Clinical trial NCT03693612
Conditions: Neoplasms
Keywords: advanced solid tumor Head and Neck Squamous Cell Carcinoma standard of care GSK3359609 urothelial carcinoma of the upper and lower urinary tract non-small cell lung cancer cutaneous melanoma Tremelimumab clear cell renal carcinoma castrate resistant prostate adenocarcinoma
Sponsor: GlaxoSmithKline
Start date: 2018-11-26; Completion date: 2021-09-16
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate if the combination of GSK3359609 and tremelimumab is safe and tolerable (Part 1) and provides significant survival benefit to subjects with relapsed/refractory (R/R) Head and Neck Squamous Cell Carcinomas (HNSCC) to warrant further clinical investigation (Part 2). Part 1 (dose escalation) will enroll subjects with advanced, selected solid tumors. Subjects will receive escalating doses of GSK3359609 and tremelimumab in combination in Part 1. Part 2 is randomized expansion and will enroll subjects with R/R HNSCC who have disease progression after receiving at least 1 platinum-based chemotherapy and at least 1 anti-programmed death receptor protein-1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy, whether in combination or separately. In Part 2, subjects will be randomized in a ratio of 2:1 to receive either GSK3359609 in combination with tremelimumab at the recommended Phase 2 dose or investigators choice of a single-agent standard of care (SOC) therapy including paclitaxel, docetaxel or cetuximab. The total duration of subjects in the study will be approximately 4 years.

Detailed description:

Arms: arm 1: In Part 1, subjects with advanced selected solid tumors will be enrolled. Subjects will be administered escalating doses of feladilimab and tremelimumab in combination. feladilimab will be administered every 3 weeks and tremelimumab will be administered every 3 weeks for 6 doses and every 12 weeks thereafter. arm 2: In Part 2, subjects with R/R HNSCC who have disease progression after receiving at least one platinum-based chemotherapy and at least one anti-PD-1/PD-L1 will be enrolled. Subjects will be administered feladilimab in combination with tremelimumab at recommended Phase 2 dose as determined from Part 1. arm 3: In Part 2, subjects with R/R HNSCC who have disease progression after receiving at least one platinum-based chemotherapy and at least one anti-PD-1/PD-L1 will be enrolled. Subjects will be administered a single agent SOC therapy of either paclitaxel, docetaxel or cetuximab as per the investigators choice.
Interventions: intervention 1: feladilimab intervention 2: Tremelimumab intervention 3: Docetaxel intervention 4: Paclitaxel intervention 5: Cetuximab
Intervention descriptions: intervention 1: feladilimab is humanized anti-ICOS agonist immunoglobulin G (IgG) 4 monoclonal antibody (mAb), which will be administered as an intravenous (IV) infusion once every 3 weeks. intervention 2: Tremelimumab is humanized anti-CTLA-4 IgG2 mAb, which will be administered as an IV infusion once every 3 weeks for 6 doses, thereafter once every 12 weeks . intervention 3: Docetaxel is a microtubule stabilizer which will be administered as an IV infusion once every 3 weeks at a dose of 75 milligrams per meter square (mg/m\^2). intervention 4: Paclitaxel is a microtubule stabilizer which will be administered as an IV infusion once weekly at a dose of 80 mg/m\^2. intervention 5: Cetuximab is a recombinant, human/mouse chimeric anti-estimated glomerular filtration rate (EGFR) mAb. Cetuximab will be administered at a loading dose of 400 mg/m\^2 followed by 250 mg/m\^2 once weekly.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Phase I/II, Open-label, Two Part Study of GSK3359609 in 
Combination with Tremelimumab in Participants with Selected, Advanced Solid Tumors
Protocol Number: 207871/Amendment 01
Compound Number:
GSK3359609
Study Phase: Phase I/Phase II
Short Title: GSK3359609 plus Tremelimumab for the Treatment of Advanced Solid 
Tumors
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 can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):
IND: 140485
EudraCT:  2018-002868-12
Approval Date: 20-SEP-2018
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.




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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
DNG Number
Amendment 1
20-Sep-2018
2018N362439 01
Original Protocol
03-Aug-2018
2018N362439 00
Amendment 1 [20-SEP-2018]
Overall Rationale for the Amendment: Protocol was amended at the request of a 
regulatory authority to provide additional clarification and guidance on specific aspects 
of the protocol as described in the table below.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.3 
Schedule of 
Activities
SoA line for EQ-5D needs to 
change in notes/footnote from 
Week 21 to Week 22
Correct typo.
Section 7.1.1
Discontinuation
of Study
Treatment
Clarification of the RECIST 
guideline to be followed in allowing 
continuation of study treatment 
beyond progression: original text 
was by iRECIST; the revised text is 
by RECISTv1.1
Request of the regulatory authority,
Section 7.1.3:
Stopping Rules
for Clinical 
Deterioration
Clarification that the decrease in 
the ECOG represents a worsening 
of performance status from 
baseline.
Request by the regulatory authority.
Section 8.1.3.1
Jensen references (2) have 
incorrect years (2014 changed to 
2015 and the 2016 changed to 
2017)
Corrected typos
Section
10.6.2.1:
Rechallenge 
Following Liver 
Stopping 
Events that are 
Possibly 
Related to 
Study 
Treatment
Modified the first bullet (addition
underlined) to read, “Investigator 
requests consideration of 
rechallenge with study treatment 
for a participant who is receiving 
compelling benefit (partial 
response or complete response)
with study treatment that exceeds 
risks, and no effective alternative 
therapy is available.
Add the following requirements:

The ALT at the time of   
Request by the regulatory authority.


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Section # and 
Name
Description of Change
Brief Rationale
rechallenge is <3x ULN 

The participant did not have 
additional risk factors for a fatal 
outcome following the initial 
injury including 
hypersensitivity, jaundice, 
bilirubin >2x ULN, (direct 
bilirubin >35% of total 
bilirubin), or INR >1.5.
Section 11. 
References
Jensen references (2) have 
incorrect years (2014 changed to
2015 and the 2016 changed to
2017)
Correct typos


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY........................................................................................10
1.1.
Synopsis.....................................................................................................10
1.2.
Schema ......................................................................................................13
1.3.
Schedule of Activities (SoA)........................................................................13
2.
INTRODUCTION....................................................................................................22
2.1.
Study Rationale ..........................................................................................22
2.2.
Background ................................................................................................23
2.3.
Benefit/Risk Assessment ............................................................................26
2.3.1.
Risk Assessment .........................................................................26
2.3.2.
Benefit Assessment.....................................................................27
2.3.3.
Overall Benefit: Risk Conclusion..................................................28
3.
OBJECTIVES AND ENDPOINTS...........................................................................28
3.1.
Part 1: Dose Escalation of GSK3359609 in Combination with 
Tremelimumab............................................................................................28
3.2.
Part 2: Cohort Expansion of the RP2D Dose Combination vs. SOC 
in R/R HNSCC............................................................................................29
4.
STUDY DESIGN ....................................................................................................30
4.1.
Overall Design ............................................................................................30
4.1.1.
Part 1: Dose Escalation of Tremelimumab and 
GSK3359609...............................................................................31
4.1.1.1.
Dose Limiting Toxicity.................................................32
4.1.1.2.
Non-Limiting Toxicities ...............................................33
4.1.1.3.
Dose Escalation Decisions and Selection of 
Part 2 Dose ................................................................34
4.1.2.
Part 2: Cohort Expansion of the RP2D Dose Combination 
vs. SOC.......................................................................................34
4.2.
Scientific Rationale for Study Design ..........................................................34
4.3.
Justification for Dose ..................................................................................35
4.3.1.
GSK3359609 Dose Rationale......................................................35
4.3.1.1.
GSK3359609 Dosing Frequency ................................35
4.3.1.2.
GSK3359609 Rationale for Fixed Dose......................36
4.3.2.
Tremelimumab Dose Rationale....................................................36
4.4.
End of Study Definition ...............................................................................37
4.4.1.
Participant Completion.................................................................37
5.
STUDY POPULATION...........................................................................................37
5.1.
Inclusion Criteria.........................................................................................38
5.2.
Exclusion Criteria........................................................................................40
5.3.
Lifestyle Considerations..............................................................................43
5.4.
Screen Failures...........................................................................................43
6.
STUDY INTERVENTION........................................................................................43
6.1.
Study Intervention(s) Administered .............................................................43
6.2.
Preparation/Handling/Storage/Accountability..............................................44


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6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................45
6.4.
Study Intervention Compliance ...................................................................45
6.5.
Concomitant Therapy..................................................................................45
6.5.1.
Permitted Medications and Non-Drug Therapies..........................46
6.5.2.
Prohibited Medications and Non-Drug Therapies.........................46
6.6.
Dose Modification and Safety Management Guidelines ..............................47
6.6.1.
General Guidelines for Immune-Related Adverse Events ............47
6.6.2.
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Immunotherapy Treatment.........................63
6.6.3.
Dose Delay..................................................................................66
6.7.
Intervention after the End of the Study........................................................66
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................67
7.1.
Discontinuation of Study Intervention..........................................................67
7.1.1.
Continuation of Treatment Upon Confirmed Disease 
Progression .................................................................................68
7.1.2.
Liver Chemistry Stopping Criteria ................................................69
7.1.2.1.
Study Intervention Restart or Rechallenge after 
Liver Stopping Criteria Met .........................................70
7.1.3.
Stopping Rules for Clinical Deterioration......................................70
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................71
7.3.
Lost to Follow Up........................................................................................71
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................72
8.1.
Efficacy Assessments.................................................................................72
8.1.1.
Tumor Imaging and Disease Assessments..................................72
8.1.1.1.
Initial Tumor Imaging..................................................73
8.1.1.2.
Tumor Imaging During the Study................................73
8.1.1.3.
End of Treatment Imaging ..........................................74
8.1.2.
Tumor Growth Kinetics ................................................................74
8.1.3.
Patient Reported Outcomes (PRO)..............................................74
8.1.3.1.
PROMIS Physical Function ........................................75
8.1.3.2.
EORTC QLQ-C30 & HN35 .........................................76
8.1.3.3.
FACT GP5..................................................................76
8.1.3.4.
PRO-CTCAE ..............................................................76
8.1.3.5.
EuroQOL Group EQ-5D 3 Level Version ....................77
8.2.
Safety Assessments ...................................................................................77
8.2.1.
Physical Examinations.................................................................77
8.2.2.
Performance Status.....................................................................77
8.2.3.
Vital Signs....................................................................................77
8.2.4.
Electrocardiograms......................................................................78
8.2.5.
Echocardiograms.........................................................................78
8.2.6.
Clinical Safety Laboratory Assessments ......................................78
8.3.
Adverse Events and Serious Adverse Events.............................................79
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................79
8.3.2.
Method of Detecting AEs and SAEs.............................................80
8.3.3.
Follow-up of AEs and SAEs.........................................................80
8.3.4.
Regulatory Reporting Requirements for SAEs .............................80
8.3.5.
Pregnancy ...................................................................................80
8.3.6.
Cardiovascular and Death Events................................................80


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8.4.
Treatment of Overdose...............................................................................81
8.5.
Pharmacokinetics .......................................................................................81
8.5.1.
Blood Sample Collection..............................................................82
8.5.2.
Sample Analysis ..........................................................................82
8.6.
Pharmacodynamics ....................................................................................82
8.7.
Genetics .....................................................................................................82
8.8.
Biomarkers .................................................................................................83
8.8.1.
Blood Biomarkers ........................................................................83
8.8.2.
Tumor Tissue Biomarkers............................................................83
8.8.3.
Immunogenicity Assessments......................................................84
8.8.4.
DNA/RNA Transcriptome and RNA expression Research ...........84
8.8.5.
Proteome Research.....................................................................84
8.9.
Health Economics/Medical Resource Utilization and Health 
Economics..................................................................................................84
9.
STATISTICAL CONSIDERATIONS........................................................................85
9.1.
Statistical Hypotheses.................................................................................85
9.1.1.
Part 1: Dose Escalation ...............................................................85
9.1.2.
Part 2: Cohort Expansion.............................................................85
9.2.
Sample Size Determination ........................................................................85
9.2.1.
Part 1: Dose Escalation ...............................................................85
9.2.2.
Part 2: Cohort Expansion.............................................................87
9.3.
Populations for Analyses ............................................................................88
9.4.
Statistical Analyses.....................................................................................89
9.4.1.
Efficacy Analyses.........................................................................89
9.4.1.1.
Overall Survival (OS)..................................................89
9.4.1.2.
Overall Response Rate (ORR) ...................................90
9.4.1.3.
Disease Control Rate (DCR) ......................................90
9.4.1.4.
Duration of Response (DOR)......................................90
9.4.1.5.
Progression Free Survival (PFS) ................................90
9.4.1.6.
Time to Response (TTR) ............................................90
9.4.1.7.
Predictive Probability of Phase 3 Success..................90
9.4.2.
Safety Analyses...........................................................................91
9.4.2.1.
Extent of Exposure .....................................................91
9.4.2.2.
Adverse Events ..........................................................91
9.4.2.3.
Clinical Laboratory Evaluations ..................................92
9.4.2.4.
Other Safety Measures...............................................92
9.4.3.
Other Analyses ............................................................................92
9.4.3.1.
Pharmacokinetic Analyses..........................................92
9.4.3.2.
Pharmacokinetic/Pharmacodynamic Analyses ...........93
9.4.3.3.
Immunogenicity Analyses...........................................93
9.4.3.4.
Translational Research Analyses ...............................93
9.4.3.5.
Tumor Kinetic Analyses..............................................93
9.5.
Interim Analyses .........................................................................................93
9.5.1.
Part 1: Dose Escalation ...............................................................93
9.5.2.
Part 2: Cohort Expansion.............................................................94
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...............................................................................................95
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................95
10.1.1.
Regulatory and Ethical Considerations ........................................95


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10.1.2.
Financial Disclosure.....................................................................95
10.1.3.
Informed Consent Process ..........................................................95
10.1.4.
Data Protection............................................................................96
10.1.5.
Dissemination of Clinical Study Data ...........................................96
10.1.6.
Data Quality Assurance ...............................................................97
10.1.7.
Source Documents ......................................................................98
10.1.8.
Study and Site Closure ................................................................98
10.1.9.
Publication Policy.........................................................................98
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................99
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................100
10.3.1.
Definition of AE..........................................................................100
10.3.2.
Definition of SAE........................................................................101
10.3.3.
Definition of Cardiovascular Events ...........................................102
10.3.4.
Recording and Follow-Up of AE and SAE..................................102
10.3.5.
Reporting of SAE to GSK...........................................................104
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................106
10.4.1.
Definition: Woman of Childbearing Potential (WOCBP) .............106
10.4.2.
Contraception Guidance ............................................................107
10.4.3.
Collection of Pregnancy Information: .........................................108
10.5.
Appendix 5: Genetics................................................................................110
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge Guidelines..................111
10.6.1.
Liver Chemistry Stopping and Monitoring Criteria ......................111
10.6.1.1.
ALT up to 2.5xULN at Baseline ................................111
10.6.1.2.
Baseline ALT up to 5xULN for Participants with 
Documented Liver Metastases/Tumor 
Infiltration..................................................................113
10.6.1.3.
Liver Chemistry Increased Monitoring Criteria 
with Continued Therapy............................................115
10.6.2.
Liver Safety Drug Restart or Re-Challenge Guidelines ..............115
10.6.2.1.
Re-challenge Following Liver Stopping Events 
that are Possibly Related to Study intervention.........115
10.6.2.2.
Re-challenge Following Transient Liver 
Stopping Events Not Related to Study 
intervention...............................................................117
10.7.
Appendix 7: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria ..........................................................119
10.7.1.
Assessment Guidelines by RECIST 1.1.....................................119
10.7.2.
Guidelines for Evaluation of Disease by RECIST 1.1.................120
10.7.3.
Evaluation of Response by iRECIST..........................................120
10.8.
Appendix 8: Creatinine Clearance Calculation Formulas ..........................127
10.9.
Appendix 9: ECOG Performance Status ...................................................129
10.10. Appendix 10: Statistical Methods for Study Design...................................130
10.10.1. Bivariate CRM Method for Part 1 Dose Escalation.....................130
10.10.1.1. Description of the Bivariate Continual 
Reassessment Method.............................................130
10.10.1.2. Logistic Model for Bivariate CRM..............................130
10.10.2. Simulation Method for Part 2 Sample Size Estimation ...............131
10.11. Appendix 11: Abbreviations and Trademarks............................................134
10.12. Appendix 12: Protocol Amendment History...............................................138


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11. REFERENCES.....................................................................................................139


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A Phase I/II, Open-label, Two Part Study of GSK3359609 in 
Combination with Tremelimumab in Participants with Selected, Advanced Solid Tumors
Short Title: GSK3359609 plus Tremelimumab for the Treatment of Advanced Solid 
Tumors
Rationale:  GSK3359609 is an inducible T cell co-stimulator (ICOS) agonist antibody 
and tremelimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
antagonist antibody. In nonclinical and clinical studies in a variety of tumors, it has been 
shown that ICOS expression on T cells is upregulated after CTLA-4 treatment.
Additionally, ICOS+CD4 T cells have been shown to have a positive association with 
response in tremelimumab treated chemotherapy-resistant malignant mesothelioma 
patients. It is hypothesized that the combination of these two agents will provide greater 
antitumoral response than either agent alone. The purpose of this study is to evaluate if 
the combination of GSK3359609 and tremelimumab is safe and tolerable (Part 1) and 
provides significant survival benefit to participants with relapsed/refractory (R/R) Head 
and Neck Squamous Cell Carcinomas (HNSCC) to warrant further clinical investigation.
Objectives and Endpoints:
PART 1
Objectives
Endpoints
Primary

Determine safety, tolerability and the 
R2PD of GSK3359609 in combination 
with tremelimumab 

Frequency and severity of DLTs, AEs, 
AESI, SAEs and AE/SAE/DLTs leading to 
dose modifications/delays/withdrawals; 
changes in laboratory, vital signs, and 
ECG safety assessment parameters
Secondary

Evaluate clinical activity of GSK3359609 
in combination with tremelimumab

ORR, DCR

Characterize the PK properties of 
GSK3359609 and tremelimumab when 
administered in combination

Cmax, Cmin, AUC (0-t) of GSK3359609 
and tremelimumab as data permit

Determine immunogenicity of 
GSK3359609 and tremelimumab when 
administered in combination

Detection and characterization of ADA 
against GSK3359609 and/or 
tremelimumab
AEs = adverse events; SAEs = serious adverse events; DLTs = dose limiting toxicities; AESI = adverse events of 
special interest; RP2D = recommended phase 2 dose; ECG = electrocardiogram; ORR = overall response rate; 
DCR = disease control rate; Cmax = maximum observed concentration; Cmin = minimum observed 
concentration; AUC (0-t) = area under the concentration-time curve over the dosing interval; ADA = anti-drug 
antibodies


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PART 2 
Objectives
Endpoints
Primary

Evaluate clinical activity of GSK3359609 
in combination with tremelimumab
compared to SOC

OS
Secondary

Further evaluate the clinical activity of 
GSK3359609 in combination with 
tremelimumab compared to SOC

ORR, DCR, PFS, TTR, DoR

Further evaluate the PK properties of 
GSK3359609 and tremelimumab when 
administered in combination

Cmax, Cmin, AUC (0-t) of GSK3359609 
and tremelimumab as data permit

Further evaluate immunogenicity of 
GSK3359609 and tremelimumab when 
administered in combination

ADA incidence 

Further evaluate the safety and 
tolerability of GSK3359609 and 
tremelimumab when administered in 
combination

Frequency and severity of AEs, AESI,
SAEs and AE/SAEs leading to dose 
modifications/delays/withdrawals; 
changes in laboratory, vital signs, and 
ECG safety assessment parameters
OS = overall survival; SOC = standard of care; ORR = overall response rate; DCR = disease control rate; PFS = 
progression-free survival; TTR = time to response; DoR = duration of response; TCR = T cell receptor; ADA = 
anti-drug antibodies; AEs = adverse events; SAEs = serious adverse events; Cmax = maximum observed 
concentration; Cmin = minimum observed concentration; AUC (0-t) = area under the concentration-time curve 
over the dosing interval.
Overall Design:
This is a Phase I/II, open-label, 2-part study of GSK3359609 in combination with 
tremelimumab. As shown in Figure 1, Part 1 is dose escalation and will enroll
participants with advanced, selected solid tumors and Part 2 is randomized expansion and
will enroll participants with R/R HNSCC who have disease progression after receiving at 
least 1 platinum-based chemotherapy and at least 1 anti-PD-1/PD-L1 therapy, whether in 
combination or separately. In Part 2, participants will be stratified by line of anti-PD-(L)1 
therapy (i.e., received in the first line or second line).
Part 1 dose escalation will initiate with 8 mg GSK3359609 and 75 mg tremelimumab
(termed dose level [DL] 1), the planned lowest dose for each agent. The highest planned 
doses are 80 mg GSK3359609 and 225 mg tremelimumab. GSK3359609 will be 
administered every 3 weeks and tremelimumab will be administered every 3 weeks for 6 
doses, followed by every 12 weeks. Tremelimumab is to be administered first as an IV 
infusion over 60 minutes. GSK3359609 will be administered as a 30-minute IV infusion 
beginning at least 1 hour and no more than 2 hours following the end of the 
tremelimumab infusion. Dose escalation will occur using a zone-based approach; each 


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zone must clear for safety prior to the next zone being opened to enrollment. Dose 
escalation will be guided by the bivariate Continuous Reassessment Method (CRM)
model until the maximum tolerated dose (MTD) or maximum administered dose (MAD)
dose combination(s) are determined. Unplanned dose combinations within the range of 
the planned doses of each agent may be investigated to support the identification of 
optimal doses to administer in combination. Additionally, doses lower than planned of 
either agent may be investigated. PK/pharmacodynamic cohort(s) may be initiated at any 
DL(s), once safety is cleared, with mandatory paired tumor sample collections to inform 
on dose selection for Part 2 of the study. 
The severity of all toxicities will be graded using National Cancer Institute - Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE) (version 5.0). The DLT observation 
period is 28 days in length and begins on the day GSK3359609 and tremelimumab are
first administered to the participant.
A single dose combination will be selected as the recommended Phase 2 dose (RP2D)
and carried forward from Part 1 into Part 2. The totality of data will be used to determine 
whether to proceed to Part 2 and which dose combination will be chosen as the RP2D.
Part 2 expansion is randomized and open-label to evaluate the efficacy of the selected 
RP2D dose combination compared to the Investigator’s choice of selected current 
standard of care (SOC) in the treatment of R/R HNSCC who have progressed after 
receiving at least 1 platinum-based chemotherapy and at least 1 anti-PD-1/PD-L1
therapy, whether in combination or separately. Randomization is 2:1 to the 
investigational and SOC arms, respectively. Part 2 will also characterize PK and 
pharmacodynamic effects. Additional tumor type cohorts may be added either as a single 
arm expansion or with an appropriate comparator if a signal is identified in Part 1, based 
on the totality of the evidence and would be the subject of a future amendment. 
Disclosure Statement: Part 1 is a single group treatment part with 1 arm. Part 2 is a 
parallel group random treatment assignment part with 2 arms. 
Number of Participants: Approximately 114 participants will be enrolled in this study; 
up to 24 in Part 1 and 90 in Part 2.
Intervention Groups and Duration: The study is comprised of 3 periods (further details 
in the Schedule of Activities (SoA).
Screening: Participants may sign the informed consent form up to 45 days prior to first 
dose and screening procedures should be completed within 30 days prior to first dose or
as described in the SoA.
Treatment: Study intervention is defined as GSK3359609 in combination with 
tremelimumab and in Part 2, participants will be randomized to study intervention or 
SOC (Part 2 only; Investigator’s choice of paclitaxel, docetaxel or cetuximab). 
Participants will receive study intervention or SOC until disease progression, 
unacceptable toxicity or death.
Follow-up: Participants will be followed for survival and subsequent anticancer therapy 
once study intervention/SOC has been discontinued. Note: Participants who discontinue 


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study intervention/SOC prior to progression or prior to confirmed progression by 
iRECIST will also be followed for progression or confirmation of progression by 
iRECIST. 
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 and is 
estimated to be up to 4 years (~2 years on treatment and ~2 years in survival follow-up); 
however, participants deriving benefit may be on study intervention beyond 2 years. 
Data Monitoring Committee: There will not be a formal data monitoring committee for 
this study. The Dose Escalation and Selection Plan will describe the process for making 
dose escalation/selection decisions and responsible personnel.
1.2.
Schema
Figure 1
Study Design Schema
1.3.
Schedule of Activities (SoA)
Protocol waivers or exemptions are not allowed except for immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the 
Schedule of Activities, are essential and required for study conduct.
The following points must be noted:
If assessments are scheduled for the same nominal time, THEN the assessments should 
occur in the following order:
1. 12-lead ECG
2. Vital signs
3. Blood draws (e.g., PK blood draws)
Note: Other assessments not listed may occur at any time; however, the timing of ALL 
the assessments must allow the blood draw to occur at the exact nominal time.
















