirements ............................................. 126 
10.10. Appendix 10: Abbreviations and Trademarks ............................................ 127 
10.11. Appendix 11: Meta-Analysis of HNSCC Studies ....................................... 131 
10.12. Appendix 12: Immune-related Diseases ................................................... 133 
10.13. Appendix 13: Protocol Amendment History ............................................... 135 
11. REFERENCES ..................................................................................................... 139 


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1. 
PROTOCOL SUMMARY 
1.1. 
Background 
1.1.1. 
Inducible T Cell Costimulatory Receptor and GSK3359609 
Inducible T cell co-stimulatory receptor (ICOS) is a co-stimulatory receptor belonging to 
the CD28/B7immunoglobulin (Ig) super family with expression restricted to T cells 
[Hutloff, 1999]. ICOS differentiates from first generation immunomodulatory antibodies 
directed against Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) and PD-1/PD-
L1 by targeting a different axis in the antitumor T cell response cascade and promoting 
activation. ICOS is weakly expressed on resting T cells yet is highly induced on CD4+ 
and CD8+ T cells upon T cell receptor (TCR) engagement with cognate antigen and 
activation. The effect of ICOS agonist activity is to promote activation of cytotoxic CD8+ 
and conventional CD4+ cells, augmenting the expansion, function and survival of these 
populations thereby resulting in an increased antitumor immune response that is durable 
[Fan, 2014; Paulos, 2010; Wakamatsu, 2013, Sharpe, 2002]. 
GSK3359609 is a humanized anti-ICOS mAb selected for its nanomolar (nM) binding to 
and agonist activity in ICOS-expressing CD4+ and CD8+ effector T cells. GSK3359609 
is specifically engineered as an IgG4 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 that would result in depletion of ICOS-positive T cells through antibody-
dependent or complement-dependent cell mediated mechanisms, 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 T cell activating potential of GSK3359609 was evaluated in multiple in vitro assay 
formats as a single agent and in combination with other immune checkpoint inhibitors. 
GSK3359609 in combination with pembrolizumab demonstrated a more robust pro-
inflammatory cytokine response, including increases in interferon gamma (IFN) 
secretion, than either single agent alone. In vivo experiments in different mouse models 
either using GSK3359609/pembrolizumab or anti-mouse ICOS in combination with PD-1 
surrogate antibodies demonstrated enhanced growth inhibition and increased survivability 
of mice compared to either agent alone. The upregulation of ICOS with the mouse anti-
PD-1 antibodies and the converse whereby ICOS mouse surrogate antibodies increased 
tumor PD-L1 expression in these in-vivo experiments further support evaluating this 
combination. Furthermore, analysis of The Cancer Genome Atlas 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. 
Refer to the GSK3359609 IB for details on the non-clinical experiments and findings 
[GlaxoSmithKline Document Number 2017N319717_03, 2020]. 


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1.1.1.1. 
GSK3359609 Clinical Experience 
INDUCE-1 (Study 204691; NCT02723955) is an ongoing, first in-human, dose 
escalation and expansion study of GSK3359609, alone and in combination with other 
agents including pembrolizumab, in participants with advanced solid tumors. Analysis 
from the dose escalation phases of GSK3359609 monotherapy (Part 1A, n=22) and 
GSK3359609 combination with pembrolizumab (Part 2A, n=36), and GSK3359609 
monotherapy pharmacokinetic (PK)/pharmacodynamic cohort (n=47) demonstrated 
GSK3359609 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 as a monotherapy 
and in combination with pembrolizumab was 3 mg/kg. A range of GSK3359609 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]. 
A summary safety analyses from a later clinical data cut-off date of 16 March 2020 that 
included all participants dosed with GSK3359609 monotherapy (n=249), which included 
participants dosed at GSK3359609 10 mg/kg (MAD), or GSK3359609 in combination 
with pembrolizumab (n= 340) showed that 42% (n=104) and 58% (n=197) of 
participants, respectively, experienced at least 1 treatment-related adverse events 
(TR-AE). In the overall Part 1 population, TR-AEs occurring in ≥5% of participants were 
fatigue (10%, n=26), asthenia (9%, n=23), diarrhea (6%, n=16), pruritis (6%, n=14), 
nausea (5%, n=13) and arthralgia (5%, n=12). Eleven participants (4%) experienced at 
least 1 Grade 3 TR-AE; none of which were Grade 5 in severity. In the overall Part 2 
population (GSK3359609 combination with pembrolizumab), TR-AEs occurring in ≥5% 
of participants were diarrhea (9%, n=32), asthenia (9%, n=32), fatigue (9%, n=29), 
pruritus (7%, n=23), aspartate aminotransferase elevations (6%, n=22), alanine 
aminotransferase elevations (6%, n=19), nausea (5%, n=17), hypothyroidism (5%, n=16) 
and rash (5%, n=16). Twenty-one participants (6%) experienced at least 1 Grade 3 TR-
AE, 3 of whom experienced at least 1 treatment-related Grade 5 event (<1%). Refer to 
GSK3359609 IB for further details [GlaxoSmithKline Document Number 
2017N319717_03, 2020]. 
1.1.2. 
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-ligand 2 (PD-L2). Based 
on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda (pembrolizumab) is indicated for the treatment of patients across a number of 
indications, which includes first-line treatment of metastatic or unresectable recurrent 
HNSCC. Pembrolizumab and nivolumab, another PD-1 inhibitor, is also considered a 
second-line/subsequent-line standard of care for patients with R/M HNSCC. 
Refer to the pembrolizumab IB [Merck, 2021] and approved labeling for detailed 
background information on MK-3475. 


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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, 2019]. 
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. 
1.1.2.1. 
Pharmaceutical and Therapeutic Background 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD-L2) 
[Greenwald, 2005; Okazaki, 2001]. 
The structure of murine PD-1 has been resolved [Zhang, 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV 
type) domain responsible for ligand binding and a cytoplasmic tail responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif, and an 
immunoreceptor tyrosine-based switch motif. Following T cell stimulation, PD-1 recruits 
the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based 
switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T cell signaling 
cascade [Okazaki, 2001; Chemnitz, 2004; Shepard, 2004; Riley, 2009]. The mechanism 
by which PD-1 down-modulates T cell responses is similar to, but distinct from, that of 
CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[Parry, 2005; Francisco, 2010]. As a consequence, the PD 1/PD-L1 pathway is an 
attractive target for therapeutic intervention. 
1.1.2.2. 
Non-clinical and Clinical Studies 
Therapeutic studies in mouse models have shown that administration of antibodies 
blocking PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells 
and ultimately leads to tumor rejection, either as a monotherapy or in combination with 
other treatment modalities [Hirano, 2005; Blank, 2004; Weber, 2010; Strome, 2003; 
Spranger, 2014; Curran, 2010; Pilon-Thomas, 2010]. Anti-mouse PD-1 or anti-mouse 
PD-L1 antibodies have demonstrated antitumor responses in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, acute myeloid leukemia and colorectal 
carcinoma [Strome, 2003; Curran, 2010; Pilon-Thomas, 2010; Nomi, 2007; Zhang, 
2004]. In such studies, tumor infiltration by CD8+ T cells and increased IFNγ, granzyme 
B and perforin expression were observed, indicating that the mechanism underlying the 
antitumor activity of PD-1 checkpoint inhibition involved local infiltration and activation 
of effector T cell function in vivo [Curran, 2010]. Experiments have confirmed the in vivo 
efficacy of anti-mouse PD-1 antibody as a monotherapy, as well as in combination with 


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chemotherapy, in syngeneic mouse tumor models (for detail refer to pembrolizumab IB; 
Merck, 2021). 
1.1.3. 
GSK3359609 Monotherapy and in Combination with 
Pembrolizumab in HNSCC 
The ongoing INDUCE-1 expansion phase is investigating GSK3359609 as a 
monotherapy (Part 1B) and GSK3359609 in combination with pembrolizumab (Part 2B) 
in participants with HNSCC. At the 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 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 line 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 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 participants with CPS <1). The median progression-free survival 
(PFS) was 5.6 months (95% CI: 2.4, 7.4) [Rischin, 2019]. 
1.2. 
Synopsis 
Protocol Title: A Randomized, Double-blind, Adaptive, Phase II/III Study of 
GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment 
of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
Short Title: INDUCE-3: A Phase II/III study of GSK3359609 in combination with 
pembrolizumab compared with pembrolizumab plus placebo in participants with PD-L1 
positive recurrent or metastatic HNSCC 
Rationale:  
KEYNOTE-048 (KN-048; NCT02358031) is a randomized, three arm study in patients 
with recurrent or metastatic (R/M) HNSCC who had not received prior systemic therapy 
in the R/M setting. In the standard first-line treatment arm patients received 
chemotherapy (platinum and fluorouracil) in combination with cetuximab based on the 
EXTREME protocol [Vermorken, 2008]. In the two experimental arms patients either 
receive pembrolizumab in combination with platinum plus fluorouracil (5FU) or alone. 
Pembrolizumab was given at a dose of 200 mg every 3 weeks (Q3W), for up to 35 cycles. 


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Pembrolizumab alone and in combination with chemotherapy compared with the 
EXTREME regimen as first-line treatment improved the survival of patients with R/M 
HNSCC. However, the degree of overall survival (OS) improvement for pembrolizumab 
alone or in combination with 5FU/platinum chemotherapy depended on the programmed 
cell death receptor 1-ligand 1 (PD-L1) combined positive score (CPS) status [Burtness, 
2018; Rischin, 2019], with OS improvement in the total PD-L1 population requiring 
pembrolizumab in combination with 5FU-platinum regimen. Although pembrolizumab 
alone did not reach statistical significance for superiority in the final OS analysis in the 
total population (HR: 0.83 [95% CI: 0.70-0.99; p-value: 0.0199), the interim analysis 
declared pembrolizumab alone as delivering non-inferior OS effect in this population. 
More importantly, the frequency of all treatment related toxicities (58.3% versus 96.9%) 
and  Grade 3 events (16.7% versus 69.0%) were much less with pembrolizumab alone 
as compared with the EXTREME regimen. The results from KN48 supported the Food 
and Drug Administration (FDA) approval of pembrolizumab alone and in combination 
with 5FU platinum chemotherapy as first-line treatment of patients with R/M HNSCC in 
the PD-L1 CPS 1 and total populations, respectively [KEYTRUDA, 2019]. In the 
European Union (EU), the European Commission approved pembrolizumab alone or in 
combination with 5FU platinum chemotherapy in the PD-L1-positive (CPS 1) 
populations [KEYTRUDA, 2019]. 
Despite the treatment advancements pembrolizumab has afforded patients with R/M 
HNSCC, there remains an unmet need due to the limited population of benefit with the 
aim to further improve disease control, a feature that if not addressed adversely impacts 
patient quality of life in the disease setting, and to improve survival across all HNSCC 
populations. 
The non-clinical data demonstrate that the activity of targeting ICOS with an agonist 
antibody is further enhanced with PD-1 blockade and that the mechanisms of action for 
each antibody are complementary with one another as evidenced by the non-clinical 
findings that treatment with a mouse anti-PD-1 antibody resulted in upregulation of 
ICOS+ cluster of differentiation (CD)4+ and CD8+ T cells in tumors and lymph nodes; 
conversely, treatment with anti-mouse ICOS antibodies increased PD-L1 levels in the 
tumor. Furthermore, when combined, the two agents resulted in a greater survival effect 
than either agent alone in syngeneic mouse tumor models (refer to Section 1.1.1). The 
preliminary clinical data from INDUCE-1 demonstrate that the combination of 
GSK3359609 with pembrolizumab exhibits promising antitumor activity in participants 
with HNSCC (refer to Section 1.1.3). 
Combining immunomodulatory agents targeting different components of the cancer 
immunity cycle [Chen, 2013] may be able to overcome the multiple mechanisms of 
immune suppression which prohibit an effective antitumor immune response. Thus, 
targeting both the ICOS and PD-1 axes may translate into enhanced clinical activity and 
expand the population that benefits with the combination of GSK3359609 (ICOS agonist 
antibody) and pembrolizumab (PD-1 blocking antibody) which is supported by the 
available non-clinical and clinical evidence. The clinical data from INDUCE-1 has 
validated the non-clinical findings whereby the 24% ORR observed with the combination 
of GSK3359609 and pembrolizumab was higher than that observed with GSK3359609 
monotherapy as described in Section 1.1.3, and higher than that reported for 


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pembrolizumab alone as first-line therapy [Burtness, 2018] or subsequent-line therapy 
[Cohen, 2019] in R/M HNSCC. The purpose of Study 209229 is to evaluate if the 
addition of GSK3359609 to pembrolizumab improves the efficacy of pembrolizumab in 
participants with PD-L1 CPS 1 R/M HNSCC. 


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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary1 
• 
Compare the efficacy of GSK3359609 in 
combination with pembrolizumab to 
pembrolizumab plus placebo in the 
Programmed Death Ligand 1 (PD-L1) 
expression positive (CPS 1) population 
and in the PD-L1 expression high (CPS20) 
population 
• 
OS in the PD-L1 CPS 1 and PD-L1 
CPS 20 populations, defined as the time 
from the date of randomization to the date 
of death due to any cause 
• 
PFS per RECIST v1.1 by investigator 
assessment the PD-L1 CPS 1 population, 
defined as the time from the date of 
randomization to the date of first 
documented disease progression or death 
due to any cause, whichever comes first 
Secondary1 
• Further compare the efficacy of 
GSK3359609 in combination with 
pembrolizumab compared with 
pembrolizumab plus placebo 
• PFS per iRECIST (iPFS) by investigator 
assessment in the PD-L1 CPS 1 population 
• PFS per RECIST v1.1 and iPFS by 
investigator assessment in the PD-L1 CPS 
20 population 
• Milestone OS rate at 12 and 24 months in 
the PD-L1 CPS 1 and CPS 20 
populations 
• ORR per RECIST v1.1 by investigator 
assessment in PD-L1 CPS 1 and CPS 20 
populations 
• DCR per RECIST v1.1by investigator 
assessment in PD-L1 CPS 1 and CPS 20 
populations 
• DoR per RECIST v1.1 by investigator 
assessment in PD-L1 CPS 1 and CPS 20 
populations 
• 
Evaluate the safety and tolerability of 
GSK3359609 in combination with 
pembrolizumab compared with 
pembrolizumab plus placebo 
• 
Frequency and severity of AEs, AESI, 
SAEs 
• 
Dose modifications (i.e., interruptions, 
discontinuations)  
• Evaluate and compare disease related 
symptoms and impact on function and health-
related quality of life (HRQoL) of 
GSK3359609/pembrolizumab versus 
pembrolizumab plus placebo 
• 
The time to deterioration in pain measured 
by the EORTC QLQ-H&N35 pain domain 
in the PD-L1 CPS 1 and CPS 20 
populations 
• 
The time to deterioration in physical 
function measured by the PROMIS PF 8c in 
the PD-L1 CPS 1 and CPS 20 
populations 
Abbreviations: AE=adverse events; AESI=adverse events of special interest; DCR=disease control 
rate; DoR=duration of response; EORTC H&N35= European Organisation for Research and 
Treatment of Cancer Head and Neck 35 Item Module; HRQoL= health-related quality of life; 
iPFS=immune-based PFS; iRECIST=immune-based Response Evaluation Criteria in Solid Tumors; 


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ORR=overall response rate; OS=overall survival; ; PFS=progression-free survival; PROMIS-PF-8c= 
Patient-Reported Outcomes Measurement Information System-Physical Function-Short Form 
1. Refer to Section 9.4.1.2 for definitions of efficacy endpoints, Section 9.1 for key 
endpoints/hypotheses and Section 9.8 or multiplicity control. 
Overall Design: 
This is a randomized, double-blind, Phase II/III study comparing a combination of 
GSK3359609 (ICOS agonist) and pembrolizumab to pembrolizumab plus placebo in 
participants with PD-L1 CPS 1 recurrent or metastatic HNSCC of the oral cavity, 
oropharynx, hypopharynx or larynx. 
The study will evaluate the efficacy of GSK3359609 in combination with pembrolizumab 
compared with pembrolizumab plus placebo as a standard first-line chemotherapy-free 
regimen in HNSCC. All participants will be stratified by 2 factors i) PD-L1 CPS status 
(CPS ≥20 vs. 1≤ CPS <20); ii) HPV status in oropharyngeal cancers (positive vs. 
negative/unknown) vs non-oropharyngeal cancers then randomly assigned in a 1:1 ratio 
to the GSK3359609/ pembrolizumab arm or pembrolizumab/placebo arm. 
A 2-in-1 adaptive Phase II/III design [Chen, 2018] is considered, with the option to 
expand the Phase II study seamlessly into Phase III confirmatory study, without changing 
the eligibility criteria, endpoints or randomization scheme. 
ORR per RECIST v1.1 will be used for the adaptive decision. This analysis will be 
conducted in the approximately first 100 participants (PD-L1 CPS 1 population) with a 
minimum follow-up of 6 months. If at this interim analysis, the outcome meets the 
defined ORR positive criterion, the study will expand from a Phase II to a Phase III 
design with 600 participants randomized. If the outcome does not meet the defined 
criteria, then the study will remain as Phase II with 374 participants randomized. 
All participants randomized are included for inference at the end of Phase II or Phase III 
regardless of the interim adaptive decision. In addition, all primary endpoints and key 
secondary endpoints are formally tested for statistical significance at the end of Phase II 
or Phase III. 
Disclosure Statement: This is a parallel group treatment study with 2 arms that is 
double-blinded. Crossover between study treatment arms is not permitted. 
Number of Participants: 
Overall, the Phase II study will randomize approximately 374 participants with a 1:1 ratio 
between the GSK3359609 in combination with pembrolizumab (Arm 1) and 
pembrolizumab and placebo (Arm 2). Based on the prevalence of PD-L1 CPS status 
reported in KN-048 [Burtness, 2018], in a target sample size of 374 participants with 
PD-L1 CPS 1 (PD-L1 positive expression), the study will enroll approximately 198 
participants with PD-L1 CPS 20 (PD-L1 high expression). 
Should the decision be made to expand the Phase II study into Phase III study an 
additional 226 participants will be randomly assigned to treatment in a 1:1 ratio between 


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the GSK3359609/pembrolizumab combination treatment arm and the 
pembrolizumab/placebo treatment arm. 
The participants randomized prior to the adaptive decision which consists of those 
participants included in the analysis for the adaptive decision will be included in Phase III 
analyses. The Phase III study will have an overall sample size of 600 participants in the 
PD-L1 CPS 1 population and 318 participants in the PD-L1 CPS 20 population. The 
overall proportion of participants by PD-L1 CPS status will be capped such that the 
maximum proportion of participants in PD-L1 CPS 20 or 1 CPS <20 will not exceed 
the planned proportion by 5% for either subgroup. 
Intervention Groups and Duration: 
The study is comprised of three periods: screening, treatment, and follow-up. The total 
duration of study participation begins with the signing of the informed consent form 
(ICF). After a screening period of up to 28 days, eligible participants will be randomly 
assigned to 1 of the 2 treatment arms. 
For participants who meet all eligibility criteria and are randomized within the study, the 
maximum duration of treatment with pembrolizumab, GSK3359609 and placebo is 
expected to be approximately 2 years, up to 35 cycles. A decision to permanently 
discontinue treatment due to disease progression may be based upon immune-based 
RECIST [iRECIST]) as disease progression per RECIST v1.1 is further evaluated for 
confirmation by imaging/clinical assessments 4 weeks later and is critical to the analysis 
of immune-based PFS (iPFS) [Seymour, 2017]. 
The follow-up period begins when study treatment is permanently discontinued; 
participants will undergo follow-up assessments for safety, PFS on first subsequent anti-
cancer therapy (PFS2) and survival as indicated in the Schedule of Activities (SoA); refer 
to Section 1.4. The total duration of study participation begins with the signing of the ICF 
through the final protocol-defined follow-up assessment for survival. 
Participants will be randomly assigned to either receive the combination of GSK3359609 
24 mg plus pembrolizumab 200 mg or placebo plus pembrolizumab 200 mg. 
GSK3359609, placebo, and 200 pembrolizumab are administered each as a 30-minute IV 
infusion once Q3W. GSK3359609 or placebo will be administered first followed by 
pembrolizumab. 
Independent Data Monitoring Committee:  
The study will use an Independent Data Monitoring Committee (IDMC). The IDMC 
membership and governance will be outlined in a separate charter. 
The IDMC will make recommendations for discontinuation or modification of the study 
based on ongoing reviews of safety data according to the Charter. In addition, the IDMC 
will also evaluate all interim efficacy data, including the adaptive decision as well as 
interim analyses of PFS and OS, and make a recommendation based on observed results 
of the study. 


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In this double-blind study, all GSK and site personnel will be restricted from access to 
interim analysis results provided to the IDMC until the conclusion of the study, unless the 
IDMC recommends significant changes to study conduct that require a protocol 
amendment. In this scenario, after receiving the IDMC recommendation and a decision 
by Chief Medical Officer (CMO), a review of the data may be required. A select group 
from GSK, as determined by the CMO will be unblinded to review the data to agree on 
future study conduct. Depending on the recommendation of the IDMC, the Sponsor may 
prepare a regulatory submission. More details will be provided in the IDMC Charter. 
1.3. 
Schema 
 
Abbreviations: CPS=combined positive score; GSK609=GSK3359609; HPV=human papilloma virus; 
ORR=overall response rate; PD-L1=programmed death ligand-1; Q3W=every three weeks; vs=versus 
1. Stratification Factors: 
• 
PD-L1 Status (CPS ≥20 vs. 1≤ CPS <20) 
• 
HPV status in oropharynx sites only (positive vs. negative/unknown) vs non-oropharynx 
2. ORR assessed by RECIST v1.1; refer to Section 9.5 for further details on adaptive decision analysis 
 


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1.4. 
Schedule of Activities (SoA) 
Table 1 
Schedule of Activities 
Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Screening Only, Safety and Disease Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
ICF can be signed up to 
45 days before 
randomization. 
Inclusion and Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Review eligibility prior 
to randomization. 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Disease History, Medical 
History (Past and Current 
Conditions; Includes Tobacco, 
Alcohol and Drug Substance 
Usage), Prior Anticancer 
Therapies; HPV status by p16 
IHC in oropharyngeal 
cancers* 
X 
 
 
 
 
 
 
 
 
 
 
 
*HPV status assessed 
by p16 IHC testing 
using CINtec p16 
Histology assay. If local 
p16 testing results are 
not available, or cannot 
be assessed by the 
specified method, a 
tumor tissue sample 
may be submitted for 
p16 testing at the 
designated central 
laboratory. 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Physical Examination  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
X 
 
Full physical exam at 
Screening;  
Not required to be 
performed on Day 1 if 
Screening exam was 
performed within 72 
hours from time of the 
scheduled first dose. 
After Screening, brief 
physical exam. Must be 
assessed within 3 days 
prior to dosing. 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
X 
 
Must be assessed within 
3 days prior to dosing. 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Serum Pregnancy Test 
(WOCBP only) 
X 
 
 
 
 
 
 
 
 
 
 
 
Required within 72 
hours prior to 
randomization. 
Monthly urine/serum 
(preference) pregnancy 
testing may also be 
performed as consistent 
with local standards 
however if a urine test 
is positive or 
borderline, or in the 
event of a missed 
menstrual period or 
suspicion of pregnancy, 
a serum β-hCG test will 
be required. 
Hepatitis B and C  
X 
 
 
 
 
 
 
 
 
 
 
 
If test otherwise 
performed within 3 
months prior to 
randomization, testing 
at screening is not 
required (refer to Table 
15) 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Hematology, Coagulation, 
Clinical Chemistry, Urinalysis 
Laboratory Assessments 
(Refer to Table 15) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
X 
 
Required within 7 days 
of randomization day 
Not required to be 
tested on Day 1 if 
Screening labs are 
within 72 hours from 
time of scheduled first 
dose. 
Must be drawn within 3 
days prior to dosing 
Thyroid Function Testing 
X 
 
 
X 
 
X 
 
X 
 
Q6W 
X 
 
Must be drawn within 3 
days prior to dosing 
ECHO or MUGA/12-lead 
ECG/ Cardiac Troponin I or T 
X 
 
 
 
 
 
 
 
 
 
 
 
After Screening, 
perform as clinically 
indicated. QT 
interval/duration will be 
corrected using 
Fridericia’s formula  


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
X 
 
Must be assessed within 
3 days prior to dosing. 
Height will be recorded 
at Screening only. 
Refer to Protocol 
Section 8.2.3. 


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Tumor Tissue Collection for 
22C3 PharmDx PD-L1 IHC 
Assay^ Testing by Central 
Laboratory 
X* 
 
 
 
 
 
 
 
 
 
 
 
*Assessment(s) can 
commence after signed 
ICF within 45 days 
prior to randomization. 
Refer to Section 5.1, 
inclusion 12. for tumor 
tissue requirements 
(i.e., whether archival 
tumor tissue is 
acceptable or fresh 
biopsy is required). 
PD-L1 IHC by central 
lab testing; evaluable 
result required prior to 
randomization.  
^The PD-L1 IHC 22C3 
pharmDx assay is US 
FDA approved and CE 
marked in the EU 
p16 IHC testing by 
central lab if local 
results not available 
(refer to Section 8; 
[oropharyngeal only]) 
*This tissue will be 
used for exploratory 
biomarkers 
AE/AESI/SAE Review 
X 
=============================→ 
X 
X 
All AEs are to be 
graded according to 
NCI-CTCAE (Version 
5.0) 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Refer to Section 8.3.1 
for time period of 
collection 
Concomitant Medication 
Review 
X 
=============================→ 
X 
X* 
*Concomitant 
medications used to 
treat AEs/AESI/SAEs 
during the follow-up 
period are to be 
reported. 
Disease Assessments 
X 
 
 
 
X* 
 
X* 
 
 
 
 
 
 
*For participants who 
received at least 1 dose 
of GSK3359609 
(feladilimab) or placebo 
scans should be 
completed at W9, W15 
and then move to 
standard practice. 
For participants who 
received only 
pembrolizumab or who 
received GSK3359609 
(feladilimab) and are 
past W15, scans should 
be completed according 
to standard practice. 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Study Treatment 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization may 
occur up to 3 days 
before Day 1; the 
preference is to 
randomize within 24 
hours before Day 1. 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Pembrolizumab 
 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
 
 
Day 1: study 
administration window 
is within 3 days of 
randomization 
 
Participants will receive 
study treatment up to 
the maximum duration 
of 35 cycles unless one 
of the following events 
occurs earlier: 
•Disease progression 
•Death 
•Unacceptable toxicity 
(refer to Protocol 
Section 6.6 and 
subsections) 
•Pregnancy (refer to 
Protocol Section 8.3.5 
for details) 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Patient Reported Outcome Assessments5 
Genetics Research  
Genetics Research Blood 
Sample 
 
X 
 
 
 
 
 
 
 
 
 
 
Optional, collected if 
genetics research 
optional consent signed; 
consent must be signed 
before sample is drawn  
Sample will be 
collected on Day 1 
predose. 
NOTE: sample may be 
collected beyond 
predose/Day 1 with 
signed consent 
Fresh Tumor Biopsy* 
 
 
 
 
 
*Optional biopsy at:  
• 
Screening in those 
participants who 
provide archival 
tumor tissue (refer 
to Section 5.1 for 
archival tissue 
requirements) 


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Procedure 
Screening  
(up to 28 Days 
Before 
Randomization) 
Treatment Period1, 4 
 
Follow-
up3 
(14 
Days) 
 
 
Notes 
 
TDV = Treatment 
Discontinuation Visit 
Day 1 
Weeks ( 3 Days) 
3 
6 
9 
12 
15 
18 
21 
>21 
TDV2
. 
Follow-up Assessments 
Survival 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Participants will be 
contacted via telephone 
contact every 12 weeks 
until death or 
participant’s 
withdrawal from further 
contact or until the last 
patient discontinues 
treatment and has had 
their last follow up for 
safety. 
Abbreviations: AE = Adverse Events; AESI = Adverse Events of Special Interest;; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS= Eastern 
Cooperative Oncology Group Performance Status; EOI= end of infusion; HPV = human papilloma virus; ICF = Informed Consent Form; MUGA = Multigated 
Acquisition Scan; Q3W = every 3 weeks; Q6W = every 6 weeks; Q12W = every 12 weeks; Q24W = every 24 weeks; SAE = Serious Adverse Events; TDV = 
Treatment Discontinuation visit; US = United States; WOCBP = woman of childbearing potential 
1. If administration of study treatment is delayed 7 days due to adverse events, assessments indicated to occur at the dosing visit can be scheduled to occur when 
dosing occurs. If administration of study treatment is delayed > 7 days due to adverse events, assessments indicated at the dosing visit are to be performed at the 
expected scheduled visit (window) with the exception of the following: PK sample collection; immunogenicity sample collection, and the PRO assessments. If 
the dosing Week visit that is delayed > 7 days occurs at a visit when disease assessments are required, then PRO assessments are required to be administered to 
the participant. 
2. Do not repeat tests that have already been performed within 3 days or scans within 6 weeks of the TDV.  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. 
3. The follow-up visits will commence after decision to permanently discontinue study treatment for any reason is made including completion of 35 cycles. . 
 


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2. 
INTRODUCTION 
Head and neck squamous cell carcinoma (HNSCC) is one of the most common 
malignancies worldwide, accounting for more than 550,000 new cases and 380,000 
deaths per year [Vos, 2017; Naghavi, 2017]. HNSCC is a heterogeneous disease, 
encompassing a variety of tumors that originate from different anatomic subsites in the 
head and neck region, and include carcinomas of the oral cavity, oropharynx, 
hypopharynx, nasopharynx, larynx, and nasal cavity/sinuses. 
The etiology of HNSCC is well-established as being multifactorial with risk factors that 
include tobacco smoking and alcohol consumption; human papilloma virus (HPV) 
infection is also an important factor in the pathophysiology and prognosis of HNSCC 
which includes playing an immunosuppressive role, mainly in the oropharyngeal region 
[Gillison, 2015; Ang, 2010; Fung, 2017]. Most patients are diagnosed with locally 
advanced disease and are usually treated with multimodal therapy including surgery, 
radiotherapy/chemotherapy and systemic therapy. 
Despite advances in surgical and radiation techniques, as well as the addition of 
chemotherapy and epidermal growth factor receptor-targeting monoclonal antibodies 
(mAbs) in the treatment of locally advanced HNSCC, more than half of patients 
eventually experience relapse or distant metastases. Most of these patients are no longer 
suitable for curative treatment approaches. For locally recurrent disease, local treatment 
options such as surgery and radiotherapy play an important role in this setting. For 
recurrent disease no longer amenable to local therapy or metastatic HNSCC, platinum-
based chemotherapy  cetuximab was the standard treatment option in the United States 
(US) before the US FDA approval of pembrolizumab in this setting. Even with current 
multi-agent chemotherapy that now includes pembrolizumab, the expected median 
survival for a patient in the incurable or metastatic relapse setting remains under 15 
months [KEYTRUDA, 2019]. 
2.1. 
Study Rationale 
KEYNOTE-048 (KN-048; NCT02358031) was a randomized, three arm study in patients 
with recurrent or metastatic (R/M) HNSCC who had not received prior systemic therapy 
in the R/M setting. In the standard first-line treatment arm patients received 
chemotherapy (platinum and fluorouracil) in combination with cetuximab based on the 
EXTREME protocol [Vermorken, 2008]. In the 2 experimental arms patients either 
receive pembrolizumab in combination with platinum plus fluorouracil (5FU) or 
pembrolizumab alone. Pembrolizumab was given at a dose of 200 mg every 3 weeks 
(Q3W), for up to 35 cycles. 
Pembrolizumab alone and in combination with chemotherapy compared with the 
EXTREME regimen as first-line treatment improved the survival of patients with R/M 
HNSCC. However, the degree of overall survival (OS) improvement for pembrolizumab 
alone or in combination with 5FU/platinum chemotherapy depended on the programmed 
cell death receptor 1-ligand 1 (PD-L1) combined positive score (CPS) status.[Burtness, 
2018; Rischin, 2019], with OS improvement in the total PD-L1 population requiring 
pembrolizumab in combination with 5FU-platinum regimen. Although pembrolizumab 


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alone compared to the EXTREME regimen did not reach statistical significance for 
superiority at the final OS analysis in the total population (HR: 0.83 [95% CI: 0.70-0.99; 
p-value: 0.0199), the analysis declared pembrolizumab alone as delivering a non-inferior 
OS effect in this population. More importantly, the frequency of all treatment related 
toxicities (58.3% versus 96.9%) and  Grade 3 events (16.7% versus 69.0%) were much 
less with pembrolizumab alone as compared with the EXTREME regimen. 
The KN-048 results supported the Food and Drug Administration (FDA) approval of 
pembrolizumab alone and in combination with 5FU platinum chemotherapy as first-line 
treatment of patients with R/M HNSCC in the PD-L1 CPS 1 and total populations, 
respectively [KEYTRUDA, 2019]. In the EU, the  European Commission approved 
pembrolizumab alone or with 5FU platinum chemotherapy in the PD-L1-positive (CPS 
1) population [KEYTRUDA, 2019].  In addition pembrolizumab alone and in 
combination with 5FU-platinum chemotherapy were incorporated into the National 
Comprehensive Cancer Network (NCCN) and the Society for Immunotherapy of Cancer 
guidelines as an option for the first-line treatment in patients with non-nasopharyngeal 
HNSCC; the choice of which pembrolizumab-based regimen may consider PD-L1 
expression status as well as other patient and disease characteristics [National 
Comprehensive Cancer Network (NCCN), 2021; Cohen, 2019]. 
However, there was a lack of improvement in PFS with pembrolizumab alone and in 
combination with chemotherapy compared with the EXTREME regimen in the overall 
population and in the PD-L1 CPS populations analyzed. Moreover, the ORR reported for 
pembrolizumab alone was 23.3 % in PD-L1 CPS 20 population, 19.1% in PD-L1 
CPS 1 population and 16.9% in the total population; which was lower than the ORR 
observed with the EXTREME regimen [Burtness, 2018; Rischin, 2019]. Despite the 
treatment advancements pembrolizumab has afforded patients with R/M HNSCC, there 
remains an unmet need due to the limited population of benefit with the aim to further 
improve disease control, a feature that if not addressed, adversely impacts patient quality 
of life in this disease setting, and to improve survival across all HNSCC populations. 
The non-clinical data demonstrate that the activity of targeting ICOS with an agonist 
antibody is further enhanced with PD-1 blockade. Further rationale for targeting the 
ICOS and PD-1 axes is supported by the non-clinical finding that treatment with a mouse 
anti-PD-1 antibody resulted in upregulation of ICOS+ cluster of differentiation (CD)4+ 
and CD8+ T cells in tumors and lymph nodes; conversely, treatment with anti-mouse 
ICOS antibodies increased PD-L1 levels in the tumor. Furthermore, when combined, the 
2 agents resulted in a greater survival effect than either agent alone in syngeneic mouse 
tumor models (refer to Section 1.1.1). The preliminary clinical data from INDUCE-1 
demonstrate that the combination of GSK3359609 with pembrolizumab exhibits 
promising antitumor activity in participants with HNSCC (refer to Section 1.1.3). 
Combining immunomodulatory agents targeting different components of the cancer 
immunity cycle [Chen, 2013] may be able to overcome the multiple mechanisms of 
immune suppression which prohibit an effective antitumor immune response and 
contribute to the progression of HNSCC [Ferris, 2015]. Thus, targeting both the ICOS 
and PD-1 axes may translate into enhanced clinical activity and expand the population 
that benefits with the combination of GSK3359609 (ICOS agonist antibody) and 


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pembrolizumab (PD-1 blocking antibody) which is supported by the available non-
clinical and clinical evidence. The clinical data from INDUCE-1 has validated the non-
clinical findings whereby the 28% ORR observed with the combination of GSK3359609 
and pembrolizumab was higher than GSK3359609 monotherapy as described in Section 
1.1.3, and higher than that reported for pembrolizumab alone as first-line therapy 
[Burtness, 2018; Rischin, 2019] or subsequent-line therapy [Cohen, 2019] in R/M 
HNSCC. The purpose of Study 209229 is to evaluate if the addition of GSK3359609 to 
pembrolizumab as first-line treatment improves the efficacy of pembrolizumab in 
participants with R/M HNSCC. 
2.2. 
Benefit/Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK3359609 [GSK3359609 IB, GlaxoSmithKline Document Number 
2017N319717_03, 2020] and pembrolizumab [Merck, 2021] can be found in the 
respective IBs. 
The following sub sections outline the risk assessment and mitigation strategy for 
GSK3359609 in combination with pembrolizumab in this protocol. 
2.2.1. 
Risk Assessment 
Of 260 participants treated with the combination of GSK3359609 (at various doses) and 
pembrolizumab in various tumor types across the dose escalation and expansion phases 
of the INDUCE-1 study, 94% experienced at least 1 adverse event regardless of causality; 
with 41% experiencing at least 1 Grade 3 event and 41% experiencing at least 1 serious 
event. The events reported with the highest frequency (10%) regardless of causality 
were anemia, fatigue, nausea, diarrhea, asthenia, pyrexia, deceased appetite, dyspnea, 
constipation, cough and vomiting; these most common all-cause AEs are consistent with 
the those reported for pembrolizumab alone [KEYTRUDA, 2019]. Regarding immune 
related events (irAEs) most have been low grade and were treated successfully; few high 
grade irAEs were considered significant or required hospitalization (i.e., hyperglycemia 
and pneumonitis). Refer to the GSK3359609 IB for further details [GlaxoSmithKline 
Document Number 2017N319717_03, 2020]. 
Table 2 outlines the risk assessment and mitigation strategy for this protocol. 


