Conditions: Neoplasms
Keywords: Non-small cell lung cancer Inducible t-cell co-stimulator (ICOS) Docetaxel Standard of care Immuno-oncology agents TIGIT Dostarlimab Jemperli GSK4428859A belrestotug EOS884448 GSK6097608 Anti-TIGIT CD-96 Anti-CD-96
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 175
Healthy volunteers: no

Brief summary:
This study will compare the clinical activity of novel regimens (in combination or as single agents) to SoC in participants with relapsed/refractory advanced NSCLC. The study will be conducted in two parts. Part 1 is an open-label, optional, non-randomized part based on safety and pharmacokinetics/pharmacodynamics (PK/PD) evaluation intended to generate additional data to qualify novel regimens for the randomized study. Part 2 is a randomized, Phase II open-label part comparing the efficacy and safety of these novel regimens with SoC. Drug name mentioned as GSK4428859A (belrestotug) and EOS884448 are interchangeable for the same compound and will be referred to as GSK4428859A/EOS884448/belrestotug.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None

Interventions: intervention 1: Docetaxel intervention 2: Feladilimab intervention 3: Ipilimumab intervention 4: GSK4428859A intervention 5: Dostarlimab intervention 6: GSK6097608
Intervention descriptions: intervention 1: Docetaxel will be administered. intervention 2: Feladilimab will be administered. intervention 3: Ipilimumab will be administered. intervention 4: GSK4428859A/EOS884448 will be administered. intervention 5: Dostarlimab will be administered. intervention 6: GSK6097608 will be administered.

Protocol document:
Prot_SAP_001.pdf: 
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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A Phase 2, Randomized, Open-label Platform Trial Utilizing a Master 
Protocol to Study Novel Regimens Versus Standard of Care Treatment in NSCLC 
Participants 
Protocol Number: 205801/Amendment 10 
Short Title: Phase 2 NSCLC Master Protocol 
Compound 
Number: 
GSK4428859A 
Study Phase: 2 
Sponsor Name and Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s):  
IND Number: 138944 
EudraCT Number: 2018-001316-29  
 
Sponsor Signatory: 
Ivan Diaz-Padilla, MD, PhD, 
Global Clinical Head, Immuno- oncology 
Oncology Clinical Development 
 
 
Approval Date: 26 Apr 2023 
 
 
 
 
© 2023 the GSK group of companies. All rights reserved. Unauthorized copying or use 
of this information is prohibited 
 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
DNG or TMF Number 
Amendment 10 
26 Apr 2023 
TMF- 16073217 
Amendment 9 
30 March 2023 
TMF-15772785 
Amendment 8 
23-May-2022 
TMF-14611949 
Amendment 7 
08-March-2022 
TMF- 14511980 
Amendment 6 
19-Nov-2021 
TMF-14000899 
Amendment 5 
02-Sep-2021 
TMF-13833961 
Amendment 4 
02-Feb-2021 
TMF-11698443 
Amendment 3 
29-Oct-2020 
2017N337080_03 
Amendment 2 
15-Jul-2019 
2017N337080_02 
Amendment 1 
20-Sep-2018 
2017N337080_01 
Original Protocol 
23-Jul-2018 
2017N337080_00 
 
Amendment 10 26 Apr 2023 
Overall Rationale for the Amendment:  
This amendment is considered substantial based on the criteria defined in EU Clinical 
Trial Regulation No 536/2014 of the European Parliament and the Council of the 
European Union because it significantly impacts the safety of participants. 
Overall rationale for the current amendment: Amendment 10 provides updated eligibility 
requirements with regards to toxicity from previous immunotherapy treatment.  
List of main changes in the protocol and their rationale: 
Section # and 
Name 
Description of Change 
Brief Rationale 
6.2 Exclusion 
Criteria, Criterion 
10. 
Updated to exclude 
participants who have 
experienced any grade of  
myocarditis with prior 
immunotherapy. 
 To further ensure participant safety 
 


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TABLE OF CONTENTS 
PAGE 
1. 
SYNOPSIS ............................................................................................................... 7 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 10 
3. 
INTRODUCTION .................................................................................................... 11 
3.1. 
Study Rationale .......................................................................................... 11 
3.2. 
Background ................................................................................................ 11 
3.3. 
Benefit/Risk Assessment ............................................................................ 12 
3.4. 
Overall Benefit-Risk Conclusion .................................................................. 13 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 13 
4.1. 
Objectives and Endpoints: Part 1 ................................................................ 13 
4.2. 
Objectives and Endpoints: Part 2 ................................................................ 13 
5. 
STUDY DESIGN .................................................................................................... 15 
5.1. 
Overall Design ............................................................................................ 15 
5.2. 
Duration of Treatment ................................................................................. 18 
5.3. 
Number of Participants ............................................................................... 18 
5.3.1. 
Sample Size: Part 1 ..................................................................... 18 
5.3.2. 
Sample Size: Part 2 ..................................................................... 19 
5.4. 
Participant Completion and End of Study Definitions .................................. 19 
5.4.1. 
Participant Completion Definitions ............................................... 19 
5.4.2. 
Study Completion Definition ......................................................... 19 
5.5. 
Scientific Rationale for Study Design .......................................................... 19 
5.5.1. 
Steering Committee and Data Monitoring Committee (Part 
2) ................................................................................................. 20 
5.6. 
Dose Justification ........................................................................................ 20 
6. 
STUDY POPULATION ........................................................................................... 21 
6.1. 
Inclusion Criteria ......................................................................................... 21 
6.2. 
Exclusion Criteria ........................................................................................ 24 
6.3. 
Lifestyle and Dietary Restrictions ................................................................ 27 
6.4. 
Screen Failures........................................................................................... 27 
6.5. 
Screening under Molecular Disease Characterization Initiative 
Study .......................................................................................................... 29 
7. 
TREATMENTS ....................................................................................................... 29 
7.1. 
Treatments Administered ............................................................................ 29 
7.2. 
Dose Modification ....................................................................................... 30 
7.2.1. 
Dose and Safety Management Guidelines ................................... 30 
7.3. 
Method of Treatment Assignment ............................................................... 33 
7.4. 
Blinding ....................................................................................................... 33 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 33 
7.5.1. 
Preparation .................................................................................. 33 
7.5.2. 
Handling ...................................................................................... 34 
7.5.3. 
Storage ........................................................................................ 34 
7.5.4. 
Accountability .............................................................................. 34 
7.6. 
Treatment Compliance ................................................................................ 34 
7.7. 
Concomitant Therapy.................................................................................. 35 


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7.7.1. 
Permitted Medications and Non-Drug Therapies .......................... 35 
7.7.2. 
Prohibited Medications and Non-Drug Therapies ......................... 36 
7.8. 
Treatment after the End of the Study .......................................................... 36 
8. 
DISCONTINUATION CRITERIA ............................................................................. 36 
8.1. 
Discontinuation of Study Treatment ............................................................ 36 
8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 38 
8.1.2. 
Study Treatment Restart/Rechallenge ......................................... 41 
8.2. 
Withdrawal from the Study .......................................................................... 41 
8.3. 
Lost to Follow-up ........................................................................................ 42 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 42 
9.1. 
General Guidance ....................................................................................... 42 
9.1.1. 
General Guidance for Treatment Continuity when 
Participants are Unable to Come into the Clinic ........................... 43 
9.2. 
Screening and Critical Baseline Assessments ............................................ 44 
9.3. 
Efficacy Assessments ................................................................................. 45 
9.3.1. 
Tumor Imaging and Disease Assessments .................................. 46 
9.3.2. 
Tumor Growth Kinetics ................................................................ 48 
9.3.3. 
Survival Follow-up ....................................................................... 48 
9.4. 
Adverse Events........................................................................................... 48 
9.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 48 
9.4.2. 
Method of Detecting AEs and SAEs ............................................. 49 
9.4.3. 
Follow-up of AEs and SAEs ......................................................... 49 
9.4.4. 
Regulatory Reporting Requirements for SAEs ............................. 49 
9.4.5. 
Cardiovascular and Death Events ................................................ 50 
9.4.6. 
Pregnancy ................................................................................... 50 
9.5. 
Safety Assessments ................................................................................... 50 
9.5.1. 
Physical Examinations ................................................................. 51 
9.5.2. 
Performance Status ..................................................................... 51 
9.5.3. 
Vital Signs .................................................................................... 51 
9.5.4. 
Electrocardiograms ...................................................................... 51 
9.5.5. 
Echocardiogram........................................................................... 52 
9.5.6. 
Clinical Safety Laboratory Assessments ...................................... 52 
9.6. 
Pharmacokinetics ....................................................................................... 53 
9.6.1. 
Blood Sample Collection .............................................................. 53 
9.6.2. 
Sample Analysis .......................................................................... 53 
9.7. 
Anti-Drug Antibodies ................................................................................... 53 
9.8. 
Genetics ..................................................................................................... 53 
9.9. 
Biomarkers ................................................................................................. 54 
9.9.1. 
Blood Biomarkers ........................................................................ 54 
9.9.2. 
Tumor Tissue ............................................................................... 54 
9.10. 
Patient-Reported Outcome Assessments ................................................... 55 
CCI


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10. STATISTICAL CONSIDERATIONS ........................................................................ 59 
10.1. 
Primary Endpoint ........................................................................................ 59 
10.1.1. 
Primary Endpoint: Part 1 .............................................................. 59 
10.1.2. 
Primary Endpoint: Part 2 .............................................................. 59 
10.2. 
Hypothesis .................................................................................................. 60 
10.2.1. 
Hypothesis: Part 1 ....................................................................... 60 
10.2.2. 
Hypothesis: Part 2 ....................................................................... 60 
10.3. 
Sample Size Determination ........................................................................ 60 
10.3.1. 
Sample Size: Part 1 ..................................................................... 60 
10.3.2. 
Sample Size: Part 2 ..................................................................... 62 
10.3.3. 
Interim Analyses .......................................................................... 63 
10.3.4. 
Statistical Operating Characteristics ............................................ 65 
10.3.5. 
Sample Size Sensitivity ................................................................ 67 
10.3.6. 
Sample Size Re-estimation .......................................................... 69 
10.4. 
Populations for Analyses ............................................................................ 69 
10.5. 
Statistical Analyses ..................................................................................... 70 
10.5.1. 
Analysis ....................................................................................... 70 
10.5.2. 
Other Secondary Analyses .......................................................... 71 
10.5.3. 
Safety Analyses ........................................................................... 72 
10.5.4. 
Pharmacokinetic Analyses ........................................................... 72 
10.5.5. 
Pharmacokinetic/Pharmacodynamic Analyses ............................. 73 
10.5.6. 
Tumor Kinetic Analyses ............................................................... 73 
10.5.7. 
Other Analyses ............................................................................ 73 
11. REFERENCES ....................................................................................................... 74 
12. APPENDICES ........................................................................................................ 80 
12.1. 
Appendix 1: Arms ....................................................................................... 80 
12.1.1. 
Standard of Care Arm 1: Docetaxel Alone (Part 2 ONLY) ............ 80 
12.1.2. 
Substudy 1 (Arm 2): Feladilimab and Docetaxel 
Combination ................................................................................ 93 
12.1.3. 
Arm 3: Feladilimab and Ipilimumab Combination ....................... 110 
12.1.4. 
Arm 4: GSK4428859A (Anti-TIGIT) and Dostarlimab (Anti-
PD-1) Combination .................................................................... 148 
12.1.5. 
Arm 5: GSK4428859A (Anti-TIGIT) plus Dostarlimab (Anti-
PD-1) plus GSK6097608 (Anti-CD96) Combination ................... 197 
12.2. 
Appendix 2: Abbreviations and Trademarks .............................................. 252 
12.3. 
Appendix 3: Clinical Laboratory Tests ....................................................... 256 
12.4. 
Appendix 4: Study Governance Considerations ........................................ 257 
12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 261 
12.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 267 
12.7. 
Appendix 7: Genetics ................................................................................ 271 
12.8. 
Appendix 8: ECOG Performance Status ................................................... 272 
12.9. 
Appendix 9: CKD-EPI and Cockcroft-Gault Formulas ............................... 273 
12.10. Appendix 10: Liver Safety: Required Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines .................... 275 
12.10.1. For Participants with ALT up to 2.5 X ULN at Baseline: ............. 275 
12.10.2. For Participants with Documented Liver Metastases and 
ALT up to 5 X ULN at Baseline: ................................................. 277 


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12.10.3. Phase 2 Liver Chemistry Increased Monitoring Criteria 
with Continued Therapy ............................................................. 279 
12.10.4. Liver Safety Drug Restart or Rechallenge Guidelines ................ 280 
12.11. Appendix 11: Country-Specific Requirements ........................................... 283 
12.12. Appendix 12: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria .......................................................... 284 
12.12.1. RECIST 1.1 Guidelines .............................................................. 284 
12.12.2. iRECIST Guidelines ................................................................... 289 
12.13. Appendix 13: Supplemental Statistical Information ................................... 295 
12.13.1. Parameters for Piecewise Weibull Distribution ........................... 295 
12.13.2. Calculation of PoS of Phase 3 Given Data from Phase 2 ........... 295 
12.14. Appendix 14: Immune-Related Diseases .................................................. 301 
12.15. Appendix 15: Protocol Amendment History ............................................... 303 
 


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1. 
SYNOPSIS 
Protocol Title: A Phase 2, Randomized, Open-label Platform Trial Utilizing a Master 
Protocol to Study Novel Regimens Versus Standard of Care Treatment in NSCLC 
Participants  
Short Title: Phase 2 NSCLC Master Protocol  
Rationale: 
Study 205801 is a randomized, Phase 2 open-label platform trial in two parts utilizing a 
master protocol to investigate the clinical activity of novel regimens compared with 
standard of care (SoC) regimens in participants with relapsed/refractory advanced non-
small cell lung cancer (NSCLC) who have prior platinum-containing chemotherapy 
regimen and an immuno-oncology agent treatment failure, such as anti-programmed cell 
death protein 1 [PD1] / PD-Ligand 1 [PD-L1] – either in combination or as separate lines. 
NSCLC is considered intrinsically resistant to immuno-oncology agents owing in part to 
its broad immune escape and suppressive features that include low antigenicity, despite 
having one of the highest frequencies of somatic mutations, and a high presence of 
regulatory T cells (Tregs). However, as shown by the single-agent response rates of anti-
PD-1 inhibitors in NSCLC, a subset of tumors are susceptible to T cell-mediated 
antitumor effects, suggesting those tumors have some degree of prior T-cell immunity. 
Since effective anticancer immune response involves stepwise multistep processes, lung 
cancers may possess or acquire features that enable them to evade immune surveillance, 
suppress immune reactivity, proliferate, and survive within an inflammatory 
microenvironment, thereby rendering an immune response ineffectual. Therefore, 
treatment modalities that incorporate combinations with agents targeting different 
processes within the immune cascade have the potential to reinstate immunosurveillance; 
these may include regimens containing chemotherapy that possess advantageous 
immunological effects to potentially improve clinical efficacy. 
Objectives and Endpoints (Part 1) 
Objectives 
Endpoints 
Primary 
To determine the safety and tolerability of novel 
regimen(s) 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
To provide a preliminary evaluation of the efficacy of 
experimental regimen(s) 
Objective Response Rate (ORR) 
Disease Control Rate (DCR) 
Characterize the pharmacokinetic properties 
of experimental regimen(s) 
PK parameters that include Cmax and Cmin for 
experimental regimen(s) (and investigational agent/s 
included in other arms), as data permit. 
 


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Objectives and Endpoints (Part 2): 
Objectives 
Endpoints 
Primary 
Determine whether experimental 
regimen(s) provide evidence for improved 
survival over SoC therapy 
Overall survival as measured by time from randomization to death 
Secondary 
Evaluate milestone survival in participants 
treated with experimental regimen(s) 
versus SoC therapy for NSCLC 
Milestone survival rate at 12 and 18 months  
Evaluate other measures of antitumor 
activity of the experimental regimen(s) 
compared with SoC therapy for NSCLC 
(RECIST 1.1 and iRECIST) 
CR, PR, SD, PD, PFS, ORR, DOR, DCR 
iCR, iPR, iUPD, iCPD, iSD 
iPFS; iORR; iDOR 
Evaluate the safety and tolerability of the 
experimental regimen(s) compared with 
SoC therapy for NSCLC 
 
Frequency and severity of AEs, AESI; SAEs and AE/SAEs leading to 
dose modifications/delays/withdrawals; changes in laboratory, vital 
signs, and safety assessment parameters, including immunogenicity 
(ADA) 
Characterize the pharmacokinetic 
properties SoC or experimental regimen(s) 
PK parameters that may include Cmax and Cmin for experimental 
regimen(s) and for SoC alone, as data permit. 
Determine immunogenicity of experimental 
regimen(s) 
ADA incidence for experimental regimen(s)  (where appropriate) 
Note: The prefix “i”, used for response related abbreviations in the above table indicates immune responses assigned 
using iRECIST. 
ADA= anti-drug antibody; AE = adverse event/s; AESI = adverse event/s of special interest; Cmax = maximum 
concentration; Cmin = minimum concentration; CPD = confirmed progression; CR = complete response; DLT = Dose 
Limiting Toxicity’ DOR = duration of response; NSCLC = non-small cell lung cancer; ORR = objective response rate; 
OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; RECIST = 
Response Evaluation Criteria In Solid Tumors; SAE = serious adverse event; SD = stable disease; SoC = standard of 
care; UPD = unconfirmed progression. 
 
Overall Design: 
This is a randomized Phase 2, open-label, platform trial utilizing a master protocol 
designed to study novel immunotherapy drug combinations compared with the current 
SoC, in the treatment of patients with advanced NSCLC who have progressed on prior 
anti-PD(L)1 and platinum-based combination chemotherapies. The study will initially 
evaluate 2 treatment regimens/arms, with additional regimens/arms added via protocol 
amendment(s) (see the Study Design schematic below).  
The study will be conducted in two parts; Part 1 is an open-label, optional, non-
randomized part based on safety and pharmacokinetics/pharmacodynamics (PK/PD) 
evaluation. Part 2 is a randomized, Phase 2, open-label part comparing the efficacy and 
safety of these novel regimens with SoC. Part 2, is structured as a series of substudies that 
share a common control arm with ongoing updating of the effect size of the control arm 
through the addition of new participants with each substudy. Each combination will be 
first evaluated in a separate study/arm for safety. This evaluation may occur prior to 
adoption into 205801 platform study (dose finding in a separate study) or as a distinct 
arm within this platform study (Part 1) prior to Part 2. If an experimental regimen meets 
graduation requirements, i.e., passes criteria for safety and preliminary clinical activity, 
they may advance to Part 2. Graduation will be the term used throughout the protocol to 


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refer to the advancement of a combination from Part 1 to Part 2. As a clarification, the 
combination will be tested in a new population that will be randomized between the 
combination and the Standard of Care. The study participants enrolled in Part 1 are not 
pooled with the study participants in Part 2. The two study populations are separate and 
distinct. Part 1 is open label single arm while Part 2 is randomized.  
For the randomized survival evaluation, participants will be stratified by histology 
(squamous vs. non-squamous) and line of PD(L)1 therapy (1st vs. 2nd line). Patients with 
NSCLC with undetermined histology (i.e. NSCLC not otherwise specified) will be 
considered as non-squamous for stratification purposes. 
Each additional treatment arm/regimen will be analyzed relative to the SoC treatment and 
is considered a substudy within the overall master protocol, as depicted below.  
Study Design 
 
 
NSCLC: non-small cell lung cancer; PD(L)1: Programmed Cell Death Protein 1 or Programmed Cell Death Ligand 1.  
Note: Randomization of participants to experimental treatment regimens/arms may not occur in parallel. It should 
also be noted that the terms ‘regimen’ and ‘arm’ may be used interchangeably throughout the document. 
Number of Participants: 
As the study uses a master protocol design, the sample size is not fixed.  
For Part 1, sample size will be defined for each regimen under the corresponding 
appendix in Section 12.1; a minimum of 3 participants will be evaluated for safety before 
further participants will be enrolled. 
The initial number of participants for Part 2 in substudy 1 is estimated to be at least 105 
(SoC arm: 35; experimental arm: 70 for substudy 1). Additional substudies and their 
corresponding experimental regimens will be added via protocol amendments. Each 


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additional experimental arm will enroll a maximum of 70 participants. Randomization to 
SoC/Arm 1 will be minimized through an alteration of the randomization ratio once 35 
participants are randomized to that arm.  
Treatment Groups and Duration: 
Study participation begins with the signing of the informed consent form (ICF) within 
45 days prior to the first dose. After a screening period of up to 28 days, eligible 
participants will be assigned a treatment arm if participating in Part 1 and receive study 
treatment (Day 1), or randomly assigned to a treatment arm (SoC or experimental) if 
participating in Part 2 and receive study treatment (Day 1).  
Unless otherwise specified in the treatment-specific appendix, investigational 
combination study treatment will continue at the indicated schedule for a maximum 
duration of approximately 2 years or up to 35 treatment visits, whichever comes first, or 
until disease progression, death, unacceptable toxicity, or withdrawal of consent. Single 
agent SoC treatment (i.e. docetaxel) may continue until disease progression, death, 
unacceptable toxicity, withdrawal of consent, or per institutional standard for docetaxel. 
After the study treatment is permanently discontinued, participants will be followed, via 
telephone contact, for survival and subsequent anticancer therapy every 12 weeks until 
death or the participant’s withdrawal from further contact. Participants permanently 
discontinuing study treatment prior to documented disease progression by iRECIST will 
also be followed every 12 weeks for disease progression or participant’s withdrawal from 
further contact. 
The study will be considered ‘finished’ once the last participant from all open treatment 
arms has completed their last survival follow-up contact. 
2. 
SCHEDULE OF ACTIVITIES (SoA) 
The Schedules of Activities can be found in the corresponding appendix for each 
arm in Section 12.1.  
• The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring.  
• Any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team 
member and then archived in the sponsor and site study files but will not 
constitute a protocol amendment. The Institutional review board/ Independent 
ethics committees (IRB/IEC) will be informed of any safety issues that require 
alteration of the safety monitoring scheme or amendment of the Informed consent 
form (ICF). 


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3. 
INTRODUCTION 
Study 205801 is an open-label platform trial utilizing a master protocol designed to 
investigate the clinical activity of novel regimens compared with standard of care (SoC) 
regimen in participants with relapsed/refractory advanced non-small cell lung cancer 
(NSCLC) who have prior platinum-containing regimen and anti‑programmed cell death 
protein 1 [PD‑1] / PD-Ligand 1 [PD-L1] treatment failure. The study will be conducted in 
two parts; Part 1 is an optional, non-randomized part based on safety and 
pharmacokinetics/pharmacodynamics (PK/PD) evaluation. Part 2 is a randomized, Phase 
2 part comparing the efficacy and safety of these novel regimens with SoC. 
3.1. 
Study Rationale 
While a subset of NSCLC tumors are responsive to immuno-oncology agents, a sizable 
portion of NSCLC tumors is considered to be intrinsically resistant to immuno-oncology 
agents, owing in part to its broad immune escape and suppressive features that include 
low antigenicity, despite having one of the highest frequencies of somatic mutations 
[Lawrence, 2013], and a high presence of regulatory T cells (Tregs). However, as shown 
by the single-agent response rates of anti-PD-1 inhibitors in NSCLC, a subset of tumors 
are susceptible to T cell-mediated antitumor effects, suggesting those tumors have some 
degree of prior T-cell immunity [Brahmer, 2015; Rittmeyer, 2017; Reck, 2016]. Since 
effective anticancer immune response involves stepwise multistep processes [Chen, 
2013], lung cancers may possess or acquire features that enable them to evade immune 
surveillance, suppress immune reactivity, proliferate, and survive within an inflammatory 
microenvironment thereby rendering an immune response ineffectual. Therefore, 
treatment modalities that incorporate combinations with agents targeting different 
processes within the immune cascade have the potential to reinstate immunosurveillance; 
these may include regimens containing chemotherapy that possess advantageous 
immunological effects to improve clinical efficacy [Galluzzi, 2015].  
3.2. 
Background 
Cancer is one of the leading causes of death worldwide, accounting for 8.8 million deaths 
in 2015. Lung cancer is the most common cause of cancer death, accounting for 
1.69 million deaths worldwide [Cancer Fact Sheet, 2017]. Globally, the incidence and 
mortality rates attributed to cancer vary across regions; nevertheless, lung cancer remains 
the leading cause of cancer death in men and the second leading cause of cancer death in 
women [Torre, 2015]. Non-small cell lung cancer accounts for the vast majority of lung 
cancer cases (up to 85%), with disease stage, histological subtype (e.g., adenocarcinoma, 
squamous, large cell, etc.), and molecular features playing a principal role in making 
treatment choices. In advanced-stage metastatic NSCLC positive for a specific molecular 
alteration (i.e., EGFR/ALK/ROS/BRAF), targeted single-agent approaches are 
recommended [NCCN, 2021; Planchard, 2018; Postmus, 2017]. In metastatic non-
squamous NSCLC, the first-line option for some patients is the approved triplet regimen 
consisting of pembrolizumab (an anti-PD-1 inhibitor) added to the 
pemetrexed/carboplatin backbone [Langer, 2016; KEYTRUDA, 2018]. An alternative 
current standard for NSCLC (squamous or non-squamous) is pembrolizumab as a single-
agent for (a) first-line treatment of metastatic NSCLC patients whose tumors have high 


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PD-L1 expression (Tumor Proportion Score [TPS] ≥50%) or, (b) in subsequent lines 
(post-platinum) of treatment of patients with metastatic NSCLC (squamous or non-
squamous) whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved 
test [Reck, 2016; KEYTRUDA, 2018]. Additional subsequent-line treatment options 
include other single-agent anti-PD-1/PD-L1 inhibitors (e.g., nivolumab and 
atezolizumab) if not administered as first-line [Brahmer, 2015; Rittmeyer, 2017]. In 
patients with advanced or metastatic non-squamous NSCLC without EGFR/ALK 
alternations and with PD-L1 TPS ≥1%, more durable responses were observed with 
pembrolizumab monotherapy compared to platinum-based chemotherapy alone, and 
support pembrolizumab as a standard first-line treatment option for all PD-L1-positive 
cancers [Lopes, 2016]. Additionally, in patients with previously untreated metastatic 
squamous NSCLC, the addition of pembrolizumab to platinum-based chemotherapy 
show significant improved survival regardless of PD-L1 expression level, and may be 
considered as a standard first-line treatment for metastatic squamous NSCLC regardless 
of PD-L1 status [Paz-Ares, 2018]. Recently, ESMO clinical practice guidelines have been 
updated to include the addition of atezolizumab to first-line chemotherapy in the 
metastatic non-small cell lung cancer setting [Planchard, 2018]. Single-agent 
chemotherapy such as pemetrexed for non-squamous NSCLC (if not used as part of the 
platinum-containing chemotherapy regimen earlier) or gemcitabine for squamous 
NSCLC or docetaxel for all NSCLC sub-types have been relegated to later lines and can 
be selected based on the patient’s treatment history, disease characteristics, and 
performance status.  
Docetaxel is approved by the US FDA and EMA as a single-agent for patients with 
locally advanced or metastatic NSCLC after platinum-based chemotherapy [TAXOTERE 
PI, 2020 and TAXOTERE SmPC 2020]. With the recent approvals of nivolumab in the 
same line of therapy, i.e., after progression on platinum-based doublet [OPDIVO PI, 
2018], docetaxel has been relegated to the status of a subsequent therapy, as noted in the 
ESMO/NCCN guidelines [Herbst, 2016; Horn, 2017; Novello, 2016; NCCN, 2019]. The 
clinical activity of older single-agent chemotherapies such as docetaxel as second-line 
treatment in NSCLC is limited with response rates in the range of 9 to 24% [Shepherd, 
2000; Hanna, 2004]. 
Patients with NSCLC that has failed both a platinum-containing chemotherapy regimen 
and an anti-PD(L)1 inhibitor (used either in combination or as separate lines of therapy) 
have a high unmet medical need for treatment advances with the potential to improve 
progression-free survival (PFS) and overall survival (OS). 
3.3. 
Benefit/Risk Assessment 
Benefits and risks for each combination partner can be found in the respective 
subsections under Section 12.1. Detailed information related to the known and expected 
benefits and risks including expected AEs of each experimental agent may be found in 
the corresponding Investigator’s Brochure (IB). Refer to the latest docetaxel product 
labels [TAXOTERE PI, 2020; TAXOTERE SmPC, 2020] for information on 
contraindications, warnings, and precautions related to the use of docetaxel. 
 