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Abbreviations: ADA = Anti-drug antibodies; AE = Adverse event; AESI = Adverse events of special interest; ANC = Absolute neutrophil count; CR = complete response; ECG = 
Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = End of infusion; EORTC QLQ-C30 and HN35 = European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire – Core 30 and head and neck 35 module; EQ-5D = EuroQOL Group EQ-5D; FACT GP5 = Functional Assessment of Cancer 
Therapy - General Physical Well Being Item 5; HIV = Human immunodeficiency virus; ICF = Informed consent form; iRECIST = Modified Response Evaluation Criteria in Solid Tumors 
1.1 for immune-based therapeutics; MUGA = Multigated acquisition scan; PBMC = peripheral mononuclear cells;  PD = Progressive Disease; PK = Pharmacokinetics; PR = Partial 
response; PRO-CTCAE Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events; PROMIS PF = Patient-Reported Outcome Measurement 
Information System – Physical Function; Q = Every; RNA = Ribonucleic acid; SAE = Serious adverse event; SOC = Standard of care; TDV = Treatment Discontinuation Visit; W = 
Week; WOCBP = Women of childbearing potential


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2.
INTRODUCTION
2.1.
Study Rationale
GSK3359609 is an inducible T cell co-stimulator (ICOS) agonist antibody and 
tremelimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonist 
antibody. In nonclinical and clinical studies in a variety of tumors, it has been shown that 
ICOS expression on T cells is upregulated after CTLA-4 treatment [Fan, 2014; Fu, 2011; 
Tang, 2013]. Additionally, ICOS+CD4 T cells have been shown to have a positive
association with response in tremelimumab treated chemotherapy-resistant malignant
mesothelioma patients [Calabrò, 2013]. It is hypothesized that the combination of these 
two agents will provide a significant antitumoral response. The purpose of this study is to 
evaluate if the combination of GSK3359609 and tremelimumab is safe and tolerable (Part 
1) and provides significant survival benefit to participants with relapsed/refractory (R/R) 
Head and Neck Squamous Cell Carcinomas (HNSCC) to warrant further clinical 
investigation (Part 2).
Part 1
In Part 1 of study 207871, study intervention will be tested at escalating dose 
combinations in participants with advanced, selected solid tumors that are 
relapsed/refractory to standard therapies to determine the best dose combination of 
tremelimumab and GSK3359609. The selection of these solid tumors was based on 
evidence of their reported response to immune checkpoint therapies [Swaika, 2015; 
Zamarin, 2015] and/or of exhibiting features indicating a greater likelihood of 
susceptibility to immune directed therapies, such as tumor mutation load or 
number/phenotype of tumor infiltrating lymphocytes [Powles, 2014].
Part 2
Head and neck cancers are the ninth most common malignancies in the world with over 
90% of these being squamous cell carcinomas [Gupta, 2016]. Although these patients are 
treated with potentially curative treatments, many develop recurrent or metastatic disease. 
This patient population continues to have a high unmet medical need, as median overall 
survival is less than 1 year [Argiris, 2017]. For recurrent, unresectable or metastatic 
disease without an option for radiation, platinum-based chemotherapy alone or in 
combination with other chemotherapeutic agents is also among the preferred first line 
treatment options [NCCN, 2018]. While immunotherapy has been shown to prolong 
progression-free survival and increase the 1-year overall survival rate over standard of 
care (SOC) single agent therapies [Ferris, 2016] and is now recommended as second line 
therapy [NCCN, 2018], the prognosis for these patients remains poor. 
R/R HNSCC was chosen as a tumor type of interest in Part 2 of this study due to the high 
unmet medical need in patients who have failed platinum-based chemotherapy and anti-
PD-(L)1 therapy. Several studies have indicated that infiltration with immune cells 
correlated with favourable clinical outcomes in HNSCC [Mandal, 2016; Ferris, 2015]. 
ICOS and CTLA-4 expression has been seen on T cells in the in-silico analysis of the 
TCGA database in a proportion of HNSCC surgically resected tumor samples and 


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multiplex IHC based studies have shown ICOS and CTLA-4 expression on TILS to a 
varying extent between HNSCC patients from surgically resected samples including both 
CD8 and CD4 T cells and both conventional and regulatory CD4 T cells [Kim, 2016]. 
The combination of an ICOS agonist antibody with a CTLA4 blocking antibody could 
enhance activation of the CD8 and CD4 T-conventional cells while controlling the T-reg 
suppressive effects and is therefore hypothesized to have a significant antitumor effect in 
HNSCC.
The choice of chemotherapy for R/R HNSCC following failure of first line therapy and 
failure of second line anti-PD-(L)1 therapy is not well defined and is based on several 
factors, including previous chemotherapy exposure, performance status, and comorbid
conditions. Several single agent chemotherapy options existed as second line therapy for 
patients who are not appropriate for a platinum-containing regimen. These agents now 
fall into the third line post-approval of the anti-PD-(L)1 agents. In the United States and 
the EU, ASCO, NCCN and ESMO recommendations include best supportive care, 
clinical trials, and single agents including paclitaxel, docetaxel, 5-fluorouracil, 
methotrexate, cetuximab, ifosfamide, bleomycin, gemcitabine, capecitabine, and 
vinorelbine [NCCN, 2018; Mesia, 2013]. Methotrexate and bleomycin have FDA 
approved indications for head and neck cancer; however, both agents are considered toxic 
in the setting of newer chemotherapy agents and methotrexate had poor performance in 
the recent Phase III study [Ferris, 2016]. Furthermore, the bleomycin label contains the 
following language, “the response to bleomycin is poorer in patients with previously 
irradiated head and neck cancer”. This population is expected to be the majority of 
participants in this study and thus bleomycin will not be included in the SOC options in 
this study. The Investigator’s choice of SOC will consist of the following agents:
cetuximab (where it is approved for use as a single agent for recurrent HNSCC), 
paclitaxel (which is incorporated into regimens in early lines of disease and is commonly 
used in late line as a single agent), and docetaxel (which appears to be the most active 
agent in the platinum refractory setting, has approved indications as a single agent and 
has demonstrated activity in this setting) [Ferris, 2016].
2.2.
Background
A model of cancer immunity is described as a cyclic multistep process that functions to 
elicit an effective antitumor response [Chen, 2013]. Each step can be negatively 
regulated, thus providing the tumor with redundant mechanisms by which to block an 
antitumor immune response. In some cases, tumors will be highly dependent on a single
mechanism, and in these cases, there is the potential to achieve significant clinical 
activity with a single agent immunomodulatory therapy. However, it is expected that 
tumors often utilize redundant mechanisms to evade antitumor immune responses and in 
these cases, combination therapies are likely required.
Robust antitumor responses including complete cure in some cancers have been achieved 
by modulating a patient’s immune system. Antibodies targeting the checkpoint receptors 
or their cognate ligands engaged in negative regulation of T cell responses, such as 
CTLA-4 and PD-1 (Programmed death receptor-1)/PD-L1 (PD Ligand), have 
demonstrated efficacy and are proven effective as anticancer immunotherapies in a broad 


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range of tumors including some solid tumors otherwise considered poorly immunogenic
[Chen, 2015; Brahmer, 2012; Topalian, 2012; Meng, 2017].
However, the majority of tumors are non-responsive to this class of agents when given as 
monotherapy as these tumors may possess features that enable them to evade immune 
surveillance, suppress immune reactivity, proliferate and survive within an inflammatory 
microenvironment. In addition, multiple mechanisms of immune suppression could exist
which may prohibit effective antitumor immune responses. In these instances, 
combination therapies will likely be required. The clinical data generated by the 
combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with 
metastatic melanoma is an example of the practice changing clinical benefit of such 
combinations [Wolchok, 2013; Larkin , 2015]
In some patients, inhibition of negative immune checkpoint pathways alone may not 
elicit an effective antitumor response. To reinstate immunosurveillance, treatment 
approaches may require combinations with agents that provide co-stimulatory signals or
target different processes within the immune cascade; these regimens may include 
chemotherapies which possess advantageous immunological effects [Galluzzi, 2015].
Immunomodulatory agents that target other components of the cancer immunity cycle are 
needed to expand the population of patients and range of tumor types that may respond to 
immunotherapy as well as enhance the magnitude and duration of antitumor responses in 
patients whose tumors are already sensitive to current immunotherapy approaches. 
Ultimately, the aim is to improve patient survival outcome in all disease settings 
including the advanced setting which is considered non-curative by nature.
GSK3359609 is a humanized IgG4 anti-ICOS agonist monoclonal antibody [Mayes,
2018] 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 
Immunoglobulin (Ig)G4 hinge-stabilized isotype, IgG4PE, to markedly decrease binding 
affinity of the Fc (Fragment crystallizable) region of the mAb to activating Fcγ receptors 
and C1q, and thereby diminish the cytotoxic potential of GSK3359609 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.
ICOS is a co-stimulatory receptor belonging to the CD28/CTLA immunoglobulin super 
family with expression restricted to T cells [Hutloff, 1999]. ICOS is weakly expressed on 
resting TH17, follicular helper T and regulatory T (Treg) cells, yet is highly induced on 
CD4+ and CD8+ T cells upon T cell receptor (TCR) engagement and activation [Paulos,
2010; Wakamatsu, 2013]. Upregulation of ICOS leads to both Th1 and Th2 cytokine 
secretion and sustained effector T cell proliferation and function [Sharpe, 2002]. A 
growing body of evidence supports the concept that activating ICOS on CD4+ and CD8+ 
effector T cells has antitumor potential.


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The rationale for targeting ICOS in cancer has been established by multiple lines of 
nonclinical and clinical evidence. Engagement of the ICOS pathway with an ICOS-L-Fc 
fusion protein is shown to have potent antitumor activity in multiple syngeneic mouse 
tumor models [Ara, 2003]. GSK3359609 has been tested in combination with anti-
CTLA-4 monoclonal antibodies (mAb) (ipilimumab) in either ex-vivo human PBMC 
assays or in a modified MLR assay. The GSK3359609 and anti-CTLA-4 combination 
resulted in a significant enhancement in IFN γ production compared to either agent alone 
in both the PBMC assay as well as the MLR assay. Refer to the GSK3359609 
Investigator’s Brochure (IB) [GSK Document Number 2017N319717_01] for further 
details. 
Tremelimumab is a human immunoglobulin (Ig)G2 mAb that is directed against CTLA-
4; cluster of differentiation [CD]152, a cell surface receptor that is expressed primarily on 
activated T cells and acts to inhibit their activation. Tremelimumab completely blocks the 
interaction of human CTLA-4 with CD80 and CD86, resulting in increased release of 
cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral 
blood mononuclear cells and whole blood [Tarhini, 2008]. Tremelimumab is being 
developed by AstraZeneca for use in the treatment of cancer. 
To date, tremelimumab has been given to more than 1500 patients as part of ongoing 
studies either as monotherapy or in combination with other anticancer agents. Refer to the 
current tremelimumab IB [AstraZeneca, 2017] for a complete summary of non-clinical 
and clinical information including safety, efficacy and pharmacokinetics.
Emerging data from patients treated with anti-CTLA-4 antibodies suggest a positive role 
of ICOS+ effector T cells in mediating an antitumor immune response. Patients with 
metastatic melanoma [Di Giacomo, 2013], urothelial [Carthon, 2010], breast 
[Vonderheide, 2010] or prostate cancer [Chen, 2009] who have increased absolute counts 
of circulating and tumor infiltrating CD4+ICOS+ and CD8+ICOS+ T cells after 
ipilimumab treatment have significantly better treatment related outcomes than patients 
where little or no increases are observed. Importantly, it was shown that ipilimumab 
changes the ICOS+ T effector to Treg ratio, reversing an abundance of Tregs pre-
treatment to a significant abundance of T effectors vs. Tregs following treatment [Liakou, 
2008; Vonderheide, 2010]. As evidenced by the clinical data, ICOS+ T effector cells may 
be a positive predictive biomarker of ipilimumab response, and activation of this 
population of cells with an ICOS agonist antibody may show enhanced clinical activity 
than either agent alone. As suggested in the literature [Melero, 2013], the complimentary 
mechanisms of actions of CTLA-4 blocking antibodies which inhibit the suppressive
action on T cells thus ‘taking off the brakes’ and activating them while combining with 
an ICOS agonist antibody which further co-stimulates the activated T cells for enhanced 
effector function and proliferation has the potential to mount a more robust immune 
antitumor response.
As evident from the clinical efficacy of antibodies directed against checkpoint inhibitors
indicated for the treatment of cancers, targeting immune checkpoint modulators is an 
established concept that has resulted in patients deriving transformational clinical benefit. 
The unique mechanistic profile of an anti-ICOS agonist antibody provides an opportunity 
to investigate the antitumor potential of targeting a T cell co-stimulator in combination


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with other immune-targeted agents that regulate key immune pathways or immune cell 
populations as well as tumor targeted agents, either in development or already in clinical 
use. The aim of this approach is to achieve synergistic antitumor responses that translate 
into improvement in patient survival.
2.3.
Benefit/Risk Assessment
GSK3359609 is being currently investigated in a Phase 1 study 204691 with doses 
ranging from 0.001 mg/kg to 3 mg/kg as monotherapy and from 0.01 mg/kg to 3 mg/kg 
in combination with a PD-1 inhibitor. GSK3359609 has been generally well tolerated in 
the 204691 study and the majority of AEs reported in participants receiving monotherapy 
were Grade 1 or Grade 2. More detailed information about the known and expected 
benefits and risks and reasonably expected AEs is provided in the GSK3359609 IB [GSK 
Document Number 2017N319717_01]. Risks with tremelimumab monotherapy include, 
but are not limited to: GI effects (colitis, diarrhea, enterocolitis and intestinal 
perforation); endocrine disorders (hypo and hyperthyroidism, hypophysitis and adrenal 
insufficiency); skin effects (rash, and pruritus); elevations in lipase and amylase and 
clinical manifestations of pancreatitis; other gastrointestinal events e.g., ulcerative colitis, 
dehydration, nausea and vomiting; hepatic events including hepatitis, and liver enzyme 
elevations; pneumonitis and ILD; nervous system events including encephalitis, 
peripheral motor and sensory neuropathies, Guillain-Barre and proximal muscle 
weakness; cytopenias including thrombocytopenia, anemia and neutropenia; infusion-
related reactions, anaphylaxis, and allergic reactions; renal events including renal failure, 
acute kidney injury, nephritis, nephrotic syndrome, autoimmune nephritis and electrolyte 
abnormalities such as hypokalemia; autoimmune diseases including autoimmune arthritis, 
Sjogren’s syndrome and giant cell temporal arteritis; hyperglycemia and diabetes 
mellitus; and pyrexia. However, while tremelimumab has been used extensively with a 
clearly defined toxicity profile, the data at the doses and schedule studied in the study is 
limited. Therefore, the combination of GSK3359609 and tremelimumab could have an 
unknown toxicity profile. More detailed information about the known and expected 
benefits and risks and reasonably expected AEs are provided in the tremelimumab IB
[AstraZeneca, 2017].
2.3.1.
Risk Assessment
The risk assessment and mitigation strategy for GSK3359609 in combination with 
tremelimumab in this protocol is outlined in Table 1. 
Table 1
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-

Participants with the following 
medical history are ineligible for
this study
o Toxicity (Grade 3) related to 
prior immunotherapy leading 
to study intervention
discontinuation 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
stimulatory mechanism of action 
of these agents.
o Active autoimmune disease 
(refer to Section 5.2)
o Severe hypersensitivity to 
another mAb

Established management 
algorithms for irAEs

Refer to Section 6.6.1 for further 
details on the identification, 
evaluation, and management of 
toxicities with a potential immune 
etiology.
Hypersensitivity reaction

Risk for infusion reactions and 
hypersensitivity is inherent to 
many mAbs [Brennan, 2010]

Participants with history of 
severe hypersensitivity to 
another mAb or to the 
chemotherapies under 
investigation including any 
ingredient used in the formulation 
are ineligible for this study 

Refer to Section 6.6.2 for further 
details on management of 
infusion reactions.
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.

Refer to Section 6.6.2 for further 
details on management of CRS.
Immune complex disease

Immune complex formation and 
deposition findings in nonclinical 
safety studies (refer to the 
individual IBs)

Clinical laboratory safety 
assessments and 
immunogenicity testing
Abbreviations: AE= adverse event; CRS=cytokine release syndrome; ICOS=inducible T cell co-stimulator; 
IB=Investigator’s brochure; mAb=monoclonal antibody; TCR=T cell receptor
2.3.2.
Benefit Assessment
This is a Phase I/II open-label study of GSK3359609 in combination with tremelimumab
conducted in participants with select advanced solid tumors that are relapsed/refractory to 
standard therapies. Both GSK3359609 and tremelimumab monotherapies and the 
combination of the two targets have demonstrated preclinical activity; however, whether 
the combination of GSK3359609 and tremelimumab together clinically will have a 


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greater antitumoral response is unknown. Therefore, any potential beneficial effect for an 
individual participant attributable to combination therapy with GSK3359609 and 
tremelimumab is unknown. 
2.3.3.
Overall Benefit: Risk Conclusion
Data from nonclinical models suggest the combination of anti-ICOS agonist and anti-
CTLA-4 antibodies has the potential for enhanced antitumor activity through 
complementary mechanisms (refer to Section 2.2). Measures are taken to minimize the 
risks to participants participating in this study (e.g., frequent safety and disease 
assessments). Therefore, the potential risks identified in association with GSK3359609 as 
a combination therapy with tremelimumab are justified by the anticipated benefits that 
may be afforded to participants with relapsed/refractory solid tumors. The participants in 
this study have exhausted other standard therapy options resulting in a great unmet 
medical need for alternate therapies. Thus, the risk to these participants is justified when 
weighed against the potential benefits of combination therapy.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Part 1: Dose Escalation of GSK3359609 in Combination with 
Tremelimumab
Objectives
Endpoints
Primary

Determine safety, tolerability and the
RP2D of GSK3359609 in combination 
with tremelimumab 

Frequency and severity of DLTs, AEs, 
AESI, SAEs and DLT/AE/SAEs leading to 
dose modifications/delays/withdrawals; 
changes in laboratory, vital signs, and 
ECG safety assessment parameters
Secondary

Evaluate clinical activity of GSK3359609 
in combination with tremelimumab

ORR, DCR

Characterize the PK properties of 
GSK3359609 and tremelimumab when 
administered in combination

Cmax, Cmin, AUC (0-t) of GSK3359609 
and tremelimumab as data permit

Determine immunogenicity of 
GSK3359609 and tremelimumab when 
administered in combination

Detection and characterization of ADA 
against GSK3359609 and/or 
tremelimumab
Exploratory

Evaluate clinical activity of GSK3359609 
in combination with tremelimumab

PFS, OS, TTR, DoR

Evaluate pharmacodynamic changes in 
markers of target engagement, immune 
cell profiles, immune activation and 
function or tumor biology post treatment 

Immunophenotyping and functional 
analysis

Other biomarkers such as gene 


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Objectives
Endpoints
compared to that at screening
expression changes, relevant transcripts, 
TCR diversity, and/or soluble analytes
AEs = adverse events; SAEs = serious adverse events; DLTs = dose limiting toxicities; AESI = adverse events of 
special interest; RP2D = recommended phase 2 dose; ORR = overall response rate; DCR = disease control rate; 
Cmax = maximum observed concentration; Cmin = minimum observed concentration; AUC (o-t) = area under the 
concentration-time curve over the dosing interval; ADA = anti-drug antibodies; PFS = progression-free survival; OS = 
overall survival; TTR = time to response; DoR = duration of response; TCR = T cell receptor.
3.2.
Part 2: Cohort Expansion of the RP2D Dose Combination vs. 
SOC in R/R HNSCC
Objectives
Endpoints
Primary

Evaluate clinical activity of GSK3359609 
in combination with tremelimumab
compared to SOC

OS
Secondary

Further evaluate the clinical activity of 
GSK3359609 in combination with 
tremelimumab compared to SOC

ORR, DCR, PFS, TTR, DoR

Further evaluate the PK properties of 
GSK3359609 and tremelimumab when 
administered in combination

Cmax, Cmin, AUC (0-t) of GSK3359609 
and tremelimumab as data permit

Further evaluate immunogenicity of 
GSK3359609 and tremelimumab when 
administered in combination

ADA incidence 

Further evaluate the safety and 
tolerability of GSK3359609 and 
tremelimumab when administered in 
combination

Frequency and severity of AEs, AESI,
SAEs and AE/SAEs leading to dose 
modifications/delays/withdrawals; 
changes in laboratory, vital signs, and 
ECG safety assessment parameters
Exploratory 

Examine potential relationships between 
anticancer activity and changes in 
markers of target engagement immune 
cell profiles, immune activation and 
function or tumor biology post treatment 
compared to that at screening

Immunophenotyping and functional 
analysis, anticancer activity parameters

Other biomarkers such as gene 
expression changes, relevant transcripts, 
TCR diversity, and/or soluble analytes

Evaluate other measures of antitumor 
activity

Evaluation of tumor growth kinetic 
parameters which may be measured by 
the following methods: including, but not 
limited to, RECIST 1.1, uni-dimensional, 


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Objectives
Endpoints
bi-dimensional, and volumetric tumor 
measurements

Explore relationship between antitumor 
activity, PK parameters, 
pharmacodynamic activity and other 
participant characteristics

Antitumor activity (CR, PR, SD, PD), 
tumor kinetic parameters, PK 
parameters, pharmacodynamic activity, 
and other participant characteristics as 
data permit

Examine potential relationships between 
anticancer activity and various 
biomarkers 

Evaluate potential markers of sensitivity
and/or resistance to the treatment

Target expression, immune phenotypes, 
HPV positivity for HNSCC tumors, TCR 
(T cell receptor) sequencing, genetic 
polymorphisms in the target or other 
related gene expression and/or tumor 
mutational burden

Evaluate disease and treatment related 
symptoms and impact on function and 
health-related quality of life

Health-related quality of life as measured 
by the EORTC-QLQ-C30 and HN35, 
PROMIS-PF, and EQ-5D

Evaluate participant-reported tolerability

PRO-CTCAE and FACT GP5
OS = overall survival; SOC = standard of care; ORR = overall response rate; DCR = disease control rate; ; PFS = 
progression-free survival; TTR = time to response; Cmax = maximum observed concentration; Cmin = minimum 
observed concentration; AUC (0-t) = area under the concentration-time curve over the dosing interval ; DoR = 
duration of response; TCR = T cell receptor; ADA = anti-drug antibodies; AEs = adverse events; SAEs = serious 
adverse events; RECIST = response evaluation criteria in solid tumors; PK = pharmacokinetic; EORTC QLQ-C30
and HN35 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 
30 and head and neck cancer 35 module; EQ-5D = = EuroQOL Group EQ-5D; FACT GP5 = Functional 
Assessment of Cancer Therapy – General Physical Well Being Item 5; PROMIS PF = Patient-Reported Outcome 
Measurement Information System – Physical Function; Impression of Change; PRO-CTCAE = Patient Reported 
Outcomes – Common Terminology Criteria for AEs
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I/II, open-label, 2-part study of GSK3359609 in combination with 
tremelimumab. As illustrated in Figure 1 in Section 1.2, Part 1 is dose escalation and will 
enroll participants with advanced, selected solid tumors and Part 2 is randomized 
expansion and will enroll participants with R/R HNSCC who have progressed after 
receiving at least 1 platinum-based chemotherapy and at least 1 anti-PD-1/PD-L1
therapy, whether in combination or separately.
Study intervention will be defined as treatment with GSK3359609 and tremelimumab, 
given in combination. In Part 2 participants will be randomized at a ratio of 2:1 to either 
the study intervention or SOC, respectively.
The study is comprised of 3 periods: screening (assessments up to 30 prior to first dose), 
treatment (until disease progression, unacceptable toxicity or death), and follow-up. The 
total duration of study participation begins with the signing of the informed consent form 


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(ICF) through the final protocol-defined follow-up assessment for survival and is 
estimated to be up to 4 years (~2 years on treatment and ~2 years in survival follow-up); 
however, participants deriving benefit may be on study intervention beyond 2 years. 
4.1.1.
Part 1: Dose Escalation of Tremelimumab and GSK3359609
In Part 1 dose escalation, eligible participants will receive GSK3359609 in combination 
with tremelimumab at a defined dosing schedule (see Section 6.1). Part 1 will initiate 
with 8 mg GSK3359609 and 75 mg tremelimumab (termed dose level [DL] 1), the 
planned lowest doses for each agent. The highest planned doses are 80 mg GSK3359609 
and 225 mg tremelimumab (termed DL6). GSK3359609 will be administered every 3 
weeks and tremelimumab will be administered every 3 weeks for 6 doses, followed by 
every 12 weeks. Tremelimumab is to be administered first as an IV infusion over 60 
minutes. GSK3359609 will be administered as a 30-minute IV infusion beginning at least 
1 hour and no more than 2 hours following the end of the tremelimumab infusion. As 
shown in Figure 1, dosing will begin at DL1 and continue using zone-based dose 
escalation rules whereby each zone must be cleared for safety prior to opening the next 
zone of DLs. 
DL1 and DL2 will enroll one participant each to obtain preliminary safety data that will 
inform the toxicity probability model; these DLs will be expanded to enroll at least two 
additional participants if a Grade 2 or above toxicity attributable to either agent or a Dose 
Limiting Toxicity (DLT) is observed. DL3, DL4, DL5, and DL6 will enroll as full safety 
cohorts, i.e., 3 to 9 participants will be enrolled for each DL guided by the bivariate CRM 
model [Neuenschwander, 2008; Neuenschwander, 2014] until the MTD or MAD dose 
combinations are determined. Unplanned DLs within the range of the planned doses of 
each agent may be investigated to support the identification of optimal doses to 
administer in combination. Additionally, doses lower than planned of either agent may be 
investigated. If a participant withdraws from the study before the completion of the 28-
day DLT evaluation period for reasons other than DLT, then the participant may be 
replaced.
In the absence of DLTs, the dose escalation rules are deterministic. Participant allocation 
in this stage is determined entirely by the preferred dose order. If DLTs are observed, a 
bivariate CRM model will be used to guide dose recommendations. This model will 
provide posterior probability of observing a DLT at all dose combination levels based on 
emerging DLT data and prior information. In addition to the zone-based escalation rule, 
dose escalation will follow two rules. First, if the next preferred DL has excessive risk of 
toxicity, then that DL cannot be assigned. Instead, a new participant will be assigned to 
the highest preferred DL without such risk of toxicity. It is noted that the recommended 
DL should not be in a zone if “lower” zones have not been “cleared”. Second, if one DL
emerges as having a much higher chance of having a DLT rate in the target toxicity 
interval (DLT rate between 16% and 33%), that DL will be opened for enrollment. This 
latter situation occurs rarely with the sample size anticipated in this study. Thus, the most 
common use of the model is to eliminate allocation to potentially unsafe doses in 
combination. Details of the bivariate CRM method are provided in Appendix 10.
Dose recommendations based on the bivariate CRM analysis will be used as guidance for 
the data review team. To ensure safety of participants, additional participants may be 


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enrolled at a current DL at the discretion of the data review team, even though a higher 
dose is recommended by CRM analysis.
PK/pharmacodynamic cohort(s) may be initiated at any DL(s), once safety is cleared, 
with mandatory paired tumor sample collections to inform on dose selection for Part 2 of 
the study. In DLs enrolling more than 1 participant, treatment will be administered at 
least three days apart between the first two participants enrolled; the third and any 
subsequent participants will be administered treatment at a minimum of 24 hours apart. 
This staggered approach allows for an initial assessment of safety in a participant accrued 
to a dose level before initiating the next participant’s treatment. 
A single dose combination will be selected as the recommended Phase 2 dose (RP2D)
and carried forward from Part 1 into Part 2. The totality of data, including 
safety/tolerability, PK, pharmacodynamic, and efficacy will be used to determine whether 
to proceed to Part 2 and which dose combination will be chosen as the RP2D.
At the time of each dose escalation decision for which the bivariate CRM model would 
be implemented, the Fixed and Adaptive Clinical Trial Simulator (FACTSTM version 6.1 
or above) will be used. The recommended dose will be the dose with the highest posterior 
probability of lying in the target toxicity interval with the additional requirement that the 
sum of the posterior probabilities of the DLT rate in the excessive toxicity or 
unacceptable toxicity range is less than 25% (see details in Section 10.10.1).
4.1.1.1.
Dose Limiting Toxicity
The severity of all toxicities will be graded using the NCI-CTCAE (version 5.0) [NCI, 
2017]. The DLT observation period is 28 days in length and begins on the day 
GSK3359609 and tremelimumab are first administrated to the participant.
A DLT is defined as an AE that meets at least one of the criteria listed in Table 2 and is 
considered by the Investigator to be clinically relevant and attributed (probably, or 
possibly) to the study intervention during the 28-day DLT observation period. An AE 
considered related to the underlying disease under study is not defined as a DLT.


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Table 2
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Febrile neutropenia 

Grade 4 neutropenia of >7 days in duration or requiring G-CSF

Grade 4 anemia 

Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia
Non-
hematologic

Grade 4 toxicity

Grade 3 pneumonitis 

Any ≥ Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days 
of the initiation of maximal supportive care

Grade 3 toxicity that does not resolve to Grade 1 or baseline within 3 days 
despite optimal supportive carea

Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 
ocular toxicity
Other

Any other toxicity considered to be dose-limiting which in the judgment of the 
Investigator and Medical Monitor that occurs within or beyond four weeks will 
be considered in the selection of the dose to recommend for expansion 
cohorts
a.
Suggested toxicity management guidelines are described in Section 6.6.1 and may include systemic 
corticosteroids for immune-related toxicities; if systemic corticosteroids use delays administration of the second 
dose(s) of study intervention and the event does not otherwise meet the DLT criteria for non-hematologic toxicity, 
the dose delay will not be considered a DLT.
If a participant experiences a DLT during the DLT observation period, the participant
may resume dosing at the same or lower dose level provided the toxicity did not meet 
study treatment discontinuation criteria and following approval by the Sponsor.
4.1.1.2.
Non-Limiting Toxicities
The following toxicities have been deemed to be non-limiting for the purposes of this 
study. These toxicities will not be taken into account for dose escalation decisions unless, 
in the opinion of the investigator and the Medical Monitor, they represent a DLT.

Grade 3 and Grade 4 clinically asymptomatic laboratory abnormalities (e.g., 
amylase or lipase)

Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy and the participant is asymptomatic

Grade 3 nausea, vomiting, or fatigue that resolves to ≤Grade 1 within 7 days with 
optimal supportive care

Grade 3 and Grade 4 infusion-related reactions (IRRs) in participants not 
receiving prophylaxis for IRRs 

Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc)


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4.1.1.3.
Dose Escalation Decisions and Selection of Part 2 Dose
A data review team, consisting (at a minimum) of the participating Investigator(s), 
Medical Monitor, pharmacokineticist, and statistician, will be responsible for determining 
whether dose escalation during Part 1 should continue as planned and for determining the 
Part 2 dose. Prior to the dose escalation/selection decision, the data review team will
review available relevant data on all AEs including non-DLTs, laboratory assessments 
and other safety evaluations, as well as available PK and pharmacodynamic data. The 
dose escalation/selection decisions and rationale will be documented in writing with 
copies maintained at each study site and in the master study files at GlaxoSmithKline 
(GSK). Further details may be found in the Dose Escalation and Selection Plan. 
4.1.2.
Part 2: Cohort Expansion of the RP2D Dose Combination vs. SOC
In Part 2, eligible participants will be randomized 2:1 to open-label GSK3359609 plus 
tremelimumab at the RP2D (n 60) or a SOC single-agent therapy of the Investigator’s 
choice to include paclitaxel, docetaxel or cetuximab (n 30). See Section 6.1 for details. 
Part 2 will employ a Bayesian analysis to estimate the predictive probability of observing 
a significant improvement of OS in a hypothetical future Phase 3 trial enrolling 345
participants (230 participants for investigational RP2D dose combination and 115 
participants for SOC), based on the treatment effect difference in OS between the two 
arms in Part 2.
4.2.
Scientific Rationale for Study Design
The combination of GSK3359609 and tremelimumab was selected based on
complementary mechanisms of action and anticipated robust antitumor activity.
Eligibility criteria require that participants have disease that has progressed after standard 
therapies or are otherwise unsuitable for standard therapies, and the criteria are intended 
to minimize the risk of adverse reactions to treatment with immunotherapies. These 
participants have an unmet medical need.
In Part 1, dose escalation will be performed using bivariate CRM model to optimize the 
allocation of participants to dose combinations with a 16-33% DLT frequency. The DLT 
criteria are based on typical oncology rules with additional modifications for toxicities 
expected for the individual agents in the combination.
In Part 2, the cohort expansion design provides efficiencies in the evaluation of 
anticancer activity of the investigational dose combination when compared with the SOC.
The GSK3359609/tremelimumab combination regimen will subsequently graduate to 
separate Phase 3 confirmatory studies if the prespecified probability threshold is met at 
the final analyses.