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Table 2 
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 
• Toxicity (≥Grade 3) 
related to prior 
immunotherapy leading 
to study treatment 
discontinuation 
• Active autoimmune 
disease (refer to 
Section 5.2 exclusion 
criterion 8) 
• Severe hypersensitivity 
to another mAb 
• Established 
management guidelines 
for irAEs/treatment 
related AEs (refer to 
Section 6.6) 
• Further details on the 
identification, 
evaluation, and 
management of 
toxicities with a 
potential immune 
etiology (refer to 
Section 6.6); refer to 
pembrolizumab 
prescribing information 
for further details 
Hypersensitivity reaction 
• Risk for infusion 
reactions and 
hypersensitivity is 
inherent to many mAbs 
[Brennan, 2010] 
• Participants with 
history of severe 
hypersensitivity to 
another mAb are 
ineligible for this study 
• Details on management 
of infusion reactions 
are included in Section 
6.6.2. 


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Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Severe cytokine release 
syndrome (sCRS) 
• ICOS is a 
costimulatory receptor 
that can stimulate 
proliferation and 
activation of T cells 
• GSK3359609 is an 
ICOS agonist that can 
co-stimulate T cell 
activation in the 
context of TCR signal 
• No CRS events have 
been reported in 
clinical programs 
investigating 
GSK3359609 (refer to 
GSK3359609 IB; 
GlaxoSmithKline 
Document Number 
2017N319717_03, 
2020) 
• Management of CRS 
events is provided in 
the Section 6.6.2. 
Immune complex disease 
Immune complex 
formation and deposition 
findings in non-clinical 
safety studies (refer to 
GSK3359609 IB; 
GlaxoSmithKline 
Document Number 
2017N319717_03, 2020) 
• Clinical laboratory 
safety assessments and 
immunogenicity testing 
is included in the study 
(refer to Table 1) 
Abbreviations: AE= adverse event; CRS=cytokine release syndrome; ICOS=inducible T cell co-
stimulatory receptor; IB=Investigator’s brochure; mAb=monoclonal antibody; SoA=schedule of activities; 
TCR=T cell receptor 
 


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2.2.2. 
Overall Benefit: Risk Conclusion 
This is a randomized, double-blinded, adaptive design, Phase II/III study of 
pembrolizumab (a standard of care) plus placebo or in combination with GSK3359609 
for first line treatment of R/M HNSCC. Regarding benefit, the focus should be on the 
following key points: first, the KN-048 results support pembrolizumab as a backbone 
agent as a standard of care for the first-line treatment of R/M HNSCC in which OS for 
pembrolizumab alone was superior to the EXTREME regimen in the PD-L1 CPS 1 
population (refer to Section 2.1); second, GSK3359609 in combination with 
pembrolizumab was shown to have a positive ORR and median PFS in a small cohort 
(n=29) of participants with PD-1/L1 treatment naïve HNSCC (refer to Section 1.1.3). The 
risks seen in participants exposed to GSK3359609 (at various doses) in combination with 
pembrolizumab are summarized in Table 2 and are consistent with those observed with 
pembrolizumab alone. Of 260 participants treated with the combination of GSK3359609 
and pembrolizumab in the INDUCE-1 study, most had at least 1 adverse event, the 
majority of which were low grade in severity. The evidence to date for the combination 
of GSK3359609 with pembrolizumab favor an acceptable safety profile and an expected 
clinical benefit in participants with HNSCC within the context of the anti-tumor effects 
observed in the small cohort of participants with HNSCC enrolled in INDUCE-1. 
Additionally, the safety profile of pembrolizumab alone is more favorable than the 
EXTREME regimen as the frequency of Grade 3 events and AEs leading to treatment 
discontinuation were markedly lower in comparison with the EXTREME regimen. 
Therefore, within the context of the significant survival effect and the favorable safety 
profile of pembrolizumab monotherapy in the first-line R/M HNSCC PD-L1 CPS 1 
population, pembrolizumab plus placebo as the control arm is supported. Moreover, 
initiating a Phase II/III adaptive design study to investigate pembrolizumab in 
combination with GSK3359609 provides participants with first-line R/M HNSCC a 
potentially favorable risk/benefit profile. 
3. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary1 
• 
Compare the efficacy of GSK3359609 in 
combination with pembrolizumab to 
pembrolizumab plus placebo in the 
Programmed Death Ligand 1 (PD L1) 
expression positive (CPS 1) population 
and in the PD-L1 expression high (CPS 
20) population 
• 
OS in PD-L1 CPS 1 and CPS 20 
populations defined as the time from the 
date of randomization to the date of death 
due to any cause 
• 
PFS per RECIST v1.1 by investigator 
assessment in PD-L1 CPS 1 population, 
defined as the time from the date of 
randomization to the date of first 
documented disease progression or death 
due to any cause, whichever comes first 
Secondary1 
• Further compare the efficacy of 
GSK3359609 in combination with 
pembrolizumab compared with 
pembrolizumab plus placebo  
• PFS per iRECIST (iPFS) by investigator 
assessment in the PD-L1 CPS 1 population 
• PFS per RECIST v1.1 and iPFS by 
investigator assessment in PD-L1 CPS 20 
population 


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Objectives 
Endpoints 
• Milestone OS rate at 12 and 24 months in 
the PD-L1 CPS 1 and CPS 20 
populations 
• ORR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and 
CPS20 populations 
• DCR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and CPS 
20 populations 
• DoR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and CPS 
20 populations 
• 
Evaluate the safety and tolerability of 
GSK3359609 in combination with 
pembrolizumab compared with 
pembrolizumab plus placebo 
• 
Frequency and severity of AEs, AESI, 
SAEs 
• 
Dose modifications (i.e., interruptions, 
discontinuations)  
• 
Evaluate and compare disease related 
symptoms and impact on function and 
health-related quality of life (HRQoL) of 
GSK3359609/pembrolizumab versus 
pembrolizumab plus placebo 
• 
The time to deterioration in pain measured 
by the EORTC QLQ-H&N35 pain domain 
in the PD-L1 CPS 1 and CPS 20 
populations 
• 
The time to deterioration in physical 
function measured by the PROMIS PF 8c in 
the PD-L1 CPS 1 and CPS 20 
populations 
Exploratory 
• 
Compare the efficacy of GSK3359609 in 
combination with pembrolizumab to 
pembrolizumab plus placebo 
• 
ORR, DoR, DCR per iRECIST 
• 
PFS2, defined as the time from the date of 
randomization to the date of second 
objective disease progression per RECIST 
v1.1, or death due to any cause, whichever 
first  
• 
Evaluate and compare disease-related 
symptoms, overall bother of treatment side 
effects, and impact on function and HRQoL 
of GSK3359609/pembrolizumab versus 
pembrolizumab plus placebo 
• 
Symptomatic AEs as measured by the 
FACT GP5 
• 
Changes in other domains of quality of life 
as measured by the selected EORTC 
IL50/51 (subset of domains of the EORTC 
QLQ-C30 and EORTC QLQ-H&N35), 
BPI-I3 and EQ-5D-3L 
• 
Evaluate healthcare resource utilization of 
participants in the GSK3359609 
combination with pembrolizumab arm 
versus participants in the placebo 
combination with pembrolizumab arm 
• 
Non-protocol healthcare encounters, such as 
provider visits, emergency room visits, 
hospitalizations, medications, tests, or 
procedures 
• 
Evaluate GSK3359609 PK properties 
• 
Summary of GSK3359609 concentrations 
and Cmax, Cmin, AUC (0-) as data permit 
• 
Determine immunogenicity of 
GSK3359609 
• 
Anti-drug antibody incidence 
• 
Explore relationship between biomarkers in 
tumor and blood, such as immune response 
biomarkers, target expression and efficacy 
endpoints 
• 
Tumor and blood-based analysis of DNA, 
RNA, and protein analytes/profiles2; OS, 
PFS, ORR, other efficacy parameters 
• 
Genetics Research: Investigate the 
relationship between host genetic variations 
and response to therapy 
• 
Germline genetic evaluations may be 
conducted for: 


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Objectives 
Endpoints 
• 
Clinical response, including 
GSK3359609/pembrolizumab or any 
concomitant medicines 
• 
Disease susceptibility, severity, and 
progression and related conditions 
Abbreviations: AE=adverse events; AESI=adverse events of special interest; Brief Pain Inventory- 
Item 3= BPI-I3; DCR=disease control rate; DNA=deoxyribonucleic acid; DoR=duration of response; 
EORTC IL50=European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Item Library 50; EORTC IL51=EORTC Item Library 51; EQ-5D-3L=EuroQoL 5 
Dimensions; FACT-GP5 = Functional Assessment of Cancer Therapy – General (Item GP5); 
HRQoL=health-related quality of life; iPFS = immune-based progression-free survival; 
iRECIST=immune-based Response Evaluation Criteria in Solid Tumors; ORR=overall response rate; 
OS=overall survival; PFS=progression-free survival; PROMIS-PF-8c= Patient-Reported Outcomes 
Measurement Information System-Physical Function-Short Form; RECIST= Response Evaluation 
Criteria in Solid Tumors; RNA=ribonucleic acid 
1. Refer to Section 9.4.1.2 for definitions of efficacy endpoints, Section 9.1 for key 
endpoints/hypotheses and Section 9.8 for multiplicity control 
2. Refer to Section 8.8 for details on biomarkers 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blind, adaptive Phase II/III study comparing a combination 
of GSK3359609 (ICOS agonist) and pembrolizumab to pembrolizumab plus placebo in 
participants with PD-L1 CPS 1 recurrent or metastatic HNSCC of the oral cavity, 
oropharynx, hypopharynx or larynx. 
The study will evaluate the efficacy of GSK3359609 (ICOS agonist) in combination with 
pembrolizumab compared with pembrolizumab as a first-line chemotherapy-free regimen 
in HNSCC. All participants will be stratified by the following factors i) PD-L1 CPS 
status (CPS ≥20 vs. 1≤ CPS <20); ii) HPV status (oropharyngeal cancers [positive vs. 
negative/unknown] vs. non-oropharyngeal cancers) then randomly assigned in a 1:1 ratio 
to the GSK3359609/pembrolizumab arm or pembrolizumab/placebo arm. 
A 2-in-1 adaptive Phase II/III design [Chen, 2018] is considered, with the option to 
expand the Phase II study seamlessly into Phase III confirmatory study, without changing 
the eligibility criteria, endpoints or randomization scheme.The study schematic is 
provided in Section 1.3. The study does not permit crossover between study treatment 
arms as one of the primary endpoints is overall survival and the study is double blinded. 
The adaptive decision will be guided by the analysis of ORR/DCR per RECIST v1.1 in 
the approximate first 100 participants (PD-L1 CPS ≥1 population) with a minimum 
follow-up of 6 months. If at this interim analysis, the outcome meets the defined ORR 
positive criterion (refer to Section 9.5), the study will expand from a Phase II to a Phase 
III design with 600 participants randomized. If the outcome does not meet the defined 
criteria, then the study will remain as Phase II with 374 participants randomized. The 
overall proportion of participants by PD-L1 CPS status will be capped such that the 
maximum proportion of participants in PD-L1 CPS20 or 1CPS <20 will not exceed the 


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planned proportion by 5% for either subgroup; refer to Section 9.2 for expected 
prevalence and planned sample size estimates. 
All participants randomized are included for inference at the end of Phase II or Phase III 
regardless of the interim adaptive decision. In addition, all primary endpoints and key 
secondary endpoints are formally tested for statistical significance at the end of Phase II 
or Phase III. 
The detailed interim analysis plan including making the adaptive decision is pre-specified 
in Section 9.5. 
4.2. 
Scientific Rationale for Study Design 
A 2-in-1 adaptive Phase II/III design [Chen, 2018] is considered as an efficient approach 
to either expand a Phase II study seamlessly into a Phase III study with pre-specified 
adaptive decision rules, by randomizing additional participants without changing the 
inclusion and exclusion criteria for enrollment, endpoints and randomization scheme. 
This approach supports the Phase III design by properly balancing the risk and benefit of 
the expansion decision. If the decision is not to expand, the study remains as a Phase II 
design and the primary analysis is conducted at the end of Phase II. 
The selection of ORR as the endpoint for the adaptive decision is supported by a meta-
analysis of data from published HNSCC studies. 
Randomization will be stratified by the following factors associated as prognostic, and 
selective of clinical benefit from pembrolizumab: 
1. PD-L1 CPS (degree of benefit from pembrolizumab alone depended on PD-L1 
status [Burtness, 2018]) 
2. HPV status (established as a prognostic factor in the oropharynx region and 
oropharyngeal cancers are staged according by HPV status [Fung, 2017; AJCC, 
2017]) 
The selection of pembrolizumab monotherapy as the control arm is supported by the data 
from KN-048; the evidence of which supported the FDA approval of pembrolizumab 
monotherapy in the first-line disease setting for patients with PD-L1 CPS 1 R/M 
HNSCC [Burtness, 2018; Rischin, 2019]. 
The primary endpoints are appropriate for this population as overall survival is the gold 
standard measure of clinical benefit and PFS by RECISTv1.1 as a direct measure of 
disease control in a randomized Phase III study setting. 
The double-blinded design will mitigate the intentional or inadvertent bias inherent to an 
open-label study. 


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4.3. 
Justification for Dose 
4.3.1. 
GSK3359609 Dose Justification 
The dose of GSK3359609 planned for registration studies in HNSCC is 24-mg 
administered Q3W. The 24 mg dose of GSK3359609 was selected based upon the 
cumulative clinical evidence to date from the first-time in human (FTIH) Study 
204691/INDUCE-1 that included preliminary efficacy data from the 
GSK3359609/pembrolizumab combination HNSCC expansion cohort, pooled 
preliminary population PK and exposure-response assessments, as well as peripheral 
target engagement and preliminary tumor biomarker assessments. Overall, GSK3359609 
clinical data demonstrate a lack of dose-dependent differences in efficacy or safety 
outcomes. A flat GSK3359609 exposure-response relationship for efficacy and safety 
was found in participants across the range of dose levels evaluated (0.001mg/kg to 
3 mg/kg). Exposures for 24-mg Q3W are expected to lie within this dose level range and 
will be close to those obtained with 0.3 mg/kg Q3W, the dose level where in the HNSCC 
cohort durable objective responses were observed in combination with 200-mg 
pembrolizumab. 
The PK disposition of GSK3359609 was evaluated after 30 minutes of IV infusion at the 
aforementioned dose level range in Study 204691. A preliminary population PK model 
(n = 251; October 2018), which characterized the influence of body weight, age, and 
other participant covariates on exposure, has been developed. Results indicate the PK 
disposition of GSK3359609 is consistent with that of other humanized mAbs, which 
typically have a low clearance (CL) and a limited central volume of distribution (Vc). 
Plasma concentration-time profiles of GSK3359609 exhibit a bi-exponential decline with 
dose-proportional increases in exposure, e.g. Cmax and Cmin. The preliminary 
comparisons of the FTIH data from Part 1 (monotherapy) versus Part 2 (pembrolizumab 
combination) demonstrate no differences in GSK3359609 exposure with concomitant 
administration of pembrolizumab; no drug-drug interaction affecting PK for the 
combination of GSK3359609 and pembrolizumab would be anticipated given that both 
are mAb catabolized via high capacity, non-specific pathways. 
The preliminary FTIH population PK analysis dataset encompassed a wide distribution of 
bodyweight, with a median of 73 kg and a range of 40.8–133 kg. Estimates (90% 
confidence intervals [CI]) of the relationship between clearance and body weight based 
on the population PK model revealed an allometric exponent (α) of 0.056 (95% CI, -
0.364– 0.475) for the CL and 0.314 (95% CI, -0.009 – 0.637) for Vc. In theory, body-
weight–based dosing would be considered most appropriate where CL scales linearly 
with patient bodyweight (α equals to 1), whereas fixed dosing would be more appropriate 
when CL is unaffected by body weight (α = 0). Given that α estimates were closer to 0 
for both CL and Vc, no advantage of weight-based dosing over fixed dosing is expected 
for GSK3359609. Distributions of GSK3359609 exposures from potential fixed doses 
administered Q3W were simulated with the preliminary FTIH population PK model and 
compared with the distributions expected from weight-based dosing regimens, using 
bodyweight distributions resampled from the Centers for Disease Control National Health 
and Nutrition Examination Survey database. These simulations reveal that a 
GSK3359609 bodyweight-based dose results in slightly higher exposure in heavier 


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weight participants, with a GSK3359609 fixed dose expected to provide more consistent 
control of PK variability across the entire bodyweight spectrum. 
As previously indicated, no MTD was established and no dose limiting toxicities were 
observed in the dose escalation cohorts over the range of GSK3359609 dose levels 
(0.001 mg/kg [~0.08 mg] to 3 mg/kg [~240 mg]) evaluated in Study 204691. An 
exposure-response, time-to-event analysis of all reported Grade 2 AEs supports the 
conclusion of similar safety outcomes across the exposure/dose range evaluated, both in 
pooled monotherapy cohorts and pembrolizumab combination cohorts. Evidence of target 
engagement and objective evidence of tumor size reduction were observed in the HNSCC 
expansion cohort at the 0.3 mg/kg dose level. Doses of 0.3 mg/kg (~24-mg) showed high 
ICOS receptor occupancy (RO) levels on CD4 and CD8 T cells over the 21-day dosing 
cycle. Concentration-ICOS RO analyses suggest bodyweight-based doses of 
approximately >0.1 mg/kg maintained approximately >~70% CD4/CD8 RO over the 
entire dosing interval. Preliminary exposure-response assessments of tumor size 
reduction at Week 9 (stratified by tumor type) demonstrate little difference in efficacy 
outcomes across the exposure/ dose range evaluated. 
Hence, the integrated body of evidence supports a 24-mg Q3W dose for evaluation in the 
pivotal studies of HNSCC in combination with pembrolizumab. The distribution of 
exposures from the 24-mg fixed dose are predicted to considerably overlap those 
obtained with the 0.3 mg/kg dose, and importantly, will maintain individual patient 
exposures within the exposure range established in the FTIH study. 
4.3.2. 
Pembrolizumab Dose Justification 
The planned dose of pembrolizumab for this study is 200 mg Q3W. This pembrolizumab 
dose and schedule is consistent with that administered in the KN-048 study and which is 
administered in combination with GSK3359609 in the ongoing INDUCE-1 study. 
Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications, 
regardless of tumor type. As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and 
exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 
weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including 
overall survival at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic 
circulation (inferred from PK data) and tumor (inferred from 
physiologically-based PK [PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer, covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and 
different treatment settings (monotherapy and in combination with chemotherapy). Five 
studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 


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Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 
mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin’s Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, 
PK data in KN001 evaluating target-mediated drug disposition conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 
mg Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over 
a wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-
dosing provides similar control of PK variability as weight-based dosing, with 
considerable overlap in the distribution of exposures from the 200 mg Q3W fixed dose 
and 2 mg/kg Q3W dose. Supported by these PK characteristics and given that fixed-dose 
has advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including follow-up for survival or until follow-up for survival is no 
longer required (refer to Section 7.1). 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study if all of the following criteria apply: 
1. Capable of giving signed informed consent/assent which includes compliance 
with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol 


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2. Male or female, age 18 years at the time consent is obtained (minimum age 
requirement per local regulatory requirements) 
3. Histological or cytological documentation of HNSCC that was diagnosed as 
recurrent or metastatic and considered incurable by local therapies 
4. Primary tumor location of the oral cavity, oropharynx, hypopharynx or larynx. 
5. No prior systemic therapy administered in the recurrent or metastatic setting (with 
the exception of systemic therapy completed >6 months prior if given as part of 
multimodal treatment for locally advanced disease, and no disease 
progression/recurrence within 6 months of the completion of systemic treatment 
with curative intent) 
6. Measurable disease per RECIST version 1.1 guidelines 
a. Note: if a participant has a solitary measurable lesion which was 
previously irradiated, that lesion must have progressed per RECIST v1.1 
definition, following completion of radiation 
7. ECOG Performance PS score of 0 or 1 
8. Adequate organ function as defined in Table 3 


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Table 3 
Definitions of Adequate Organ Function 
System 
Laboratory Values 
Hematologica 
ANC 
1.5x109/L 
Hemoglobin 
9 g/dL 
Platelets 
100x109/L 
Hepatic 
Albumin 
2.5 g/dL 
ALT 
2.5xULN or ≤5xULN for 
participants with documented liver 
metastases 
Total bilirubin 
Bilirubin ≤1.5xULN (isolated 
bilirubin > 1.5xULN is acceptable if 
bilirubin is fractionated and direct 
bilirubin <35%) 
Coagulation 
INR OR PT 
aPTT  
1.5 × ULN unless participant is 
receiving anticoagulant therapy as 
long as PT or aPTT is within 
therapeutic range of intended use of 
anticoagulants 
Renal 
Calculated CrClb 
30 mL/min 
Cardiac 
Ejection fractionc 
≥50% 
Abbreviations: aPTT = activated partial thromboplastin time ANC = Absolute neutrophil count; ALT = 
alanine aminotransferase; CrCl = creatinine clearance; ECHO=echocardiogram; eGFR=estimated 
glomerular filtration rate; INR = international normalization ratio; MUGA= multigated acquisition scan; PT 
= prothrombin time; TSH = thyroid-stimulating hormone; ULN = upper limit of normal; WNL = within 
normal limits 
a. 
Participants may be transfused or receive growth factor treatment to meet minimum hematologic values 
up to 7 days prior to determining eligibility 
b. Estimated CrCl/eGFR is required to be calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) or Cockcroft-Gault formula; either formula is acceptable and must be 
consistently used for each participant throughout the study (refer Appendix 6). 
c. 
MUGA is acceptable if ECHO is not available; for each participant the same modality must be used for 
all subsequent evaluations  
9. Life expectancy of at least 12 weeks 
10. Female participants: must not be pregnant (as confirmed by a negative serum 
beta-human chorionic gonadotrophin [-hCG] test in females of reproductive 
potential; for further details refer to Section 10.4), not breastfeeding, and at least 
one of the following conditions apply: 
a. Not a woman of childbearing potential (WOCBP) as defined in Section 
10.4.1. 


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b. A WOCBP who agrees to use a method of birth control from 30 days prior 
to randomization and for at least 120 days after the last dose of study 
treatment. Refer to Section 10.4.2 for permitted contraceptive methods; 
contraceptive use should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
c. The investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy 
11. Male participants with female partners of child-bearing potential: must agree to 
use a highly effective contraception while receiving study treatment and for at 
least 120 days after the last dose of study treatment and refrain from donating 
sperm during this period. Refer to Section 10.4.2 for permitted contraceptive 
methods; contraceptive use should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
12. Provide tumor tissue from excisional or core biopsy (fine needle aspirates and 
bone biopsies are not acceptable) acquired within 2 years prior to date of PD-L1 
immunohistochemistry (IHC) testing by central laboratory. 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 previously acquired tumor 
tissue (i.e., archival tumor tissue) was acquired > 2 years or is 
unavailable//unsuitable for PD-L1 testing.  
13. Have PD-L1 IHC CPS 1 status by central laboratory testing (refer to Section 5.4 
for definition of screen failure based on PD-L1 CPS restrictions) 
a. A specific PD-L1 CPS status may be required to fulfill eligibility (refer to 
Section 9.2 for details on estimated number of participants by PD-L1 CPS 
status) if a PD-L1 CPS status cap is implemented (study population 
proportion by PD-L1 CPS status will not exceed 5% of the planned 
proportions of the PD-L1 CPS subgroups (CPS 20 and  1 CPS <20) 
14. Have results from testing of HPV status for oropharyngeal cancer (refer to Section 
8 and Table 1 for details on testing requirements) 
 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Prior therapy with an anti-PD-1/L1/L2 and/or anti-ICOS directed agent 
2. Systemic approved or investigational 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 date of randomization 
3. Has high risk of bleeding (examples include but not limited to tumors encasing or 
infiltrating a major vessel [i.e. carotid, jugular, bronchial artery] and/or exhibits 
other high-risk features such as an arteriovenous fistula) 
NOTE: Principal investigator should consult the GSK Medical Monitors to confirm 
eligibility of patients with disease features that may confer a high risk of tumor 
associated hemorrhage.  
4. Active tumor bleeding 
5. Grade 3 or Grade 4 hypercalcemia 
6. Major surgery  28 days prior to randomization. Participants must have also fully 
recovered from any surgery (major or minor) and/or its complications before 
randomization 
7. Toxicity from previous anticancer treatment that includes: 
a. Grade 3/Grade 4 toxicity considered related to prior immunotherapy and 
that led to treatment discontinuation 
b. Toxicity related to prior treatment that has not resolved to Grade 1 
(except alopecia, hearing loss, endocrinopathy managed with replacement 
therapy, and peripheral neuropathy which must be Grade 2) 
8. Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including granulocyte colony-
stimulating factor, granulocyte-macrophage colony-stimulating factor, 
recombinant erythropoietin) within 14 days prior to randomization 
9. Central nervous system (CNS) metastases, with the following exception: 
Participants with asymptomatic CNS metastases who are clinically stable and 
have no requirement for steroids for at least 14 days prior to randomization 
Note: Participants with carcinomatous meningitis or leptomeningeal spread are 
excluded regardless of clinical stability 
10. Invasive malignancy or history of invasive malignancy other than disease under 
study within the last 3 years, except as noted below: 


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a. Any other invasive malignancy for which the participant was definitively 
treated, has been disease-free for 3 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 study 
b. Curatively treated non-melanoma skin cancer or successfully treated in 
situ carcinoma 
c. Low-risk early stage prostate cancer defined as follows: Stage T1c or T2a 
with a Gleason score ≤ 6 and prostatic-specific antigen <10 ng/mL either 
treated with definitive intent or untreated in active surveillance that has 
been stable for the past year prior to randomization 
11. Autoimmune disease (current or history; refer to Table 19) or syndrome that 
required systemic treatment within the past 2 years 
Note: Replacement therapies which include physiological doses of corticosteroids 
for treatment of endocrinopathies (for example, adrenal insufficiency) are not 
considered systemic treatments 
12. Has a diagnosis of immunodeficiency or is receiving systemic steroids (>10 mg 
oral prednisone per day or equivalent) or other immunosuppressive agents within 
7 days prior to randomization 
Note:  
a) 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, up to a maximum of 10 mg prednisone per day or equivalent 
b) Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication) are permitted. 
13. Receipt of any live vaccine within 30 days prior randomization 
14. Prior allogeneic/autologous bone marrow or solid organ transplantation 
15. Has current pneumonitis or history of non-infectious pneumonitis that required 
steroids or other immunosuppressive agents 
Note: post-radiation changes in the lung related to prior radiotherapy and/or 
asymptomatic radiation-induced pneumonitis not requiring treatment (Grade 1) 
may be permitted if agreed upon by the investigator and Medical Monitor. 
16. Recent history (within the past 6 months) of uncontrolled symptomatic ascites, 
pleural or pericardial effusions 


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17. Recent history (within the past 6 months) of gastrointestinal obstruction that 
required surgery, acute diverticulitis, inflammatory bowel disease, or intra-
abdominal abscess 
18. Recent history of allergen desensitization therapy within 4 weeks of 
randomization 
19. History or evidence of cardiac abnormalities within the 6 months prior to 
randomization which include: 
a. Serious, uncontrolled cardiac arrhythmia or clinically significant 
electrocardiogram abnormalities including second degree (Type II) or 
third-degree atrioventricular block 
b. Cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting or 
bypass grafting 
c. Congestive heart failure (Class II, III, or IV) as defined by the New York 
Heart Association functional classification system 
d. Symptomatic pericarditis 
20. Cirrhosis or current unstable liver or biliary disease per investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice. 
Note: Stable non-cirrhotic, chronic liver disease (including Gilbert's syndrome or 
asymptomatic gallstones) or hepatobiliary involvement of malignancy is 
acceptable if participant otherwise meets entry criteria 
21. Active infection requiring systemic therapy 
22. Known HIV infection, or positive test for hepatitis B active infection (presence of 
hepatitis B surface antigen), or hepatitis C active infection (refer to Table 15) 
23. History of severe hypersensitivity to monoclonal antibodies or any ingredient 
used in the study treatment formulations (refer to Table 4) 
24. Known history of active tuberculosis 
25. Any serious (Grade 3) and/or unstable pre-existing medical condition (aside 
from malignancy)  
26. Any psychiatric disorder, or other condition that could interfere with participant's 
safety, obtaining informed consent, or compliance to the study procedures in the 
opinion of the investigator 


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27. Pregnant, breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of study treatment 
28. Is currently participating in (unless in follow-up phase and 4 weeks have elapsed 
from last dose of prior investigational agent), or has participated in a study of an 
investigational agent or has used an investigational device within 4 weeks prior to 
date of randomization 
Note: Participants who have entered the follow-up phase of an investigational study 
may participate provided it has been 4 weeks after the last dose of the previous 
investigational agent. 
5.3. 
Lifestyle Considerations 
There are no dietary restrictions nor lifestyle restrictions other than the contraceptive 
requirements defined in Section 10.4. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but do not meet 1 or more eligibility criteria and therefore are not subsequently 
randomized. If participants are required to have a specific positive PD-L1 CPS status 
based on Competent Authority and/or IRB/Ethics Committee restrictions, or an 
Investigator’s decision, then a participant who is not otherwise randomized due to a 
PD-L1 CPS result will be considered a screen failure. 
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened; rescreened participants will be assigned a new participant number. 
6. 
STUDY INTERVENTION 
Refer to the Schedule of Activities for administration of study interventions. 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term study intervention or study treatment may be used in the 
protocol and study supportive documents (e.g., study reference manual) interchangeable 
and apply to an individual study drug or the combination of study drugs. 
6.1. 
Study Intervention(s) Administered 
For participants who meet all eligibility criteria and are randomized within the study, the 
maximum duration of treatment with pembrolizumab, GSK3359609 and placebo is 


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expected to be approximately 2 years up to 35 cycles. A decision to permanently 
discontinue treatment due to disease progression may be based upon immune-based 
RECIST (iRECIST) as disease progression per RECIST v1.1 guideline is further 
evaluated per iRECIST for confirmation by imaging/clinical assessments 4 weeks later 
and is critical to the analysis of immune-based PFS (iPFS) [Seymour, 2017]. 
Participants will be randomly assigned to either receive the combination of GSK3359609 
24 mg plus pembrolizumab 200 mg or placebo plus pembrolizumab 200 mg. 
GSK3359609, placebo, and pembrolizumab are each administered as a 30-minute IV 
infusion once Q3W. GSK3359609 or placebo will be administered first followed by 
pembrolizumab. 
GSK3359609, pembrolizumab, and placebo (refer to Table 4) will be administered 
intravenously to participants at each study site under medical supervision of an 
investigator or designee. GSK3359609/Placebo will be administered first followed by the 
infusion of pembrolizumab. The date and time of administration will be documented in 
the source documents and reported in the electronic case report form (eCRF). Participants 
should remain under observation at the study site post-study treatment infusion per the 
judgement of the investigator or as per institutional guidelines or regulatory requirements. 
The study reference manual (SRM) contains details on product administration and 
specific instructions for the preparation of both GSK3359609 and pembrolizumab 
infusions, and administration of these infusions. The description, preparation and 
administration of placebo is provided in the SRM. 
Table 4 
Study Intervention Description and Administration 
 
Study Agent1 
Product Name: 
GSK3359609 
Pembrolizumab 
Placebo 
Product Description 
Humanized anti-
ICOS IgG4 mAb 
Humanized anti-PD-1 
IgG4 mAb 
Sterile normal saline 
Dosage form 
/strength: 
10 mg/mL solution 
100 mg/4 mL 
solution/25 mg/mL 
0.9% Sodium 
Chloride for Injection  
Planned dosage 
level(s): 
24 mg 
200 mg 
N/A 
Route of 
Administration  
IV infusion 
IV infusion 
IV infusion 
Dosing instructions/ 
Frequency: 
 
Administer diluted 
product /once Q3W 
(refer to SRM for 
infusion time) 
Administer diluted 
product /once Q3W 
(refer to SRM for 
infusion time) 
Administer product 
/once Q3W (refer to 
SRM for infusion 
time) 
Packaging and 
Labelling  
Provided in vials 
labelled as required 
per country 
requirement. 
Provided in vials 
labelled as required 
per country 
requirement. 
Provided by the site 
unless required by the 
Sponsor as per 
country requirement 
Study Arm 
1  
1 and 2 
2 
Manufacturer 
GSK 
Merck 
N/A 
Abbreviations: GSK=GlaxoSmithKline; IgG4=immunoglobulin G4; IV-intravenous; mAb=monoclonal 
antibody; mg=milligram; ml=millilitre; N/A=not applicable; PD-1=programmed cell death receptor1; 
Q3W=every three weeks; SRM=study reference manual 


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1. Refer to GSK3359609 [GlaxoSmithKline Document Number 2017N319717_03, 2020] and 
Pembrolizumab IB [Merck, 2021] for formulation description 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM. 
5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Randomization will occur centrally using an Interactive Response Technology (IRT); 
refer to the SRM for detail on randomization process. Participants will be randomly 
assigned to a study treatment arm in a 1:1 ratio to either receive the combination of 
GSK3359609 24 mg plus pembrolizumab 200 mg or placebo plus pembrolizumab 
200 mg. 
Randomization will be stratified according to the following factors: 
1. PD-L1 CPS status (CPS ≥20 vs. 1≤ CPS <20) 
2. HPV status (oropharyngeal cancers [positive vs. negative/unknown] vs. non-
oropharyngeal cancers). 
The overall proportion of participants by PD-L1 CPS status will be capped by the IRT 
such that the maximum proportion of participants in PD-L1 CPS 20 or 1 CPS <20 will 
not exceed the planned proportion by 5% for either subgroup. 
This is a double-blind study. The participant, the investigator and site staff involved in 
the treatment administration or clinical management of the participants will remain 