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3.4. 
Overall Benefit-Risk Conclusion 
There is biologic rationale to study these novel combinations in this setting based on 
complementary modes of action on the immune system, with the potential for antitumor 
activity that exceeds either agent’s monotherapy activity in preclinical models. Based on 
the current safety profiles (See Section 12.1 for details) and docetaxel labeling 
[TAXOTERE PI, 2020; TAXOTERE SmPC, 2020], potential overlapping toxicities with 
combination therapies are anticipated to be manageable. However, it is unknown whether 
the combination regimens will have clinical activity in NSCLC that exceeds the SoC 
treatment. Considering the overall poor outlook for patients who have failed prior 
therapies and recognizing the risk minimization strategies proposed, any potential risks 
are justified by the anticipated benefits to participants with advanced NSCLC.  
4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
Objectives and Endpoints: Part 1  
Objectives 
Endpoints 
Primary 
To determine the safety and tolerability of novel 
regimen(s) 
AEs, SAEs, DLTs, changes in safety/laboratory 
assessment parameters, dose modifications 
Secondary 
To provide a preliminary evaluation of the efficacy of 
experimental regimen(s) 
Objective Response Rate (ORR) 
Disease Control Rate (DCR) 
Characterize the pharmacokinetic properties 
of experimental regimen(s) 
PK parameters that include Cmax and Cmin for 
experimental regimen(s) (and investigational agent/s 
included in other arms), as data permit. 
Exploratory 
4.2. 
Objectives and Endpoints: Part 2 
Objectives 
Endpoints 
Primary 
Determine whether experimental 
regimen(s) provide evidence for improved 
survival over SoC therapy 
Overall survival as measured by time from randomization to death 
Secondary 
Evaluate milestone survival in participants 
treated with experimental regimen(s) 
versus SoC therapy for NSCLC 
Milestone survival rate at 12 and 18 months  
Evaluate other measures of antitumor 
activity of the experimental regimen(s) 
compared with SoC therapy for NSCLC 
(RECIST 1.1 and iRECIST) 
CR, PR, SD, PD, PFS, ORR, DOR, DCR 
iCR, iPR, iUPD, iCPD, iSD 
iPFS; iORR; iDOR 
CCI


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Objectives 
Endpoints 
Evaluate the safety and tolerability of the 
experimental regimen(s) compared with 
SoC therapy for NSCLC 
 
Frequency and severity of AEs, AESI; SAEs and AE/SAEs leading to 
dose modifications/delays/withdrawals; changes in laboratory, vital 
signs, and safety assessment parameters, including immunogenicity 
(ADA) 
Characterize the pharmacokinetic 
properties of SoC or experimental 
regimen(s) 
PK parameters that may include Cmax and Cmin for experimental 
regimen(s) and for SoC alone, as data permit. 
Determine immunogenicity of experimental 
regimen(s) 
ADA incidence for experimental regimen(s) (where appropriate) 
Exploratory 
Note: The prefix “i”, used for response related abbreviations in the above table indicates immune responses assigned 
using iRECIST. 
AE = adverse event/s; AESI = adverse event/s of special interest; Cmax = maximum concentration; Cmin = minimum 
concentration; CPD = confirmed progression; CR = complete response; DLT = Dose Limiting Toxicity’ DOR = duration 
of response; 
 
 
 
; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; 
 
 
; RECIST = Response Evaluation Criteria In 
Solid Tumors; SAE = serious adverse event; SD = stable disease; SoC = standard of care; TMB = Tumor Mutational 
Burden; UPD = unconfirmed progression. 
CCI
CCI
CCI


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is an, open-label, platform trial in two parts utilizing a master protocol to study 
novel drug combinations compared with the current SoC in the treatment of patients with 
advanced NSCLC who have progressed on prior anti-PD(L)1 and platinum-based 
combination chemotherapies. Part 1 is a non-randomized, safety and PK/PD evaluation, 
Part 2 is a randomized, Phase 2 comparing the efficacy and safety of novel regimens with 
docetaxel as the SoC control arm (Arm 1). Novel combinations will be evaluated in 
separate substudies. As shown in Figure 1, the study will initially evaluate the efficacy of 
feladilimab in combination with SoC (docetaxel) (Arm 2) compared with SoC alone as 
the standard subsequent-line chemotherapy (substudy 1) in NSCLC. Additional arms will 
be added via protocol amendment based on emerging nonclinical and clinical data. No 
treatment crossover is allowed in this study. 
Each novel combination will first be evaluated for safety. This evaluation may occur 
prior to adoption into the 205801 platform study (dose finding in a separate study) or as a 
distinct arm within this platform study (Part 1) prior to Part 2. Following the initial safety 
evaluation, additional participants for each regimen and/or dose may be enrolled to 
further evaluate safety and PK/PD (refer to Section 12.1 for details for each experimental 
regimen).  Once an experimental regimen qualifies for transition evaluation, additional 
participants will be enrolled to Part 2. Within Part 2, participants will be randomized to 
receive either SoC or the experimental treatment. Part 2 treatment arms may be dropped 
based on interim OS results (Section 10.3.3). Part 1 is open label single arm while Part 2 
is randomized. Combinations that proceed to Part 2 will be tested in a new group of 
participants, separate from Part 1 participants, that will be randomized between the 
combination and the Standard of Care. The study participants enrolled in Part 1 are not 
pooled with the study participants in Part 2. The two study populations are separate and 
distinct. Data from Part 1 and 2 will not be combined. 
The data generated from each experimental regimen and associated control arm data are 
considered a substudy within the overall platform study, as depicted in Figure 1.  


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Figure 1 
Study Design 
 
NSCLC: non-small cell lung cancer; PD(L)1: Programmed Cell Death Protein 1 and Programmed Cell Death 
Ligand 1.  
Note: Randomization of participants to experimental regimens may not occur in parallel. It should be noted that 
the terms ‘regimen’ and ‘arm’ may be used interchangeably throughout the document. Between 10-20% of newly 
enrolled participants in substudies (depending upon the number of experimental arms in the trial) will be 
randomized to SoC once the initial 35 participants have been enrolled on control arm. 
 
Interim safety and efficacy data for Part 2 will be reviewed by an Independent Data 
Monitoring Committee (IDMC), independent of the study team. Additional details will be 
provided in an IDMC Charter. A Steering Committee of lead investigators on study will 
also be established to provide guidance for key decisions such as introduction of new 
arms and graduation of existing arms. 
At study start, participants will be randomized 1:2 to Arm 1 (SoC) and Arm 2, i.e., 33% 
and 67%, respectively. As new substudies are initiated, the randomization ratio will be as 
described below in Table 1. Between 10-20% of newly enrolled participants in 
subsequent substudies (depending upon the number of experimental arms in the trial) will 
be randomized to SoC once the initial 35 participants have been enrolled on control.  
The 1:4 randomization for a 2-arm trial is for subsequent substudies where a new 
experimental arm enters the trial and the SoC arm has already enrolled more than 
35 participants, and all other experimental arms are no longer enrolling (e.g. completed 
accrual, or stopped due to toxicity findings, or other reason). Similarly, the 1:4:4 
randomization for a 3-arm trial is for subsequent substudies where 2 new arms enter after 
the SoC arm has already enrolled more than 35 participants, and all other experimental 
arms are no longer enrolling (e.g. completed accrual, or stopped due to toxicity findings, 
or other reason). 


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Table 1 
Randomization Ratio and Proportion of Participants Randomized to 
the SoC Arm When There Are Concurrent Arms 
 
Randomization Ratio 
 
 ≤35th participants 
>35th participants 
Two arms  
(SoC and one treatment) 
1:2 SoC:Each Trt 
1:4 SoC:Each Trt 
Three arms  
(SoC + two treatments) 
1:2 SoC:Each Trt 
1:4 SoC:Each Trt 
Four arms  
(SoC + three treatments) 
1:1 SoC:Each Trt 
1:3 SoC:Each Trt 
Five arms or more 
(SoC + four or more treatments) 
1:1 SoC:Each Trt 
1:2 SoC:Each Trt 
 
The study will employ a Bayesian decision-making framework based on the predictive 
probability of observing a significant improvement in OS in a future Phase 3 trial (see 
Section 10.5.1 for details). 
Interim analysis of OS in Part 2 will be performed for each substudy after approximately 
45 events (experimental arm and SoC combined) and a minimum of 18 events from 
experimental arm have been observed. Note, events from the SoC arm will be counted 
from the initial study start (i.e. SoC events from substudy 1 will be counted with any 
further events observed in subsequent substudies). Participants will continue to be 
enrolled during interim analyses. The final analysis for each substudy will be performed 
once a minimum number of events have been observed. At the final analysis, the 
experimental regimen within a substudy may be recommended for proceeding to a Phase 
3 trial if it meets the predefined criteria for clinical activity. Details of the interim 
analysis and predefined criteria are provided in Section 10.3.3 and Section 10.3.4. 
The requirements for the experimental regimens to advance from earlier Phase 1 studies 
to the current Phase 2 study (205801) include:  
1. Determination of the recommended Phase 2 dose (RP2D) regimen  
2. Adequate safety data of the combination at the RP2D  
3. For the novel/novel combinations, evidence of potential antitumor activity in the 
range of the comparator (currently docetaxel) in an unselected solid tumor 
population.  
Additional experimental regimens or populations with the appropriate SoC arm may be 
introduced to the current design via protocol amendments; these experimental arm(s) may 
include novel agents other than the aforementioned agents (Figure 1). A biomarker-
driven approach may be implemented for any of the experimental arms as an enrichment 
strategy whereby participants will be stratified based on a biomarker test result prior to 
treatment allocation. The rationale for the biomarker-driven approach in selecting 
participants most likely to derive clinical benefit from that particular regimen will be 
fully delineated in the amendment(s). 


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5.2. 
Duration of Treatment 
The study consists of 3 periods: screening, treatment, and follow-up. The total duration of 
study participation begins with the signing of the informed consent form (ICF). 
Participants will provide informed consent within 45 days prior to the first dose. After a 
screening period of up to 28 days, eligible participants will be assigned a treatment arm if 
participating in Part 1 and receive study treatment (Day 1) or randomly assigned to a 
treatment arm (SoC or experimental) if participating in Part 2 and receive study treatment 
(Day 1) as specified in the SoA for each arm (Section 12.1).  
Combination study treatment will continue to be administered at the indicated schedule 
for a maximum duration of approximately 2 years or up to 35 treatment visits (unless 
noted otherwise in sections specific to each arm), whichever comes first, or until disease 
progression as determined by iRECIST, death, unacceptable toxicity, or other protocol-
defined criteria are met. Single agent SoC treatment (i.e., docetaxel) may continue until 
disease progression, death, unacceptable toxicity, withdrawal of consent, or per 
institutional standard for docetaxel. After study treatment is permanently discontinued, 
participants will be followed for adverse events (AEs).  
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs [Seymour, 2017]. Participants who attain a 
confirmed complete response (CR) per iRECIST, have received at least 2 additional 
doses of study treatment beyond the date the initial CR was declared, and have been 
treated for a minimum of 6 months, may discontinue study treatment; and these 
participants will continue with the scheduled disease assessments (Section 9.3.1). 
Participants may be permitted to resume study treatment upon disease progression 
following consultation between the treating investigator and the Sponsor/Medical 
Monitor, and upon written consent by the participant. See Section 8.1 for specific 
conditions under which a participant may continue study treatment beyond disease 
progression. 
Participants who permanently discontinue study treatment will enter the survival 
follow-up period of the study and undergo the assessments as indicated in Section 9. 
5.3. 
Number of Participants 
As the study uses a master protocol design, the sample size for the study overall is not 
fixed. Participants enrolled to Part 1 will be separate from those enrolled to Part 2. 
5.3.1. 
Sample Size: Part 1  
For Part 1, sample size will be defined for each regimen under the corresponding 
appendix in Section 12.1; a minimum of 3 participants will be evaluated for safety during 
the 21 day DLT period before further participants will be enrolled. 
 


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5.3.2. 
Sample Size: Part 2 
The initial number of participants in Part 2 is estimated to be at least 105 in substudy 1 
(SoC arm: 35; experimental arm: 70). Additional experimental regimens may be added 
via protocol amendments and will be considered as another substudy. Each additional 
experimental arm will enroll a maximum of 70 participants. The minimum sample size 
for the SoC arm is 35 with additional participants randomized to SoC concurrently with 
additional experimental arms/substudies. Further randomization to SoC will be 
minimized once 35 patients are enrolled in the first substudy. Refer to Table 1 in Section 
5.1 and Section 10.3 for additional details on sample size determinations.  
Participants who discontinue in Part 2 will not be replaced in this study. See Section 10.4 
for definitions of the populations for analyses. 
5.4. 
Participant Completion and End of Study Definitions 
5.4.1. 
Participant Completion Definitions 
A participant will be considered to have completed the study if the participant dies during 
the study treatment period or follow-up period, whichever is sooner, or is still in follow-
up at the time of the final analysis. The cause of death will be documented in the 
CRF/eCRF. A participant will be considered to have withdrawn from the study if the 
participant has not died and is lost to follow-up, has withdrawn consent, at the 
investigator’s discretion is no longer being followed or if the study is closed/terminated. 
5.4.2. 
Study Completion Definition 
Substudy completion: A substudy is considered to have completed once the agreed 
number of events has been reached, survival follow up for remaining patients may not be 
needed.  
 
An arm may close during Part 1 for safety or tolerability reasons or if an insufficient 
number of responders in Part 1 of that arm have been observed. 
 
The end of study is defined as the completion of the last participant’s required study visit, 
telephone contact, or death, as applicable, in the last substudy.  
5.5. 
Scientific Rationale for Study Design 
The study will employ a platform design utilizing a master protocol to compare 
experimental therapies with a common SoC treatment. Novel regimens may enter Part 2 
via protocol amendment(s) once adequate safety and preliminary clinical activity data are 
obtained. If sufficient safety and preliminary clinical activity data are not available for a 
proposed regimen from other studies, these data may be obtained during a safety and 
PK/PD evaluation option in this study in Part 1. Once a regimen has passed criteria for 
safety and preliminary clinical activity, the treatment arm/regimen will be analyzed 
relative to the SoC treatment (Part 2) and is considered a substudy within the overall 
master protocol. In addition, different disease settings may be investigated via protocol 
amendment(s) and would introduce the SoC treatment for that setting. This design 


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provides efficiencies in the evaluation of experimental therapies by using a common 
control arm and discontinuing therapies that are deemed ineffective at interim time points 
while continuing randomization into substudies that may be more efficacious and be 
subsequently evaluated in confirmatory studies. The SoC arm will remain open to 
random assignment and the anticancer activity of experimental regimens in substudies 
that enter the study later will be compared with the overall population treated by the SoC 
therapy. Thus, the SoC population will always include contemporaneous as well as 
historical data.  
5.5.1. 
Steering Committee and Data Monitoring Committee (Part 2) 
A Steering Committee of lead investigators on study and representatives of the Sponsor 
study team will be established to provide guidance for key decisions such as introduction 
of new arms and graduation of existing arms. The remit, membership, and roles and 
responsibilities of the Steering Committee will be described in a charter. 
An IDMC, independent of the study team, will be established to monitor efficacy and 
safety during the course of the trial. The remit, membership, and roles and responsibilities 
of the Data Monitoring Committee will be described in a charter. 
Key decisions of the Steering Committee as well as the IDMC will be documented and 
reported to regulatory agencies if requested, all participating principal investigators (PIs) 
and if required, Institutional Review Boards (IRBs)/Independent Ethics Committees 
(IECs) as appropriate with impactful decisions communicated as priority.  
5.6. 
Dose Justification 
Dose justification for all study drugs are located in the arm-specific appendices (Section 
12.1). 


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6. 
STUDY POPULATION 
Participants are eligible to be included in the study only if all of the criteria in Section 6.1 
and Section 6.2 apply. In addition, participants must fulfill additional inclusion/exclusion 
criteria for at least one arm. Criteria for each individual arm can be found in the 
respective appendices for each arm, reported in Section 12.1. 
Prospective approval of protocol deviations to recruitment and enrollment criteria 
(waivers or exemptions) is not permitted.  
6.1. 
Inclusion Criteria 
1. Capable of giving signed informed consent/assent as described in Section 12.4 
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 at the time consent is obtained 
   Note: Participants in Korea must be age 19 years or older at the time consent is 
obtained.    
3. Histologically or cytologically confirmed diagnosis of NSCLC (squamous or non-
squamous) and: 
a. Documented disease progression based on radiographic imaging, during or 
after a maximum of 2 lines of systemic treatment for locally/regionally 
advanced recurrent, Stage IIIb/Stage IIIc/Stage IV or metastatic disease  
Two components of treatment must have been received in the same line or as 
separate lines of therapy:  
i. 
no more than or less than 1 line of platinum-containing chemotherapy 
regimen, and  
ii. 
no more than or less than 1 line of PD(L)1 mAb containing regimen. 
Notes: 
o PD(L)1 mAb received during a previous clinical trial may meet 
this requirement upon consultation with study medical monitor. 
o Participants who received a regimen similar to the PACIFIC 
regimen [chemoradiotherapy followed by PD(L)1] as part of 
SoC AND have relapsed within one year from the first dose of 
chemoradiotherapy would fulfill the protocol requirement for 
platinum-based chemotherapy treatment and PD-1/L1 
treatment. This would be considered a single line of treatment 
for the purpose of PD(L)1 line of therapy stratification. 
o PD(L)1 mAb can be administered with the platinum-based 
chemotherapy regimen and this would count as a single line of 
therapy. 
o PD(L)1 mAb may be counted as a prior treatment if the agent 
is approved in at least 1 country for the treatment of cancer.  


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o Participants who have completed 2 years of pembrolizumab or 
another PD(L)1 mAb, discontinue from that therapy, 
experience disease progression, and are then retreated with 
PD(L)1, will be considered as having had one line of PD(L)1 
therapy. 
o Adjuvant or neo-adjuvant systemic anticancer therapy will not 
count toward the 2 lines of therapy unless disease recurs during 
the first year following the start of adjuvant chemotherapy. 
b. Participants with known BRAF molecular alterations must have had disease 
progression after receiving the locally available SoC treatment for the 
molecular alteration. 
c. Participants who received prior anti-PD(L)1 therapy must fulfill the following 
requirements: 
o Have achieved a CR, PR or SD and subsequently had disease progression 
(per RECIST 1.1 criteria) either on or after completing PD(L)1 therapy 
o Have not progressed or recurred within the first 12 weeks of PD(L)1 
therapy, either clinically or per RECIST 1.1 criteria 
 
4. Measurable disease, presenting with at least 1 measurable lesion per RECIST 1.1 
(see Appendix 12 for definition of a measurable lesion) 
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 
0 or 1 
6. A tumor tissue sample obtained at any time from the initial diagnosis of NSCLC to 
time of study entry is mandatory. Although a fresh tumor tissue sample obtained 
during screening is preferred, archival tumor specimen is acceptable. See Study 
Reference Manual (SRM) and Section 9.9.2 for further details on tumor tissue 
requirements. 
7. Adequate organ function as defined in Table 2.  


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Table 2 
Definitions of Adequate Organ Function 
System 
Laboratory Values 
Hematologica 
ANC (Absolute Neutrophil Count) 
1.5 x 109/L (≥1500/µL) 
Hemoglobin 
9 g/dL or ≥5.6 mmol/L 
Platelets 
100 x 109/L (≥100 000/µL) 
Hepatic 
Albumin 
≥2.5 g/dL 
Total bilirubin 
 
 
Patients with Gilbert’s Syndrome (only if direct bilirubin 35%) 
1.5 x ULN (isolated bilirubin >1.5 x ULN is 
acceptable if bilirubin is fractionated and 
direct bilirubin <35%) 
3.0 x ULN 
ALT (SGPT) 
2.5 x ULN, OR  
≤5 X ULN for participants with documented 
liver metastases 
Renal 
Calculated CrClb 
≥30 mL/min 
Abbreviations: ALT = alanine aminotransferase; CrCL = creatinine clearance; SGPT = serum glutamate-pyruvate 
transaminase; ULN = upper limit of normal. 
a.   Participants may be transfused or receive growth factor treatment to meet minimum hematologic values up to 7 
days prior to determining eligibility. Absolute Lymphocyte Count will be included in the baseline assessment, but 
no range limit requirement for eligibility. 
b.   Calculated CrCL is required to be calculated using the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) or Cockcroft-Gault formula. Either formula is acceptable and must be consistently utilized for each 
participant throughout the study (Appendix 9). 
 
8. A male participant must agree to use a highly effective contraception as detailed in 
Appendix 6 of this protocol during the treatment period and for at least 120 days 
after the last dose of study treatment and refrain from donating sperm during this 
period. Unless otherwise specified under each arm in Section 12.1 
Note: If the participant is randomized to the SoC regimen only, duration of 
contraception should be as per local label.  
9. A female participant is eligible to participate if she is not pregnant (see 
Appendix 6), not breastfeeding, and at least 1 of the following conditions apply: 
i. 
Not a woman of childbearing potential (WOCBP) as defined in 
Appendix 6  
 
OR 
 
ii. 
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 6 during the treatment period and for at least 120 days after the 
last dose of study treatment.  
Note: If the participant is randomized to the SoC regimen only, duration 
of contraception should be as per local label. 
10. Life expectancy of at least 12 weeks 


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6.2. 
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 treatment): 
a. Docetaxel at any time 
b. Any of the investigational agents being tested in the current study, refer 
to Section 12.1 for additional information 
c. Systemic approved or investigational anticancer therapy within 30 days 
or 5 half-lives of the drug, whichever is shorter. At least 14 days must 
have elapsed between the last dose of prior anticancer agent and the 
first dose of study drug is administered.  
d. Prior radiation therapy: permissible if at least one non-irradiated 
measurable lesion is available for assessment per RECIST version 1.1 
or if a solitary measurable lesion was irradiated, objective progression 
is documented. A wash out of at least 2 weeks before start of study 
drug for radiation of any intended use is required. 
2. Received >2 prior lines of therapy for NSCLC, including participants with BRAF 
molecular alterations. (See inclusion criterion #3 for eligible lines of therapy 
guidance) 
Note: Patients with known molecular alterations with therapeutic options available 
(e.g., EGFR, ALK, ROS1) are excluded from participation in this study, unless no 
other therapeutic options are available locally.  
3. Invasive malignancy or history of invasive malignancy other than disease under 
study within the last 2 years, except as noted below: 
• Any other invasive malignancy for which the participant was definitively 
treated, has been disease-free for at least 2 years and in the opinion of the 
principal investigator and GSK Medical Monitor will not affect the evaluation 
of the effects of the study treatment on the currently targeted malignancy, may 
be included in this clinical trial.  
• Curatively treated non-melanoma skin cancer or successfully treated in situ 
carcinoma of the skin.  
4. Carcinomatous meningitis (regardless of clinical status) and uncontrolled or 
symptomatic central nervous system (CNS) metastases.  
 
Note: Participants with previously treated brain metastases may participate 
provided they are asymptomatic (any neurologic symptoms have returned to 
baseline [participants may be receiving stable doses of anticonvulsants]), 
radiographically stable (without evidence of progression by imaging for at least 4 


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weeks prior to the first dose of study treatment), have no evidence of new or 
enlarging brain metastases, and are clinically stable off steroids for at least 2 
weeks prior to study treatment.  
5. Major surgery 28 days of first dose of study treatment. 
6. Autoimmune disease (current or history) or syndrome that required systemic 
treatment within the past 2 years (Refer to Appendix 14). Replacement therapies 
which include physiological doses of corticosteroids for treatment of 
endocrinopathies (for example, adrenal insufficiency) are not considered systemic 
treatments.  
Note: Participants with controlled Type 1 diabetes mellitus (T1DM) are eligible. 
7. Receiving systemic steroids (>10 mg oral prednisone or equivalent) or other 
immunosuppressive agents within 7 days prior to first dose of study treatment. 
Note: Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication) are permitted. Use of inhaled  
corticosteroids, local steroid injection, or steroid eye drops is allowed.  
8. Prior allogeneic/autologous bone marrow or solid organ transplantation. 
9. Receipt of any live vaccine within 30 days prior to first dose of study treatment.  
Refer to the SRM for clarity on COVID-19 vaccines. 
10. Toxicity from previous anticancer treatment that includes: 
a. ≥ Grade 3 toxicity considered related to prior immunotherapy and that led to 
treatment discontinuation. 
b. History of myocarditis of any grade during a previous treatment with 
immunotherapy 
c. Toxicity related to prior treatment that has not resolved to ≤Grade 1 (except 
alopecia, hearing loss, endocrinopathy managed with replacement therapy, 
and peripheral neuropathy which must be ≤Grade 2). 
11. History (current and past) of idiopathic pulmonary fibrosis, pneumonitis (for past 
pneumonitis exclusion only if steroids were required for treatment), interstitial 
lung disease, or organizing pneumonia.  
 
Note: post-radiation changes in the lung related to prior radiotherapy and/or 
asymptomatic radiation-induced pneumonitis not requiring treatment may be 
permitted if agreed upon by the investigator and Medical Monitor. 
12. Recent history (within the past 6 months) of uncontrolled symptomatic ascites, 
pleural or pericardial effusions 


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13. Recent history (within the past 6 months) of gastrointestinal obstruction that 
required surgery, acute diverticulitis, inflammatory bowel disease, or intra-
abdominal abscess 
14. History or evidence of cardiac abnormalities within the 6 months 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. 
NOTE:  Participants with Troponin and/or NT-ProBNP/BNP ≥2 x ULN will 
require a cardiologist or locally appropriate specialist review to identify 
underlying conditions that may meet exclusion criteria or that may require 
increased monitoring on study. In addition, consider cardiologist or locally 
appropriate specialist review for potentially significant ECG abnormalities such 
as AV block (except for first degree), new cardiac arrhythmias, or frequent 
premature ventricular contractions (PVCs). Please inform the Sponsor regarding 
these participants. 
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 if participant otherwise meets entry criteria. 
16. Active infection requiring systemic therapy ≤7 days prior to first dose of study 
treatment.  
17. Known human immunodeficiency virus infection 
18. History of severe hypersensitivity to monoclonal antibodies or hypersensitivity to 
any of the study treatment(s) or their excipients. 
19. Requires ongoing therapy with a medication that is a strong inhibitor or inducer of 
the cytochrome 3A4 (CYP3A4) enzyme (Flockhart, 2018). This criterion is 
applicable to only those participants in treatment arms containing docetaxel. 
20. Any serious and/or unstable pre-existing medical (aside from malignancy), 
psychiatric disorder, or other condition that could interfere with participant’s 
safety, obtaining informed consent, or compliance to the study procedures in the 
opinion of the investigator 


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21. Pregnant or lactating female participants 
22. Is currently participating in or has participated in a study of an investigational 
device within 4 weeks prior to the first dose of study treatment.  
23. Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months 
prior to first dose of study intervention 
24. Positive hepatitis C antibody test result at screening or within 3 months prior to 
first dose of study intervention. 
NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. 
25. Positive hepatitis C RNA test result at screening or within 3 months prior to first 
dose of study treatment.  
NOTE: Test is optional and participants with negative Hepatitis C antibody test are 
not required to also undergo Hepatitis C RNA testing.  
 
26. Receipt of transfusion of blood products (including platelets or red blood cells) or 
administration of colony-stimulating factors (including granulocyte colony 
stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, and 
recombinant erythropoietin) within 14 days before the first dose of study intervention. 
 
6.3. 
Lifestyle and Dietary Restrictions 
No lifestyle restrictions are planned for this study however male participants with 
partners of childbearing potential and women of childbearing potential must utilize 
appropriate contraception as described in Section 12.6.  
Participants should maintain a normal diet unless modifications are required to manage 
an AE such as diarrhea, nausea, or vomiting. However, foods that are CYP3A inhibitors 
must not be consumed during the study for those participants in Part 2 on Docetaxel arm. 
Grapefruit, star fruit, and pomegranate are known to be CYP3A inhibitors, and should not 
be consumed for 2 weeks before the first dose of docetaxel and for at least 2 weeks after 
the last dose of docetaxel. Note that consumption of CYP3A4 inhibitors such as these 
may significantly increase the levels of docetaxel. St. John’s Wort is a CYP3A inducer, 
and the consumption of St. John’s Wort or products containing St. John’s Wort may 
reduce the levels of docetaxel.  
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized/entered in the study. 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 


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eligibility. 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. 
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. 


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6.5. 
Screening under Molecular Disease Characterization 
Initiative Study 
Participants may be initially screened under GSK protocol 213299 (a molecular disease 
characterization initiative study) where it is IRB/IEC approved at a site and then referred 
to this study 205801. Screening assessments performed under protocol 213299 may be 
accepted for the enrollment into this GSK protocol 205801 to avoid any repeat screening 
tests. 
Baseline Biopsy: 
If a biopsy was acquired under GSK protocol 213299, tissue blocks/slides from this 
biopsy may be used for additional screening or baseline analyses required by this 
protocol (205801). Another biopsy may be needed for treatment specific screening at 
baseline in cases where there is not enough remaining material from biopsy acquired 
under GSK protocol 213299. 
Screening/Baseline Imaging and Other Assessments: 
If radiographic imaging was performed under GSK protocol 213299, those images may 
be used for screening/baseline disease assessment. Images must meet the acceptable 
scanning modalities and anatomical coverage required for this protocol (205801). 
Additional scans may be needed to meet inclusion/exclusion criteria, safety requirements, 
or other anatomical areas as required by this protocol (205801). Additional scans are 
required if imaging falls outside the screening/baseline acceptable visit window. 
Please refer to SRM for more information.  
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant per the 
study protocol. 
7.1. 
Treatments Administered 
The term study treatment(s) is used throughout the protocol as a general descriptor for 
any or all treatment arms/regimens or the individual agents. 
All investigational agents utilized in this study will be provided to sites by the Sponsor. 
Docetaxel will be sourced locally from commercial stock, except in countries where local 
regulations mandate that the Sponsor supply all study treatment(s) required for the trial.  
As additional substudies are initiated, treatment details for experimental regimens from 
those substudies will be provided in Section 12.1. 