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4.3.
Justification for Dose
4.3.1.
GSK3359609 Dose Rationale
Preliminary PK data from study 204691 was utilized to develop a population PK model 
and estimate median steady-state peak and trough exposures at different fixed doses. The 
8, 24, 80, and 240 mg dose corresponds to an approximate 0.1, 0.3, 1, and 3 mg/kg dose 
assuming median body weight of 80 kg as described in Section 4.3.1.2.
The functional effect of GSK3359609 has been characterized in several in vitro
experiments yielding different activity coefficients depending on cell type, co-stimulation 
status, and cytokines analysed. The ICOS receptor occupancy (RO) based on CD4+ or 
CD8+ T cells at any given systemic exposure of GSK3359609 can be predicted by 
employing the in vitro potency values generated from different binding/activation assays 
in the range of 0.09 to 4.14 µg/mL as listed in Table 3.
Sufficiently high CD4+ RO is expected at peak exposures (89% to >99% RO) as well as 
at trough exposures (69% to >99% RO) at steady-state with a GSK3359609 dose of
80 mg. 
Collectively, based on the safety and exposure data from the Phase 1 study and the 
predicted target engagement, 8, 24, and 80 mg doses are proposed to be evaluated in 
combination with tremelimumab in this study. No drug-drug interaction related changes 
are expected in GSK3359609 PK with tremelimumab co-administration. Additionally, 
doses lower than the planned lowest 8 mg dose may be investigated based on emerging 
data.
Table 3
Projected CD4+ Receptor Occupancy from Population PK Predicted 
Median Steady-state Peak and Trough Exposures of GSK3359609 
based on in vitro potency estimates.
Dose
(mg)
Cmax
(g/mL)
C
(g/mL)
RO based on Kd
[0.09 g/mL]
(%)
RO based on T-
cell binding 
[0.989 g/mL] (%)
RO based on IFN
release (bound) 
[4.14 g/mL] (%)
At 
Cmax
At C
At 
Cmax
At C
At 
Cmax
At C
8
3.47
0.919
97.5
91.1
77.8
48.2
45.6
18.2
24
10.3
2.73
99.1
96.8
91.3
73.4
71.4
39.8
80
34.7
9.23
99.7
99.0
97.2
90.3
89.3
69.0
240
103.6
27.3
99.9
99.7
99.1
96.5
96.2
86.8
Refer to GSK3359609 IB [GSK Document Number 2017N319717_01] for further 
details. 
4.3.1.1.
GSK3359609 Dosing Frequency
The systemic half-life of GSK3359609 is approximately 25 days based on the 
preliminary population PK analysis of exposure data from ongoing study 204691. The 
existing GSK3359609 Q3W regimen in the ongoing clinical study is also consistent with 


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the Q3W dosing regimen typical with IgG4 based monoclonal antibody therapies. Thus, 
GSK3359609 will be dosed Q3W in combination with tremelimumab. 
4.3.1.2.
GSK3359609 Rationale for Fixed Dose
Therapeutic monoclonal antibodies are often dosed based on body-size due to the concept 
that this reduces inter-participant variability in drug exposure. However, body-weight 
dependency of PK parameters does not always explain the observed variability in the 
exposure of monoclonal antibodies [Zhao, 2017]. The advantage of body-weight based 
versus fixed dosing in this study was evaluated through population PK modelling and 
simulation efforts. A preliminary population PK model was developed from monotherapy 
dose escalation (data up to doses of 1 mg/kg; n 19 participants). 
Simulations were performed by considering body weight distribution similar to that 
observed in the preliminary dataset. At the 5th percentile of body weight (40 47 kg), there 
was a 70-100% increase in median steady-state AUC(0-); GSK3359609 exposures 
higher than these increases have been evaluated in the Phase 1 study 204691 with the 
3 mg/kg dose regimen. At the 95th percentile of body weight (107 118 kg), there was a 
23-32% decrease in median steady-state AUC(0-) as compared to the median 80 kg 
exposure providing adequate RO with the minimal lowering of exposure. A similar 
outcome is expected for steady-state Cmax and trough concentrations between body 
weight-based and fixed dosing. 
Overall, these preliminary population PK simulations indicate that using fixed dosing 
would result in a similar range of exposures as that of body weight-based dosing. Also, 
fixed dosing offers the advantage of reduced dosing errors, reduced drug wastage, 
shortened preparation time, and improved ease of administration. Thus, switching to a 
fixed dose based on a reference body weight of 80 kg is reasonable and appropriate.
4.3.2.
Tremelimumab Dose Rationale
Tremelimumab is an IgG2 mAb against human CTLA-4. In clinical studies, 
Tremelimumab exhibited dose-proportional PK following IV infusion following single 
IV doses of 0.1 to 15 mg/kg. Refer to tremelimumab IB [AstraZeneca, 2017] for further 
details.
The current study will administer tremelimumab as a flat dose regimen of 75 mg and 
225 mg approximating the 1 mg/kg and 3 mg/kg regimens already evaluated in multiple 
tremelimumab mono- and combination therapy studies. Tremelimumab has also been 
evaluated at a 10 mg/kg dose in combination with durvalumab, an anti-PD-L1 antibody, 
where tremelimumab was administered as 10 mg/kg Q4W for 6 cycles followed by 
10 mg/kg Q12W [Antonia, 2016]. The dosing regimen for the proposed doses in this 
study is Q3W for the first six doses and Q12W thereafter. This Q3W dosing frequency 
for tremelimumab matches the GSK3359609 Q3W dosing frequency providing greater 
patient convenience. The overall tremelimumab systemic exposures with the highest 
proposed 225 mg regimen (225 mg Q3W for 6 cycles followed by 225 mg Q12W) in the 
current study are expected to be well below the exposures observed with 10 mg/kg 
regimen (10 mg/kg Q4W for 6 cycles followed by 10 mg/kg Q12W) studied as 


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monotherapy and combination therapy. No drug-drug interaction related changes are 
expected in GSK3359609 PK with tremelimumab co-administration.
4.4.
End of Study Definition
The end of the study is defined as the date of the completion of the last participant’s 
required follow-up visit or contact after study intervention/SOC discontinuation, death, or 
final visit or contact following discontinuation for any reason.
4.4.1.
Participant Completion
For Part 1, dose escalation, participants will be considered as having completed the study 
if they:

complete screening assessments, and receive at least two doses of study 
intervention or receive one dose but experience a DLT, and are observed during 
the 28-day DLT observation period, and the follow-up visit for safety (if 
required), or 

complete screening assessments and have died while receiving study intervention
or during the follow-up period for safety
For Part 2, the dose expansion part of the study, participants will be considered as having 
completed the study if they:

complete the screening assessments, and receive at least one dose of study 
intervention or SOC, and discontinue study intervention or SOC for reasons other 
than lost to follow-up or non-compliance, and complete the follow-up visit for 
safety (if required), and are followed until death, or

complete screening assessments and have died while receiving study intervention
or SOC or during the post-study follow-up period for safety
Document the cause of death in the eCRF.
A participant will be considered to have withdrawn from the study if the participant has 
not died and is lost to follow-up, has withdrawn consent, at the investigator’s discretion is 
no longer being followed or if the study is closed/terminated.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.


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5.1.
Inclusion Criteria
Participants are eligible to be included in the study only 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 ICF and in this protocol.
2. Male or female, aged 18 years or older.
3. Body weight ≥ 30 kg.
4. Histological or cytological documentation of an invasive malignancy that was 
diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the 
following tumor types: 
a.
Part 1:
i. Cutaneous Melanoma
ii. Head and Neck Squamous Cell Carcinoma (HNSCC) (oral cavity, 
larynx, oropharynx, hypopharynx, nasal cavity/paranasal sinuses)
iii. Non-Small Cell Lung Cancer (Squamous and Non-squamous)
iv. Urothelial carcinoma of the upper and lower urinary tract
v. Clear Cell Renal Carcinoma
vi. Castrate Resistant Prostate Adenocarcinoma 
b. Part 2:
Head and Neck Squamous Cell Carcinoma (oral cavity, larynx, pharynx, 
paranasal sinuses)
5. Part 1 only: Disease that has progressed after standard therapy for the specific tumor 
type, or for which standard therapy has proven to be ineffective, intolerable, or is 
considered inappropriate, or if no further standard therapy exists, or where standard 
therapy is refused. May be anti-PD-1/anti-PD-L1 experienced or naïve. 
6. Part 2 only: Disease that has progressed after receiving platinum-based chemotherapy 
(unless medically contraindicated or discontinued due to toxicity) and anti-PD-1/anti-
PD-L1 therapy (in combination or as separate lines of therapy in either sequence).
7. Measurable disease per response evaluation criteria in solid tumors (RECIST) version 
1.1 guidelines. Palpable lesions that are not measurable by radiographic or 
photographic evaluations may not be utilized as the only measurable lesion. Any 
measurable lesion biopsied at Screening cannot be followed as a target/index lesion 
unless agreed upon by GSK.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 
1.
9. Adequate organ function as defined in Table 4.


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Table 4
Definitions of Adequate Organ Function
System
Laboratory Values
Hematologica
Absolute neutrophil count
1.5x109/L
Absolute lymphocyte count
800/mm3
Hemoglobin
9 g/dL
Platelets
100x109/L
Hepatic
Albumin
2.5 g/dL
ALT
2.5xUpper Limit of Normal (ULN) 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%)
Renal
Calculated CrClb
30 mL/min
Cardiac
Ejection fractionc
≥50%
a.
Participants may be transfused or receive growth factor treatment to meet minimum hematologic values up to 7 
days prior to determining eligibility
b.
Calculated CrCl is required to be calculated using one of the formulas described in Appendix 8. Either formula is 
acceptable and must be used consistently for each participant throughout the study.
c.
Multigated acquisition scan (MUGA) is acceptable if ECHO is not available; if measured with ECHO or MUGA, the 
same modality must be used for all subsequent evaluations (refer to Section 8.2.5). 
10. A female participant is eligible to participate if she is not pregnant (see Appendix 4), 
not breastfeeding, and at least one of the following conditions apply:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4; 
or,
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4
while receiving study intervention and for at least 180 days after the last dose 
of study intervention. Note: If the participant is randomized to the SOC
regimen only, then the duration of contraception after the last dose of SOC
should be based on the package insert and Institutional guidelines. 
11. A male participant must agree to use a highly effective contraception as detailed in 
Appendix 4 of this protocol while receiving study intervention and for at least 180 
days after the last dose of study intervention and refrain from donating sperm during 
this period. Note: If the participant is randomized to the SOC regimen only, then the 
duration of contraception after the last dose of SOC should be based on the package 
insert and Institutional guidelines.
12. Agree to collection of tumor tissue:


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a.
Part 1 and Part 2: Archival tumor tissue collected any time from the initial 
diagnosis of invasive malignancy; a fresh tumor biopsy will be required if 
archival specimen is unavailable prior to first dose.
b. Part 1 PK/pharmacodynamic cohort(s): Archival tissue as noted in point (a)
above. Paired tumor biopsies: tumor tissue collected any time after completion 
of dosing of the last therapy and prior to first dose and an on-treatment biopsy.
c.
Part 2: A minimum of 15 participants from each arm will be required to 
provide paired tumor biopsies (in addition to the archival tissues as noted in 
point (a) above): tumor tissue collected any time after completion of dosing of 
the last therapy and prior to first dose and an on-treatment biopsy.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Received prior treatment with the following therapies; calculation is based on date of 
last therapy to date of first dose of study intervention or SOC:
a.
CTLA-4 (including tremelimumab) or ICOS-directed therapies at any time.
b. ≥4 lines of prior anticancer treatment:
i. In participants that relapse or progress within 1 year from the 
beginning of adjuvant or concurrent therapy, the adjuvant/concurrent 
therapy is considered first line therapy
c.
Systemic anticancer therapy or investigational therapy within 30 days, or 5
half-lives, whichever is shorter; at least 14 days must have elapsed between 
the date of the last prior therapy to the date of first dose of study intervention
or SOC.
2. Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is 
available for assessment per RECIST v1.1 or if a solitary measurable lesion was 
irradiated, objective progression is documented. At least 14 days must have elapses 
between the date of the last dosage of radiation and the first dose of study 
intervention/SOC.
3. Invasive malignancy or history of invasive malignancy other than disease under study 
within the last two years, except as noted below:
a.
Any other invasive malignancy for which the participant was definitively 
treated, has been disease-free for ≤2 years and in the opinion of the 
Investigator and Medical Monitor will not affect the evaluation of the effects 
of the study intervention or SOC on the currently targeted malignancy, may be 
included in this clinical study.


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b. Curatively treated non-melanoma skin cancer or successfully treated in-situ 
carcinoma
4. Toxicity from previous anticancer treatment that includes:
a.
≥Grade 3 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, vitiligo, hearing loss, endocrinopathy managed with replacement 
therapy, and peripheral neuropathy which must be ≤Grade 2).
5. Central nervous system (CNS) metastases, with the following exception: Participants 
with previously treated CNS metastases who are clinically stable and had no 
requirement for steroids during at least 14 days prior to first dose of study 
intervention or SOC. 
Note: Participants with carcinomatous meningitis or leptomeningeal spread are 
excluded regardless of clinical stability.
6. Major surgery 28 days of first dose of study intervention or SOC.
Note: Tracheostomy is not considered major surgery.
7. Autoimmune disease (current or history) or syndrome that required systemic 
treatment within the past 2 years. Replacement therapies which include physiological 
doses of corticosteroids for treatment of endocrinopathies (i.e., adrenal insufficiency) 
are not considered systemic treatments.
8. Recent history (within 24 weeks) of gastrointestinal obstruction that required surgery, 
acute diverticulitis, inflammatory bowel disease, or intra-abdominal abscess.
9. Receiving systemic steroids (≥10 mg oral prednisone or equivalent) or other 
immunosuppressive agents within 7 days prior to first dose of study intervention or 
SOC.
Note: Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication) are permitted. 
10. Prior allogeneic/autologous bone marrow or solid organ transplantation.
11. Received live-virus vaccine within 30 days from start of study intervention or SOC.
Note: Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (for example, FluMist™) 
are live attenuated vaccines and are not allowed.
12. Current or history of idiopathic pulmonary fibrosis, pneumonitis (for past, participant 
is excluded if steroids were required), interstitial lung disease or organizing 
pneumonia


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Note: Post-radiation changes in the lung and/or asymptomatic radiation-induced 
pneumonitis not requiring treatment may be permitted if agreed upon by the 
Investigator and Medical Monitor.
13. Recent history (within 24 weeks) of uncontrolled, symptomatic ascites, pleural or 
pericardial effusions.
14. History or evidence of cardiac abnormalities within the 24 weeks prior to enrollment 
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.
Symptomatic pericarditis.
15. Current unstable liver or biliary disease per Investigator assessment defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease 
(including Gilbert’s syndrome or asymptomatic gallstones) is acceptable.
16. Active infection requiring systemic therapy.
17. Known human immunodeficiency virus infection; positive test for hepatitis B active 
infection (presence of hepatitis B surface antigen) or hepatitis C active infection; refer 
to Table 16 for additional details.
18. History of severe hypersensitivity to monoclonal antibodies, the Standard of Care 
agents, including any ingredient used in the formulation, based on which treatment 
the participant is to receive.
19. Any serious and/or unstable pre-existing medical (aside from malignancy), 
psychiatric disorder, or other conditions that could interfere with participant’s safety, 
obtaining informed consent or compliance to the study procedures, in the opinion of 
the Investigator.
20. For participants receiving SOC: Requires therapy with a medication that may alter the 
PK of the SOC agent (e.g., strong inducers or inhibitors of CYP3A4 for participants 
receiving docetaxel or paclitaxel) during the study treatment period. Please refer to 
the package insert for the agent the participant is to receive. 
21. For participants receiving SOC: Any contraindication, per the package insert and/or 
Institutional guidelines, to the treatment the participant is to receive. 


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5.3.
Lifestyle Considerations
Participants should refrain from donating blood while participating in this study.
Participants should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea, or vomiting. For participants receiving SOC, the 
Investigator should refer to the applicable package insert and/or Institutional guidelines 
for foods to avoid during the study treatment period (e.g., grapefruit, star fruit and 
pomegranate are known CYP3A4 inhibitors and should not be consumed while receiving 
docetaxel or paclitaxel). 
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are never subsequently assigned a randomization number. 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 
SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants must be assigned a new unique participant 
number that is different from the initial number.
6.
STUDY INTERVENTION
6.1.
Study Intervention(s) Administered
GSK3359609 and tremelimumab will be provided to sites by the study Sponsor. 
Investigator’s choice of SOC in Part 2 (paclitaxel, docetaxel or cetuximab) will be 
provided by the site per standard of care.
The route of administration for all agents is IV, thus they should be administered to 
participants at each study site under medical supervision of an Investigator or designee
(see Table 5).
Tremelimumab is to be administered first as an IV infusion over 60 minutes. 
GSK3359609 will be administered as a 30-minute IV infusion beginning at least 1 hour 
and no more than 2 hours following the end of the tremelimumab infusion. Infusion time 
of each may be adjusted based on infusion-related reactions.
Standard of care agents should be administered as per local and Institutional guidelines
(Table 6). Participants may receive necessary premedication regimens according to the 
approved product label or standard practice (i.e., corticosteroids, antihistamines, etc).


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Table 5
Description and Administration of Study Interventions
Study Intervention
Product Name:
GSK3359609
Tremelimumab
Product 
Description
Humanized anti-ICOS agonist IgG4 
mAb
Humanized anti-CTLA-4 IgG2 mAb
Dosage form 
/strength:
10 mg/mL solution
20 mg/mL solution
Planned dosage 
level(s):
Part 1: Dose escalation GSK3359609/tremelimumab: 8 mg/75 mg; 
8 mg/225 mg; 24 mg/75 mg; 24 mg/225 mg; 80 mg/75 mg; 80 mg/225 mg
Part 2: RP2D determined from Part 1
Route of 
Administration 
IV infusion
IV infusion
Dosing 
instructions/
Frequency:
Administer diluted product/Q3W
Administer diluted product/Q3W for 6 
doses then Q12W thereafter
Manufacturer
GSK
MedImmune
Table 6
Standard of Care Agents
Product Name:
Docetaxel
Paclitaxel
Cetuximab
Description
Microtubule stabilizer/
small molecule
Microtubule stabilizer/
small molecule
Recombinant, 
human/mouse 
chimeric anti-EGFR 
mAb
Dosage form/strength
Refer to package 
insert
Refer to package 
insert
Refer to package 
insert
Dosage/frequency
75 mg/m2
administered once 
every 3 weeks
80 mg/m2
administered once 
weekly
Administer a loading 
dose of 400 mg/m2
followed by 
250 mg/m2 once 
weekly
Route of 
administration
IV infusion
IV infusion
IV infusion
6.2.
Preparation/Handling/Storage/Accountability
Refer to the Study Reference Manual (SRM) for instructions on the preparation of 
investigational study interventions (both GSK3359609 and tremelimumab). Standard of 
Care agents should be prepared and handled per local and Institutional guidelines.

The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for each study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.


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
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.

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).

Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.

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
In Part 2 of the study, once determined to be eligible for the study, all participants will be 
centrally randomized using an Interactive Voice/Web Response System (IVRS/IWRS). 
Before the study is initiated, the telephone number and call-in directions for the IVRS
and/or the log in information and directions for the IWRS will be provided to each site. 
This is an open-label study; however, participants will be randomized to study 
intervention or SOC in Part 2 of the study using an IVRS/IWRS to reduce potential bias.
6.4.
Study Intervention Compliance
Study interventions will be intravenously administered to participants at the site. 
Administration will be documented in the source documents and reported in the CRF.
6.5.
Concomitant Therapy
Participants will be instructed to inform the Investigator prior to starting any new 
medications from the screening visit until discontinuation of study intervention. Any 
permitted concomitant medication(s), including non-prescription medication(s) and 
herbal product(s), taken during the study will be recorded in the eCRF. The minimum 
requirement for reporting is drug name, dose, dates of administration, and the reason for 
medication.
Questions regarding concomitant medications must be directed to GSK for clarification.


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If changes are made to the list of permitted/prohibited medications in the future, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites by letter.
For participants randomized to SOC, refer to the drug interaction information in the 
product package inserts for precautions and prohibited concomitant medications related 
to the SOC chosen by the Investigator. 
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, and treatment with antibiotics, 
antiemetics, antidiarrheals, and analgesics, as appropriate. Seasonal flu vaccine is 
permitted as an injection only, i.e., intra-nasal flu vaccine is not permitted. Elective 
palliative surgery or radiation may be permitted on a case-by-case basis in consultation 
with GSK Medical Monitor.
The following medications are permitted as indicated:
a.
Bisphosphonates and receptor activator of nuclear factor-kappaB ligand (RANKL) 
inhibitors (e.g., denosumab): Participants are required to have been on a stable dose 
for at least 4 weeks prior to receiving first dose of study intervention. Prophylactic 
use in participants without evidence or history of bone metastasis is not permitted, 
except for the treatment of osteoporosis.
b.
Growth factors: Initiation of growth factors is not permitted during the first 4 weeks 
of study intervention, unless clinically indicated for toxicity management and agreed 
upon by the Investigator and the GSK Medical Monitor.
c.
Steroids: Participants with pre-existing conditions requiring steroids are permitted to 
continue taking up to a maximum of 10 mg of prednisone or equivalent provided the 
participant has been on a stable dose for at least 28 days before first dose of study 
intervention; see exclusion criteria in Section 5.2 for further requirements. Steroids 
used for premedication of SOC and hypersensitivity reactions (e.g., CT scan 
premedication) are permitted.
d.
Treatment with cannabinoids prescribed by a Physician are permitted.
6.5.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited before the first dose of study intervention/SOC
(see Section 5.2 for specific time requirements) and during the study treatment period:
a.
Anticancer therapies other than those referred to as study intervention 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
c.
Live vaccines such as intra-nasal flu vaccine (see exclusion criteria in Section 5.2 for 
further details).


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d.
For participants receiving SOC, any medication that may alter the PK of the SOC 
agent (e.g., strong inducers or inhibitors of CYP3A4 for participants receiving 
docetaxel or paclitaxel) as per the package insert and/or Institutional guidelines.
6.6.
Dose Modification and Safety Management Guidelines
Distinct safety management guidelines, including dose modification algorithms, are 
provided in this section for participants treated with the combination of GSK3359609 and 
tremelimumab.
Please note: In instances where the Investigator is directed to permanently discontinue 
study intervention per Table 7, this is mandatory for tremelimumab and at the discretion 
of the Investigator for GSK3359609. However, GSK3356909 may only be restarted if the 
event resolves to ≤ Grade 1 within 14 days AND has been stable at ≤ Grade 1 for at least 
7 days and requires approval from the Medical Monitor. 
Refer to SOC prescribing information or standard practice guidelines for the management 
of AEs or potential safety-related issues. 
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.
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, 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. 
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 7, though irAEs may occur in 
nearly all organs, some of them not noted in the guidelines. Note: This guidance does not 
apply to participants randomized to SOC in Part 2.
Before administration of study intervention, investigators are to review a participant’s 
AEs, concomitant medications, and clinical evaluation results, e.g., vital signs, laboratory 
results, ECG, ECOG PS, physical examination findings, responses, etc. as outlined in the 
Schedule of Activities (Section 1.3) 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 


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colitis, uveitis, hepatitis, pneumonitis, diarrhea, endocrine disorders, and specific 
cutaneous toxicities, as well as other events that may be immune mediated. 
Table 7
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs
General Instructions for dose modifications:
Grade 1
No dose modifications
Grade 2
Hold study intervention until Grade 2 resolution to Grade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study intervention can be resumed once event stabilizes to Grade ≤1 after completion of steroid 
taper.
Participants with endocrinopathies who may require prolonged or continued steroid replacement 
can be retreated with study intervention on the following conditions:

The event stabilizes and is controlled.

The participant is clinically stable as per Investigator clinical judgement.

Doses of prednisone are at ≤10 mg/day or equivalent.
Consider whether study intervention should be permanently discontinued in events with high 
likelihood for morbidity and/or mortality (e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines) when they do not rapidly improve to Grade <1 upon 
treatment with systemic steroids and following full taper.
Grade 3
Depending on the individual toxicity, study intervention may be permanently discontinued. Please 
refer to guidelines below.
Note: For Grade ≥3 asymptomatic amylase or lipase levels, hold study intervention, and if 
complete work up shows no evidence of pancreatitis, study intervention may be continued or 
resumed.
Note: Study intervention should be permanently discontinued in Grade 3 events with high 
likelihood for morbidity and/or mortality – e.g., myocarditis, or other similar events even if they 
are not currently noted in the guidelines.
Grade 4
Permanently discontinue study intervention.
Note: There are some exceptions to permanent discontinuation of study drug for Grade 4 events 
(e.g., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).
Additionally, permanently discontinue study intervention for the following conditions:

Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or equivalent) within 12 weeks 
after last dose of study intervention.

Recurrence of a previously experienced Grade 3 treatment-related AE following resumption of dosing.
General Instructions for toxicity management:
It is possible that events with an inflammatory or immune-mediated mechanism could occur in nearly all organs, some 
of them not noted specifically in these guidelines. Whether specific irAEs (and/or laboratory indicators of such events) 
are noted in these guidelines or not, participants should be thoroughly evaluated to rule out any alternative etiology 
(e.g., disease progression, concomitant medications, and infections) to a possible immune-mediated event. In the 
absence of a clear alternative etiology, all such events should be managed as if they were immune related. General 
recommendations follow.

Symptomatic and topical therapy should be considered for low grade (Grade 1 or 2, unless otherwise 
specified) events. 

For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) events, promptly start prednisone 1 
to 2 mg/kg/day PO or IV equivalent.

Some events with high likelihood for morbidity and/or mortality (e.g., myocarditis, or other similar events even 
if they are not currently noted in the guidelines) should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if clinical suspicion is high and/or 
there has been clinical confirmation. Consider, as necessary, discussing with the Medical Monitor, and 
promptly pursue specialist consultation.

If symptoms recur or worsen during corticosteroid tapering (28 days of taper), increase the corticosteroid 
dose (prednisone dose [e.g., up to 2 to 4 mg/kg/day PO or IV equivalent]) until stabilization or improvement 
of symptoms, then resume corticosteroid tapering at a slower rate (>28 days of taper).

More potent immunosuppressives such as TNF inhibitors (e.g., infliximab) (also refer to the individual 


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sections of the irAEs for specific type of immunosuppressive) should be considered for events not 
responding to systemic steroids. Progression to use of more potent immunosuppressives should proceed 
more rapidly in events with high likelihood for morbidity and/or mortality (e.g., myocarditis, or other similar 
events even if they are not currently noted in the guidelines) when these events are not responding to 
systemic steroids.

With long-term steroid and other immunosuppressive use, consider need for Pneumocystis jirovecii
pneumonia (PJP, formerly known as Pneumocystis carinii pneumonia) prophylaxis, gastrointestinal 
protection, and glucose monitoring.

Discontinuation of study intervention is not mandated for Grade 3/Grade 4 inflammatory reactions attributed 
to local tumor response (e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study intervention in this situation should be based upon a benefit-risk analysis for that 
participant.
Specific Immune-Related AEs:
Immune-related 
AEs
Severity grade 
(CTCAEv5.0) or 
conditions 
Dose Modification / 
General Guidance 
Toxicity Management
Pneumonitis / 
Interstitial Lung 
Disease (ILD)
Any Grade
Monitor participants for signs and 
symptoms of pneumonitis or ILD (new 
onset or worsening shortness of breath 
or cough). Participants should be 
evaluated with imaging and pulmonary 
function tests, including other diagnostic 
procedures as described below.
Initial work-up may include clinical 
evaluation, monitoring of oxygenation via 
pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution 
CT scan.
Grade 1
(asymptomatic, 
clinical or 
diagnostic 
observations only; 
intervention not 
indicated)
No dose modifications 
required. However, 
consider holding study 
intervention dose as 
clinically appropriate and 
during diagnostic work-up 
for other etiologies.