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blinded to each participant’s assigned study treatment throughout the course of the study. 
Site unblinded staff will provide the investigative blinded staff with prepared blinded 
GSK3359609 or placebo infusion solutions, packaged identically in order to maintain the 
blinding, for administration at scheduled infusion visits. Refer to the SRM for 
information on labelling and dispensing procedures to mitigate unblinding. In the event a 
participant’s study treatment assignment is unblinded to the blinded site staff and/or the 
participant, the participant is permitted to continue/remain in the study; the site must 
notify the GSK’s clinical research associate (CRA) within 24 hours. 
GSK personnel or delegates, except GSK staff involved in the review/monitoring of site 
pharmacy records and GSK clinical supplies group, will remain blinded to each 
participant’s assigned study treatment throughout the course of the study. 
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the intervention 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the participant’s intervention assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy. 
In the event of a medical emergency, Investigators may unblind a participant’s treatment 
assignment immediately through the IRT system by accessing a participant’s home 
screen using the Subjects tab and clicking the Unblind button. Further details may be 
found in the SRM and the IRT manual. 
6.4. 
Study Intervention Compliance 
• 
All study agents will be intravenously administered to participants at the site. 
Administration will be documented in the source documents and reported in the 
eCRF. Refer to the SRM for further details. 
6.5. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1. 
Permitted Medications and Non-drug Therapies 
All participants should receive full supportive care during the treatment course of the 
study, including transfusion of blood and blood products, growth factors and treatment 
with antibiotics, antiemetics, antidiarrheals, and analgesics, bisphosphonates or other 
medications as appropriate. Seasonal flu vaccine is permitted as an injection only, that is, 


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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): permitted for treatment of bone 
metastasis or other indicated conditions such as hypercalcemia provided 
participants have been on a stable dose for at least 4 weeks prior to 
randomization date. Note: prophylactic use in participants without evidence or 
history of bone metastasis is not permitted, except for the treatment of 
osteoporosis. 
b. Steroids: refer to Section 6.6 and the associated sub-sections for acceptable 
use while participant is receiving study treatment. Participants with pre-
existing conditions requiring steroids are permitted to continue taking up to a 
maximum of 10 mg of prednisone per day or equivalent provided the 
participant has been on a stable dose for at least 28 days before date of 
randomization; refer to exclusion criterion 9 in Section 5.2 for further 
requirements. 
6.5.2. 
Prohibited Medications and Non-drug Therapies 
The following medications are prohibited before the date of randomization (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 Intervention/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 6.5.1 ) 
b. Any investigational drug (s) other than those referred to as Study 
Intervention/Treatment 
c. Live vaccines such as intra-nasal flu vaccine 
d. Steroids at >10 mg of prednisone per day or equivalent; refer to Section 6.5.1 for 
permitted use of steroids in cases where prescribed for the treatment of immune 
related adverse events. 
6.5.2.1. 
Anti-cancer Therapy After Study Intervention Discontinuation 
Treatment with ICOS or ICOS ligand directed/targeted agents as post study anti-cancer 
therapy are prohibited for participants who permanently discontinue study treatment. 
6.6. 
Dose Modification 
Distinct safety management guidelines, including dose modification algorithms, are 
provided in this section for: 
• 
GSK3359609 
• 
Pembrolizumab 


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Please note: In instances where the investigator is directed to permanently discontinue 
study treatment, the instructions are mandatory as described in Section 7.1. 
All AEs are to be graded according to NCI-CTCAE (version 5.0) [NCI, 2017]. All dose 
modifications and the reason(s) for the dose modification must be documented in the 
eCRF. 
Refer to pembrolizumab prescribing information [KEYTRUDA, 2019] for additional 
information regarding the background and the management of other AEs or potential 
safety-related issues. The investigator may consult the GSK Medical Monitor on study 
treatment modifications (i.e., holds or discontinuation) or on the management of AEs. 
6.6.1. 
General Guidelines for Immune-Related Adverse Events 
AEs associated with immunotherapy treatment may be immune-mediated. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after 
the last dose of treatment, or during the treatment course, and may affect more than one 
body system simultaneously. Therefore, early recognition of and initiation of treatment 
for these events is critical to reduce potential complications. Based on existing data from 
the study 204691, most treatment-related AEs were Grade 1 or 2, managed with 
supportive care and if appropriate the administration of corticosteroids. 
For suspected irAEs, ensure adequate evaluation to confirm the etiology or exclude other 
causes. Additional procedures or tests such as, but not limited to, bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue treatment and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with immunotherapies are provided in Table 5. 
Before administration of study treatment, investigators are to review a participant’s AEs, 
concomitant medications, and clinical evaluation results, e.g., vital signs, laboratory 
results, ECOG PS, physical examination findings, responses, etc. as outlined in the 
Schedule of Activities (Table 1) to monitor for new or worsening irAEs and ensure 
continues dosing is appropriate. 
Adverse Events of Special Interest (AESI) 
AESI are defined as events of potential immunologic etiology, including irAEs. 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. 
Table 5 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs 
General instructions: 
• Corticosteroid taper should be initiated upon irAE improving to Grade 1 and 
continue to taper over at least 4 weeks. 
• For situations where immunotherapy treatment has been withheld, treatment can 
be resumed after irAE has been reduced to Grade 1 and corticosteroid has been 


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tapered. Immunotherapy treatment should be permanently discontinued if irAE 
does not resolve or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks of last dose of study treatment.  
• 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first 
followed by oral steroid. Other immunosuppressive treatment should be initiated 
if irAEs cannot be controlled by corticosteroids. 
Immune-related 
AEs 
Severity 
Grade or 
Condition 
(CTCAEv5.0) 
Action Taken 
to: 
GSK3359609a/ 
Pembrolizumab 
Management: 
Corticosteroid 
and/or Other 
Therapies 
Monitoring and 
Follow-up 
Respiratory 
Pneumonitis  
Grade 2 
Withhold  
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Add 
prophylactic 
antibiotics for 
opportunistic 
infections 
• 
Monitor 
participants for 
signs and 
symptoms of 
pneumonitis. 
• 
Evaluate 
participants with 
suspected 
pneumonitis with 
radiographic 
imaging and initiate 
corticosteroid 
treatment. 
Grade 3 or 
Grade 4, or 
recurrent 
Grade 2 
Permanently 
discontinue 
Gastrointestinal 
Diarrhea / Colitis  Grade 2 or 
Grade 3 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor 
participants for 
signs and 
symptoms of 
enterocolitis (i.e., 
diarrhea, abdominal 
pain, blood or 
mucus in stool with 
or without fever) 
and of bowel 
perforation (i.e., 
peritoneal signs and 
ileus). 
• 
Participants with ≥ 
Grade 2 diarrhea 
suspecting colitis 
should consider GI 
consultation and 
performing 
endoscopy to rule 
out colitis.  
• 
Participants with 
diarrhea/colitis 
should be advised 
to drink liberal 
quantities of clear 
fluids. If sufficient 
oral fluid intake is 
not feasible, fluid 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 


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Immune-related 
AEs 
Severity 
Grade or 
Condition 
(CTCAEv5.0) 
Action Taken 
to: 
GSK3359609a/ 
Pembrolizumab 
Management: 
Corticosteroid 
and/or Other 
Therapies 
Monitoring and 
Follow-up 
and electrolytes 
should be 
substituted via IV 
infusion. 
Hepatobiliary 
AST / ALT 
elevation or 
increased 
bilirubin 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
• 
Monitor with liver 
function tests 
(consider weekly or 
more frequently 
until liver enzyme 
value returned to 
baseline or is 
stable. 
• 
Refer to Appendix 
8 for liver safety 
required actions 
and follow-up 
assessments and 
study treatment 
guidelines. 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
• 
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by 
taper 
Endocrine 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
New onset 
T1DM or  
Grade 3 or 
Grade 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure 
Withholdb 
• 
Initiate insulin 
replacement 
therapy for 
participants 
with T1DM  
• 
Administer an 
anti-
hyperglycemic 
in participants 
with 
hyperglycemia  
• 
Monitor 
participants for 
hyperglycemia or 
other signs and 
symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated. 
• 
Monitor for signs 
and symptoms of 
hypophysitis 
(including 
hypopituitarism and 
adrenal 
insufficiency). 
Grade 3 or 
Grade 4  
Withhold or 
permanently 
discontinueb  
Hyperthyroidism  Grade 2 
Continue 
• 
Treat with non-
selective beta-
blockers (e.g., 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs 
and symptoms of 
thyroid disorders. 
Grade 3 or 
Grade 4  
Withhold or  
Permanently 
discontinueb 
Hypothyroidism 
Grade 2, 
Grade 3, or 
Grade 4 
Continue 
• 
Initiate thyroid 
replacement 
hormones (e.g., 
levothyroxine 
• 
Monitor for signs 
and symptoms of 
thyroid disorders 


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Immune-related 
AEs 
Severity 
Grade or 
Condition 
(CTCAEv5.0) 
Action Taken 
to: 
GSK3359609a/ 
Pembrolizumab 
Management: 
Corticosteroid 
and/or Other 
Therapies 
Monitoring and 
Follow-up 
or liothyronine) 
per standard of 
care 
Renal 
Nephritis: Grade 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
• 
Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by 
taper 
• 
Monitor changes of 
renal function 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
Cardiovascular 
Myocarditis 
Grade 2, 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
• 
Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes. 
Neurological 
Neurological 
Toxicities 
Grade 2 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes. 
Grade 3 or 
Grade 4 
Permanently 
discontinue 
Skin 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
• 
Based on severity 
of AE administer 
corticosteroids 
• 
Ensure adequate 
evaluation to confirm 
etiology and/or 
exclude other causes. 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 
Other 
All other 
immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent 
Grade 2 
Withhold or 
discontinue 
based on the 
type of event 
• 
Based on 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate 
evaluation to 
confirm etiology or 
exclude other 
causes 
Grade 4 or 
recurrent 
Grade 3  
Permanently 
discontinue 
Abbreviations: AE=adverse events; ALT=alanine aminotransferase; AST= aspartate aminotransferase; 
CTCAE=common terminology criteria for adverse events; DRESS=Drug Rash with Eosinophilia and 
Systemic Symptom; GI=gastrointestinal irAE=immune-related AE; IV=intravenous; kg=kilogram; 
mg=milligram; SJS=Stevens-Johnson Syndrome; T1DM=Type 1 diabetes mellitus; TEN=toxic epidermal 
necrolysis 
a. 
The actions taken for GSK3359609 infer an action required for placebo due to the blinded design. 
b. The decision to withhold or permanently discontinue study treatment is at the discretion of the 
investigator or treating physician. If control is achieved or Grade 2, study treatment may be resumed. 
c. 
The events that require discontinuation include but are not limited to encephalitis, and other clinically 
important irAEs (e.g., vasculitis and sclerosing cholangitis).  


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6.6.2. 
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Immunotherapy Treatment  
Infusion reactions are a well-documented AE associated with the administration of mAb. 
Infusion reactions typically develop within 30 minutes to 2 hours after initiation of drug 
infusion, although symptoms may be delayed for up to 48 hours. The incidence of 
infusion reactions varies by mAb agent, and there are multiple mechanisms known to 
lead to infusion-related reactions including both IgE-dependent anaphylactic and non-IgE 
dependent anaphylactoid hypersensitivities. Cytokine release syndrome, and when 
severe, cytokine “storm”, has been identified as a sequela of the immune system 
activation associated with infusion reactions. 
Infusion reactions may affect any organ system in the body; most are mild in severity, 
although severe and even fatal reactions occur. As a group, infusion reactions (including 
both cytokine-mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur 1 to 2 days after administration. The 
NCI-CTCAE (version 5.0) for grading adverse reactions during chemotherapy 
administration has a scale for grading the severity of infusion reactions and separate 
grading scales for allergic reactions and anaphylaxis. While use of these separate grading 
scales may be useful for classifying the nature of an infusion reaction for research 
purposes, they are less useful for clinical care, since it may not be obvious if the 
participant is having an allergic infusion reaction or a non-allergic infusion reaction.  
Clinically, an infusion reaction may present with flushing, itching, urticaria, and/or 
angioedema, repetitive cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
pain. Refer to Table 7 for dose modification and treatment guidance for immunotherapy 
infusion reactions. 
To better understand the underlying etiology of these events, serum tryptase, C-reactive 
protein (CRP), ferritin, and a cytokine panel should be drawn during the occurrence of an 
infusion reaction/CRS of any grade as outlined in Table 6. The serum tryptase, CRP and 
ferritin panels should be performed at the investigator’s designated local laboratory. 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. 


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Table 6 
Infusion-Related Reaction Laboratory Panel 
Analyte 
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*^, IL1, IL2*, IL4, I-6*^, 
IL8*, IL10*, IL12p70, and IL13) 
* 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; IFNγ = Interferon gamma; 
TNFα =Tumor necrosis factor alpha; IL = Interleukin.  
a. 
Performed by investigator designated local laboratory if available; otherwise performed by GSK 
designated laboratory 
b. Performed by a GSK designated laboratory; note: in participants enrolled from China sites, only the 
analytes bolded and italicized will be tested. 
The guidelines provided in Table 7 are suggestions. Investigators and site staff may also 
follow their site standard operating procedures for the treatment of these events. 
Table 7 
Infusion Reaction Dose Modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
• 
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator. 
• 
None 
Grade 2 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs. 
• 
Stop Infusion 
• 
Additional appropriate medical 
therapy may include but is not 
limited to: 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDs 
o 
Acetaminophen 
o 
Narcotics 
• 
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator 
• 
If symptoms resolve within 1 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will 
be held until symptoms resolve 
and the participant should be 
premedicated for the next 
scheduled dose 
Participants who develop Grade 2 
toxicity despite adequate 
• 
Participant may be premedicated 
1.5hr (± 30 minutes) prior to 
infusion of study drugs with: 
o 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
o 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 


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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
premedication should be 
permanently discontinued from 
further study treatment 
Grades 3 or Grade 4 
Grade 3: Prolonged 
(i.e., not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: Life-
threatening; pressor or 
ventilatory support 
indicated 
• 
Stop Infusion 
• 
Additional appropriate medical 
therapy may include but is not 
limited to: 
o 
Epinephrine** 
o 
IV fluids 
o 
Antihistamines 
o 
NSAIDs 
o 
Acetaminophen 
o 
Narcotics 
o 
Oxygen 
o 
Pressors 
o 
Corticosteroids 
• 
Increase monitoring of vital 
signs as medically indicated 
until the participant is deemed 
medically stable in the opinion 
of the investigator 
• 
Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Participant is permanently 
discontinued from further study 
treatment. 
• 
No subsequent dosing 
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration. For further information, please refer to the Common 
Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 
Abbreviations: CTCAE=common terminology criteria for adverse events; hr=hour; IV=intravenous; 
mg=milligram; ml=millilitres; NSAID=nonsteroidal anti-inflammatory drug; po=per os [by mouth] 
6.7. 
Intervention after the End of the Study 
Participants receiving study treatment at the time of the final analysis may continue to 
receive study treatment until treatment is discontinued as indicated in Section 7.1. At the 
time of the interim analysis for the adaptive decision or at other interim/final analyses 
(refer to Section 9.5), the IDMC may make a recommendation regarding the continuation 
of study treatment based on the outcome; this decision will be communicated to 
Investigators whereby subsequent communication to participants may be required.  
Participants who permanently discontinue study treatment will not receive any additional 
treatment from GSK. The investigator is responsible for ensuring that consideration has 
been given to the post-study care based on the participant’s medical condition. Refer to 
SoA (Table 1) and Section 7.1 for details on the follow-up assessments required for 
participants who permanently discontinued study treatment. Refer to Section 6.5.2.1 on 
prohibited post-study therapies. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Participants will receive study treatment for the duration indicated in Section 6.1 as 
applicable, unless one of the following events occurs earlier:  
• Disease progression  
• Death 
• Unacceptable toxicity (refer to Section 6.6 and subsections) 
• Pregnancy (refer to Section 8.3.5 for details) 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
• Deviation(s) from the protocol or non-compliance with study requirements 
• Request of the participant or proxy (withdrawal of consent by participant or 
proxy) 
• Discretion of the investigator  
• Participant is lost to follow-up 
• Closure or termination of the study  
Participants who have disease progression by RECIST v1.1 may continue study treatment 
up to the protocol specified 35 cycles at the discretion of the Investigator to confirm 
progression as per iRECIST guidelines. Nevertheless, the consideration to continue study 
treatment should be balanced by clinical judgment as to whether the participant is 
clinically stable. Continuation on study treatment is contingent upon the following 
conditions: 
• 
Absence of clinical signs or symptoms indicating clinically significant disease 
progression 
• 
ECOG PS has not worsened, or worsening by no more than 1 point from 
baseline 
• 
Absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (e.g., CNS metastasis, respiratory failure due to tumor 
compression, or spinal cord compression) requiring urgent alternative medical 
intervention. 
• 
No significant, unacceptable, or irreversible toxicities related to study treatment. 
All participants who permanently discontinue study treatment for any reason (except 
consent withdrawn) will have safety assessments at the time of discontinuation and 
during follow-up as specified in the SoA. 


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The primary reason study treatment was permanently discontinued must be documented 
in the participant’s medical records and eCRF. If the participant voluntarily discontinues 
from treatment due to toxicity, ‘adverse event (AE)’ 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. Refer to the SoA for assessments to be performed at 
the time study treatment is permanently discontinued and for evaluations that need to be 
completed. 
All participants who permanently discontinue study treatment without disease 
progression will be followed for progression according to the protocol-defined on-
treatment disease assessment schedule in the SoA until one or more of the following 
occur: 
• 
a new anticancer therapy is initiated  
• 
disease progression  
• 
death 
All participants who permanently discontinue study treatment for any reason, except 
withdrawal of consent (refer to Section 7.2), will be followed for survival every 12 weeks 
until death or until last patient discontinues treatment and has had their last follow up for 
safety.  
The every 12-week schedule (refer to Table 1 SoA for details of frequency of all 
assessments during follow-up period) should begin once study treatment has been 
permanently discontinued. 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.). 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in Appendix 8 and Section 6.6.1 
or 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant.  
7.1.1.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
with study intervention unless: 


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• 
GSK Medical Governance approval is granted 
• 
Ethics and/or IRB approval is obtained, if required, and 
• 
Separate consent for intervention restart/rechallenge is signed by the participant 
Refer to Appendix 8 and Section 10.8.1 for details. 
If GSK Medical Governance approval to restart/rechallenge participant with study 
intervention is not granted, then participant must permanently discontinue study 
intervention 
and may continue in the study for protocol-specified follow up assessments. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons. This is expected to be 
uncommon. 
• 
At the time of withdrawing from the study, if possible, an early treatment 
discontinuation visit should be conducted. Refer to SoA (Table 1) for the 
assessments at the time of study discontinuation. 
• 
The participant will be permanently discontinued both from the study 
intervention and from the study at that time. 
• 
If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• 
A participant will be considered to have withdrawn from the study if the 
participant has not died and is lost to follow-up. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• 
Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 


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• 
Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• 
Study procedures and their timing are summarized in the SoA.  
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log or equivalent to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
• 
The maximum volume of blood collected from each participant from Screening 
through Week 21 of the study treatment phase is estimated not to exceed 180 mL 
• 
Note: Repeat or unscheduled blood samples may be taken for safety reasons 
or for technical issues with the samples; these estimates are not included in 
the calculated maximum 
Screening 
All screening assessments must be performed within 28 days prior to randomization 
unless otherwise specified. The ICF may be signed within 45 days prior to 
randomization; archival tumor tissue collection or tumor tissue biopsy procedure can be 
performed as of 45 days prior to randomization after participant ICF obtained. 
The term ‘baseline’ refers to the assessment performed during the screening period prior 
to first dose of study treatment that serves as a comparison or control. For example, the 
baseline laboratory assessment is the laboratory assessment performed prior to first dose. 
Refer to SoA (Table 1) for additional details on assessments required at Screening and 
prior to start of study treatment. 
The following assessments are required during screening: 
• Demographic parameters such as year of birth and sex will be captured 
• Medical history including cardiovascular medical history, tobacco use, and other 
risk factors will be assessed as related to the inclusion/exclusion criteria 


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• Disease characteristics including medical, surgical, and treatment history (best 
response to prior therapy [radiotherapy and systemic] will be recorded), date of 
initial diagnosis, primary tumor location, stage at initial diagnosis, histology, HPV 
status (if available, by the CINtec p16 histology assay; required in oropharyngeal 
cancers, refer to Table 1), tumor genetic/genomic features and current sites of 
disease will be taken as part of the disease history/status. 
• Tumor tissue sent to central laboratory (refer to Section 5.1, inclusion criterion 12 
for tissue requirements) for the following required screening assessments: 
o PD-L1 protein expression using the PD-L1 IHC 22C3 pharmDx assay by 
central laboratory testing; an CPS 1 result is required for eligibility 
▪ NOTE: the PD-L1 IHC 22C3 pharmDx is US FDA approved and CE 
marked in the EU 
o p16 IHC using the CINtec p16 histology assay for the assessment of HPV 
status (only required in oropharyngeal cancers and if results not available by 
local laboratory testing) 
Baseline lesion assessments per RECIST v1.1 guideline [Eisenhauer, 2009] are required 
within 28 days randomization and include: 
• Computed tomography (CT) scan with contrast of the chest and abdomen (must 
include complete imaging of the liver 
o Note: Although a CT scan is preferred, magnetic resonance imaging (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. 
The method used to document baseline status must be used consistently 
throughout disease assessment visits to facilitate direct comparison. Refer to 
RECIST 1.1 guidelines for use of fluorodeoxyglucose-positron emission 
tomography (FDG-PET)/CT; this modality is permitted provided the CT portion 
is with contrast and is of diagnostic quality [Eisenhauer, 2009; Seymour, 2017]. 
• MRI/CT scan of head and neck region with IV gadolinium/contrast, respectively 
• MRI of brain with and without IV gadolinium (if clinically indicated) 
• Bone scan (if clinically indicated) 
• Clinical disease assessment for palpable/visible lesions 
• Other areas as indicated by the participant’s underlying disease present prior to 
screening 
Refer to Section 8.1 for baseline documentation of target and non-target lesions. 
Safety and laboratory assessments (refer to Section 8.2 and Section 8.2.6) required at 
baseline include: 
• 
Physical examination (refer to Section 8.2.1) 
• 
ECOG Performance Status (refer to Section 8.2.2) 
• 
Vital Signs (refer to Section 8.2.3) 


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• 
Concomitant medication 
o Recorded starting from screening through post-study treatment follow-up.  
o Record all medications the participant is taking including prescription 
medications, over-the-counter drugs or preparations, and herbal 
preparations including any cannabinoids and/or recreational drugs used. 
o At a minimum, the drug name, route of administration, dose, and frequency 
of dosing, along with start and stop dates must be recorded. 
• 
Electrocardiogram (ECG; refer to Section 8.2.4) 
• 
Echocardiogram (ECHO; refer to Section 8.2.5) 
• 
Laboratory assessments (refer to Section 10.2). 
Follow-up assessments 
Participants who permanently discontinue study treatment for any reason, except 
withdrawal of consent (refer to Section 7.2), will be followed for survival every 12 
weeks (14 days) until death. 
8.1. 
Efficacy Assessments 
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]. The primary measure of response-based 
efficacy endpoints is according to RECIST v1.1 definitions as assessed by the 
Investigator. Scans will be collected centrally; refer to Section 9.7 for details on response 
assessment by BICR. 
Additionally, iRECIST guidelines may used in the assessment of response/progression to 
account for the unique tumor kinetics observed with immunotherapeutic agents which 
may manifest as an increase in tumor burden then later is followed by regression 
suggesting the apparent observed neoplastic growth representing transient lymphocyte 
infiltration. Thus, participants with disease progression by RECIST version 1.1 
guidelines may have a confirmatory disease assessment no sooner than 4 weeks after the 
date disease progression was declared in order to confirm disease progression by 
iRECIST guidelines. Confirmatory scans may be done as per clinical standard of care and 
at the discretion of the Investigator up to the protocol specified 35 cycles.  The visit level 
responses and treatment-based decisions will incorporate iRECIST guidelines [Seymour, 
2017]. 
Refer to the SoA (Table 1) for the frequency of disease assessments post Screening. 
Imaging of the head/neck, chest and abdomen is required at each disease assessment visit 
and at confirmation of disease progression; the same modality used at Screening must 
remain consistent throughout the study duration. Other imaging modalities and regions 
assessed at Screening and required to measure/evaluate the target and nontarget lesions 
are required at each visit and for confirmation of disease progression. 
A random BICR audit will be performed at the time of the primary PFS analysis. 
Participant BICR randomization designation will not be known to the investigators; refer 
to Section 9.7 for details. 


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All imaging scans and clinical assessments (i.e., photographs) performed at Screening 
and at each disease assessment visit, including unscheduled assessment visits, are 
required to be uploaded at each visit occurrence for BICR. Refer to the imaging manual 
for details on imaging/clinical assessment requirements and submission guidelines. 
8.1.1. 
Disease Assessments 
• 
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). 
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). 
• 
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 of the chest, and abdomen, or if contra-indicated, MRI, is required at each 
post-baseline assessment. To ensure comparability between the baseline and 


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subsequent assessments, the same method of assessment and the same technique will 
be used when assessing response. 
• 
Refer to the SoA for the frequency of disease assessment. Assessments must be 
performed on a calendar schedule and should not be affected by dose 
interruptions/delays. 
• 
Participants whose disease responds (either CR or PR) may 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.  
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
• A complete physical examination performed at Screening will include, at a 
minimum, assessment of the cardiovascular, respiratory, gastrointestinal, and 
neurological systems.  
• A brief physical examination performed at each subsequent visit 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. 
8.2.2. 
Performance Status 
Performance status will be assessed using the ECOG scale at each visit; refer to 
Appendix 5. 
8.2.3. 
Vital Signs 
• Vital signs will be measured after 5 minutes of rest and will include temperature, 
systolic and diastolic blood pressure, pulse rate, respiratory rate, and oxygen 
saturation (measured by pulse oximetry). Blood pressure should be taken in the 
same position throughout the study and captured in the eCRF. 
• Vital signs will be measured more frequently if warranted by clinical condition 
of the participant. 
• If a participant develops fever and infusion related reaction or cytokine release 
syndrome is suspected, refer to management guidelines (Section 6.6.2). 
• Height will be recorded at Screening only. 
• Weight will be measured and recorded (in kilograms) at baseline and at every 
treatment visit. 


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8.2.4. 
Electrocardiograms 
A 12-lead ECG will be performed at Screening as indicated in the SoA using an ECG 
machine that calculates the heart rate and measures PR, QRS, and QT intervals. The QT 
interval corrected for heart rate or RR interval using Fridericia’s formula may be by 
machine or manual calculation. ECG after Screening will be performed as clinically 
indicated. 
8.2.5. 
Echocardiograms 
Echocardiogram will be performed at Screening to assess cardiac ejection fraction for the 
purpose of study eligibility, as specified in the SoA and Section 5.1. Additional ECHO 
assessments may be performed if clinically warranted. 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. 
8.2.6. 
Clinical Safety Laboratory Assessments 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. The clinical laboratory tests will be 
performed by local laboratory unless otherwise indicated. 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor.  
• 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (Refer to 
Section 7).  


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All AEs are to be graded according to NCI-CTCAE (version 5.0) [NCI, 2017]. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All AESIs and SAEs will be collected from the start of treatment until 90 days 
after the last dose of study treatment at the time points specified in the SoA (refer 
to Appendix 3 for details on SAEs). However, any SAEs assessed as related to 
study participation (e.g., study treatment, protocol-mandated procedures, invasive 
tests, or change in existing therapy) will be recorded from the time a participant 
consents to participate in the study. 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 ad SAEs must continue to be collected until 30 days after 
last dose of study treatment. 
• All AEs will be collected from the start of study treatment until 30 days after the 
last dose of study treatment at the time points specified in the SoA (Table 1). 
• Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded in the Medical History/Current 
Medical Conditions section of the CRF and not in the AE section. 
• All SAEs will be recorded and reported to the Sponsor or designee immediately 
and under no circumstance should this exceed 24 hours. The investigator will 
submit any updated SAE data to the Sponsor within 24 hours of learning of the 
event. 
• Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the Sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3. 
• 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-
ended and non-leading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AESIs will be 
followed until events are resolved, stabilized, otherwise explained, or the participant is 
lost to follow-up as defined in Section 7.3. Further information on follow-up procedures 
is given in Appendix 3. 


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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.  
• 
The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
• If a participant becomes pregnant while on study treatment, study treatment must 
be immediately discontinued. 
• Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until 120 days 
after the last dose of study treatment.  
• If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Section 10.3.3 and all deaths, whether or not 
they are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF 
will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.  
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 


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8.3.7. 
Events of Clinical Interest 
Selected events that may be non-serious or serious adverse events and are considered as 
Events of Clinical Interest (ECI) in this study protocol and must be reported to the 
Sponsor. 
Events of clinical interest include:  
1. An overdose of Study Treatment (GSK3359609/Pembrolizumab), as defined in 
Section 8.4, that is not associated with clinical symptoms or abnormal laboratory 
results. 
2. An elevated AST (aspartate aminotransferase) or ALT (alanine aminotransferase) 
lab value that is greater than or equal to 3X the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2X the upper limit 
of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be made available. It may also be 
appropriate to conduct additional evaluation for an underlying etiology in the setting of 
abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to 
proceed with additional evaluation will be made through consultation between the study 
investigators and the GSK Medical Monitor. However, abnormalities of liver blood tests 
that do not meet the criteria noted above are not ECIs for this study. 
8.4. 
Treatment of Overdose 
In the event there is an overdose of GSK3359609 and/or pembrolizumab the investigator 
must: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AEs/SAEs and laboratory abnormalities for at 
least 130 days. 
3. Obtain a 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 ECI; refer to Section 8.3.7 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. 


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8.4.1. 
GSK3359609 
An overdose of GSK3359609 is defined as administration of a dose that is >240 mg (>10 
times the 24 mg intended dose). There is no specific antidote for overdose with 
GSK3359609. 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. 
8.4.2. 
Pembrolizumab 
An overdose of pembrolizumab is defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. 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. 
8.5. 
Pharmacokinetics 
• Plasma samples will be collected for measurement of GSK3359609 
concentrations at the timepoints specified in the SoA. Refer to the Q2 laboratory 
manual for instructions on the collection and handling of the plasma samples. The 
actual date and time (24-hour clock time) of each sample will be recorded. 
• Samples will be used to evaluate the PK of GSK3359609. Samples collected for 
analyses of GSK3359609 plasma concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. If appropriate, 
de-identified drug concentration information may be analysed prior to study unblinding. 
In that case, GSK Clinical Pharmacology Modelling Simulation analysts will have access 
to a blinded population PK dataset (including, but not limited to, concentration, actual 
dosing information, demographics, and some vital sign and laboratory information, but 
excluding adverse event and efficacy information) at several time points (e.g., prior to 
each interim analysis) throughout the trial for population PK model 
development/refinement. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Refer to Appendix 7 for information regarding genetics research. 
A blood sample for deoxyribonucleic acid (DNA) isolation will be collected from 
participants who have consented to participate in the genetics analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study. 


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In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
Details on blood volume collected, the processes for collection, shipment and destruction 
of these samples can be found in Q2 laboratory manual. 
8.8. 
Biomarkers 
• 
Collection of samples for biomarker research is also part of this study. The 
following samples for biomarker research are required and will be collected 
from all participants in this study as specified in the SoA: 
• Whole blood for peripheral blood mononuclear cell (PBMC) isolation. The 
PBMC may be used for biomarker assays including but not limited to TCR 
diversity, functional assays and immune cell phenotyping etc. 
• Plasma at baseline and on-treatment timepoints specified in the SoA. The 
sample may be used to extract and analyze cell-free DNA (cfDNA) and/or 
cell-free ribonucleic acid (cfRNA) as well as other soluble factors and 
proteins. 
• Archival tumor tissue (refer to Section 8.8.3): tumor tissue acquired within 
2 years prior to randomization is required otherwise fresh tumor biopsy 
performed at Screening will be required. 
• 
Optional samples for biomarker research to be obtained from participants at the 
following timepoints: 
• Tumor biopsy at Screening in those participants providing archival tissue 
(i.e., archival tumor tissue meets the protocol defined time requirements) 
• Tumor tissue biopsy during the treatment period in participants with a 
mixed tumor response and/or disease progression. 
• 
Tumor tissue biopsy at the completion of 35 cycles of study treatment 
• 
Samples may be tested for ICOS expression, germline and/or somatic mutations 
including and tumor mutation burden, gene expression, TCR sequences and/ or 
any other DNA, RNA or protein-based biomarker that may emerge from other 
studies using the test drugs, to evaluate their association with the efficacy 
endpoints to the study treatments. 
• 
In addition, with the participant’s consent, samples will be stored, and analysis 
may be performed on biomarker variants thought to play a role in the 
mechanism of action, sensitivity or resistance or could support future 
combinations. Analyses may include associations of biomarker variants with 
efficacy endpoints.  
Furthermore, the samples and any biomarker data generated may be used to support the 
development and filing of a diagnostic. 