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7.2. 
Dose Modification 
Dose modifications, including interruptions and reductions, may occur for the 
management of AEs according to the current product label for SoC (e.g., docetaxel) and 
guidelines provided in the protocol for investigational agents. 
Note: If a participant, randomized to an experimental treatment arm, experiences a 
toxicity attributable to one of the drugs in the combination, the investigator may 
discontinue the responsible drug but continue treatment with the other drug. In all such 
scenarios, the SoA applicable to the active treatment(s) must be followed.  
Additional dose modification guidelines for specific experimental regimens will be 
provided in Section 12.1 as needed when new substudies are initiated.  
7.2.1. 
Dose and Safety Management Guidelines 
7.2.1.1. 
General Guidelines for Immune-Related Adverse Events (irAEs) 
AEs associated with immunotherapy treatment may be immune-mediated. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after 
the last dose of treatment, or during the treatment course, and may affect more than one 
body system simultaneously. Therefore, early recognition of and initiation of treatment 
for these events is critical to reduce potential complications.  
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 and/or immuno-modulators. Dose modification and toxicity management 
guidelines for irAEs associated with immunotherapies are provided for each arm in the 
respective subsections under Section 12.1.  
Note: This guidance does not apply to participants randomized to Arm 1 SoC 
chemotherapy in Part 2. 
Before administration of study treatment, investigators are to review a participant’s AEs, 
concomitant medications, and clinical evaluation results, e.g., vital signs, laboratory 
results, ECOG PS, physical examination findings, responses, etc. as outlined in the 
Schedule of Activities (Section 12.1) to monitor for new or worsening irAEs and ensure 
continued dosing is appropriate.  
Adverse Events of Special Interest (AESI) 
AESI are considered to be Infusion Related Reactions (IRRs) and those of potential 
immunologic etiology, including irAEs. Such events recently reported after treatment 
with other immune modulatory therapy include, but are not limited to, the following: 
pneumonitis, nephritis, hepatitis, colitis, immune related endocrinopathies (such as 
thyroiditis or hypophysitis) or immune related cutaneous toxicities, to include rashes 
confirmed via biopsy to be immune-mediated.  
AESIs will be reported within 24 hours if the event meets the criteria for a serious event.  


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Dose modification and toxicity management guidelines for irAEs are provided for each 
arm in the respective subsections under Section 12.1. 
7.2.1.2. 
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-dependent 
anaphylactic and non-IgE dependent anaphylactoid hypersensitivities. Cytokine release 
syndrome (CRS), and when severe, cytokine “storm”, has been identified as a sequela of 
the immune system activation associated with infusion reactions. 
Infusion reactions may affect any organ system in the body. Most are mild in severity, 
although severe and even fatal reactions occur. As a group, infusion reactions (including 
both cytokine-mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur 1 to 2 days after administration. The NCI-
CTCAE (version 5.0) for grading adverse reactions during chemotherapy administration 
has a scale for grading the severity of infusion reactions and separate grading scales for 
allergic reactions and anaphylaxis. While use of these separate grading scales may be 
useful for classifying the nature of an infusion reaction for research purposes, they are 
less useful for clinical care, since it may not be obvious if the participant is having an 
allergic infusion reaction or a non-allergic infusion reaction.  
Clinically, an acute-onset infusion reaction may present with flushing, itching, urticaria, 
and/or angioedema, repetitive cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
pain. Dose modification and treatment guidance for immunotherapy infusion reactions 
are provided for each arm in the respective subsections under Section 12.1. 
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 3. Only if not possible to collect 
at the occurrence of the event, samples should be drawn as soon as possible after the 
event and within 24 hours. The serum tryptase, CRP and ferritin panels must be 
performed at the investigator’s designated local laboratory. The serum cytokine panel 
will be performed at a GSK designated laboratory. These data will aid in the classifying 
(albeit retrospectively) the etiology of the infusion reaction AE. Infusion-related reaction 
management guidelines are provided for each study arm in Section 12.1.  


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Table 3 
Infusion-Related Reaction Laboratory Panel 
Biomarker 
Relationship to Adverse Event 
Serum tryptasea 
IgE-related infusion reaction (Allergic/anaphylaxis) 
[Schwartz, 2006] 
Serum CRPa 
Elevated in CRS [Lee, 2014] 
Serum ferritina 
Elevated in CRS [Lee, 2014] 
Serum cytokine panelb 
(IFN-γ*^, TNF-α*^, IL-2*, IL-4, IL-6*^, IL-8*, IL-10*, IL-
12p70, and IL-13) 
* Reported to be elevated in CRS [Lee, 2014] 
^ Consistently reported as elevated in CRS [Lee, 
2014] 
CRP = C-reactive protein; CRS = Cytokine release syndrome; IFNγ = Interferon gamma; TNFα = Tumor necrosis 
factor alpha; IL = Interleukin.  
a. Performed by investigator designated local laboratory if available; otherwise performed by GSK designated 
laboratory 
b. Performed by GSK designated laboratory 
 
7.2.1.3. 
Management Guidance of Chemotherapy-related Toxicities 
Refer to Table 4 and Table 5 for guidance on specific chemotherapy-related AEs; refer to 
chemotherapy prescribing information or standard practice guidelines for the 
management of these AEs, other AEs or potential safety-related issues. 
Table 4 
Dose Reductions for Docetaxel-related Hematologic Events 
Chemotherapy Regimen 
Toxicity 
Actiona 
Docetaxel 
• 
ANC <1.5x109/L, platelets 
<75x109/L, or hemoglobin <9g/dL 
(after transfusion if needed) 
 
 
 
 
• 
Febrile neutropenia 
• 
Hold docetaxel until 
recovery: ANC 1.5x109/L, 
platelets 100x109/L  
• 
Recovery within 7 days, 
resume 100% of previous 
dose; >7 days, resume 80% 
of previous dose 
• 
Hold docetaxel; upon 
recovery, if ANC <500/mm3 
for more than 7 days, 
resume at 55 mg/mm2 
a. 
Resume treatment with chemotherapy after resolution as indicated; treatment with other study treatment may 
continue unless otherwise instructed. 
Table 5 
Dose Reductions for Docetaxel-related Non-Hematologic Events 
Chemotherapy Regimen 
Toxicity 
Actiona 
Docetaxel 
• 
Grade 3/Grade 4 event (including 
severe or cumulative cutaneous 
reactions), except peripheral 
neuropathy 
 
 
• 
Grade 3/Grade 4 peripheral 
neuropathies 
 
• 
Hold docetaxel upon recovery 
to Grade 1/baseline, resume 
treatment at 55 mg/mm2 
 
• 
Consider permanent 
discontinuation; discuss with 
Medical Monitor  
a. 
Resume treatment with chemotherapy after resolution as indicated; treatment with other study treatment may 
continue unless otherwise instructed. 


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Refer to docetaxel prescribing information or standard practice guidelines for the 
management of these AEs, other AEs or potential safety-related issues [TAXOTERE PI, 
2020]. 
7.2.1.4. 
Dose Delay for Toxicity or Other Illness 
If there is a dose delay between 1 and 7 days, the procedures required at the original 
scheduled visit (including dosing) should be performed as soon as possible. Refer to the 
SRM for instructions regarding assessments to be collected and how to record data in the 
eCRF. 
If the delay is 8 days, the visit and dose(s) will be considered missed. The procedures at 
the next regularly scheduled visit should be performed (with dosing), and subsequent 
visits will follow Q3W.  
Participants with infusion delays greater than 3 weeks due to toxicity should discontinue 
study drug(s) unless the treating investigator and Sponsor/Medical Monitor agree there is 
strong evidence supporting continued treatment.  
 
7.3. 
Method of Treatment Assignment 
Once determined to be eligible for the study, all participants will be centrally randomized 
using an Interactive Web Response System (IWRS). Before the study is initiated, the 
directions for the IWRS and log in information will be provided to each site. Once 
determined to be eligible for the study, participants must be randomized via IWRS. Study 
drug shipment will be managed via IWRS. Sites must allow up to 7 business days for 
shipment of study drug. 
Study treatment will be dispensed at the study visits summarized in SoA for treatments 
found within the SoA for each arm (Section 12.1). 
7.4. 
Blinding 
This is an open-label study. Sites will record the treatment assignment on the applicable 
eCRF. 
7.5. 
Preparation/Handling/Storage/Accountability 
7.5.1. 
Preparation 
Refer to the SRM for instructions on the preparation of investigational study treatments. 
Refer to the package insert for docetaxel preparation instructions.  
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. 
1. Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 


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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. 
2. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
3. Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.  
 
7.5.2. 
Handling 
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and generation of aerosols or mists. In case of 
unintentional occupational exposure notify the monitor, Medical Monitor, and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS) or equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK. 
7.5.3. 
Storage 
All study treatment 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. 
Refer to the SRM for storage condition specifications and temperature monitoring 
requirements. 
7.5.4. 
Accountability 
• Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. 
• The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposal records). 
• Further guidance and information for final disposition of unused study treatment 
are provided in the SRM.  
7.6. 
Treatment Compliance 
Study treatments will be intravenously administered to participants at the site. 
Administration will be documented in the source documents and reported in the eCRF. 


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7.7. 
Concomitant Therapy 
Participants will be instructed to inform the investigator prior to starting any new 
medications from the time of the first dose of study treatment until discontinuation of 
study treatment. Any permitted concomitant medication(s), including non-prescription 
medication(s) and herbal product(s), taken during the study will be recorded in the eCRF. 
The minimum requirement for reporting is drug name, dose, dates of administration, and 
the reason for medication. 
Questions regarding concomitant medications must be directed to the GSK Medical 
Monitor for clarification. 
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.  
Refer to the drug interaction information in the product package inserts for precautions 
and prohibited concomitant medications related to docetaxel treatment [TAXOTERE PI, 
2020; TAXOTERE SmPC, 2020]. 
7.7.1. 
Permitted Medications and Non-Drug Therapies 
Participants receiving docetaxel should receive premedication/supplementation regimens 
according to the approved product label or standard practice. All participants should 
receive full supportive care during the treatment course of the study, including 
transfusion of blood and blood products, and treatment with antibiotics, antiemetics, 
antidiarrheals, and analgesics, as appropriate. Seasonal flu vaccine is permitted as an 
injection only, that is, intra-nasal flu vaccine is not permitted. Refer to the SRM for 
permitted COVID-19 vaccines. 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: Please also refer to Section 12.1 
for medications specific to each experimental combination. 
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 treatment. Prophylactic use 
in participants without evidence or history of bone metastasis is not permitted, except 
for the treatment of osteoporosis. 
b. Growth factors: Prophylactic use of growth factors are not permitted during study 
treatment, unless clinically/therapeutically indicated for toxicity management.  
c. 
Steroids: Refer to Section 7.2.1 and the associated sub-sections for acceptable use 
while participant in on study treatment. Participants with pre-existing conditions 
requiring steroids are permitted to continue taking up to a maximum of 10 mg of 
prednisone or equivalent provided the participant has been on a stable dose for at 
least 28 days before first dose of study treatment; see exclusion criteria in Section 6.2 
for further requirements. Steroids used for chemotherapy premedication are 
permitted. 


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d. Prescribed medicinal cannabinoids are permitted during the study as palliative 
therapy. 
7.7.2. 
Prohibited Medications and Non-Drug Therapies 
The following medications are prohibited before the first dose of study treatment (see 
Section 6.2 for specific time requirements) and while on treatment in this study: Please 
also refer to Section 12.1 for medications specific to each experimental combination. 
• Anticancer therapies other than those referred to as Study Treatment that include, 
but are not limited to chemotherapy, immunotherapy, biologic therapy, hormonal 
therapy (other than physiologic replacement), surgery, and radiation therapy 
(other than palliative intervention as described in Section 7.7.1). 
• Any investigational drug(s) other than those referred to as Study Treatment. 
• Refer to the SRM for guidance on COVID-19 and other vaccines.  
• Strong CYP3A4 inhibitors and inducers for participants receiving docetaxel alone 
or in combination with another study drug (use as premedication is permitted). 
• Herbal preparations or related over the counter (OTC) preparations containing 
herbal ingredients that are known to affect CYP3A isoenzymes (e.g., St. John’s 
Wort) either during or within 2 weeks prior to the first dose of docetaxel. 
7.8. 
Treatment after the End of the Study 
The study participants will not receive any additional treatment from GSK after 
permanent discontinuation of study treatment. The investigator is responsible for 
ensuring that consideration is given to the post-study care of the participant’s medical 
condition. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Participants will receive study treatment for the scheduled time period as indicated in 
Section 12.1 but must discontinue treatment if one of the following events occurs earlier:  
• 
Confirmed disease progression (iCPD as determined by iRECIST) 
• 
death 
• 
unacceptable toxicity, including meeting stopping criteria for liver chemistry 
abnormalities as defined in Appendix 10 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
• 
deviation(s) from the protocol or non-compliance with study requirements 
• 
request of the participant or proxy (withdrawal of consent by participant or proxy) 
• 
discretion of the investigator  


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• 
participant is lost to follow-up 
• 
closure or termination of the study  
Continuation of Treatment Upon Disease Progression 
Participants who have disease progression (unequivocal disease progression) by RECIST 
1.1 may continue study treatment at the discretion of the Investigator with approval from 
the Medical Monitor, and upon separate written consent of the participant. Continuation 
on study treatment with 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 treatment. 
Termination of a Substudy/Experimental Arm 
If a substudy/experimental arm is terminated based on interim results and a participant is 
currently active in the substudy, receiving study treatment, and in the opinion of the 
investigator is deriving benefit from that treatment without evidence of disease 
progression, the participant may continue to receive study treatment upon agreement 
between the Sponsor and the investigator.  
Study Termination  
If the study is terminated by the Sponsor for reasons unrelated to safety or efficacy and a 
participant is currently active in the study, the Sponsor will notify the investigator of the 
study termination, further enrollment in the study will be terminated, and the Sponsor 
will communicate to investigative sites the discontinuation procedures and plans for 
discontinuation of patients from study treatment.  
Termination Due to Toxicity 
If the participant discontinues from treatment due to toxicity, the relevant AE will be 
recorded on the eCRF as the primary reason for permanent discontinuation.  
Termination from Study Treatment 
If a participant discontinues study treatment for reasons other than disease progression, 
does not have evidence of disease progression and chooses to continue in the study, the 
participant will continue study assessments according to the visit schedule described in 
the SoA for the specific arm in Section 12.1. The participant will be followed until 
disease progression by iRECIST or the start of a new systemic anti-cancer therapy, 
whichever comes first. 


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Procedures Following Discontinuation 
The primary reason for permanent study treatment discontinuation must be documented 
in the participant’s medical records and eCRF. 
Once a participant has permanently discontinued from study treatment, the participant 
will not be allowed to be retreated but will remain on the observational phase of the study 
for survival follow-up.  
All participants who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in the SoA 
for the specific substudy in Section 12.1.   
All participants who permanently discontinue study treatment without disease 
progression will be followed for survival according to the protocol schedule until one or 
more of the following occur: 
• 
death 
• 
withdrawal of consent for the observational phase of survival follow-up 
In the observational phase of the study, all participants who permanently discontinue 
study treatment will be followed via telephone contact every 12 weeks from the date the 
last dose for survival and new anticancer therapy, including radiotherapy, until death or 
withdrawal from further contact. New anticancer therapy information should be reported 
in the eCRF for those participants who die before the first follow-up contact. 
Decisions regarding dose interruptions or modifications for reasons other than 
management of events as already described in this section and elsewhere in this protocol 
will be made by the investigator in consultation with the Medical Monitor based on the 
clinical evaluation of the participant. 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when a participant 
meets one of the conditions outlined Figure 2 or Figure 3, based on baseline ALT: 


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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 Appendix 10. 
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 
the participant is clinically deteriorating and unlikely to receive any benefit from 
continued study treatment. 
In cases where deterioration was assessed to have occurred after a clinical event that, in 
the investigator’s opinion, is attributable to disease progression and is unlikely to reverse 
with continued study treatment or managed by supportive care (e.g., bisphosphonates 
and/or bone directed radiotherapy, thoracentesis, or paracentesis for accumulating 
effusions), study treatment should be discontinued. In these cases, the decision to 
continue treatment must be discussed with the Sponsor’s Medical Monitor and written 
consent by the participant must be obtained. Examples of events that may, in the 
investigator’s opinion, indicate a lack of clinical benefit include, but are not limited to, 
the following: 


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• 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. 
See Section 8.1 above for specific requirements when considering continuation of 
treatment.  
8.1.2. 
Study Treatment Restart/Rechallenge 
Study treatment 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. 
If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then participant must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow-up assessments. 
Refer to Section 12.10 for additional information. 
8.2. 
Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons. No further assessments will be required and the 
investigator must document this in the site study records. 
• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a participant withdraws from the study after providing study samples, GSK will 
retain those samples and any results from sample testing prior to participant 
withdrawal, as described in the informed consent. However, if a participant requests 
destruction of their samples at the time of withdrawal, the investigator should alert 
GSK and document this in the site study records. Once notified, GSK will ensure no 
new testing will be performed on the sample and the sample will be destroyed.  
• A participant will be considered to have withdrawn from the study if the participant 
has not died and is lost to follow-up. 
• Refer to the SoA for data to be collected at the time of study discontinuation and for 
any further evaluations that need to be completed. 


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8.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The following actions 
must be taken if a participant fails to return to the clinic for a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
9. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures are summarized in the SoA tables within each arm Appendix (Section 
12.1): Table for Screening assessments, Treatment Period assessments, and Treatment 
Discontinuation Visit [TDV] and Follow-Up assessments. Visit windows, as allowable, 
are notated in the SoA tables.  
9.1. 
General Guidance 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. Protocol waivers or exemptions are not allowed 
except for immediate safety concerns. Therefore, adherence to the study design 
requirements, including those specified in the SoA are essential and required for study 
conduct.  
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. 
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 another clinical trial within the screening window (e.g. 
imaging studies) and obtained prior to signing of the study informed consent may be used 
for screening/baseline assessments provided the procedures fulfill the protocol defined 
specifications and has been performed within the protocol indicated timeframe. 


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The following points must be noted: 
• 
Informed consent must be signed by a participant before any study required 
procedures are performed. However, procedures conducted as part of the routine 
clinical management (e.g., imaging studies) and conducted prior to signing of the 
study informed consent may be used for screening/baseline assessments provided 
the procedure fulfills the protocol defined specifications and has been performed 
within the protocol indicated timeframe. 
• 
If assessments are scheduled for the same nominal time, then the assessments 
must occur in the following order: 
1. 12-lead ECG 
2. Vital signs 
3. Blood draws 
Note: The timing of the assessments must allow the blood draw to occur at the 
exact nominal time. 
• 
The timing and number of planned study assessments, including safety, biomarker 
or other assessments may be altered during the course of the study based on 
emerging data to ensure appropriate monitoring.  
• 
The change in timing or addition of time points for any planned study assessments 
must be approved by the relevant GSK study team member and then archived in 
the study Sponsor and site study files, but this will not constitute a protocol 
amendment.  
• 
No more than approximately 1375 mL of blood will be collected from each 
participant over the full course of study treatment (2 years). 
9.1.1. 
General Guidance for Treatment Continuity when Participants are 
Unable to Come into the Clinic 
Prior to utilization of any of the measures outlined in this section, discussion and 
approval must be obtained from Sponsor/contract research organization.  
It is expected that sites participating in clinical studies will make every effort to ensure 
proper monitoring and well-being of enrolled participants by adhering to safety 
monitoring as outlined in the SoA (Section 12.1). The use of local laboratories and local 
radiology centers to reduce the need for a participant to come into the clinic is supported, 
if deemed necessary for the well-being of the participant. These local facilities should be 
added to regulatory documents, as required. 
Any restrictions in place at the site that will impact monitoring and/or participant access 
to the site and care providers should be communicated to the Sponsor/contract research 
organization.  
A global telemedicine platform that allows for continued monitoring of AEs, concomitant 
medications, protocol deviations, etc., may be engaged. Discussions around utilization of 


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this technology should be held on a per-site basis, and appropriate documentation of 
utilization should be captured.  
In general, for participants with limited possibility to travel or decreased capacity to come 
to the clinic, replace non-dosing in-person visits with phone contact or alternative 
location for assessment (e.g., local laboratories and imaging centers, at-home collection 
of patient reported outcomes [PROs]).  
9.2. 
Screening and Critical Baseline Assessments 
All screening assessments must be performed within 28 days prior to the first dose unless 
otherwise specified. The ICF may be signed within 45 days prior to first dose. 
The term ‘baseline’ refers to the assessment performed during the screening period prior 
to first dose of study treatment that serves as a comparison or control. For example, the 
baseline laboratory assessment is the laboratory assessment performed prior to first dose.  
Refer to SoA for each arm (Section 12.1) for additional details on assessments required at 
Screening and prior to start of study treatment. All assessments performed must be 
documented in the site source documents. 
The following assessments are required during screening: 
• Demographic parameters such as year of birth and sex will be captured. 
 
• Medical history including cardiovascular medical history, tobacco use, and other risk 
factors will be assessed as related to the inclusion/exclusion criteria.  
• Disease characteristics including medical, surgical, and treatment history including 
radiotherapy, date of initial diagnosis, stage at initial diagnosis according to the 8th 
Edition of TNM for Lung Cancer by the Union for International Cancer Control 
[UICC], histology, tumor genetic/genomic features sand current sites of disease will 
be taken as part of the medical history and disease status. Scans from imaging studies 
performed prior to screening may be requested for assessment of baseline lesions. 
Details concerning prior anticancer therapy (for example, systemic and radiation 
therapy), including best response to prior systemic therapy will be recorded. 
 
• If available, any antibiotic use within 90 days prior to the first dose of study should 
ideally be recorded to help inform the effect of antibiotics on clinical outcome 
through its manipulation of the immune system. 
 
• PD-L1 protein expression by IHC in patients with NSCLC is commonly utilized to 
determine PD-L1 status prior to initiation of treatment with a PD-L1 inhibitor. PD-L1 
expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, 
Dako 28-8, or Dako 22C3) must be recorded in the eCRF, if known. 
Baseline lesion assessments required within 28 days prior to the first dose of study 
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• 
Computed tomography (CT) scan with contrast of the chest and abdomen 
Note: Although a CT scan is preferred, magnetic resonance imaging (MRI) may 
be used as an alternative method of baseline disease assessment, especially for 
those participants where a CT scan is contraindicated due to allergy to contrast, 
provided the method used to document baseline status is used consistently 
throughout study treatment to facilitate direct comparison. When MRI is used for 
disease assessment, a non-contrast CT of the chest should also be performed, to 
evaluate the lungs. Refer to RECIST 1.1 guidelines for use of 
fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT [Eisenhauer, 
2009; Seymour, 2017]. 
• 
MRI of brain with and without IV gadolinium (if clinically indicated) 
• 
Bone scan (if clinically indicated) 
• 
Clinical disease assessment for palpable/visible lesions 
• 
Other areas as indicated by the participant’s underlying disease present prior to 
screening 
Refer to Section 9.3.1 for baseline documentation of target and non-target lesions.  
Safety and laboratory assessments (Section 9.5) required at baseline include: 
• 
Physical examination 
• 
ECOG Performance Status 
• 
Vital Signs 
• 
Concomitant medication 
o Recorded starting from screening through post-study follow-up.  
o Record all medications the participant is taking including prescription 
medications, over-the-counter (OTC) drugs or preparations, and 
herbal preparations including any cannabinoids and/or recreational 
drugs used. 
o At a minimum, the drug name, route of administration, dose, and 
frequency of dosing, along with start and stop dates must be recorded. 
• 
Electrocardiogram 
• 
Echocardiogram 
• 
Laboratory assessments  
9.3. 
Efficacy Assessments 
Planned time points for all efficacy assessments are listed in in each specific arm SoA 
Tables within Section 12.1.  


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9.3.1. 
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.  
Additionally, iRECIST guidelines will be used in the assessment of response/progression 
to account for the unique tumor kinetics observed with immunotherapeutic agents which 
may manifest as an increase in tumor burden then later is followed by regression 
suggesting the apparent observed neoplastic growth representing transient lymphocyte 
infiltration. Following approval by the medical monitor and signed informed consent to 
continue treatment post-progression (Section 8.1), participants with disease progression 
by RECIST version 1.1 guidelines should have a confirmatory disease assessment no 
sooner than 4 weeks after the date disease progression was declared in order to confirm 
disease progression by iRECIST guidelines. The visit level responses and treatment-
based decisions will incorporate iRECIST guidelines [Seymour, 2017].  
Refer to the SoA for each arm (Section 12.1) for the frequency of disease assessments 
post screening. 
A description of the adaptations and iRECIST process is provided in Appendix 12, with 
additional details in the iRECIST publication [Seymour, 2017]. A summary of imaging 
and treatment requirements after first radiologic evidence of progression provided in 
Table 54 and illustrated as a flowchart in Figure 11 in Appendix 12.  
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. For the abdomen and pelvis (if performed), 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, 
or when mandated by local practice. 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:  
• Imaging must include the chest and abdomen. 
• 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 is acceptable if MRI is medically contraindicated.  
• 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 


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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 (if performed) and long bones. 
In the event a photograph is taken of a particular lesion, the site will submit the 
photograph to the central imaging vendor. Refer to the site central imaging vendor 
manual technical requirements for photograph submission.  
9.3.1.1. 
Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to first dose. 
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior 
to first dose and can be assessed by the central imaging vendor.  
9.3.1.2. 
Tumor Imaging During the Study 
The first on-study imaging assessment must be performed 6 weeks after the first dose of 
study treatment. Subsequent tumor imaging must be performed every 6 weeks until Week 
49 and every 12 weeks thereafter. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression is identified by the investigator.  
Objective response 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 (Appendix 12), 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, following 
approval of treatment continuation by the medical monitor and signed consent by the 
participant. Participants who have unconfirmed disease progression may continue 
treatment at the discretion of the investigator until progression is confirmed by the site, 
provided they have met the conditions detailed in Appendix 12.  
9.3.1.3. 
End of Treatment Imaging 
For participants who discontinue study treatment due to disease progression, tumor 
imaging does not need to be repeated at the TDV. If previous imaging was obtained 
within 6 weeks prior to the date of discontinuation, then imaging at treatment 
discontinuation is not mandatory.  
For participants who discontinue study treatment without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor 


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imaging using the same imaging schedule used while on treatment until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first.  
9.3.2. 
Tumor Growth Kinetics 
To evaluate the effect of study therapy on the growth rate of individual tumor lesions, 
pre-baseline images (within approximately 12 months before the baseline scan; images 
obtained >12 months prior to the baseline scan may also be accepted upon consultation 
with Medical Monitor) will be requested to support exploratory investigation of tumor 
growth kinetics. Up to 3 pre-baseline scans may be requested and submitted to the central 
imaging vendor. Only those participants who consent to this collection will have their 
pre-baseline images submitted to the central vendor for these analyses.  
CT/MRI of the chest and abdomen with IV contrast are preferred, if available, and per 
local standard of practice. The same modality used at study baseline imaging is 
encouraged to be submitted, but not required. If performed, imaging of the brain along 
with any other areas of disease that were imaged in the 6 months prior to baseline scan 
may also be submitted. PET images are not required but may be submitted; and, the CT 
portion (with IV contrast if possible) of a PET/CT examination is acceptable if no other 
CT examinations are available.  
9.3.3. 
Survival Follow-up 
After a participant receives the last dose of study treatment, he or she will enter the 
survival follow-up period. Follow-up for survival and new anticancer therapy (including 
radiotherapy) will occur every 12 weeks until death, completion or termination of the 
overall study, or withdrawal of consent. Follow-up will be conducted via telephone 
contact. 
9.4. 
Adverse Events 
The definitions of AEs and SAEs are provided in Appendix 5. 
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). Adverse 
events must be assessed and documented at each patient contact. 
9.4.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• 
All AESIs and SAEs will be collected from the start of treatment until 90 days after 
the last dose of study treatment at the time points specified in the SoA (Section 2). 
However, any AESI or SAEs assessed as related to study participation (e.g., study 
treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK product will be recorded from the time a participant 
consents to participate in the study. If subsequent anti-cancer treatment is initiated 


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during the 90-day follow-up period yet <30 days after the date study treatment was 
discontinued, AESI and SAEs must continue to be collected until 30 days after last 
dose of study treatment and documentation of the subsequent anticancer treatment 
will be recorded in the eCRF. 
• 
All AEs will be collected from the start of study treatment until 30 days after the last 
dose of study treatment at the time points specified in the SoA (Section 2). 
• 
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded in the Medical History/Current Medical 
Conditions section of the CRF and not in the AE section. 
• 
All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 5. The 
investigator will submit any updated SAE data to the Sponsor within 24 hours of it 
being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the Sponsor. 
• 
The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in 
Appendix 5. 
9.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence.  
9.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AESIs (Section 7.2.1 
and Section 9.4.1), will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up (as defined in Section 8.3). If subsequent 
anti-cancer treatment is initiated during the 90-day follow-up period yet <30 days after 
the date study treatment was discontinued, AESI and SAEs must continue to be collected 
until 30 days after last dose of study treatment and documentation of the subsequent 
anticancer treatment will be recorded in the eCRF. Further information on follow-up 
procedures is given in Appendix 5.  
9.4.4. 
Regulatory Reporting Requirements for SAEs 
• 
Prompt notification by the investigator to the Sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study treatment under clinical investigation are 
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• 
The Sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The Sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
Sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
Sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements. 
 