Monitor and closely follow up in 2 to 4 
days for clinical symptoms, pulse 
oximetry (resting and exertion), and 
laboratory work-up and then as clinically 
indicated.

Consider Pulmonary and Infectious 
disease consult.
Grade 2
(symptomatic; 
medical 
intervention 
indicated; limiting 
instrumental 
activities of daily 
living [ADLs])
Hold study intervention 
until Grade 2 resolution to 
Grade ≤1.
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4.
If toxicity improves to 
Grade ≤1, then the 
decision to reinitiate 
study intervention will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper.

Monitor symptoms daily and consider 
hospitalization.

Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent).

Reimage as clinically indicated.

If no improvement within 3 to 5 days, 
additional workup should be considered 
and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started

If still no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab.

Once the participant is improving, 


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gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics,
antifungals, or anti-PJP treatment.

Consider pulmonary and infectious 
disease consult.

Consider, as necessary, discussing with 
Medical Monitor.
Grade 3 or 4
(Grade 3: severe 
symptoms; limiting 
self-care ADL; 
oxygen indicated)
(Grade 4: life-
threatening
respiratory 
compromise; 
urgent intervention 
indicated [e.g., 
tracheostomy or 
intubation])
Permanently discontinue 
study intervention.

Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent.

Obtain Pulmonary and Infectious 
disease consult; consider, as necessary, 
discussing with Medical Monitor.

Hospitalize the participant.

Supportive care (e.g., oxygen).

If no improvement within 3 to 5 days, 
additional workup should be considered 
and prompt treatment with additional 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks dose) started. 
Caution: rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Diarrhea / Colitis
Any Grade

Monitor for symptoms that may be 
related to diarrhea/enterocolitis (e.g., 
abdominal pain, cramping, or changes in 
bowel habits such as increased 
frequency over baseline or blood in 
stool) or related to bowel perforation 
(e.g., sepsis, peritoneal signs, and 
ileus).

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, other 
medications, or infections), including 
testing for clostridium difficile toxin, etc.

Steroids should be considered in the 
absence of clear alternative etiology, 
even for low-grade events, to prevent 
potential progression to higher grade 
event.

Monitor for symptoms that may be 
related to diarrhea/enterocolitis 
(abdominal pain, cramping, or changes 
in bowel habits such as increased 
frequency over baseline or blood in 
stool) or related to bowel perforation 
(such as sepsis, peritoneal signs, and 
ileus).

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, other 


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medications, or infections), including 
testing for clostridium difficile toxin, etc.

Steroids should be considered in the 
absence of clear alternative etiology, 
even for low-grade events, to prevent 
potential progression to higher grade 
event.

Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis.
Grade 1
(Diarrhea: stool 
frequency of <4 
over baseline per 
day)
(Colitis: 
asymptomatic; 
clinical or 
diagnostic 
observations only)
No dose modifications.

Monitor closely for worsening symptoms.

Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide. Use probiotics as 
per treating physician’s clinical 
judgment.
Grade 2
(Diarrhea: stool 
frequency of 4 to 6 
over baseline per 
day) 
(Colitis: abdominal 
pain; mucus or 
blood in stool)
Hold study intervention 
until resolution to Grade 
≤1.
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4.
If toxicity improves to 
Grade ≤1, then study 
intervention can be 
resumed after 
completion of steroid 
taper.

Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, dietary changes (e.g., 
American Dietetic Association colitis 
diet), and loperamide and/or 
budesonide.

Promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

If event is not responsive within 3 to 5 
days or worsens despite prednisone at 1 
to 2 mg/kg/day PO or IV equivalent, GI 
consult should be obtained for 
consideration of further workup, such as 
imaging and/or colonoscopy, to confirm 
colitis and rule out perforation, and 
prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started.

If still no improvement within 3 to 5 days 
despite 2 to 4 mg/kg IV 
methylprednisolone, promptly start 
immunosuppressives such as infliximab 
at 5 mg/kg once every 2 weeks. Caution: 
it is important to rule out bowel 
perforation and refer to infliximab label 
for general guidance before using
infliximab.

Consider, as necessary, discussing with 
Medical Monitor if no resolution to Grade 
≤1 in 3 to 4 days.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Grade 3 or 4
(Grade 3 diarrhea: 
stool frequency of 
≥7 over baseline 
Grade 3
Permanently discontinue if 
toxicity does not improve 
to Grade ≤1 within 14 

Promptly initiate empiric IV 
methylprednisolone 2 to 4 mg/kg/day or 
equivalent.

Monitor stool frequency and volume and 


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per day; Grade 4 
diarrhea: life 
threatening 
consequences)
(Grade 3 colitis: 
severe abdominal 
pain, change in 
bowel habits, 
medical 
intervention 
indicated, 
peritoneal signs; 
Grade 4 colitis: life-
threatening 
consequences, 
urgent intervention 
indicated)
days; study intervention 
can be resumed after 
completion of steroid 
taper.
Grade 4
Permanently discontinue 
study intervention. 
maintain hydration.

Urgent GI consult and imaging and/or 
colonoscopy as appropriate.

If still no improvement within 3 to 5 days 
of IV methylprednisolone 2 to 
4 mg/kg/day or equivalent, promptly start 
further immunosuppressives (e.g., 
infliximab at 5 mg/kg once every 2 
weeks). Caution: Ensure GI consult to 
rule out bowel perforation and refer to 
infliximab label for general guidance 
before using infliximab.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Hepatitis 
(elevated liver 
function tests 
[LFTs])
Any grade

Monitor and evaluate LFTs: AST, AST, 
alkaline phosphatase, bilirubin.

Evaluate for alternative etiologies (e.g., 
viral hepatitis, disease progression, 
concomitant medications). 
Grade 1
(AST or ALT >ULN 
and ≤3.0xULN 
and/or bilirubin > 
ULN and 
≤1.5xULN)
No dose modifications. If 
event worsens, treat as 
Grade 2.

Continue LFT monitoring per protocol.
Grade 2
(AST or 
ALT >3.0xULN and 
≤5.0xULN and/or 
bilirubin >1.5xULN 
and ≤3.0xULN)
Refer to Section 7.1.1 for 
stopping criteria and 
required follow up. 
ONLY if labs do not meet 
stopping criteria:
Study intervention 
should be held until 
Grade 2 resolution to 
Grade ≤1. 
If toxicity improves to 
Grade ≤1 or baseline, 
resume study 
intervention after 
completion of steroid 
taper.
If toxicity worsens, then 
treat as Grade 3 or 4. 

Regular and frequent checking of LFTs
(e.g., every 1 to 2 days) until elevations 
of these are improving or resolved.

If no resolution to Grade ≤1 in 1 to 2 
days, consider, as necessary, 
discussing with Medical Monitor.

If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

If still no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day of prednisone 
PO or IV equivalent, consider additional 
work up and start prompt treatment with 
IV methylprednisolone 2 to 4 mg/kg/day.

If still no improvement within 3 to 5 days 
despite 2 to 4 mg/kg/day of IV 
methylprednisolone, promptly start 
immunosuppressives (i.e., 
mycophenolate mofetil). Discuss with 
Medical Monitor if mycophenolate 
mofetil is not available. Infliximab 
should NOT be used.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Grade 3 or 4
(Grade 3: AST or 
ALT >5.0xULN and 
Refer to Section 7.1.1 for 
stopping criteria and 
required follow up. 

Promptly initiate empiric IV 
methylprednisolone at 1 to 4 mg/kg/day 
or equivalent.


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≤20.0xULN and/or 
bilirubin >3.0xULN 
and ≤10.0xULN)
(Grade 4: AST or 
ALT >20xULN 
and/or 
bilirubin >10xULN)

If still no improvement within 3 to 5 days 
despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with 
immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with 
Medical Monitor if mycophenolate is not 
available. Infliximab should NOT be 
used.

Perform hepatology consult, abdominal 
workup, and imaging as appropriate.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Nephritis or renal 
dysfunction
(elevated serum 
creatinine)
Any Grade

Consult with nephrologist.

Monitor for signs and symptoms that 
may be related to changes in renal 
function (e.g., routine urinalysis, 
elevated serum BUN and creatinine, 
decreased creatinine clearance, 
electrolyte imbalance, decrease in urine 
output, or proteinuria).

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression or 
infections).

Steroids should be considered in the 
absence of clear alternative etiology 
even for low-grade events (Grade 2), in 
order to prevent potential progression to 
higher grade event.
Grade 1
(Serum creatinine 
> 1 to 1.5 x 
baseline; > ULN to 
1.5xULN)
No dose modifications.

Monitor serum creatinine weekly and 
any accompanying symptoms.
o If creatinine returns to baseline, 
resume its regular monitoring per 
study protocol.
o If creatinine worsens, depending on 
the severity, treat as Grade 2, 3, or 
4.

Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics.
Grade 2
(serum creatinine 
>1.5 to 3.0 x 
baseline; >1.5 to 
3.0 x ULN)
Hold study intervention 
until resolution to Grade 
≤1 or baseline. 
If toxicity worsens, then 
treat as Grade 3 or 4.
If toxicity improves to 
Grade ≤1 or baseline, 
then resume study 
intervention after 
completion of steroid 
taper.

Consider symptomatic treatment, 
including hydration, electrolyte 
replacement, and diuretics.

Carefully monitor serum creatinine every 
2 to 3 days and as clinically warranted.

Consult nephrologist and consider renal 
biopsy if clinically indicated.

If event is persistent (>3 to 5 days) or 
worsens, promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

If event is not responsive within 3 to 5 
days or worsens despite prednisone at 1 
to 2 mg/kg/day PO or IV equivalent, 


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additional workup should be considered 
and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day 
started.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.

When event returns to baseline, resume 
study intervention and routine serum 
creatinine monitoring per study protocol.
Grade 3 or 4
(Grade 3: serum 
creatinine >3.0 x 
baseline; >3.0 to 
6.0 x ULN; Grade 
4: serum creatinine 
>6.0 x ULN)
Permanently discontinue 
study intervention.

Carefully monitor serum creatinine on 
daily basis.

Consult nephrologist and consider renal 
biopsy if clinically indicated.

Promptly start prednisone 1 to 
2 mg/kg/day PO or IV equivalent.

If event is not responsive within 3 to 5 
days or worsens despite prednisone at 1 
to 2 mg/kg/day PO or IV equivalent, 
additional workup should be considered 
and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
started.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Rash
(excluding bullous 
skin formations)
Any Grade

Monitor for signs and symptoms of 
dermatitis (rash and pruritus).

IF THERE IS ANY BULLOUS 
FORMATION, THE MEDICAL 
MONITOR SHOULD BE CONTACTED 
AND STUDY DRUG DISCONTINUED.
Grade 1
No dose modifications.

Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream).
Grade 2
For persistent (>1 to 2 
weeks) Grade 2 events, 
hold scheduled study 
intervention until resolution 
to Grade ≤1 or baseline.
If toxicity worsens, then 
treat as Grade 3.
If toxicity improves to 
Grade ≤1 or baseline, 
then resume 
intervention after 
completion of steroid 
taper.

Obtain dermatology consult.

Consider symptomatic treatment, 
including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and 
topical therapy (e.g., urea cream).

Consider moderate-strength topical 
steroid.

If no improvement of rash/skin lesions 
occurs within 3 to 5 days or is worsening 
despite symptomatic treatment and/or 
use of moderate strength topical steroid, 
consider, as necessary, discussing with 
Medical Monitor and promptly start 
systemic steroids such as prednisone 1 
to 2 mg/kg/day PO or IV equivalent.

Consider skin biopsy if the event is 
persistent for >1 to 2 weeks or recurs.
Grade 3 or 4
Grade 3

Consult dermatology.


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Hold study intervention 
until resolution to Grade 
≤1 or baseline.
If temporarily holding the 
study intervention does not 
provide improvement of 
the Grade 3 skin rash to 
Grade ≤1 or baseline 
within 30 days, then 
permanently discontinue 
study intervention.
Grade 4
Permanently discontinue 
study intervention.

Promptly initiate empiric IV 
methylprednisolone 1 to 4 mg/kg/day or 
equivalent.

Consider hospitalization.

Monitor extent of rash [Rule of Nines].

Consider skin biopsy (preferably more 
than 1) as clinically feasible.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.

Consider, as necessary, discussing with 
Medical Monitor.
Endocrinopathy
(e.g., 
hyperthyroidism, 
hypothyroidism, 
Type 1 diabetes 
mellitus, 
hypophysitis, 
hypopituitarism, 
and adrenal 
insufficiency; 
exocrine event of 
amylase/lipase 
increased also 
included in this 
section)
Any Grade

Consider consulting an endocrinologist 
for endocrine events.

Consider, as necessary, discussing with 
Medical Monitor.

Monitor participants for signs and 
symptoms of endocrinopathies. Non-
specific symptoms include headache, 
fatigue, behavior changes, changed 
mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness.

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression 
including brain metastases, or 
infections).

Depending on the suspected 
endocrinopathy, monitor and evaluate 
thyroid function tests: TSH, free T3 and 
free T4 and other relevant endocrine 
and related labs (e.g., blood glucose and 
ketone levels, HgA1c).

For modest asymptomatic elevations in 
serum amylase and lipase, 
corticosteroid treatment is not indicated 
as long as there are no other signs or 
symptoms of pancreatic inflammation.

If a participant experiences an AE that is 
thought to be possibly of autoimmune 
nature (e.g., thyroiditis, pancreatitis, 
hypophysitis, or diabetes insipidus), the 
investigator should send a blood sample 
for appropriate autoimmune antibody 
testing.
Grade 1 
(including those 
with asymptomatic 
endocrinopathy)
No dose modifications.

Monitor participant with appropriate 
endocrine function tests.

For suspected 
hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to 
guide assessment of early-morning 
ACTH, cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, 


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and prolactin levels, as well as 
cosyntropin stimulation test (though it 
may not be useful in diagnosing early 
secondary adrenal insufficiency).

If TSH < 0.5xLLN, or TSH >2xULN, or 
consistently out of range in 2 
subsequent measurements, include free 
T4 at subsequent cycles as clinically 
indicated and consider consultation of 
an endocrinologist.
Grade 2
(including those 
with symptomatic 
endocrinopathy)
For Grade 2 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study intervention dose 
until participant is clinically 
stable.
If toxicity worsens, then 
treat as Grade 3 or 
Grade 4.
Study intervention can be 
resumed once event 
stabilizes and after 
completion of steroid 
taper.
Participants with 
endocrinopathies who may 
require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
intervention on the 
following conditions:
The event stabilizes and 
is controlled.
The participant is 
clinically stable as per 
investigator or treating 
physician’s clinical 
judgement.
Doses of prednisone are 
≤10 mg/day or 
equivalent.

Consult endocrinologist to guide 
evaluation of endocrine function and, as 
indicated by suspected endocrinopathy 
and as clinically indicated, consider 
pituitary scan.

For all participants with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type 1 DM, 
and as guided by an endocrinologist, 
consider short term corticosteroids (e.g., 
1 to 2 mg/kg/day methylprednisolone or 
IV equivalent) and prompt initiation of 
treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex 
hormones).

Isolated hypothyroidism may be treated 
with replacement therapy, without study 
intervention interruption, and without 
corticosteroids.

Isolated Type 1 diabetes mellitus (DM) 
may be treated with appropriate diabetic 
therapy, without study intervention 
interruption, and without corticosteroids.

Once participants on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.

For participants with normal endocrine 
workup (laboratory assessment or MRI 
scans), repeat laboratory 
assessments/MRI as clinically indicated.
Grade 3 or 4
For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism and Type 
1 diabetes mellitus, hold 
study intervention dose 
until endocrinopathy 
symptom(s) are controlled. 
Study intervention can be 
resumed once event 
stabilizes and after 
completion of steroid 
taper.
Participants with 

Consult endocrinologist to guide 
evaluation of endocrine function and, as 
indicated by suspected endocrinopathy 
and as clinically indicated, consider 
pituitary scan. Hospitalization 
recommended.

For all participants with abnormal 
endocrine work up, except those with 
isolated hypothyroidism or Type 1 DM, 
and as guided by an endocrinologist, 
promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent, as well as relevant hormone 


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endocrinopathies who may 
require prolonged or 
continued steroid 
replacement (e.g., adrenal 
insufficiency) can be 
retreated with study 
intervention on the 
following conditions:
The event stabilizes and 
is controlled.
The participant is 
clinically stable as per 
investigator or treating 
physician’s clinical 
judgement.
Doses of prednisone are 
≤10 mg/day or 
equivalent.
replacement (e.g., hydrocortisone, sex 
hormones).

For adrenal crisis, severe dehydration, 
hypotension, or shock, immediately 
initiate IV corticosteroids with 
mineralocorticoid activity.

Isolated hypothyroidism may be treated 
with replacement therapy, without study 
intervention interruption, and without 
corticosteroids.

Isolated Type 1 diabetes mellitus may 
be treated with appropriate diabetic 
therapy, without study intervention 
interruption, and without corticosteroids.

Once participants on steroids are 
improving, gradually taper 
immunosuppressive steroids (as 
appropriate and with guidance of 
endocrinologist) over ≥28 days and 
consider prophylactic antibiotics, 
antifungals, and anti-PJP treatment.
Neurotoxicity
(to include but not 
be limited to limbic 
encephalitis and 
autonomic 
neuropathy, 
excluding 
Myasthenia Gravis 
and Guillain-Barre)
Any Grade

Participants should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes, or medications).

Monitor participant for general 
symptoms (headache, nausea, vertigo, 
behavior change, or weakness).

Consider appropriate diagnostic testing 
(e.g., electromyogram and nerve 
conduction investigations).

Perform symptomatic treatment with 
neurological consult as appropriate.
Grade 1
No dose modifications.

See “Any Grade” recommendations 
above.
Grade 2
For acute motor 
neuropathies or 
neurotoxicity, hold study 
intervention dose until 
resolution to Grade ≤1.
For sensory 
neuropathy/neuropathic 
pain, consider holding 
study intervention dose 
until resolution to Grade 
≤1.
If toxicity worsens, then 
treat as Grade 3 or 4.
Study intervention can be 
resumed once event 
improves to Grade ≤1 and 
after completion of steroid 
taper.

Consider, as necessary, discussing with 
the Medical Monitor.

Obtain neurology consult.

Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine).

Promptly start systemic steroids 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent.

If no improvement within 3 to 5 days 
despite 1 to 2 mg/kg/day prednisone PO 
or IV equivalent, consider additional 
workup and promptly treat with 
additional immunosuppressive therapy 
(e.g., IV immunoglobulin therapy [IVIG]).
Grade 3 or 4
Grade 3
Hold study intervention
dose until resolution to 
Grade ≤1.

Consider, as necessary, discussing with 
Medical Monitor.

Obtain neurology consult.

Consider hospitalization.


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Permanently discontinue 
study intervention if Grade 
3 irAE does not resolve to 
Grade ≤1 within 30 days.
Grade 4
Permanently discontinue 
study intervention.

Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent.

If no improvement within 3 to 5 days 
despite IV corticosteroids, consider 
additional workup and promptly treat 
with additional immunosuppressants 
(e.g., IVIG).

Once stable, gradually taper steroids 
over ≥28 days.
Peripheral 
neuromotor 
syndromes
(such as Guillain-
Barre and 
myasthenia gravis)
Any Grade

The prompt diagnosis of immune-
mediated peripheral neuromotor 
syndromes is important, since certain 
participants may unpredictably 
experience acute decompensations that 
can result in substantial morbidity or in 
the worst case, death. Special care 
should be taken for certain sentinel 
symptoms that may predict a more 
severe outcome, such as prominent 
dysphagia, rapidly progressive 
weakness, and signs of respiratory 
insufficiency or autonomic instability.

Participants should be evaluated to rule 
out any alternative etiology (e.g., 
disease progression, infections, 
metabolic syndromes or medications). It 
should be noted that the diagnosis of 
immune-mediated peripheral 
neuromotor syndromes can be 
particularly challenging in participants 
with underlying cancer, due to the 
multiple potential confounding effects of 
cancer (and its treatments) throughout 
the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is 
essential to have a low threshold to 
obtain a neurological consult.

Neurophysiologic diagnostic testing 
(e.g., electromyogram and nerve 
conduction investigations, and “repetitive 
stimulation” if myasthenia is suspected) 
are routinely indicated upon suspicion of 
such conditions and may be best 
facilitated by means of a neurology 
consultation.

It is important to consider that the use of 
steroids as the primary treatment of 
Guillain-Barre is not typically considered 
effective. Participants requiring 
treatment should be started with IVIG 
and followed by plasmapheresis if not 
responsive to IVIG.
Grade 1
No dose modifications.

Consider, as necessary, discussing with 
the Medical Monitor.

Care should be taken to monitor 
participants for sentinel symptoms of a 


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potential decompensation as described 
above.

Obtain a neurology consult.
Grade 2
Hold study intervention 
dose until resolution to 
Grade ≤1.
Permanently discontinue 
study intervention if it does 
not resolve to Grade ≤1 
within 30 days or if there 
are signs of respiratory 
insufficiency or autonomic 
instability.

Consider, as necessary, discussing with 
the Medical Monitor.

Care should be taken to monitor 
participants for sentinel symptoms of a 
potential decompensation as described 
above.

Obtain a neurology consult

Sensory neuropathy/neuropathic pain 
may be managed by appropriate 
medications (e.g., gabapentin or 
duloxetine).
MYASTHENIA GRAVIS:

Steroids may be successfully used to 
treat myasthenia gravis. It is important to 
consider that steroid therapy (especially 
with high doses) may result in transient 
worsening of myasthenia and should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist.

Participants unable to tolerate steroids 
may be candidates for treatment with 
plasmapheresis or IVIG. Such decisions 
are best made in consultation with a 
neurologist, considering the unique 
needs of each participant.

If myasthenia gravis-like neurotoxicity is 
present, consider starting AchE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis.
GUILLAIN-BARRE:

It is important to consider here that the 
use of steroids as the primary treatment 
of Guillain-Barre is not typically 
considered effective.

Participants requiring treatment should 
be started with IVIG and followed by 
plasmapheresis if not responsive to 
IVIG.
Grade 3 or 4
(severe or life-
threatening events)
Grade 3
Hold study intervention 
dose until resolution to 
Grade ≤1.
Permanently discontinue 
study intervention if Grade 
3 irAE does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency or 
autonomic instability.
Grade 4
Permanently discontinue 
study intervention.

Consider, as necessary, discussing with 
Medical Monitor.

Recommend hospitalization.

Monitor symptoms and obtain 
neurological consult.
MYASTHENIA GRAVIS:

Steroids may be successfully used to 
treat myasthenia gravis. They should 
typically be administered in a monitored 
setting under supervision of a consulting 
neurologist.

Participants unable to tolerate steroids 
may be candidates for treatment with 


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plasmapheresis or IVIG.

If myasthenia gravis-like neurotoxicity 
present, consider starting AchE inhibitor 
therapy in addition to steroids. Such 
therapy, if successful, can also serve to 
reinforce the diagnosis.
GUILLAIN-BARRE:

It is important to consider here that the 
use of steroids as the primary treatment 
of Guillain-Barre is not typically 
considered effective.

typically considered effective.

Participants requiring treatment should 
be started with IVIG and followed by 
plasmapheresis if not responsive to 
IVIG.
Myocarditis
Any Grade
Discontinue drug 
permanently if biopsy-
proven immune-mediated 
myocarditis.

The prompt diagnosis of immune-
mediated myocarditis is important, 
particularly in participants with baseline 
cardiopulmonary disease and reduced 
cardiac function. 

Consider, as necessary, discussing with 
the Medical Monitor.

Monitor participants for signs and 
symptoms of myocarditis (new onset or 
worsening chest pain, arrhythmia, 
shortness of breath, peripheral edema). 
As some symptoms can overlap with 
lung toxicities, simultaneously evaluate 
for and rule out pulmonary toxicity as 
well as other causes (e.g., pulmonary 
embolism, congestive heart failure, 
malignant pericardial effusion). A 
Cardiology consultation should be 
obtained early, with prompt assessment 
of whether and when to complete a 
cardiac biopsy, including any other 
diagnostic procedures.

Initial work-up should include clinical
evaluation, BNP, cardiac enzymes, 
ECG, echocardiogram (ECHO), 
monitoring of oxygenation via pulse 
oximetry (resting and exertion), and 
additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall 
motion abnormalities when needed.

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, other 
medications, or infections).
Grade 1
(asymptomatic with 
laboratory (e.g., 
BNP) or cardiac 
imaging 
abnormalities)
No dose modifications 
required unless clinical 
suspicion is high, in which 
case hold study 
intervention dose during 
diagnostic work-up for 

Monitor and closely follow up in 2 to 4 
days for clinical symptoms, BNP, cardiac 
enzymes, ECG, ECHO, pulse oximetry 
(resting and exertion), and laboratory 
work-up as clinically indicated.

Consider using steroids if clinical 


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other etiologies. If study 
intervention is held, 
resume after complete 
resolution to Grade 0.
suspicion is high.
Grade 2, 3 or 4
(Grade 2: 
Symptoms with 
mild to moderate 
activity or exertion)
(Grade 3: Severe 
with symptoms at 
rest or with minimal 
activity or exertion; 
intervention 
indicated)
(Grade 4: Life-
threatening 
consequences; 
urgent
intervention 
indicated (e.g., 
continuous IV 
therapy or 
mechanical 
hemodynamic 
support))
Grade 2
Hold study intervention 
dose until resolution to 
Grade 0. If toxicity rapidly 
improves to Grade 0, then 
the decision to reinitiate 
study intervention will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of steroid 
taper. If toxicity does not 
rapidly improve, 
permanently. Discontinue 
study intervention.
Grade 3 or 4
Permanently discontinue 
study intervention.

Monitor symptoms daily, hospitalize.

Promptly start IV methylprednisolone 2 
to 4 mg/kg/day or equivalent after 
Cardiology consultation has determined 
whether and when to complete 
diagnostic procedures including a 
cardiac biopsy.

Supportive care (e.g., oxygen).

If no improvement within 3 to 5 days 
despite IV methylprednisolone at 2 to 
4 mg/kg/day, promptly start 
immunosuppressive therapy such as 
TNF inhibitors (e.g., infliximab at 
5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance 
before using infliximab.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment.
Myositis / 
Polymyositis 
(“Poly/myositis”)
Any Grade

Monitor participants for signs and 
symptoms of poly/myositis. Typically, 
muscle weakness/pain occurs in 
proximal muscles including upper arms, 
thighs, shoulders, hips, neck and back, 
but rarely affects the extremities 
including hands and fingers; also,
difficulty breathing and/or trouble 
swallowing can occur and progress 
rapidly. Increased general feelings of 
tiredness and fatigue may occur, and 
there can be new-onset falling, difficulty 
getting up from a fall, and trouble 
climbing stairs, standing up from a 
seated position, and/or reaching up.

If poly/myositis is suspected, a 
Neurology consultation should be 
obtained early, with prompt guidance on 
diagnostic procedures. Myocarditis may 
co-occur with poly/myositis; refer to 
guidance under Myocarditis. Given 
breathing complications, refer to 
guidance under Pneumonitis/ILD. 

Given possibility of an existent (but 
previously unknown) autoimmune 
disorder, consider Rheumatology 
consultation.

Consider, as necessary, discussing with 
the Medical Monitor.

Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, 


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LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein 
level, urine myoglobin, and additional 
laboratory work-up as indicated, 
including a number of possible 
rheumatological/antibody tests (i.e., 
consider whether a rheumatologist 
consultation is indicated and could guide 
need for rheumatoid factor, antinuclear 
antibody, anti-smooth muscle, 
antisynthetase [such as anti-Jo-1], 
and/or signal-recognition particle 
antibodies). Confirmatory testing may 
include electromyography, nerve 
conduction studies, MRI of the muscles, 
and/or a muscle biopsy. Consider 
Barium swallow for evaluation of 
dysphagia or dysphonia.

Participants should be thoroughly 
evaluated to rule out any alternative 
etiology (e.g., disease progression, other 
medications, or infections).
Grade 1
(mild pain)
No dose modifications.

Monitor and closely follow up in 2 to 4 
days for clinical symptoms and initiate 
evaluation as clinically indicated.

Consider Neurology consult.