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Samples may be stored for a maximum of 15 years (or according to local regulations) 
following the last participant’s last visit for the study at a facility selected by the sponsor 
to enable further analysis of biomarker responses to study intervention. 
8.8.1. 
RNA Research 
Transcriptome studies will be conducted using either next generation sequencing (NGS) 
based technologies, targeted probe set and/or alternative equivalent technologies, which 
facilitates the simultaneous measurement of the relative abundances of thousands of 
ribonucleic acid (RNA) species resulting in a transcriptome profile for each blood and/ or 
tumor sample. This will enable the evaluation of baseline transcriptome profiles or any 
changes upon treatment with the study drugs that may correlate with response to the 
combination of GSK3359609 and Pembrolizumab. This may include tumor and/or 
immune cells from blood as well as from tumor tissues. 
RNA expression studies may be conducted using quantitative reverse transcriptase 
polymerase chain reaction (RT-qPCR), and/or alternative equivalent technologies, which 
can facilitate the simultaneous measurement of the relative abundances of RNA species 
resulting in an RNA expression profile for each blood and/or tumor tissue samples. The 
RNAs assayed may be those involved with the pathogenesis of HNSCC; the biology of 
ICOS-ICOSL or PD-1-PD-L1 signaling pathways and may help identify responder 
populations to the combination of GSK3359609 and pembrolizumab or pembrolizumab 
and placebo. The RNAs that code for these proteins and/or regulatory RNAs may also be 
studied. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
8.8.2. 
DNA Research  
DNA analysis using either whole exome and/or targeted sequencing of circulating tumor 
DNA from plasma and/or tumor will be performed. T cell repertoire analysis for clonality 
and diversity of TCRs at baseline and on treatment may also be evaluated. 
8.8.3. 
Tumor Tissue 
All participants will provide archival tumor tissue or if not available or evaluable for 
screening assessments (refer to Section 5.1 inclusion 12 and SoA [Table 1]) then a fresh 
pre-treatment biopsy. Fresh biopsy will be optional at Screening for those participants 
providing archival tissue. The tumor tissue collected (archival or fresh biopsy material) 
will be evaluated by methods that include PD-L1 IHC testing (using the US FDA 
approved and CE-marked EU PD-L1 IHC 22C3 pharmDx assay), other IHC tests and 
may include multiplex immunofluorescence technologies or other methods for evaluating 
the expression of phenotypic and functional immune cell markers on tumor infiltrating 
lymphocytes (TIL) and other immune cells as well as markers on tumor cells. 
Additionally, tumor tissue may undergo DNA/RNA-based genetic/genomic profiling 
(i.e., tumor mutation burden, T cell receptor diversity) which may include sequencing 
technologies that provide DNA/RNA sequence information. In addition, when possible, 
similar analyses will be performed on tumor tissue obtained upon progression. These 


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samples may also be evaluated for predictive measures of efficacy; if a predictive 
biomarker is identified, these tissues may be used for the development of a diagnostic 
test. Details for the sample collection, processing, storage and shipment will be provided 
in the SRM and Q2 laboratory manual. 
8.8.4. 
Blood Samples 
Plasma and/or serum samples are collected at baseline, during treatment and at disease 
progression to evaluate soluble factors such as cytokines, chemokines and other secreted 
proteins as well as cfDNA/cfRNA. 
 PBMC samples will be collected at baseline, during treatment and at disease progression 
and may be used for evaluating the expression of phenotypic and functional immune cell 
markers as well as for evaluating the polyfunctionality of immune cells and to test any 
novel biology emerging from other ICOS studies. 
Other biomarkers may be evaluated as determined by additional data. Details for the 
samples collection, processing, storage and shipment will be provided in the SRM and 
Q2 laboratory manual. 
8.9. 
Immunogenicity 
Antibodies to GSK3359609 will be evaluated in serum samples collected from all 
participants according to the SoA. Additionally, serum samples should also be collected 
at the final visit from participants who discontinued study intervention or were withdrawn 
from the study. These samples will be tested by the sponsor or sponsor's designee. 
Serum samples will be screened for antibodies binding to GSK3359609 and the titer of 
confirmed positive samples will be reported. Other analyses may be performed to verify 
the stability of antibodies to GSK3359609 and/or further characterize the 
immunogenicity of GSK3359609. 
The detection and characterization of antibodies to GSK3359609 will be performed using 
a validated assay method by or under the supervision of the sponsor. All samples 
collected for detection of antibodies to study intervention will also be evaluated for 
GSK3359609 concentration to enable interpretation of the antibody data. Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of 
GSK3359609. 
8.10. 
Medical Resource Utilization and Health Economics 
Healthcare resource utilization (HCRU) will be collected for all participants randomized 
to study treatment and may be used to conduct exploratory economic analyses. HCRU 
includes non-protocol healthcare encounters, such as provider visits, emergency room 
visits, hospitalizations (including ward, admission and discharge dates, and primary 
discharge diagnosis), medications, tests, or procedures. 


T M F -1 3 8 4 2 2 3 0  
C O N FI D E N TI A L  
2 0 9 2 2 9  
 
7 7  
 
8. 1 1.  
P ati e nt R e p ort e d O ut c o m e s  
T he bel o w q uesti o n nair es t o assess patie nt -re p orte d s y m pt o ms, f u ncti o ni n g, a n d 
treat me nt t olera bilit y d uri n g t he st u d y will be a d mi nistere d at t he ti me -p oi nts i n dicate d i n 
S o A  (Ta ble 1 ). T h e q uesti o n naires will be a d mi nistere d t o partici pa nts i n differe nt 
re gi o ns base d o n t he a vaila bilit y of tra nslate d v ersi o ns; f urt her details o n t he  partici pa nt 
q uesti o n naires ca n b e f o u n d i n t he S R M.  
P R O  
C o nce pts  
E O R T C I L 5 0  
Select d o mai ns of t he E O R T C -Q L Q -C 3 0  ge neral 
ca ncer m o d ule  
E O R T C I L 5 1  
Select d o mai ns of t he E O R T C Q L Q -H & N 3 5 
ca ncer s pecific s y m pt o m m o d ule  
B PI - I 3 
Pai n se verit y 
P R O MI S -S F  P F 8 c  
P h ysical f u n cti o n  
P GI S/ P GI C  
Patie nt gl o b al i m pressi o n of se verit y/c ha n ge  
E Q -5 D -3 L  
H R Q o L, f or utilit y assess me nts  
F A C T -G P 5  
O verall t o xicit y b ur de n  
 
8. 1 1. 1.  
E O R T C It e m Li br ar y 5 0 a n d 5 1: S el e ct D o m ai n s fr o m t h e 
E ur o p e a n Or g a ni z ati o n f or R e s e ar c h a n d Tr e at m e nt of C a n c er 
Q u alit y of Lif e Q u e sti o n n air e 3 0 -it e m C or e m o d ul e ( E O R T C Q L Q-
C 3 0)  a n d 3 5 -It e m H e a d a n d N e c k M o d ul e ( E OR T C Q L Q -H & N 3 5)  
T he E O R T C Q L Q -C 3 0 is t he c o re m o d ule d esi g n e d t o c o ver a br oa d ra n ge of ca ncer 
patie nts a n d is i nte n de d t o be s u p ple me nte d wit h disease -s pecific s u b-s cal es as necessar y 
t o assess Q o L as pects partic ular t o a gi ve n t y pe of ca ncer a n d t o i m pr o ve t h e s pecificit y 
a n d se nsiti vit y of meas ure me nt [ S pra n gers , 1 9 9 3; Aar o ns o n , 1 9 9 3]. Select  d o mai ns fr o m 
t he E O R T C Q L Q-C 3 0 will be a d mi nistere d  a n d will be referre d t o as t he E O R T C I L 5 0 . 
T he E O R T C Q L Q -H & N 3 5 is a hea d a n d n ec k s pecific m o d ule wit h m ulti -ite m scales 
[Bj or dal , 1 9 94 ]. T he m o ut h pai n, s wall o wi n g, s peec h pr o ble ms, o pe ni n g m o ut h, 
c o u g hi n g, fee di n g t u be, a n d tr o u ble wit h s ocial eati n g d o mai ns will be a d mi nistere d  a n d 
will be referre d t o as t he E O R T C I L 5 1 . 
8. 1 1. 2.  
Br i ef P ai n I n v e nt or y S h ort -F or m - It e m 3 ( B PI-I 3) 
T he Bri ef Pai n I n ve nt or y S h ort F or m was desi g ne d t o assess pai n a n d its i m pact i n 
ca ncer. Ite m 3 me as ures ‘ pai n at its w orst’ i n t he last 2 4 h o urs usi n g a n u m erical r ati n g 
scale of 0  
 t o 1 0 
) scal e [Cleela n d , 1 9 9 4].  
8. 1 1. 3.  
T h e P ati e nt -R e p ort e d O ut c o m e s M e a s ur e m e nt I nf or m ati o n 
S y st e m - S h ort F or m P h y si c al F u n cti o n - 8 it e m ( P R O MI S S F P F 
8 c)  
T he Patie nt -Re p orte d O utc o mes Meas ure me nt I nf or mati o n S yste m ( P R O MI S) is a 
u ni versall y a p plica ble s et of i nstr u me nts meas uri n g patie nt -
C CI
re p ort e d healt h acr oss 
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different patient populations developed by the US National Institutes for Health (NIH) 
[Cella, 2007). The PROMIS-SF PF assesses physical function and measures self-reported 
capability rather than actual performance of physical activities. This includes the 
functioning of one’s upper extremities (dexterity), lower extremities (walking or 
mobility), and central regions (neck, back), as well as instrumental activities of daily 
living, such as running errands. 


T M F -1 3 8 4 2 2 3 0  
C O N FI D E N TI A L  
2 0 9 2 2 9  
 
7 9  
 
8. 1 1. 4.  
P ati e nt Gl o b al I m pr e s si o n It e m s  ( P GI S a n d P GI C) 
T he Patie nt Gl o bal I m pressi o n of Se v erit y ( P GI S) assesses gl o bal i m pressi o n of 
s y m pt o ms se verit y at bas eli ne a n d s u bse q ue nt ti m e p oi nts. T he sec o n d q uesti o n, t he 
Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C) ser ves t o rate t he gl o bal c ha n ge i n 
s y m pt o ms at s u bse q ue nt ti me p oi nts. I n a d diti o n t o eval uati n g s y m pt o m se verit y a n d 
c ha n ge, t hes e q uesti o ns ser ve as a nc h ors t o esta blis h t hres h ol ds of cli nicall y mea ni n gf ul 
c ha n ge f or t he q uesti o n n aires i n t he st u d y [ G u y , 1 9 7 6]. 
8. 1 1. 5.  
E ur o p ol Q u e sti o n n air e ( E Q -5 D -3 L)  
T he E Q -5 D -3 L is a sta n d ar di ze d i nstr u me nt f or us e as a meas ure of healt h utilit y. It is 
desi g ne d f or self -c o m pleti o n or i nter vie w a d mi nistrati o n a n d is c o g niti vel y si m ple, ta ki n g 
o nl y a fe w mi n utes t o c o m plete. 
T he E Q -5 D -3 L self -assess me nt q uesti o n naire has 2 parts. T he first part c o nsists of 5 
ite ms c o veri n g 5 di me nsi o ns ( m o bilit y, self-care, us ual acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ d e pressi o n). Eac h di me nsi o n is meas ure d b y a 3 -p oi nt Li k ert scal e ( n o pr o ble ms, 
s o me or m o derate pr o ble ms, a n d u na ble or e xtre m e pr o ble ms). Res p o n de nts are as k e d t o 
c h o ose o ne le v el t hat refl ects t heir " o w n healt h state t o da y" f or eac h of t he 5 di me nsi o ns. 
Res p o n de nts ca n be t he n classifie d i nt o o ne of 2 4 3 disti nct hea lt h states. T he sec o n d part 
is a 2 0-c m vis ual a nal o g u e scale ( E Q -V A S) t hat has e n d p oi nts la belle d " b est i ma gi na ble 
healt h state" a n d " w orst i ma gi na bl e healt h state" a nc h ore d at 1 0 0 a n d 0, res pecti vel y. 
Res p o n de nts are as ke d t o i n dicate h o w t he y rate t h eir o w n healt h b y dra wi n g a li ne fr o m 
a n a nc h or b o x t o t hat p oi nt o n t he E Q -V A S w hic h best re pres e nts t heir o w n healt h o n t hat 
da y. E Q -5 D -3 L healt h st ates are c o n verte d t o a si n gle s u m mar y i n d e x b y a p pl yi n g a 
f or m ula t hat esse ntiall y attac hes wei g hts t o eac h of t he le vels i n eac h di me nsi o n. T he 
f or m ula is base d o n t he v al uati o n of E Q-5 D -3 L  healt h states fr o m ge neral p o p ulati o n 
sa m ples. 
8. 1 1. 6.  
F u n cti o n al A s s e s s m e nt of C a n c er T h er a p y –  G e n er al P o p ul ati o n 
( F A C T-G P 5)  
T he F A C T -G ( n o w i n V ersi o n 4) is a 2 7 -ite m c o m pilati o n of ge n eral q u esti o ns di vi de d 
i nt o 4 pri mar y Q o L d o m ai ns: P h ysi cal Well-Bei n g, S ocial/ Fa mil y Well -Bei n g, E m oti o nal 
Well -Bei n g, a n d F u ncti o nal W ell -Bei n g [ Cella , 1 9 9 3]. It is c o nsi dere d a p pr o priate f or use 
wit h partici pa nts wit h a n y f or m of ca n cer a n d has als o bee n use d a n d vali date d i n ot her 
c hr o nic ill ness c o n diti o n ( e. g., HI V/ AI D S a n d m ulti ple scler osis) a n d i n t he ge n eral 
p o p ulati o n ( usi n g a sli g htl y m o difie d versi o n ). 
T he F A C T -G scal e has b ee n  de v el o pe d a n d v ali date d [ Cella , 1 9 9 3] a n d is wi del y us e d t o 
meas ure H R Q o L i n p atie nts wit h a br oa d ra n ge of ca ncer dia g n oses [ Lee , 2 0 0 4]. T he 
F A C T G P 5 ite m is a si n gle ite m fr o m t he F A C T -G, w hic h assesses h o w b ot hers o me t he 
si de effects of treat me nt are f or ca n cer patie nts. T he recall peri o d is t he past 7 da ys, a n d 
t he ite m has a 5-cate g or y res p o nse scale ra n gi n g fr o m “ 0 = 
” t o “ 4 = 
”. 
T his ite m is bei n g i ncl u de d t o assess t he o verall t olera bilit y of treat me nt fr o m t he 
partici pa nt’s pers pecti ve.
C CI
 
C CI


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
9.1.1. 
Primary Hypotheses 
The following primary hypotheses will be tested: 
Overall Survival (OS) 
• Hypothesis (H1): GSK3359609 in combination with pembrolizumab prolongs OS 
compared with pembrolizumab/placebo in participants with PD-L1 CPS1 
R/M HNSCC. 
• Hypothesis (H2): GSK3359609 in combination with pembrolizumab prolongs OS 
compared with pembrolizumab/placebo in participants with PD-L1 CPS20 
R/M HNSCC. 
Progression-free Survival (PFS) 
• Hypothesis (H3): GSK3359609 in combination with pembrolizumab prolongs 
PFS by investigator assessment compared with pembrolizumab/placebo in 
participants with PD-L1 CPS1 R/M HNSCC. 
9.1.2. 
Key Secondary Hypotheses 
The following key secondary hypotheses will be tested: 
Immune-based progression-free Survival (iPFS) 
• Hypothesis (H4): GSK3359609 in combination with pembrolizumab prolongs 
iPFS by investigator assessment compared with pembrolizumab/placebo in 
participants with PD-L1 CPS1 R/M HNSCC. 
Time to Deterioration (TTD) in Pain 
• Hypothesis (H5): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Pain (measured by EORTC QLQ H&N 35 pain domain) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS1 R/M HNSCC. 
• 
Hypothesis (H6): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Pain (measured by EORTC QLQ H&N 35 pain domain) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS20 R/M HNSCC. 
TTD in Physical Functioning 
• 
Hypothesis (H7): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Physical Functioning (measured by PROMIS PF 8c) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS1 R/M HNSCC. 


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• Hypothesis (H8): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Physical Functioning (measured by PROMIS PF 8c) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS20 R/M HNSCC. 
9.2. 
Sample Size Determination 
The 2-in-1 adaptive Phase II/III study design [Chen, 2018] allows expanding the Phase II 
study seamlessly into a Phase III confirmatory study; refer to Section 4 for details of the 
study design. 
The Phase II study will randomize approximately 374 participants with a 1:1 ratio 
between the GSK3359609 in combination with pembrolizumab arm and the 
pembrolizumab/placebo arm. Assuming the prevalence rate of PD-L1 CPS ≥20 among 
the PD-L1 CPS ≥1 population is 53%, a sample size of 374 PD-L1 CPS 1 participants 
will provide approximately 198 PD-L1 CPS 20 participants. 
Should expanding the Phase II study into a Phase III be decided, a total of 600 
participants with PD-L1 CPS 1 will be randomized in a 1:1 ratio between the 
GSK3359609 in combination with pembrolizumab arm and the pembrolizumab/placebo 
arm, including those participants already enrolled. Participants already used for the 
decision making in the ongoing study will be included in Phase III analyses. The Phase 
III study will have an overall sample size of 600 participants. Assuming the 
aforementioned prevalence rate of PD-L1 CPS status, a sample size of 600 participants 
with PD-L1 CPS 1 status will provide 318 PD-L1 CPS 20 participants. 
The study is event-driven, and the sample size calculation is driven by overall survival 
events. The assumptions for the sample size and power calculation apply to the study 
whether it remains as a Phase II study (i.e. without expansion) or expands to a Phase III 
study (i.e. with expansion). 
Overall Survival (OS) 
A long-term survival benefit, observed as a long-lasting plateau towards the tail of the 
survival curve, and a delayed treatment effect, observed as a late separation in survival 
curves between the experimental and control arms, have been reported in randomized 
clinical trials among participants treated with immuno-oncology drugs. 
Given the OS data reported in the KN-048 clinical trial, a long-term survival benefit in 
the pembrolizumab/placebo arm and potential non-proportional hazards with a delayed 
treatment effect are anticipated. Therefore, the sample size and power calculation of OS 
in PD-L1 CPS 1 participants and PD-L1 CPS 20 participants are based on the 
following assumptions: 
1. Overall survival in the pembrolizumab/placebo arm follows a piecewise 
exponential distribution with the milestone OS rates in the 


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pembrolizumab/placebo arm the same as the rates in the pembrolizumab arm 
reported in the KN-048 trial.  
That is, the survival rates at 6, 12, 24 and 36 months are approximately 71%, 
50.4%, 28.9% and 22.1%, respectively, with a median survival of 12.3 months for 
PD-L1 CPS1 participants in the pembrolizumab/placebo arm; the survival rates 
at 6, 12, 24 and 36 months are approximately 74%, 56.4%, 35.3% and 29.3%, 
respectively, with a median survival of 14.9 months for PD-L1 CPS20 
participants in the pembrolizumab/placebo arm 
2. True hazard ratio between GSK3359609 in combination with pembrolizumab and 
the pembrolizumab/placebo arm is time varying leading to a delayed treatment 
effect with a lag-time of 6 months. For the first 6 months from randomization, a 
hazard ratio of 1 is assumed in PD-L1 CPS 1 and CPS 20 participants. For the 
time beyond 6 months from randomization, a hazard ratio of ~0.512 and ~0.446 is 
assumed in PD-L1 CPS 1 and CPS 20 participants, respectively  
3. An enrollment period of ~15 months if the study remains as a Phase II study, and 
an enrollment period of ~19 months if the study expands to a Phase III study  
4. Yearly drop-out rate of 5%. 
Progression-free Survival (PFS)/Immune-based Progression-free Survival (iPFS) 
The power calculation of PFS/iPFS in PD-L1 CPS 1 participants is based on the 
following assumptions: 
1. PFS/iPFS in the pembrolizumab/placebo arm follows a piecewise exponential 
distribution with the milestone PFS/iPFS rates in the pembrolizumab/placebo arm 
the same as the rates in the pembrolizumab arm reported in the KN-048 trial.  
That is, the PFS/iPFS rates at 6 and 12 months are approximately 28.7% and 
20.6%, respectively, with a median PFS/iPFS of 3.2 months for PD-L1 CPS 1 
participants in the pembrolizumab/placebo arm 
2. True hazard ratio for PFS/iPFS between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm of 0.61 for PD-L1 CPS 
1 participants 
3. If the study remains as a Phase II study, an enrollment period of 15 months and a 
minimum of 14-month follow-up after enrollment completion 
If the study expands to a Phase III study, an enrollment period of 19 months and a 
minimum of 9-month follow-up after enrollment completion  
4. Yearly dropout rate of 10%. 
9.2.1. 
Remain as a Phase II Study 
Overall Survival 
The final OS analysis in the PD-L1 CPS1 and CPS20 participants for a Phase II study 
(i.e. without expansion) will be carried out after approximately 244 deaths in PD-L1 


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CPS1 participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm, barring early stopping for 
futility or efficacy. It is expected that approximately 113 deaths in PD-L1 CPS20 
participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm. 
With the above numbers of OS events and before any alpha re-allocation, the study 
provides, a 79.8% power in the PD-L1 CPS1 participants and a 60% power in the PD-
L1 CPS20 participants to demonstrate superiority of OS of GSK3359609 in 
combination with pembrolizumab relative to pembrolizumab plus placebo at the pre-
specified initial alpha (one-sided) level of 2.49%. Please refer to Section 9.8 for details in 
the alpha spending. 
Progression-free Survival/Immune-based progression-free Survival 
The estimated numbers of PFS/iPFS events for a Phase II study (i.e. without expansion) 
at the final PFS evaluation are estimated to be 281 in the PD-L1 CPS1 participants.  
The estimated number of PFS/iPFS events in the PD-L1 CPS1 participants provides a 
67.6% power for detecting a HR of 0.61 in PFS/iPFS in the PD-L1 CPS1 participants at 
the alpha level of 0.01% (one-sided). 
9.2.2. 
Expand to a Phase III Study 
Overall Survival 
The final OS analysis in the PD-L1 CPS1 and CPS20 participants for a Phase III study 
(i.e. with expansion) will be carried out after approximately 367 deaths in the PD-L1 
CPS1 participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm, barring early stopping for 
futility or efficacy. It is expected that approximately 171 deaths in PD-L1 CPS20 
participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm. 
With the above numbers of OS events and before any alpha re-allocation, the study 
provides a 90.1% power in the PD-L1 CPS1 participants and a 73.5% power in the PD-
L1 CPS20 participants to demonstrate superiority of OS of GSK3359609 in 
combination with pembrolizumab relative to pembrolizumab plus placebo at the pre-
specified initial alpha (one-sided) level of 2.49%. 
Progression-free Survival/Immune-based Progression-free Survival 
The estimated numbers of PFS/iPFS events for a Phase III study (i.e. with expansion) at 
the final PFS evaluation are estimated to be 432 in the PD-L1 CPS1 participants. 
The estimated number of PFS/iPFS events in the PD-L1 CPS1 participants provides a 
92.5% power for detecting a HR of 0.61 in PFS/iPFS in the PD-L1 CPS1 participants at 
the alpha level of 0.01% (one-sided). 


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The family-wise type I error rate for the primary hypotheses on PFS and OS as well as 
the key secondary hypotheses on iPFS, TTD in pain and TTD in PF is strongly controlled 
at the alpha level of 2.5% (one-sided). The strategy to address multiplicity issues with 
regards to multiple efficacy endpoints, multiple populations and interim analyses are 
described in Section 9.5 and Section 9.8. 
The study is considered to have met the study primary objective if GSK3359609 in 
combination with pembrolizumab is superior to pembrolizumab administered with 
placebo on either PFS OR OS in PD-L1 CPS1 participants.  
9.2.3. 
Sample Size Sensitivity 
In the case that there is no violation of the proportional hazards in OS between 
GSK3359609 in combination with pembrolizumab and the pembrolizumab/placebo arm 
throughout the entire course of the study, the powers in OS for PD-L1 CPS 1 
participants and PD-L1 CPS 20 participants are estimated below.  
Specifically, a constant OS hazard ratio of 0.71 in PD-L1 CPS 1 participants and 0.67 in 
PD-L1 CPS 20 participants is assumed, in addition to the assumptions in the distribution 
of the survival curve, the enrollment duration and the drop-out rate as described in the OS 
sample size calculation in Section 9.2. It is assumed that the sample size and the number 
of OS events at each look in the proportional hazard case follow the expected number in 
the non-proportional hazards case (details in Section 9.5).  
If the study remains as a Phase II trial, the study provides a 75.3% power to detect a 
hazard ratio of 0.71 in OS for PD-L1 CPS 1 participants, and a 55.6% power to detect a 
hazard ratio of 0.67 in OS for PD-L1 CPS 20 participants, respectively, under the 
proportional hazards assumption at the one-sided alpha level of 2.49%.  
If the study expands to a Phase III trial, the study provides a 90.1% power to detect a 
hazard ratio of 0.71 in OS for PD-L1 CPS 1 participants, and a 73.5% power to detect a 
hazard ratio of 0.67 in OS for PD-L1 CPS 20 participants, respectively, under the 
proportional hazards assumption at the one-sided alpha level of 2.49%.  
The sample size, power calculations, and simulations were performed in the software 
EAST 6 and R (package “gsDesign”). 
9.3. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
All Screened 
All participants who sign the ICF. 
Intent-to-treat 
All randomized participants whether or not randomized 
intervention was administered.  


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Population 
Description 
This population will be based on the study intervention to 
which the participant was randomized and will be the 
primary population for the analysis of efficacy data. 
Safety 
All randomized participants who take at least 1 dose of 
study intervention. Participants will be analysed according 
to the intervention received. 
Pharmacokinetic 
The Pharmacokinetic Population will consist of those 
participants in the Safety Population from whom at least 1 
PK sample has been obtained and analysed. This population 
will be the primary population for PK analyses. 
Details on the populations for analyses will be included in the statistical analysis plan. 


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9.4. 
Statistical Analyses 
This section summarizes key analysis elements; complete details of the planned analysis 
methodologies will be included in the statistical analysis plan. If, after the study has 
begun, but prior to any unblinding, changes made to primary and/or key secondary 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E9). 
Changes to exploratory or other non-confirmatory analyses made after the protocol has 
been finalized, but prior to unblinding, will be documented in the statistical analysis plan 
and referenced in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. 
Primary and secondary endpoints will be included in the main CSR. A separate final CSR 
will report updated key safety analyses at the end of study. Further details will be 
outlined in the statistical analysis plan. 
9.4.1. 
Efficacy Analyses 
The intention-to-treat (ITT) population that includes all randomized participants will 
serve as the primary population for the efficacy analyses.  
Stratified statistical analyses will be based on the following stratification factors, PD-L1 
expression (CPS 20 vs. 1 CPS <20), and HPV status (positive vs. negative). 
Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors will 
be combined as the HPV negative group in the stratified analyses. Details will be 
documented in the statistical analysis plan. 
An outline of the analysis strategy for efficacy endpoints is presented in Table 8. Details 
are outlined in Section 9.4.1.1 and Section 9.4.1.2 and will be further delineated in the 
statistical analysis plan. 


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Table 8 
Analysis Strategy for Key Efficacy Endpoints 
Endpoint 
Statistical Method1 
Analysis 
Population 
Missing Data Approach 
OS 
Test: Stratified log-rank test to 
assess the treatment difference 
Estimation: Stratified Cox model 
with Efron’s tie handling method to 
assess the magnitude of treatment 
difference 
ITT 
Model based 
• 
Censoring rule(s) 
PFS/iPFS 
Test: Stratified log-rank test to 
assess the treatment difference 
Estimation: Stratified Cox model 
with Efron’s tie handling method to 
assess the magnitude of treatment 
difference 
ITT 
Model based 
• 
Censoring rule(s) 
 
ORR/DCR per 
RECIST v1.1 
Stratified Miettinen and 
Nurminen’s method with sample 
size weights 
ITT 
Participants with missing 
data are considered non-
responders and 
conservatively included in 
denominator 
Duration of 
Response per 
RECIST v1.1 
Summary statistics using Kaplan-
Meier method 
All 
Responders 
in ITT 
Non-responders are 
excluded from analysis 
Abbreviations: DCR=disease control rate; iPFS=immune based progression-free survival; 
iRECIST=immune-based response evaluation criteria in solid tumors; ITT=intent-to-treat; ORR=overall 
response rate; OS=overall survival; PFS=progression-free survival 
1. Statistical models are described in further detail in the statistical analysis plan. Statistical analyses of 
PFS, ORR, DCR, and duration of response per RECIST v1.1 and iRECIST follow similarly. 
9.4.1.1. 
Primary Analyses 
Overall Survival  
OS is defined as the interval of time from the date of randomization to the date of death 
due to any cause. Participants without documented death will be censored at last known 
alive date. 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. 
The treatment difference in survival will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The 
hazard ratio and its 95% confidence interval from the stratified Cox model with a single 
treatment covariate will be reported.  
The max-combo test, Restricted Mean Survival Time (RMST) method, or piecewise HR 
method may be conducted as appropriate to account for the possible non-proportional 
hazards effect. Additional analyses of OS adjusting for the effect of subsequent treatment 
may be performed based on recognized methods, if a sufficient proportion of participants 
switch. The choice of the method will be based on an examination of the appropriateness 
of the data to the assumptions required by the method. To further account for the possible 
confounding effect, a supplementary analysis of OS censoring participants at the time of 
initiation of new therapy will be performed. 


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Progression-Free-Survival per RECIST 1.1 
Progression-free-survival (PFS) per RECIST 1.1 is defined as the time from the date of 
randomization to the date of the first documented disease progression per RECIST 1.1 
based on investigator assessment, or death due to any cause, whichever occurs first. 
A summary of the assignments for progression and censoring dates for the primary 
analysis of PFS per RECIST v1.1 is specified in Table 9. Supplementary analyses of PFS 
per RECIST v1.1 with different censoring rules will be delineated in the statistical 
analysis plan. 
Table 9 
Censoring Rules for Primary Analysis of PFS per RECIST 1.1 
Situation 
Primary Analysis 
No or incomplete baseline disease assessments 
and the participant has not died 
Censored at the date of randomization 
No post-baseline disease assessments and the 
participant has not died 
Censored at the date of randomization 
With post-baseline disease assessments, new 
anticancer treatment is not initiated and no 
documented PD or death 
Censored at the date of last adequate1 radiological 
disease assessment 
With post-baseline disease assessments and new 
anticancer treatment is initiated (prior to 
documented PD or death)2 
Censored at the date of last adequate radiological 
disease assessment on or prior to the initiation of 
new anticancer treatment 
PD or death documented after 1 missed disease 
assessment 
Progressed at the date of documented PD3 or death 
PD or death documented after 2 missed disease 
assessments 
Censored at the date of last adequate radiological 
disease assessment prior to the 2 missed disease 
assessment  
Abbreviations: CR=complete response; PD=progressive disease; PFS=progression-free survival; 
PR=partial response; RECIST=response evaluation criteria in solid tumors; SD=stable disease 
1. An adequate assessment is defined as an assessment where the investigator assessed response is CR, 
PR, or SD. 
2. If PD and new anti-cancer therapy occur on the same day, it is assumed that the progression was 
documented first (i.e. outcome is progression; the date is the date of the assessment for progression). 
3. The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new 
lesion); or (ii) Date of radiological assessment showing unequivocal progression in non-target lesions, 
or (iii) Date of last radiological assessment of measured lesions (if progression is based on increase in 
sum of measured lesions). 
The non-parametric Kaplan-Meier method will be used to estimate the PFS curves. The 
treatment difference in PFS will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess 
the magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. 
The hazard ratio and its 95% confidence interval from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported. 
In case the proportional hazards assumption is not valid in PFS, the max-combo test, 
RMST method or piecewise HR as appropriate may be performed for PFS to account for 
the possible non-proportional hazards effect. 


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9.4.1.2. 
Secondary Analyses 
Progression-Free Survival per iRECIST (iPFS) 
Progression-free survival per iRECIST (iPFS) is one of the key secondary endpoints of 
this study. It is defined as the interval of time from the date of randomization to the date 
of the first documented disease progression confirmed consecutively per iRECIST based 
on investigator assessment, or death due to any cause, whichever occurs first. 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the 
terms unconfirmed progressive disease (iUPD) and confirmed progressive disease 
(iCPD).  
The progression event date (iPD date) to be used in the calculation of PFS per iRECIST 
should be the first date of documented iUPD provided that iCPD is confirmed at the next 
assessment. If iUPD occurs, but is disregarded because of later iSD, iPR, or iCR, that 
iUPD date should not be used as the progression event date. 
If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the 
iUPD date will be used as iPD date in the following scenarios: 
• Participant discontinues study treatment because the participant was judged not to 
be clinically stable  
• Participant does not undergo further response assessments due to any reason (i.e., 
participant refusal, protocol non-compliance, or participant death) 
•  Next timepoint response of iUPD, and iCPD never occurs 
Determination of dates of iPFS events and dates for censoring in the secondary analysis 
of iPFS are summarized in Table 10.  


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Table 10 
Censoring Rules for Analysis of iPFS 
Situation 
Primary Analysis 
No or incomplete baseline disease assessments 
and the participant has not died 
Censored at the date of randomization 
No post-baseline disease assessments and the 
participant has not died 
Censored at the date of randomization 
With post-baseline disease assessments,  
new anticancer treatment is not initiated, and no 
iPD date or death 
Censored at the date of last radiological disease 
assessment 
With post-baseline disease assessments,  
new anticancer treatment is initiated (prior to iPD 
date or death)1  
Censored at the date of last radiological disease 
assessment on or prior to the initiation of new 
anticancer treatment 
iPD date or death after 1 missed disease 
assessment 
Progressed at the iPD date2 or death 
iPD date or death documented after 2 missed 
disease assessments 
Censored at the date of last radiological disease 
assessment prior to the 2 missed disease 
assessment  
Abbreviations: iPD=immune-based progressive disease; iPFS=progression-free survival per iRECIST 
1. If the iPD date and new anti-cancer therapy occur on the same day, it is assumed that the progression 
was documented first (i.e. outcome is progression; the date is the date of the assessment for 
progression). 
2. The earliest date of radiological assessments of lesion in which progression criteria are met for the iPD 
date. 
The non-parametric Kaplan-Meier method will be used to estimate the iPFS curves. The 
treatment difference in iPFS will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess 
the magnitude of the treatment difference (i.e., hazard ratio) between the treatment arms. 
The hazard ratio and its 95% confidence interval from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported. 
In case the proportional hazards assumption is not valid for iPFS, the RMST method or 
piecewise HR as appropriate may be conducted for iPFS to account for the possible non-
proportional hazards effect. 
OS rate at 12 and 24 months 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. 
OS rate at 12 months and 24 months and the corresponding 95% CI will be estimated 
from the Kaplan-Meier analysis. 
Objective Response Rate/Disease Control Rate  
ORR per RECIST v1.1 is defined as the proportion of the participants who have a 
complete response (CR) or partial response (PR) as the best overall response per RECIST 
v1.1 based upon investigator assessment. 
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 of 15 weeks per 
RECIST v1.1 based upon investigator assessment. 