9.4.5. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 5 and all deaths, if they are 
considered SAEs, specific cardiovascular and death sections of the eCRF will be required 
to be completed. These sections include questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.  
The CV (cardiovascular) eCRFs are presented as queries in response to reporting of 
certain cardiovascular MedDRA terms. The cardiovascular information should be 
recorded in the specific cardiovascular section of the eCRF within 1 week of receipt of a 
cardiovascular 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. 
9.4.6. 
Pregnancy 
• 
Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until 120 days 
after the last dose of study treatment. For participants randomized to the SoC only 
arm, pregnancy details with be collected after the start of study treatment and until at 
least 3 days after the last dose of study treatment (or per institutional standard). 
• 
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 Section 9.4.4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
9.5. 
Safety Assessments 
Planned time points for safety assessments are provided within each arm SoA Appendix 
(Section 12.1). Additional time points for safety testing may be added during the study 


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based on newly available data to ensure appropriate safety monitoring. PK and ADA 
samples will also be collected for safety. See Section 9.6 and Section 9.7 for additional 
information. 
9.5.1. 
Physical Examinations 
• A complete physical examination performed at Screening will include, at a 
minimum, assessment of the cardiovascular, respiratory, gastrointestinal, skin and 
neurological systems.  
• A brief physical examination performed at each subsequent visit (refer to SoA 
tables for each arm in Section 12.1), will include, at a minimum, assessments of 
the skin, lungs, cardiovascular system, and abdomen (liver and spleen).  
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• Physical examinations may be performed within one day of dosing (i.e., as 
opposed to the day of dosing), if necessary. 
9.5.2. 
Performance Status 
Performance status will be assessed using the ECOG scale at each visit, on the day of 
treatment or within 24 hours prior to dosing, if necessary (Appendix 8). 
9.5.3. 
Vital Signs 
• Vital signs will be measured after 5 minutes of rest and will include temperature, 
systolic and diastolic blood pressure, pulse rate, respiratory rate, and oxygen 
saturation (measured by pulse oximetry). Blood pressure should be taken in the 
same position throughout the study and captured in the eCRF.  
• Vital signs will be measured more frequently if warranted by clinical condition 
of the participant.  
• On days where vital signs are measured multiple times, temperature does not 
need to be repeated unless clinically indicated. 
• If a participant develops fever and infusion related reaction or cytokine release 
syndrome is suspected, refer to management guidelines (Section 7.2.1). 
• Height will be recorded at Screening only. 
• Weight will be measured and recorded (in kilograms) at baseline and every other 
treatment visit.  
• Vital signs must be recorded prior to dosing on treatment days. 
9.5.4. 
Electrocardiograms 
A 12-lead ECG will be obtained at screening using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcF intervals; manual 
calculation of QTcF is permitted. ECGs may be repeated during the study as clinically 
indicated, unless noted otherwise in the SoA for each arm under Section 12.1. 


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Cardiologist or locally approved specialist review is required if abnormal results are 
obtained and confirmed as described in Table 34 and Table 46 (Cardiac Investigations).  
9.5.5. 
Echocardiogram 
Echocardiograms (ECHO) will be performed locally at baseline to assess cardiac ejection 
fraction for study eligibility, as specified in the SoA (Section 12.1). Additional ECHO 
assessments may be performed if clinically warranted. The evaluation of the 
echocardiography should include an evaluation for 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. 
9.5.6. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 3 for the list of clinical laboratory tests to be performed and to the 
SoA for each arm (Section 12.1) for the timing and frequency.  
The investigator must review the laboratory report prior to administration of study 
treatments, document this review, and record any clinically relevant changes occurring 
during the study in the AE section of the CRF. The laboratory reports must be filed with 
the source documents. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the investigator to 
be more severe than expected for the participant's condition. 
All protocol required safety laboratory assessments, as defined in Table 51 must be 
conducted in accordance with the SoA for each arm. Reference ranges for all safety 
parameters must be provided to the site by the laboratory responsible for the assessments. 
All study-required safety laboratory assessments will be performed at the institution’s 
local laboratory. Laboratory safety assessments required prior to dosing may be 
performed up to 3 days prior to dosing, if necessary. 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. 
For all other protocol required blood and tissue sample collections, laboratory requisition 
forms must be completed, and samples must be clearly labeled with the participant 
number, protocol number, site/center number, and visit date. Details for the preparation 
and shipment of samples 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. 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study treatment 
must be repeated until the values return to normal or baseline. If such values do not return 


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to normal within a period judged reasonable by the investigator, the etiology must be 
identified, and the Sponsor notified. 
9.6. 
Pharmacokinetics  
Planned time points for all pharmacokinetics assessments are listed in the SoA for each 
arm (Section 12.1).  
9.6.1. 
Blood Sample Collection 
Blood samples for PK analysis are to be collected as indicated in the SoA. 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. If additional study drugs are added to this study 
for which PK samples are required, details will be provided in the SRM. 
9.6.2. 
Sample Analysis 
PK analysis will be performed for participants as indicated in each SoA. Concentrations 
of the study treatments will be determined using validated bioanalytical methodologies. 
Once the analysis has been completed, for any remaining samples may be analyzed for 
other compound-related metabolites. Refer to the SRM for further details. 
9.7. 
Anti-Drug Antibodies 
The actual date and time of each blood sample collection will be recorded for each 
specific analyte. Details of blood sample collection (including volume to be collected), 
processing, storage, and shipping procedures are provided in the SRM. 
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring. In the event of a hypersensitivity reaction that is either clinically significant 
in the opinion of the investigator, or leads to the participant withdrawing from the study 
treatment, blood samples must be taken from the participant for immunogenicity testing 
at the timepoints indicated in the arm specific SoAs (Section 12.1).  
9.8. 
Genetics 
Planned time points for all genetics-related assessments are listed in in the SoA for each 
arm (Section 12.1). 
A whole 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 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study. 


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In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Appendix 7 for further information regarding genetic research. Details on processes 
for collection and shipment and destruction of these samples can be found in the SRM. 
9.9. 
Biomarkers 
Planned time points for all biomarker assessments are listed in the SoA for each arm 
(Section 12.1). 
9.9.2. 
Tumor Tissue 
9.9.2.1. 
Screening Biopsies 
Part 1: All participants are required to provide fresh tumor tissue AND archival tumor 
tissue samples at screening prior to start of study treatment, unless specified otherwise in 
the SoA of each regimen in the respective subsections under Section 12.1.  
Part 2: Tumor tissue at screening (either archival or fresh biopsy if archival tissue is 
unavailable) is required for all participants in Part 2. Fresh tumor tissue AND an archival 
tissue sample obtained during screening are required for at least 20 participants for each 
arm.  
CCI


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Participants with inaccessible tumor or those participants that do not consent to the tumor 
biopsy procedure may be enrolled provided an archival specimen is submitted. However, 
no participant will be allowed on study without either an archival specimen OR a fresh 
biopsy. The archival specimen may have been obtained at any time from the time of 
initial diagnosis to time of study entry. Sufficient and evaluable tumor tissue for protocol 
specified testing needs to be provided (reference SRM for more details). 
9.9.2.2. 
On-Treatment Biopsies 
Part 1: All participants are required to provide paired fresh biopsies at screening and on-
treatment at week 7 (± 8 days), unless specified otherwise in the SoA of each regimen in 
the respective subsections under Section 12.1.  
Part 2: Fresh biopsy collected at week 7 (± 8 days) is optional for participants in Part 2, if 
tumor is amenable to biopsy and upon participant’s consent; However, paired fresh tumor 
biopsies collected at screening and week 7 (± 8 days) is required for at least 20 
participants for each arm. 
Enrollment may become limited during the study, as required, to ensure collection of 
fresh tissue samples as noted. 
 
Additional optional fresh tumor tissue sample will be collected at Week 19 (± 8 days) at 
the time of imaging assessment and/or at the time of confirmed PR or PD, upon 
participant consent (± 8 days).  
When feasible, tumor imaging should be completed prior to tissue collection to avoid 
potential radiographic alterations due to the biopsy procedure. 
 
These tissues will be evaluated by IHC or other potential methods, including image 
analysis, for expression of phenotypic and functional immune cell markers on tumor 
infiltrating lymphocytes (TIL) and other immune cells as well as immune signaling 
markers on tumor cells to understand the anti-tumor responses. In addition, when 
possible, similar analyses will be performed on tumor tissue obtained upon progression. 
Additionally, tumor tissue may be sequenced to assess T-cell diversity (TCR diversity) as 
well as evaluated for any DNA/RNA/protein changes correlating with response, 
including tumor mutational load assessments. 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. 
9.10. 
Patient-Reported Outcome Assessments 
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Table 6 
PRO Outcomes Assessed in Study 205801 
Instrument  
Role 
Rationale & Overview 
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10. 
STATISTICAL CONSIDERATIONS  
10.1. 
Primary Endpoint 
10.1.1. 
Primary Endpoint: Part 1 
The primary endpoint for Part 1 is the incidence of AEs, SAEs, DLTs, changes in 
safety/laboratory assessment parameters, and dose modifications.  
A key secondary endpoint for Part 1 is Objective Response Rate (ORR) using RECIST 
1.1 by investigator assessment. ORR is defined as the percentage of participants with a 
best overall response of CR or PR at any time. 
10.1.2. 
Primary Endpoint: Part 2 
The primary endpoint for Part 2 is OS. OS is defined as the interval from date of 
randomization to the date of death, irrespective of the cause of death. If a participant does 
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not have a documented date of death or is lost to follow-up, time of death will be 
censored at the date of last contact. 
10.2. 
Hypothesis 
10.2.1. 
Hypothesis: Part 1 
The primary objective of Part 1 is to establish the safety and tolerability of the 
experimental combination regimen of each arm.  
10.2.2. 
Hypothesis: Part 2 
The primary objective of Part 2 is to determine whether the experimental arms prolong 
overall survival relative to standard of care. The null hypothesis is that there is no 
difference in overall survival between each experimental arm and the SoC and alternative 
hypothesis is that the experimental regimen improves overall survival over the SoC. The 
predictive probability inference approach will be used as the basis for both interim and 
final decision making. The predictive probability of success (PoS) in future Phase 3 study 
(phase 3 success being defined as a statistically significant log-rank test with 1-sided 
alpha=0.025) will be calculated as a measure of the improvement in OS in the 
experimental arm compared with the SoC arm. A cutoff of 43% or greater for the PoS of 
future Phase 3 study, approximately corresponding to an observed HR no greater than 0.8 
in a substudy, will be implemented as the criteria for an experimental regimen to be 
considered for proceeding to Part 2. As this is a signal finding study and not 
confirmatory, each experimental arm will be compared to control in a pairwise fashion 
with no adjustment for multiple comparisons. 
10.3. 
Sample Size Determination 
10.3.1. 
Sample Size: Part 1 
For Part 1, sample size will be defined for each regimen under the corresponding 
appendix in Section 12.1.   
The FDA approved dose of docetaxel provides the following outcomes, based on the 
validated data.  
  
Study 
  
TAX 317 
Control for 317 
TAX320 
Control for 320 
  
Docetaxel 75 
mg/m2 n=55  
Best Supportive 
Care n=49  
Docetaxel 75 
mg/m2 n=125  
Vinorelbine or 
Ifosfamide n=123  
95% CI (Risk Ratio) 
(0.35, 0.88) 
(0.63, 1.06) 
Median Survival  
(95% CI) 
7.5 months  
(5.5, 12.8) 
4.6 months  
(3.7, 6.1) 
5.7 months  
(5.1, 7.1) 
5.6 months  
(4.4, 7.9) 


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Study 
  
TAX 317 
Control for 317 
TAX320 
Control for 320 
  
Docetaxel 75 
mg/m2 n=55  
Best Supportive 
Care n=49  
Docetaxel 75 
mg/m2 n=125  
Vinorelbine or 
Ifosfamide n=123  
% 1-year Survival  
(95% CI) 
37% (24, 50) 
12% (2, 23) 
30% (22, 39) 
20% (13, 27) 
Time to Progression  
(95% CI) 
12.3 weeks 
(9.0, 18.3) 
7.0 weeks  
(6.0, 9.3) 
8.3 weeks  
(7.0, 11.7) 
7.6 weeks  
(6.7, 10.1) 
Response Rate  
(95% CI) 
5.5%  
(1.1, 15.1) 
N/A 
5.7%  
(2.3, 11.3) 
0.8%  
(0.0, 4.5) 
 
Additional information is available from the control arm of the FDA approved label for 
pembrolizumab where docetaxel was used as a control. The following table summarize 
those data. 
Endpoint 
 Docetaxel 75 mg/m2 every 3 weeks n=152 
OS Deaths (%) 
86 (57%) 
OS Median in months 
8.2 (6.4, 10.7) 
PFS Events 
118 (78%) 
PFS Median in months 
4.1 (3.6, 4.3) 
ORR 
8% (4, 13) 
Median duration of response in months (range) 
8.1 (2.1+, 8.8+) 
 
Examining the confidence intervals for docetaxel response rates across not only the FDA 
approved package inserts, but other published studies show that while the point estimates 
for response rate may vary, the 95% Confidence Intervals around the point estimates 
remain in the 5%-15% range. Consequently, using a 10% Response Rate as a benchmark 
is reasonable based on available data. Data from 205801 platform study Substudy 1, if 
available, may be used to calibrate this assumption of the docetaxel monotherapy 
response rate for the futility analysis. 
 


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10.3.2. 
Sample Size: Part 2 
In Part 2, 70 participants in each experimental arm and a minimum of 35 participants in 
the SoC arm will be randomized. Sample size and associated operating characteristics 
were evaluated via simulation.  
The 8-month milestone survival in the SoC arm is estimated to be ~40% in squamous cell 
lung cancer (Brahmer, 2015), ~60% in non-squamous lung cancer (Borghaei, 2015), and 
~50% in PD-L1 positive population (Herbst, 2016). The participant population in the 
current study is expected to be a mixed population with both squamous and non-
squamous lung cancer participants; therefore, mean target rate is assumed to be ~50% 
(Figure 4). 
For the target effect of experimental regimens, there is a potential delayed effect at 
treatment start and sustained effect after prolonged follow-up (Brahmer, 2015; Borghaei, 
2015). The survival probability in these arms is expected to overlap in the SoC arm for up 
to 4 months from start of treatment followed by a separation. It is hypothesized that 
percentage of surviving participants is maintained at 20% after 24 months (Figure 4).  
Under the alternative hypothesis three-piece piecewise Weibull distributions are used to 
describe the survival distribution of each experimental arm and two-piece piecewise 
Weibull distributions are used to describe the survival curve of docetaxel (Refer to 
Appendix 13 for simulation parameters). Details of the piecewise Weibull model are 
provided in the statistical appendix (Section 12.13). Using this modeling approach for the 
primary endpoint of OS, the assumed survival curve for the SoC arm is presented using 
blue dashes and the target survival curve for the experimental arm is presented as the 
solid red curve in Figure 4. Based on these two curves, the hazard ratio is approximately 
0.58.      
Sample size was chosen by simulating the entire platform in which 4 experimental arms 
enter the master protocol at different points in time. Enrollment of 9 participants per 
month is assumed. Interim and final analyses are performed based on predetermined 
decision rules as specified in Section 10.3.3 and Section 10.5.1, respectively.  The 
planned Phase 3 sample size is 300 (150 participants per arm and a total of 210 events).  
The future phase 3 trial will use the log-rank (frequentist) test and the decision rule at 
interim and end of phase 2 will use the (Bayesian) predictive probability, given the 
results in phase 2, that the future log-rank test in phase 3 study will be significant, thus, 
resulting in a methodology that is a mixture of Bayesian and frequentist. Simulations 
assess the Operating Characteristics of the predictive probability decision criteria under 
the null and alternative hypotheses, as described in Section 10.3.4. A cutoff of 43% or 
greater for the PoS of future phase 3 study, approximately corresponding to an observed 
HR ≤ 0.8 for each substudy, is used as a guide for future development of each 
experimental arm. Sample size was calculated under the simulated survival curves shown 
in Figure 4.  
The final analysis of OS for a substudy will be performed when approximately 85 death 
events have occurred in the experimental arm and SoC arm combined, and the last 
participant in that substudy has been randomized for at least 6 months. In the case death 
events occur at a rate lower than expected due to potentially prolonged survival benefit, 


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to avoid substantial delay of final analysis for a substudy, the primary analysis for a 
substudy may be conducted once approximately 75 events have occurred and the last 
participant in that substudy has been randomized for at least 6 months, at the discretion of 
the Sponsor. A minimum of 35 events are needed from the experimental arm for both 
primary and final analysis. 
Assuming the true HR≈0.58, 85 death events will provide 94.2% probability (power) of 
achieving the guidance criteria with future phase 3 study success ≥ 43%. In the case of 
primary analysis being performed with 75 death events, it will provide 88.3% probability 
of achieving the guidance criteria. If the true HR is 1, 85 and 75 death events will have 
16.6% and 18.2% Type I error, respectively. 
Figure 4 
Assumed Survival Probability Under Alternative Hypothesis in 
Experimental Regimens (Red) and  
Docetaxel (Blue) 
 
 
10.3.3. 
Interim Analyses 
10.3.3.1. 
Interim Analyses: Part 1 
An interim evaluation of futility in terms of ORR may be conducted for an arm if data 
permits. Details for futility analyses are provided in the respective subsection for each 
arm in Appendix Section 12.1.  
 


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10.3.3.2. 
Interim Analyses: Part 2 
This is a platform study utilizing a master protocol designed so that additional 
experimental arms may enter and leave the trial at different time points as determined by 
pre-specified decision criteria.  
Part 2 of the study will be conducted under the auspices of an IDMC and steering 
committee. The membership and activities are outlined in the IDMC and steering 
committee charters. This committee will review all available interim safety and efficacy 
data as the study progresses. Interim analyses will be performed approximately every 6 
months depending on the amount of additional data accrued.   
Interim Analyses for OS 
An interim analysis of OS will be conducted for each substudy after approximately 45 
events (experimental arm and SoC combined) and a minimum of 18 events from 
experimental arm have been observed. Note, events from the SoC arm will be counted 
from the initial study start (i.e. SoC events from substudy 1 will be counted with any 
further events observed in subsequent substudies). Stopping guidelines will be provided 
as part of the IDMC charter. Final decisions on termination of an arm will be based on 
the totality of the data. 
Final analysis for Graduation  
The final analysis for each substudy will occur after observing 85 events (experimental 
regimen and SoC combined) and the last participant in a substudy has been randomized 
for at least 6 months. A minimum of 35 events are needed from the experimental arm for 
the final analysis of that substudy. In the case of death events occur at a rate slower than 
expected due to potentially prolonged survival benefit, to avoid substantial delay of final 
analysis for a substudy, primary analysis for a substudy may be conducted once 
approximately 75 events have occurred and at least 35 events observed in the 
experimental arm, and the last participant in that substudy has been randomized for at 
least 6 months, at the discretion of the Sponsor. A cutoff of 43% or greater for the PoS of 
future phase 3 study is used as graduation criteria for an experimental regimen to be 
considered for proceeding to Part 2. The final decision of proceeding to Part 2 will be 
based on the totality of data. An experimental regimen may be discontinued at any time 
due to safety concerns. 
Additional details of the interim analysis will be provided in the RAP and IDMC charter. 


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10.3.4. 
Statistical Operating Characteristics 
For Part 1, please see details under the corresponding appendix for each arm in Section 
12.1.  
For Part 2, simulations were carried out to determine the operating characteristics for the 
primary comparisons for Part 2. The simulation results are presented in Table 7 and Table 
8. Since the randomization ratios for subsequent studies range from 1:4 to 1:2 (as shown 
in Table 1), the simulations for subsequent studies were performed for both 1:4 and 1:2 
scenarios. Table 7 shows simulation results for 85 events at final analysis as planned and 
Table 8 shows simulation results for the primary analysis with 75 events in the case 
primary analysis is decided to be conducted.  
The simulations on OS are based on the following assumptions: 
1. 
The sample size for the experimental arm is 70 for all substudies. The 
sample size for the control arm is 35 for substudy 1, and for subsequent 
studies it follows dynamic randomization ratios as described in Table 1.  
2. 
The required minimum number of death events in the experimental arm 
are 18 for the interim analysis and 35 for the final (or primary) analysis. 
3. 
The survival curve for the SoC arm and the experimental arm are assumed 
to be same as presented in Figure 4, with target HR≈0.58. The Weibull 
parameters of each curve used for the simulations are detailed in Section 
12.13.1. 
4. 
The recruitment rate is approximately 9 participants per month. 
5. 
The start date of Part 2 of subsequent studies is ~34 months after the start 
date of substudy 1. 
6. 
The futility threshold for interim analysis is 5% or less for the PoS of 
future phase 3 study , as described in Appendix C of the IDMC charter.  
7. 
A cutoff of 43% or greater for the PoS of future phase 3 study is used as 
graduation criteria for each experimental arm. 
It is noted that the simulations were performed for single substudy scenario instead of 
multiple experimental arms randomized concurrently. Although concurrent 
randomization may potentially affect the enrolment speed, since substudies are event 
driven, it is not expected to lead to substantial change of the operating characteristics 
except for timing of interim and final analysis.  


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Table 7 
Statistical Operating Characteristics for Target Effect (HR ≈ 0.58) and 
Null Effect (HR=1) for 85 Events at Interim and Final Analysis  
Treatment 
Effect 
Scenarios 
Substudies 
Number of Participants in 
SoC Arm 
Interim Analysis of OS 
Final Analysis (85 events) 
Participants 
from 
Substudy 1 
Participants 
from 
Subsequent 
Substudy 
Average 
Events 
Prob. of 
Futility 
Average 
Events 
Power or 
Type I error 
(Pred. 
prob.≥43%) 
SoC 
Trt 
SoC 
Trt 
HR ~ 0.58 
Substudy 1 
35 
NA 
17.4 
27.6 
3.4% 
33.1 
51.9 
94.2% 
Subsequent 
substudy 
(ratio 1:4) 
35 
18 
40.8 
18 
9.3% 
47.8 
37.3 
81.9% 
Subsequent 
substudy 
(ratio 1:2) 
35 
35 
46.1 
18 
9.2% 
58.4 
35 
76.3% 
HR =1 
Substudy 1 
35 
NA 
15 
30 
19.0% 
28.3 
56.7 
16.6% 
Subsequent 
substudy 
(ratio 1:4) 
35 
18 
39.9 
18 
22.6% 
45.3 
39.7 
14.9% 
Subsequent 
substudy 
(ratio 1:2) 
35 
35 
44.5 
18 
22.0% 
53 
35.4 
15.6% 
Note: The simulation did not incorporate the minimum requirement of 6 months from randomization date of the last 
participant to analysis date.  
Table 8 
Statistical Operating Characteristics for Target Effect (HR ≈ 0.58) and 
Null Effect (HR=1) for 75 Events at Primary Analysis 
Treatment 
Effect 
Scenarios 
Substudies 
Number of Participants in SoC 
Arm 
Primary Analysis (75 events) 
Participants 
from 
Substudy 1 
Participants 
from 
Subsequent 
Substudy 
Average Events 
Power or 
Type I error 
(Pred. 
prob.≥43%) 
SoC 
Trt 
HR ~ 0.58 
Substudy 1 
35 
NA 
29.8 
45.2 
88.3% 
Subsequent substudy 
(ratio 1:4) 
35 
18 
47 
35 
76.7% 
Subsequent substudy 
(ratio 1:2) 
35 
35 
58.4 
35 
76.3% 
HR =1 
Substudy 1 
35 
NA 
25 
50 
18.2% 
Subsequent substudy 
(ratio 1:4) 
35 
18 
44.2 
35 
16.2% 
Subsequent substudy 
(ratio 1:2) 
35 
35 
52.8 
35 
15.6% 
Note: The simulation did not incorporate the minimum requirement of 6 months from randomization date of the last 
participant to analysis date.  
 


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10.3.5. 
Sample Size Sensitivity 
It is expected that the statistical operating characteristics will be dependent on 
assumptions around target treatment effects and survival curve of SoC. Evaluations of 
sensitivity analysis were performed varying one assumption at a time (See Table 9, Table 
10, Figure 5, and Figure 6). Sensitivity analysis with respect to HR was conducted using 
simulations under two scenarios: HR=0.48 and HR=0.70. For the case where HR=0.48, 
the target survival curve for the experimental arm is presented in Figure 6A using the 
thick solid orange curve and the assumed survival curve for SOC is presented using blue 
dashes. For the case where the HR=0.70, the target survival curve for the experimental 
arm in Figure 6B is presented using the thick solid green curve and the assumed survival 
curve for SOC is presented using blue dashes. The experimental target survival curve 
(with HR=0.58 relative to SOC) is also presented (with notation) in both figures. 
Sensitivity analysis simulation results showing the operating characteristics of the 
predictive probability decision criteria under these 2 scenarios (HR=0.48 and HR=0.70) 
are presented in Table 9. 
Table 9 
Sensitivity Analysis to Evaluate the Assumption of Treatment 
Effects  
Treatment 
Effect 
Scenarios 
Substudies 
Number of Participants in 
SoC 
Interim Analysis of OS 
Final Analysis (85 events) 
Participants 
from 
Substudy 1 
Participants 
from 
Subsequent 
Substudy 
Average 
Events 
Prob. of 
Futility 
Average 
Events 
Overall 
Power (Pred. 
prob.≥43%) 
SoC 
Trt 
SoC 
Trt 
Greater 
than 
Target 
Effect 
(HR ≈ 
0.48)1 
Substudy 1 
35 
NA 
18.3 
26.7 
1.8% 
34.3 
50.7 
99.2% 
Subsequent 
substudy 
(ratio 1:4) 
35 
18 
41.1 
18 
6.6% 
48.9 
36.4 
93.9% 
Subsequent 
substudy 
(ratio 1:2) 
35 
35 
46.9 
18 
6.5% 
61.1 
35 
90.0% 
Lower 
than 
Target 
Effect 
(HR ≈ 
0.7)2 
Substudy 1 
35 
NA 
16.6 
28.4 
6.3% 
31.6 
53.4 
76.8% 
Subsequent 
substudy 
(ratio 1:4) 
35 
18 
40.4 
18 
12.6% 
46.9 
38.2 
61.7% 
Subsequent 
substudy 
(ratio 1:2) 
35 
35 
45.5 
18 
13.0% 
56.2 
35.1 
56.3% 
1 Greater than target effect as shown in Figure 6A (Solid Orange Curve). 
2 Lower than Target effect as shown in Figure 6B (Solid Green Curve). 
Note: The simulation did not incorporate the minimum requirement of 6 months from randomization date of the last 
participant to analysis date.  


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Sample size sensitivity analysis is also performed assuming higher survival probability of 
SoC, while the survival probability of experimental arm does not change. The simulation 
results are presented in Table 10. 
 
Table 10 
Sensitivity Analysis with Higher Survival Probability in SoC (median 
survival = 9 months as described in solid blue line in Figure 5) 
Substudies 
Number of Participants in 
SoC Arm 
Interim Analysis of OS 
Final Analysis (85 events) 
Participants 
from 
Substudy 1 
Participants 
from 
Subsequent 
Substudy 
Average Events 
Prob. of 
Futility 
Average 
Events 
Power or Type I 
error (Pred. 
prob.≥43%) 
SoC 
Trt 
SoC 
Trt 
Substudy 1 
35 
NA 
16.7 
28.3 
5.9% 
32.3 
52.7 
83.8% 
Subsequent 
substudy 
(ratio 1:4) 
35 
18 
40.4 
18 
12.8% 
47.1 
37.9 
66.1% 
Subsequent 
substudy 
(ratio 1:2) 
35 
35 
45.5 
18 
12.2% 
56.8 
35.1 
61.0% 
Note: The simulation did not incorporate the minimum requirement of 6 months from randomization date of the last 
participant to analysis date. 
 