Consider, as necessary, discussing with 
the Medical Monitor.
Grade 2
(moderate pain 
associated with 
weakness; pain 
limiting 
instrumental ADLs)
Hold study intervention 
dose until resolution to 
Grade ≤1.
Permanently discontinue 
study intervention if it 
does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency.

Monitor symptoms daily and consider 
hospitalization.

Obtain Neurology consult, and initiate 
evaluation.

Consider, as necessary, discussing with 
the Medical Monitor.

If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving 
input from Neurology consultant 

If clinical course is not rapidly 
progressive, start systemic steroids 
(e.g., prednisone 1 to 2 mg/kg/day PO or 
IV equivalent); if no improvement within 
3 to 5 days, continue additional work up 
and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day

If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of immunosuppressive 
therapy such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab.

Once the participant is improving, 


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gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment.
Grade 3 or 4
(pain associated 
with severe 
weakness; limiting 
self-care ADLs; 
severe or life-
threatening events)
Grade 3
Hold study intervention 
dose until resolution to 
Grade ≤1.
Permanently discontinue 
study intervention if Grade 
3 irAE does not resolve to 
Grade ≤1 within 30 days 
or if there are signs of 
respiratory insufficiency.
Grade 4
Permanently discontinue 
study intervention.

Monitor symptoms closely; recommend 
hospitalization.

Obtain Neurology consult, and complete 
full evaluation.

Consider, as necessary, discussing with 
the Medical Monitor.

Promptly start IV methylprednisolone 2 
to 4 mg/kg/day systemic steroids along
with receiving input from Neurology 
consultant.

If after start of IV methylprednisolone at 
2 to 4 mg/kg/day there is no 
improvement within 3 to 5 days, 
consider start of immunosuppressive 
therapy such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg every 2 weeks). 
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab.

Consider whether participant may 
require IVIG, plasmapheresis.

Once the participant is improving, 
gradually taper steroids over ≥28 days 
and consider prophylactic antibiotics, 
antifungals, or anti-PJP treatment.
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 
monoclonal antibodies (mAbs). Infusion reactions typically develop within 30 minutes to 
2 hours after initiation of drug infusion, although symptoms may be delayed for up to 48 
hours. The incidence of infusion reactions varies by mAb agent, and there are multiple 
mechanisms known to lead to infusion-related reactions including both IgE-dependant 
anaphylactic and non-IgE dependent anaphylactoid hypersensitivities. Cytokine release 
syndrome, and when severe, cytokine “storm”, has been identified as a 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 one to two days after administration. The 
NCI-CTCAE (version 5.0) [NCI, 2017] 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. 


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Clinically, infusion reactions 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. See Table 9 and Table 10 for dose modification and treatment guidance for 
GSK3359609 and tremelimumab infusion reactions, respectively.
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 8. The serum tryptase, CRP and 
ferritin panels may be performed at the Investigator’s designated local laboratory, if 
available. The serum cytokine panel will be performed at a GSK designated laboratory. 
These data will aid in the classifying (albeit retrospectively) the etiology of the AE.
Table 8
Biomarker Panel
Biomarker
Relationship to Adverse Event
Serum tryptasea
IgE-related infusion reaction (Allergic/anaphylaxis) 
[Schwartz, 2006]
Serum CRPa
Elevated in CRS [Lee, 2014]
Serum ferritina
Elevated in CRS [[Lee, 2014]
Plasma cytokine panelb
(IFN-γ*^, TNF-α*^, IL-2*, IL-4, IL-5*, IL-6*^, IL-8*, IL-10*, IL-
12p70, IL-13, and IL-17)
*  Reported to be elevated in CRS [Lee, 2014]
^ Consistently reported as elevated in CRS [Lee, 
2014]
CRP=C-reactive protein; CRS= Cytokine release syndrome; IFN-g = Interferon gamma; TNF-a = Tumor necrosis factor 
alpha; IL = Interleukin. 
a.
Performed by Investigator designated local laboratory if available; otherwise performed by GSK designated 
laboratory
b.
Performed by GSK designated laboratory
These guidelines are suggestions. Investigators and site staff may also follow their site 
standard operating procedures for the treatment of these events.


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Table 9
Immunotherapy Infusion Reaction Dose Modification and Treatment 
Guidelines for GSK3359609
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:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
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 pre-medicated for the 
next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment
Participant may be pre-
medicated 1.5h (± 30 
minutes) prior to infusion 
of GSK3359609 with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the 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 drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the NCI-CTCAE v5.0 [NCI, 2017]


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Table 10
Immunotherapy Infusion Reaction Dose Modification and Treatment 
Guidelines for Tremelimumab
NCI-
CTCAE 
Grade
Treatment
Premedication at 
Subsequent Dosing
Any 
Grade
Management per Institutional standard at the discretion of investigator.
Monitor participants for signs and symptoms of infusion-related reactions 
(e.g., fever and/or shaking chills, flushing and/or itching, alterations in heart 
rate and blood pressure, dyspnea or chest discomfort, skin rashes etc) and 
anaphylaxis (e.g., generalized urticaria, angioedema, wheezing, 
hypotension, tachycardia).
Grade 1
The infusion rate of tremelimumab may be decreased by
50% or temporarily interrupted until resolution of the event.
Acetaminophen and/or antihistamines may be administered per Institutional 
standard at the discretion of the investigator.
Consider premedication 
per Institutional standard 
prior to subsequent doses
Grade 2
The infusion rate of tremelimumab may be decreased 50% or temporarily 
interrupted until resolution of the event (up to 4 hours).
Subsequent infusions may be given at 50% of the initial infusion rate.
Acetaminophen and/or antihistamines may be administered per Institutional 
standard at the discretion of the investigator.
Consider premedication 
per Institutional standard 
prior to subsequent doses
Grade 3/4
Permanently discontinue.
Manage severe infusion-related reactions per Institutional standards (e.g.,
IM epinephrine, followed by IV diphenhydramine and ranitidine, and IV 
glucocorticoid).
6.6.3.
Dose Delay
For GSK3359609 in combination with tremelimumab, if there is a dose delay between 1
and 7 days, the procedures at the original scheduled visit (including dosing) should be 
performed as soon as possible. Subsequent visits will follow as originally scheduled. If 
the delay is 8 days, the visit and dose(s) will be considered missed. The procedures at 
the next scheduled visit should be performed as originally scheduled, and subsequent 
visits will continue to follow Q3W. For all dose delays, disease assessments should 
continue as per Section 8.1.1.2. Participants with infusion delays greater than three weeks 
due to toxicity should discontinue study intervention unless the treating Investigator and 
Sponsor/Medical Monitor agree there is strong evidence supporting continued treatment. 
For participants requiring elective surgery or radiation therapy, every effort should be 
made to wait one to two weeks after the last dose of study intervention before performing 
surgery or starting radiation. Study intervention should not be administered again until 
one to two weeks after recovery from surgery or radiation (refer to Section 6.5.1 for 
details on permitted medications and non-drug therapies).
For participants randomized to receive SOC, Investigators should follow the applicable 
package insert and/or Institutional guidelines for dose delays. Protocol-defined 
assessments (e.g., safety assessments, disease assessments) should continue as outlined in 
the SoA, Section 1.3
6.7.
Intervention after the End of the Study
The study participants will not receive any additional treatment from GSK after 
permanent discontinuation of study intervention. The Investigator is responsible for 


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ensuring that consideration is given to the post-study care of the participant’s medical 
condition.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
Participants will receive study intervention or SOC for the scheduled period as indicated 
in the SoA, unless one of the following events occurs earlier: 

disease progression (as determined by iRECIST)

death

unacceptable toxicity, including meeting stopping criteria for liver chemistry 
abnormalities, QTc prolongation or clinical deterioration 
In addition, study intervention or SOC may be permanently discontinued for any of the 
following reasons:

Deviation(s) from the protocol

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

Study intervention must be permanently discontinued in the case of pregnancy
A participant may withdraw consent at any time; no further assessments will be required 
and the Investigator must document this in the site study records.
All participants who discontinue from study intervention or SOC (early or permanent) for 
any reason will have safety assessments at the time of discontinuation and during follow-
up as specified in the SoA.
All participants who permanently discontinue study intervention or SOC without disease 
progression will be followed for progression according to the protocol-defined on-
treatment disease assessment schedule until one or more of the following occur:

a new anticancer therapy is initiated

disease progression

death
Participants permanently discontinuing study intervention after progression by RECIST 
1.1 but prior to confirmed progression by iRECIST should be followed to confirm 
progression (see Table 18).


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All participants who permanently discontinue study intervention or SOC for any reason 
will be followed for survival and new anticancer therapy (including radiotherapy) every 
12 weeks until death, termination of the overall study or an arm by the Sponsor. The 
every 12-week schedule should begin once the study intervention/SOC has been 
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.).
Early discontinuation of GSK3359609 and tremelimumab (early discontinuation will not 
per se constitute permanent discontinuation) may be considered for participants who have 
attained a confirmed complete response per RECIST 1.1 and who received study 
intervention for at least 24 weeks and had at least two treatments of GSK3359609 beyond 
the date when the initial CR was declared; these participants will undergo disease 
assessments at a frequency of 12 weeks. These participants may be permitted to resume 
study intervention upon disease progression following consultation with the Investigator 
and GSK Medical Monitor and upon written consent by the participant. If study 
intervention is restarted, participants will be required to resume assessments outlined in 
the SoA in Section 1.3. See Section 7.1.1 for specific conditions under which a 
participant may continue study intervention beyond disease progression.
If the study is terminated by the Sponsor for reasons unrelated to safety, and a participant 
is currently active in the study, receiving study intervention, and is deriving benefit from 
that intervention without evidence of disease progression in the opinion of the 
Investigator, the participant may continue to receive study intervention upon agreement 
between the Sponsor and Investigator.
7.1.1.
Continuation of Treatment Upon Confirmed Disease Progression
Participants who have confirmed disease progression (unequivocal disease progression)
by RECIST 1.1 may continue study intervention at the discretion of the Investigator with 
approval from the Medical Monitor, and upon separate written consent of the participant. 
Continuation on study intervention with confirmed disease progression is contingent 
upon the following conditions:

participant has documented clinical benefit

absence of clinical signs or symptoms indicating clinically significant disease 
progression

no decline in ECOG performance status

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 intervention


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7.1.2.
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 the algorithm in Figure 2 or for 
participants with documented liver metastases in Figure 3.
Figure 2
Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
for Participants with ALT up to 2.5 X ULN at Baseline


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Figure 3
Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
for Participants with documented liver metastases with ALT up to 5 
X ULN at Baseline
The details on follow-up procedures are outlined in Section 10.6.
7.1.2.1.
Study Intervention Restart or Rechallenge after Liver Stopping Criteria 
Met
Study intervention restart or rechallenge is not allowed after liver chemistry stopping 
criteria are met by any participant in this study unless:

GSK Medical Governance approval is granted.

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the participant.
Refer to Section 10.6 for additional information.
7.1.3.
Stopping Rules for Clinical Deterioration
To adequately assess the antitumor effect of immunotherapeutic agents, it is reasonable to 
allow participants experiencing apparent progression as defined by RECIST 1.1
guidelines to continue to receive treatment until progression is confirmed at the next 
imaging assessment at least 4 weeks later as indicated by iRECIST guidelines. 
Nevertheless, these considerations should be balanced by clinical judgment as to whether 


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the participant is clinically deteriorating and unlikely to receive any benefit from 
continued study intervention.
In cases where deterioration was assessed to have occurred after a clinical event that, in 
the Investigator’s opinion, is attributable to disease progression and is unlikely to reverse 
with continued study intervention or managed by supportive care (e.g., bisphosphonates 
and/or bone directed radiotherapy, thoracentesis, or paracentesis for accumulating 
effusions), study intervention should be discontinued. In these cases, the decision to 
continue treatment must be discussed with the Sponsor’s Medical Monitor. Examples of 
events that may, in the Investigator’s opinion, indicate a lack of clinical benefit include, 
but are not limited to, the following:

Worsening of ECOG PS from baseline by at least 2 points 

Skeletal related events defined by the following:
o
pathologic bone fracture in the region of cancer involvement
o
cancer related surgery to bone, and/or 
o
spinal cord or nerve root compression

Development of new CNS metastases

Any setting where the initiation of new antineoplastic therapy has been deemed 
beneficial to the participant even in the absence of any such documented clinical 
event.
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.
If the subject voluntarily discontinues from study intervention due to toxicity, ‘adverse 
event’ will be recorded as the primary reason for permanent discontinuation in the eCRF.   
At the time of discontinuation from the study intervention or SOC, if possible, a
treatment discontinuation visit should be conducted, as shown in the SoA. See the SoA 
for data to be collected at the time of study intervention/SOC discontinuation and follow-
up and for any further evaluations that need to be completed.
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 


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schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study are handled as part of Appendix 1.
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 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 amount of blood collected from each participant from screening 
through Week 10, including any extra assessments that may be required, will not 
exceed 480 mL. If a participant completes 2 years of study intervention and all 
required assessments, no more than 850 mL of blood will be collected. 
o Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
8.1.1.
Tumor Imaging and Disease Assessments
RECIST 1.1 will be used in the assessment of disease burden (target and non-target 
lesions determination) at screening and as the primary measure of tumor response 
endpoints. iRECIST will be used by the Investigator to assess tumor response and 
progression and make treatment decisions. 


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A description of the adaptations and iRECIST process is provided in Appendix 7, with 
additional details in the iRECIST publication [Seymour, 2017]. A summary of imaging 
and treatment requirements after first radiologic evidence of progression is provided in 
Table 18 and illustrated as a flowchart in Figure 4 in Appendix 7. 
Tumor images will be obtained and transmitted to a central imaging vendor for potential 
central review. The process for tumor imaging and transmission to the central imaging 
vendor are detailed in the Imaging Manual. Tumor imaging is strongly preferred to be 
acquired by IV/oral contrast enhanced CT. When CT with iodinated contrast is 
contraindicated or when mandated by local practice, MRI may be used. MRI is the 
preferred modality for imaging the brain and spine. The same imaging modality, ideally 
the same scanner, scanning technique and the use of contrast should be used for a 
participant throughout the study to optimize reproducibility and accuracy of assessment 
of existing and new tumor burden. 
Notes: 
1.
Imaging must include the chest, abdomen, and pelvis.
2.
Brain imaging should be conducted, if clinically indicated, at screening and 
throughout the study for evaluation of brain metastases. MRI is preferred however 
CT imaging with IV contrast is acceptable if MRI is medically contraindicated. 
3.
Bone scans are optional for participants with a history of bone metastases or for 
those participants with new bone pain. Any supplemental imaging done to support a 
positive or negative bone scan, such as plain X-rays that may be acquired for 
correlation, should be submitted to the central imaging vendor.
All bone scan abnormalities at screening that could indicate metastases should be 
evaluated by X-ray, CT, or MRI to determine if they represent malignant lesions. If a 
bone scan was performed within 6 weeks prior to the first dose it does not need to be 
repeated (in the absence of new or worsening clinical symptoms suggesting bone 
involvement). Typically bone scanning will be performed using bone scintigraphy; 
however, positron emission tomography (PET) scan ([18F]-fluorodeoxyglucose or [18F]-
fluoride) is acceptable, providing coverage is sufficient to evaluate total spine, clavicle, 
ribs, pelvis and long bones.
8.1.1.1.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 30 days prior to Day 1. 
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality, is performed within 30 days prior to 
Day 1 and can be assessed by the central imaging vendor. 
8.1.1.2.
Tumor Imaging During the Study
The first on-study imaging assessment must be performed 9 weeks after the first dose of 
study intervention or SOC. Subsequent tumor imaging must be performed every 6 weeks 
until Week 52 and every 12 weeks thereafter. Imaging timing should follow calendar 
days and should not be adjusted for dosing delays. Imaging should continue to be 


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performed until confirmed disease progression is identified by the Investigator, per 
iRECIST (Appendix 7). 
Objective response (CR or PR) must be confirmed by a repeat imaging assessment. 
Tumor imaging to confirm PR or CR must be performed at least 4 weeks after the first 
indication of a response is observed. Participants will then return to regular scheduled 
imaging, starting with the next scheduled imaging time point. Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later and tumor imaging may resume at the subsequent 
scheduled imaging time point. 
Per iRECIST, disease progression should be confirmed by the site at least 4 weeks and up 
to 8 weeks after site-assessed first radiologic evidence of PD. Participants who have 
unconfirmed PD may continue study intervention at the discretion of the Investigator
until progression is confirmed by the site, provided they have met the conditions detailed 
in Appendix 7.
8.1.1.3.
End of Treatment Imaging
Disease assessments at the TDV and during follow-up should be performed as outlined in 
Section 7.1.
8.1.2.
Tumor Growth Kinetics
To evaluate the effect of study intervention on the growth rate of individual tumor 
lesions, pre-baseline images (within 6 months before the baseline scan) will be requested 
to support exploratory investigation of tumor growth kinetics. Up to 3 pre-baseline scans 
may be requested and submitted. Only those participants who consent to this collection 
will have their pre-baseline images submitted to the central vendor for these analyses.
8.1.3.
Patient Reported Outcomes (PRO)
Planned time points for all assessments related to PROs are listed in the SoA and will 
apply to Part 2 of the study only. PRO assessments will be administered based on the 
availability of appropriate translated versions.  Cancer can have a profound impact on 
patients’ health related quality of life (HRQL); both the symptoms of the disease as well 
as the tolerability profile of treatments impact HRQL. The patient-reported outcomes 
(PRO) in this study (Table 11) aim to measure changes in HNSCC symptoms (EORTC-
HN35), physical functioning (PROMIS-PF), and symptomatic side effects and 
tolerability (PRO-CTCAE and FACT-G Item 5). Cancer related HRQL will be measured 
with the EORTC-QLC-C30 and EQ-5D-3L. 


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Table 11
PRO Outcomes Assessed in Study 207871
Instrument 
Role
Rationale & Overview
EORTC QLQ-C30 
EORTC QLQ-HN35
Disease specific 
HRQoL
The current standard in disease-specific instruments for assessing cancer 
(specific type as well) HRQoL in clinical trials. A modular system of 
instruments consisting of the core 30 items (C30) and HN35 module.
PROMIS – PF
Physical 
Function in 
Cancer 
Physical function can be affected by both disease symptoms and 
treatment-related adverse events, and needs to be evaluated separately. 
Physical function questions will be selected from the PROMIS PF item 
bank.
FACT GP5
Symptomatic 
AEs (Global)
Single question from the well-established FACT-G (V4), to assess overall 
tolerability from participant’s perspective 
PRO-CTCAE 
Symptomatic 
AEs (Specific)
A standard and flexible approach to describe and evaluate symptomatic 
adverse events as they are experienced and reported by participants
themselves. 
EQ-5D-3L
Health Status
The EQ-5D is a generic instrument for describing and valuing health. It is 
based on a descriptive system that defines health in terms of 5 
dimensions:  Mobility, Self-Care, Usual Activities, Pain/Discomfort, and 
Anxiety/Depression. 
EORTC QLQ-C30 and HN35 = European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire – Core 30 and head and neck cancer 35 module; FACT GP5 = Functional Assessment of Cancer 
Therapy – General Physical Well Being Item 5; PROMIS PF = Patient-Reported Outcome Measurement Information 
System – Physical Function; Impression of Change; PRO-CTCAE = Patient Reported Outcomes – Common 
Terminology Criteria for AEs; EQ-5D-3L = EuroQOL Group EQ-5D 3 Level Version.
Completion of PRO Questionnaires
PRO questionnaires are to be administered at the beginning of the visits specified in the 
SoA in the order presented in the electronic device. To avoid biasing responses, the 
participants should not be told the results of diagnostic tests prior to completing the 
questionnaires. Adequate time must be allowed to complete all items on the 
questionnaires, and if necessary, the participant must be encouraged to complete any 
missing items.
8.1.3.1.
PROMIS Physical Function
PROMIS (Patient Reported Outcome Measurement Information System) is a set of self-
report measurement tools developed by the US National Institutes for Health (NIH) 
[Rose, 2014]. The PROMIS Physical Function item bank is a domain-based item bank 
developed using modern psychometric theory, containing questions assessing physical 
function across a range of baseline functional status.
The most recent version of the PROMIS Physical Function Item Bank (version 2.0) 
contains 165 items that assess a range of abilities. There also exists a 45-Item PROMIS-
Cancer Item Bank (PROMIS Ca Bank version 1.1) [Jensen, 2015; Jensen, 2017]
containing a subset of items that may be relevant to patients with cancer. Participants 
enrolled will self-complete a subset of PROMIS Physical Function items.


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8.1.3.5.
EuroQOL Group EQ-5D 3 Level Version
EQ-5D is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal 
[EuroQol, 1990]. The EQ-5D is applicable to a wide range of health conditions and 
treatments and provides a simple descriptive profile and a single index value for health 
status that can be used in the clinical and economic evaluation of health care. The EQ-
5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities pain/discomfort and anxiety/depression. Each dimension has 3 levels: no 
problems, some problems, extreme problems. The respondent is asked to indicate his/her 
health state by selecting the most appropriate statement in each of the 5 dimensions. The 
EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable 
health state’. This information can be used as a quantitative measure of health outcome as 
judged by the individual respondents.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA. These should be 
performed and assessed pre-dose on dosing days. These are required at a minimum and 
may be performed more frequently as clinically appropriate (e.g., for weekly dosing of 
SOC agents). Additional time points for safety testing may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring.
8.2.1.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight 
will also be measured and recorded.
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). Weight will also be measured 
and recorded. 

Height will be recorded at Screening only.
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 (Appendix 9).
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 via 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. 


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
If a participant develops fever and infusion related reaction or cytokine release 
syndrome is suspected, refer to management guidelines (Section 6.6 and 
subsections).
8.2.4.
Electrocardiograms
Single12-lead ECG will be obtained using an ECG machine that automatically calculates 
the heart rate and measures the PR, QRS, QT, and QTcF intervals; manual calculation of 
QTcF is permitted. In addition to the times indicated in the SoA, an ECG may be 
repeated as clinically indicated. 
8.2.5.
Echocardiograms
Echocardiograms (ECHO) will be performed locally at screening to assess cardiac 
ejection fraction for study eligibility, as specified in the SoA (Section 1.3). Additional 
ECHO assessments may be performed if clinically warranted. The evaluation of the 
echocardiography should include an evaluation for left ventricular ejection fraction 
(LVEF) and both right and left-sided valvular lesions. Multigated Acquisition Scan 
(MUGA) can be used in lieu of ECHO (if not feasible) 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 protocol-required laboratory tests to be performed and 
to the SoA for the timing and frequency. All protocol-required safety laboratory 
assessments will be performed at the institution’s local laboratory. Reference ranges for 
all safety parameters must be provided to the site by the laboratory responsible for the 
assessments. The results of each test must be recorded in the eCRF. If additional non-
protocol specified laboratory assessments are performed at the institution’s local 
laboratory and result in a change in participant management or are considered clinically 
significant by the Investigator (for example, SAE or AE or dose modification) the results 
must also be recorded in the eCRF.
Laboratory results obtained during Screening should be used to determine eligibility 
criteria. In situations where laboratory results are outside the permitted range, the 
Investigator may opt to retest the participant and the subsequent screening result, if 
within range, may be used to confirm eligibility.
For all other protocol-required blood and tissue sample collections, laboratory requisition 
forms must be completed and samples must be clearly labelled with the participant 
number, protocol number, site/center number, and visit date. Details for the preparation 
and shipment of samples that are required to be tested by a central laboratory will be 
provided by the laboratory and are detailed in the laboratory manual. Refer to the SRM 
for appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws. 
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 eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 


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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.
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, SOC or 
the study, or that caused the participant to discontinue the study intervention or SOC (see 
Section 7). 
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 intervention or SOC at the time points specified in the SoA (Section
1.3). However, any AESI or SAEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in existing therapy) 
or related to a GSK product will be recorded from the time a participant consents to 
participate in the study. If subsequent anticancer treatment is initiated during the 90-day 
follow-up period, AESIs and SAEs must continue to be collected and documentation of 
the subsequent anticancer treatment will be recorded in the eCRF.
All AEs will be collected from the start of study intervention or SOC until 30 days after 
discontinuing study intervention or SOC at the time points specified in the SoA (Section
1.3.
Medical occurrences that begin before the start of study intervention/SOC but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF not 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, as indicated in Appendix 3. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the 
study participation. 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 intervention/SOC or study participation, the 
Investigator must promptly notify the Sponsor.


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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 AESI (as defined in 
Section 6.6.1) will be followed until the event is 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.
8.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to the Sponsor of an 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 SAEs) 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
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until 180 days after 
the last dose of study intervention.
If a pregnancy is reported, the Investigator should inform GSK within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 


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be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs 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 eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
8.4.
Treatment of Overdose
An overdose of GSK3359609 is defined as administration of a dose that is at least 50% 
greater than the intended dose. An overdose of tremelimumab is defined as 
administration of a dose that is greater than the protocol-defined dose.
In the event of an overdose of either GSK3359609 or tremelimumab 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 sample for PK analysis within 28 days from the date of the last dose of study 
intervention if requested by the Medical Monitor (determined on a case-by-case 
basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
There is no specific antidote for overdose with either GSK3359609 or tremelimumab. 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.
Refer to the instructions in the approved product labels in the event of an overdose of 
docetaxel, paclitaxel or cetuximab. Contact the Medical Monitor immediately and closely 
monitor the participant for AEs/SAEs.
8.5.
Pharmacokinetics
Planned time points for all pharmacokinetics assessments are listed in Table 12 and in the 
SoA.


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8.5.1.
Blood Sample Collection
The actual date and time of each blood sample collection will be recorded. The timing of 
PK samples may be altered and/or PK samples may be obtained at additional time points 
to ensure adequate PK monitoring. 
Details on PK blood sample collection, processing, storage, and shipping procedures are 
provided in the SRM/laboratory manual. Windows for sample collection are provided in 
the SRM.
Table 12
Blood sample collection schedule for PK and ADA
Sample Times for Plasma Levels of GSK3359609

Pre-dose on treatment visits at Weeks 1, 2, 4, 7, 10, 13, 16, 19, 25, then every 12 weeks.

End of Infusion in Weeks 1, 19 and 25

End of Infusion +4 hours in Week 1

Additional PK samples to be collected at every pharmacodynamic sample which is collected on the non-
treatment visits
Sample Times for Serum Levels of Tremelimumab

Pre-dose on treatment visits at Weeks 1, 2, 4, 7, 10, 13, 16, then every 12 weeks.

End of Infusion in Week 1

End of Infusion +4 hours in Week 1

Additional PK samples to be collected at every pharmacodynamic sample which is collected on the non-
treatment visits
Samples Times for Serum Anti-Drug Antibody Samples GSK3359609

Pre-dose on treatment visits at Weeks 1, 4, 7, 10, 13, 16, 19, 22, 25, every 12 weeks. 

At the Treatment Discontinuation Visit.

On non-treatment visit days draw at any time.

For participants with a positive ADA at the last visit, draw one additional sample at 6 months after the last 
dose. 
Samples Times for Serum Anti-Drug Antibody Samples Tremelimumab 

Pre-dose on treatment visits at Weeks 1, 4, 7, 10, 13, 16 then every 12 weeks.

At the Treatment Discontinuation Visit.

On non-treatment visit days draw at any time.

For participants with a positive ADA at the last visit, draw one additional sample at 6 months after the last 
dose.
8.5.2.
Sample Analysis
PK analysis will be performed on samples as indicated in the SoA and Table 12. 
Concentrations of the study interventions will be determined using validated bioanalytical 
methodologies. 
8.6.
Pharmacodynamics
Pharmacodynamic parameters evaluated in this study are presented in Section 8.8 on 
biomarkers.
8.7.
Genetics
A 6mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 


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optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection, shipment and destruction of these samples can be found in the laboratory 
manual/SRM.
8.8.
Biomarkers
8.8.1.
Blood Biomarkers
Blood samples for biomarkers will be collected as whole blood, plasma, and serum. 
Whole blood may be utilized to assess receptor occupancy by GSK3359609 and 
tremelimumab, immune cell numbers, phenotype, activation and function. Additionally, 
whole blood will be used to isolate PBMCs and then preserved and stored for flow 
cytometry of additional cell types, subsequent functional analysis or genetic analysis and 
their relationship to clinical responses, and changes in response to treatment. PBMCs 
may also be evaluated for genomic (DNA) and gene expression (RNA) or protein 
alterations to determine treatment-related changes in immune-related signatures. Plasma 
and serum samples may be used for analysis of circulating soluble factors in relation to T 
cell activation, cfDNA, exosomes and circulating proteins. Factors to be analyzed may 
include but are not limited to cytokines, chemokines, soluble receptors, cfDNA, 
antibodies against tumor, self-tumor mutations, gene expression; genetic analysis (DNA, 
RNA or protein) or viral antigens. 
If predictive biomarkers are identified in the blood samples, these samples may be used 
for the development of a diagnostic test.
8.8.2.
Tumor Tissue Biomarkers
In Part 1 and Part 2, for all participants, archival tumor tissue will be required (or a fresh 
biopsy if no archival is available). Fresh paired biopsies (defined as a pre-treatment 
sample, collected any time after end of previous therapy and prior to first dose of study 
intervention/SOC, and an on-treatment sample collected at Week 7) are recommended, 
but not mandatory, EXCEPT as noted below:

In the PK/Pharmacodynamic cohort(s), paired biopsies are required.