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Stratified Miettinen and Nurminen’s method will be used for comparison of the 
ORR/DCR between two treatment groups. The difference in ORR/DCR and its 95% 
confidence interval from the stratified Miettinen and Nurminen’s method with strata 
weighting by sample size with a single treatment covariate will be reported. 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. 
Duration of Response  
Duration of response (DoR) per RECIST v1.1 is defined as the time from first 
documented evidence of CR or PR until first documented disease progression per 
RECIST v1.1 based upon investigator assessment or death due to any cause, whichever 
occurs first, among participants who demonstrated CR or PR as the best overall response 
per RECIST v1.1. If sample size permits, DoR per RECIST v1.1 will be summarized 
descriptively using Kaplan-Meier medians and quartiles. 
9.4.1.3. 
Exploratory Analyses 
An exploratory analysis of ORR per iRECIST will be performed using the stratified 
Miettinen and Nurminen’s method. The corresponding 95% CI for ORR will also be 
provided. Participants with unknown or missing responses will be treated as non-
responders, i.e., these participants will be included in the denominator when calculating 
percentages of response. 
If sample size permits, DoR per iRECIST will be summarized descriptively using 
Kaplan-Meier medians and quartiles.  
An exploratory analysis of PFS2, defined as the time from randomization to subsequent 
disease progression per RECIST 1.1 based on investigator assessment after initiation of 
first new anti-cancer therapy, or death from any cause, whichever first, will be carried 
out. Participants alive and for whom a second objective disease progression has not been 
observed will be censored at the last time known to be alive and without second objective 
disease progression. 
Further details of efficacy analyses will be described in the statistical analysis plan. 
9.4.2. 
Safety Analyses 
The safety population will serve as the primary population for the analyses of safety data 
in this study. Safety analyses will follow a tiered approach [Crowe, 2009] as shown in 
Table 11. The tiers differ with respect to the analyses that will be performed. Tier 1 safety 
endpoints that will be critical to inferential testing for statistical significance will be 
provided with p-values and 95% confidence intervals for between-group comparisons. 
For this protocol, there are no Tier 1 events. All safety parameters will be considered 
Tier 2 or Tier 3. Tier 2 parameters will be assessed via point estimates with 95% CI 
provided for between-group comparisons; only point estimates by treatment group are 


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provided for Tier 3 safety parameters. The between-treatment difference will be analyzed 
using the Miettinen and Nurminen method. 
Based on emerging external data, the analysis strategy for safety endpoints may be 
modified to improve the integrity and efficiency of the design. Should this happen, the 
change will be documented elsewhere, if not in a protocol amendment, at the earliest time 
before any unblinding of the data. Refer to the statistical analysis plan for further details. 
Table 11 
Analysis Strategy for Safety Parameters 
Safety Tier 
Safety Endpoint 
95% CI for 
Treatment 
Comparison 
Descriptive 
Statistics 
Tier 2 
Any AE 
X 
X 
Any Serious AE 
X 
X 
Any Grade 3-5 AE 
X 
X 
Any Treatment-Related AE 
X 
X 
Any Treatment-Related Serious AE 
X 
X 
Any Grade 3-5 and Treatment-Related AE 
X 
X 
Dose Modification due to AE 
X 
X 
Discontinuation due to AE 
X 
X 
Death 
X 
X 
Specific AEs, SOCs (incidence ≥ 4 of 
participants in 1 of the treatment groups) 
X 
X 
Tier 3 
Specific AEs, SOCs (incidence < 4 of 
participants in both treatment groups) 
 
X 
Change from Baseline Results (Labs, ECGs, 
Vital Signs) 
 
X 
Abbreviations: AE=adverse event; CI=confidence intervals; ECG=electrocardiogram; SOC=system organ 
class 
9.4.3. 
Patient Reported Outcomes 
EORTC IL50 and IL51(subset of domains from the EORTC QLQ-C30 and H&N35 
respectively) are not pure efficacy or safety endpoints because they are affected by both 
disease symptoms and treatment tolerability in addition to HRQoL domains. 
The time to deterioration (TTD) curves in Pain measured by the EORTC QLQ-H&N35 
pain domain (included in the EORTC IL51) and the TTD in Physical Function (PF) 
measured by the PROMIS PF 8c will be analysed in the ITT population using the non-
parametric Kaplan-Meier method. 
The treatment effect in TTD in Pain and PF will be assessed separately by the stratified 
log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference (i.e., hazard 
ratio) between the treatment arms. The hazard ratio and its 95% confidence interval from 
the stratified Cox model with Efron’s method of tie handling and with a single treatment 
covariate will be reported.  
For both Pain and PF, TTD will be defined as the time from the date of randomization to 
the date of first definitive meaningful deterioration in score compared to baseline. The 
deterioration has to be: 


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- 
Meaningful, i.e. greater than a clinically meaningful within-individual 
change in score, as defined below; 
- 
Definitive, i.e. all subsequent assessment of the score are also showing a 
clinically meaningful deterioration compared to baseline, or no further 
score is available for the patients for any reason (including disease 
progression or death) 
Patients who don’t show meaningful deterioration will be censored at the time of the last 
available PRO assessment. 
As no threshold for meaningful within-individual change is established for the EORTC 
QLQ-H&N35 pain domain score or PROMIS PF 8c score, the value for use in the TTD 
analyses will be determined using blinded interim data. These analyses will be performed 
before study unblinding and the value will be set-up before database lock. The full 
procedure for determination of meaningful within-person change in EORTC QLQ-
H&N35 pain domain score and PROMIS PF 8c score will be fully described in the 
clinical statistical analysis plan or in a standalone analysis plan as appropriate. It will 
include anchor-based approach using the patient global impression of severity and change 
as an anchor, and possibly other clinical anchors (e.g. ECOG status). Supportive 
distribution-based methods may be applied as sensitivity analyses. 
The selected domains from the EORTC IL50, EORTC IL51, BPI-I3 and EQ-5D-3L 
changes will be summarized as part of the exploratory analysis. Longitudinal and 
descriptive data analysis can be used to evaluate patient reported outcomes. The detailed 
PRO analysis plan will be included in and the statistical analysis plan. 
9.4.4. 
Other Exploratory Analyses 
PK, pharmacodynamic, biomarker exploratory analyses, and health economic assessment 
will be described in the statistical analysis plan. Theses exploratory analyses may be 
presented separately from the main CSR. 
9.5. 
Interim Analyses 
Adaptive Decision Making 
The analysis for adaptive decision will be conducted using ORR/DCR per RECIST v1.1 
based on investigator assessment when approximately the first 100 PD-L1 CPS ≥1 
participants have a minimum follow-up of 6 months. 
The adaptive decision criteria will be positive if there is at least 8% improvement of ORR 
in the GSK3359609 in combination with pembrolizumab arm comparing with the 
pembrolizumab/placebo arm in PD-L1 CPS ≥1 population. Table 12 presents the 
operating characteristics of the adaptive decision criteria based on the improvement of 
ORR. Confirmation of CR and PR is not required in the adaptive decision making. 
1) If the ORR outcome per RECIST v1.1 is positive with ∆ORR≥8% in PD-L1 
CPS ≥1 population, the study continues to an originally planned Phase III sample 
size for a definitive Phase III evaluation. 


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2) If the ORR/DCR outcome per RECIST v1.1 is negative with ∆ORR<0% and 
∆DCR<0% in PD-L1 CPS ≥1 population, the study may stop for futility 
depending on the recommendation of IDMC based on the totality of the data; 
refer to the IDMC charter for details. 
3) Otherwise, the study will continue as planned Phase II sample size for a definitive 
Phase II evaluation. 
Table 12  
Operating Characteristics of the Adaptive Decision Based on the 
PD-L1 CPS ≥1 Population 
IA Probability 
ΔORR = (ORR.GSK3359609/Pembrolizumab – 
ORR.Pembrolizumab/Placebo) 
True ΔORR1 
0% 
4% 
8% 
16% 
20% 
Stopping for futility2 
 ∆ORR<0% 
45% 
27% 
14% 
2% 
1% 
Continuation with Phase II 
 ∆ORR≥0% and ∆ORR<8% 
40% 
42% 
35% 
15% 
7% 
Expansion to Phase III 
 ∆ORR≥8% 
15% 
31% 
51% 
83% 
92% 
Abbreviations: CPS=combine positive score; IA=interim analysis; PD-L1=programmed death ligand-1; 
ORR=overall response rate 
1. The probability is estimated based on 50,000 simulations and it is assumed that the ORR of the 
Pembrolizumab/Placebo arm is 19% in the simulations. 
2. The final futility decision is based on both ORR and DCR; the probability of futility will be lower. 
A meta-analysis was performed using published PD-1/L1 treated studies in HNSCC; the 
analysis only included data from PD-1/L1 regimens that did contain chemotherapy. The 
selection of ORR as the endpoint for the adaptive decision is supported by results of the 
meta-analysis which showed that median OS is significantly positively correlated with 
ORR (refer to Section 10.11 for details). There is no penalty in alpha spending for the 
option to expand Phase II to Phase III, given that neither OS nor PFS are negatively 
correlated with ORR per RECIST v1.1 based on this meta-analysis (Section 10.11). 
All participants from the study are used for statistical inference at the end of Phase II or 
Phase III regardless of the interim expansion decision. In addition, all the primary and 
key secondary endpoints are formally tested for statistical significance at the end of Phase 
II or Phase III. 
PFS/iPFS Analysis and Interim Analyses of OS 
The study is designed to have 1 PFS/iPFS analysis and 2 OS analyses in PD-L1 CPS ≥1 
participants. Two OS analyses will be performed in PD-L1 CPS ≥20 participants. The 
safety of the treatment will also be assessed at the interim analysis. 
The timing of PFS/iPFS analysis and the OS interim analysis is triggered by the pre-
specified number of PFS events in the PD-L1 CPS ≥1 population. 
At the time of PFS/iPFS analysis, the OS interim analysis will be conducted in PD-L1 
CPS ≥1 participants to allow for early stopping of the study due to efficacy or allow for 


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non-binding futility analysis. PD-L1 CPS ≥20 participants will be tested sequentially if 
OS is significant in PD-L1 CPS ≥1 participants. 
The timing of the final OS analysis in the PD-L1 CPS ≥1 and CPS ≥20 participants will 
be triggered by the pre-specified number of OS events in the PD-L1 CPS ≥1 population. 
The nominal significance levels for the interim and final analyses of OS will be 
determined by the Lan-DeMets spending function based upon the O’Brien-Fleming 
boundary. The futility bounds of this study are non-binding and the bounds are 
considered guidance rather than strict bounds. 
Table 13 summarizes the information fraction, sample size and decision guidance for the 
planned PFS/iPFS and OS analyses as a Phase II study. Table 14 summarizes the 
information fraction, sample size and decision guidance for the planned PFS/iPFS and 
OS analyses as a Phase III study. 
Efficacy boundaries and non-binding futility boundaries are based on initially assigned 
type I error rate before any alpha re-allocation and projected number of events at study 
milestones. The actual boundaries will be determined from the actual number of events at 
the time of the specified interim analysis using the alpha- and beta- spending functions. 
Actual futility bounds will be updated if overall beta is changed with respect to alpha re-
allocation. 
Results of all interim analyses, including the adaptive decision, PFS/iPFS analysis, and 
OS interim analysis, will be reviewed by an independent data monitoring committee 
(IDMC). Further details of interim analyses will be provided in the IDMC Charter. Any 
change to the planned event size will be described in the statistical analysis plan before 
any unblinding of the data. 


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Table 13 
Summary of Timing, Sample Size and Decision Guidance at the 
Planned PFS and OS Analyses as a Phase II Study 
Analysis 
Key 
Endpt 
Population 
Expected 
Number of 
Events 
(Information 
Fraction) 
Efficacy Boundary1 
 
Non-Binding Futility 
Boundary1 
p-value 
Cumulative 
alpha 
 
p-value 
Cumulative 
beta 
PFS FA, 
OS IA 
(H1-H4) 
PFS/ 
iPFS 
CPS1 
~281 (100%) 
0.0001 
0.0001 
NA 
NA 
OS 
CPS1 
~205 (84%) 
0.0144 
0.0144 
0.4483 
0.0101 
CPS202 
~95 (84.1%) 
0.0144 
0.0144 
0.5546 
0.0184 
OS FA 
(H1, H2) 
OS 
CPS1 
~244 (100%) 
0.0208 
0.0249 
0.0208 
0.2474 
CPS202 
~113 (100%) 
0.0208 
0.0249 
0.0208 
0.4440 
Abbreviations: CPS=combined positive score; Endpt=endpoint; FA=final analysis; H=hypothesis; 
HR=hazard ratio; IA=interim analysis; NA=not applicable 
1. Efficacy boundaries and non-binding futility boundaries are based on initially assigned type I error rate 
(one-sided) before any alpha re-allocation and projected number of events at study milestones. Actual 
efficacy boundaries will be based on actual numbers of events available at study milestones and actual 
futility bounds will be updated if overall beta is changed with respect to re-allocation. 
2. The descendant OS hypothesis in PD-L1 CPS20 participants will be tested only if the parent OS 
hypothesis in PD-L1 CPS1 participants is significant. 
Table 14 
Summary of Timing, Sample Size and Decision Guidance at the 
Planned PFS and OS analyses as a Phase III Study 
Analysis 
Key 
Endpt 
Population 
Expected 
Number of 
Events 
(Information 
Fraction) 
Efficacy Boundary1 
 
Non-Binding Futility 
Boundary1 
p-value 
Cumulative 
alpha 
 
p-value 
Cumulative 
beta 
PFS FA, 
OS IA 
(H1-H4) 
PFS/ 
iPFS 
CPS1 
~432 (100%) 
0.0001 
0.0001 
NA 
NA 
OS  
 
CPS1 
~295 (80.4%) 
0.0124 
0.0124 
0.4775 
0.0020 
CPS202 
~137 (80.1%) 
0.0122 
0.0122 
0.5927 
0.005 
OS FA 
(H1, H2) 
OS 
CPS1 
~367 (100%) 
0.0213 
0.0249 
0.0213 
0.0991 
CPS202 
~171 (100%) 
0.0213 
0.0249 
0.0213 
0.2648 
Abbreviations: CPS=combined positive score; Endpt=endpoint; FA=final analysis; H=hypothesis; 
HR=hazard ratio; IA=interim analysis; NA=not applicable 
1. Efficacy boundaries and non-binding futility boundaries are based on initially assigned type I error rate 
(one-sided) before any alpha re-allocation and projected number of events at study milestones. Actual 
efficacy boundaries will be based on actual numbers of events available at study milestones and actual 
futility bounds will be updated if overall beta is changed with respect to re-allocation. 
2. The descendant OS hypothesis in PD-L1 CPS20 participants will be tested only if the parent OS 
hypothesis in PD-L1 CPS1 participants is significant. 


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9.6. 
Independent Data Monitoring Committee 
The study will use an IDMC. The IDMC membership and governance will be outlined in 
a separate charter. 
The IDMC will make recommendations for discontinuation or modification of the study 
based on ongoing reviews of safety data according to the Charter. In addition, the IDMC 
will also evaluate all interim efficacy data, including the adaptive decision, PFS/iPFS 
analysis and OS interim analysis, and make a recommendation based on observed results 
of the study. 
In this double-blind study, all GSK and site personnel will be restricted from access to 
interim analysis results provided to the IDMC until the conclusion of the study, unless the 
IDMC recommends significant changes to study conduct that require a protocol 
amendment. In this scenario, after receiving the IDMC recommendation and a decision 
by Chief Medical Officer (CMO), a review of the data may be required. A select group 
from GSK, as determined by the CMO will be unblinded to review the data to agree on 
future study conduct. Depending on the recommendation of the IDMC, the Sponsor may 
prepare a regulatory submission. More details will be provided in the IDMC Charter. 
9.7. 
Blinded Independent Central Review Auditing 
A random sample-based BICR auditing approach will be used to assess whether bias 
exists in estimation of PFS hazard ratio between investigator assessments and BICR 
assessments [Stone, 2015] if the study expands to a Phase III trial. The study is currently 
designed as a randomized, double-blind study. The risk of investigator bias can be 
mitigated in a properly double-blinded randomized study [Dodd, 2008]. 
The objective of the sample-based BICR approach is to corroborate the analysis results of 
the investigator-assessed PFS and to assist in the evaluation of potential bias in 
investigator-assessed PFS in PD-L1 CPS ≥1 participants if the study expands to a Phase 
III trial. The BICR audit approach is not intended to provide an alternative means of 
definitive analysis.  
Evaluation bias will be assessed through the use of measure proposed by Stone et al 
[Stone, 2015]. The hazard ratio (HRR), where HRR is defined as the ratio of the hazard 
ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for 
the investigator assessments. Larger values of HRR are suggestive of a less acceptable 
bias. The maximum acceptable HRR will be derived based on the graded approach 
[Stone, 2015]. For example, in order to preserve two-thirds of the observed HR based on 
investigator assessment, the maximum acceptable HRR is 1.213 if the full study HR 
based on investigator assessment for PFS in PD-L1 CPS ≥1 participants is 0.61. 
If the sample HRR is within the range specified by the maximum acceptable HRR, it is 
concluded that the sample is sufﬁcient to rule out meaningful levels of bias, and no 
further scans will be assessed by the BICR; otherwise the BICR will be performed in all 
PD-L1 CPS ≥1 participants.  


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The audit size of the sample-based BICR will be 45% of all PD-L1 CPS ≥1 participants if 
the study expands to a Phase III trial. Assuming the correlation in the logarithm of HRs 
between investigator assessment and BICR is 0.8, with the maximum acceptable HRR of 
1.213 and the testing of evaluation of bias is conducted at the 10% alpha level, and 72% 
of participants have an event according to investigator assessment and 67% according to 
BICR, the audit size of 45% will ensure that the specificity is ~93.7% in PD-L1 CPS ≥1 
participants. 
Further details on the BICR auditing approach will be included in the statistical analysis 
plan. 
9.8. 
Multiplicity 
The trial uses the graphical method [Maurer, 2013] to provide strong multiplicity control 
for multiple hypotheses as well as interim analyses. 
The family-wise type I error for this study is strongly controlled at 2.5% (one-sided).  
Figure 1 shows the initial one-sided alpha-allocation for PFS/iPFS, OS, and key PRO 
endpoints. Hypotheses presented as nodes in squares are divided into three subfamilies 
presented in ellipsoids. The weights for re-allocation from each subfamily/hypothesis to 
the others are represented on the lines connecting hypotheses. The multiplicity control 
strategy applies whether the study remains as a Phase II trial or expands to a Phase III 
trial. 
Figure 1 
Multiplicity Testing Strategy for Comparisons Between GSK3359609 
in Combination with Pembrolizumab and Pembrolizumab 
Administered with Placebo 
 
 
Abbreviations: CPS = combined positive score; H = hypothesis; I = GSK3359609; iPFS = progression-
free survival per iRECIST; OS = overall survival; P = pembrolizumab; PF=physical function; PFS = 
progression-free survival per RECIST v1.1; PD-L1 = programmed cell death receptor 1-ligand 1; 
TTD=time to deterioration 
1. The alpha level assigned to a subfamily will be rolled over only if the hypotheses within the subfamily 
are all significant based on the weight for re-allocation presented on the dashed lines connecting 
subfamilies. Within each subfamily, the weights for re-allocation from each hypothesis to the others 
are represented on the solid lines connecting hypotheses.  
2.  = 5/6 if both hypotheses in the OS subfamily (i.e. PD-L1 CPS1 and PD-L1 CPS20 participants) 
are significant at the time of PFS/iPFS analyses; if the OS hypothesis is not significant in either 
population at the time of PFS/iPFS analyses, then  = 1 at the final OS analysis.  


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The alpha re-allocation for PFS/iPFS, OS and key PRO endpoints is further explained 
below: 
Overall Survival 
• An initial alpha level of 2.49% is allocated to the OS hypothesis in the PD-L1 
CPS1 participants. 
• If PFS and iPFS tests are both significant in PD-L1 CPS1 participants, the OS 
hypothesis in the PD-L1 CPS1 participants will be tested at 2.5% (re-allocated 
alpha). 
• OS in the PD-L1 CPS20 participants is tested sequentially at the same overall 
alpha level as that of OS in PD-L1 CPS1 participants if GSK3359609 in 
combination with pembrolizumab demonstrates superiority to pembrolizumab 
plus placebo in OS in PD-L1 CPS1 participants. If OS is not significant in PD-
L1 CPS1 participants, the formal conclusion of statistical significance on OS in 
PD-L1 CPS20 participants will not be drawn. 
The following alpha- and beta-spending functions are used in the OS hypothesis of 
PD-L1 CPS1 participants and PD-L1 CPS20 participants. 
• For the OS hypothesis, the alpha-spending function based on Lan-DeMets 
O’Brien-Fleming approximation spending function and the beta-spending 
function based on the Hwang-Shih-DeCani boundary method with a gamma 
parameter of -20 are constructed to implement group sequential boundaries that 
control the type I error rate as well as allow for non-binding futility analysis. 
Section 9.5 demonstrates the planned analyses as well as bounds and boundary properties 
for OS hypothesis testing. Efficacy boundaries and non-binding futility boundaries are 
based on initially assigned type I error rate before any alpha re-allocation and projected 
number of events at study milestones. The actual boundaries will be determined from the 
actual number of events at the time of the specified interim analysis using the alpha- and 
beta- spending functions. Actual futility bounds will be updated if overall beta is changed 
with respect to alpha re-allocation. 
Progression-free Survival/Immune-based Progression-free Survival 
• An initial alpha level of 0.01% is allocated to the PFS hypothesis in PD-L1 
CPS1 participants. 
• If the OS hypotheses in both PD-L1 CPS1 participants and PD-L1 CPS20 
participants are significant at the time of the OS interim analysis, the PFS 
hypothesis in PD-L1 CPS1 participants will be tested at 0.425% (re-allocated 
alpha). 
• If the PFS hypothesis in PD-L1 CPS1 is significant, the hypothesis of iPFS in 
PD-L1 CPS1 will be tested sequentially at the same alpha level. 


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Key Patient Reported Outcomes (TTD in Pain, TTD in PF) 
• Only if GSK3359609 in combination with pembrolizumab demonstrates 
superiority to pembrolizumab plus placebo in OS in both populations (PD-L1 
CPS1 participants and PD-L1 CPS20 participants), will key secondary PRO 
endpoints be tested. The alpha level from OS hypothesis will be propagated to key 
PRO hypotheses. 
• If OS meets superiority in both populations at the time of the OS interim analysis, 
a total of 2.075% alpha level will be propagated to key PRO hypotheses. 
• If OS meets superiority in both populations at the time of the final OS analysis but 
PFS or iPFS fails to demonstrate superiority in PD-L1 CPS1 participants, a total 
of 2.49% alpha level will be propagated to key PRO hypotheses.  
• If OS meets superiority in both populations at the time of the final OS analysis 
and PFS and iPFS both demonstrate superiority in PD-L1 CPS1 participants, a 
total of 2.5% alpha level will be propagated to key PRO hypotheses. 
• The alpha level propagated from OS will be equally split between TTD in Pain 
and TTD in PF in PD-L1 CPS ≥1 participants, with the possibility to further 
propagate the levels between each other. 
• If 1 of 2 key PRO hypotheses in PD-L1 CPS ≥1 participants is rejected based on 
the re-allocated alpha level, the key PRO hypotheses in PD-L1 CPS ≥20 
participants can be tested based on the (updated) weight, with the possibility to 
further propagate the levels between each other. 
• Based on the re-allocated cumulative alpha level, the nominal significance level 
for each key PRO endpoint will be calculated based on the Lan-DeMets O’Brien-
Fleming approximation alpha-spending function. 
Details on multiplicity will be provided in the statistical analysis plan. 


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.2. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  


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• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 
10.1.3. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
10.1.4. 
Dissemination of Clinical Study Data 
• Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  
• 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. 
• GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis. 
• The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with GSK Policy. 
• GSK intends to make anonymized patient-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding 
10.1.5. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 


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• The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
• Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.6. 
Source Data 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
• 
Definition of what constitutes source data can be found in SRM and Monitoring 
Plan 
10.1.7. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 


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completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 15 will be performed by local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
• 
Pregnancy Testing Refer to Section 5.1 Inclusion Criteria for screening 
pregnancy criteria. 
• 
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study. 
Table 15 
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 
Coagulation 
INR or PT 
aPTT 
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 
Other Screening Testsc 
Hepatitis B (HBsAg)d 
Hepatitis C (Hep C antibody)d 
Serum -hCG Pregnancy test (as needed for women of child 
bearing potential) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; -hCG = beta-human 
chorionic gonadotropin; BUN = blood urea nitrogen; eGFR=estimated glomerular filtration rate; HBsAg = 
Hepatitis B surface antigen; RBC = red blood cells; SGOT = serum glutamic oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; T3 = triiodothyronine; T4 = thyroxine; WBC = white blood 
cells; INR = International Normalized Ratio; PT = Prothrombin Time; aPTT = Activated Partial 
Thromboplastin Time 


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a. 
Required if local laboratory testing is available 
b. Creatinine clearance/eGFR is also required to be calculated using one of the formulas provided in 
Section 10.6 
c. 
HIV testing for eligibility is not required unless mandated by local health authority. Tuberculosis 
testing is not required unless mandated by local health authorities. 
d. Central laboratory testing will be performed if local laboratory testing not available. 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. 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 


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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 the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 


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Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers other than the 
cancer under study, 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. 
10.3.3. 
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 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
10.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the 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. 


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• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of severity for each AE and SAE reported 
during the study and will assign a grade according to the NCI-CTCAE v5.0 
[NCI, 2017].  
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 


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Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
10.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE 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, then the site can report this information on a paper SAE 
form (see next section) or to the Medical Monitor by telephone. 
• 
Contacts for SAE reporting can be found in SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the X/medical monitor or the SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in SRM.  


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
GSK3359609 and pembrolizumab may have adverse effects on a fetus in utero. 
Furthermore, it is not known if pembrolizumab has transient adverse effects on the 
composition of sperm. In order to participate in the study, participants of childbearing 
potential must adhere to the contraception requirement as indicated in Section 5.1 and 
Section 10.4.2. If there is any question that a participant of childbearing potential will not 
reliably comply with the requirements for contraception, that participant should not be 
entered into the study 
10.4.1. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required.  


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• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
10.4.2. 
Contraception Guidance: 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 5.1:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 16 when having 
penile-vaginal intercourse with a woman of childbearing potential  
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for the duration of the study and for at least 120 days after the 
last dose of study treatment. 
Female participants 
Table 16 
Highly Effective Contraceptive Methods 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD)  
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year 
when used consistently and correctly. 


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• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a. Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for those participating in clinical studies. 
b. Failure rate of <1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
c. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the 
primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not 
acceptable methods of contraception. Male condom and female condom should not be used 
together (due to risk of failure with friction) 
10.4.3. 
Collection of Pregnancy Information: 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. 
• 
After obtaining the necessary signed informed consent from the pregnant 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. 
• 
The female 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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Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• 
A spontaneous abortion (occurring at < 22 weeks gestational age) or still birth 
(occurring at > 22 weeks gestational age) 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 intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
Any female participant who becomes pregnant while participating  
• 
will discontinue study intervention. 


T M F -1 3 8 4 2 2 3 0  
C O N FI D E N TI A L  
2 0 9 2 2 9  
 
1 1 6  
 
1 0. 5.  
A p p e n di x  5:  E C O G P erf or m a n c e St at u s  
Gr a de  
Descri pti o ns  
[Ok e n , 1 9 8 2] 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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10.6. 
Appendix 6: Renal Function Measures 
CKD-EPI Formula 
Chronic Kidney Disease (CKD) stage: Kidney Disease Outcomes Quality Initiative 
(KDOQI) CKD stages 3/4/5 defined by estimated glomerular filtration rate (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. 
Cockcroft-Gault Formula 
The Cockcroft-Gault formula is a commonly-used surrogate marker for actual creatinine 
clearance (CrCl) and employs creatinine measurements and a participant's weight (kg) to 
predict the clearance.  
If the participant is obese (>30% over ideal body weight), use ideal body weight in 
calculation of estimated CrCl. 
If the participant is below ideal body weight, use actual body weight in calculation of 
estimated CrCl. 
Cockcroft-Gault Formula for serum creatinine in mmol/L 
 
 
 
CrCl (mL/min)= 
Q X (140-age [years]) X actual body weight (kg)a 
 
814 X serum creatinine (mmol/L) 
Q=0.85 for females 
Q=1.0 for males 
OR 
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974] 
Male participants: 
 
 
 
50.0 kg + (2.3 kg X each inch over 5 feet) 
or 
50.0 kg + (0.906 kg X each cm over 152.4 cm) 
Female 
participants: 
 
 
 
45.5 kg + (2.3 kg X each inch over 5 feet) 
or 
45.5 kg + (0.906 kg X each cm over 152.4 cm) c 


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Cockcroft-Gault Formula for serum creatinine in mg/dL 
 
For example: 
For a male participant with actual body weight = 90.0 kg and height = 68 inches, the 
calculation would be as follows: 
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg 
This participants’s actual body weight is >30% over ideal body weight. In this case, the 
participant’s ideal body weight of 68.4 kg should be used in calculating estimated 
creatinine clearance 


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10.7. 
Appendix 7: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis 
• 
DNA samples will be used for research related to study intervention or HNSCC and 
related diseases. They may also be used to develop tests/assays including diagnostic 
tests related to study intervention or study interventions of this drug class, and 
HNSCC. Genetic research may consist of the analysis of one or more candidate 
genes or the analysis of genetic markers throughout the genome or analysis of the 
entire genome (as appropriate) 
• 
DNA samples will be analyzed as described in exploratory study 
objectives/endpoints (refer to Section 3). A detailed description of analyses will be 
documented in a statistical analysis plan prior to initiation of analyses. Planned 
analyses and results of genetic investigations will be reported either as part of the 
clinical statistical analysis plan and clinical study report (CSR), or in a separate 
genetics statistical analysis plan and report, as appropriate. Additional analyses may 
be conducted if it is hypothesized that this may help further understand the clinical 
data.  
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study treatments of this class. The 
results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on study intervention (or study 
interventions of this class) or HNSCC continues but no longer than 15 years after the 
last participant last visit or other period as per local requirements. 


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10.8. 
Appendix 8: Liver Safety: Required Actions, Follow-up 
Assessments and Study Intervention Rechallenge 
Guidelines 
Figure 2 
Liver Stopping Algorithm and Monitoring Event Algorithm1 
 
1.Study intervention refers to study drugs that comprise a study treatment arm. The 
algorithm/guideline applies to all study drugs. 
Table 17 
Liver Chemistry Stopping Criteria –Liver Stopping Event 
Event 
Criteria 
ALT-absolute 
Both ALT  8xULN and 2X baseline value 
ALT Increase 
Both ALT  3xULN and  1.5 X 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 and cannot be 
monitored weekly for 4 weeks 


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Symptomatic3 
Both ALT  3xULN and ≥ 1.5x baseline value associated with 
symptoms (new or worsening) believed to be related to liver 
injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping 
Event4 
Actions 
Follow Up Assessments 
• Immediately discontinue study drug(s) 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and 
complete SAE data collection tool if the 
event also meets the criteria for an SAE2 
• Perform liver event follow up 
assessments  
• Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (see MONITORING 
below) 
• Do not restart/rechallenge participant 
with study drug(s) unless allowed per 
protocol and GSK Medical Governance 
approval is granted(refer to Section 
7.1.1.1)  
• If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
drug(s) and may continue participant in 
the study for any protocol specified 
follow up assessments  
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin and 
INR) and perform liver event follow up 
assessments within 24 hours 
• Viral hepatitis serology5 
• Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show downward 
trend 
• Blood samples for pharmacokinetic 
(PK) analysis of each study drug, 
obtained within 48 hours after last 
dose6 
• Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH) 
• Fractionate bilirubin, if total 
bilirubin2xULN 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report 
form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, other 
over the counter medications 
• Record alcohol use on the liver event 
alcohol intake case report form 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins) 


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• Monitor participant twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin and 
INR) and perform liver event follow up 
assessments within 24-72 hours 
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in participants with definite or 
likely acetaminophen use in the 
preceding week [James, 2009]). 
NOTE: not required in China 
• Liver imaging (ultrasound, magnetic 
resonance, or computerized 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study drug(s) 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)  
4. Study drugs refer to all drugs that comprise a study treatment arm. Refer to the central laboratory 
manual for instructions on sample requirements for follow-up tests performed at central laboratory. 
5. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or 
if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody.  
6. Record the date/time of the PK blood sample draw and the date/time of the last dose of study drug 
prior to blood sample draw on the CRF. 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. Instructions 
for sample handling and shipping are in the SRM. 


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Table 18 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring 
Event 
Criteria 
Actions 
ALT 3xULN and ≥ 1.5x baseline 
value and not meeting any stopping 
criteria without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks. 
 
• Notify the GSK medical monitor within 
24 hours of learning of the abnormality 
to discuss participant safety.  
• Participant can continue study drug(s) 
• Participant must return weekly for 
repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until 
they resolve, stabilize or return to 
within baseline  
• If at any time participant meets the liver 
chemistry stopping criteria, proceed as 
described above 
• If, after 4 weeks of monitoring, ALT 
<3xULN and <1.5 X baseline value, 
and bilirubin <2xULN, monitor 
participants twice monthly until liver 
chemistries normalize or return to 
within baseline 
10.8.1. 
Study Intervention Rechallenge Guidelines 
10.8.1.1. 
Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment 
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered 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 
• 
Serious adverse event or fatality has earlier been observed with drug 
rechallenges [Hunt, 2010; Papay, 2009] 


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• 
Evidence of drug-related preclinical 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: 
• 
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 Institutional Review Board 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 should be permanently discontinued. 
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
rechallenge.  
• 
GSK to be notified of any adverse events, as per Section 10.3. 
10.8.1.2. 
Restart Following Transient Resolving Liver Stopping Events NOT 
Related to Study Treatment 
Restart refers to resuming study intervention following liver stopping events in which 
there is a clear underlying cause (other than DILI) of the liver event (e.g. biliary 
obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is 
not permitted following liver stopping event when the underlying cause was alcohol-
related hepatitis. 


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Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• 
Possible study intervention-induced liver injury has been excluded by the 
investigator and the study team. This includes the absence of markers of 
hypersensitivity (otherwise unexplained fever, rash, eosinophilia). If study 
intervention-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 10.8.1.1 will apply. 
• 
There is no evidence of alcohol-related hepatitis 
• 
Ethics Committee or Institutional Review Board 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 Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart. 
• 
GSK to be notified of any adverse events, as per Section 10.3. 
.


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10.9. 
Appendix 9: Country-specific Requirements 
Not Applicable. 