Figure 5 
Survival of SoC (solid blue line) is Higher than Target Survival of 
SoC (dotted blue line) 
 


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Figure 6 
Survival Curves of Experimental Arms in Greater Than Expected 
Survival (A: Orange Solid Line) and Less Than Expected Survival (B: 
Green Solid Line) 
 
10.3.6. 
Sample Size Re-estimation 
Sample size re-estimation is not planned for this study. 
10.4. 
Populations for Analyses 
For analysis purposes, the following populations are defined: 
The Intent to Treat Population (ITT) is defined as all participants who were 
randomized to treatment regardless of whether the participants actually received study 
treatment. All efficacy endpoints will be evaluated based on this population.  
The Safety Population is defined as all participants who receive at least 1 dose of SoC or 
experimental regimen based on actual treatment received. All safety endpoints will be 
evaluated based on this population.  
The PK Population will consist of all participants from the ITT Population from whom a 
blood sample is obtained and analyzed for PK concentration.  
DLT-evaluable participants are defined as all participants who take at least 1 dose of 
study intervention and are followed for the DLT observation period or are withdrawn 
within the DLT observation period due to meeting the DLT criteria and no 
resolution/recovery per dose modifications and toxicity management guidelines. (Note: 
participants enrolled in a PK/PD cohort at a previously cleared dose will not be included 
in the DLT evaluable population). 


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10.5. 
Statistical Analyses 
This is a platform study utilizing a master protocol with different arms for each 
experimental regimen(s), the statistical analyses will be conducted separately for each 
arm. Data will be listed and summarized according to the GSK reporting standards, 
where applicable. Complete details of the analysis will be documented in the Reporting 
and Analysis Plan (RAP). Any changes to the analysis plan described in this protocol will 
be documented in the RAP and final clinical study report (CSR).  
10.5.1. 
Analysis 
10.5.1.1. 
Part 1 Analysis 
The primary objective of Part 1 is to establish the safety and tolerability of experimental 
regimens prior to transition to Part 2 of the study.  
 
Safety and tolerability will be guided using the methodology and associated dose decision 
rule as described in the respective subsection for each substudy in Appendix Section 
12.1. However, to ensure safety of participants, dose recommendations based on the 
statistical methodology can be overridden at the discretion of the Medical Monitor, 
especially in the event of DLT. 
 
10.5.1.2. 
Part 2 Primary Efficacy Analysis 
The primary endpoint for Part 2 is OS. The primary analysis is HR and its 95% 
confidence interval from the Cox model with a single treatment covariate. The PoS of 
future phase 3 study will also be reported. A cutoff of 43% or greater for the PoS of 
future phase 3 study is used as a guide for future development of each experimental arm. 
The theorem and details for the calculation of PoS are provided in Appendix Section 
12.13.2. 
10.5.1.2.1. Sensitivity Analysis 
To evaluate the exchangeability assumption between non-concurrent and concurrent SoC 
data, sensitivity analyses will be conducted to evaluate time-dependency in the SoC arm. 
The exchangeability assumption will be examined by comparing overall survival between 
non-concurrent and concurrent SoC data, by using Cox’s proportional hazard model with 
indicator in control data (0: nonconcurrent, 1: concurrent data) as a covariate. If there is a 
difference in OS between non-concurrent and concurrent SoC, this difference will be 
further investigated or examined. Sensitivity analysis will be conducted if there is 
evidence of a violation of the exchangeability assumption. An example of a sensitivity 
analysis is one where only the concurrent data will be included (i.e., no non-concurrent 
data are used) in evaluating the treatment effect of the experimental regimen at data 
analysis.  


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10.5.1.3. 
Key Secondary Endpoint 
The key secondary endpoints are the milestone survival rates at 12 and 18 months, which 
will be estimated using the Kaplan-Meier method. The milestone survival and the 
differences between the experimental arm and SoC will be presented. The details of the 
analysis will be further discussed in RAP.  
10.5.2. 
Other Secondary Analyses 
10.5.2.1. 
Anticancer Activity Analyses 
The ITT Population will be used for anticancer activity analyses. Anticancer activity will 
be evaluated based on clinical evidence and response criteria. The response data will be 
summarized by each treatment (iRECIST will be used for response endpoints and disease 
measurements for iORR, iDCR, iDOR and iPFS; RECIST 1.1 guidelines will be used for 
response endpoints and disease measurements for ORR, DCR, DOR and PFS).  
ORR, DCR, DOR, PFS, and OS as well as iORR, iDCR, iDOR and iPFS will be 
calculated and summarized.  
• 
ORR or iORR is defined as the percentage of participants with a best overall 
confirmed CR or PR at any time as per disease-specific criteria.  
• 
DCR or iDCR is defined as the percentage of participants with a confirmed CR + PR 
at any time, plus SD 12 weeks. 
• 
DOR or iDOR is defined as the first documented evidence of CR or PR until disease 
progression or death due to any cause among participants who achieve an overall 
response (i.e., unconfirmed or confirmed CR or PR). Censoring rules will follow 
those of the PFS analysis. TTR is defined as the interval from the first dose of study 
treatment to the date of the first documented CR or PR. 
• 
PFS or iPFS defined as time from the date of randomization to the date of disease 
progression per clinical or radiological assessment or death due to any cause, 
whichever occurs earlier. For the analysis of PFS, if the participant received 
subsequent anticancer therapy prior to the date of documented events, PFS will be 
censored at the last adequate assessment (e.g., assessment where visit level response 
is CR, PR or SD) prior to the initiation of therapy. Otherwise, if the participant does 
not have a documented date of event, PFS will be censored at the date of the last 
adequate assessment. 
At each interim analysis, if a participant does not have an event or is lost to follow-up, 
the participant will be censored at the last contact date (OS) or last imaging date (PFS). 
Further details on rules of censoring will be provided in the RAP. PFS and OS will be 
summarized using the Kaplan-Meier method. 
 


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10.5.3. 
Safety Analyses 
The Safety Population will be used for the analysis of safety data. All safety endpoints 
(e.g., adverse event data, clinical laboratory assessments, vital signs, etc.) will be 
summarized according to the scheduled, nominal visit at which they were collected and 
across all on-treatment time points. Complete details of the safety analyses will be 
provided in the RAP. 
10.5.3.1. 
Extent of Exposure 
The number of participants administered study treatment will be summarized according 
to the duration of therapy.  
10.5.3.2. 
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).  
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, AESIs and AEs leading to dose modifications for toxicity 
management if irAEs of study treatment. 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.  
The incidence of deaths and the primary cause of death will be summarized.  
10.5.3.3. 
Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (version 5.0). Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criteria will be summarized 
using proportions. Further details will be provided in the RAP.  
10.5.3.4. 
Other Safety Measures 
Data for vital signs will be summarized based on predetermined criteria identified to be 
of potential clinical concern. Further details will be provided in the RAP.  
10.5.4. 
Pharmacokinetic Analyses 
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 conducted by non-compartmental 
methods under the direction of CPMS. The following PK parameters may be determined 
as data permit:  
• 
maximum observed concentrations (Cmax) 


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• 
trough concentrations (Ctrough or Cmin) 
• 
Any additional PK parameters that may be calculated as data permit, e.g., area under 
the plasma or serum concentration-time curve (AUC(0-t)) will be presented in the 
study report  
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK. 
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by cohort.   
The data from this study may be combined with the data from other studies for a 
population PK analysis. The details of such analysis will be outlined in a separate RAP; 
results of this analysis may be reported separately. 
10.5.5. 
Pharmacokinetic/Pharmacodynamic Analyses 
If deemed appropriate and if data permit, exploratory Pharmacokinetic / 
Pharmacodynamic analyses such as exposure-response relationships between exposure 
(e.g., dose, Cmax or Cmin) and safety/efficacy/PD parameters (e.g.: anti-tumor response, 
biomarkers) may be conducted. The details of such PK/PD analyses will be outlined in a 
separate RAP; results of these analyses may be included in a report separate from the 
clinical study report. The data from this study may be combined with the data from other 
studies, which may be reported separately. 
 
10.5.6. 
Tumor Kinetic Analyses 
Exploratory analyses may be performed to evaluate the effect of study treatment 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 a separate RAP. 
The data from this study may be combined with the data from other studies, which may 
be reported separately. 
10.5.7. 
Other Analyses 
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11. 
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12. 
APPENDICES 
12.1. 
Appendix 1: Arms 
12.1.1. 
Standard of Care Arm 1: Docetaxel Alone (Part 2 ONLY) 
12.1.1.1. 
Protocol Amendment 4 Summary of Changes Specific to Docetaxel 
Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.1.2 
Added physical exam for 
dosing visits. 
To align with the changes made 
to the other substudies Schedule 
of Activities. 
Schedule of Activities 
Section 12.1.1.2 
Removed details on 
number of slides for tissue 
sample to be sent by site. 
Decided this detail should be 
included in the SRM instead and 
was removed from protocol. 
Schedule of Activities 
Section 12.1.1.2 
Clarified that Docetaxel 
PK samples do not need to 
be collected after cycles 
have been completed. 
To provide clarity and address 
site questions. 
Schedule of Activities 
Section 12.1.1.2 
At the follow up visit, 
footnote added: If the 
participant dies before the 
first follow up, any 
subsequent anticancer 
therapy or radiotherapy 
should be recorded in the 
eCRF. 
To record any subsequent 
therapy the participant may have 
received after study 
discontinuation, if they die 
before first follow up is 
completed. 
Schedule of Activities 
Section 12.1.1.2 
Added footnote: 
Pre: predose sample to be 
collected prior to dosing per 
institutional guidance, as 
long as it is collected prior 
to dosing of the 
corresponding agent; EOI: 
End of infusion sample is in 
reference to EOI of the 
corresponding agent. 
To clarify the sample collection 
reference for predose and EOI. 
 


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Protocol Amendment 3 Summary of Changes Specific to Docetaxel Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.1.2 
Added Schedule of 
Activities specific to 
docetaxel only treatment. 
To provide individual 
specific Schedule of 
Activities Table specific to 
standard of care arm in Part 
2. 
Study Treatment Section 
12.1.1.3 
Added required cycles for 
docetaxel. 
Provide additional 
guidance to align with 
standard practices for 
docetaxel administration. 
 


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12.1.1.2. 
Schedule of Activities Specific to Arm 1 Docetaxel (Part 2) 
The timing and number of planned study assessments, including [safety, pharmacokinetic, ADA, biomarker or others] assessments may be 
altered during the course of the study based on newly available data. 
 
Table 11 
Schedule of Activities – Screening: Standard of Care Arm 1: Docetaxel Alone 
Screening Study 
Assessments 
Screening1  
Notes 
Visit Window 
≤4 Weeks 
 
Informed Consent1 
X 
1. All screening assessments must be performed within 4 weeks (28 days) prior to first dose of study treatment unless otherwise 
specified. The informed consent may be signed within 45 days prior to first dose. 
 
Participant Registration2 
X 
2. Participants will be registered in RAMOS NG at screening. 
Inclusion/Exclusion Criteria 
X 
Review eligibility prior to randomization. 
Demographics, Medical History 
(including alcohol and tobacco 
use), Prior Medications, 
Disease History12 
X 
12. All known mutations should be entered in the eCRF as disease history. 
Prior Anticancer Treatment, 
Radiotherapy 
X 
 
Screening Safety 
AE/SAE/AESI Assessment3 
X 
3. After the initial AE/SAE report, the investigator is required to proactively follow each participant at subsequent visits/contacts. 
Refer to Section 9.4 for further details. 
ECOG PS 
X 
 
Physical Examination 
X 
 
Vital Signs, Height and Weight4 
X 
4. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. Height is recorded at Screening 
only. Record weight in kilograms. 
12-lead ECG 
X 
 
Echocardiogram or MUGA 
scan5 
X 
5. ECHO required at Screening within 28 days prior to first dose of study treatment, and during treatment phase if clinically 
indicated. MUGA scan may be used if ECHO not feasible.  
Screening Local Laboratory Assessments (Safety) 
Hepatitis B and C6 
X 
 


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Screening Study 
Assessments 
Screening1  
Notes 
Visit Window 
≤4 Weeks 
 
Serum β-hCG (for women of 
childbearing potential) 
≤3d 
Clinical Chemistry6, 
Coagulation6, Hematology6, 
Thyroid function6 
X 
6. Refer to Appendix 3 for a complete list of required assessments. Required within 7 days of randomization day. If Hepatitis B 
and C was performed within 3 months prior to first dose of SoC, repeat testing at screening is not required; otherwise, this testing 
is mandatory. 
Calculated CrCl7 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. See Appendix 9. 
Troponin I or Troponin T 
X 
 
Urinalysis6 
X 
 
Screening Other Laboratory Assessments 
PD-L1 expression by IHC8 
X 
8. PD-L1 expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, Dako 28-8, or Dako 22C3) must be 
recorded in the eCRF, if known. Note: Test is not required to be performed by the site if not previously performed. 
Screening Disease Assessments 
 
Tumor Imaging9 
X 
9. Diagnostic quality CT scan of chest and abdomen with contrast must be obtained within 28 days of first dose. Baseline brain 
scan (MRI with and without IV gadolinium) should be obtained within 6 weeks of first dose if history of CNS disease or if clinically 
indicated. Bone scan should be obtained within 6 weeks of first dose if clinically indicated. See additional information regarding 
bone scans in Section 9.3.1. 
Pre-Baseline scans for Tumor 
Growth Kinetics10 
X 
10. Upon participant consent, up to 3 pre-baseline scans (within 12 months before the baseline scan) will be collected to assess 
tumor growth rate to support exploratory investigation of tumor growth kinetics (See Section 9.3.2 for details on images for 
submission). 
Screening Tumor Biopsies 
Fresh tumor tissue sample and 
Archival tumor11 
X 
11. Part 2: Tumor tissue at screening (either archival or fresh biopsy if archival tissue is unavailable), is required for all participants 
in Part 2: Fresh tumor tissue at screening is required in addition to an archival tissue for at least 20 participants in the SoC arm. 
Participants with inaccessible tumor or those participants that do not consent to the tumor biopsy procedure may be enrolled 
provided archival specimen is submitted. The archival specimen may have been obtained at any time from the time of initial 
diagnosis to time of study entry. Note: Enrollment may become limited during the study, as required, to ensure collection of fresh 
tissue samples as noted. 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; β-hCG = β -human chorionic gonadotropin; CKD-EPI = chronic kidney disease epidemiology 
collaboration; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG PS = Eastern Cooperative Oncology Group 
performance status; eCRF = electronic case report form; IHC = Immunohistochemistry; IWRS = interactive web response system; MRI = magnetic resonance imaging; MUGA = 
multi-gated acquisition; SAE = serious adverse event.  
 


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Table 12 
Schedule of Activities – Treatment Period: Standard of Care Arm 1: Docetaxel Alone 
On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted (Visits occur once every 3 weeks during treatment period) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
1. Once determined to be eligible, participants must be 
randomized via IWRS. Drug shipments will be managed via 
IWRS. Sites must allow up to 7 business days for shipment of 
study drug. Randomization can be done prior to Day 1, but no 
more than 3 days prior to Day 1. (Refer to SRM). 
Study treatments1 
Part 2 ONLY 
Docetaxel/SOC arm2 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
2. For those participants randomized to the SOC arm – 
docetaxel can be discontinued after 6 cycles as according to 
local prescribing information. Participants should receive 
premedication prior to receiving docetaxel as per local 
standards. 
On Treatment Safety  
AE/SAE/AESI 
Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3. After the initial AE/SAE report, the investigator is required to 
proactively follow each participant at subsequent visits/contacts. 
All SAEs and non-serious AESIs will be followed until the event 
is resolved, stabilized, otherwise explained, or the participant is 
lost to follow-up. 
ECOG PS** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. the 
first Q6W visit is Week 31, then Week 37, etc.). 
Physical Examination** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
** Physical examinations and ECOG may be performed within 
one day of dosing (i.e., as opposed to the day of dosing), if 
necessary.  
Vital Signs and Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Vital signs include blood pressure, temperature, pulse, 
respiratory rate, and oxygen saturation. Weight is to be recorded 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted (Visits occur once every 3 weeks during treatment period) 
at every other treatment visit in kilograms. Vital signs are to be 
performed predose on treatment days. 
On Treatment Local Laboratory Assessments (Safety) – assessments may be performed up to 3 days prior to treatment 
Serum β-hCG (for women 
of childbearing potential)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5. Monthly urine pregnancy testing may also be performed as 
consistent with local standards however if a urine test is positive 
or borderline, or in the event of a missed menstrual period or 
suspicion of pregnancy, a serum β-hCG test will be required. 
Clinical Chemistry, 
Hematology, 
Coagulation6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6. Refer to Appendix 3 for a complete list of required 
assessments. Laboratory testing may be performed one day 
prior to dosing if necessary. Not required to be tested on Day 1 if 
screening labs are within 72 hours from time of scheduled first 
dose.  
Thyroid function tests 
 
 
X 
 
X 
 
X 
 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. the 
first Q6W visit is Week 31, then Week 37, etc.). 
Calculated CrCl7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. 
Either formula is acceptable and must be consistently utilized for 
each participant throughout the study. See Appendix 9. 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted (Visits occur once every 3 weeks during treatment period) 
On Treatment Disease Assessments 
Tumor Imaging/Response 
Assessment8 
 
 
X 
 
X 
 
X 
 
X 
X8 
8. Diagnostic quality CT scan of chest and abdomen with 
contrast is required every 6 weeks (±1 week) until Week 49 and 
every 12 weeks thereafter. Imaging/clinical assessments should 
be performed as indicated in Section 9.2. The same method of 
assessment is required throughout the study. Brain scan (MRI 
with and without IV gadolinium) and bone scan to be performed 
as clinically indicated during the treatment period. If a participant 
has achieved a PD, CR, or PR in the previous radiologic 
assessment, a repeat scan should be performed after at least 4 
weeks to confirm the response.  
On Treatment Patient-Reported Outcomes/Health-Related Quality of Life: completed in Part 2 ONLY 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted (Visits occur once every 3 weeks during treatment period) 
 
 
 
 
On Treatment Biomarkers 
On Treatment Tumor biopsies 
Fresh tumor tissue 
sample13 
 
 
X 
 
 
 
X13 
 
 
 
 
13. At least 20 participants in the SoC arm will have paired fresh 
tumor biopsies collected at Screening (prior to randomization) 
and Week 7 (±8 days). If tumor is amenable to biopsy and upon 
patient consent. 
Additional optional fresh tumor tissue sample will be collected at 
Week 19 at the time of imaging assessment and at the time of 
confirmed PR or PD (± 8 days), upon participant consent. Note: 
Enrollment may become limited during the study, as required, to 
ensure collection of fresh tissue samples as noted. 
On Treatment Pharmacokinetics  
Plasma SoC PK14 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
14. Draw sample  at: predose on Day 1 only; at end of SoC 
infusion (within 5 minutes) for all marked visits; and draw an 
additional sample between 2 and 5 hours after end of SoC 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted (Visits occur once every 3 weeks during treatment period) 
infusion for all marked visits. There is a +5 minute window 
allowance for the EOI time points. 
PK samples do not need to be collected after docetaxel cycles 
have been completed. 
On Treatment Pharmacogenetics 
Genetic research 15 
X 
 
 
 
 
 
 
 
 
 
 
15. Informed consent for optional genetic research must be 
obtained before collecting this sample. It is recommended that 
the optional research sample  be taken at the first opportunity 
after a participant has met all eligibility requirements before Day 
1 or on Day 1. 
Abbreviations: ; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CKD-EPI = Chronic kidney disease epidemiology 
collaboration; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = 
Eastern Cooperative Oncology Group performance status; EOI = End of infusion; 
 
 
r; IRR = infusion related reaction; 
 
 PD = Progressive Disease; 
; PR = Partial response; Pre = Predose; 
 
 
 SAE = Serious adverse event. 
Pre: predose sample to be collected prior to dosing per institutional guidance, as long as it is collected prior to dosing of the corresponding agent; EOI: End of infusion sample is in 
reference to EOI of the corresponding agent. 
 
 
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Table 13 
Schedule of Activities – Treatment Discontinuation Visit (TDV) and Follow-Up: Standard of Care Arm 1: Docetaxel 
Alone 
TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
+ 10 days 
 
 
Anticancer Treatment 
 
X* 
*If the participant dies before the first follow up, any subsequent anticancer therapy or radiotherapy should be 
recorded in the eCRF. 
 
*Follow up for survival will no longer be required once 85 events are reached for this arm. 
Concomitant 
Medications 
X 
 
 
TDV and Follow Up Safety 
AE/SAE/AESI 
Assessment2 
X 
 
2. After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. Refer to Section 9.4.1 and Section 9.4.3 for further details. 
ECOG PS 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs and Weight3 
X 
 
3. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. 
TDV and Follow Up Local Laboratory Assessments 
Clinical Chemistry  
X 
 
 
Serum β-hCG (for 
women of childbearing 
potential) 
X 
 
 
Hematology 
X 
 
 
Thyroid function tests 
X 
 
 
Calculated CrCl 
X 
 
Urinalysis 
X 
 
TDV and Follow Up Disease Assessments 
Tumor 
Imaging/Response 
Assessment4 
X 
 
4. At the TDV, CT scan is required only if the last disease assessment did not show PD and was performed ≥6 
weeks before TDV. For participants who discontinue study treatment without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor imaging using the 
same imaging schedule used while on treatment until the start of a new anticancer treatment, disease 


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TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
+ 10 days 
 
 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. See 
additional information in Section 9.3.1  
Telephone call for 
survival status1a 
 
X 
 
TDV and Follow Up Tumor Biopsies 
Fresh tumor tissue 
sample 
X5 
 
5. If possible and upon participant consent, obtain an optional tumor tissue sample at time of confirmed PD or 
PR. 
TDV and Follow Up Patient-Reported Outcomes/Health-Related Quality of Life 
 
 
 
 
 
 
 
 
 
TDV and Follow Up Biomarkers 
Abbreviations: AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CR = complete response; CrCl = Creatinine 
clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology Group performance status; 
eCRF = Electronic case report form; 
 
 
; PD = Progressive Disease;
 
 PR = Partial response; 
 
; SAE = Serious adverse event; TDV = Treatment Discontinuation Visit 
1. The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to the 
start of subsequent anticancer therapy. If participant attends clinic for scheduled visit and decision is made to discontinue treatment, site can use this visit as the TDV and complete all 
assessments. 
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1a. Survival Follow-Up is the Observational Phase of the study. Participants will be followed for survival and subsequent anticancer therapy every 12 weeks after the last dose of study 
treatment, via telephone contact. Participants will be contacted every 12 weeks (±7 days) until death or participant’s withdrawal from further contact. Subsequent anticancer treatment 
and death date will be documented in the eCRF 
 


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12.1.1.3. 
Study Treatment 
Table 14 
Description and Administration of Docetaxel 
Name 
Docetaxel 
Description 
Microtubule stabilizer 
small molecule 
Dosage form/strength 
Refer to package insertb,c  
Dosage 
75 mg/m2 
Route of administration 
IV infusion 
Dosing instructionsa/frequency 
Administer diluted product/once Q3W 
a. 
Refer to the Study Reference Manual for detailed instructions on dosage and administration requirements. 
b. 
TAXOTERE PI, 2020; TAXOTERE SmPC, 2020. 
c. 
Docetaxel will be sourced locally from commercial stock, except in countries where regulatory authorities mandate 
that the Sponsor supply all study treatment(s) required for the conduct of a clinical trial. 
All participants randomly assigned to docetaxel-containing arms should be premedicated 
with oral corticosteroids (such as dexamethasone 16 mg per day or its equivalent) per 
local standards (e.g., 8 mg twice daily) for 3 days starting 1 day prior to docetaxel 
administration to reduce the incidence and severity of fluid retention as well as the 
severity of hypersensitivity reactions [TAXOTERE PI, 2020; TAXOTERE SmPC, 2020]. 
Intravenous corticosteroid premedication may also be utilized per local standard and at 
the discretion of the investigator.  
Docetaxel should be given for 6 cycles and may be discontinued after 6 cycles at the 
discretion of the investigator.  
The SRM will contain details on product handling, storage, preparation, and 
administration. Docetaxel will be administered according to the package insert and/or 
local standard. 
12.1.1.4. 
Dose Justification 
The dosage of docetaxel for this study, as a single agent and in combination, will be 
75mg/m2 Q3W, as described in the labels [TAXOTERE PI, 2020; TAXOTERE SmPC, 
2020] which is approved (a) as a single-agent for patients with locally advanced or 
metastatic NSCLC after platinum-based chemotherapy, and (b) in combination with 
cisplatin for unresectable, locally advanced or metastatic NSCLC for patients who have 
not received prior chemotherapy. 
12.1.1.5. 
Treatment of Overdose 
In the event of docetaxel overdose, refer to the instructions in the approved product label. 
Contact the Medical Monitor immediately and closely monitor the participant for AEs. 


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12.1.2. 
Substudy 1 (Arm 2): Feladilimab and Docetaxel Combination 
12.1.2.1. 
Protocol Amendment 5 Summary of Changes Specific to Feladilimab 
and Docetaxel Combination  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.2.2 
Added footnote to TDV 
SoA for survival follow up 
requirements 
To remove the survival 
follow up requirement for 
Substudy 1 when 85 events 
are reached as this will 
trigger final analysis   
 
Protocol Amendment 3 Summary of Changes Specific to Feladilimab and Docetaxel 
Combination  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.1.2 
Added Schedule of 
Activities specific to 
docetaxel only treatment. 
To provide individual 
specific Schedule of 
Activities Table specific to 
standard of care arm in Part 
2. 
Clinical Safety Summary 
Section 12.1.2.4.1, 
GSK3359609 PK/PD 
Summary Section 
12.1.2.5.1, GSK3359609 
Dose Rationale Section 
12.1.2.5.2 
Updated safety and PK/PD 
for GSK3359609. 
To align with 
GSK3359609 IB update 
version 5 and recent 
clinical data. 
 
 


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Protocol Amd 10 
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12.1.2.2. 
Schedule of Activities Specific to Feladilimab and Docetaxel Combination (Substudy 1) 
Table 15 
Schedule of Activities – Screening: Substudy 1 (Arm 2): Feladilimab and Docetaxel Combination 
Screening Study 
Assessment 
Screening1  
Notes 
Visit Window 
≤4 Weeks 
 
Informed Consent1 
X 
1. All screening assessments must be performed within 4 weeks (28 days) prior to first dose of study treatment unless otherwise 
specified. The informed consent may be signed within 45 days prior to first dose. 
 
Participant Registration2 
X 
2. Participants will be registered in RAMOS NG at screening. 
Inclusion/Exclusion Criteria12 
X 
12. All known mutations should be entered in the eCRF as disease history. 
Demographics, Medical History 
(including tobacco use), Prior 
Medications, Disease History 
X 
 
Anticancer Treatment 
X 
Screening Safety 
AE/SAE/AESI Assessment3 
X 
3. After the initial AE/SAE report, the investigator is required to proactively follow each participant at subsequent visits/contacts. 
All SAEs and non-serious AESIs will be followed until the event is resolved, stabilized, otherwise explained, or until the participant 
is lost to follow-up. 
ECOG PS 
X 
 
Physical Examination 
X 
 
Vital Signs, Height and Weight4 
X 
4. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. Height is recorded at Screening 
only. Record weight in kilograms. 
12-lead ECG 
X 
 
Echocardiogram or MUGA 
scan5 
X 
5. ECHO required at Screening within 28 days prior to first dose of study treatment, and during treatment phase if clinically 
indicated. MUGA scan may be used if ECHO not feasible.  
Screening Local Laboratory Assessments (Safety) 
Hepatitis B and C6 
X 
 
Serum β-hCG (for women of 
childbearing potential) 
≤3d 
Clinical Chemistry6, 
Coagulation6, Hematology6, 
Thyroid function6 
X 
6. Refer to Appendix 3 for a complete list of required assessments. Laboratory testing performed within 14 days of first dose of 
study intervention does not need to be repeated unless clinically indicated. If Hepatitis B and C testing was performed within 3 
months prior to first dose of study intervention or SoC, repeat testing at screening is not required; otherwise, this testing is 
mandatory. 
Calculated CrCl7 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. See Appendix 9. 