In Part 2, a minimum of 15 participants in each arm will be required to provide 
paired biopsies Additional participants may be requested for paired biopsies if 
>30% of the 15 paired tissue samples are not evaluable.
For all participants in this study, a fresh biopsy is recommended at the time of disease 
progression or response confirmation.


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These tissues will be evaluated by immunohistochemistry (IHC) or other potential
methods for expression of phenotypic and functional immune cell markers. For some 
participants with cancer types that may be virally mediated, for e.g., HNSCC of the 
oropharynx, these tissues may be utilized to assess the HPV (human papilloma virus) 
status either by a p16 IHC or other HPV testing methods. Additionally, tumor tissue may 
be utilized for DNA and/or RNA sequencing for exploratory biomarker evaluations 
including but not limited to T cell diversity (TCR diversity), mutational load, DNA 
polymorphisms (target, Fc receptor etc.), tumor antigen-specific T cell assessments as 
well as expression of RNA and protein changes. These samples may also be evaluated for 
predictive measures of response to include in the biomarker-selected population. If a 
predictive biomarker is identified, these tissues may be used for the development of a 
diagnostic test. 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.
8.8.3.
Immunogenicity Assessments
Antibodies to GSK3359609 and tremelimumab (ADA) will be evaluated in serum
samples collected from all participants according to the SoA and Table 12. The actual 
date and time of each blood sample collection will be recorded. The timing of ADA
samples may be altered and/or ADA samples may be obtained at additional time points to 
ensure adequate ADA monitoring.’
Serum samples will be screened for antibodies binding to GSK3359609 and to 
tremelimumab and the titer of confirmed positive samples will be reported. Other 
analyses may be performed to verify the stability of antibodies to GSK3359609 and to 
tremelimumab and/or further characterize the immunogenicity of GSK3359609 and of 
tremelimumab.
The detection and characterization of antibodies to GSK3359609 and to tremelimumab
will be performed using a validated assay method for each either by or under the 
supervision of the Sponsor. Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of the study interventions, GSK3359609 and 
tremelimumab. 
8.8.4.
DNA/RNA Transcriptome and RNA expression Research
Samples for the assessments of blood biomarkers and tumor biomarkers are described in 
Section 8.8.1 and in Section 8.8.2, respectively.
8.8.5.
Proteome Research
See Section 8.8.1 for information on proteome research.
8.9.
Health Economics/Medical Resource Utilization and Health 
Economics
The PROs used in this study are presented in Section 8.1.3 and subsections.


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9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
9.1.1.
Part 1: Dose Escalation 
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested in Part 1. The primary focus will be on determining the recommended
dose for further exploration, the safety profile and the PK profile.
9.1.2.
Part 2: Cohort Expansion
The primary endpoint for Part 2 is OS and primary analysis is to perform Bayesian 
predictive probability of Phase 3 study success based on survival data. 
The hypotheses about the overall survival of the study intervention (RP2D dose 
combination) and SOC are detailed below.
The null hypothesis is:
H0: There is no difference in overall survival between the study intervention and the SOC
The alternative hypothesis is:
HA: The study intervention improves overall survival over the SOC
9.2.
Sample Size Determination
A maximum of 114 participants will be enrolled into the study. Up to 24 participants will 
be enrolled in Part 1 dose escalation and 90 participants will be enrolled in Part 2 dose 
expansion. 
9.2.1.
Part 1: Dose Escalation
The total number of participants to be enrolled in Part 1 will depend on the number of 
participants needed to characterize the individual dose cohorts for determination of the 
MTDs or MADs. With the pre-specified maximum sample size of 24 participants,
simulations were conducted to determine the average sample size and percentage of times 
each dose would be selected under three different scenarios, assuming the bivariate CRM 
dose recommendations are followed, e.g., an increasing toxicity scenario, a low toxicity 
scenario, and a threshold toxicity scenario. For each scenario, 1000 clinical trials were 
simulated. The average sample sizes over the 1000 clinical trials simulated under the 
three scenarios were 20.2, 22.7, and 22.7, respectively. Details of the scenarios are 
provided in Table 14. The dose combinations in the table are the pre-selected dose
combinations that are projected to be used in the study. The actual dose combinations 
used during the conduct of the study may be different.
For the simulations, the selected reference doses were 24 mg for GSK3359609 and 75 mg 
for tremelimumab. The priors for each pair of parameters (α, β) for the toxicity model for 


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each drug are specified via a bivariate normal distribution (as in the single drug CRM), 
with a separate mean and standard deviation (s.d.) for ln(α) and ln(β), and a correlation 
term. The parameters (s.d.) of the model are
ln(1) -3 (10), ln(1) 1(10), 
ln(2) -3 (10), ln(2) 1(10), 
ρ1  ρ2 0.1
where ln() and ln() for each drug are assumed to be distributed as bivariate normal
with correlation ρ. The prior for the interaction term η is assumed to follow the standard 
normal distribution N(0,1).
In addition, the prior DLT information collected from former clinical trials of 
tremelimumab in combination with durvalumab and the on-going GSK3359609 
monotherapy clinical trial are incorporated into the calculation of DLT probability (note: 
DLT information for tremelimumab monotherapy clinical trial is not available). For each 
dose combination, a prior observed number of DLTs and number of observations are 
specified in Table 13.
Table 13
Prior Observed DLTs and Number of Observations
GSK3359609 (mg)
0
8
24
80
Tremelimumab (mg)
225
2/34
0/0
0/0
0/0
75
0/57
0/0
0/0
0/0
0
0/0
0/15
0/29
0/32
The simulation results for dose selection under various scenarios based on the priors of 
parameter (α, β) and prior DLT information are shown in Table 14. It is noted that the
simulation results are entirely based on bivariate CRM model for every dose escalation 
recommendation; however, per the Part 1 design, bivariate CRM model would not be 
employed until the first DLT occurs.




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arm, and 345 participants (230 in the study intervention and 115 in the SOC arm) in the 
hypothetical Phase 3 study, if the true effect of study intervention is as expected (Figure 
5), the power will be 82.5%.
Table 15
Operating Characteristics for Part 2 Design
Sample Size 
Success Criterion 
for Phase 3
Number of Events for Final 
Analysis
Power 
Alpha
90
> 60%
72
82.5%
0.087
If the null hypothesis is true, i.e. the OS of study intervention does not have significant 
difference compared with the SOC, the type I error (alpha) would be 0.087. 
Note that the sample size for Part 2 may be re-evaluated upon completion of Part 1 when 
emerging efficacy data of Part 1are available.
Details about the simulation method for the sample size determination are provided in
Appendix 10.
9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants who were screened for eligibility
Enrolled 
All participants who passed screening and entered the study. Included are: 
Participants in Part 1 who receive at least one dose of tremelimumab or 
GSK3359609; Participants who are randomized for Part 2.
Intent to Treat (ITT)
All participants who are randomized in the study. This will be the primary 
population for Part 2 efficacy analyses.
All Treated
All participants who receive at least one dose of SOC or tremelimumab or 
GSK3359609. This will be the population for safety and efficacy analyses for Part 
1 and safety analyses for Part 2.
PK
All participants from the All Treated population for whom a PK sample is obtained
and analysed. This will be the primary population for PK analyses.
Pharmacodynamic
All participants from the All Treated population for whom a 
pharmacodynamic/biomarker sample is obtained and analysed. This will be the 
primary population for Pharmacodynamic/Biomarker analyses.
Additional analysis populations may be defined in the Reporting and Analysis Plan 
(RAP).


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9.4.
Statistical Analyses
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given participant will depend on efficacy and 
tolerability, the duration of follow-up will vary between participants. Consequently, there 
will be no imputation for missing data. 
Demographic and baseline characteristics will be summarized.
9.4.1.
Efficacy Analyses
Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to RECIST 1.1 [Eisenhauer, 2009] and 
iRECIST as outlined in Appendix 7 of the protocol. iRECIST will be used to determine
treatment decisions and RECIST 1.1 will be used for the primary analysis of anticancer 
activity.
The ITT population will be used for anticancer activity analyses for Part 2, and All 
Treated Population will be used for anticancer activity analyses for Part 1. Since this is an
early phase study, anticancer activity will be evaluated based on clinical evidence and 
response criteria. If data warrant, the response data will be summarized by part and dose 
level. Correlation analysis may be conducted to explore any relationship between the 
biomarkers and tumor response based on RECIST 1.1. Full details will be specified in the 
RAP.
9.4.1.1.
Overall Survival (OS)
For Part 1 participants, overall survival is defined as time from the date of first dose to
the date of death due to any cause. For Part 2 participants, overall survival is defined as 
time from the date of randomization to the date of death due to any cause. For the 
analysis of overall survival (OS), the last date of known contact will be used for those 
participants who have not died at the time of analysis; such participants will be 
considered censored. OS will be summarized for Part 2 using Kaplan-Meier estimates 
along with 2-sided 95% CI at the time of final analysis. Log-rank tests will be performed 
for Part 2 data to compare the overall survival between the study intervention and the 
SOC.


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9.4.1.2.
Overall Response Rate (ORR)
ORR is defined as percentage of participants with confirmed complete response or partial 
response at any time as per RECIST 1.1. The observed ORR and 95% exact confidence 
interval (CI) will be reported for final analyses.
9.4.1.3.
Disease Control Rate (DCR)
DCR is defined as percentage of participants with confirmed complete response or partial 
response or at least 18 weeks of stable disease. DCR and 95% exact confidence interval 
(CI) will be reported for final analyses.
9.4.1.4.
Duration of Response (DOR)
DOR is defined as time from the first documented evidence of response until the first 
documented sign of disease progression or death among participants who achieve a 
response (CR or PR). DOR will be summarized descriptively using Kaplan-Meier 
method. 
9.4.1.5.
Progression Free Survival (PFS)
For Part 1 participants, PFS duration is defined as the time from the date of first dose to 
first documented evidence of disease progression or death (regardless of cause of death), 
whichever comes first. For Part 2 participants, PFS duration is defined as the time from 
the date of randomization to first documented evidence of disease progression or death 
(regardless of cause of death), whichever comes first. PFS will be summarized using 
Kaplan-Meier estimates along with 2-sided 95% Cis for final analysis. 
9.4.1.6.
Time to Response (TTR)
TTR is defined as the time from the first dose to the first documented evidence of CR or 
PR for participants with a confirmed CR or PR. TTR will be summarized descriptively
using Kaplan-Meier estimates along with 2-sided 95% Cis for final analysis.
9.4.1.7.
Predictive Probability of Phase 3 Success
The predictive probability of Phase 3 study success with respect to OS will provide 
evidence whether the study will graduate into a future Phase 3 trial based on the Part 2 
survival data.
The primary comparison of OS between the study intervention and SOC will be analysed 
by a log rank test with treatment as fixed effect. The hazard ratio (HR) will be derived 
based on the ratio of the hazard rates in the study intervention and SOC observed from 
the Part 2 overall survival data. The predictive probability of success for the hypothetical 
Phase 3 study will be calculated as detailed below, assuming both the data and prior 
follow normal distributions. By using conjugate prior, we can obtain a closed-form
solution for posterior and predictive distribution of θ
log(HR) at the end of Part 2 of the 
study.
Minimal-informative prior of θ:


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θ ∼N(θ0, V0), where θ0 0 ,V0
4.5/n0 for a randomization ratio 2:1. N0 is the number of
events in prior and assumed to be a small value 0.1 for the noninformative prior
Posterior distribution of θ given Part 2 overall survival results X (the estimated log
Hazard Ratio at the final analysis):
θ | ∼N(
, Vpost),
where
m
;
             Vpost
 1/(1/vp2+1/v0);
and Vp2 1/nt+1/nc, where nt and nc are the expected number of events in the study
intervention arm and SOC arm, respectively.
Then, the predictive distribution of Phase 3 log(HR) Y given Part 2 results X is:
Y∣X,∼N(
, 4.5/m + Vpost),
where X is the estimated log Hazard Ratio from final analysis of Part 2, and Y is 
predictive distribution of log Hazard Ratio in the future Phase 3 study. M is the expected
number of events in the future Phase 3 trial and is pre-specified as 240, which is
approximately 70% of the sample size in Phase 3.
One thousand predictive distributions are sampled and the predictive probability of Phase 
3 success is calculated based on the proportion of test statistics less than -1.96
(corresponding to one-sided type I error of 0.025) out of samplings drawn from the 
predictive distribution. The test statistic is Phase 3 signal/noise ratio of HR between the 
study intervention and SOC. 
9.4.2.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs) will be summarized 
according to the scheduled, nominal visit at which they are collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP.
9.4.2.1.
Extent of Exposure
The number of participants administered study intervention or SOC will be summarized 
according to the duration of therapy.
9.4.2.2.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the Investigator according to the NCI-CTCAE (version 5.0) [NCI, 
2017].


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Events will be summarized by frequency and proportion of total participants, by system 
organ class and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, SAEs and AEs leading to discontinuation of study intervention. AEs, if 
listed in the NCI-CTCAE (version 5.0) will be summarized by the maximum grade. 
Otherwise, the AEs will be summarized by maximum intensity.
Characteristics (e.g., number of occurrences, action taken, grade, etc.) of AEs of special 
interest will be summarized separately.
The incidence of deaths and the primary cause of death will be summarized.
9.4.2.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to the NCI-CTCAE (version 5.0) [NCI, 2017]. Laboratory test 
results outside the reference ranges that do not have an associated NCI-CTCAE criteria 
will be summarized using proportions. Further details will be provided in the RAP.
9.4.2.4.
Other Safety Measures
Data for vital signs and electrocardiograms (ECGs) will be summarized based on 
predetermined criteria identified to be of potential clinical concern (PCI). Further details 
will be provided in the RAP.
9.4.3.
Other Analyses
PK, pharmacodynamic, immunogenicity (ADA) and biomarker exploratory analyses will 
be described in the RAP. The population PK analysis and pharmacodynamic analyses 
may be presented separately from the main clinical study report (CSR). 
9.4.3.1.
Pharmacokinetic Analyses
Pharmacokinetic Parameters
PK analysis will be the responsibility of the Clinical Pharmacology Modeling and 
Simulation (CPMS) Department, GSK.
PK analysis of drug concentration-time data will be performed by non-compartmental 
methods under the direction of CPMS, Quantitative Sciences, GSK. The following PK 
parameters will be determined for GSK3359609 and tremelimumab separately, if data 
permit:  

maximum observed plasma concentration (Cmax)

minimum observed plasma concentration (Cmin)

area under the plasma concentration-time curve AUC(0-t) (repeat dosing).


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Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics & Programming.
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by dose level/cohort for each part, and for 
GSK3359609 and tremelimumab separately. 
9.4.3.2.
Pharmacokinetic/Pharmacodynamic Analyses
If deemed appropriate and if data permit, exposure response relationship between 
GSK3359609/tremelimumab (e.g., dose, concentration, Cmax, or AUC) and clinical 
endpoints (e.g., antitumor response, biomarkers) may be conducted. The details of such 
exposure-response analysis will be outlined in the RAP.
9.4.3.3.
Immunogenicity Analyses
Results of anti-drug antibodies (ADA) testing will be reported at the end of the study and 
will include incidence and titer. The presence or absence of antibodies to GSK3359609 
and tremelimumab in dosed participants will be analysed, then be summarized 
descriptively and/or graphically presented, respectively. Further details will be provided 
in the RAP.
9.4.3.4.
Translational Research Analyses
The results of translational research investigations will be reported separately from the 
main clinical study report (CSR). All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data.
Further details on the translational research analyses will be addressed in the RAP or a 
separate biomarker RAP.
9.4.3.5.
Tumor Kinetic Analyses
Exploratory analyses may be performed to evaluate the effect of study intervention on the 
growth kinetics of individual tumor lesions. These analyses may include tumor lesion 
measurements from imaging scans performed earlier in the disease course (i.e., prior to 
screening scans).
If deemed necessary, additional statistical analyses will be discussed in RAP.
9.5.
Interim Analyses
9.5.1.
Part 1: Dose Escalation
In Part 1, interim analyses will be performed to determine if a dose-escalation is 
appropriate and to support the dose escalation decision following the completion of each 
dose cohort. The primary driver for the dose- scalation decision(s) in Part 1 will be safety 
and tolerability of each dose cohort. The DLT information along with preliminary safety 


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data, including AEs, changes in laboratory values and other safety parameters, and 
available PK/pharmacodynamic data will be evaluated for each dose escalation cohort 
prior to making dose escalation decisions.
Further details regarding such analyses will be provided in the RAP.
9.5.2.
Part 2: Cohort Expansion
No interim analysis for futility or efficacy will be performed in Part 2. The study team 
may evaluate safety, PK and Pharmacodynamic data and make the recommendation to 
discontinue the study at any time due to safety concerns. 


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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 (GCP) 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.
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3.
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
Investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant’s agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.1.4.
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.
10.1.5.
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. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
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GSK will also provide the Investigator with the full summary of the study results. The 
Investigator is encouraged to share the summary results with the study participants, as 
appropriate.
The procedures and timing for public disclosure of the 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 participant-level data from this study 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 
study participants are used to maximum effect in the creation of knowledge and 
understanding
10.1.6.
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. 
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 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. 


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10.1.7.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in the Investigator Site File.
10.1.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
10.1.9.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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10.2.
Appendix 2: Clinical Laboratory Tests
Table 16
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
LDH
Coagulation
INR or PT
aPTT
Cardiac Function
Troponin I or Troponin T
Thyroid Function
Thyroid stimulating hormone
Free T4
Free T3 (when clinically indicated)
Pancreatic Function
Amylase
Lipase
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Other Screening Tests
Hepatitis B (HbsAg)
Hepatitis C (Hep C antibody)c
Serum -hCG Pregnancy test (for women of child bearing potential)
HIV testing 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; -hCG=beta-human chorionic 
gonadotropin; BUN=blood urea nitrogen; HbsAg=Hepatitis B surface antigen; RBC=red blood cells; SGOT=serum 
glutamic oxaloacetic transaminase; SGPT= serum glutamic pyruvic transaminase; T3= triiodothyronineT4= 
thyroxine; WBC = white blood cells; INR = International Normalized Ratio; PT = Prothrombin Time; aPTT = 
Activated Partial Thromboplastin Time
a.
Required if local laboratory testing is available
b.
Creatinine clearance is also required to be calculated using the formula provided in Appendix 8.
c.
Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory 
negative Hepatitis C RNA test is obtained. Hepatitis C RNA Test is optional with negative Hepatitis C antibody 
test.












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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 at the beginning of this protocol and in the 
SRM on the Sponsor/Medical Monitor Contact Information page.


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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definition: 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/SOC, 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. 
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.


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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 17 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 180 days after the last dose of study treatment if 
receiving GSK3359609 and tremelimumab.
In addition, male participants must refrain from donating sperm for duration of study and 
for at least 180 days after the last dose of GSK3359609 and tremelimumab.
If the participant is randomized to SOC, then the duration of contraception after the last 
dose is at per the package insert and/or Institutional guidelines. 
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 17. 
Table 17
Highly Effective Contraceptive Methods

CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

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


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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.
Male condoms must be used in addition to hormonal contraception. 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 for this 
study. 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. This applies only to male participants who receive GSK3359609 plus 
tremelimumab.

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 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 or SOC.


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10.5.
Appendix 5: 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 GSK3359609 or in selected, 
advanced solid tumors and related diseases. They may also be used to develop 
tests/assays including diagnostic tests) related to GSK3359609, and in selected, 
advanced solid tumors. 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 for by using appropriate descriptive and/or statistical 
analysis methods. A detailed description of any planned analyses will be documented 
in a RAP prior to initiation of the analysis.

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to GSK3359609 or study interventions 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 GSK3359609 (or study interventions 
of this class) or in selected, advanced solid tumors continues but no longer than 15 
years after the last participant last visit or other period as per local requirements.


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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge 
Guidelines
10.6.1.
Liver Chemistry Stopping and Monitoring Criteria
10.6.1.1.
ALT up to 2.5xULN at Baseline
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow-up Assessments following ANY Liver Stopping Event
Actions
Follow-up Assessments

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
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 intervention unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to language within this 
Appendix) 

If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study intervention and may 
continue participant in the study for any 
protocol specified follow-up assessments 

Viral hepatitis serology4

Only in those with underlying chronic hepatitis B at 
study entry (identified by positive hepatitis B surface 
antigen) quantitative hepatitis B DNA and hepatitis 
delta antibody5. 

Blood sample for pharmacokinetic (PK) analysis, 
obtained 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 


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MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow-up assessments within 24-72 
hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
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).

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]). 

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 intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin 
on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where 
needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention 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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10.6.1.2.
Baseline ALT up to 5xULN for Participants with Documented Liver 
Metastases/Tumor Infiltration
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT absolute
Both ALT 5xULN and 2x baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5
Cannot Monitor
Both ALT 3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 
weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value associated with symptoms (new 
or worsening) believed to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately discontinue study treatment
Report the event to GSK within 24 hours
Complete the liver event eCRF 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 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (refer to 
guidance in this Appendix) 
If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
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 hrs
Viral hepatitis serology4
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend
Only in those with underlying chronic hepatitis 
B at study entry (identified by positive hepatitis 
B surface antigen) quantitative hepatitis B DNA 
and hepatitis delta antibody5.  
Blood sample for pharmacokinetic (PK) 
analysis, obtained 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 


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Monitor participants 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 hrs 
Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline
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)
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]). 
Liver imaging (ultrasound, magnetic 
resonance, or computerised 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 treatment for that participant if ALT 3xULN and bilirubin 
2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5
which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); the threshold value stated will not apply to participants
receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash or eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the 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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10.6.1.3.
Liver Chemistry Increased Monitoring Criteria with Continued Therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks

Notify the GSK Medical Monitor within 24 hours of 
learning of the abnormality to discuss participant
safety. 

Participant can continue study intervention  

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 
bilirubin <2xULN, monitor participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
10.6.2.
Liver Safety Drug Restart or Re-Challenge Guidelines
If participant meets liver chemistry stopping criteria do not restart/re-challenge 
participant with study intervention unless all the following conditions are met:

GSK Medical Governance approval is granted (as described below)

IRB/IEC approval is obtained, if required

Separate consent for treatment restart/re-challenge is signed by the participant
If GSK Medical Governance approval to restart/re-challenge 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.
10.6.2.1.
Re-challenge Following Liver Stopping Events that are Possibly 
Related to Study intervention
Re-challenge refers to resuming study intervention following drug-induced liver injury 
(DILI). Because of the risks associated with re-challenge 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 re-challenge is considered to be favorable.
Following DILI, drug re-challenge is associated with a 13% mortality across all drugs in 
prospective studies [Andrade, 2009]. Clinical outcomes vary by drug with nearly 50% 


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fatality with halothane re-administered within 1 month of initial injury. However, some 
drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug re-challenge outcome include the following:

Hypersensitivity [Andrade, 2009] with initial liver injury (e.g., fever, rash, 
eosinophilia) 

Jaundice or bilirubin >2 x ULN with initial liver injury (direct bilirubin >35% of 
total)

Participant currently exhibits severe liver injury defined by ALT >3 x ULN, bilirubin 
>2 x ULN (direct bilirubin >35% of total), or INR >1.5

SAE or fatality has been observed with drug rechallenges [Papay, 2009; Hunt, 2010]

Evidence of drug-related preclinical liability (e.g., reactive metabolites; 
mitochondrial impairment) [Hunt, 2010]
Approval by GSK for re-challenge with study intervention can be considered under the 
following conditions:

Investigator requests consideration of re-challenge with study intervention for a 
participant who is receiving compelling benefit (partial response or complete 
response) with study intervention that exceeds risk, and no effective alternative 
therapy is available

The ALT at the time of rechallenge is <3x ULN

The participant did not have additional risk factors for a fatal outcome following the
initial injury including hypersensitivity, jaundice, bilirubin >2x ULN (direct bilirubin
>35% of total bilirubin), or INR >1.5.

IRB/IEC approval for re-challenge with study intervention must be obtained, as 
required. 

If the re-challenge 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 intervention 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 intervention. Documentation of informed consent must be 
recorded in the study chart. 

Study intervention must be administered at the dose specified by GSK.

Participants approved by GSK Medical Governance for re-challenge with study 
intervention 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 intervention re-challenge, participant meets protocol-defined liver 
chemistry stopping criteria, study intervention must be permanently discontinued. 


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
GSK Medical Monitor, and the IRB/IEC as required, must be informed of the 
participant’s outcome following study intervention re-challenge. 

GSK must be notified of any AEs as per Section 8.3.
10.6.2.2.
Re-challenge Following Transient Liver Stopping Events Not Related to 
Study intervention
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, and acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, and the study 
intervention should not be associated with human leukocyte antigen (HLA) markers of 
liver injury.
Approval by GSK for study intervention restart can be considered under the following 
conditions:

Investigator requests consideration for study intervention 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 
<3 x ULN).

Possible study intervention-related liver injury has been excluded by the Investigator
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study intervention has an 
identified genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
intervention-related liver injury cannot be excluded, the guidance on re-challenge in 
Section 10.6.2.1 will apply.

There is no evidence of alcoholic hepatitis.

IRB/IEC approval of study intervention restart must be obtained, as required.

If restart of study intervention 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 intervention administration including the possibility of recurrent, more 
severe liver injury or death.

The participant must also provide signed informed consent specifically for the study 
intervention restart. Documentation of informed consent must be recorded in the 
study chart.

Study intervention must be administered at the dose specified by GSK.

Participants approved by GSK Medical Governance for restarting study intervention
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 intervention restart, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.


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
GSK Medical Monitor, and the IRB/IEC as required, must be informed of the 
participant’s outcome following study intervention restart.

GSK must be notified of any AEs, as per Section 8.3.


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10.7.
Appendix 7: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria
10.7.1.
Assessment Guidelines by RECIST 1.1
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.

All measurements must be taken and recorded in millimeters (mm), using a ruler 
or calipers.

Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments 
of disease. However, FDG-PET can be useful in confirming new sites of disease 
where a positive FDG-PET scans correlates with the new site of disease present 
on CT/MRI or when a baseline FDG-PET was previously negative for the site of 
the new lesion. FDG-PET may also be used in lieu of a standard bone scan 
providing coverage allows interrogation of all likely sites of bone disease and 
FDG-PET is performed at all assessments.

If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast. The method of 
assessment must be noted as CT on the eCRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required.
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion must be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences must be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible, the same 
scanner should be used.
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray.
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.


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10.7.2.
Guidelines for Evaluation of Disease by RECIST 1.1
Measurable and Non-Measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm. If 
the slice thickness is greater than 5 mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest X-ray.