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10.10. 
Appendix 10: Abbreviations and Trademarks 
Abbreviations 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
AUC(0-t) 
Area under the plasma concentration-time curve from time 
0 to the time of the last quantifiable concentration) 
AUC(0-) 
Area under the concentration-time curve over the dosing 
interval 
-hCG 
Beta-human chorionic gonadotropin 
BPI-I3 
Brief Pain Inventory- Item 3 
cfDNA 
cell-free DNA 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum observed concentration 
Cmin 
Minimum Observed Concentration; 
CNS 
Central Nervous System 
CPD 
Confirmed Progressive Disease 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRP 
C Reactive Protein 
CRS 
Cytokine Release Syndrome 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated Protein 4  
CV 
Cardiovascular 
DCR 
Disease Control Rate 
DILI 
Drug-induced Liver Injury 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
ECHO 
Echocardiogram 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EORTC IL50 
European Organization for Research and Treatment of 
Cancer Item Library 50 (a subset of domains from the 
EORTC QLQ-C30) 
EORTC IL51 
European Organization for Research and Treatment of 
Cancer Item Library 51 (a subset of domains from the 
EORTC QLQ-HN35) 


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EORTC QLQ C30 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire – 30 item Core 
Module 
EU 
European Union 
FACT-G 
Functional Assessment of Cancer Therapy - General 
Fc 
Fragment Crystallizable 
FcR 
FC-gamma Receptor 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose Positron Emission Tomography 
FTIH 
First-time-in-human 
GSK 
GlaxoSmithKline 
H 
Hypothesis 
HNSCC 
Head and Neck Squamous Cell Carcinoma/Cancer 
HPV 
Human Papilloma Virus 
HRQoL 
Health-related Quality of Life 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use 
ICOS 
Inducible T Cell Co-Stimulatory Receptor 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committees 
IFN 
Interferon, gamma 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL 
Interleukin 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
iRECIST 
Immune-based RECIST 
IRR 
Infusion-related Reactions 
IRT 
Interactive Response Technology 
IV 
Intravenous 
kg 
Kilogram(s) 
KN 
KEYNOTE 
LVEF 
Left Ventricular Ejection Fraction 
mAb 
Monoclonal Antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
g 
Microgram(s) 
mg 
Milligram(s) 
mmHg 
Millimeters of Mercury 
mL 
Milliliter(s) 
MRI 
Magnetic Resonance Imaging 
MSDS 
Material Safety Data Sheet 


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MSEC 
Millisecond(s) 
MTD 
Maximum Tolerated Dose 
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 
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 
PK 
Pharmacokinetics 
PR 
Partial Response 
PS 
Performance Status 
Q2W 
Every 2 Weeks 
Q3W 
Every 3 Weeks 
Q6W 
Every 6 Weeks 
Q12W 
Every 12 Weeks 
QTc 
QT interval duration corrected 
R/M 
Recurrent/Metastatic 
RANKL 
Receptor Activator of Nuclear Factor-kappa B Ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
RO 
Receptor Occupancy 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SRM 
Study Reference Manual 
TCR 
T Cell Receptor 
TDV 
Treatment Discontinuation Visit 
TIL 
Tumor Infiltrating Lymphocytes 
TNF 
Tumor Necrosis Factor, alpha 
Treg 
T Regulatory Cells 
TSH 
Thyroid Stimulating Hormone 
TTD 
Time to Deterioration 
ULN 
Upper Limit of Normal 
UPD 
Unconfirmed Progressive Disease 
UPM 
Unit Probability Mass 
US 
United States 
WOCBP 
Woman of Childbearing Potential 


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Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Keytruda 


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10.11. 
Appendix 11: Meta-Analysis of HNSCC Studies 
The meta-analysis includes the following HNSCC studies in the first-line and subsequent 
line disease setting: KN-012, KN-055, KN-040, KN-048, Checkmate-141, and Condor. 
Figure 3 
Median OS versus ORR in PD-1/L1 Arms Without Chemotherapy 
 
Abbreviations: ORR=overall response rate; OS=overall survival; PD-1/L1=programmed cell death 
receptor 1/ligand-1 
1. Note: The size of the circle indicates the relative sample size 


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Figure 4 
Median PFS versus ORR in PD-1/L1 Arms Without Chemotherapy 
 
Abbreviations: ORR=overall response rate; PFS=progression-free survival; PD-1/L1=programmed cell 
death receptor 1/ligand-1 
Note: The size of the circle indicates the relative sample size


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10.12. 
Appendix 12: Immune-related Diseases 
Table 19 
Potential Immune-mediated Diseases 
Neuroinflammatory Disorders 
Musculoskeletal Disorders 
Skin Disorders 
• 
Cranial nerve disorders, 
including 
paralyses/paresis (e.g. 
Bell’s palsy) 
• 
Optic neuritis 
• 
Multiple sclerosis  
• 
Transverse myelitis 
• 
Guillain-Barré 
syndrome, including 
Miller Fisher syndrome 
and other variants 
• 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis 
• 
Myasthenia gravis, 
including Lambert-
Eaton myasthenic 
syndrome  
• 
Immune-mediated 
peripheral neuropathies 
and plexopathies, 
(including chronic 
inflammatory 
demyelinating 
polyneuropathy, 
multifocal motor 
neuropathy and 
polyneuropathies 
associated with 
monoclonal 
gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic Scleroderma 
(Systemic sclerosis), 
including diffuse 
systemic form and 
CREST syndrome 
• 
Idiopathic 
inflammatory 
myopathies, including 
Dermatomyositis, 
Polymyositis, 
• 
Antisynthetase 
syndrome 
• 
Rheumatoid arthritis 
and associated 
conditions including 
Juvenile chronic 
arthritis and Still’s 
disease) 
• 
Polymyalgia 
rheumatica  
• 
Spondyloarthritis, 
including ankylosing 
spondylitis, reactive 
arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 
• 
Psoriatic arthropathy 
• 
Relapsing 
polychondritis 
• 
Mixed connective 
tissue disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous 
skin diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localized Scleroderma 
(Morphoea) 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary 
cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune 
cholangitis. 
• 
Inflammatory Bowel 
disease, including 
Crohn’s disease, 
ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis 
• 
Celiac disease 
• 
Autoimmune 
pancreatitis 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s 
disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular 
autoimmune syndrome 
• 
Autoimmune 
hypophysitis 


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


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10.13. 
Appendix 13: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
DOCUMENT HISTORY 
Document 
Date 
Document Number 
Amendment 2 
19-MAY-2020 
2019N403389_03 
Amendment 1-UK1 
10-FEB-2020 
2019N403389_02 
Amendment 1 
24-OCT-2019 
2019N403389_01 
Original Protocol 
20-AUG-2019 
2019N403389_00 
 
Amendment 2 [19-MAY-2020] 
Overall Rationale for the Amendment: The rationale for the amendment was to include 
eligibility criteria to restrict the population to have recurrence > 6 months from 
completion of chemo-radiation therapy, to address complications of rapid disease 
progression such as increased risk of tumor associated bleeding that is inherent to the 
underlying disease of  HNSCC and clarification regarding unstable medical condition. 
Additional updates included accounting for the possibility of a non-proportional hazard 
effect and tail effect in the statistical plan; definition of second course of study treatment 
that was expanded to include participants who complete 35 cycles of study treatment. 


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Section # and 
Name 
Description of Change Brief Rationale 
Section 1.1.3 – 
GSK3359609 
Monotherapy and in 
Combination with 
Pembrolizumab in 
HNSCC 
Updated the clinical 
data 
Clinical data changed based on later 
data-cut 
Section 1.2 –
Synopsis; Section 
2.1 –Study Rationale 
Updated the 
background on 
pembrolizumab 
marketing application 
status in Europe 
Pembrolizumab  chemotherapy were 
approved by EC for the first-line 
treatment of PD-L1 CPS 1 
recurrent/metastatic HNSCC 
Section 1.4 –
Schedule of 
Activities 
Added a window for 
Physical Examinations, 
added Coagulation 
assessments, added 
notes for 
immunogenicity, blood 
sample for genetics 
research; fresh tumor 
and patient reported 
outcomes (PRO) 
collections 
To provide clarity for assessments 
Section 3 – 
Objectives and 
Endpoints 
Added objective and 
endpoint to support the 
healthcare resource 
utilization assessment 
Exploratory objective was 
inadvertently omitted 
Section 5.1–
Inclusion Criteria 
Revised criterion 4 to 
restrict the population 
to have recurrence > 
6 months from 
completion of chemo-
radiation therapy. 
Revised the reference 
date for age of archival 
tumor tissue to thePD-
L1 testing date. 
Updated to address population with 
rapid progression. .Reference date for 
PD-L1 testing would be used to 
determine age of archival tissue not 
randomization date. 


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Section # and 
Name 
Description of Change Brief Rationale 
Section 5.2–  
Exclusion Criteria 
Added criteria for 
exclusion of patients 
with high risk of 
bleeding and 
clarification for the 
definition of 
severe/unstable 
medical conditions 
In response to high risk of bleeds that 
are an  inherent feature in HNSCC; 
provided clarification to eligibility 
requiring definition which included 
Grade 3/Grade 4 hypercalcemia 
Section 6.1 – Study 
Intervention(s) 
Administered 
Added that participants 
should remain under 
observation at the study 
site post-study 
treatment infusion per 
the judgement of the 
investigator 
Clarified maximum 35 
cycles  of study 
treatment is 
approximately 2 years 
In response to request from an EC to 
provide guidance on observation 
period post infusions 
Clarification that maximum duration 
of study treatment is defined by 
cycles not time. 
Section 7.1 – 
Discontinuation of 
Study Intervention 
Added language to 
address retreatment 
defined as Second 
Course 
To allow participants to have the 
option for  retreatment upon 
progression after achieving a 
response/stable disease 
Section 8.8 –  
Biomarkers and 
Section 8.8.3  – 
Tumor Tissue 
Added additional 
information on 
timepoints for optional 
tumor tissue biopsy 
collections 
To clarify timepoints of tissue 
collections 
Section 9.2  – 
Sample Size 
Determination 
Updated OS scenarios 
to account for the 
possibility of non-
proportional hazards 
and long term 
benefit/tail effect. 
Updated PFS based on 
revised assumptions. 
In KEYNOTE-48 a delayed treatment 
effect and tail effect were observed in 
OS. Additionally, PFS assumption 
rates in the pembrolizumab arm are 
based on those reported in the KN-
048 trial. 


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Section # and 
Name 
Description of Change Brief Rationale 
Section 9.2.1 – 
Remain as a Phase II 
Study; Section 9.2.2 
– Expand to a Phase 
III Study 
Updated alpha spend 
based on revised 
allocation of alpha for 
OS and PFS; also 
updated associated 
power. 
To allocate less to PFS to require 
higher threshold to declare statistical 
significance. Power is updated based 
on non-proportional assumptions and 
tail effect for OS 
Section 9.2.3 – 
Sample Size 
Sensitivity 
Created sample size 
determination and 
power  
Power is updated based on 
proportional assumptions and tail 
effect for OS as a sensitivity analysis 
Section 9.5 – Interim 
Analysis 
Updated the number of 
OS analysis in the CPS 
20 population from 3 
to 2 
Under the non-proportional hazard 
assumption for OS, the 1 interim 
analysis for the CPS 20 population 
retains acceptable power 
Section 9.7– Blinded 
Independent Central 
Review 
Updated BICR auditing 
size strategy and the 
maximum acceptable 
HRR, 
To align with revised HR 
assumptions for PFS 
Section 9.8 – 
Multiplicity 
Updated alpha spend 
based on revised 
allocation of alpha for 
OS and PFS. Other 
updates based on 
revised assumptions 
To allocate less to PFS to require 
higher threshold to declare statistical 
significance 
Section 10.14  – 
Second Treatment 
Course 
Created SoA table for 
Treatment Phase 
To present the assessments required 
 


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11. 
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SAP_001.pdf: 
0 
 
 
 
Reporting and Analysis Plan 
Study ID:  209229 
Official Title of Study:  A Randomized, Double-blind, Adaptive, Phase II/III Study of GSK3359609 or 
Placebo in Combination with Pembrolizumab for First-Line Treatment of PD-L1 Positive 
Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
NCT ID: NCT04128696 
Date of Document: 12-JUL-2021 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
209229 
 
 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Statistical Analysis Plan (SAP) 
Title Page 
Protocol Title: A Randomized, Double-blind, Adaptive, Phase II/III Study of 
GSK3359609 or Placebo in Combination with Pembrolizumab for First-Line Treatment 
of PD-L1 Positive Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma 
Protocol Number: 209229  
Compound Number: GSK3359609 
 
Short Title: A Phase II/III study of GSK3359609 in combination with pembrolizumab 
compared with pembrolizumab plus placebo in participants with PD-L1 positive recurrent 
or metastatic HNSCC (INDUCE-3) 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Legal Registered Address:   980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clinicaltrials.gov 
EudraCT 
IND 
NCT04128696 
2019-002263-99 
143221 
Effective Date: Refer to document date 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


 
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SAP AUTHOR(S): 
Author 
Date 
02-JUL-2021 
Principal Statistician, Oncology Clinical Statistics 
SAP TEAM REVIEW CONFIRMATIONS (E-MAIL CONFIRMATION): 
Approver 
Date of E-mail 
Confirmation 
09-JUL-2021 
Physician Project Leader, Oncology Clinical 
Development 
 
08-JUL-2021 
Clinical Investigation Leader, Oncology Clinical 
Development 
09-JUL-2021 
Safety Development Leader, Pharmacovigilance 
Safety & Medical Governance 
09-JUL-2021 
Lead Programmer, Oncology Clinical Programming 
 
Health Outcomes 
 Oncology Value Evidence 
and Outcomes 
08-JUL-2021 
 
Senior Medical Writer, Medical Writing Science 
09-JUL-2021 
 Clinical Pharmacology Modelling & 
Simulation 
12-JUL-2021 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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3 
 
Clinical Statistics Line Approval (eSignature): 
Approver 
 Early IO Clinical Statistics Head 
 
PPD
PPD


 
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3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION .................................................................................................... 10 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan .......................... 10 
1.2. 
Objectives, Endpoints and Estimands ......................................................... 10 
1.2.1. 
Objectives and Endpoints ............................................................ 10 
1.2.2. 
Estimands .................................................................................... 13 
1.3. 
Study Design .............................................................................................. 16 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA .......................................... 17 
2.1. 
Multiple Comparisons and Multiplicity ......................................................... 18 
3. 
SAMPLE SIZE DETERMINATION ......................................................................... 21 
3.1. 
Sample Size Sensitivity ............................................................................... 23 
4. 
ANALYSIS SETS ................................................................................................... 23 
4.1. 
Protocol Deviations ..................................................................................... 24 
5. 
STATISTICAL ANALYSES ..................................................................................... 25 
5.1. 
General Considerations .............................................................................. 25 
5.1.1. 
General Methodology .................................................................. 25 
5.1.2. 
Baseline Definition ....................................................................... 25 
5.1.3. 
Multicenter Studies ...................................................................... 26 
5.2. 
Primary Endpoint(s) Analysis ...................................................................... 26 
5.2.1. 
Definition of Endpoint(s) ............................................................... 26 
5.2.2. 
Main Analytical Approach ............................................................ 28 
5.2.2.1. 
Statistical Methodology Specification .......................... 29 
5.2.2.2. 
Statistical Methodology Specification .......................... 30 
5.2.3. 
Sensitivity Analyses ..................................................................... 31 
5.2.4. 
Supplementary Analyses ............................................................. 31 
5.2.5. 
Subgroup analyses ...................................................................... 31 
5.3. 
Secondary Endpoint(s) Analysis ................................................................. 31 
5.3.1. 
Key/Confirmatory Secondary Endpoint(s) .................................... 31 
5.3.1.1. 
Definition of Endpoint ................................................. 31 
5.3.1.2. 
Main analytical approach ............................................ 34 
5.3.2. 
Supportive Secondary Endpoint(s) .............................................. 35 
5.4. 
Tertiary/Exploratory Endpoint(s) Analysis ................................................... 39 
5.4.1. 
Pharmacodynamic and Biomarker Analyses ................................ 39 
5.5. 
Other Safety Analyses ................................................................................ 39 
5.5.1. 
Extent of Exposure ...................................................................... 39 
5.5.2. 
Deaths ......................................................................................... 39 
5.5.3. 
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study and Other 
Significant Adverse Events .......................................................... 40 
5.5.4. 
Pregnancies ................................................................................. 40 
5.5.5. 
Additional Safety Assessments .................................................... 40 
5.5.5.1. 
Laboratory Data .......................................................... 40 
5.5.5.2. 
Vital Signs .................................................................. 41 
5.5.5.3. 
ECG ........................................................................... 41 
5.5.5.4. 
Performance Status .................................................... 41 


 
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5.6. 
Other Analyses ........................................................................................... 41 
5.6.1. 
Blinded Independent Central Review (BICR) Auditing Plan ......... 41 
5.7. 
Interim Analyses ......................................................................................... 41 
5.7.1. 
Adaptive Decision Making ............................................................ 42 
5.7.2. 
PFS/iPFS Analysis and Interim OS Analysis ................................ 42 
5.8. 
Additional Analyses Due to the COVID-19 Pandemic ................................. 44 
5.8.1. 
Protocol Deviations ...................................................................... 44 
5.8.2. 
Additional Displays for Participants with a COVID-19 
Infection ....................................................................................... 44 
5.8.3. 
Safety .......................................................................................... 44 
5.8.3.1. 
Assessment of COVID-19 Adverse Events ................. 44 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 45 
6.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 45 
6.1.1. 
List of Abbreviations .................................................................... 45 
6.1.2. 
Trademarks ................................................................................. 46 
6.2. 
Appendix 2: Graphical Testing Strategy Between and Within 
Subfamilies ................................................................................................. 47 
6.3. 
Appendix 3: Extended Time Without an Adequate Assessment .................. 49 
6.4. 
Appendix 4: EORTC QLQ-C30 Scoring Information .................................... 51 
6.5. 
Appendix 5: BICR Implementation Plan ...................................................... 52 
7. 
REFERENCES ....................................................................................................... 54 
 
 


 
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Version history 
This Statistical Analysis Plan (SAP) for study 209229 is based on the protocol 
amendment 3 (GlaxoSmithKline Document Number TMF-13842230) dated 29-JUN-
2021.  
Table 1 
SAP Version History Summary 
SAP 
Version 
Approval Date 
Change 
Rationale 
1 
12-NOV-2019 
Not Applicable 
Original version 
2 
26-JAN-2021 
General updates 
Updated to align with 
protocol amendment 2 and 
correction of minor 
typographical errors 
2 
26-JAN-2021 
Added exploratory 
analysis of healthcare 
resource utilization 
added. 
Updated to align with 
protocol amendment 2. 
2 
26-JAN-2021 
Added max-combo 
analysis method. 
To further detect and 
evaluate the treatment 
effect when the 
proportional hazards 
assumption is violated. 
2 
26-JAN-2021 
Updated the date of 
treatment start to the date 
of randomization in the 
definition of best overall 
response per RECIST 
and iRECIST. 
Corrected for clarification 
purpose. 
2 
26-JAN-2021 
Added additional 
analyses due to the 
COVID-19 pandemic. 
To examine the impact of 
the COVID-19 pandemic 
which began after the 
finalization of protocol 
amendment 1. 
2 
26-JAN-2021 
Added the 
implementation details 
of the blinded 
independent central 
review (BICR) based on 
the outcome of the 
To clarify the 
implementation strategy of 
the BICR. 


 
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SAP 
Version 
Approval Date 
Change 
Rationale 
adaptive decision and the 
BICR auditing. 
2 
26-JAN-2021 
Updated infusion to 
cycle when summarizing 
the exposure data.  
To align the terminology. 
2 
26-JAN-2021 
Removed the expected 
timing of analyses. 
It is sufficient to include 
the number of expected 
events as the study is event 
driven.  
2 
26-JAN-2021 
Removed reference to 
overall summary score 
derivation in EORTC 
QLQ-C30. 
Not applicable when all 
domains are not 
administered. 
2 
26-JAN-2021 
Clarified that 
participants receiving a 
second course of 
treatment will be 
included in the analysis 
of PFS2. 
Updated to align with 
protocol amendment 2. 
2 
26-JAN-2021 
Added COVID-19 
Analysis Set. 
Additional subset of safety 
set for COVID-19 related 
analyses. 
2 
26-JAN-2021 
Updated Enrolled 
Analysis Set definition. 
For clarification of how to 
handle randomization and 
dosing errors.  
2 
26-JAN-2021 
Cisplatin-resistant 
subgroup removed. 
Not a relevant subgroup of 
interest. Given the 
population, the time to 
recurrence subgroup 
analysis is sufficient.  
2 
26-JAN-2021 
Added clarification of 
requirements for second 
course treatment safety 
analyses. 
Clarification required 
following protocol 
amendment 2. 
2 
26-JAN-2021 
Clarifications added to 
the PFS primary and 
supplementary analysis 
scenarios. 
Logic clarification 
required. 


 
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7 
 
SAP 
Version 
Approval Date 
Change 
Rationale 
3 
19-FEB-2021 
Added an analysis set 
definition for response 
analysis at adaptive 
decision making 
Added to clarify who will 
be included in the response 
analysis for interim 
analysis 1, which is aligned 
with response assessment 
schedule, allowing for a 1 
week visit window. 
3 
19-FEB-2021 
Clarified that the point 
estimate refers to the 
percentage of 
participants with an 
event in the tiered 
approach to safety 
analyses.  
To clarify what point 
estimate should be derived. 
3 
19-FEB-2021 
Added BOR and iBOR 
summaries. Added 95% 
exact confidence 
intervals for within-
treatment estimates of 
ORR/DCR, and similarly 
for iORR/iDCR. 
To aide data interpretation 
and for alignment with 
GSK standards. 
3 
19-FEB-2021 
Restructured the 
ORR/DCR definition 
section and clarified that 
a one week visit window 
should be considered 
when defining durable 
SD to be considered in 
the derivation of DCR. 
Removed example SD 
derivation. Similar 
updates made for iSD 
and iDCR. 
To align with visit 
schedule and clarify the 
difference between the 
derivation of SD as BOR 
vs durable SD included in 
the derivation of DCR 
(similarly for iSD and 
iDCR). Removed example 
to avoid misinterpretation. 
3 
19-FEB-2021 
Clarified the weighting 
strategy for the stratified 
Miettinen and 
Nurminen’s Method. 
Numerous weighting 
strategies are available. 
Text expanded (already 
stating the use of sample 
size weighting) for 
clarification. 
3 
19-FEB-2021 
General updates 
Correction of minor 
typographical and 
formatting errors 


 
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209229 
 
 
 
8 
 
SAP 
Version 
Approval Date 
Change 
Rationale 
4 
Refer to document 
date 
Intent-to-Treat analysis 
set changed to Modified 
Intent-to-Treat  
To address change in study 
design following IA, where 
decision was made to 
discontinue ICOS/placebo. 
Participants randomized or 
first dosed after this date 
will be excluded from 
efficacy analyses. 
4 
Refer to document 
date 
Removal of 
supplementary, 
sensitivity, BICR and 
subgroup analyses for 
the purposes of an 
abbreviated CSR. Some 
exploratory analyses 
may be performed and 
reported outside of the 
CSR. Minimally required 
safety to be included. For 
safety analyses, the 
between-treatment 
difference will not be 
analyzed. 
Early study termination.  
4 
Refer to document 
date 
Removed reference to 
reporting of 
retreated/second course 
treatment. 
No patients received 
second course treatment 
prior to early termination, 
so analysis no longer 
required. 
4 
Refer to document 
date 
Clarified process for 
determining the 
deterioration threshold 
for TTD in pain and 
physical function.  
Due to early study 
termination, blinded data 
will be pooled across 
209229 and 209227 studies 
and threshold analysis will 
be completed following 
database lock.  
4 
Refer to document 
date 
General updates 
Correction of minor 
typographical and 
formatting errors 


 
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9 
 
SAP 
Version 
Approval Date 
Change 
Rationale 
4 
Refer to document 
date 
Targeted number of 
events will not be 
updated in the case of 
early study termination 
Adds no value to revise 
following decision to 
terminate study 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 209229. Details of the planned interim analysis, in addition to the 
final analyses, are provided. The main CSR will be an abbreviated report including all 
primary and secondary endpoints. The final CSR will report updated key safety analyses 
after LSLV. 
Additional detail with regards to data handling conventions and the specification of data 
displays will be provided in the Output and Programming Specification (OPS) document. 
1.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Due to the early termination of the study, the SAP has been developed for the purposes of 
an abbreviated CSR for reporting of primary and secondary endpoints and for the final 
safety update.  
Intent-to-Treat Analysis Set changed to a Modified Intent-to-Treat. Participants who were 
first dosed or randomized after the date of dear investigator letter (DIL) requesting 
immediate discontinuation of GSK3359609/placebo will be excluded. The date of the 
DIL is the 13th April.  
For the abbreviated CSR, supplementary, sensitivity, BICR and subgroup analyses will 
not be performed. Some exploratory analyses may be performed and reported outside of 
the CSR. Minimally safety analyses will be performed. For safety analyses, the between-
treatment difference will not be analyzed.  
1.2. 
Objectives, Endpoints and Estimands 
1.2.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
Compare the efficacy of GSK3359609 in 
combination with pembrolizumab to 
pembrolizumab plus placebo in the 
Programmed Death Ligand 1 (PD-L1) 
expression positive (CPS ≥1) population and 
in the PD-L1 expression high (CPS ≥20) 
population. 
• 
OS in PD-L1 CPS 1 and CPS 20 
populations defined as the time from the date 
of randomization to the date of death due to 
any cause. 
• 
PFS per RECIST v1.1 by investigator 
assessment in PD-L1 CPS 1 population, 
defined as the time from the date of 
randomization to the date of first documented 
disease progression or death due to any cause, 
whichever comes first 
Secondary Objectives 
Secondary Endpoints 
• 
Further compare the efficacy of GSK3359609 
in combination with pembrolizumab 
compared with pembrolizumab plus placebo 
• 
PFS per iRECIST (iPFS) by investigator 
assessment in the PD-L1 CPS 1 population 


 
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Objectives 
Endpoints 
• 
PFS per RECIST v1.1 and iPFS by 
investigator assessment in PD-L1 CPS 20 
population 
• 
Milestone OS rate at 12 and 24 months in the 
PD-L1 CPS 1 and CPS 20 populations 
• 
ORR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and CPS20 
populations 
• 
DCR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and CPS 
20 populations 
• 
DoR per RECIST v1.1 by investigator 
assessment in the PD-L1 CPS 1 and CPS 
20 populations 
• 
Evaluate the safety and tolerability of 
GSK3359609 in combination with 
pembrolizumab compared with 
pembrolizumab plus placebo 
• 
Frequency and severity of AEs, AESI, SAEs 
• 
Dose modifications (i.e., interruptions, 
discontinuations) 
• 
Evaluate and compare disease related 
symptoms and impact on function and health-
related quality of life (HRQoL) of 
GSK3359609/pembrolizumab versus 
pembrolizumab plus placebo 
• 
The time to deterioration in pain measured by 
the EORTC QLQ-H&N35 pain domain in the 
PD-L1 CPS 1 and CPS 20 populations 
• 
The time to deterioration in physical function 
measured by the PROMIS PF 8c in the PD-L1 
CPS 1 and CPS 20 populations 
Exploratory Objectives 
Exploratory Endpoints 
• 
Compare the efficacy of GSK3359609 in 
combination with pembrolizumab to 
pembrolizumab plus placebo 
• 
ORR, DoR, DCR per iRECIST 
• 
PFS2, defined as the time from the date of 
randomization to the date of second objective 
disease progression per RECIST v1.1, or 
death due to any cause, whichever first 
• 
Evaluate and compare disease-related 
symptoms, overall bother of treatment side 
effects, and impact on function and HRQoL of 
GSK3359609/pembrolizumab versus 
pembrolizumab plus placebo 
• 
Symptomatic AEs as measured by the FACT 
GP5 
• 
Changes in other domains of quality of life as 
measured by the selected EORTC IL50/51 
(subset of domains of the EORTC QLQ-C30 
and EORTC QLQ-H&N35), BPI-I3 and EQ-
5D-3L  
• 
Evaluate healthcare resource utilization of 
participants in the GSK3359609 combination 
with pembrolizumab arm versus participants 
• 
Non-protocol healthcare encounters, such as 
provider visits, emergency room visits, 
hospitalizations, medications, tests, or 
procedures 


 
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Objectives 
Endpoints 
in the placebo combination with 
pembrolizumab arm  
• 
Evaluate GSK3359609 PK properties 
• 
Summary of GSK3359609 concentrations and 
Cmax, Cmin, AUC (0- ) as data permit 
• 
Determine immunogenicity of GSK3359609 
• 
Anti-drug antibody (ADA) incidence 
• 
Explore relationship between biomarkers in 
tumor and blood, such as immune response 
biomarkers, target expression and efficacy 
endpoints 
• 
Tumor and blood-based analysis of DNA, 
RNA, and protein analytes/profiles; OS, PFS, 
ORR, other efficacy parameters 
• 
Genetics Research: Investigate the 
relationship between host genetic variations 
and response to therapy 
• 
Germline genetic evaluations may be 
conducted for: 
• 
Clinical response, including 
GSK3359609/ pembrolizumab or any 
concomitant medicines 
• 
Disease susceptibility, severity, and 
progression and related conditions  
Abbreviations: AE=adverse events; AESI=adverse events of special interest; Brief Pain Inventory-Item 
3=BPI-I3; DCR=disease control rate; DNA=deoxyribonucleic acid; DoR=duration of response; 
EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire 30-item Core Module; EORTC H&N35=EORTC Head and Neck 35 Item Module; EQ-
5D-3L=EuroQoL 5 Dimensions; FACT-GP5 = Functional Assessment of Cancer Therapy – General 
(Item GP5); HRQoL= health-related quality of life; iPFS = immune-based progression-free survival; 
iRECIST=immune-based Response Evaluation Criteria in Solid Tumors; ORR=overall response rate; 
OS=overall survival; PFS=progression-free survival; PROMIS-PF-8c= Patient-Reported Outcomes 
Measurement Information System-Physical Function-Short Form; RECIST= Response Evaluation 
Criteria in Solid Tumors; RNA=ribonucleic acid 
 


 
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13 
 
1.2.2. 
Estimands 
Primary and key secondary study objectives are presented in Table 2 with additional 
information, including prespecified estimands with related attributes. 
Due to early study termination, only the primary estimands will be reported in the main 
CSR.  
Table 2 
Estimands 
Objective 
(Hypothesis1) 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint2 
Populatio
n of 
interest 
(Analysis 
Set)  
Intercurrent Event 
Strategy3 
Population 
Level 
Summary 
Measure 
Primary 
Objective 1:  
To demonstrate 
the superiority of 
GSK3359609 in 
combination 
with 
pembrolizumab 
compared to 
pembrolizumab 
plus placebo in 
OS in PD-L1 
CPS ≥1 and CPS 
≥20 R/M 
HNSCC 
(H1, H2) 
Primary  
OS, defined 
as the 
interval of 
time from 
the date of 
randomizati
on to the 
date of 
death due to 
any cause 
 
CPS ≥1 
R/M 
HNSCC, 
CPS ≥20 
R/M 
HNSCC 
(mITT) 
 
• 
New anti-cancer 
therapy: treatment 
policy 
• 
Treatment 
discontinuation: 
treatment policy 
Hazard ratio 
for 
GSK33596
09+pembrol
izumab vs. 
placebo+pe
mbrolizuma
b 
Primary 
Objective 2:  
To demonstrate 
the superiority of 
GSK3359609 in 
combination 
with 
pembrolizumab 
compared to 
pembrolizumab 
plus placebo in 
PFS in PD-L1 
CPS ≥1 R/M 
HNSCC 
(H3) 
Primary 
 
PFS, 
defined as 
the time 
from the 
date of 
randomizati
on to the 
date of the 
first 
objectively 
documented 
disease 
progression 
per RECIST 
v1.1 based 
on 
investigator 
assessment, 
or death due 
to any 
cause, 
whichever 
occurs first. 
CPS ≥1 
R/M 
HNSCC 
(mITT) 
• 
New anti-cancer 
therapy: hypothetical 
• 
Treatment 
discontinuation: 
treatment policy 
• 
≥2 missed disease 
assessments: 
hypothetical 
• 
Death: composite 
Hazard ratio 
for 
GSK33596
09+pembrol
izumab vs. 
placebo+pe
mbrolizuma
b  


 
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Objective 
(Hypothesis1) 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint2 
Populatio
n of 
interest 
(Analysis 
Set)  
Intercurrent Event 
Strategy3 
Population 
Level 
Summary 
Measure 
Key Secondary 
Objective 1:  
To demonstrate 
the superiority of 
GSK3359609 in 
combination 
with 
pembrolizumab 
compared to 
pembrolizumab 
plus placebo in 
iPFS in PD-L1 
CPS ≥1 R/M 
HNSCC 
(H4) 
Primary 
 
iPFS 
 
CPS ≥1 
R/M 
HNSCC 
(mITT) 
• 
New anti-cancer 
therapy: hypothetical 
• 
Treatment 
discontinuation: 
treatment policy 
• 
≥2 missed disease 
assessments: 
hypothetical 
• 
Death: composite 
Hazard ratio 
for 
GSK33596
09+pembrol
izumab vs. 
placebo+pe
mbrolizuma
b 
Key Secondary 
Objective 2:  
To demonstrate 
the superiority of 
GSK3359609 in 
combination 
with 
pembrolizumab 
compared to 
pembrolizumab 
plus placebo in 
TTD in pain in 
PD-L1 CPS ≥1 
and CPS ≥20 
R/M HNSCC 
(H5, H6) 
Primary 
 
TTD in 
pain 
 
CPS ≥1 
R/M 
HNSCC, 
CPS ≥20 
R/M 
HNSCC 
(mITT) 
• 
New anti-cancer 
therapy: hypothetical 
• 
Treatment 
discontinuation: 
treatment policy 
• 
Disease progression 
per RECIST v1.1 or 
iRECIST: treatment 
policy 
• 
Death: treatment 
policy 
• 
≥2 missed 
corresponding PRO 
assessments if at least 
one missed 
assessment is due to 
the participant being 
too ill: hypothetical 
Hazard ratio 
for 
GSK33596
09+pembrol
izumab vs. 
placebo+pe
mbrolizuma
b 
Key Secondary 
Objective 3:  
To demonstrate 
the superiority of 
GSK3359609 in 
combination 
with 
pembrolizumab 
compared to 
pembrolizumab 
plus placebo in 
TTD in PF in 
PD-L1 CPS ≥1 
and CPS ≥20 
R/M HNSCC 
Primary 
 
TTD in 
PF 
 
CPS ≥1 
R/M 
HNSCC, 
CPS ≥20 
R/M 
HNSCC 
(mITT) 
• 
New anti-cancer 
therapy: hypothetical 
• 
Treatment 
discontinuation: 
treatment policy 
• 
Disease progression 
per RECIST v1.1 or 
iRECIST: treatment 
policy 
• 
Death: treatment 
policy 
Hazard ratio 
for 
GSK33596
09+pembrol
izumab vs. 
placebo+pe
mbrolizuma
b 


 
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15 
 
Objective 
(Hypothesis1) 
Estimand 
Category  
Estimand 
Variable/ 
Endpoint2 
Populatio
n of 
interest 
(Analysis 
Set)  
Intercurrent Event 
Strategy3 
Population 
Level 
Summary 
Measure 
(H7, H8) 
• 
≥2 missed 
corresponding PRO 
assessments if at least 
one missed 
assessment is due to 
the participant being 
too ill: hypothetical 
Abbreviations: iPFS = immune-based progression-free survival; iRECIST=immune-based Response 
Evaluation Criteria in Solid Tumors; mITT =Modified Intent-to-Treat;  OS = overall survival; PF = 
physical function; PFS = progression free survival; PRO = Patient Reported Outcomes; RECIST= 
Response Evaluation Criteria in Solid Tumors; TTD = time to deterioration. 
1. 
Refer to Section 2 for details in the hypotheses. 
2. 
Refer to Section 5 for the definition of variable/endpoint. 
3. 
Refer to Section 5.2.1 and Section 6.3 for details in the two or more missed disease assessments. 
 


 
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1.3. 
Study Design 
Overview of Study Design and Key Features 
 
Abbreviations: CPS=combined positive score; GSK609=GSK3359609; HPV=human papilloma 
virus; ORR=overall response rate; PD-L1=programmed death ligand-1; Q3W=every three weeks; 
vs=versus 
1. Stratification Factors: 
a. 
PD-L1 Status (CPS ≥20 vs. 1≤ CPS <20) 
b. HPV status in oropharynx sites only (positive vs. negative/unknown) vs non-oropharynx) 
2. ORR assessed by RECIST v1.1; refer to Section 9.5 of protocol for further details on adaptive 
decision analysis. 
Design 
Features 
• 
Design: This is a randomized, double-blind, multicentre, parallel, adaptive, phase 
II/III study comparing a combination of GSK3359609 (ICOS agonist) and 
pembrolizumab to pembrolizumab plus placebo in participants with PD-L1 CPS 1 
recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) of 
the oropharynx, oral cavity, hypopharynx or larynx. 
• 
If at the interim adaptive analysis, the outcome meets the defined ORR positive 
criterion, the study will be expanded from a Phase II to a Phase III design with a 
total of 600 participants randomized. If the outcome does not meet the defined 
criteria, then the study will remain as Phase II with 374 participants randomized. 
• 
All participants will be stratified by two factors i) PD-L1 CPS status (CPS ≥20 vs 
1≤ CPS <20); and ii) HPV status in oropharyngeal cancers (positive vs 
negative/unknown) vs non-oropharyngeal cancers then randomly assigned in a 1:1 
ratio to the GSK3359609/pembrolizumab arm or pembrolizumab with placebo arm. 
• 
The study is comprised of three periods: screening, treatment, and follow-up. The 
total duration of study participation begins with the signing of the informed consent 
form (ICF) through the final protocol-defined follow-up assessment for survival. 
o 
For participants who meet all eligibility criteria and are randomized within the 
study, the maximum duration of treatment with pembrolizumab, GSK3359609 
and placebo is expected to be approximately 2 years, up to 35 cycles.  
o 
The follow-up period begins when study treatment is permanently 
discontinued; participants will undergo follow-up assessments for safety, PFS 
on first subsequent anti-cancer therapy (PFS2) and survival as indicated in the 
Schedule of Activities (SoA) in the protocol.  
 