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Screening Study 
Assessment 
Screening1  
Notes 
Visit Window 
≤4 Weeks 
 
Troponin I or Troponin T 
X 
 
Urinalysis6 
X 
 
Screening Other Laboratory Assessments 
PD-L1 expression by IHC8 
X 
8. PD-L1 expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, Dako 28-8, or Dako 22C3) must be 
recorded in the eCRF, if known. Note: Test is not required to be performed by the site if not previously performed. 
Screening Disease Assessments 
Tumor Imaging9 
X 
9. Diagnostic quality CT scan of chest and abdomen with contrast must be obtained within 28 days of first dose. Baseline brain 
scan (MRI with or without IV gadolinium) should be obtained within 6 weeks of first dose if history of CNS disease or if clinically 
indicated. Bone scan should be obtained within 6 weeks of first dose if clinically indicated. See additional information regarding 
bone scans in Section 9.3.1. 
Pre-Baseline scans for Tumor 
Growth Kinetics10 
X 
10. Upon participant consent, up to 3 pre-baseline scans (within 6 months before the baseline scan) will be collected to assess 
tumor growth rate to support exploratory investigation of tumor growth kinetics (See Section 9.3.2 for details on images for 
submission). 
Screening Tumor Biopsies 
Fresh tumor tissue sample and 
Archival tumor11 
X 
11. Fresh tumor tissue sample AND an archival tissue sample obtained during screening is mandatory for at least 15 participants 
per study arm. 
Participants with inaccessible tumor or those participants that do not consent to the tumor biopsy procedure may be enrolled 
provided archival specimen is submitted. However, no participant will be allowed on study without either an archival specimen OR 
a fresh biopsy. The archival specimen may have been obtained at any time from the time of initial diagnosis to time of study entry. 
If only 10 unstained archival slides are available, participant may be considered eligible upon consultation/approval of the GSK 
Medical Monitor. Note: Enrollment may become limited during the study, as required, to ensure collection of fresh tissue samples 
as noted. 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; β-hCG = β -human chorionic gonadotropin; CKD-EPI = chronic kidney disease epidemiology 
collaboration; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG PS = Eastern Cooperative Oncology Group 
performance status; eCRF = electronic case report form; IHC = Immunohistochemistry; IWRS = interactive web response system; MRI = magnetic resonance imaging; MUGA = 
multi-gated acquisition; SAE = serious adverse event.  
 
 
 


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Protocol Amd 10 
96 
Table 16 
Schedule of Activities – Treatment Period: Substudy 1 (Arm 2): Feladilimab and Docetaxel Combination 
On Treatment Study 
Assessment 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
1. Once determined to be eligible, participants must be 
randomized via IWRS. Drug shipments will be managed via 
IWRS. Sites must allow up to 7 business days for shipment of 
study drug. 
Study treatments1 
Administer Feladilimab 
(GSK3359609)* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
Q3W 
*Feladilimab (GSK3359609) must be administered first. 
Administration of Docetaxel must be started 1 hour and no more 
than 2 hours after the end of feladilimab (GSK3359609) infusion. 
Docetaxel2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W2 
Q3W2 
2. Docetaxel will be administered according to the package 
insert and/or local standard. 
Chemotherapy premedication indicated on the day of dosing 
should be administered after feladilimab (GSK3359609) EOI. 
On Treatment Safety  
AE/SAE/AESI 
Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3. After the initial AE/SAE report, the investigator is required to 
proactively follow each participant at subsequent visits/contacts. 
All SAEs and non-serious AESIs will be followed until the event 
is resolved, stabilized, otherwise explained, or the participant is 
lost to follow-up. 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. the 
first Q6W visit is Week 31, then Week 37, etc.). 
Physical Examination** 
X 
 
 
X 
 
 
X 
X 
X 
Q6W* 
Q6W* 
** Physical examinations may be performed within one day of 
dosing (i.e., as opposed to the day of dosing), if necessary. 
Vital Signs and Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Vital signs include blood pressure, temperature, pulse, 
respiratory rate, and oxygen saturation. Weight is to be recorded 


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On Treatment Study 
Assessment 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
at every other treatment visit in kilograms. Vital signs are to be 
performed predose on treatment days. 
On Treatment Local Laboratory Assessments (Safety) – assessments may be performed up to 3 days prior to treatment 
Serum β-hCG (for women 
of childbearing potential)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5. Monthly urine pregnancy testing may also be performed as 
consistent with local standards however if a urine test is positive 
or borderline, or in the event of a missed menstrual period or 
suspicion of pregnancy, a serum β-hCG test will be required. 
Clinical Chemistry, 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6. Refer to Appendix 3 for a complete list of required 
assessments. Laboratory testing performed within 14 days of 
first dose does not need to be repeated unless clinically 
indicated. Laboratory testing may be performed one day prior to 
dosing if necessary. 
Thyroid function tests 
 
 
X 
 
X 
 
X 
 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. the 
first Q6W visit is Week 31, then Week 37, etc.). 
Calculated CrCl7 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. 
Either formula is acceptable and must be consistently utilized for 
each participant throughout the study. See Appendix 9. 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
On Treatment Disease Assessments 
Tumor Imaging/Response 
Assessment8 
 
 
X 
 
X 
 
X 
 
X 
X8 
8. Diagnostic quality CT scan of chest and abdomen with 
contrast is required every 6 weeks (±1 week) until Week 49 and 
every 12 weeks thereafter, until disease progression is 
confirmed by iRECIST. The same method of assessment is 
required throughout the study. Brain scan (MRI with or without IV 
gadolinium) and bone scan to be performed as clinically 
indicated during the treatment period. If a participant has 
achieved a PD, CR, or PR in the previous radiologic 
assessment, a repeat scan should be performed after at least 4 
weeks to confirm the response. See additional information in 
Section 9.3.1. 


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On Treatment Study 
Assessment 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Patient-Reported Outcomes/Health-Related Quality of Life 
On Treatment Biomarkers 
On Treatment Tumor biopsies 
Fresh tumor tissue 
sample 
 
 
X 
 
 
 
X13 
 
 
 
 
13. At least 15 participants per treatment arm will have paired 
fresh tumor biopsies collected at Screening (prior to 
randomization) and Week 7 (± 8 days), if tumor is amenable to 
biopsy and upon participant consent.  
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On Treatment Study 
Assessment 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Additional optional fresh tumor tissue sample will be collected at 
Week 19 at the time of imaging assessment and at the time of 
confirmed PR or PD (± 8 days), upon participant consent. Note: 
Enrollment may become limited during the study, as required, to 
ensure collection of fresh tissue samples as noted. 
On Treatment Pharmacokinetics and Anti-Drug Antibodies (ADA) 
Plasma SoC PK14 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
14. For Arm 1 and Arm 2: Draw sample (2 mL) at: predose on 
Day 1 only; at end of SoC infusion (within 5 minutes) for all 
marked visits; and draw an additional sample between 2 and 5 
hours after end of SoC infusion for all marked visits. There is a 
+5 minute window allowance for the EOI time points. 
Plasma Feladilimab 
(GSK3359609; ICOS 
Agonist) PK15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X15 
15. For Arm 2 only: Draw sample (2 mL) at predose for all 
marked visits. Additional samples also drawn at the following 
time points: Week 1 (Day 1) at end of infusion (EOI) (within 5 
minutes) and EOI+4h. EOI samples also drawn at Week 13 and 
Week 25. After Week 25, draw samples every 12 weeks at 
predose only. There is a +5 minute window allowance for the 
EOI time points. 
Serum Feladilimab 
(GSK3359609; ICOS 
Agonist) ADA16 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
16. For Arm 2 only: Draw sample (4 mL) at predose on ALL 
treatment visits; then starting with Week 25 predose samples to 
be collected every 12 weeks. Draw a sample at any time during 
visit for non-treatment visits. For participants with a positive ADA 
result at last regular visit an additional sample will be drawn at 6 
months after the last dose. 
Serum samples will be collected and tested for the presence of 
antibodies that bind to investigational agents as deemed 
appropriate. Feladilimab serum samples may also be tested for 
presence of antibodies that bind to Chinese Hamster Ovary 
(CHO) host cell proteins such as phospholipase B- like (PLBL2). 


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On Treatment Study 
Assessment 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Serum: IRR lab panel17 
 
 
 
 
 
 
 
 
 
 
 
17. Assessment ONLY required in participant experiencing 
anaphylaxis, serious hypersensitivity, or AEs related to study 
treatment administration that led to withdrawal from the study. 
Refer to Table 3 for list of analytes. Predose analysis will be 
performed on the serum sample collected for feladilimab 
(GSK3359609) immunogenicity assessments. 
On Treatment Pharmacogenetics 
Genetic research18 
X 
 
 
 
 
 
 
 
 
 
 
18. Informed consent for optional genetic research must be 
obtained before collecting this sample. It is recommended that 
the optional research sample) be taken at the first opportunity 
after a participant has met all eligibility requirements before Day 
1 or on Day 1. 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CKD-EPI = Chronic 
kidney disease epidemiology collaboration; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = End of infusion; 
 
 
 IRR = infusion related reaction; 
 
; PD = Progressive Disease;
; PR = 
Partial response; 
 
 SAE = Serious adverse event. 
 
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Table 17 
Schedule of Activities – Treatment Discontinuation Visit (TDV) and Follow-Up: Substudy 1 (Arm 2): Feladilimab 
and Docetaxel Combination 
TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
+ 10 days 
 
 
Anticancer Treatment 
 
X* 
*Follow up for survival will no longer be required once 85 events are reached for this arm. 
Concomitant 
Medications 
X 
 
 
TDV and Follow Up Safety 
AE/SAE/AESI 
Assessment2 
X 
 
2. 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 will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up. 
ECOG PS 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs and Weight3 
X 
 
3. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. 
TDV and Follow Up Local Laboratory Assessments 
Clinical Chemistry  
X 
 
 
Serum β-hCG (for 
women of childbearing 
potential) 
X 
 
 
Hematology 
X 
 
 
Thyroid function tests 
X 
 
 
Calculated CrCl 
X 
 
Urinalysis 
X 
 
TDV and Follow Up Disease Assessments 
Tumor 
Imaging/Response 
Assessment4 
X 
 
4. At the TDV, CT scan is required only if the last disease assessment did not show PD and was performed ≥6 
weeks before TDV. 
Telephone call for 
survival status1a 
 
X* 
*Follow up for survival will no longer be required once 85 events are reached for this arm. 
TDV and Follow Up Tumor Biopsies 
Fresh tumor tissue 
sample 
X5 
 
5. If possible, obtain an optional tumor tissue sample at time of confirmed PD or PR. 


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TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
+ 10 days 
 
 
TDV and Follow Up Patient-Reported Outcomes/Health-Related Quality of Life 
 
 
 
 
 
 
 
 
 
 
 
TDV and Follow Up Biomarkers 
Abbreviations: AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CR = complete response; CrCl = Creatinine 
clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology Group performance status; 
eCRF = Electronic case report form; 
 
 
; PD = Progressive Disease; 
 
 PR = Partial response; 
 
; SAE = Serious adverse event; TDV = Treatment Discontinuation Visit 
 
1. The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to the 
start of subsequent anticancer therapy. 
1a. Survival Follow-Up is the Observational Phase of the study. Participants will be followed for survival and subsequent anticancer therapy every 12 weeks after the last dose of study 
treatment, via telephone contact. Participants will be contacted every 12 weeks (±7 days) until death or participant’s withdrawal from further contact. Subsequent anticancer treatment 
will be documented in the eCRF. 
 
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12.1.2.3. 
Study Treatments 
Table 18 
Description and Administration of Arm 2 Study Treatments 
Name 
Docetaxel 
Feladilimab (GSK3359609; 
ICOS Agonist) 
Description 
Microtubule stabilizer 
small molecule 
Humanized anti-ICOS IgG4 
mAb 
Dosage form/strength 
Refer to package inserta 
Solution for injection/ 
10 mg/mL  
Dosage 
75 mg/m2 
80 mg 
Route of administration 
IV infusion 
IV infusionb 
Dosing instructionsa/frequency 
Administer diluted 
product/once Q3W 
Administer diluted 
product/once Q3W 
a. 
TAXOTERE PI, 2020; TAXOTERE SmPC, 2020 
d. 
The study reference manual contains the details on product handling, storage, preparation, and administration. 
In feladilimab (ICOS Agonist)-containing arms, feladilimab will be administered first as 
a 30-minute IV infusion (infusion time may be adjusted based on infusion related 
reactions). The administration of the second agent in these arms must be started 1 hour 
and no more than 2 hours after the end of feladilimab infusion. Chemotherapy 
premedication indicated on the day of dosing should be administered after feladilimab 
EOI. Docetaxel will be administered according to the package insert and/or local 
standard. Participants should remain under observation at the study site post-study 
treatment infusion per the judgement of the investigator or as per institutional guidelines 
to monitor for potential infusion reactions or other adverse events.  
12.1.2.4. 
Rationale for ICOS Agonist/Docetaxel Combination 
Cancer immunity is described as a multistep process that elicits 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 are 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. Robust antitumor responses including complete cure have been achieved in some 
cancers by modulating the patient’s immune system. Antibodies targeting the checkpoint 
receptors or their cognate ligands engaged in negative regulation of T cell responses, such 
as CTLA-4 and PD-1/PD-L1, have demonstrated efficacy as anticancer immunotherapies 
in a broad range of tumors including some solid tumors otherwise considered poorly 
immunogenic. 
However, a majority of tumors are non-responsive to this class of agents. One reason for 
the lack of response could be the existence of multiple mechanisms of immune 
suppression in the tumor microenvironment which prohibits 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]. 
In some patients, inhibition of negative immune checkpoint pathways alone may not 
elicit an effective antitumor response, and additional co-stimulatory signals may be 


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necessary to mount an effective response. 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. The ultimate aim is to improve the 
survival outcome in all disease settings including the advanced setting. 
Feladilimab is a humanized IgG4 anti-ICOS monoclonal antibody [Mayes, 2018] selected 
for its nanomolar (nM) binding to and agonist activity in ICOS-expressing CD4+ and 
CD8+ effector T cells. Feladilimab is specifically engineered as an Immunoglobulin 
(Ig)G4 hinge-stabilized isotype, IgG4PE, to markedly decrease binding affinity of the Fc 
(Fragment crystallizable) region of the mAb to activating Fcγ receptors and C1q, and 
thereby diminish the cytotoxic potential of feladilimab 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 of the CD28/CTLA immunoglobulin super family with 
expression restricted to T cells [Horn, 2018]. ICOS is weakly expressed on resting TH17, 
follicular helper T and regulatory T (Treg) cells and yet is highly induced on CD4+ and 
CD8+ T cells upon T cell receptor (TCR) engagement and activation [Parmar, 1998, 
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. 
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]. 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] and 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 
confer an advantage by mounting a more robust immune antitumor response. 
Similar to the combination of platinum-containing chemotherapy with immuno-oncology 
agents (anti-PD-1) in metastatic non-squamous disease, i.e., the incorporation of the anti-
PD-1 inhibitor, pembrolizumab, to the pemetrexed/carboplatin backbone in the first-line 


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metastatic non-squamous disease is an example for the IO agents to provide a higher 
degree of benefit including a prolonged benefit combined with the immediate cytotoxic 
effects of the chemotherapy. The ICOS agonist/docetaxel combination has the potential 
to deliver a similar promise to later line NSCLC participants building on the existing 
docetaxel standard of care.  
Chemotherapy can promote tumor immunity by inducing immunogenic cell death as part 
of its intended therapeutic effect, as well as modulating distinct features of tumor 
immunobiology [Emens, 2015]. In preclinical models, combinations with various 
chemotherapy agents including docetaxel and platinum-based treatments with anti-PD-L1 
treatment showed increased efficacy associated with increased frequency of intratumoral 
subsets without antagonizing functional changes mediated by anti-PD-L1 [Cubas, 2016]. 
Combination of anti-ICOS surrogate antibody with carboplatin and paclitaxel showed 
some increase efficacy in the CT26 tumor model [Kilian, 2017a; Kilian, 2017b; Kilian, 
2017c; Kilian, 2017d]. 
12.1.2.4.1. Clinical Safety Summary 
As of the feladilimab Investigator Brochure data cutoff date of 16 March 2020, 249 
participants received at least 1 dose of monotherapy feladilimab in study 204691 at the 
following dose levels: 0.001 mg/kg (n=1), 0.003 mg/kg (n=1), 0.01 mg/kg (n=2), 0.03 
mg/kg (n=7), 0.10 mg/kg (n=25), 0.30 mg/kg (n=56), 1.0 mg/kg (n=126), 3.0 mg/kg 
(n=24), and 10 0 mg/kg (n=7). In these 249 participants, the most common AEs 
(occurring in 15% of participants overall regardless of dose level or relationship) were 
anemia (22%), asthenia (21%), nausea (19%), fatigue (18%), diarrhea (16%), and 
vomiting (15%).  
In study 204691, 10 participants received at least 1 dose of feladilimab 80 mg in 
combination with docetaxel 75 mg/m2 once every 3 weeks (safety cohort), 9 participants 
(90%) experienced at least 1 ≥Grade 3 AE, 2 of whom experienced Grade 5 events: 1 
participants had Grade 5 aspiration pneumonia and the other participant had Grade 5 
methicillin-resistant staphylococcus aureus (MRSA) chest infection and Grade 5 lower 
respiratory infection. Seven participants (70%) experienced at least 1 serious adverse 
event (SAE) of Grade 3; Grade 3: fatigue, dyspnea (1 event), hyponatremia, aspiration 
pneumonia, respiratory failure, hypotension, and diarrhea Grade 5: aspiration pneumonia, 
lower respiratory tract infection and staphylococcal infection. The Grade 5 events were 
reported in 2 participants (1 participant with aspiration pneumonia; 1 participant with 
lower respiratory tract infection and staphylococcal infection); the 3 events were not 
considered related to study treatment and the primary cause of death in both cases was 
sepsis.  
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  
 


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12.1.2.5. 
Dose Justification (Substudy 1) 
12.1.2.5.1. Feladilimab Pharmacokinetics and Pharmacodynamics Summary 
The PK of feladilimab was evaluated after 30 minutes of IV infusion at doses from 0.001 
mg/kg to 10.0 mg/kg every 3 weeks (Q3W) in participants with solid tumors in Study 
204691. The plasma PK samples (received prior to the 2020 IB update cutoff date of 16 
March 2020) were analyzed with a validated bioanalytical method with a lower limit of 
quantitation (LLOQ) of 0.1 µg/mL. 
As of 16 March 2020, preliminary PK data in monotherapy cohorts were available in 1 
participant at 0.003 mg/kg, 2 participants at 0.01 mg/kg, 7 participants at 0.03 mg/kg, 25 
participants at 0.1 mg/kg, 52 participants at 0.3 mg/kg, 123 participants at 1.0 mg/kg, 23 
participants at 3.0 mg/kg, and 7 participants at 10.0 mg/kg dose. Preliminary PK data in 
pembrolizumab combination cohorts were available in 5 participants at 0.01 mg/kg, 
5 participants at 0.03 mg/kg, 13 participants at 0.1 mg/kg, 244 participants at 0.3 mg/kg, 
38 participants at 1.0 mg/kg, and 18 participants at 3.0 mg/kg dose. Preliminary PK data 
in GSK3174998 combination cohorts were available in 5 participants each at 8 and 24 mg 
and 1 participant at 80 mg fixed dose. Preliminary PK data in chemotherapy combination 
cohorts of the safety run-in were available in 55 participants at 80 mg fixed dose of 
feladilimab.  
Based on these preliminary data, the median plasma concentration-time profiles of 
feladilimab exhibit a bi-exponential decline. There are no changes in GSK3359609 PK 
when co-administered at doses from 0.01 to 3.0 mg/kg with biologic or chemotherapy 
partners. Furthermore, median feladilimab plasma PK profiles after dosing at 8, 24, and 
80 mg fixed doses were superimposable to the median PK profiles observed with 0.1, 0.3, 
and 1.0 mg/kg doses. Preliminary plasma PK parameters of feladilimab computed using 
noncompartmental analysis methods (AUC, C, and Cmax) calculated over the first dosing 
interval (up to 503 hours) exhibit approximate dose proportional increases in feladilimab 
exposure over the range of 0.01 to 10.0 mg/kg doses. Observed exposures (AUC and C) 
from body-weight based dose of 1.0 mg/kg (combined monotherapy and combination 
cohorts) and corresponding fixed dose equivalent of 80 mg (chemotherapy safety run-in) 
overlap with each other, indicating similar exposures can be achieved with a fixed dosing 
regimen. Preliminary population PK estimated geometric mean systemic half-life (t1/2) of 
feladilimab is approximately 19 days.  
Based on the preliminary data, median CD4 and CD8 receptor occupancy (RO) was 
maintained at or above 70% during the dosing interval of first cycle for doses 0.3 mg/kg 
as shown in Figure 7.  
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  
 


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Figure 7 
Median CD4+ and CD8+ Receptor Occupancy (%RO) During the First 
Cycle of Feladilimab Administration as Monotherapy 
 
Feladilimab Dosing Frequency 
The systemic half-life of feladilimab is approximately 19 days based on the preliminary 
population PK analysis of data from ongoing study 204691. The existing feladilimab 


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Q3W regimen in the ongoing clinical study is also consistent with the Q3W dosing 
regimen typical with other IgG4 based monoclonal antibody therapies. The docetaxel 
label prescribes a Q3W regimen. Thus, feladilimab will be dosed Q3W in combination 
with docetaxel. Combination of feladilimab with any other treatment in other arms of this 
study may have a different dosing regimen as deemed appropriate.  
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 all or even a majority of observed 
variability in the exposure of monoclonal antibodies [Zhao, 2017]. Hence, the selection 
of body-weight based versus fixed dosing in this study was evaluated through population 
PK modelling and simulation efforts.  
A preliminary population PK model (N = 637 participants; March 2020), which 
characterized the influence of body weight, age, and other participant covariates on 
exposure was developed. Results of this analysis indicate a feladilimab fixed dose is 
appropriate for trial participants across the bodyweight spectrum. Simulations show a 
feladilimab body weight-based dose results in slightly higher exposure in heavier weight 
participants and a feladilimab fixed dose results in slightly higher exposures in lighter 
participants. However, the range of exposures are similar between body-weight based and 
fixed dosing across the entire body weight spectrum and the exposures are maintained 
well within established clinical boundaries of safety at doses in the range of 24 to 80 mg 
Q3W (the highest studied dose in monotherapy deemed tolerable was 10 mg/kg or ~800 
mg). This suggests that there is no advantage of body-weight based dosing over fixed 
dosing and that lighter patients will not be more susceptible to treatment-related adverse 
events arising from marginal increases in exposure.  
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, a feladilimab 
fixed dose for Substudy 1 based on a reference body weight of 80 kg is reasonable and 
appropriate. 
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  
12.1.2.5.2. Feladilimab Dose Rationale (Substudy 1) 
Based on the preliminary PK data described above in Section 12.1.2.5.1 and target 
engagement shown in Figure 7, median CD4 and CD8 receptor occupancy was 
maintained at or above 70% during the dosing interval of first cycle for doses ≥0.3 
mg/kg. 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 the proposed 80 mg 
dose in substudy 1. 


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Collectively, based on the safety and exposure data from the Phase 1 study and the 
predicted target engagement, the 80-mg dose will be evaluated in combination with 
docetaxel in this study. No drug-drug interaction related changes are expected in 
feladilimab PK with docetaxel co-administration. The currently planned 80 mg 
feladilimab dose may be adjusted lower to 24 mg or increased to 240 mg based on any 
emerging safety, exposure and/or pharmacodynamic data. 
12.1.2.5.3. Docetaxel Dose Rationale 
Docetaxel is a semisynthetic taxane approved in different tumor indications. The dosage 
of docetaxel as a single agent and in combination for several tumor indications, including 
NSCLC and HNSCC, is 75 mg/m2, every three weeks; thus, this dose and schedule was 
selected in combination with feladilimab. There are no drug-drug interaction related 
changes expected in docetaxel PK on co-administration with feladilimab. 
12.1.2.6. 
Treatment of Overdose 
An overdose is defined as administration of a dose that is at least 50% greater than the 
intended dose. In the event of an overdose, the investigator must: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 130 days. 
3. Obtain a plasma sample for PK analysis within 28 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).  
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.  
There is no specific antidote for overdose with the experimental treatments being 
evaluated in this study. 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.  
 


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12.1.3. 
Arm 3: Feladilimab and Ipilimumab Combination 
12.1.3.1. 
Protocol Amendment 5 Summary of Changes Specific to Feladilimab 
and Ipilimumab Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.3.2 
Added footnote to SoAs (on-
treatment and TDV) for 
biomarker, PK, and ADA 
samples SoA  
To align with decision to no 
longer collect samples from 
participants in this arm  
Schedule of Activities 
Section 12.1.3.2 
Added footnote to TDV SoA 
for survival follow up 
requirements 
To remove the survival follow 
up requirement for this arm   
Dose Modification and 
Management 
Guidelines Section 
12.1.3.10 
Moved dose modification 
guidelines to this section 
from the master protocol  
To include the dose 
modification guidelines 
specific to the regimen in this 
arm  
Safety Evaluation 
Section 12.1.3.11 
Moved Part 1 Analysis text 
from master protocol  
To avoid duplication and 
better clarify the analysis for 
this arm 
Risk-benefit Section 
12.1.3.14 
Moved risk management and 
mitigation strategy to this 
section from the master 
protocol  
To include risk management 
and mitigation strategy 
specific to the regimen in this 
arm  
 
Protocol Amendment 4 Summary of Changes Specific to Feladilimab and 
Ipilimumab Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.3.2 
Added physical exam for 
dosing visits. 
As this is a new combination 
being tested, decision was 
made to require a physical 
exam at every dosing visit. 
Schedule of Activities 
Section 12.1.3.2 
Time window for plasma 
feladilimab end of infusion 
PK was extended from 5 
min to 15 min 
To allow the site a longer time 
window to collect the end of 
infusion PK sample 


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Schedule of Activities 
Section 12.1.3.2 
Removed details on number 
of slides for tissue sample to 
be sent by site. 
Decided this detail should be 
included in the SRM instead 
and was removed from 
protocol. 
Schedule of Activities 
Section 12.1.3.2 
Added creatinine clearance 
to screening assessments 
To correct the omission of 
creatinine clearance. 
Schedule of Activities 
Section 12.1.3.2 
At the follow up visit, 
footnote added: If the 
participant dies before the 
first follow up, any 
subsequent anticancer 
therapy or radiotherapy 
should be recorded in the 
eCRF. 
To record any subsequent 
therapy the participant may 
have received after study 
discontinuation, if they die 
before first follow up is 
completed. 
Futility Evaluation 
Section 12.1.3.12 
Clarify ipilimumab cohort 
will start at 3mg/kg dose. 
To align with study strategy. 
Schedule of Activities 
Section 12.1.3.2 
Added footnote: 
Pre: predose sample to be 
collected prior to dosing per 
institutional guidance, as 
long as it is collected prior 
to dosing of the 
corresponding agent; EOI: 
End of infusion sample is in 
reference to EOI of the 
corresponding agent. 
To clarify the sample 
collection reference for 
predose and EOI. 
Schedule of Activities 
Section 12.1.3.2 
Added in the TDV SOA:  
In the event of 
hypersensitivity reaction that 
is clinically significant 
and/or leads to study 
treatment discontinuation, an 
additional sample should be 
collected at 24 weeks post 
last dose of study treatment. 
To correct the omission of 
hypersensitivity collection of 
ADA samples at TDV and 
added sample collection for 
feladilimab. 


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12.1.3.2. 
Schedule of Activities Specific to Ipilimumab and Feladilimab Combination  
The timing and number of planned study assessments (including safety, pharmacokinetic, ADA, biomarker or other assessments) may 
be altered during the course of the study based on newly available data. 
Table 19 
Schedule of Activities – Screening: Arm 3: Ipilimumab and Feladilimab Combination 
Screening Study 
Assessments 
Screening1  
Notes 
Visit Window ≤4 Wk 
 
 
Informed Consent1 
X 
1. All screening assessments must be performed within 4 weeks (28 days) prior to first dose of study treatment unless otherwise 
specified. The informed consent may be signed within 45 days prior to first dose. 
Participant Registration2 
X 
2. Participants will be registered in RAMOS NG at screening. 
Inclusion/Exclusion Criteria 
X 
Review eligibility prior to randomization. 
Demographics, Medical History 
(incl. alcohol & tobacco use), 
Prior Medications, Disease 
History12 
X 
12. All known mutations should be entered in the eCRF as disease history. 
Prior Anticancer Treatment, 
Radiotherapy 
X 
 
Screening Safety 
AE/SAE/AESI Assessment3 
X 
3. After the initial AE/SAE report, the investigator is required to proactively follow each participant at subsequent visits/contacts. 
Refer to Section 9.4 for further details. 
ECOG PS 
X 
 
Physical Examination 
X 
 
Vital Signs, Height and Weight4 
X 
4. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. Height is recorded at Screening 
only. Record weight in kilograms. 
12-lead ECG 
X 
 
Echocardiogram or MUGA 
scan5 
X 
5. ECHO required at Screening within 28 days prior to first dose of study treatment, and during treatment phase if clinically 
indicated. MUGA scan may be used if ECHO not feasible.  