Additionally, lymph nodes can be considered pathologically enlarged and 
measurable if:
15 mm in the short axis when assessed by CT or MRI (slice thickness recommended to 
be no more than 5 mm). At baseline and follow-up, only the short axis will be measured.
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques 
Measurable disease: The presence of at least one measurable lesion. Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 
Note: non-measurable only disease is not allowed per protocol.
10.7.3.
Evaluation of Response by iRECIST
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs. iRECIST will be used to assess tumor response and 
progression, and make treatment decisions. When clinically stable, participants should 
not be discontinued until progression is confirmed according to the rules described 
below. This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first 
few months after the start of immunotherapy, and then experience subsequent disease 
response. These data will be captured in the clinical database.
Clinical stability is defined as meeting all of the following: 


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
Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable may be discontinued from study intervention
at site-assessed first radiologic evidence of PD. It is strongly preferred to obtain the 
repeat tumor imaging, when feasible, for confirmation of PD by iRECIST. 
In a clinically unstable participant, if the Investigator decides to continue treatment, 
following consultation with the Sponsor Medical Monitor, the participant may continue 
to receive study intervention. The tumor assessment should be repeated at least 4 weeks 
and up to 8 weeks later to confirm PD by iRECIST. Images should continue to be sent in 
to the central imaging vendor for potential central review. 
If repeat imaging does not confirm PD per iRECIST and the participant continues to be 
clinically stable, study intervention may continue and follow the regular imaging 
schedule. If PD is confirmed, participants will be discontinued from study intervention.
If a participant has confirmed radiographic progression (iCPD) as defined below, study 
intervention should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, continuation of study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section
8.1 and submitted to the central imaging vendor. 
Description of the iRECIST Process for Assessment of Disease Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct 
iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 the Investigator 
will decide whether to continue a participant on study intervention until repeat imaging is 
obtained (using iRECIST for participant management (see Table 18 and Figure 4). This 
decision should be based on the participant’s overall clinical condition. (See discussion of 
clinical stability in Section 1.2 above.) 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 
1.1, including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% 
and ≥5 mm from nadir


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o Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable 
new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions 
Target. The sum of diameters of these lesions will be calculated, and kept distinct from 
the sum of diameters for target lesions at baseline. All other new lesions will be followed 
qualitatively as New Lesions Non-target.
Assessment at the Confirmatory Imaging
At the confirmatory imaging visit assessment, the participant will be classified as 
progression confirmed (with an overall response of iCPD), or as showing persistent 
unconfirmed progression (with an overall response of iUPD), or as showing disease 
stability or response (iSD/iPR/iCR). Timing of confirmatory imaging is described in 
Section 8.1.
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of 
the following occurs:

Any of the factors that were the basis for the initial iUPD show worsening
o For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o For new lesions, worsening is any of these:
An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point 
Visible growth of new non-target lesions 
The appearance of additional new lesions


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
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen. This may correspond to the next visit in the original visit 
schedule. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows 
radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, 
and the confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and 
the participant continues to be clinically stable, study intervention may continue and 
follow the regular imaging schedule. If PD is confirmed, participants will be discontinued 
from study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, 
but the participant is achieving a clinically meaningful benefit, continuation of study 
intervention may be considered following consultation with the Sponsor. In this case, if 
study intervention is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 8.1 and submitted to the central imaging 
vendor.
Detection of Progression at Visits After Pseudo-Progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is 
indicated by any of the following events:


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
Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire study, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, doing so for the 
first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the 
confirmatory imaging the burden of new lesions has increased from its smallest value (for 
new target lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD 
cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion 
burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication 
[Seymour, 2017].


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Table 18
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
intervention at the 
Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment
No additional 
imaging required.
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled imaging 
visit.
Continue study 
intervention at the 
Investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study 
intervention at the 
Investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if condition 
has improved and/or 
clinically stable per 
Investigator’s discretion. 
Next tumor imaging 
should occur according 
to the regular imaging 
schedule.
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = 
iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors 1.1.


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Figure 4
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator




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


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by third party copyright laws and therefore have been excluded.


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10.10.
Appendix 10: Statistical Methods for Study Design
10.10.1.
Bivariate CRM Method for Part 1 Dose Escalation
10.10.1.1. Description of the Bivariate Continual Reassessment Method
The bivariate CRM model-based design is a Bayesian adaptive dose escalation scheme 
that assumes a 5-parameter Bayesian logistic regression model [Neuenschwander, 2014]
for the toxicity rate based on doses. The CRM method is fully adaptive and makes use of 
all DLT information, therefore is expected to locate the target dose level efficiently.
Dose escalation decisions will be held after participants within any given cohort have 
been observed for 28 days of DLT observation period after starting the study 
intervention. At the time of each dose escalation decision, the Fixed and Adaptive 
Clinical Trial Simulator (FACTSTM version 6.1 or higher [Tessella, Abington, United 
Kingdom]) will be used to obtain the posterior probabilities that the DLT rate for that 
dose lies in each of 4 toxicity intervals (under dosing, target dose range, excessive 
toxicity, and unacceptable toxicity) for each potential dose. The CRM estimates, for each 
potential dose combination level, the posterior probabilities that the DLT rate lies in each 
of four toxicity ranges:

[0%, 16%) Under dosing

[16%, 33%) Target toxicity

[33%, 60%) Excessive toxicity

[60%, 100%] Unacceptable toxicity
The recommended dose will be the dose with the highest posterior probability of having a 
toxicity rate in the target interval with the additional requirement that the sum of the 
posterior probabilities of the DLT rate in the excessive toxicity or unacceptable toxicity
range is less than 25%. The use of over dose control limits the risk of exposing 
participants in the next cohort to an unsafe dose combination by ensuring the posterior 
probability of the DLT rate exceeding 33% at any dose is capped at 25%. An updated 
estimate of the toxicity curve will be provided at the time of each dose escalation 
meeting. Note that de-escalation as well as escalation is possible using this method.
Dose recommendations based on the bivariate CRM analysis will be used as guidance for 
the Safety Committee. To ensure safety of participants, additional participants may be 
enrolled at a current dose level at the discretion of the Safety Committee, even though a 
higher dose is recommended by CRM analysis.
10.10.1.2. Logistic Model for Bivariate CRM
A 5-parameter logistic model will be used for bivariate CRM analysis to guide dose 
selection during Part 1 dose escalation. This model will estimate the probability of 
observing a DLT at each combination dose in the study as DLT information becomes 
available.
The logistic model that used for describing the dose-toxicity relationship is: 


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where Pij is the probability of DLT at dose d1i (of drug 1) in combination with dose d2j (of 
drug 2), P1i is the probability of DLT if single agent drug 1 at dose d1i is administered, P2j
is the probability of DLT if single agent drug 2 at dose d2j is administered,  
, 
, and d1s and d2t are the reference doses for drug 1 and drug 2, 
respectively. Η is the interaction term. Α and β are Bayesian priors.
10.10.2.
Simulation Method for Part 2 Sample Size Estimation
The sample size estimation for Part 2 cohort expansion is based on simulation. Figure 5
shows the flow chart of simulation.




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Figure 6
Simulated overall survival for study intervention (red line) and SOC
(blue line)
The key variables/parameters used for the simulation are:
Accrual rate
5 participants/Month
No. of events at final analyses
72
Hypothetical Phase 3 sample size
345
No. of events for hypothetical Phase 3 analysis
240
Prior information for log(HR)
~N (0, 45)
Success criterion at final analyses
Predictive probability of Ph3 success > 60%
Type I error for the hypothetical Phase 3 trial
0.025 (one-sided)


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10.11.
Appendix 11: 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)
-hCG
Beta-human chorionic gonadotropin
ccRCC
Clear Cell Renal Cell Carcinoma
CD28
Cluster of Differentiation 28
cfDNA
cell-free DNA
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum observed concentration
Cmin
Minimum Observed Concentration;
CNS
Central Nervous System
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete Response
CrCl
Creatinine Clearance
CRM
Continual Reassessment Method
CRP
C Reactive Protein
CRPC
Castrate Resistant Prostate Cancer
CRF
Case Report Form
CRS
Cytokine Release Syndrome
CT
Computed tomography
CTFG
Clinical Trial Facilitation Group
CTLA-4
Cytotoxic T-Lymphocyte-Associated Protein 4 
CV
Cardiovascular
CYP3A
Cytochrome P 3A
DCR
Disease Control Rate
DILI
Drug-induced Liver Injury
dL
Deciliter
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DoR
Duration of Response
EC
Effective Concentration
ECG
Electrocardiogram
ECHO
Echocardiography
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
ECOG-PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form


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eGFR
Estimated Glomerular Filtration Rate
EORTC QLQ-C30 and 
H&N35
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core 30 and Head and 
Neck Cancer 35 Module
FACT GP5
Functional Assessment of Cancer Therapy General 
Population
FACTS
Fixed and Adaptive Clinical Trial Simulator
FDG-PET
Fluorodeoxyglucose positron emission tomography
g
Gram
GCP
Good Clinical Practice
G-CSF
Granulocyte- Colony stimulating factor
GI
Gastrointestinal
GSK
GlaxoSmithKline
HPV
Human Papilloma Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
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-Stimulator
ICOS-L-Fc
Inducible T Cell Co-Stimulator Ligand Fragment 
crystallizable region of an Antibody
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
IEC
Independent Ethics Committees
IFN
Interferon, gamma
IL
Interleukin
Ig
Immunoglobulin
INR
International Normalized Ratio
iPR
iRECIST progressive disease
irAE
Immune-related Adverse Event
IRB
Institutional Review Board
IRR
Infusion-related Reactions
iRECIST
Modified RECIST 1.1 for Immune-based Therapeutics
iSD
iRECIST stable disease
iUPD
iRECIST unconfirmed progressive disease
IV
Intravenous
IVIG
IV Immunoglobulin
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
KDOQI
Kidney Disease Outcomes Quality Initiative
kg
Kilogram(s)
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
m2
Square Meters 


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mAb
Monoclonal Antibody
MAD
Maximum Administered Dose
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
min
Minute
mm
Millimeters
mmHg
Millimeters of Mercury
mL
Milliliter(s)
MPM
Malignant pleural mesothelioma
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
msec
Millisecond(s)
MTD
Maximum Tolerated Dose
MUGA
Multigated Acquisition Scan
NCI-CTCAE
National Cancer Institute Common Toxicity Criteria for 
Adverse Events 
NSCLC
Non-small-cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over the Counter
PBMC
Peripheral Blood Mononuclear Cell
PD
Progressive Disease
PD-1
Programmed death receptor protein-1
PD-L1
Programmed death-ligand 1
R/R
Relapsed/Refractory
RP2D
Recommended Phase 2 Dose
PFS
Progression-free Survival
PI
Principal Investigators
PJP
Pneumocystis jirovecii pneumonia
PK
Pharmacokinetics
PO
Per oral
PP
Predictive probability
PR
Partial Response
PRO-CTCAE
Patient Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events
PS
Performance Status
Q3W
Every 3 Weeks
Q6W
Every 6 Weeks
Q12W
Every 12 Weeks
QoL
Quality of Life
QTc
Corrected QT interval duration, corrected
QTcB
QT interval corrected by Bazett’s Formula
QTcF
QT interval corrected by Fridericia’s Formula
RANKL
Receptor Activator of Nuclear Factor-kappa B Ligand
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors


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RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
Scr
Serum Creatinine
sCRS
Severe Cytokine Release Syndrome
SD
Stable Disease
SoA
Schedule of Activities
SOC
Standard of Care
SRM
Study Reference Manual
TCR
T Cell Receptor
TDV
Treatment Discontinuation Visit
Th1
Type 1 T helper (cells)
Th2
Type 2 T helper (cells)
Th17
T helper 17 (cells)
TNF
Tumor Necrosis Factor, alpha
Treg
T Regulatory Cells
TTR
Time to Response
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
FluMist
FACTS


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10.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).


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SAP_001.pdf: 
 
 
 
Reporting and Analysis Plan  
 
Study ID:  207871 
 
Official Title of Study: A Phase I/II, Open-label, Two Part Study of GSK3359609 in 
Combination with Tremelimumab in Subjects with Selected, Advanced Solid 
Tumors 
 
Date of Document: 16-DEC-2020 
 
 




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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.2.1. 
PART 1: Dose Escalation .............................................................. 6 
2.2.2. 
PART 2: Cohort Expansion ............................................................ 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses................................................................................. 11 
2.4.1. 
Part 1: Dose Escalation ............................................................... 11 
2.4.2. 
Part 2: Cohort Expansion ............................................................. 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.1.1. 
Part 1: Dose Escalation ............................................................... 12 
3.1.2. 
Part 2: Cohort Expansion ............................................................. 13 
3.2. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 16 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 17 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 17 
5.2. 
Baseline Definitions .................................................................................... 18 
5.3. 
Multicentre Studies ..................................................................................... 19 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 20 
5.4.1. 
Covariates and Other Strata ........................................................ 20 
5.4.2. 
Examination of Subgroups ........................................................... 20 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 20 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 20 
6. 
STUDY POPULATION ANALYSES ....................................................................... 21 
6.1. 
Overview of Planned Study Population Analyses ........................................ 21 
6.2. 
Disposition of Participants ........................................................................... 21 
6.3. 
Protocol Deviations ..................................................................................... 22 
6.4. 
Demographic and Baseline Characteristics ................................................. 22 
6.5. 
Concomitant Medications ............................................................................ 23 
6.6. 
Disease Characteristics .............................................................................. 23 
6.7. 
Prior Anti-cancer Therapy ........................................................................... 23 
6.8. 
Subsequent Anti-cancer Therapies ............................................................. 24 
6.9. 
Treatment Compliance and Exposure ......................................................... 24 
7. 
PRIMARY ENDPOINT ANALYSES ........................................................................ 26 
7.1. 
Definition of Endpoints ................................................................................ 26 
7.2. 
Statistical Analyses / Methods .................................................................... 26 
7.3. 
Primary Exploratory Analysis ...................................................................... 27 


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8. 
SECONDARY ENDPOINT ANALYSES .................................................................. 29 
8.1. 
Efficacy Analysis ......................................................................................... 29 
8.1.1. 
Definition of Endpoints ................................................................. 29 
8.1.2. 
Statistical Analyses / Methods ..................................................... 33 
8.2. 
Pharmacokinetic Analyses .......................................................................... 36 
8.2.1. 
Endpoint / Variables ..................................................................... 36 
8.2.2. 
Summary Measure ...................................................................... 36 
8.2.3. 
Population of Interest ................................................................... 37 
8.2.4. 
Statistical Analyses / Methods ..................................................... 37 
8.3. 
Immunogenicity Analyses ........................................................................... 38 
9. 
EXPLORATORY ENDPOINT ANALYSIS ............................................................... 39 
9.1. 
Efficacy Analysis ......................................................................................... 39 
9.2. 
Pharmacodynamic and Biomarker Analyses ............................................... 39 
9.2.1. 
Endpoint / Variables ..................................................................... 39 
9.2.2. 
Summary Measure ...................................................................... 39 
9.2.3. 
Population of Interest ................................................................... 40 
9.3. 
Pharmacokinetic/Pharmacodynamic Analyses ............................................ 40 
9.4. 
Pharmacogenetic Analyses ........................................................................ 40 
9.5. 
Patient Reported Outcomes ........................................................................ 40 
10. SAFETY ANALYSES ............................................................................................. 41 
10.1. 
Adverse Events Analyses ........................................................................... 41 
10.2. 
Adverse Events of Special Interest Analyses .............................................. 42 
10.3. 
Deaths and Serious Adverse Events ........................................................... 43 
10.4. 
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events ........................................................................................................ 43 
10.5. 
Pregnancies ................................................................................................ 44 
10.6. 
Clinical Laboratory Analyses ....................................................................... 44 
10.7. 
Liver Function Analyses .............................................................................. 45 
10.8. 
Other Safety Analyses ................................................................................ 46 
10.8.1. 
Vital Signs .................................................................................... 46 
10.8.2. 
Performance Status ..................................................................... 47 
10.8.3. 
ECG ............................................................................................. 47 
10.8.4. 
LVEF ........................................................................................... 47 
11. ADDITIONAL ANALYSES DUE TO THE COVID-19 PANDEMIC ........................... 48 
12. REFERENCES ....................................................................................................... 49 
13. APPENDICES ........................................................................................................ 50 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 50 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 51 
13.3. 
Appendix 3: Assessment Windows ............................................................. 52 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 52 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 53 
13.4.1. 
Study Phases .............................................................................. 53 
13.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 54 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 55 


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13.5.1. 
Reporting Process ....................................................................... 55 
13.5.2. 
Reporting Standards .................................................................... 55 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 56 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 57 
13.6.1. 
General ........................................................................................ 57 
13.6.2. 
Study Population .......................................................................... 59 
13.6.3. 
Safety .......................................................................................... 60 
13.6.4. 
Pharmacokinetic .......................................................................... 61 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 62 
13.7.1. 
Premature Withdrawals ................................................................ 62 
13.7.2. 
Handling of Missing Data ............................................................. 62 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 66 
13.8.1. 
ECG ............................................................................................. 67 
13.8.2. 
Vital Signs .................................................................................... 67 
13.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 68 
13.9.1. 
Abbreviations ............................................................................... 68 
13.9.2. 
Trademarks ................................................................................. 70 
13.10. Appendix 10: List of Data Displays.............................................................. 71 
13.10.1. Data Display Numbering .............................................................. 71 
13.10.2. Mock Example Shell Referencing ................................................ 71 
13.10.3. Deliverables ................................................................................. 71 
13.10.4. Study Population Tables .............................................................. 72 
13.10.5. Efficacy Figures ........................................................................... 76 
13.10.6. Safety Tables ............................................................................... 77 
13.10.7. Safety Figures ............................................................................. 82 
13.10.8. Pharmacokinetic Tables ............................................................... 83 
13.10.9. Pharmacokinetic Figures ............................................................. 84 
13.10.10. ICH Listings ................................................................................. 85 
13.10.11. Non-ICH Listings .......................................................................... 91 
13.11. Appendix 11: Example Mock Shells for Data Displays ................................ 93 
 














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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
3.1.1. 
Part 1: Dose Escalation 
In Part 1, interim analyses will be performed to determine if a dose-escalation is 
appropriate and to support the dose escalation decision recommended by the bivariate 
CRM analysis following the completion of each dose cohort, i.e. once all participants in a 
dose cohort complete the determinative 28 day DLT observation period, including 
replacement participants. For dose escalation phase, the Dose Limiting Toxicity (DLT) 
information along with preliminary safety data, including AEs, changes in laboratory 
values and other safety parameters, and available PK/pharmacodynamic data will be 
evaluated using unblinded data for all dose escalation cohorts in each zone (see Section 
4.1 of the protocol) prior to making dose escalation decisions. 
Review of preliminary data will be performed after completion of each cohort. 
Preliminary safety and study population data may include a demographic summary, 
adverse event (AE) summary, AE summary by maximum toxicity category, SAE listing, 
listing of AEs that are reported to be DLT’s. No formal outputs will be produced by 
statistics and programming. For dose escalation decisions, reviews of Spotfire output will 
be performed.   
Further, after the first instance of a DLT and for each subsequent cohort, the 
recommended dose from the bivariate CRM analysis and updated posterior estimates of 
the probabilities of being in each dose-toxicity range may be provided. The Fixed and 
Adaptive Clinical Trial Simulator (FACTS) (Version 6.1 or higher) software from 
Tessella will be used to perform bivariate CRM analyses. These posterior estimates will 
not be reported in the CSR. 
To perform the bivariate CRM analysis, the priors for each pair of parameters (α, β) for 
the Bayesian logistic regression model for each drug are specified via a bivariate normal 
distribution, with a separate mean and standard deviation (s.d.) for ln(α) and ln(β), and a 
correlation term. The parameters (s.d.) of the model are 
ln(1)=-3 (10), ln(1)=1(10),  
ln(2)=-3 (10), ln(2)=1(10),  
ρ1= ρ2=0.1 
where ln() and ln() for each drug are assumed to be distributed as bivariate normal 
with correlation ρ. The prior for the interaction term η is assumed to follow the standard 
normal distribution N(0,1). 
Refer to Section 9.2.1 and Section 10.10.1 of the CSP for more details of the bivariate 
CRM model. 


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The bivariate CRM analysis will only provide guidance for dose escalation based on 
toxicity alone. The GSK study team, in collaboration with study investigators, will 
review all relevant data (using Spotfire visualisations and site feedback and any other 
relevant source of data) to support: 
• 
whether the current dose had acceptable toxicity, and 
• 
the decision regarding the next dose level based on the totality of the data including 
PK, pharmacodynamic/biomarker data when available. 
• 
the decision of the recommended Phase 2 dose (RP2D) based on the totality of the 
data including but not limited to PK and pharmacodynamics/biomarkers data when 
available. 
Once the total planned number of participants have completed the 28 day DLT 
observation period for Part 1, data from all dose levels will be reviewed in order to 
identify the R2PD. The totality of data, including safety/tolerability, PK, 
pharmacodynamic, and efficacy will be used to determine whether to proceed to Part 2 
and which dose combination will be chosen as the RP2D. Outputs  to facilitate this 
review are described in Section 13.10.  
3.1.2. 
Part 2: Cohort Expansion 
No formal interim analysis for futility or efficacy is planned to be performed in Part 2. 
The study team may evaluate safety, PK and Pharmacodynamic data and make the 
recommendation to discontinue the study at any time due to safety concerns.  
3.2. 
Final Analyses 
For participants who meet all eligibility criteria and enroll into the study, the maximum 
duration of treatment is expected to be two years. The maximum follow-up period for 
safety assessments will be 90 days from the date of the last dose of study treatment. The 
expected maximum follow-up period for survival and subsequent anti-cancer therapy will 
be two years from the date of the last dose of study treatment. Participants deriving 
benefit from study treatment may remain on study beyond 2 years. 
 
All participants who permanently discontinue study treatment for any reason will be 
followed for survival, disease progression (if not already confirmed by iRECIST) and 
new anti-cancer therapy (including radiotherapy) every 12 weeks until death, termination 
of the overall study or an arm /cohort by the sponsor. 
 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. After 72 events have occurred for participants enrolled in Part 2, which is 80% of the 
total sample size of Part 2 or all participants have completed the study as defined in 
the protocol, whichever comes first. (This will no longer apply as study is 
terminating after Part 1) 
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 


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3. Randomization codes have been distributed according to RandAll NG procedures. 
Note: the study is not blinded, therefore, criteria for unblinding do not need to be met.  
 




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4.1. 
Protocol Deviations 
Important protocol deviations (including but not limited to deviations related to study 
inclusion/exclusion criteria, participant safety or interpretability of the trial data, or 
conduct of the trial) will be summarised and listed. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [V3.0]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised in the protocol deviations dataset. Although a per 
protocol population is not included, cases of site misconduct, any suspected 
fraudulent activity or other serious protocol deviations may warrant parameter, 
participant or site level exclusion from analysis populations. These will be 
captured in a note to file following study team review and agreement. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all deviations from inclusion/exclusion criteria 
specified in the protocol will also be provided. This summary will be based on data as 
recorded on the inclusion/exclusion page of the eCRF. 
Protocol deviations related to the COVID-19 pandemic will contain the prefix COVID19. 




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the last Part 1 participant completes the 28 day DLT observation period will be assigned 
to Part 2. All other participants will be assigned to Part 1. 
Part 1 participants dosed at the RP2D meeting the additional Part 2 inclusion/exclusion 
criteria will not be included in the Part 2 analyses.  
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions below) 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 and it is not otherwise possible to determine whether the 
assessment was performed pre- or post-dose, Day 1 assessments are assumed to be taken 
prior to first dose and may be used as baseline. Furthermore, if there are multiple 
assessments on the same day, the mean of the pre-dose assessments performed on that 
day will be taken. The latest non-missing average prior to dosing on Day 1 will be used 
as baseline.  For laboratory data, baseline will be the latest non-missing pre-dose value 
from central lab. If no central lab value is available, the latest non-missing pre-dose value 
from local lab will be used. For participants who did not receive study treatment during 
the study, baseline will be defined as the latest, non-missing 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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6. 
STUDY POPULATION ANALYSES 
In this multicentre global study, enrolment will be presented by country and investigative 
site using the enrolled population where applicable. 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Treated population for Part 1 and 
the ITT population for Part 2, unless otherwise specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
disease characteristics at initial diagnosis and at screening, prior anti-cancer therapy, 
surgical/medical procedures, substance use, duration of follow up, exposure and 
treatment compliance will be based on GSK Core and Oncology Data Standards. 
Separate displays will be presented for each study part, unless otherwise specified. 
Details of the planned displays are presented in Appendix 10: List of Data Displays. 
6.2. 
Disposition of Participants 
A summary of the number of participants in each of the analysis populations described in 
Section 4 will be provided, based on the screened population. A listing of participants 
excluded from each analysis populations will also be provided, based on the screened 
population. Number of participants based on the Enrolled population will be summarized 
by country and site for each study part. Participants planned and actual treatment received 
will be listed. 
The number and percentage of participants who met eligibility criteria and entered the 
study, who failed screening for any reason and therefore were not entered into the study, 
and participants who met eligibility criteria but were not needed will be summarized for 
the screened population. Reasons for failure for those subjects who failed screening will 
also be summarized in the display and listed. A participant may have more than one 
reason for screen failure.  
A summary of participant status (completed, ongoing, withdrawn) and reason for study 
withdrawal will be provided. This display will show the number and percentage of 
participants who have completed the study, are ongoing or have withdrawn from the 
study, including primary and secondary (if any) reasons for study withdrawal. Reasons 
for study withdrawal will be presented in the order they are displayed in the eCRF 
(Electronic Case Report Form).  
 
For Part 1 participants will be considered to have completed the study if they fulfil one of 
two criteria: 
1. Complete screening assessments, receive at least two doses of study treatment (or 
receive one dose but experience a dose limiting toxicity (DLT), are observed 
during the 28 day DLT observation period), and complete the treatment 


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discontinuation visit and the follow-up visit for safety (this will be considered 
‘completed follow-up’) 
2. Completed screening assessment and have died while receiving study treatment or 
during post-study treatment follow-up period for safety.  
For Part 2, participants will be considered as completing the study if they complete 
screening assessments, receive at least one dose of study treatment, discontinue study 
treatment for reasons other than lost to follow-up or non-compliance, and complete the 
study treatment discontinuation visit and follow-up visits or have died while receiving 
study treatment or during post-treatment follow-up period.   
In the event the Sponsor decides to close the study, participants receiving ongoing study 
treatment or ongoing in follow-up will be considered as completed the study (under 
‘completed follow-up’ for Part 1 participants). The end of the study in this case is defined 
as the completion of the last participant’s required visit.  
A listing of reasons for study withdrawal will also be produced for the enrolled 
population. 
A single, overall summary of the number and percentage of participants who entered, 
withdrew from and completed each study part will be displayed. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of participants who are ongoing or discontinued study treatment and a 
summary of the primary reasons for discontinuation of study treatment. Reasons for study 
treatment discontinuation will be presented in the order they are displayed in the eCRF.  
A listing of reasons for treatment discontinuation will be generated. The listing will 
include date of discontinuation, last dose date, and primary reasons for study treatment 
discontinuation. 
6.3. 
Protocol Deviations 
Important protocol deviations will be summarized and listed and will include 
inclusion/exclusion deviations as well as other deviations. See Section 4.1 for details.  
A separate listing of inclusion/exclusion criteria deviations as captured on the eCRF will 
also be provided. 
6.4. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, height, baseline body 
weight, and line of anti-PD(L)1 therapy [for Part 2 only]) will be listed and summarized. 
Age, height and weight will be summarized using the mean, standard deviation, 
minimum, median, and maximum. In addition, age will also be categorized and 
summarized by 18-64, 65-74, 75-84, and ≥85 and by 18-64 and ≥65. The count and 
percentage will be computed for race, ethnicity and sex. The summary of demographic 
data will be displayed for each cohort and overall.  


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A separate summary of age ranges based on the Enrolled population will be provided. 
Age will be summarized in categories: 18-64, 65-84, and ≥85. Race and racial 
combinations will also be summarized. 
6.5. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary and 
summarized and listed. The summary of concomitant medications will show the number 
and percentage of participants taking concomitant medications by Ingredient. Multi-
ingredient products will be summarized by their separate ingredients rather than as a 
combination of ingredients.  
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes Amoxycillin on two separate 
occasions, the participant is counted only once under the ingredient “Amoxycillin”. In the 
summary of concomitant medications, the ingredients will be summarized by the base 
only, using CMBASECD and CMBASE. 
All medications, regardless of onset date will be included in the summary and listing. 
Blood products or blood supportive care products with onset date after the start of study 
treatment will be included in the summary tables. The frequency and percentage of 
participants using blood products and blood supportive care products after the start of 
study treatment will be provided. Supportive listings will also be provided. 
6.6. 
Disease Characteristics 
Disease history and characteristics at initial diagnosis and screening (where relevant: 
primary tumor type, lesion status, time since initial diagnosis in weeks, stage, time since 
last progression in weeks) will be summarized. Indicators (yes/no) for the following, 
collected at screening, will also be summarized:  measurable disease, non-target lesions, 
and metastatic disease. Past and current medical conditions reported at screening will be 
summarized by cancer-related and non-cancer related categories.  Disease history and 
characteristics, as well as these medical conditions, will be presented in data listings. 
A summary and listing of disease burden at baseline will be provided. Information on 
sites of metastatic disease at screening will be summarized and listed. 
6.7. 
Prior Anti-cancer Therapy 
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by type of therapy and listed. A listing of prior anti-cancer therapy will show 
the relationship between Anatomical Therapeutic Chemical (ATC) Level 1, ingredient, 
and verbatim text; therapies will be classified by type (chemotherapy, immunotherapy, 
hormonal therapy, radiotherapy, and biologic therapy, radioactive therapy, small 
molecule targeted therapy, vaccine).  
A summary of the number of prior anti-cancer therapy regimens/lines by type will also be 
produced. 