Study 
intervention 
• 
GSK3359609, placebo, and pembrolizumab are each administered as a 30-minute 
IV infusion once Q3W.  
• 
GSK3359609 or placebo will be administered first followed by pembrolizumab. 
Study 
intervention 
Assignment 
• 
Participants will be randomly assigned to either receive the combination of 24 mg 
GSK3359609 plus 200 mg pembrolizumab (GSK3359609/pembrolizumab) or 
placebo plus 200 mg pembrolizumab (placebo/pembrolizumab) in a 1:1 allocation 
ratio after stratification.  
Interim 
Analysis 
• 
The study is designed to have one interim analysis (IA) for adaptive decision 
making, one PFS/iPFS primary analysis (final analysis) and two OS analyses (one 


 
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17 
 
Overview of Study Design and Key Features 
IA and one final analysis) in PD-L1 CPS ≥1 participants. Two OS analyses will be 
performed in PD-L1 CPS ≥20 participants.  
o 
IA1: The interim analysis for adaptive decision making will be conducted 
using ORR/DCR per RECIST v1.1 based on investigator assessment when 
approximately the first 100 PD-L1 CPS ≥1 participants have a minimum 
follow-up of 6 months. 
o 
IA2: At the time of PFS/iPFS primary analysis, the OS interim analysis will be 
conducted in PD-L1 CPS ≥1 participants to allow for early stopping of the 
study due to efficacy or allow for non-binding futility analysis. The timing of 
PFS/iPFS analysis and the OS interim analysis is triggered by the pre-specified 
number of PFS events in PD-L1 CPS ≥1 population. 
o 
FA: The timing of the final OS analysis in the PD-L1 CPS ≥1 participants and 
CPS ≥20 participants will be triggered by the pre-specified number of OS 
events in the PD-L1 CPS ≥1 population. 
• 
The number of events for the PFS and OS analyses are specified in the protocol and 
is dependent on whether the study is expanded to Phase III or remains as Phase II. 
• 
The study will use an IDMC. The safety of the study intervention will be 
monitored. 
Multiplicity 
• 
The type I error rate is controlled at 2.5% with an initial assignment of 0.01% for 
PFS and 2.49% for OS.  
• 
Alpha will be re-allocated as detailed in the multiplicity testing strategy in Section 
2.1. 
2. 
STATISTICAL HYPOTHESES / SUCCESS CRITERIA 
The following primary hypotheses will be tested: 
Overall Survival (OS) 
• Hypothesis (H1): GSK3359609 in combination with pembrolizumab prolongs 
OS compared with pembrolizumab/placebo in participants with PD-L1 CPS 
≥1 R/M HNSCC. 
• Hypothesis (H2): GSK3359609 in combination with pembrolizumab prolongs 
OS compared with pembrolizumab/placebo in participants with PD-L1 CPS 
≥20 R/M HNSCC. 
Progression-free Survival (PFS) 
• Hypothesis (H3): GSK3359609 in combination with pembrolizumab prolongs 
PFS by investigator assessment compared with pembrolizumab/placebo in 
participants with PD-L1 CPS ≥1 R/M HNSCC. 
The following key secondary hypotheses will be tested: 
Immune-based progression-free Survival (iPFS) 
• Hypothesis (H4): GSK3359609 in combination with pembrolizumab prolongs 
iPFS by investigator assessment compared with pembrolizumab/placebo in 
participants with PD-L1 CPS ≥1 R/M HNSCC.  


 
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Time to Deterioration (TTD) in Pain 
• Hypothesis (H5): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Pain (measured by EORTC IL51) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS ≥1 R/M HNSCC. 
• Hypothesis (H6): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Pain (measured by EORTC IL51) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS ≥20 R/M HNSCC. 
TTD in Physical Functioning 
• Hypothesis (H7): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Physical Functioning (measured by PROMIS PF 8c) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS ≥1 R/M HNSCC. 
• Hypothesis (H8): GSK3359609 in combination with pembrolizumab prolongs 
TTD in Physical Functioning (measured by PROMIS PF 8c) compared with 
pembrolizumab/placebo in participants with PD-L1 CPS ≥20 R/M HNSCC. 
The study is considered to have met the study primary objective if GSK3359609 in 
combination with pembrolizumab is superior to pembrolizumab with placebo on either 
PFS or OS in PD-L1 CPS ≥1 participants. 
2.1. 
Multiple Comparisons and Multiplicity 
The primary comparisons of interest are the comparisons between 
GSK3359609/pembrolizumab and placebo/pembrolizumab in PFS/iPFS in the PD-L1 
CPS ≥1 participants, as well as in OS, TTD in Pain, and TTD in PF in the PD-L1 CPS ≥1 
population and the PD-L1 CPS ≥20 population.  
The study employs the graphical method [Maurer, 2013] to provide strong multiplicity 
control for multiple hypotheses as well as interim analyses.  
The graphical approach is based on closed testing procedures using weighted group 
sequential Bonferroni tests for the intersection hypotheses. Under the mild monotonicity 
condition on the error spending functions which is met in this study, it allows the use of 
sequentially rejective graphical procedures in group sequential trials and controls the 
family wise error rate in the strong sense. By defining weighted directed graphs, it 
defines a weighting strategy between and within subfamilies which consist of a subset of 
null hypotheses each. 


 
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Figure 1 
Multiplicity Testing Strategy for Comparisons Between GSK3359609 
in Combination with Pembrolizumab and Pembrolizumab 
Administered with Placebo 
 
 
Abbreviations: CPS = combined positive score; H = hypothesis; I = GSK3359609; iPFS = progression-free 
survival per iRECIST; OS = overall survival; P = pembrolizumab; PF=physical function; PFS = 
progression-free survival per RECIST v1.1; PD-L1 = programmed cell death receptor 1-ligand 1; 
TTD=time to deterioration 
1. The alpha level assigned to a subfamily will be rolled over only if the hypotheses within the subfamily 
are all significant based on the weight for re-allocation presented on the dashed lines connecting 
subfamilies. Within each subfamily, the weights for reallocation from each hypothesis to the others are 
represented on the solid lines connecting hypotheses.  
2.  = 5/6 if both hypotheses in the OS subfamily (i.e. PDL1 CPS1 and PD-L1 CPS20 participants) are 
significant at the time of PFS/iPFS analyses; if the OS hypothesis is not significant in either population 
at the time of PFS/iPFS analyses, then  = 1 at the final OS analysis.  
The family-wise type I error for this study is strongly controlled at 2.5% (one-sided). 
Figure 1 shows the initial one-sided alpha-allocation for PFS/iPFS, OS, and key PRO 
endpoints. The multiplicity control strategy applies whether the study remains as a Phase 
II trial or expands to a Phase III trial.  
A one-sided alpha was chosen as, in this placebo-controlled study, pembrolizumab is 
given in both treatment arms. It is not expected that the combination of GSK3359609 and 
pembrolizumab would lead to a detrimental effect due to the active pembrolizumab on 
both arms and the favourable toxicity profile to date from the addition of GSK3359609 to 
the SoC. Although the one-sided testing is proposed, as described in Section 9.4.1.1 of 
the protocol, the 95% two-sided confidence intervals of the treatment effects (hazard ratio 
for time-to-event endpoints) will be reported, which would provide conclusions on the 
negative results if there is any statistically significant detrimental effect.  Section 6.2 
presents the algorithm and the associated application of the graphical testing strategy 
illustrated in Figure 1. The R package gMCP [Rohmeyer, 2011] is available to provide 
functions and graphical user interfaces for graph based multiple test procedures. 
The alpha re-allocation for PFS/iPFS, OS, and key PRO endpoints is further explained 
below.  
Overall Survival 
• An initial alpha level of 2.49% is allocated to the OS hypothesis in PD-L1 CPS ≥1 
participants.  


 
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• When PFS and iPFS test are both significant in PD-L1 CPS ≥1 participants, the 
OS hypothesis in PD-L1 CPS1 participants will be tested at 2.5% (re-allocated 
alpha). 
• OS in PD-L1 CP ≥20 participants is tested sequentially at the same overall alpha 
level if GSK3359609 in combination with pembrolizumab demonstrates 
superiority to pembrolizumab plus placebo in OS in PD-L1 CPS ≥1 participants. 
If OS is not significant in PD-L1 CPS ≥1 participants, the formal conclusion of 
statistical significance on OS in PD-L1 CPS ≥20 participants will not be drawn. 
The following alpha- and beta-spending functions are used in OS hypothesis of PD-L1 
CPS ≥1 participants and PD-L1 CPS ≥20 participants. 
• For the OS hypothesis, the alpha-spending function based on Lan-DeMets 
O’Brien-Fleming approximation spending function [Lan, 1983] and the beta-
spending function based on the Hwang-Shih-DeCani boundary method [Hwang, 
1990] with a gamma parameter of -20 are constructed to implement group 
sequential boundaries that control the type I error rate as well as allow for non-
binding futility analysis. Refer to Section 5.7.2 for details in the information 
fractions. 
There is a total of 2 OS analyses in each of the PD-L1 CPS ≥1 and CPS ≥20 participants. 
Section 5.7.2 demonstrates the bounds and boundary properties for OS hypothesis testing.  
Efficacy boundaries and non-binding futility boundaries are based on initially assigned 
type I error rate before any alpha re-allocation and projected number of events at study 
milestones. The actual boundaries will be determined from the actual number of events at 
the time of the specified interim analysis using the alpha- and beta- spending functions. 
Actual futility bounds will be updated if overall beta is changed with respect to alpha 
roll-over. 
Progression-free Survival/Immune-based progression-free Survival 
• An initial alpha level of 0.01% is allocated to the PFS hypothesis in PD-L1 CPS 
≥1 participants.  
• When OS hypotheses in both populations (PD-L1 CPS1 participants and PD-L1 
CPS 20 participants) are significant at the time of the OS interim analysis, the 
PFS hypothesis in PD-L1 CPS ≥1 participants may be tested at 0.425% (re-
allocated alpha). 
• If the PFS hypothesis in PD-L1 CPS 1 is significant, the hypothesis of iPFS in 
PD-L1 CPS 1 will be tested sequentially at the same alpha level.  
Key Patient Reported Outcomes (TTD in Pain, TTD in PF) 
• Only if GSK3359609 in combination with pembrolizumab demonstrates 
superiority to pembrolizumab plus placebo in OS in both populations (PD-L1 
CPS ≥1 participants and PD-L1 CPS ≥20 participants), will key secondary PRO 
endpoints be tested. The alpha level from OS hypothesis will be propagated to key 
PRO hypotheses. 


 
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• If OS meets superiority in both populations at the time of the OS interim analysis, 
a total of 2.075% alpha level will be propagated to key PRO hypotheses.  
• If OS meets superiority in both populations at the time of the final OS analysis but 
PFS or iPFS fails to demonstrate superiority in PD-L1 CPS 1 participants, a total 
of 2.49% alpha level will be propagated to key PRO hypotheses.  
• If OS meets superiority in both populations at the time of the final OS analysis 
and PFS and iPFS both demonstrate superiority in PD-L1 CPS 1 participants, a 
total of 2.5% alpha level will be propagated to key PRO hypotheses. 
• The alpha level propagated from OS will be equally split between TTD in Pain 
and TTD in PF in PD-L1 CPS ≥1 participants, with the possibility to further 
propagate the levels between each other. 
• If one of two key PRO hypotheses in PD-L1 CPS ≥1 participants is rejected based 
on the re-allocated alpha level, the key PRO hypotheses in PD-L1 CPS ≥20 
participants can be tested based on the (updated) weight, with the possibility to 
further propagate the levels between each other. 
• Based on the re-allocated cumulative alpha level, the nominal significance level 
for each key PRO endpoint will be calculated based on the Lan-DeMets O’Brien-
Fleming approximation alpha-spending function. 
3. 
SAMPLE SIZE DETERMINATION 
The 2-in-1 adaptive Phase II/III study design [Chen, 2018] allows expanding the Phase II 
study seamlessly into a Phase III confirmatory study; refer to Section 4 of the protocol for 
details of the study design. 
The Phase II study will randomize approximately 374 participants with a 1:1 ratio 
between the GSK3359609 in combination with pembrolizumab arm and the 
pembrolizumab/placebo arm. The study is event-driven, and the sample size calculation 
is driven by overall survival events.  
Assuming the prevalence rate of PD-L1 CPS ≥20 among the PD-L1 CPS ≥1 population is 
53%, a sample size of 374 PD-L1 CPS 1 participants will provide approximately 198 
PD-L1 CPS 20 participants. 
A long-term survival benefit, observed as a long-lasting plateau towards the tail of the 
survival curve, and a delayed treatment effect, observed as a late separation in survival 
curves between the experimental and control arms; have been reported in randomized 
clinical trials among participants treated with immuno-oncology drugs.  
Given the OS data reported in the KN-048 clinical trial, a long-term survival benefit in 
the pembrolizumab/placebo arm and potential non-proportional hazards with a delayed 
treatment effect are anticipated. Refer to protocol Section 9.2 for details, including power 
calculation and sample size assumptions. 


 
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Remain as a Phase II Study 
The final OS analysis in the PD-L1 CPS 1 and CPS 20 participants for a Phase II study 
(i.e. without expansion) will be carried out after approximately 244 deaths in PD-L1 CPS 
1 participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm, barring early stopping for 
futility or efficacy. It is expected that approximately 113 deaths in PD-L1 CPS 20 
participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm.  
With the above numbers of events and before any alpha re-allocation, the study provides 
a 79.8% power in the PD-L1 CPS ≥1 participants and a 60% power in the PD-L1 CPS 
≥20 participants to demonstrate superiority of OS of GSK3359609 in combination with 
pembrolizumab relative to pembrolizumab plus placebo at the pre-specified initial alpha 
(one-sided) level of 2.49%. 
The estimated numbers of PFS/iPFS events for a Phase II study at the final PFS 
evaluation are estimated to be 281 in the PD-L1 CPS ≥1 participants.  
The estimated number of PFS/iPFS events in the PD-L1 CPS ≥1 participants provides a 
67.6% power for detecting a HR of 0.61 in PFS/iPFS in the PD-L1 CPS ≥1 participants at 
the alpha level of 0.01% (one-sided).  
Expand to a Phase III Study 
Should expanding the Phase II study into a Phase III be decided, a total of 600 
participants will be randomized in a 1:1 ratio between the GSK3359609 in combination 
with pembrolizumab arm and the pembrolizumab/placebo arm, including those 
participants already enrolled. Participants already used for the decision making in the 
ongoing study will be included in Phase III analyses. The Phase III study will have 
overall sample size of 600 participants. Assuming the aforementioned prevalence rate of 
PD-L1 CPS status, a sample size of 600 participants with PD-L1 CPS 1 status will 
provide 318 PD-L1 CPS 20 participants. 
The final OS analysis in the PD-L1 CPS 1 and CPS20 participants for a Phase III study 
(i.e. with expansion) will be carried out after approximately 367 deaths in the PD-L1 CPS 
1 participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm, barring early stopping for 
futility or efficacy. It is expected that approximately 171 deaths in PD-L1 CPS 20 
participants have occurred between the GSK3359609 in combination with 
pembrolizumab arm and the pembrolizumab/placebo arm.  
With the above numbers of OS events and before any alpha re-allocation, the study 
provides a 90.1% power in the PD-L1 CPS ≥1 participants, and a 73.5% power in the 
PD-L1 CPS ≥20 participants to demonstrate superiority of OS of GSK3359609 in 
combination with pembrolizumab relative to pembrolizumab plus placebo at the pre-
specified initial alpha (one-sided) level of 2.49%. 


 
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The estimated numbers of PFS/iPFS events for a Phase III study (i.e. with expansion) at 
the final PFS evaluation are estimated to be 432 in the PD-L1 CPS ≥1 participants.  
The estimated number of PFS/iPFS events in the PD-L1 CPS ≥1 participants provides a 
92.5% power for detecting a HR of 0.61 in PFS/iPFS in the PD-L1 CPS ≥1 participants at 
the alpha level of 0.01% (one-sided).  
3.1. 
Sample Size Sensitivity 
In the case that there is no violation of the proportional hazards in OS between 
GSK3359609 in combination with pembrolizumab and the pembrolizumab/placebo arm 
throughout the entire course of the study; the powers in OS for PD-L1 CPS 1 and PD-
L1 CPS 20 participants are summarized in protocol Section 9.2.3. 
4. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened 
• All participants who sign the ICF. 
• Study population  
Enrolled 
• All participants who entered the study.  
• Participants who were randomized or 
dosed in error are included in the 
enrolled population. 
• Note that screening failures (who never 
passed screening even if rescreened) 
and participants screened but never 
enrolled into the study (Reserve, Not 
Used) are excluded from the Enrolled 
analysis set as they did not enter the 
study. 
• This population will be based on the 
study intervention the participant was 
randomized to. 
• Study population  
Modified Intent-
To-Treat (mITT) 
• All randomized participants whether or 
not randomized intervention was 
administered, excluding those who 
were first dosed or randomized after 
the date of dear investigator letter 
(DIL) requesting immediate 
discontinuation of GSK3359609 
/placebo. The date of the DIL is the 
13th April.  
• This analysis set will be based on the 
study intervention to which the 
participant was randomized and will be 
the primary analysis set for the analysis 
of efficacy data. 
• Study population 
• Efficacy 


 
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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
• Any participants who receives a study 
intervention randomization number 
will be considered to have been 
randomized. 
Safety 
• All randomized participants who take 
at least 1 dose of study intervention. 
• Participants will be analyzed according 
to the actual study intervention 
received. 
• Participants will be assigned to the 
actual study intervention group of 
GSK3359609 + Pembrolizumab if the 
participant received any dose of 
GSK3359609. 
• Safety  
• Immunogenicity 
COVID-19 
• All participants in the Safety set who 
had a confirmed, probable or suspected 
COVID-19 case diagnosis. 
 
• Baseline 
Characteristics, 
COVID-19 
Assessments, 
Treatment 
Compliance and 
Exposure, 
Medical History 
and Laboratory 
Data 
IA1  
• All randomized participants whether or 
not randomized intervention was 
administered, who have a minimum of 
22 weeks follow-up from date of 
randomization to the time of data cut 
off, regardless of death or study 
withdrawal.   
• This analysis set will be based on the 
study intervention to which the 
participant was randomized to. 
• IA1 efficacy 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized for the mITT analysis set. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorized in the protocol deviations SDTM dataset.  


 
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o This dataset will be the basis for the summaries of important protocol deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the eCRF. 
5. 
STATISTICAL ANALYSES 
5.1. 
General Considerations 
5.1.1. 
General Methodology 
The modified Intent-to-Treat (mITT) analysis set will be used for all study population 
analyses, efficacy analyses and PRO analyses, unless otherwise specified. The safety 
analysis set will be used for all safety analyses, unless otherwise specified. 
Stratified statistical analyses (the stratified logrank test, the stratified Cox model and the 
stratified max-combo test) will be based on the following stratification factors, PD-L1 
expression (CPS ≥20 vs. 1≤ CPS <20), and HPV status (positive vs. negative). 
Participants with oropharynx HPV negative/unknown and non-oropharyngeal tumors will 
be combined as the HPV negative group in the stratified analyses. The analyses will be 
performed based on the data collected in Interactive Response Technology (IRT) at 
randomization will be used, even if it is subsequently discovered that these values were 
incorrect.  
In the case of a substantial amount of wrong stratification assigned at the time of 
randomization, a sensitivity analysis may be performed based on the data collected in the 
CRF (or vendor data if collected outside of eCRF). 
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (std), median, minimum and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
Unless otherwise specified, subsequent anticancer therapy will include systemic 
anticancer therapy, follow-up radiotherapy that is not palliative, or on treatment or 
follow-up cancer-related surgery/procedures that are not palliative or diagnostic in nature.   
5.1.2. 
Baseline Definition 
For all endpoints unless otherwise specified 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 participants who did not receive study treatment during the study, baseline 
will be defined as the latest, non-missing collected value. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 


 
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5.1.3. 
Multicenter Studies 
In this multicenter global study, enrollment will be presented by country and site. 
Data from all participating centers will be integrated and no controlling for center-effect 
will be considered in the statistical analyses. It is anticipated that participant accrual will 
be spread thinly across centers and summaries of data by center would unlikely be 
informative and will not be provided. 
5.2. 
Primary Endpoint(s) Analysis 
5.2.1. 
Definition of Endpoint(s) 
Overall Survival (OS) 
Overall Survival (OS) is defined as the interval of time from the date of randomization to 
the date of death due to any cause. 
 
Participants without documented death will be censored at last known alive date. The last 
date will be determined by the maximum collection/assessment date from among selected 
data domains within the clinical database; details will be provided in a separate Output 
and Programming Specification (OPS) document. When calculating overall survival, all 
deaths including those following subsequent anti-cancer therapy will be included. 
Progression-Free-Survival per RECIST v1.1 
Progression-free-survival (PFS) per RECIST v1.1 by investigator assessment is defined 
as the time from the date of randomization to the date of the first objectively documented 
disease progression per RECIST v1.1 based on investigator assessment, or death due to 
any cause, whichever occurs first. 
The date of disease progression is defined as the date of radiological disease progression 
based on imaging data per RECIST v1.1. For cases where symptomatic progression is 
documented by the investigator, the derived response based on tumor assessment data 
will be utilized.  
For participants who receive subsequent anticancer therapy, the following additional 
rules will apply: 
• If a participant has only a baseline visit or does not have an adequate post-baseline 
radiological assessment on or prior to the date of initiation of anticancer therapy, PFS 
will be censored at the date of randomization. 
• If anticancer therapy 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 radiological assessment on or prior to the initiation of anticancer therapy 
(i.e., if an assessment occurs on the same day as the start of new anticancer therapy, 
the assessment will be used as it is assumed that the assessment occurred prior to the 
administration of new anticancer therapy). The date of the last adequate radiological 
assessment will be used as the censoring date. 


 
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• If the start date of anticancer therapy is partial, the imputation rules described in the 
OPS will be applied. 
Since PFS is interval censored, extended loss to follow-up prior to PD or death increases 
the uncertainty when the event occurs. As such, PFS will be analyzed censoring for 
extended time without an adequate assessment to account for missed response 
assessments prior to disease progression or death. Specifically, if there are two or more 
assessments which are missing followed by an assessment of PD or death, PFS will be 
censored at the last adequate assessment prior to PD or death. 
A summary of the assignments for progression and censoring dates for the primary 
analysis of PFS per RECIST v1.1 is illustrated in Table 3.  


 
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Table 3 
Censoring Rules for Primary Analysis of PFS per RECIST v1.1 
Situation 
Primary Analysis 
No or incomplete baseline disease assessments 
and the participant has not died 
Censored at the date of randomization 
No adequate1 post-baseline disease assessments 
(prior to anticancer therapy, if initiated) and the 
participant has not died2 
Censored at the date of randomization 
With adequate1 post-baseline disease 
assessments, new anticancer treatment is not 
initiated, and no documented PD or death 
Censored at the date of last adequate1 radiological 
disease assessment 
With adequate1 post-baseline disease 
assessments before start of new anticancer 
therapy, and new anticancer treatment is 
initiated (prior to documented PD or death)3 
Censored at the date of last adequate1 radiological 
disease assessment on or prior to starting new 
anticancer treatment 
PD or death documented after 1 missed disease 
assessment4 
Progressed at the date of documented PD5 or death, 
whichever occurs first 
PD or death documented after 2 missed disease 
assessments4,6 
Censored at the date of last adequate1 radiological 
disease assessment prior to the 2 missed disease 
assessment7  
Abbreviations: CR=complete response; PD=progressive disease; PFS=progression-free survival; 
PR=partial response; RECIST=response evaluation criteria in solid tumors; SD=stable disease 
1. An adequate assessment is defined as an assessment where the investigator assessed response is CR, 
PR, or SD  
2. If participant has documented PD but no other adequate assessments, see scenarios below. 
3. If PD and new anti-cancer therapy occur on the same day, it is assumed that the progression was 
documented first (i.e., outcome is progression; the date is the date of the assessment for progression). 
4. The case where PD or death documented after the initiation of new anticancer treatment is described 
above and is not included in this situation. 
5. The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new 
lesion); or (ii) Date of radiological assessment showing unequivocal progression in non-target lesions, 
or (iii) Date of last radiological assessment of measured lesions (if progression is based on increase in 
sum of measured lesions). 
6. Refer to Section 6.3 for details in extended time without an adequate assessment. 
7. The date of randomization will be used if there are no adequate post-baseline assessments. 
5.2.2. 
Main Analytical Approach 
Due to early study termination, only the main analytical approaches using primary 
estimands will be completed for the main CSR. 
Overall Survival (OS) 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves for 
OS. Kaplan-Meier plots of OS will be presented by study intervention. Kaplan-Meier 
estimates for the median overall survival and the first and third quartiles will be 
presented, along with 95% CIs. CIs for quartiles will be estimated using Brookmeyer-
Crowley method (Brookmeyer, 1982). The treatment difference in survival will be 
assessed by the stratified log-rank test. 
A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The 
hazard ratio (HR) and its corresponding 95% confidence interval from the stratified Cox 


 
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model with a single treatment covariate will be reported separately for the PD-L1 CPS ≥1 
and CPS ≥20 group. 
OS in PD-L1 CPS ≥20 participants will be tested sequentially at the 2.49% alpha level if 
GSK3359609 in combination with pembrolizumab demonstrates superiority to 
pembrolizumab with placebo in OS in PD-L1 CPS 1 participants. If OS is not 
significant in PD-L1 CPS 1 participants, the formal conclusion of statistical significance 
on OS in PD-L1 CPS ≥20 participants will not be drawn.  
5.2.2.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
OS 
Model Specification 
• 
OS will be estimated using Kaplan-Meier analysis for each study intervention (PROC 
LIFETEST). The median, 25th and 75th percentiles of OS will be estimated and 
corresponding 95% Confidence intervals will be estimated using the Brookmeyer-Crowley 
method (Brookmeyer, 1982). 
• 
Comparison of distributions of OS between study interventions will be based on the stratified 
log-rank test (PROC LIFETEST).  
• 
A stratified Cox proportional hazard model with Efron's method of tie handling and study 
intervention as the sole explanatory variable will be used to assess the magnitude of the 
treatment difference (i.e., the hazard ratio) in OS between study interventions (PROC 
PHREG). 
Model Checking & Diagnostics 
• 
The proportional hazards assumption will be assessed prior to model fitting using the 
following methods: 
o Kaplan-Meier plot by study intervention: A non-parallel pattern is an indication of 
violation of the proportional hazard assumption. 
o Plot of log(-log(survival)) versus log(time) by study intervention: A non-parallel pattern is 
an indication of violation of the proportional hazard assumption. 
o Plot of Schoenfeld residuals versus time: A non-zero slope is an indication of a violation 
of the proportional hazard assumption. 
o Evaluation of time-dependency of treatment effect by adding an interaction term of 
treatment and time in the Cox model. If the interaction term is significant (p< 0.05), it is 
considered that the proportional hazards assumption is violated. 
If one or more of the procedures above demonstrates clear violation of the proportional hazards 
assumption in OS, it is considered the proportional hazards assumption does not hold. Hazard 
ratio and corresponding 95% CI estimated from the Cox model will still be reported.  
Model Results Presentation 
• 
Kaplan-Meier estimates for the median overall survival and the first and third quartiles will be 
presented, along with 95% CIs.  
• 
The p-value from the stratified log-rank test will be reported. 
• 
The hazard ratio and the corresponding 95% confidence interval from the Cox model will be 
reported. 


 
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Subgroup Analyses 
• 
The stratified log-rank test and Cox proportional hazard model proportional hazard model 
analysis will be repeated in the subgroup analyses defined in Section 5.2.5 if data permit.  
Progression-Free Survival per RECIST v1.1 (PFS) 
A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The 
hazard ratio and its 95% confidence interval from the stratified Cox model with a single 
treatment covariate will be reported for PD-L1 CPS ≥1 and PD-L1 CPS ≥20 participants. 
Kaplan-Meier plots of PFS will be presented by study intervention. Summaries of 
number and percentage of participants experiencing a PFS event and the type of event 
(PFS per RECIST v1.1 or death) will be provided along with median PFS and the first 
and third quartiles and 95% CIs for each treatment.  
5.2.2.2. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
PFS per RECIST v1.1 based on investigator assessment 
Model Specification 
• 
PFS will be analyzed across study interventions using Kaplan-Meier analysis (PROC 
LIFETEST). The median, 25th and 75th percentiles of PFS will be estimated and 
corresponding 95% Confidence intervals will be estimated using the Brookmeyer-Crowley 
method (Brookmeyer,1982). 
• 
Comparison of distributions of PFS between study interventions will be based on the 
stratified log-rank test (PROC LIFETEST).  
• 
A stratified Cox proportional hazard model with Efron's method of tie handling and study 
intervention as the sole explanatory variable will be used to assess the magnitude of the 
treatment difference (i.e., the hazard ratio) in PFS between the study interventions (PROC 
PHREG). 
Model Checking & Diagnostics 
• 
The proportional hazards assumption will be assessed prior to model fitting using the 
following methods: 
o Kaplan-Meier plot by study intervention: A non-parallel pattern is an indication of 
violation of the proportional hazard assumption. 
o Plot of log(time) against log(-log(survival)) by study intervention: A non-parallel pattern is 
an indication of violation of the proportional hazard assumption. 
o Plot of Schoenfeld residuals for treatment: A non-zero slope is an indication of a 
violation of the proportional hazard assumption. 
o Evaluation of time-dependency of treatment effect by adding an interaction term of 
treatment and time in the Cox model. If the interaction term is significant (p< 0.05), it is 
considered that the proportional hazards assumption is violated. 
• 
If one or more of the procedures above demonstrates clear violation of the proportional 
hazards assumption in PFS, it is considered the proportional hazards assumption does not 
hold. Hazard ratio and corresponding 95% CI estimated from the Cox model will still be 
reported.  


 
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Model Results Presentation 
• 
Kaplan-Meier estimates for the median PFS and the first and third quartiles will be 
presented, along with 95% CIs.  
• 
The p-value from the stratified log-rank test will be reported. 
• 
Hazard ratio and corresponding 95% confidence interval from the Cox model will be 
reported. 
5.2.3. 
Sensitivity Analyses 
Due to early study termination, sensitivity analyses will not be performed for the main 
CSR.  
5.2.4. 
Supplementary Analyses 
Due to early study termination, supplementary analyses will not be performed for the 
main CSR.  
5.2.5. 
Subgroup analyses 
Due to early study termination and minimal available data, subgroup analyses will not be 
performed for the main CSR.  
5.3. 
Secondary Endpoint(s) Analysis 
5.3.1. 
Key/Confirmatory Secondary Endpoint(s) 
5.3.1.1. 
Definition of Endpoint 
Progression-Free Survival per iRECIST (iPFS) 
Progression-free survival per iRECIST (iPFS) is one of the key secondary endpoints of 
this study. It is defined as the interval of time from the date of randomization to the date 
of the first documented disease progression confirmed consecutively per iRECIST based 
on investigator assessment, or death due to any cause, whichever occurs first. 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the 
terms unconfirmed progressive disease (iUPD) and confirmed progressive disease 
(iCPD).  
The progression event date (iPD date) to be used in the calculation of PFS per iRECIST 
should be the first date of documented iUPD provided that iCPD is confirmed at the next 
assessment.  
If more than one assessment is recorded as iUPD then the final occurrence prior to iCPD 
will be used. The exception to the rule would be when consecutive iUPDs followed by 
iCPD, the first occurrence of iUPDs in a row prior to iCPD will be used. For example, if 
a participant has iUPD at time points 1 and 2 and iCPD at time point 3, then iPD date 
would be the date of time point 1. If iUPD occurs, but is disregarded because of later iSD, 
iPR, or iCR, that iUPD date should not be used as the progression event date. 


 
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If progression is not confirmed and there is no subsequent iSD, iPR, or iCR, then the 
iUPD date will be used as iPD date in the following scenarios: 
• Participant discontinues study intervention because the participant was judged not 
to be clinically stable  
• Participant does not undergo further response assessments due to any reason (i.e., 
participant refusal, protocol non-compliance, or participant death) 
• Next timepoint response of iUPD, and iCPD never occurs 
For the purpose of confirmation of progression per iRECIST, assessments that are not 
done or are not evaluable will be disregarded and the next evaluable assessment be 
considered the ‘next assessment’. For example, an iUPD followed by an assessment that 
was not done or not evaluable, and then another unconfirmed progressive disease 
qualifying for the criteria of iCPD, would be indicative of iCPD. 
Determination of dates of iPFS events and dates for censoring in the iPFS analysis are 
summarized in Table 4.  


 
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Table 4 
Censoring Rules for Analysis of iPFS 
Situation 
Primary Analysis 
No or incomplete baseline disease assessments 
and the participant has not died 
 
Censored at the date of randomization 
No post-baseline disease assessments and the 
participant has not died 
Censored at the date of randomization 
With post-baseline disease assessments,  
new anticancer treatment is not initiated, and no 
iPD date or death 
Censored at the date of last adequate2 radiological 
disease assessment 
With post-baseline disease assessments,  
new anticancer treatment is initiated (prior to iPD 
date or death)1  
Censored at the date of last adequate2 radiological 
disease assessment on or prior to starting new 
anticancer treatment 
iPD date or death after 1 missed disease 
assessment4 
Progressed at iPD date3 or death 
iPD date or death documented after 2 missed 
disease assessments4,5 
Censored at the date of last adequate radiological 
disease assessment prior to the 2 missed disease 
assessment  
Abbreviations: iPD=immune-based progressive disease; iPFS=progression-free survival per iRECIST 
1. 
If iPD and new anti-cancer therapy occur on the same day, it is assumed that the progression was 
documented first (i.e. outcome is progression; the date is the date of the assessment for progression). 
2. 
An adequate assessment is defined as an assessment where the investigator assessed response is iCR, 
iPR, or iSD  
3. 
The earliest date of radiological assessments of lesion in which progression criteria are met for the 
iPD. 
4. 
The case where iPD date or death documented after the initiation of new anticancer treatment is 
described above and is not included in this situation. 
5. 
Refer to Section 6.3 for details in extended time without an adequate assessment. 
Time to Deterioration (TTD) in Pain and Physical Function (PF) 
Time to deterioration (TTD) is defined as the time from randomization to the first 
definitive meaningful deterioration from baseline in the EORTC IL51 pain domain score 
and the TTD in Physical Function (PF) score. Deterioration is defined as an increase in 
the EORTC IL51 pain domain and a decrease in physical function as measured by the 
PROMIS PF 8c. Specifically, the deterioration has to be: 
- 
Meaningful, i.e. greater than a clinically meaningful within-individual change in 
score, as defined below; 
- 
Definitive, i.e. all subsequent assessment of the score are also showing a clinically 
meaningful deterioration compared with baseline, or no further score is available 
for the participants for any reason (including discontinuation, disease progression 
or death). 
Participants who don’t show meaningful deterioration will be censored at the time of the 
last available PRO assessment within the pain domain of EORTC IL51 for TTD in pain 
or within PROMIS PF 8c for TTD in PF. For TTD in pain or TTD in PF, the 
determination of dates of deterioration events and dates for censoring are summarized in 
Table 5.  