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Screening Study 
Assessments 
Screening1  
Notes 
Visit Window ≤4 Wk 
 
 
Screening Local Laboratory Assessments (Safety) 
Hepatitis B and C6 
X 
 
Serum β-hCG (for women of 
childbearing potential) 
≤3d 
Clinical Chemistry6, 
Coagulation6, Hematology6, 
Thyroid function6 
X 
6. Refer to Appendix 3 for a complete list of required assessments. Required within 7 days of randomization day. Not required to 
be tested on Day 1 if screening labs are within 72 hours from time of scheduled first dose. Must be drawn predose or up to 3 days 
prior to dosing. If Hepatitis B and C was performed within 3 months prior to first dose of study intervention or SoC, repeat testing 
at screening is not required; otherwise, this testing is mandatory. 
Calculated CrCl7 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. See Appendix 9. 
Troponin I or Troponin T 
X 
 
Urinalysis6 
X 
 
Screening Other Laboratory Assessments 
PD-L1 expression by IHC7 
X 
7. PD-L1 expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, Dako 28-8, or Dako 22C3) must be 
recorded in the eCRF, if known. Note: Test is not required to be performed by the site if not previously performed. 
Screening Disease Assessments 
 
Tumor Imaging8 
X 
8. Diagnostic quality CT scan of chest and abdomen with contrast must be obtained within 28 days of first dose. Baseline brain 
scan (MRI with and without IV gadolinium) should be obtained within 6 weeks of first dose if history of CNS disease or if clinically 
indicated. Bone scan should be obtained within 6 weeks of first dose if clinically indicated. See additional information regarding 
bone scans in Section 9.3.1. 
Pre-Baseline scans for Tumor 
Growth Kinetics9 
X 
9. Upon participant consent, up to 3 pre-baseline scans (within 12 months before the baseline scan) will be collected to assess 
tumor growth rate to support exploratory investigation of tumor growth kinetics (See Section 9.3.2 for details on images for 
submission). 


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Screening Study 
Assessments 
Screening1  
Notes 
Visit Window ≤4 Wk 
 
 
Screening Tumor Biopsies 
Fresh tumor tissue sample and 
Archival tumor10 
X 
10. Part 1: All participants are required to have tumor tissue available (archival or fresh biopsy) prior to start of study treatment. A 
fresh biopsy is required if archival tissue is unavailable. Following Part 1 initial safety evaluation (up to first 10 participants), for the 
additional participants enrolled to assess further safety as well as PK/PD, fresh tumor tissue AND archival tumor tissue samples 
at screening are required prior to start of study treatment. 
Part 2: Tumor tissue at screening (either archival or fresh biopsy if archival tissue is unavailable), is required for all participants in 
Part 2. Fresh tumor tissue at screening is required in addition to an archival tissue for at least 20 participants for this arm. 
Participants with inaccessible tumor or those participants that do not consent to the tumor biopsy procedure may be enrolled 
provided an archival specimen is submitted. The archival specimen may have been obtained at any time from the time of initial 
diagnosis to time of study entry. Note: Enrollment may become limited during the study, as required, to ensure collection of fresh 
tissue samples as noted. 
‘Abbreviations: AE = adverse event; AESI = adverse events of special interest; β-hCG = β -human chorionic gonadotropin; CKD-EPI = chronic kidney disease epidemiology 
collaboration; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG PS = Eastern Cooperative Oncology Group 
performance status; eCRF = electronic case report form; IHC = Immunohistochemistry; IWRS = interactive web response system; MRI = magnetic resonance imaging; MUGA = 
multi-gated acquisition; SAE = serious adverse event. 
 


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Table 20 
Schedule of Activities – Treatment Period: Arm 3: Ipilimumab and Feladilimab Combination 
On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
1. Once determined to be eligible, participants must be 
randomized via IWRS. Drug shipments will be managed via 
IWRS. Sites must allow up to 7 business days for shipment 
of study drug. Randomization can be done prior to Day 1, 
but no more than 3 days prior to Day 1. (Refer to SRM). 
Study treatments1 
Administer Feladilimab 
(GSK3359609)* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
*Feladilimab (GSK3359609) must be administered within 
±3 days of scheduled visit unless otherwise indicated. 
Refer to Section 5.2 for maximum duration of study 
treatment. 
feladilimab (GSK3359609) will be administered first and 
ipilimumab will be administered at least 30 minutes and no 
longer than one hour following feladilimab (GSK3359609) 
EOI. 
Administer Ipilimumab2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
2. Feladilimab (GSK3359609) will be administered first and 
ipilimumab will be administered at least 30 minutes and no 
longer than one hour following feladilimab (GSK3359609) 
EOI. Refer to Section 5.2 for maximum duration of study 
treatment. 
Dosing interval can be extended to Q6W for toxicity or 
intolerance 
On Treatment Safety  
AE/SAE/AESI Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3. After the initial AE/SAE report, the investigator is required 
to proactively follow each participant at subsequent 
visits/contacts. All SAEs and non-serious AESIs will be 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up. 
ECOG PS** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. 
the first Q6W visit is Week 31, then Week 37, etc.), unless 
more frequent assessments are clinically indicated. 
Physical Examination** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
** Physical examinations and ECOG may be performed 
within 24 hours prior to dosing (i.e., as opposed to the day 
of dosing), if necessary. 
Vital Signs and Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Vital signs include blood pressure, temperature, pulse, 
respiratory rate, and oxygen saturation. Weight is to be 
recorded at every other treatment visit in kilograms. Vital 
signs are to be performed predose on treatment days. 
On Treatment Local Laboratory Assessments (Safety) – assessments may be performed up to 3 days prior to treatment 
Serum β-hCG (for women of 
childbearing potential)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5. Monthly urine pregnancy testing may also be performed 
as consistent with local standards however if a urine test is 
positive or borderline, or in the event of a missed menstrual 
period or suspicion of pregnancy, a serum β-hCG test will 
be required. 
Clinical Chemistry, 
Hematology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6. Refer to Appendix 3 for a complete list of required 
assessments. Laboratory testing may be performed one 
day prior to dosing if necessary. Not required to be tested 
on Day 1 if screening labs are within 72 hours from time of 
scheduled first dose.  
Thyroid function tests 
 
 
X 
 
X 
 
X 
 
X 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from Week 25 (i.e. 
the first Q6W visit is Week 31, then Week 37, etc.). 
Calculated CrCl7 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault 
formula. Either formula is acceptable and must be 
consistently utilized for each participant throughout the 
study. See Appendix 9. 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
On Treatment Disease Assessments 
Tumor Imaging/Response 
Assessment8 
 
 
X 
 
X 
 
X 
 
X 
X8 
8. Diagnostic quality CT scan of chest and abdomen with 
contrast is required every 6 weeks (±1 week) until Week 49 
and every 12 weeks thereafter. Imaging/clinical 
assessments should be performed as indicated in Section 
9.2. The same method of assessment is required 
throughout the study. Brain scan (MRI with and without IV 
gadolinium) and bone scan to be performed as clinically 
indicated during the treatment period. If a participant has 
achieved a PD, CR, or PR in the previous radiologic 
assessment, a repeat scan should be performed after at 
least 4 weeks to confirm the response.  
On Treatment Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY  
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
On Treatment Biomarkers21 
On Treatment Tumor biopsies22 
Fresh tumor tissue sample13 
 
 
X 
 
 
 
X13 
 
 
 
 
13.Part 1: For participants in the safety evaluation for each 
substudy, fresh biopsies at week 7 (± 8 days) is optional. 
Following Part 1 initial safety evaluation (up to 10 
participants), the additional participants enrolled to assess 
further safety as well as PK/PD are required to provide a 
fresh biopsy obtained at week 7 (± 8 days).  
22. On treatment biopsy for participants in the PK/PD 
cohort is no longer required for ongoing participants in this 
arm. 
Part 2: Fresh biopsy collected at week 7 (± 8 days) is 
optional for participants in Part 2, if tumor is amenable to 
biopsy and upon participant consent. However, fresh biopsy 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
at week 7 (± 8 days) is required for at least 20 participants 
for this arm who also provided a fresh biopsy at screening. 
Additional optional fresh tumor tissue sample will be 
collected at Week 19 at the time of imaging assessment 
and at the time of confirmed PR or PD (± 8 days), upon 
participant consent. Note: Enrollment may become limited 
during the study, as required, to ensure collection of fresh 
tissue samples as noted. 
On Treatment Pharmacokinetics and Anti-Drug Antibodies (ADA) 
Plasma Feladilimab 
(GSK3359609; ICOS 
Agonist) PK14, 23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X14 
14. Draw sample (2 mL) at predose for all marked visits. 
Additional samples also drawn at the following time points: 
Week 1 (Day 1) at end of infusion (EOI) (within 15 minutes) 
and EOI+4h. EOI samples also drawn at Week 13 and 
Week 25. After Week 25, draw samples every 12 weeks at 
predose only. There is a +15 minutes window allowance for 
the EOI time points. 
23. Collection of on treatment ICOS PK is no longer 
required for ongoing participants in this arm. 
Ipilimumab PK24 
Pre, 
EOI* 
Pre, 
EOI 
Pre, 
EOI 
Pre, 
EOI 
Pre, 
EOI 
Pre, 
EOI 
Pre, 
EOI15 
 
 
Pre15 
Pre15 
*Part 1 ONLY: Additional collection time points for PKs on 
day 8 (± 2 days) and day 15 (± 3 days). 
15. To be collected predose, EOI every 3 weeks until Week 
19, then predose only every 18 weeks thereafter. If 
ipilimumab is given on a differing scheduling frequency, pre 
and EOI should be collected relative to dosing on infusion 
days only. 
24. Collection of on treatment ipilimumab PK is no longer 
required for ongoing participants in this arm. 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
Serum Feladilimab 
(GSK3359609; ICOS 
Agonist) ADA16, 25 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
16. Draw sample (4 mL) at predose on ALL treatment visits; 
then starting with Week 25 predose samples to be collected 
every 12 weeks. Draw a sample at any time during visit for 
non-treatment visits. Serum samples will be collected and 
tested for the presence of antibodies that bind to 
investigational agents as deemed appropriate. Feladilimab 
serum samples may also be tested for presence of 
antibodies that bind to Chinese Hamster Ovary (CHO) host 
cell proteins such as phospholipase B- like (PLBL2). 
25. Collection of on treatment ICOS ADA is no longer 
required for ongoing participants in this arm. 
  
Serum Ipilimumab ADA17, 26 
Pre 
Pre 
Pre 
Pre 
Pre 
Pre 
Pre18 
 
 
Pre18 
Pre18 
17. Serum samples are required to be collected prior to 
dosing (i.e., predose) on each dosing day and at the 
indicated assessment visits following study treatment 
discontinuation, and one sample collected 12 weeks post 
last dose of study treatment. In the event of hypersensitivity 
reaction that is clinically significant and/or leads to study 
treatment discontinuation, serum samples should be 
collected 30 days, 12 weeks, and 24 weeks post last dose 
of study treatment. 
18. To be collected every 3 weeks until Week 19, then 
every 18 weeks thereafter. 
26. Collection of on treatment ipilimumab ADA is no longer 
required for ongoing participants in this arm. 
Serum: IRR lab panel19 
 
 
 
 
 
 
 
 
 
 
 
19. Assessment ONLY required in participant experiencing 
anaphylaxis, serious hypersensitivity, or AEs related to 
study treatment administration that led to withdrawal from 
the study. Refer to Table 3 for list of analytes. Predose 
analysis will be performed on the serum sample collected 


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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 
49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days unless otherwise noted. (Visits occur once every 3 weeks during treatment period) 
for feladilimab (GSK3359609) and/or ipilimumab 
immunogenicity assessments. 
On Treatment Pharmacogenetics 
Genetic research20 
X 
 
 
 
 
 
 
 
 
 
 
20. Informed consent for optional genetic research must be 
obtained before collecting this sample. It is recommended 
that the optional research sample be taken at the first 
opportunity after a participant has met all eligibility 
requirements before Day 1 or on Day 1. 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CKD-EPI = Chronic 
kidney disease epidemiology collaboration; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = End of infusion; 
 
 
 ICOS = inducible T Cell co-stimulator; IRR = infusion related reaction; 
 
; PD = Progressive Disease; 
 PR = 
Partial response; Pre = Predose; 
 
; SAE = Serious adverse event. 
Pre: predose sample to be collected prior to dosing per institutional guidance, as long as it is collected prior to dosing of the corresponding agent; EOI: End of infusion sample is in 
reference to EOI of the corresponding agent. 
 
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Table 21 
Schedule of Activities – Treatment Discontinuation Visit and Follow-Up: Arm 3: Ipilimumab and Feladilimab 
Combination 
TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit 
 
Survival 
Follow-Up 
Notes 
Visit Window 
+ 10 days 
 
 
Anticancer Treatment 
 
X* 
* Follow up for survival is no longer required for participants in this arm. 
 
  
  
Concomitant 
Medications 
X 
 
 
TDV and Follow Up Safety 
AE/SAE/AESI 
Assessment2 
X 
 
2. After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. Refer to Section 9.4.1 and Section 9.4.3 for further details.. 
ECOG PS 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs and Weight3 
X 
 
3. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. 
TDV and Follow Up Local Laboratory Assessments 
Clinical Chemistry  
X 
 
 
Serum β-hCG (for 
women of childbearing 
potential) 
X 
 
 
Hematology 
X 
 
 
Thyroid function tests 
X 
 
 
Calculated CrCl 
X 
 
Urinalysis 
X 
 
TDV and Follow Up Disease Assessments 
Tumor 
Imaging/Response 
Assessment4 
X 
 
4. At the TDV, CT scan is required only if the last disease assessment did not show PD and was performed ≥6 
weeks before TDV. For participants who discontinue study treatment without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor imaging using the 
same imaging schedule used while on treatment until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. See 
additional information in Section 9.3.1. 


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TDV and Follow Up 
Assessments 
Treatment 
Discontinuation Visit 
 
Survival 
Follow-Up 
Notes 
Visit Window 
+ 10 days 
 
 
Telephone call for 
survival status1a 
 
X* 
*Follow up for survival is no longer required for participants in this arm.  
TDV and Follow Up Tumor Biopsies 
Fresh tumor tissue 
sample 
X5 
 
5. If possible, obtain an optional tumor tissue sample at time of confirmed PD or PR. 
TDV and Follow Up Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY 
 
 
 
 
 
 
 
 
 
 
 
TDV and Follow Up Biomarkers10 
TDV and Follow Up Pharmacokinetics and Anti-Drug Antibodies (ADA)9 
Feladilimab 
(GSK3359609) ADA 
 
X7,8 
7. To be collected 30 days post last dose and 12 weeks post last dose. 
8. In the event of hypersensitivity reaction that is clinically significant and/or leads to study treatment 
discontinuation, an additional sample should be collected at 24 weeks post last dose of study treatment. 
9. Collection of follow up PK and ADA samples is no longer required for ongoing participants in this arm. 
Feladilimab 
(GSK3359609) PK 
 
X7 
Ipilimumab ADA  
 
X7,8 
Ipilimumab PK 
 
X7 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; CR = complete 
response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology 
Group performance status; eCRF = Electronic case report form;
 
 
 PD = Progressive Disease; 
, 
 
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 PR = Partial response; 
 
; SAE = Serious adverse event; TDV = Treatment Discontinuation Visit 
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12.1.3.3. 
Rationale for the ICOS Agonist/Ipilimumab Combination 
Ipilimumab is a recombinant, human monoclonal IgG1 kappa antibody that binds to 
CTLA-4. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal 
antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 
CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and 
proliferation, including the activation and proliferation of tumor infiltrating T-effector 
cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which 
may contribute to a general increase in T cell responsiveness, including the anti-tumor 
immune response [YERVOY Prescribing Information, 2020]. Yervoy (ipilimumab) alone 
and in combination with nivolumab  platinum-based chemotherapy is indicated for the 
treatment of patients across a number of indications which include metastatic melanoma 
and NSCLC. 
Inducible t-cell costimulator (ICOS) is a co-stimulatory receptor belonging to the 
CD28/CTLA immunoglobulin super family with expression restricted to T cells [Hutloff, 
1999]. ICOS is weakly expressed on resting TH17, follicular helper T and Treg cells yet 
is highly induced on CD4+ and CD8+ T cells upon T cell receptor (TCR) engagement 
and activation [Paulos, 2010; Wakamatsu, 2013]. Upregulation of ICOS leads to both 
Th1 and Th2 cytokine secretion and sustained effector T cell proliferation and function 
[Sharpe, 2002]. A growing body of evidence supports the concept that activating ICOS 
on CD4+ and CD8+ effector T cells has antitumor potential. 
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]. 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] and 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 cell ratio, reversing an 
abundance of Tregs cell pre-treatment to a significant abundance of T effectors vs. Tregs 
cells relative to cells 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 confer an advantage by mounting a more robust immune 
antitumor response. 
The T cell activating potential of feladilimab was evaluated in multiple assay formats as a 
single agent and in combination with other immune checkpoint inhibitors. Ex-vivo 
studies were conducted with PBMC isolated from healthy human donors pre-activated 
with anti-CD3 alone or anti-CD3/anti-CD28. Soluble feladilimab either alone or in 
combination with ipilimumab demonstrated a more robust pro-inflammatory cytokine 
response than either single agent alone. A modified allogenic mixed lymphocyte reaction 
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stimulated dendritic cells differentiated from freshly isolated monocytes from another 
donor, was also employed to evaluate feladilimab in combination with ipilimumab. 
Significant increases in IFNγ secretion were observed for feladilimab combined with 
ipilimumab as compared to either agent alone, supporting clinical evaluation of this 
combination.  
In vivo studies using ICOS-/- and ICOS-ligand (L)-/- mice demonstrated the requirement 
of ICOS signaling in mediating the anti-tumor activity of an anti-CTLA-4 antibody in the 
B16/F10 melanoma syngeneic tumor model [Fu, 2011]. Mice lacking ICOS or ICOS-L 
had significantly decreased survival rates compared to wild-type mice after anti-CTLA-4 
antibody treatment suggesting a combination of anti-CTLA-4 treatment with an anti-
ICOS agonist may provide robust anti-tumor responses. In a separate study, B16 tumors 
engineered to overexpress ICOS-L were found to be significantly more sensitive to anti-
CTLA-4 treatment as compared to a B16/Bl6 tumor cells transduced with a control 
protein [Fan, 2014]. Treatment with mouse anti-CTLA-4 mouse antibody induced ICOS 
on CD4+ and CD8+ T cells in the tumor, spleen and blood, a pattern comparable to the 
ipilimumab clinical response showing that interplay between receptor induction extended 
to CTLA-4.  
To support the combination of feladilimab with ipilimumab (anti-CTLA-4 mAb), the 
nonclinical toxicology findings of ipilimumab as a single agent was reviewed. The 
nonclinical toxicology profiles of ipilimumab is well characterized and indicates that 
combination toxicology studies in monkeys would not likely provide any relevant data 
that would inform clinical risk assessments. Risk mitigation measures for potential 
clinically relevant risks associated with feladilimab combination therapy based on these 
nonclinical assessments or clinical safety data are described in this protocol. In 
intravenous repeat-dose toxicology studies in monkeys, ipilimumab was generally well 
tolerated. Immune-mediated adverse reactions were observed infrequently and included 
colitis (which resulted in a single fatality), dermatitis and infusion reaction (possibly due 
to acute cytokine release resulting from a rapid injection rate) [Hanaizi, 2012]. In a 
monkey reproductive toxicology study, administration of ipilimumab to cynomolgus 
monkeys from the onset of organogenesis through delivery resulted in higher incidences 
of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and 
higher incidences of infant mortality in a dose-related manner. The clinical relevance of 
these findings are well characterized and risk mitigation measures are described in this 
protocol.  
Refer to the GSK3359609 Investigator’s Brochure (IB) [GSK Document Number 
2017N319717_03; 2020] for further details.  
 
 
 
 


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12.1.3.4. 
Clinical Safety Summary  
12.1.3.4.1. Feladilimab  
As of the feladilimab Investigator Brochure data cutoff date of 16 March 2020, 249 
participants received at least 1 dose of monotherapy feladilimab in study 204691 at the 
following dose levels: 0.001 mg/kg (n=1), 0.003 mg/kg (n=1), 0.01 mg/kg (n=2), 0.03 
mg/kg (n=7), 0.10 mg/kg (n=25), 0.30 mg/kg (n=56), 1.0 mg/kg (n=126), 3.0 mg/kg 
(n=24), and 10 .0 mg/kg (n=7). In these 249 participants, the most common AEs 
(occurring in 15% of participants overall regardless of dose level or relationship) were 
anemia (22%), asthenia (21%), nausea (19%), fatigue (18%), diarrhea (16%), and 
vomiting (15%).  
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  
12.1.3.4.2. Ipilimumab  
The most common adverse reactions (5%) with ipilimumab as a single agent are fatigue, 
diarrhea, pruritis, rash, and colitis. The most common adverse reactions (20%) with 
ipilimumab in combination with nivolumab are fatigue, rash, pruritis, diarrhea, 
musculoskeletal pain, cough, pyrexia, decreased appetite, nausea, abdominal pain, 
arthralgia, headache, vomiting, dyspnea, dizziness, hypothyroidism, and decreased 
weight. 
For more details on specific indications, adverse reactions and ipilimumab dosage refer to 
the prescribing information [YERVOY Prescribing Information, 2020]. 
 
12.1.3.5. 
Dose Justification 
12.1.3.5.1. Feladilimab Pharmacokinetics and Pharmacodynamics 
The PK of feladilimab was evaluated after 30 minutes of IV infusion at doses from 0.001 
mg/kg to 10.0 mg/kg every 3 weeks (Q3W) in participants with solid tumors in Study 
204691. The plasma PK samples (received prior to the 2020 IB update cutoff date of 16 
March 2020) were analyzed with a validated bioanalytical method with a LLOQ of 0.1 
µg/mL. 
As of 16 March 2020, preliminary PK data in monotherapy cohorts were available in 1 
participant at 0.003 mg/kg, 2 participants at 0.01 mg/kg, 7 participants at 0.03 mg/kg, 25 
participants at 0.1 mg/kg, 52 participants at 0.3 mg/kg, 123 participants at 1.0 mg/kg, 23 
participants at 3.0 mg/kg, and 7 participants at 10.0 mg/kg dose. Preliminary PK data in 
pembrolizumab combination cohorts were available in 5 participants at 0.01 mg/kg, 
5 participants at 0.03 mg/kg, 13 participants at 0.1 mg/kg, 244 participants at 0.3 mg/kg, 
38 participants at 1.0 mg/kg, and 18 participants at 3.0 mg/kg dose. Preliminary PK data 
in GSK3174998 combination cohorts were available in 5 participants each at 8 and 24 mg 
and 1 participant at 80 mg fixed dose. Preliminary PK data in chemotherapy combination 


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cohorts of the safety run-in were available in 55 participants at 80 mg fixed dose of 
feladilimab.  
Based on these preliminary data, the median plasma concentration-time profiles of 
feladilimab exhibit a bi-exponential decline. There are no changes in feladilimab PK 
when co-administered at doses from 0.01 to 3.0 mg/kg with biologic or chemotherapy 
partners. Furthermore, median feladilimab plasma PK profiles after dosing at 8, 24, and 
80 mg fixed doses were superimposable to the median PK profiles observed with 0.1, 0.3, 
and 1.0 mg/kg doses. Preliminary plasma PK parameters of feladilimab computed using 
noncompartmental analysis methods (AUC, C, and Cmax) calculated over the first dosing 
interval (up to 503 hours) exhibit approximate dose proportional increases in feladilimab 
exposure over the range of 0.01 to 10.0 mg/kg doses. Observed exposures (AUC and C) 
from body-weight based dose of 1.0 mg/kg (combined monotherapy and combination 
cohorts) and corresponding fixed dose equivalent of 80 mg (chemotherapy safety run-in) 
overlap with each other, indicating similar exposures can be achieved with a fixed dosing 
regimen. Preliminary population PK estimated geometric mean systemic half-life (t1/2) of 
feladilimab is approximately 19 days.  
Based on the preliminary data, median CD4 and CD8 receptor occupancy was maintained 
at or above 70% during the dosing interval of first cycle for doses 0.3 mg/kg as shown 
in Figure 8.  
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  


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Figure 8 
Median CD4+ and CD8+ Receptor Occupancy (%RO) During the First 
Cycle of Feladilimab Administration as Monotherapy 
 
Feladilimab Dosing Frequency 
The systemic half-life of feladilimab is approximately 19 days based on the preliminary 
population PK analysis of data from ongoing study 204691. The existing feladilimab 


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Q3W regimen in the ongoing clinical study is also consistent with the Q3W dosing 
regimen typical with other IgG4 based monoclonal antibody therapies. Thus, feladilimab 
will be dosed Q3W in combination with ipilimumab. Combination of feladilimab with 
any other treatment in other arms of this study may have a different dosing regimen as 
deemed appropriate.  
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 all or even a majority of observed 
variability in the exposure of monoclonal antibodies [Zhao, 2017]. Hence, the selection 
of body-weight based versus fixed dosing in this study was evaluated through population 
PK modelling and simulation efforts.  
A preliminary population PK model (N = 637 participants; March 2020), which 
characterized the influence of body weight, age, and other participant covariates on 
exposure was developed. Results of this analysis indicate a feladilimab fixed dose is 
appropriate for trial participants across the bodyweight spectrum. Simulations show a 
feladilimab body weight-based dose results in slightly higher exposure in heavier weight 
participants and a feladilimab fixed dose results in slightly higher exposures in lighter 
participants. However, the range of exposures are similar between body-weight based and 
fixed dosing across the entire body weight spectrum and the exposures are maintained 
well within established clinical boundaries of safety at doses in the range of 24 to 80 mg 
Q3W (the highest studied dose in monotherapy deemed tolerable was 10 mg/kg or ~800 
mg). This suggests that there is no advantage of body-weight based dosing over fixed 
dosing and that lighter patients will not be more susceptible to treatment-related adverse 
events arising from marginal increases in exposure.  
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, a feladilimab 
fixed dose based on a reference body weight of 80 kg is reasonable and appropriate. 
Refer to GSK3359609 IB [GSK Document Number 2017N319717_03] for further 
details.  
12.1.3.5.2. Feladilimab Dose Rationale (Arm 3) 
Based on the preliminary PK data described above in Section 12.1.3.5.1 and target 
engagement shown in Figure 8, median CD4 and CD8 receptor occupancy was 
maintained at or above 70% during the dosing interval of first cycle for doses ≥0.3 
mg/kg. 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 the proposed 24 mg 
dose in arm 3. 
Collectively, based on the safety and exposure data from the Phase 1 study and the 
predicted target engagement, a 24-mg dose will be evaluated in combination with 


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ipilimumab in this study. No drug-drug interaction related changes are expected in 
feladilimab PK with ipilimumab co-administration. The currently planned feladilimab 
dose for this arm is the same as that used in the phase 2/3 studies for recurrent or 
metastatic (R/M) head and neck squamous cell carcinoma/cancer (HNSCC). 
12.1.3.5.3. Ipilimumab Dose Rationale 
The dose for ipilimumab for this study is 1 mg/kg or 3 mg/kg administered intravenously 
every 3 weeks. 
The 1 mg/kg or 3 mg/kg doses were selected based on approvals in multiple tumor types, 
both as monotherapy and in combination with nivolumab. [YERVOY Prescribing 
Information, 2020]. 


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12.1.3.6. 
Study Treatments 
Table 22 
Description and Administration of Arm 3 Study Treatments 
Name 
Ipilimumab 
Feladilimab (GSK3359609; 
ICOS agonist)  
Description 
CTLA-4 inhibitor 
Humanized anti-ICOS IgG4 
mAb 
Dosage form/strength 
50 mg/ 10 mL Solution;  
5 mg/mL 
Solution for injection/ 
10 mg/mL  
Dosage 
1 mg/kg, 
3 mg/kg 
24 mg 
Route of administration 
IV infusion 
IV infusiona 
Dosing instructionsa/frequency 
Administer diluted 
product/once Q3W (refer to 
SRM for infusion time) 
Administer diluted 
product/once Q3W 
a: The study reference manual contains the details on product handling, storage, preparation, and administration. 
In the ipilimumab + feladilimab containing arm, feladilimab will be administered first as 
a 30minute IV infusion (infusion time may be adjusted in the event an infusion reaction 
occurs) under medical supervision of an investigator or designee. The administration of 
the ipilimumab must be started at least 30 minutes and no more than one hour following 
the end of the feladilimab infusion under medical supervision of an investigator or 
designee.  
Participants should remain under observation at the study site post-study treatment 
infusion per the judgement of the investigator or as per institutional guidelines. Refer to 
Section 12.1.3.10, Table 24 for details on the management of participants experiencing 
infusion reactions. 
 
The date(s), start time(s) and stop time(s) of administration of each study drug will be 
documented in the source documents and reported in the eCRF. The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
Infusions may be administered up to 72 hours before or after the planned date of 
treatment for administrative reasons only (e.g., scheduling an infusion around a holiday). 
The 72-hour window does not apply to completion of study treatment administration 
interrupted by an infusion reaction. Refer to Section 7.2.1.4 for criteria governing dose 
interruptions or delays.  
Details on preparation and administration of feladilimab and ipilimumab are described in 
the study reference manual (SRM) and ipilimumab package insert, respectively.  