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Prior cancer related surgeries will be summarized alongside type, and all prior surgical 
procedures will be and listed. 
6.8. 
Subsequent Anti-cancer Therapies 
The number and percentage of participants that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, 
radiotherapy and cancer-specific surgery as post study treatment anti-cancer therapy will 
be summarized. Time from study treatment discontinuation to the first post study 
treatment anti-cancer therapy will also be included in this summary table.  
Follow-up anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by ingredient. A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, 
small molecule targeted therapy, radiotherapy and cancer-specific surgery and details of 
the anti-cancer therapy (radiotherapy site, surgical procedure, or drug name for 
chemotherapy, hormonal, immunotherapy, biologic therapy) for each participant will be 
provided. 
6.9. 
Treatment Compliance and Exposure 
Individual participant summary listings of study treatment exposure and dose 
modifications (e.g., number of dose reductions, dose delays, missed doses, dose 
interruptions and incomplete infusions) for each component will be provided.  
Extent of exposure to GSK3359609, tremelimumab and SOC will be summarized and 
listed, separately. 
The duration of exposure to study treatment in weeks, defined as (treatment stop date – 
treatment start date + 1) divided by 7, will be summarized. Descriptive statistics 
including mean, median, standard deviation, minimum, and maximum will be calculated 
for time on study treatment. Moreover, time on study treatment will be categorized in 
different time period: <9 weeks, 9 – 18 weeks, 18 – 24 weeks, 24 – 48 weeks and >= 48 
weeks.  
The cumulative dose, infusion dose intensity and relative dose intensity (%) will also be 
summarized for each drug component using mean, median, standard deviation, minimum, 
and maximum. The cumulative dose is the sum of the actual dose administered during 
each infusion for a participant throughout the study.  
The dose intensity is calculated by cycles which consist of 3-week periods for 
GSK3359609, Tremelimumab and Docetaxel; and a 1 week period for Paclitaxel and 
Cetuximab. The dose intensity is calculated by cumulative dose divided by expected 
duration of exposure (last infusion date – first infusion date + cycle length in days)/cycle 
length in days). The relative dose intensity (%) is the dose intensity divided by planned 
dose per cycle. 


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Dose delays will be summarised by number of delays and reasons for the delays. Dose 
interruptions will be summarised by number of interruptions, duration of interruptions 
and reason for interruptions. 
All dose interruptions, incomplete infusions, and dose delays will be listed separately. 
Any overdose will also be listed if applicable. 
Dose modifications (dose interruptions and dose delays) and Dose limiting toxicity 
(DLT) will also be summarized and listed according to GSK Core Data Standards.  


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7. 
PRIMARY ENDPOINT ANALYSES  
The primary endpoint analyses planned for Part 1 of the study can be found in Section 10: 
Safety Analyses. 
The primary endpoint analyses for Part 2 are stated in the section below. 
The primary population of interest for Part 2 will be the Intent-To-Treat (ITT) population 
summarized by randomized treatment arm. This will be the population for figures, 
listings and summaries of OS data. 
7.1. 
Definition of Endpoints 
Overall Survival (OS) 
The endpoint for primary analyses for Part 2 is Overall Survival (OS), defined as the 
interval of time (in weeks) from randomization to the date of death due to any cause.  
 
In the absence of confirmation of death, survival time will be censored at the last date the 
participant is known to be alive at (i.e. their last known alive date). Often, this will be the 
date of last contact. Participants lacking data beyond the date of randomization will have 
their survival times censored at the date of randomization. When calculating overall 
survival, all deaths following subsequent anti-cancer therapy will be included. 
The distribution of OS for each treatment arm at the time of final analyses will be 
estimated using the Kaplan-Meier method. The median, 25th and 75th percentiles of OS 
will be estimated and corresponding 2-sided 95% confidence intervals will be estimated 
using the Brookmeyer-Crowley method (1982).  The treatment difference in survival will 
be assessed by the stratified log-rank test.  
7.2. 
Statistical Analyses / Methods 
Overall Survival (OS) 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
OS will be summarised using descriptive statistics, graphically presented (where 
appropriate) and listed. 




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phase 2, under the null hypothesis of equality of hazards in phase 3 the one-sided 2.5% 
alpha level logrank test (two-sided 5% test) is statistically significant if  
𝑍𝑝3 < −1.96   𝑜𝑟 𝑒𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡𝑙𝑦,      𝑦=  log(ℎ𝑟
̂𝑝3) < −1.96 ∗𝑠𝑒
̂𝑝3
 . 
If −1.96 ∗𝑠𝑒
̂𝑝3
2  exceeds the one-sided upper 60% prediction limit (20% two-sided upper 
limit) we are no less than 60% confident in a successful phase 3 result.   The confidence 
level in a successful phase 3 result is one minus the probability of the observed phase 2 
result and an unsuccessful phase 3 result or something more extreme, and is given by 
 
1 −Φ
(
  log(ℎ𝑟
̂𝑝2) −(−1.96 ∗𝑠𝑒
̂𝑝3
 )
√sê 𝑝2
2 + sê 𝑝3
2
)
  
 
Φ
(
 − log(ℎ𝑟
̂𝑝2) −1.96 ∗𝑠𝑒
̂𝑝3
 
√sê 𝑝2
2 + sê 𝑝3
2
)
  
 
where Φ(𝑡) is the cdf of a standard normal distribution. 










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2 An adequate assessment is defined as an assessment where the investigator assessed response is CR, PR, or SD. 
3 If PD and New anti-cancer therapy occur on the same day, assume the progression was documented first (e.g. 
outcome is progression and the date is the date of the assessment of progression). If anti-cancer therapy is started 
prior to any adequate assessments, censoring date should be the date of first dose. 
8.1.2. 
Statistical Analyses / Methods 
 Unless otherwise specified, endpoints / variables defined in this section will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. For ORR, DCR, TTR, and DoR, 2-sided 95% exact confidence limits will be 
provided. 
Details of the planned displays are provided in Section 13.10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Overall response rate (ORR)  
The number and percentage of participants BOR will be summarized by cohort for Part 1 
and treatment arm for Part 2. ORR will be reported per both RECIST v1.1 and iRECIST 
as defined in Section 8.1.1. 
Participants with Not Evaluable or missing response will be treated as non-responders; 
i.e. they will be included in the denominator when calculating the percentage. 
ORR and the associated 2-sided 95% exact confidence limits will be provided by 
cohort/treatment arm for each part.  
Disease control rate (DCR)  
The number and percentage of participants BOR will be summarized by cohort for Part 1 
and treatment arm for Part 2. DCR will be reported per both RECIST v1.1 and iRECIST 
as defined in Section 8.1.1. 
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.  
DCR will be summarized and the associated 2-sided 95% exact confidence limits will be 
provided separately by cohort/treatment arm for each part. 
Progression Free Survival (PFS) 
The distribution of PFS for each treatment arm will be estimated using the Kaplan-Meier 
method. Summaries of the number and percentage of participants experiencing a PFS 
event and the type of event will be provided along with the median, 25th and 75th 
percentiles of PFS will be estimated and corresponding 95% confidence intervals will be 
estimated using the Brookmeyer-Crowley method (1982).  
The date of documented disease progression will be defined as the date of disease 
progression by iRECIST based on eCRF entries. If an assessment occurs over multiple 








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For tmax, median, maximum, minimum, arithmetic mean, 95% confidence interval, and 
standard deviation will be calculated. The first point, last point and number of points used 
in the determination of z will be included on the listing of the derived parameters. 
 
All PK parameters will be reported to at least 3 significant digits, but to no more 
significant digits than the precision of the original data. 
8.2.3. 
Population of Interest  
All pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified. All summaries, figures and data listings will use cohort/treatment labels 
specified in Section 5.1. 
8.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Section 13.10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if participants have well defined plasma profiles).  
8.2.4.1. 
Dose proportionality  
If data permits, dose proportionality will be assessed using power model for: 
• AUC(0- τ), Cmax, and Cmin in Week 1  
• Cmax and Cmin in Week 19 
 
Dose proportionality of GSK3359609 Cmax following single dose administration and 
AUC(0-) and Cmax following repeat dose administration will be evaluated using the 
power model as described below: 
 
log (pharmacokinetic parameter) = a + b * log(dose)  
where a is the intercept and b is the slope. 
Both the intercept and slope will be fitted as fixed effects.  If there is sufficient data, the 
model may also be fit with the intercept and/or slope as random effects depending on the 
ability of the model to converge and on estimation of variance-covariance matrix.  The 
mean slope and corresponding 90% confidence interval will be estimated from the power 
model.   
8.2.4.2. 
Accumulation 
To assess accumulation, ANOVA with a fixed effect term for day and a random effect 
term for participant will be performed on log-transformed Ctrough for each treatment 
group (dose level) separately.  The observed accumulation ratio (Ro) will be estimated by 


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exponentiating the difference in least squares means (Dose 6 – Dose 1) and the associated 
90% confidence interval. 
8.3. 
Immunogenicity Analyses 
Immunogenicity/ Anti-drug antibodies (ADA) testing will occur in dosed participants 
then analyzed, summarized descriptively and listed. 
Immunogenicity information will be listed by participant and a summary of the number 
of participants that are negative and positive for the presence of the antibodies will be 
provided at each timepoint and overall for the participant.  Drug tolerance of the assays 
will be taken into account in categorizing results at each timepoint as positive, negative, 
or inconclusive.  A positive result at any timepoint means that the participant’s overall 
category is positive. 
To assess immunogenicity of GSK3359609 and Treme, serum will be tested for the 
presence of anti-GSK3359609 antibodies and anti-Treme antibodies using antibody 
assays. For the binding assay, there will be 3-steps testing schema: screening, 
confirmation and titration steps.  A screening assessment is performed which produces a 
result of positive or negative. For samples with a positive screening result, a confirmatory 
assay is then performed, which also produces a result of positive or negative. If a sample 
has a positive confirmation result, a titer value will also be obtained to quantify the 
degree of binding in the titration assay step. Participants will be viewed as positive for the 
binding assay if the confirmatory assay was positive. 
For the incidence of patients with positive binding antibody, a table will be produced 
summarizing results for the binding antibody assay by dose level and visit. The table will 
include the number and proportion of participants in each result category for each visit 
(including TDV visit). Binding confirmatory assay results will be categorized as 
negative, transient positive (defined as a single positive immunogenic response that does 
not occur at the final/TDV assessment) or persistent positive (defined as a positive 
immunogenic response at least 2 consecutive assessments or a single result at the 
final/TDV assessment).   
A separate table will be produced to summarize the median, min and max titer values 
among all visits by dose level and part.  


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9. 
EXPLORATORY ENDPOINT ANALYSIS 
9.1. 
Efficacy Analysis 
The exploratory analyses for Part 1 will be performed for PFS, OS, TTR and DoR.  The 
exploratory analyses for Part 1 will be based on the All Treated population, unless 
otherwise specified. 
Progression Free Survival (PFS) 
For Part 1 participants, PFS duration is defined as the time from the date of first dose to 
first documented evidence of disease progression or death (regardless of cause of death), 
whichever comes first. 
Summaries of the number and percentage of participants experiencing a PFS event and 
the type of event will be provided by cohort along with the median, 25th and 75th 
percentiles of PFS and corresponding 95% confidence intervals will be estimated using 
the Brookmeyer-Crowley method (1982).  
Overall Survival (OS) 
For Part 1, OS is defined as the interval of time (in weeks) from first dose to the date of 
death due to any cause. 
Summaries of the number and percentage of participants experiencing a OS event and the 
type of event will be provided by cohort along with the median, 25th and 75th percentiles 
of OS and corresponding 95% confidence intervals will be estimated using the 
Brookmeyer-Crowley method (1982).  
Time to Response (TTR) and Duration of Response (DoR) 
Summaries of the number and percentage of participants experiencing a response event 
and the type of event will be provided by cohort along with the median, 25th and 75th 
percentiles of response and corresponding 95% confidence intervals will be estimated 
using the Brookmeyer-Crowley method (1982).  
9.2. 
Pharmacodynamic and Biomarker Analyses 
9.2.1. 
Endpoint / Variables 
Data obtained from the pharmacodynamic samples will be descriptively and/or 
graphically summarized. These include serum sICOS, plasma cytokines, tumor biopsy 
material and protein expression by IHC. 
9.2.2. 
Summary Measure 
The results of these biomarker investigations will be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
(absolute value/change from baseline) and/or graphically summarized or as appropriate to 
the data.  


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Exploratory analyses may be performed to examine potential relationships between anti-
cancer activity and changes in markers of target inhibition or tumor biology (e.g., 
biomarkers, relevant transcripts, and/or proteins) or between anti-cancer activity and 
potential markers of sensitivity.  
Additional exploratory analyses may be performed to further characterize the novel 
biomarkers. 
9.2.3. 
Population of Interest 
The pharmacodynamic analyses will be based on the PD population, unless otherwise 
specified. 
9.3. 
Pharmacokinetic/Pharmacodynamic Analyses 
If warranted, exploratory PK/Pharmacodynamic analyses will be conducted to inform 
dose selection decisions. 
9.4. 
Pharmacogenetic Analyses 
Further details on PGx analyses discussed in the protocol may be identified /addressed in 
a separate PGx RAP, if applicable. 
9.5. 
Patient Reported Outcomes 
Patient reported outcomes will not be analysed as data is not collected for part 1. 
 
 
 


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10. 
SAFETY ANALYSES 
The safety analyses are the Primary analyses for Part 1 and Secondary for Part 2.  All 
safety analysis will be based on the All Treated population, unless otherwise specified. 
Changes from baseline in all serially collected safety endpoints (laboratory tests, vital 
signs, ECG parameters) will be summarized according to the scheduled, nominal visit at 
which they are collected and across all on treatment time points using a “worst-case” 
analysis. Data for vital signs and electrocardiograms (ECGs) will be summarized based 
on predetermined criteria identified to be of potential clinical concern (PCI). 
10.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Section 13.10: List of Data Displays. All summaries 
analyses and listings will present all adverse events. AEs will be coded to the preferred 
term (PT) level using the Medical Dictionary for Regulatory Affairs (MedDRA version 
20.1 or higher) and grouped by system organ class (SOC) and adverse events of special 
interest (AESI) groupings.  AEs will be graded by the investigator according to the NCI-
CTCAE version 5.0 or higher.  Unless otherwise specified AEs will be presented for 
Parts 1 and 2 separately.  
A summary of number and percentage of participants with any adverse events by 
maximum grade will be produced. The maximum grade throughout the duration of event 
rather than the severity grade at onset will be used to determine the severity grade 
recorded by a participant at each level of summarization. AEs will be sorted by System 
Organ Class (SOC) and Preferred term (PT) in descending order of total incidence. The 
summary will use the following algorithms for counting the participants: 
• 
Preferred term row: Participants experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum 
grade/intensity. 
• 
System organ class (SOC) rows: Each participant is counted only once at the 
maximum toxicity grade/intensity at each SOC level per dose level received, 
although they may have several different preferred term events within the same 
SOC.   
• 
Adverse events of special interest (AESI):  As defined in the protocol.  Each 
participant is counted only once at the maximum toxicity grade/intensity at each dose 
combination received. 
• 
Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum grade/intensity no matter how many events they have. 
The summary tables will be displayed in descending frequency of total incidence by SOC 
and Preferred Term (PT), and by alphabetic order when PT with equal incidence within 
the SOC. If maximum toxicity grade is missing but the toxicity grade at onset is 
available, then this will be used instead. If both are missing and there are no other events 


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with a toxicity grade for the participant, at each level of summarization, then this event 
will be displayed in an “unknown” row. 
In addition, the number and percentage of participants with AEs (all grades) will be 
summarized and displayed in descending frequency of total incidence by SOC and PT.  
A separate summary will be provided for study treatment related AEs. A study treatment 
related AE is defined as an AE for which the investigator classifies the relationship to any 
of the study treatments as “Yes” or as determined by the study team. A conservative 
(worst-case scenario) approach will be taken to handle missing relatedness data, i.e. the 
summary table will include events with the relationship to study treatment as ‘Yes’ if 
missing. The summary table will be displayed in descending frequency of total incidence 
by SOC and PT. 
Summaries for treatment-related adverse events will be produced and summarized by 
frequency (number and percentage of total participants) and maximum severity (grade), 
by system organ class and preferred term. If listed in the NCI-CTCAE (version 5.0), 
these summaries will be by the maximum grade.  
A summary of the number and percentage of participants and the number of occurrences 
of common 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. 
A listing of all AEs will be provided.  
10.2. 
Adverse Events of Special Interest Analyses 
Current adverse events of special interest (AESIs) include AEs of any grade that may 
have a potential immunologic aetiology. AESIs have been selected based on pre-clinical 
and clinical experience across the ICOS program by the safety review team. AESIs for 
GSK3359609 are pneumonitis, colitis, hepatitis, endocrinopathies, myocarditis, nephritis 
and renal function, skin adverse reactions, and other potentially immune-mediated AEs, 
and infusion-related reactions as specified in Appendix 6 (Section 13.6.3).  
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional AESIs, therefore the list of terms to be used for each event of interest 
and the specific events of interest will be based on the safety review team agreements in 
place at the time of reporting. The list of identified AESIs along with the MedDRA code 
can be found in Section 13.6.3. Summaries of the number and percentage of participants 
with these events will be summarized by TOI of AESIs, preferred term and maximum 
toxicity grade in one table.  
In addition, AESIs will be listed separately. 


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10.3. 
Deaths and Serious Adverse Events 
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 by the primary cause of death in the order listed in the CRF. 
A supportive listing will be generated to provide participant-specific details on 
participants who died.  
The incidence of deaths and the primary cause of death will be summarized. 
A summary of the number and percentage of participants and the number of occurrences 
of serious, drug-related serious, fatal serious, and drug-related fatal serious adverse 
events will be created for disclosure requirements to regulatory agencies. 
All SAEs will also be tabulated based on the number and percentage of participants who 
experienced the events. The summary tables will be displayed in descending order of 
total incidence by SOC and PT. 
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment 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 treatment as ‘Yes’ or missing.  
Study treatment-related SAEs will be summarized by GSK3359609, tremelimumaband 
SOC separately. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
participant-level details will be generated for: 
• 
Fatal SAEs  
• 
Non-Fatal SAEs 
Separate supportive listings with participant-level details will be generated for fatal and 
non-fatal SAEs, respectively. The fatal and non-fatal SAEs will be listed by dose level for 
Part 1 and treatment arm for Part 2, including the relationship with treatment.  
A listing of deaths will be generated to provide participant-specific details on participants 
who died. 
10.4. 
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  
• 
AEs leading to Withdrawal from the Study 


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A summary of the number and percentage of participants with adverse events leading to 
permanent discontinuation of study treatment will be displayed by overall frequency.  
 
Similar outputs will be produced for non-serious treatment-related adverse events and 
common (5 or 10%) adverse events as stated below: 
 
• Common (>10%) AEs 
• Common (5%) Grade 3-5 AEs 
• Common (5%) treatment-related Grade 3-5 AEs 
• Non-serious treatment-related AEs 
 
10.5. 
Pregnancies  
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If participants become pregnant while on 
the study, the information will be included in the narratives and no separate table or 
listing will be produced. 
10.6. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Section 13.10: List of Data Displays. 
The assessment of laboratory toxicities will examine the laboratory tests listed in 
Appendix 2 in the protocol. 
Laboratory grades will be evaluated using NCI-CTCAE v5.0. However, some tests are 
not graded using NCI-CTCAE. For hematology, Red Blood Cell (RBC) is not gradable 
by NCI-CTCAE v5.0. For clinical chemistry, BUN and creatinine clearance are not 
gradable by NCI-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 NCI-CTCAE v5.0 in both directions.  
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by NCI-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.  
For lab tests that are not gradable by NCI-CTCAE v5.0, summaries of worst-case 
changes from baseline with respect to normal range will be generated. Decreases to low, 
changes to normal or no changes from baseline and increases to high will be summarized 


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for the worst-case post-baseline. If a participant has a decrease to low and an increase to 
high during the same time interval, then the participant is counted in both the “Decrease 
to Low” categories and the “Increase to High” categories.   
Separate summary tables for haematology, chemistry and urinalysis tests will be 
produced. Liver function, thyroid function and pancreatic laboratory tests will be 
included with chemistry tests. Cardiac function, coagulation will be included with 
haematology tests. 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to the NCI-CTCAE (version 5.0) [NCI, 2017]. Laboratory test 
results outside the reference ranges that do not have an associated NCI-CTCAE criteria 
will be summarized using proportions. 
Detailed derivation of baseline assessment is specified in Section 5.2. 
Unscheduled data will only be included in “post-baseline” summaries for capturing a 
worst case across all scheduled and unscheduled visits after the first dose of study 
medication. 
 
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 visit. 
Supporting listing of laboratory data for participants with grade 3 and above will be 
provided. A separate listing of laboratory data with character values will also be 
provided. 
A character lab value starting with ‘<X’ or ‘>X’ will be displayed in listings but will not 
be imputed with a numeric value thus will not be included for summaries.  
10.7. 
Liver Function Analyses 
Summaries of 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 ALT ≥3×ULN and overall bilirubin ≥2×ULN 
(with direct bilirubin 35% of total bilirubin, if direct bilirubin is measured) OR (ALT 
≥3×ULN and INR >1.5, if INR is measured). Note that INR measurement is not 
required, and the threshold value stated will not apply to participants receiving 
anticoagulants. 
A listing of liver function tests for participants meeting Hy’s law will be generated. A 
listing of participants with liver function test toxicity grade ≥3 will also be provided. 
Summaries of 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 all events of ALT ≥3xULN and bilirubin ≥2xULN 
(>35% direct bilirubin) or ALT ≥3xULN and International Normalized Ratio (INR)>1.5, 


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which may indicate severe liver injury.  An e-DISH plot of maximum post baseline total 
bilirubin versus maximum post baseline ALT will be created. 
Liver function test (LFT) patient profiles plots for participants experiencing an ALT, 
AST or total bilirubin of toxicity grade 2 or above will be produced. A trellis display of 
LFT shifts from baseline to maximum values will be provided. Each dose level will be 
presented in a separate row and each liver function test in a separate column. A matrix 
display of maximum post-baseline values of each of the LFT tests will also be produced 
with different symbols for each dose level. 
A summary of the number of participants with on-treatment liver re-challenges, 
adaptations and recovery will be provided. A re-challenge is defined as an ALT 
elevation, followed by interruption of study treatment, and subsequently an ALT value of 
Grade 1 or below on or prior to re-starting study treatment, where the ALT elevation 
means ALT>3xULN and ≤3xULN at baseline. An adaptation is defined as an ALT 
elevation followed by an ALT assessment returning to baseline grade or below without 
any interruption to study treatment between the ALT elevation and normalization. A 
recovery is defined as an ALT elevation followed by an ALT Grade 1 or below for 2 
consecutive visits or Grade 1 or below for one visit if participant discontinued study 
treatment and there is no data available. 
10.8. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. LVEF and Performance 
status will be summarized and listed based on GSK Oncology Data Standard. The details 
of the planned displays are presented in Section 13.10: List of Data Displays. 
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. 
10.8.1. 
Vital Signs 
Values of vital signs (Systolic and diastolic blood pressure (BP), heart rate, temperature 
and weight) as well as the change from baseline will be summarized by scheduled visit 
using mean, median, standard deviation, minimum and maximum.  
In addition, vital signs values will be categorized (inclusively) as follows: 
• 
Systolic BP (mmHg): Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159) and 
Grade 3 (≥160) 
• 
Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), and Grade 
3 (≥100) 
• 
Heart rate (beats/min): <60, 60-100, and >100 
• 
Temperature (°C): ≤35, >35-<38, ≥38 


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Summaries of increase in systolic and diastolic blood pressure from the baseline with 
respect to the categories defined above will be performed. These summaries will display 
the number and percentage of participants with increase to grade 2 and increase to grade 
3 in the worst case post-baseline.  
10.8.2. 
Performance Status 
ECOG performance status will be summarized at baseline and each post-baseline 
scheduled visit. Summaries will use frequency and percentage of participants at each 
planned assessment time. A summary of change from baseline by scheduled visits will be 
performed, as well as the worst case post-baseline and the best case post-baseline changes 
during the study (improved, no change, deteriorated).  
A supporting listing will also be provided.  
10.8.3. 
ECG 
ECG is only standardly collected at the screening visit (within 30 days prior to first dose 
of study treatment) and Day 1, then is only required during the treatment phase if 
clinically indicated. The ECG findings will therefore only be summarized using mean, 
median, standard deviation, minimum and maximum at the screening and baseline (day 
1) visits. No post-baseline and change from baseline summaries will be provided but all 
values collected will be listed. 
10.8.4. 
LVEF 
ECHO/MUGA is only standardly collected at the screening visit (within 30 days prior to 
first dose of study treatment) and is only required during the treatment phase if clinically 
indicated. The LVEF (%) will therefore only be summarized using mean, median, 
standard deviation, minimum and maximum at the screening visit. No post-baseline and 
change from baseline summaries will be provided but all values collected will be listed. 


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11. 
ADDITIONAL ANALYSES DUE TO THE COVID-19 
PANDEMIC 
Listings will be produced to summarize the COVID-19 pandemic study/visit impact and 
any assessment and diagnosis information. 
Visits and assessments missed due to the COVID-19 pandemic, together with visits 
conducted remotely, will be listed by participant. 
A participant is defined as having a suspected, probable or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
A listing of participants with a suspected, probable or confirmed COVID-19 infection, 
and of COVID-19 test results will be based on GSK Core Data Standards. 
In addition to the overall summary of important protocol deviations, a listing of protocol 
deviations related to COVID-19 will also be produced.  
 
 
 


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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 1982 Mar 1:29-41.   
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guidelines (version 1.1). 
Eur J Cancer. 2009; 45:228-47. 
Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics 53, 983-997.  
NCI. National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. 
NCI, NIH, DHHS. November 27, 2017. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statistics Med. 2008;27:2420-2439. 
Neuenschwander B, Matano A, Tang Z, Roychoudhury S, Wandel S. A Bayesian 
Industry Approach to Phase I Combination Trials in Oncology. Chapter 6 “Statistical 
Methods in Drug Combination Trials”. Chapman & Hall/CRC. 2014. 
Protocol Amendment 01 (2018N362439_01): A Phase I/II, Open-label, Two Part Study 
of GSK3359609 in Combination with Tremelimumab in Participants with Selected, 
Advanced Solid Tumors, 20 September 2018 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 
2017; 18: e143-52. 
 
 


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13. 
APPENDICES 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
There is no planned per protocol analysis for this study. 
 
 


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13.2. 
Appendix 2: Schedule of Activities 
See Section 1.3 of the protocol. 


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13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
Not applicable. 




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13.4.2. 
Treatment Emergent Flag for Adverse Events 
Not applicable. 








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Duration and Elapsed Time 
• Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are calculated as the 
stop date minus the start date plus one. 
• For elapsed time (e.g., the time since initial diagnosis): 
o If the reference date is on or after the event date, then the elapsed time is the reference date 
minus the event date + 1 
o If the reference date is before the event date, then the elapsed time is the reference date minus 
the event date 
• 
For time to event (TTE) durations such as PFS  
o To report in months, divide the number of days by 30.4375 
o To report in weeks, divide the number of days by 7 
o To report in years, divide the number of days by 365.25.  
These algorithms for time to event return decimal numbers and ignore the actual numbers of days in 
the months or years between start date and stop date. The “year” used in these algorithms is 365.25 
days long, and the “month” is one twelfth of that year. 
• 
For converting all other durations (e.g., duration of adverse events, duration of exposure, age) to 
weeks, months or years use the following: 
o To report the duration in weeks divide the number of days by 7 
o To report the duration in months use: (YEAR(stopdate + 1) – YEAR(startdate)) * 12 + 
(MONTH(stopdate + 1) – month(startdate) – 1) + (DAY(stopdate + 1) > = DAY(startdate)) 
o To report the duration in years use:intck(‘year’, startdate, stopdate + 1) – (month(stopdate + 1) < 
month(startdate) or (month(stopdate + 1) = month(startdate) and day(stopdate + 1) < 
day(startdate))) 
These algorithms return whole numbers for months and years, accurately accounting for the actual 
numbers of days in the months or years between the start date and the stop date. 
 
























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13.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
SAS 
 
 
WinNonlin 
 
 














































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13.11. 
Appendix 11: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 


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