 
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Table 5 
Censoring Rules for Analysis of TTD 
Situation 
Primary Analysis 
No or incomplete baseline corresponding PRO 
assessments 
Censored at the date of randomization 
No post-baseline corresponding PRO 
assessments  
Censored at the date of randomization 
With post-baseline corresponding PRO 
assessments, new anticancer treatment is not 
initiated, and no deterioration 
Censored at the date of last available corresponding 
PRO assessment 
With post-baseline corresponding PRO 
assessments,  
and new anticancer treatment is initiated (prior 
to deterioration)1 
Censored at the date of last available corresponding 
PRO assessment on or prior to starting new 
anticancer treatment 
Deterioration after 1 missed corresponding 
PRO assessment2 
Deteriorated at the date of deterioration 
Deterioration after 2 missed corresponding 
PRO assessments if at least one missed 
assessment is due to the participant being too 
ill2,3  
Censored at the date of last available corresponding 
PRO assessment prior to the 2 missed 
corresponding PRO assessment  
1. If deterioration and new anti-cancer therapy occur on the same day, it is assumed that the deterioration 
was documented first (i.e. outcome is deterioration; the date is the date of deterioration). 
2. The case where deterioration observed after the initiation of new anticancer treatment is described 
above and is not included in this situation. 
3. In the case of deterioration after 2 missed corresponding PRO assessments and all missed 
assessments are due to reason other than that participant is too ill, it censors at the date of last 
corresponding PRO assessment on or prior to starting new anticancer treatment as the situation of with 
post-baseline corresponding PRO assessments, and new anticancer treatment is initiated (prior to 
deterioration), i.e. missing corresponding PRO assessments are ignored in this case. Refer to Section 
6.3 for details in extended time without an adequate assessment. 
As no threshold for meaningful within-individual change is established for the EORTC 
IL51 pain domain score or PROMIS PF 8c score, the value for use in the TTD analyses 
will be determined using pooled blinded data from study 209229 and 209227. The 
threshold may be finalised following study database lock and will be reported in the main 
CSR. The full procedure for determination of meaningful within-person change in 
EORTC IL51 pain domain score and PROMIS PF 8c score will be fully described  in a 
standalone SAP. It will include using an anchor-based approach that utilizes the patient 
global impression of severity and change as an anchor, and possibly other clinical 
anchors (e.g. ECOG status). Supportive distribution-based methods may be applied as the 
sensitivity analysis. 
5.3.1.2. 
Main analytical approach 
Progression-free-survival per iRECIST 
If the PFS hypothesis in PD-L1 CPS1 is significant, the hypothesis of iPFS in PD-L1 
CPS1 will be tested sequentially at the same alpha level. The statistical analysis and 
reporting of iPFS follows the same method as PFS described in Section 5.2.2. Censoring 
rules for PFS per iRECIST are given in Table 4. 


 
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Time to Deterioration (TTD) in Pain and Physical Function (PF) 
The time to deterioration (TTD) in Pain measured by the EORTC IL51 pain domain and 
the TTD in Physical Function (PF) measured by the PROMIS PF 8c will be analyzed 
separately for the PD-L1 CPS ≥ 1 and CPS ≥ 20 group using the non-parametric Kaplan-
Meier method. Kaplan-Meier plots of TTD will be presented by study intervention. 
Kaplan-Meier estimates for the median TTD and the first and third quartiles will be 
presented, along with 95% CIs. CIs for quartiles will be estimated using the Brookmeyer-
Crowley method (Brookmeyer, 1982). The TTD for both treatment groups will be 
compared by the stratified log-rank test. 
A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The 
hazard ratio and its 95% confidence interval from the stratified Cox model with a single 
treatment covariate will be reported separately for the PD-L1 CPS ≥ 1 and CPS ≥ 20 
group. Participants with no post-baseline assessments will be considered censored at day 
1 and participants without definitive meaningful clinical deterioration for the PRO score 
will be treated as censored for that PRO score at the last visit.  
Only if GSK3359609 in combination with pembrolizumab demonstrates superiority to 
pembrolizumab plus placebo in OS in both populations (PD-L1 CPS ≥1 participants and 
PD-L1 CPS ≥20 participants), will key secondary PRO endpoints be tested. The alpha 
level from OS hypothesis will be propagated to key PRO hypotheses as described in 
Section 2.1. 
5.3.2. 
Supportive Secondary Endpoint(s) 
PFS per RECIST v1.1 and iPFS in PD-L1 CPS ≥20 
PFS per RECIST v1.1 and iPFS in PD-L1 CPS ≥20 participants will be analyzed and 
reported similarly to the primary analysis of PFS and iPFS in PD-L1 CPS ≥1 participants 
as described in Section 5.2.2 and Section 5.3.1.2 respectively. 
OS rate at 12 and 24 months 
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. 
OS rate at 12 months and 24 months and the corresponding 95% CI will be estimated 
from the Kaplan-Meier analysis will be reported separately for the PD-L1 CPS ≥1 and 
CPS ≥20 group.  The confidence intervals will be based on the Brookmeyer-Crowley 
method (Brookmeyer, 1982). 
If no participants have follow-up duration exceeding the OS milestone, the corresponding 
summary will not be produced.  
A supportive summary of the duration of follow-up will also be produced, presenting the 
minimum, maximum, median and 25th and 75th percentiles.  


 
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Objective Response Rate (ORR) and Disease Control Rate (DCR) per RECIST v1.1 
Best Overall Response (BOR) 
• The best overall response is the best response recorded from the date of 
randomization until disease progression or initiation of new anti-cancer therapy, 
whichever is earlier, as assessed by the investigator per RECIST v1.1. The order 
from best to worst of the available responses is CR, PR, stable disease (SD), 
progressive disease (PD) and not evaluable (NE).  
• As a randomized double-blind study in which primary endpoints are OS and PFS, 
the confirmation of CR and PR is not required. 
• A subject without any adequate post-baseline assessments will have a BOR of NE. 
• To be assigned a status of SD as the best overall response, the minimum criteria for 
SD duration must be met. Since disease assessment starts at week 9 and a window 
of  7 days is allowed, 56 days since the date of randomization will be used as the 
minimum criteria for SD duration.  
ORR per RECIST v1.1 is defined as the proportion of the participants who have a 
complete response (CR) or partial response (PR) as the best overall response per RECIST 
v1.1 based upon investigator assessment. 
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 the percentage of participants with SD durability 
meeting the minimum time of 15 weeks per RECIST v1.1 based upon investigator 
assessment. A status of SD≥15 weeks will be assigned if the follow-up disease 
assessment has met the SD criteria at least once after the date of randomization at a 
minimum of 14 weeks (98 days) considering a one-week visit window. 
The number and percentage of participants achieving BOR of CR, PR, SD, PD, NE, as 
well as those meeting SD durability requirements (SD≥15 weeks) will be provided 
separately for the PD-L1 CPS ≥1 and CPS ≥20 participants.  
The number and percentage of participants achieving ORR and DCR per RECIST v1.1 
will be provided separately for the PD-L1 CPS ≥1 and CPS ≥20 participants. The 2-sided 
95% exact (Clopper-Pearson) confidence limits for the binomial proportion will also be 
included.  
Stratified Miettinen and Nurminen’s method will be used for comparison of the 
ORR/DCR between two treatment groups. The difference in ORR/DCR and its 95% 
confidence interval from the stratified Miettinen and Nurminen’s method with strata 
weighting by sample size [Chow, 2003] (i.e. where larger strata carry more weight as 
compared to smaller strata) with a single treatment covariate will be reported separately 
for the PD-L1 CPS ≥1 and CPS ≥20 participants. 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. 


 
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Duration of Response (DoR) per RECIST v1.1 
Duration of response (DoR) per RECIST v1.1 is defined as the time from first 
documented evidence of CR or PR until first documented disease progression per 
RECIST v1.1 based upon investigator assessment or death due to any cause, whichever 
occurs first, among participants who demonstrated CR or PR as the best overall response 
per RECIST v1.1. Censoring rule will follow those for the primary analysis of PFS per 
RECIST v1.1.  
If the number of participants with a best overall response of CR or PR permits, the 
Kaplan-Meier method will be used to estimate the survival curves for DoR per RECIST 
v1.1.  The Kaplan-Meier estimates for the median DoR and the first and third quartiles, 
along with 95% CIs estimated using the Brookmeyer-Crowley method (Brookmeyer, 
1982) will be reported separately for the PD-L1 CPS ≥1 and CPS ≥20 group by study 
intervention. 
Adverse Events/Serious Adverse Events 
The safety analyses will be based on the safety analysis set, unless otherwise specified.  
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards.  
An overview summary of AEs, including but not limited to, counts and percentages of 
participants with any AE, AEs related to study intervention, Grade 3+ AEs, Grade 3+ 
AEs related to study intervention, AEs leading to permanent discontinuation of study 
intervention, study intervention related AEs leading to permanent discontinuation of 
study intervention, AEs leading to dose delays, SAEs, SAEs related to study intervention, 
fatal SAEs, and fatal SAEs related to study intervention and AESIs will be produced. 
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Affairs (the latest MedDRA dictionary version at the time of reporting) and graded by the 
investigator according to the NCI-CTCAE v5.0 [NCI, 2017].   
A summary of number and percentage of participants with any adverse events by 
maximum grade will be produced. AEs will be sorted by System Organ Class (SOC) and 
Preferred term (PT) in descending order. 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 
grade. 
• 
Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum grade no matter how many events they have. 
The frequency and percentage of AEs (all grades) will also be summarized and displayed 
in descending order by PT only.  
A separate summary will be provided for study intervention-related AEs by PT and 
maximum grade. A study intervention-related AE is defined as an AE for which the 


 
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investigator classifies the possible relationship to study intervention as “Yes”. A 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 intervention as ‘Yes’ or missing.  
All SAEs will be tabulated based on the number and percentage of participants who 
experienced the event by SOC and PT. A separate summary will also be provided for 
study intervention-related (fatal and non-fatal) SAEs. The summary tables will be 
displayed by PT.   
A study intervention-related SAE is defined as an SAE for which the investigator 
classifies the relationship to study intervention as “Yes”. 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 intervention as ‘Yes’ or missing. 
A summary of fatal AEs by PT will also be produced. 
A summary of non-serious AEs that occurred in strictly 5% of the participants or above 
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 by System Organ Class (SOC) and Preferred Term (PT) in descending 
order of total incidence. 
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced.  
Adverse Events of Special Interest (AESI) 
The summary of event characteristics will be provided for each AESI (refer to protocol 
for details) respectively, including number of participants with any event, number of 
events, number of participants with any event that is serious, number of participants with 
any event that is related to study intervention, number of occurrences (one, two, three or 
more), maximum grade, outcomes and the action taken for the event. 
The percentage will be calculated in two ways, one with number of participants with 
event as the denominator and the other with total number of participants as the 
denominator.   
The worst-case approach will be applied at participant level for the maximum grade, i.e. a 
participant will only be counted once as the worst-case from all the events experienced by 
the participant.  
For action taken to an event, a participant will be counted once under each action. 
Summary statistics showing the time to onset and the duration of the first occurrence for 
AESI may also be presented as appropriate. 
Dose Modifications 
The summaries of dose modifications (dose interruptions, missed doses and dose delays) 
will be provided if the data warrant. All the dose interruptions, missed doses and dose 
delays will be listed separately if data warrant. 


 
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Dose interruptions will be summarized by number of interruptions and reasons for 
interruption.  
5.4. 
Tertiary/Exploratory Endpoint(s) Analysis 
Due to early study termination, with the exception of the below endpoints, exploratory 
endpoint analyses will not be performed.  
5.4.1. 
Pharmacodynamic and Biomarker Analyses 
The pharmacodynamic and biomarker analysis as well as germline genetic evaluation 
may be performed. If performed, these may be defined separately in an independent 
analysis plan and reported outside of the main CSR.   
5.5. 
Other Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
A final CSR at the end of study will contain only key safety analyses and will be 
conducted after LSLV for the final CSR. Details around which safety outputs will be 
created for the final CSR will be provided in the OPS.  
5.5.1. 
Extent of Exposure 
Extent of exposure to GSK3359609 and Pembrolizumab will be summarized separately 
and overall, for the Safety Set. 
The number of study intervention cycles administered will be summarized with mean, 
median, standard deviation, minimum, and maximum. The number and percentage of 
participants who received a given number of cycles (<4, 4-6, and >6) will be reported. 
Dose intensity (dose delivered per 3-week period on treatment) will be summarized using 
mean, median, standard deviation, minimum, and maximum. 
Missed doses will be summarized. Dose delays will be summarized by number of delays, 
reasons for the delays, and delay duration (days). The mean, standard deviation, median, 
minimum value, and maximum value will be computed for the duration of delay as well 
as the number and percentage of the delays ≤21, 22-42, and >42 days.  
The duration of exposure to study intervention (days) will be calculated and summarized 
using mean, median, standard deviation, minimum, and maximum.  
5.5.2. 
Deaths 
All deaths will be summarized based on the number and percentage of participants. This 
summary will classify participants by time of death relative to the last dose of medication 
(>30 days or ≤30 days) and analyze the primary cause of death in the order listed in the 
CRF. The relationship to COVID-19 infection will also be summarised. A supportive 
listing will be generated to provide participant-specific details on participants who died.  


 
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5.5.3. 
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events 
The following categories of AEs will be summarized separately in descending order of 
total incidence by PT only and separate supportive listings will be generated with 
participant level details for those participants: 
• 
AEs leading to discontinuation of study treatment  
A listing of all other significant adverse events will be produced. 
5.5.4. 
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, or the female partner of a male participant becomes pregnant during the study, 
the information will be included in the narratives and no separate table or listing will be 
produced. 
5.5.5. 
Additional Safety Assessments  
Laboratory evaluations including the analyses of chemistry, hematology, coagulation, 
cardiac function, thyroid function and routine urinalysis laboratory tests and other 
screening tests will be based on GSK Core Data Standards.  
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of participants with non-missing value at each 
particular visit. 
5.5.5.1. 
Laboratory Data 
The assessment of laboratory toxicities will examine the laboratory tests listed in 
Appendix 2 in the protocol. Laboratory grades will be evaluated using CTCAE v5.0. 
However, some tests are not graded using CTCAE. For hematology, Red Blood Cell 
(RBC) is not gradable by CTCAE v5.0. For clinical chemistry, BUN and creatinine 
clearance are not gradable by CTCAE v5.0. For sodium, potassium, calcium, glucose, 
and magnesium there will be two bi-directional parameters (hyper and hypo) created and 
the tests will be graded by CTCAE v5.0 in both directions. 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
chemistry, hematology, coagulation and thyroid function lab tests that are gradable by 
CTCAE v5.0. These summaries will display the number and percentage of participants 
with a maximum post-baseline grade increasing from their baseline grade. Any increase 
in grade from baseline will be summarized along with any increase to a maximum grade 
of 3 and any increase to a maximum grade of 4. Missing baseline grade will be assumed 
as grade 0. For laboratory tests that are graded for both low and high values, summaries 
will be done separately and labelled by direction, e.g., sodium will be summarized as 
hyponatremia and hypernatremia separately. 


 
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Liver function laboratory tests will be included with chemistry lab tests. A listing of liver 
monitoring/stopping events will also be produced, where appropriate. 
Hepatobiliary laboratory events including possible Hy’s law cases will be provided in 
addition to what has been described above. Possible Hy’s law cases are defined as any 
elevated alanine aminotransferase (ALT) ≥3×upper limit of normal (ULN) and total 
bilirubin ≥2×ULN, or ALT≥3×ULN and INR>1.5.  Hy’s law cases where ALT ≥3×ULN 
and total bilirubin ≥2×ULN, with alkaline phosphatase (ALP) <2×ULN at the time of 
bilirubin elevation will also be considered. Total bilirubin ≥2×ULN can be within 28 days 
following the ALT elevation and if direct bilirubin is available on the same day, it must 
be >35% of total bilirubin.  
5.5.5.2. 
Vital Signs 
Summaries of grade increase in systolic blood pressure (SBP) and diastolic blood 
pressure (DBP) will not be produced.   
5.5.5.3. 
ECG 
A 12-lead ECG will be performed at Screening to calculate the heart rate and 
measurements such as PR, QRS, and QT intervals. ECG after Screening will be 
performed as clinically indicated. Data will not be summarized. 
5.5.5.4. 
Performance Status 
ECOG performance status will be summarized at baseline only, for the mITT Analysis 
Set.  
5.6. 
Other Analyses 
5.6.1. 
Blinded Independent Central Review (BICR) Auditing Plan 
Due to early study termination, BICR will not be performed. 
5.7. 
Interim Analyses 
The Independent Data Monitoring Committee (IDMC) will make recommendations for 
discontinuation or modification of the study based on ongoing reviews of safety data 
according to the IDMC Charter. In addition, the IDMC will also evaluate all interim 
efficacy data, including the adaptive decision, PFS/iPFS analysis and OS interim 
analysis, and make a recommendation based on observed results of the study. 
In this double-blind study, all GSK and site personnel will be restricted from access to 
interim analysis results provided to the IDMC until the conclusion of the study, unless the 
IDMC recommends significant changes to study conduct that require a protocol 
amendment. In this case a select group from GSK will be unblinded to review the data to 
agree on future study conduct. 
Due to early study termination as a result of the adaptive decision making, only the 
adaptive decision interim analysis will be performed, as planned.  


 
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5.7.1. 
Adaptive Decision Making 
The analysis for adaptive decision will be conducted using ORR/DCR per RECIST v1.1 
based on investigator assessment when approximately the first 100 PD-L1 CPS ≥1 
participants have a minimum follow-up of 6 months.  
The adaptive decision making will be guided by the analysis in the PD-L1 CPS ≥1 
participants in the IA1 analysis set, i.e. those with a minimum follow-up of 22 weeks 
from date of randomization to the data cut off, regardless of death or study withdrawal. 
This is aligned with the one week visit window for the Week 21 assessment.   
The adaptive decision criteria will be positive if there is at least 8% improvement of ORR 
in the GSK3359609 in combination with pembrolizumab arm comparing with the 
pembrolizumab/placebo arm in PD-L1 CPS ≥1 population. Confirmation of CR and PR is 
not required in the adaptive decision making.  
1) If the ORR outcome per RECIST v1.1 is positive with ∆ORR≥8% in PD-L1 CPS 
≥1 population, the study continues to an originally planned Phase III sample size 
for a definitive Phase III evaluation. 
2) If the ORR/DCR outcome per RECIST v1.1 is negative with ∆ORR<0% and 
∆DCR<0% in PD-L1 CPS ≥1 population, the study may stop for futility 
depending on the recommendation of IDMC based on the totality of the data; 
refer to the IDMC charter for details. 
3) Otherwise, the study will continue as planned Phase II sample size for a definitive 
Phase II evaluation. 
5.7.2. 
PFS/iPFS Analysis and Interim OS Analysis 
The below planned analyses will not be performed due to early study termination. 
The study is designed to have one PFS/iPFS analysis and two OS analyses in PD-L1 
CPS ≥1 participants. Two OS analyses will be performed in PD-L1 CPS ≥20 participants. 
The safety of the treatment will also be assessed at the interim analysis. 
The timing of PFS/iPFS analysis and the OS interim analysis is triggered by the pre-
specified number of PFS events in the PD-L1 CPS ≥1 population. 
At the time of PFS/iPFS analysis, the OS interim analysis will be conducted in PD-L1 
CPS ≥1 participants to allow for early stopping of the study due to efficacy or allow for 
non-binding futility analysis. PD-L1 CPS ≥20 participants will be tested sequentially if 
OS is significant in PD-L1 CPS ≥1 participants. 
The timing of the final OS analysis in the PD-L1 CPS ≥1 and CPS ≥20 participants will 
be triggered by the pre-specified number of OS events in the PD-L1 CPS ≥1 population 
The nominal significance levels for the interim and final analyses of OS will be 
determined by the Lan-DeMets spending function based upon the O’Brien-Fleming 
boundary. The futility bounds of this study are non-binding and the bounds are 
considered guidance rather than strict bounds. 


 
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Table 6 summarizes the information fraction, sample size and decision guidance for the 
planned PFS/iPFS and OS analyses as a Phase II study. Table 7 summarizes the 
information fraction, sample size and decision guidance for the planned PFS/iPFS and 
OS analyses as a Phase III study. 
Table 6 
Summary of Sample Size and Decision Guidance at the Planned PFS 
and OS Analyses as a Phase II Study 
Analysis 
Key 
Endpt 
Population 
Expected 
Number of 
Events 
(Information 
Fraction) 
Efficacy Boundary1 
 
Non-Binding Futility 
Boundary1 
p-value 
Cumulative 
alpha 
p-value 
Cumulative 
beta 
PFS FA, 
OS IA 
(H1-H4) 
PFS/ 
iPFS 
CPS1 
~281 (100%) 
0.0001 
0.0001 
NA 
NA 
OS 
CPS1 
~205 (84%) 
0.0144 
0.0144 
0.4483 
0.0101 
CPS20 
~95 (84.1%) 
0. 0144 
0.0144 
0.5546 
0.0184 
OS FA 
(H1,H2)2 
OS 
CPS1 
~244 (100%) 
0.0208 
0.0249 
0.0208 
0.2474 
CPS20 
~113 (100%) 
0.0208 
0.0249 
0.0208 
0.4440 
Abbreviations: CPS=combined positive score; Endpt=endpoint; FA=final analysis; H=hypothesis; 
HR=hazard ratio; IA=interim analysis; NA=not applicable 
1. Efficacy boundaries and non-binding futility boundaries are based on initially assigned type I error rate 
(one-sided) before any alpha re-allocation and projected number of events at study mile stones. Actual 
efficacy boundaries will be based on actual numbers of events available at study milestones and actual 
futility bounds will be updated if overall beta is changed with respect to re-allocation. 
2. The descendant OS hypothesis in PD-L1 CPS20 participants will be tested only if the parent OS 
hypothesis in PD-L1 CPS1 participants is significant. 
Table 7 
Summary of Sample Size and Decision Guidance at the Planned PFS and OS 
analyses as a Phase III Study 
Analysis 
Key 
Endpt 
Population 
Expected 
Number of 
Events 
(Information 
Fraction) 
Efficacy Boundary1 
 
Non-Binding Futility 
Boundary1 
p-
value 
Cumulative 
alpha 
 
p-value 
Cumulative 
beta 
PFS FA, 
OS IA 
(H1-H4) 
PFS/ 
iPFS 
CPS1 
~432 
(100%) 
0.0001 
0.0001 
NA 
NA 
OS  
 
CPS1 
~295 
(80.4%) 
0.0124 
0.0124 
0.4775 
0.0020 
CPS20 
~137 
(80.1%) 
0.0122 
0.0122 
0.5927 
0.0050 
OS FA 
(H1,H2)2 
OS 
CPS1 
~367 
(100%) 
0.0213 
0.0249 
0.0213 
0.0991 
CPS20 
~171 
(100%) 
0.0213 
0.0249 
0.0213 
0.2648 
Abbreviations: CPS=combined positive score; Endpt=endpoint; FA=final analysis; H=hypothesis; 
HR=hazard ratio; IA=interim analysis; NA=not applicable 
1. Efficacy boundaries and non-binding futility boundaries are based on initially assigned type I error rate 
(one-sided) before any alpha re-allocation and projected number of events at study mile stones. Actual 


 
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efficacy boundaries will be based on actual numbers of events available at study milestones and actual 
futility bounds will be updated if overall beta is changed with respect to re-allocation. 
2. The descendant OS hypothesis in PD-L1 CPS ≥20 participants will be tested only if the parent OS 
hypotheses in PD-L1 CPS ≥1 participants is significant. 
5.8. 
Additional Analyses Due to the COVID-19 Pandemic 
5.8.1. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, a separate listing of 
all protocol deviations related to COVID-19 will be produced for the Enrolled Analysis 
Set, where important protocol deviations will be flagged. 
5.8.2. 
Additional Displays for Participants with a COVID-19 Infection 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if they answer “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF.  
A listing of the numbers of participants with a suspected, probable or confirmed COVID-
19 infection, and COVID-19 test results and additional symptoms will be produced, 
based on the COVID-19 Analysis Set.  
 
5.8.3. 
Safety 
5.8.3.1. 
Assessment of COVID-19 Adverse Events 
A Standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
The incidence of AEs and SAEs (Fatal and Non-Fatal) of COVID-19, COVID-19 AEs 
leading to study drug discontinuation, and COVID-19 AEs by severity, will be obtained 
from standard AE and SAE summaries.  


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1: Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AIC 
Akaike's Information Criteria 
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 
BICR 
Blinded Independent Central Review 
BOR 
Best Overall Response 
BPI-I3 
Brief Pain Inventory- Item 3 
Cmax 
Maximum observed concentration 
Cmin 
Minimum Observed Concentration 
CI 
Confidence Interval 
CPD 
Confirmed Progressive Disease 
CPS 
Combined Positive Score 
CR 
Complete Response 
CSR 
Clinical Study Report 
CTCAE 
Common Term Criteria for Adverse Events 
DCR 
Disease Control Rate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of Response 
ECG 
Electrocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Record Form 
EORTC QLQ 
C30 
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire – 30 item Core Module 
EORTC 
H&N35 
European Organization for Research and Treatment of Head and Neck 
35 Item Module 
EQ-5D-3L 
EuroQoL 5 Dimensions 3 Levels 
FACT-G 
Functional Assessment of Cancer Therapy - General 
GSK 
GlaxoSmithKline 
HNSCC 
Head and Neck Squamous Cell Carcinoma/Cancer 
HPV 
Human Papilloma Virus 
HRQoL 
Health-related Quality of Life 
IA 
Interim Analysis 
IA1 
Interim Analysis 1 
ICF 
Informed Consent Form 
ICOS 
Inducible T Cell Co-Stimulatory Receptor 
iCPD 
immune-based Confirmed Progressive Disease 


 
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Abbreviation 
Description 
iCR 
immune-based Complete Response 
IDMC 
Independent Data Monitoring Committee  
iPFS 
immune-based progression-free survival 
iPR 
immune-based Partial Response 
iRECIST 
immune-based Response Evaluation Criteria in Solid Tumors 
iSD 
immune-based Stable Disease 
iUPD 
immune-based Unconfirmed Progressive Disease 
LVEF 
Left Ventricular Ejection Fraction 
mITT 
Modified Intent-To-Treat 
OPS 
Output and Programming Specification 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-L1 
Programmed Death-Ligand 1 
PF 
Physical Function 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PRO 
Patient Reported Outcomes 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
Q3W 
Every Three Weeks 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Order Class 
TTD 
Time to Deterioration 
 
6.1.2. 
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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6.2. 
Appendix 2: Graphical Testing Strategy Between and Within 
Subfamilies 
Let α be the total family-wise type I error, α = 2.5% (one-sided). In Figure 1, the 
elementary subfamily is represented by the node shown in ellipsoid with the local 
significance level αS = αWS shown inside the node, where WS representing the associated 
initial weight for the subfamily S, S = PFS, OS, or PRO. The transition weights gij for re-
allocation between any two subfamilies i and j are represented on the dashed lines 
connecting subfamilies, where gij indicates the fraction of the significance level at the 
initial node (parent subfamily i) that is added to the significance level at the terminal 
node (descendent subfamily j) if all hypotheses in the subfamily i are rejected. The alpha 
level assigned to a descendent subfamily will be rolled over to the descendant subfamily 
based on the transition weight only if all hypotheses within the parent subfamily are 
significant.  
Similarly, the elementary hypothesis is represented by the node shown in square with the 
initial local significance level αSwi for the hypothesis Hi (i є {1, 2} if S = OS; i є {3, 4} if 
S = PFS; i є {5, 6, 7, 8} if S = PRO) shown inside the node. The transition weights for re-
allocation between any two hypotheses are represented on the solid lines connecting 
hypotheses within the subfamily S, S = OS, PFS, or PRO, where αS denotes type I error 
rate for the corresponding subfamily.  
Let Hi, i є I = {1, …, h} denote the ith hypothesis, t = {1, 2, …, k} denote the tth planned 
interim analysis, and α denote the overall Type I error rate in I. The following algorithm 
shows the general sequentially rejective graphical testing procedures in group sequential 
trials based on consonant closed weighted Bonferroni tests using group sequential 
boundaries.  


 
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Algorithm: 
Step 0: Set t = 1. 
Step 1: At interim analysis t, compute unadjusted p-values pi,t and nominal 
significance levels 𝛼𝑖,𝑡
∗(αwi(I)) for i є I. 
Step 2: Select j є I such that pj,t ≤ 𝛼𝑗,𝑡
∗(αwj(I)) and reject Hj; go to step 3; 
 
If no such j exists and t < k, the trial can be continued with t → t+1; go to 
step 1 in this case, otherwise stop. 
Step 3: Update the graph:  
 
I → I \ {j} 
 
𝑤𝑙(𝐼) → {𝑤𝑙(𝐼) + 𝑤𝑗(𝐼)𝑔𝑗𝑙,   𝑙 є I,
0,                    𝑜𝑡ℎ𝑒𝑟𝑤𝑖𝑠𝑒 
𝑔𝑙𝑘 → {
𝑔𝑙𝑘+ 𝑔𝑙𝑗𝑔𝑗𝑘
1− 𝑔𝑙𝑗𝑔𝑗𝑙,   𝑙, 𝑘 є I, 𝑙≠ 𝑘, 𝑔𝑙𝑗𝑔𝑗𝑙< 1 
0,                                           𝑜𝑡ℎ𝑒𝑟𝑤𝑖𝑠𝑒
 
Step 4: If |I| ≥ 1, go to Step 1; otherwise stop. 
 


 
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6.3. 
Appendix 3: Extended Time Without an Adequate 
Assessment 
PFS/iPFS 
Given the scheduled disease assessment (i.e. starts at week 9 and then every 6 weeks; if 
study treatment discontinued after Week 51 then assessments will be every 12 weeks 
thereafter until the start of subsequent systemic anticancer therapy), the definition of 2 
missed disease assessments will change. The following rules will be used for identifying 
the duration of extended time without an adequate assessment for PFS.  
If the time difference between the event (PD/death) and last adequate disease assessment 
prior to the new anticancer therapy is more than the window, PFS will be censored at the 
last adequate disease assessment prior to the event (PD/death) and the new anticancer 
therapy. 
• If the event is after Week 15 + 7 days and on or prior to week 51 +  7 days, then a 
subject will be identified as extended time without an adequate assessment if the 
subject did not have an adequate assessment during the time period of 98 days (12 
weeks + 2-week windows) prior to the event; 
• Else if the event is after Week 51 + 7 days and on or before Week 75 - 7 days then a 
subject will be identified as extended time without an adequate assessment if the 
subject did not have an adequate assessment during the time period of 140 days (18 
weeks + 2-week windows). 
• Else if the event is after Week 75 - 7 days then a subject will be identified as extended 
time without an adequate assessment if the subject did not have an adequate 
assessment during the time period of 182 days (24 weeks + 2-week windows). 
Similar rules can be applied to the iPFS. For iPFS, if the time difference between 
iPD/death date and last adequate disease assessment prior to the new anticancer therapy 
is more than the window, iPFS will be censored at the last adequate disease assessment 
prior to iPD/death and the new anticancer therapy. The same window specified for PFS 
above will apply to iPFS. 
TTD in Pain/PF 
Given the scheduled PRO assessment for EORTC QLQ-H&N35 Pain domain and 
PROMIS PF 8c (i.e. every 3 weeks till Week 21 and every 6 weeks afterwards), the 
definition of 2 missed disease assessments will change. The following rules will be used 
for identifying the duration of extended time without an adequate assessment for TTD in 
Pain or TTD in PF.  
If the time difference between the event (deterioration) and last adequate corresponding 
PRO assessment prior to the new anticancer therapy is more than the window, TTD will 
be censored at the last available assessment prior to the event (deterioration) and the new 
anticancer therapy. 


 
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• If the event is after Week 6 + 7 days and on or prior to week 21 + 7 days, then a 
subject will be identified as extended time without an adequate assessment if the 
subject did not have an adequate assessment during the time period of 56 days (6 
weeks + 2-week windows) prior to the event; 
• If the event is after Week 21 + 7 days and on or prior to week 33 - 7 days, then a 
subject will be identified as extended time without an adequate assessment if the 
subject did not have an adequate assessment during the time period of 77 days (9 
weeks + 2-week windows) prior to the event; 
• Else if the event is after Week 33 - 7 days then a subject will be identified as extended 
time without an adequate assessment if the subject did not have an adequate 
assessment during the time period of 98 days (12 weeks + 2-week windows). 


 
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6.4. 
Appendix 4: EORTC QLQ-C30 Scoring Information 
Scores for each scale and single-item measure are averaged and transformed linearly to a 
score ranging from 0–100. (see below image for details). A high score for functional 
scales and for Global Health Status/QoL represent better functioning ability or HRQoL, 
whereas a high score for symptom scales and single items represents significant 
symptomatology [Basch, 2014].   
 
Handling of missing items 
Single-item measures: if the item is missing, the score S will be set to missing.  
Scales requiring multiple items: if at least half of the items from the scale are available, 
the score S will be calculated based on available items. If more than half of the items 
from the scale are missing, the score S will be set to missing (Fayers, 2001). 
CCI
CCI - This section contained 
Clinical Outcome Assessment 
data collection questionnaires or 
indices, which are protected by 
third party copyright laws and 
therefore have been excluded.


 
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6.5. 
Appendix 5: BICR Implementation Plan 
Depending on the results of the adaptive decision making and the PFS analysis, BICR if 
conducted will be performed in a random sampling of participants (BICR audit) or all 
participants (100% BICR) as shown in Figure 2. The decision of full study BICR will be 
guided by the analysis results of PFS per RECIST v1.1 in the CPS ≥1 population. 
Figure 2 
BICR Implementation Plan 
 
Abbreviations: BICR = Blinded Independent Central Review; INV = investigator assessment; PFS = 
progression-free survival. 
1. 
The sample BICR will be initiated prior to the databased lock of the PFS analysis when the study 
expands to phase III. The sampling schema will be generated by SDAC in batches where the first 
batch will be initiated close to the data base lock and the dynamic allocation will be used in the 
subsequent batch to ensure the balance across stratification factors.   
2. 
SDAC will perform the analysis and the bias evaluation follows the method described in Section 
5.6.1. 
3. 
Based on the bias evaluation, the IDMC may recommend using PFS per BICR instead of investigator 
assessment and a corresponding protocol amendment may be warranted upon the IDMC 
recommendation.  
 
If the study remains as a phase II study, BICR on all participants will be performed only 
when the primary analysis of PFS per RECIST v1.1 by investigator assessment 
demonstrates a statistically significant treatment effect.  
In this case, BICR will be initiated after the database lock of the PFS analysis and bias 
will be evaluated for PFS based on the full study data.  
If the study expands to phase III, a random sample-based BICR auditing approach will be 
performed.  
If the BICR audit shows no evidence of investigator bias in favor of the GSK3359609 in 
combination with pembrolizumab arm and the PFS analysis results by BICR also 


 
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corroborate the results by investigator assessment, the treatment effect in PFS remains to 
be estimated based on investigator assessment. 
If bias cannot be excluded based upon the audit but the primary analysis of PFS per 
RECIST v1.1 by investigator assessment demonstrates a statistically significant treatment 
effect, BICR will be conducted for all participants and bias will be further evaluated 
based on all participants.  
If bias cannot be excluded based upon the audit and there is no evidence of a statistically 
significant treatment effect based on the primary analysis of PFS per RECIST v1.1 by 
investigator assessment, the third-party core imaging laboratory will not perform BICR 
for the remaining participants.  
When full BICR is conducted and bias cannot be excluded based on the full BICR, the 
treatment effect in PFS will be estimated using the BICR results upon the 
recommendation of IDMC. Otherwise, the treatment effect in PFS remains to be based on 
investigator assessment and the analyses based on the BICR data are considered as 
supportive. 


 
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