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12.1.3.7. 
Concomitant Therapy 
Please refer to Section 7.7  
12.1.3.8. 
Treatment of Overdose 
12.1.3.8.1. Feladilimab Overdose 
An overdose of feladilimab is defined as administration of a dose that is >240 mg (>10 
times the 24 mg intended dose). In the event of an overdose, the investigator must: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 130 days from the date of the overdose. 
3. Obtain a plasma sample for PK analysis within 28 days from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).  
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.  
There is no specific antidote for overdose with the experimental treatments being 
evaluated in this study. 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.  
12.1.3.8.2. Ipilimumab Overdose 
According to ipilimumab prescribing information, no information is available on 
overdosage. In case of overdose symptomatic treatment has to be applied; there are no 
known antidotes for the compound. 
In the event of an overdose, the investigator must: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 130 days from the date of the overdose. 
3. Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis). 
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF. 


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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. 
12.1.3.9. 
 Treatment Duration for Ipilimumab 
Participants enrolled will be treated until disease progression, intolerable toxicity, 
informed consent withdrawal or death. Combination study treatment will continue to be 
administered at the indicated schedule for a maximum duration of approximately 2 years 
or up to 35 treatment visits, whichever comes first. Refer to Section 5.2. for additional 
details regarding follow up after discontinuation of study treatment. 
12.1.3.10. Dose modification and Management Guidelines 
The dose of feladilimab cannot be reduced or modified.  
No dose reductions are allowed for ipilimumab. Dose Modification Guidelines for 
immune related Adverse Events are listed in Section 7.2.1.1.  
If either GSK3359606 or ipilimumab is held or discontinued for any toxicity, the other 
study drug must also be held or discontinued, unless discussed otherwise with Medical 
Monitor. 
12.1.3.10.1. 
General Guidelines for Immune-Related Adverse Events (irAEs) 
AEs associated with immunotherapy treatment may be immune-mediated. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after 
the last dose of treatment, or during the treatment course, and may affect more than one 
body system simultaneously. Therefore, early recognition of and initiation of treatment 
for these events is critical to reduce potential complications. Based on existing data from 
the study 204691, most treatment-related AEs were Grade 1 or 2, managed with 
supportive care and if appropriate the administration of corticosteroids. 
For suspected irAEs, ensure adequate evaluation to confirm the etiology or exclude other 
causes. Additional procedures or tests such as, but not limited to, bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue treatment and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs 
associated with immunotherapies are provided in Table 23.  
Table 23 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs 
General instructions: 
• 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
• 
For situations where immunotherapy treatment has been withheld, treatment can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Immunotherapy treatment should 
be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
• 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.
C
C
I 
- 
T
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i
s 
s
e
c


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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12.1.3.10.2. 
Dose Modification and Toxicity Management of Infusion-Reactions 
Related to Immunotherapy Treatment 
Table 24 
Immunotherapy Infusion Reaction Dose Modification and Treatment 
Guidelines 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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12.1.3.10.3. 
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, 
but are not limited to, the following: pneumonitis, nephritis, hepatitis, colitis, immune 
related endocrinopathies (such as thyroiditis or hypophysitis) or immune related 
cutaneous toxicities, to include rashes confirmed via biopsy to be immune-mediated.  
AESIs will be reported within 24 hours if the event meets the criteria for a serious event.  
12.1.3.11. Safety Evaluation 
All the regimen qualification activities in Part 1 are based on the premise that a proposed 
dose for each component, informed by prior experience, will be evaluated to go forward 
to Part 2. If the Part 1 regimen qualification process confirms the dose combination, the 
combination will proceed to Part 2. If the Part 1 regimen qualification process does not 
confirm the dose combination, further evaluation in the 205801 platform study of that 
combination will stop. 
 
The combination cohort of feladilimab with ipilimumab will test 24 mg feladilimab in 
combination with either 1mg/kg ipilimumab or 3mg/kg ipilimumab. The arm assessing 
the combination of 24 mg feladilimab with 1 mg/kg ipilimumab will be conducted 
independently from the arm assessing the combination of 3 mg/kg ipilimumab with 24 
mg feladilimab. There will be no dose escalation or de-escalation for either combination 
partner. Further evaluation of a combination demonstrated to result in toxicity as 
described in Table 27 at the rate defined in Table 25, will be stopped.  
 
Safety and tolerability will be guided using a modified toxicity probability interval 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


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(mTPI) approach with some additional modifications due to only one dose level being 
evaluated. The mTPI design is an extension of the toxicity probability interval method 
and employs a simple beta-binomial hierarchic model [Ji, 2010]. Decision rules are based 
on calculating the unit probability mass (UPM) of three intervals corresponding to under 
dosing, proper dosing, and overdosing in terms of toxicity. Specifically, the under-dosing 
interval is defined as (0, pT – ε1), the overdosing interval as (pT + ε2, 1), and the proper 
dosing interval as (pT – ε1, pT + ε2), where pT is the target toxicity rate, ε1 and ε2 are 
small fractions, such as 0.05, to account for the uncertainty around the true target toxicity. 
The three dosing intervals are associated with three different dose decisions. Given an 
interval and a probability distribution, the UPM of that interval is defined as the 
probability of the interval divided by the length of the interval. The mTPI design 
calculates the UPMs for the three dosing intervals, and the one with the largest UPM 
implies the corresponding dose-finding decision. For example, if the over-dosing interval 
has the largest UPM, decision will be to stop further evaluation.  
 
Initial safety and tolerability of the combination will be evaluated within the first 21 days 
(DLT period). Evaluation of the available safety data over the first 21 days of treatment 
for each participant enrolled is required from at least 3 participants before a decision is 
made to enroll additional participants. The maximum number of participants assigned to 
either dose level will be at the discretion of the Sponsor in consultation with the 
investigators. If no more than one of the first three participants treated with 24 mg 
feladilimab + 1 mg/kg ipilimumab experience safety findings (DLTs) meeting the criteria 
described in Table 27, an additional 6-7 participants will be treated with 24 mg 
feladilimab + 1mg/kg ipilimumab.  
If a participant withdraws from the study before the completion of the 21-day DLT 
evaluation period for reasons other than DLT, then the participant may be replaced to 
achieve the three-participant required minimum. The decision to declare the combination 
tolerable will occur following review of the safety, PK and PD data and joint discussion 
by the GSK Medical Monitor and investigators. Membership, roles and accountabilities, 
and the process for safety review and meeting frequency is outlined in the Study 
Reference Manual.  
The mTPI design assumptions include the following: 
(i) 
A maximum of 10 participants will complete the DLT evaluation period; 
(ii) 
The true underlying toxicity rate for feladilimab falls within the range from 25% 
to 33% and targets at 30%. 
(iii) 
Maximum probability that the dose exceeds the target toxicity is 95%; however 
an additional safety rule will be applied if the maximum sample size of 10 is 
reached whereby the dose will be considered non-tolerated if there is greater than 
70% posterior probability that the true DLT rate is >30% 
Participants will be enrolled in cohorts of 3-4 and decisions will be made after all patients 
within a cohort complete the DLT evaluation period.  
The monitoring rules guiding dose decision are provided in Table 25. The tolerability 
decision framework using the mTPI method were generated based on a beta/binomial 


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model and pre-calculated before study initiation. The entries in the Dose Decision Rules 
table below represent dose-finding decision points at which a determination is made 
whether the combination remains safe for continued testing using the data generated in 
the cohort of interest.. In other studies utilizing mTPI, these points are often denoted as 
“E”, “S”, and “D”, denoting the thresholds governing escalating the dose, staying at the 
same dose, or de-escalating the dose, respectively. However in this study, as there is no 
dose escalation or de-escalation, the thresholds mark the criteria used to determine 
whether the doses of the combination are tolerated and therefore, permit continued 
treatment of additional participants at the same combination dose. If a dose combination 
is not tolerated per Table 25 and Table 27, further evaluation of that dose combination 
will be stopped without exploration of other dose levels of either or both combination 
partners.  
As an example, the scenario in which one of the first three participants in Part 1 
experience a DLT is represented in the cell marking the intersections of row ‘1’ and 
column ‘3’ in Table 25. According to the model underlying the mTPI, such a scenario 
predicts the actual rate of toxicity to be within the acceptable, predetermined range, 
therefore allowing treatment of additional three participants at the same dose 
combination. The scenario in which one of these three additional participants experience 
DLT, is represented in the cell marking the intersection of row ‘2’ and column ‘6’, 
allowing treatment of an additional four participants according to the model. If two of 
these four additional participants experience DLTs, the combination will not be 
considered as tolerated and no additional participants will be treated in this combination. 
not continue because of unacceptable toxicity. If the combination is considered tolerated, 
additional participants will be enrolled to further evaluate safety and PK/PD. No formal 
evaluation of DLTs will be performed after the 21 day period, however other measures of 
safety will continue to be monitored. 


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Table 25 
Dose Decision Rules 
  
Number Treated 
  
  
#DLTs 
3 
6 
10 
0 
Tolerated 
Not applicable 
Not applicable 
1 
Enroll 3 
Tolerated 
Tolerated 
2 
Stop 
Enroll 4 
Tolerated 
3 
Stop 
Stop 
Tolerated 
4 
  
Stop 
Stop 
5 
  
Stop 
Stop 
6 
  
Stop 
Stop 
7 
  
  
Stop 
8 
  
  
Stop 
9 
  
  
Stop 
10 
  
  
Stop 
 
12.1.3.12. Futility evaluation 
Once an arm transitions through the initial safety evaluation as described above, 
additional participants will be enrolled to that arm, up to a maximum of 15 participants to 
provide further evaluation of safety and tolerability and: 
1. Preliminary PK/pharmacodynamic characteristics (i.e., measures of target 
engagement and functional effects such as receptor occupancy and cytokine 
release) and 
2. Evaluation of antitumor activity. 
In these participants, tumor biopsy at Screening and Week 7 will be required (refer to 
SOA tables for each arm Section 12.1 or further details).  
An interim evaluation of futility in terms of ORR will be conducted after the first 10 
participants have had at least two post baseline RECIST assessments. A maximum of 15 
participants will be enrolled to allow for 10 evaluable participants to be assessed for 
futility. If no objective responses are observed in 10 evaluable participants, development 
of the experimental regimen may be stopped. Decisions will be made after evaluation of 
other endpoints and will be based on the totality of data, including the Disease Control 
Rate endpoint. 


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Table 26 
Planned Dose Levels for Feladilimab and Ipilimumab  
Dose Level 
Ipilimumab (mg/kg) 
Feladilimab 
(GSK3356909) (mg) 
Safety (n) 
PK/PD (n) 
Total (n) 
1 
1 
24 
3-6 
6-19 
9-25 
2 
3 
24 
3-10 
N/A 
3-10 
 
The ipilimumab combination cohort will initiate at the 3mg/kg dose in combination with 
feladilimab 24 mg. If the 3mg/kg ipilimumab dose meets the dose limiting toxicity 
definition as described below, a second cohort of 3-10 participants will be dosed at 
1mg/kg ipilimumab plus 24 mg feladilimab to explore a lower dose.  
12.1.3.13. Dose Limiting Toxicity 
The severity of all toxicities will be graded using National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 5.0) [NCI, 2017]. The 
DLT observation period is 21 days in length and begins on the day feladilimab is first 
administrated to the participant. 
 
A DLT is defined as an AE that meets at least one of the criteria listed in Table 27 and is 
considered by the investigator to be clinically relevant and attributed (probably or 
possibly) to the study treatment during the 21-day DLT observation period. An AE 
considered related to the underlying disease under study it is not defined as a DLT. A 
safety event can still be included for DLT consideration after the 21 day window. 
 
Table 27 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition 
Hematologic 
• Febrile neutropenia as defined by CTCAE v5 
• Grade 4 neutropenia of >7 days in duration or requiring G-CSF 
• Grade 4 anemia of any duration  
• Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with bleeding 
Non- hematologic 
• Grade 4 toxicity 
• Grade 3 pneumonitis of any duration 
• Grade 3 toxicity that does not resolve to ≤Grade 1 or baseline within 3 days despite optimal 
supportive carea 
• Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 ocular toxicity 
• Following events are not considered DLTs 
o 
Grade 3 and Grade 4 asymptomatic electrolyte abnormalities that are corrected within 
24 hours without clinical sequelae 
o 
Grade 3 nausea, vomiting, or fatigue that resolves to Grade 1 within 7 days with 
optimal supportive care 
o 
Grade 3 and Grade 4 infusion reactions in participants not receiving prophylaxis for 
IRRs (refer to Section 7.2.1.2 for details on IRR management)  


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Toxicity 
DLT Definition 
Other 
• Toxicity that results in permanent discontinuation of feladilimab monotherapy or feladilimab 
and agent in combination during the first four weeks of treatment 
• Grade 3/Grade 4 toxicity that results in a participant not receiving the expected doses of a 
regimen in Cycle 1, defined by 21 days 
• Any other toxicity considered to be dose-limiting that occurs beyond four weeks will be 
considered in the selection of the dose to recommend for expansion cohorts 
• Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT 
a. Suggested toxicity management guidelines as described in Section 7.2.1.2 may include systemic corticosteroids 
for immune-related toxicities; if systemic corticosteroids use delays administration of the second dose of study 
treatment and the event does not otherwise meet the DLT criteria for non- hematologic toxicity, the dose delay 
will not be considered a DLT.  
CTCAE=Common Toxicity Criteria for Adverse Events; DLT = Dose-limiting toxicity; G-CSF =Granulocyte colony-
stimulating factor; GSK =GlaxoSmithKline; IRR=infusion related reaction 
 
If a participant experiences a DLT during the DLT observation period, the participant 
may resume dosing provided the toxicity did not meet study treatment discontinuation 
criteria and following approval by the Sponsor. In cases where retreatment is considered, 
refer to Section 12.1.3.10.1 for selection of the dose and schedule of ipilimumab in 
combination with feladilimab. Participants may reduce the dose intensity of ipilimumab 
one or two times.  
 
Toxicity management and dose modification guidelines described in Section 7.2.1.2 are 
provided for those AEs of special interest that, although not observed in nonclinical 
studies, may be expected with the administration of immune directed therapies such as 
feladilimab and ipilimumab.  
 
Guidance for the identification, evaluation, and the established algorithms for the 
treatment management of immune-related adverse events (irAEs) including dose 
modification algorithms are provided in Section 7.1 and Section 7.2. These guidelines are 
based on the experience of irAE management following the development of immune 
check-point inhibitors such as ipilimumab and pembrolizumab.  
 
If there is a delay in administration of study treatment, refer to Section 7.2.1.4 for 
guidance on planning of subsequent study visits. 
 
12.1.3.14. Risk-Benefit Assessment for Ipilimumab combined with Feladilimab 
Feladilimab is intended to be a first-in-class anti-ICOS agonist antibody for the treatment 
of cancers of different histology. It is expected to differentiate from first generation 
immunomodulatory antibodies directed against Cytotoxic T-Lymphocyte-Associated 
Protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/PD-Ligand-1 (PD-L1) 
by targeting a different axis in the antitumor T cell response cascade and promoting 
activation of a co-stimulatory receptor instead of blocking an inhibitory checkpoint 
receptor. The effect of ICOS agonist activity is to promote the expansion and function of 
cytotoxic CD8+, and effector CD4+ T cells, resulting in improved antitumor immune 
responses that are durable. Due to the restricted expression of ICOS on activated T cells, 
it is expected that feladilimab may result in a more favorable safety profile as compared 


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with other antibodies that target co-stimulatory T cell receptors constitutively expressed 
on naïve T cells. 
Nevertheless, some tumors may engage multiple mechanisms to escape immune-
mediated antitumor effects thus combining an ICOS agonist with agents that target 
different pathways within the immune cascade may be required for achieving the desired 
clinical effect. Accordingly, as ICOS agonists stimulate IFN  production which induces 
PD-L1 expression on tumor cells and within the tumor microenvironment [Mimura, 
2018], this may facilitate the therapeutic benefit of PD-1/L1 blockade within tumors that 
have low levels of PDL1 expression. Several studies have underscored the co-expression 
of PD-1 and ICOS on tumor--infiltrating lymphocytes (TILs) and anti-PD-1-responsive 
peripheral T cells, as well as complementarity between inhibition of the PD-1/L1 axis and 
co-stimulation via the ICOS/L axis [Kamphorst, 2017; Gros, 2014; Beyrend, 2019]. 
Clinical studies and a series of nonclinical studies support the combination approach of 
an anti-ICOS agonist with immune checkpoint inhibitors or other agents that modulate 
the immune system distinct from ICOS biology. 
Although there is no clinical experience with the combination of feladilimab with 
ipilimumab, given the currently available safety data and the low likelihood of drug-drug 
interactions between feladilimab with ipilimumab, combination therapy may have an 
acceptable safety profile. Additionally, the combination may provide anti-tumor effect in 
participants with advanced NSCLC. The current nonclinical and clinical safety 
information for feladilimab and ipilimumab, used as single agents, provide support for 
their use in combination in the target patient population. 
This is the first study testing the combination of feladilimab with ipilimumab in 
participants with advanced NSCLC that have been treated with standard therapies. Study 
participants may benefit from medical tests and screening performed during the study. 
Any potential benefit of the addition of ipilimumab to feladilimab is unknown. Data 
obtained in this study may help identify individuals more likely to benefit or have side-
effects from ipilimumab plus feladilimab. 
Based on the status of ipilimumab as a marketed product with documented anticancer 
activity and an acceptable safety profile and feladilimab as an agent with close to a one 
thousand patient experience with preliminary signals of activity in NSCLC and a 
manageable toxicity profile, the potential benefit to risk is favorable to proceed with the 
combination in the context of a controlled monitored study with an initial safety 
clearance and rule out futility screening to confirm the potential risks and benefits. 
 
The following sub sections outline the risks and mitigation strategies for this 
protocol for ipilimumab. Refer to the latest ipilimumab US product insert (USPI) and the 
EU SmPC for additional details. Feladilimab risk assessment and mitigation 
strategies are in the master protocol (Section 3.3). 
 


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Table 28 
Risk Assessment and Mitigation Strategy: Ipilimumab 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immune-related 
AEs 
 
 
 
• Inflammatory AEs such as diarrhea/colitis, 
pneumonitis, nephritis, and hepatotoxicity 
are well established as treatment emergent 
AEs with immune-modulating agents and are 
consistent with the immune-stimulatory 
mechanism of action of these agents. (refer 
to the latest SmPC and/or USPI for 
YERVOY) 
 
• Participants with the following medical 
history are ineligible for this study 
o Toxicity ( Grade 3) related to prior 
immunotherapy leading to study 
treatment discontinuation  
o Active autoimmune disease (refer to 
Section 6.2 exclusion criterion 6) 
o Severe hypersensitivity to another 
mAb 
• Established management algorithms for 
immune-related adverse events (irAEs)  
• Refer to Section 7.2.1.1 for further 
details on the identification, evaluation, 
and management of toxicities with a 
potential immune etiology.  
Infusion and 
hypersensitivity 
reactions and 
potential CRS 
• 
Risk for infusion reactions and 
hypersensitivity is inherent to many mAbs 
[Brennan, 2010] (refer to the latest SmPC 
and/or USPI for YERVOY) 
 
• Participants with history of severe 
hypersensitivity to another mAb or to the 
chemotherapies under investigation 
including any ingredient used in the 
formulation are ineligible for this study.  
• Refer to Section 7.2.1.2 for further 
details on management of infusion 
reactions.  
• Refer to Section 7.2.1.2 for further 
details on management of CRS 
Immune complex 
disease 
• Immune complex formation and deposition 
findings (refer to the latest SmPC and/or 
USPI for YERVOY) 
• Clinical laboratory safety assessments 
and immunogenicity testing 
 
Table 29 below provides an outline of the risk assessment and mitigation strategy for 
GSK3359609 (feladilimab). More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events of feladilimab may be found in 
the IB [GSK Document Number 2017N319717_03]. 
 
 
 
 
 
 
 
 


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Table 29 
Risk Assessment and Mitigation Strategy GSK3359609 (feladilimab) 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immune-related 
AEs 
 
 
 
• Inflammatory AEs such as diarrhea/colitis, 
pneumonitis, nephritis, and hepatotoxicity 
are well established as treatment emergent 
AEs with immune-modulating agents and are 
consistent with the immune-stimulatory 
mechanism of action of these agents.  
 
• Participants with the following medical 
history are ineligible for this study 
o Toxicity (Grade 3) related to prior 
immunotherapy leading to study 
treatment discontinuation  
o Active autoimmune disease (refer to 
Section 6.2 exclusion criterion 6) 
o Severe hypersensitivity to another 
mAb 
• Established management algorithms for 
immune-related adverse events (irAEs)  
• Refer to Section 7.2.1.1 for further 
details on the identification, evaluation, 
and management of toxicities with a 
potential immune etiology.  
Infusion-related 
reactions (IRRs) 
which include 
hypersensitivity 
and potential 
cytokine release 
syndrome (CRS) 
• Risk for infusion reactions and 
hypersensitivity is inherent to many mAbs 
[Brennan, 2010]  
• The overall rate of IRRs with feladilimab is 
low and there have been no cases of CRS 
observed across the clinical program of 
feladilimab [GSK Document Number 
2017N319717_03, 2020]. 
 
• Participants with history of severe 
hypersensitivity to another mAb or to the 
chemotherapies under investigation 
including any ingredient used in the 
formulation are ineligible for this study.  
• Refer to Section 7.2.1.2 for further 
details on management of infusion 
reactions and details on CRS 
management.  
Immune complex 
disease 
• Immune complex formation and deposition 
findings in nonclinical safety studies [GSK 
Document Number 2017N319717_03, 2020] 
• Clinical laboratory safety assessments 
and immunogenicity testing 
Abbreviations: AE = adverse event; IB = Investigator’s Brochure; ICOS = inducible T-cell co-stimulator; LPS = 
lipopolysaccharide; mAb = monoclonal antibody; TCR = T-cell receptor. 
 
12.1.3.15. Additional Study Population Criteria: Arm 3 
None. 


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12.1.3.16. References 
Beyrend, G., et al., PD-L1 blockade engages tumor-infiltrating lymphocytes to co-express 
targetable activating and inhibitory receptors. J Immunother Cancer, 2019. 7(1): p. 217. 
Fan X, Quezada SA, Sepulveda Ma, Sharma P, Allison JP. Engagement of the ICOS 
pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J 
Exp Med. 2014; 211:715-725. 
Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor 
responses mediated by anti-CTLA-4 therapy. Cancer Res. 2011; 71:5445-5454. 
Gros A., et al., PD-1 identifies the patient-specific CD8(+) tumor-reactive 
repertoire infiltrating human tumors. J Clin Invest, 2014. 124(5): p. 2246-59. 
Hanaizi Z, van Zwieten-Boot B, Calvo G, Lopez AS, van Dartel M, Camarero J, et al. 
The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of 
advanced (unresectable or metastatic) melanoma in adults who have received prior 
therapy: summary of the scientific assessment of the Committee for Medicinal Products 
for Human Use. Eur J Cancer, 2012   
Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, et al. 
ICOS is an inducible T cell co-stimulator structurally and functionally related to CD28. 
Nature. 1999; 397:263-266. 
Kamphorst, A.O., et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after 
PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A, 2017. 114(19): 
p. 4993-4998. 
Mimura K., The JL, Okayama H, et al.. PD-L1 expression is mainly regulated by 
interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 
2018; 109: 43-53. 
Sharpe AH, Freeman GJ. The B7-CD28 Superfamily. Nat Rev Immunol. 2002; 2:116- 
126. 
Wakamatsu E1, Mathis D, Benoist C. Convergent and divergent effects of costimulatory 
molecules in conventional and regulatory CD4+ T cells. PNAS. 2013; 110:1023-1028. 
YERVOY [Prescribing Information]. Princeton, NJ. Bristol-Myers Squibb Company; 
2020. 
YERVOY [Summary of Product Characteristics]. Dublin, Ireland. Bristol-Myers Squibb 
Company; 2020. 
 


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12.1.4. 
Arm 4: GSK4428859A (Anti-TIGIT) and Dostarlimab (Anti-PD-1) 
Combination 
12.1.4.1. 
Protocol Amendment 9 Summary of Changes Specific to GSK4428859A 
and Dostarlimab Arm 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.4.2 
(Table 30, Table 31 
and Table 32) 
Dose modification and 
Management 
Guidelines (Section 
12.1.4.11 and Table 
34) 
 
 
 
 
 
 
 
 
 
 
Addition of text to clarify 
that the following 
investigations will require a 
Cardiologist or locally 
appropriate specialist 
review;  
1. 
 
 
  
 
 
 
 
 
 
 
 
 
  
Addition of text to clarify 
that the Sponsor will need to 
be informed regarding these 
participants 
Addition of text to clarify 
that investigators are 
required to review all safety 
laboratory assessments 
before dosing..  
Modifications were made to 
provide additional monitoring 
requirements and management 
of cardiac abnormalities in the 
event of 
 
 
 
 
 
 
Section 12.1.4.15 and 
Table 38 
 
 
 
 
  
 
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Protocol Amendment 8 Summary of Changes Specific to GSK4428859A and 
Dostarlimab Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.4.2 
(Table 30, Table 31 
and Table 32) 
Schedule of Activities 
Section 12.1.4.2 
(Table 31 and Table 
32) 
Dose modification and 
Management 
Guidelines (Section 
12.1.4.11 and Table 
34) 
 
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Protocol Amendment 7 Summary of Changes Specific to GSK4428859A and 
Dostarlimab Arm  
 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.4.2 
(Table 31 and Table 
32) 
 
Protocol Amendment 6 Summary of Changes Specific to GSK4428859A and 
Dostarlimab Arm 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.4.2 
(Table 31) 
Removed the timing 
between infusions  
Moved details of timing 
between infusions to the 
Pharmacy Manual to allow 
flexibility as new data from 
ongoing studies become 
available  
Schedule of Activities 
Section 12.1.4.2 
(Table 31) 
Updated assessment 
title/heading of whole blood 
to specify flow cytometry 
To clarify the intent for the 
whole blood sample  
Schedule of Activities 
Section 12.1.4.2 
(Table 31) 
Updated note # 17, under the 
IRR sample 
To clarify when an IRR 
sample is required to be taken 
Schedule of Activities 
Section 12.1.4.2 
(Table 32) 
Included a 60 day and 90 
day after last dose safety lab 
assessments during follow 
up   
To address request from 
regulatory agency to include 
safety lab assessments during 
follow up  
Schedule of Activities 
Section 12.1.4.2 
(Table 32) 
Updated the time window 
for treatment discontinuation 
visit to specify it is within 
To clarify the time window 
and align with the footnote 
included in the SOA 
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Section # and Name 
Description of Change 
Brief Rationale 
30 days of study treatment 
discontinuation 
Clinical Safety 
Summary: 
GSK4428859A 
Section 12.1.4.4.1 
Added number of  
participants 
), showing 
favorable results in Phase 1 
dose-finding study of 
GSK4428859A 
To include omitted data  
Dose Justification: 
GSK4428859A 
Pharmacokinetics and 
Pharmacodynamics 
Section 12.1.4.6.1 
Corrected t1/2 range of 
GSK4428859A  
To correct typo 
Study Treatments 
Section 12.1.4.7 
Removed the timing for 
observation after completion 
of study treatment 
administration  
Moved details of observation 
period to the Pharmacy 
Manual to allow flexibility as 
new data from ongoing studies 
become available  
Dose Modification and 
Management 
Guidelines Section 
12.1.4.10 
To include the most recent 
safety data from the ongoing 
FTIH study 
Dose Modification and 
Management 
Guideline Section 
12.1.4.11 
Table 34: Corrected Grade 0 
for AEs to AEs resolved 
To align with grading of AEs 
as there is no Grade 0 
GSK4428859A Dose 
Rationale (Arm 4) 
Section 12.1.4.6.2 
Updated language around 
the dose rationale for in vitro 
evaluation of GSK4428859 
Corrected prior error in 
information reported to align 
with Investigator Brochure  
Dose Limiting 
Toxicity Section 
12.1.4.14 
To clarify that the time 
window is after completion of 
the DLT period  
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Section # and Name 
Description of Change 
Brief Rationale 
Risk-Benefit 
Assessment of 
GSK4428859A and 
Dostarlimab combined  
12.1.4.15 
To clarify protocol 
requirements to collect sample 
in the case of an infusion 
reaction  
Additional Inclusion 
Criteria: Arm 4 
Section 12.1.4.16.1 
Added inclusion criteria: 
-Male contraception is not 
required for this arm 
To update contraception 
requirements for males 
participating in this arm  
All Sections 
Defined abbreviations  
Added abbreviations that were 
omitted in error  
 
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12.1.4.2. 
Schedule of Activities Specific to the GSK4428859A and Dostarlimab Combination 
The timing and number of planned study assessments (including safety, pharmacokinetic, ADA, biomarker or other assessments) may 
be altered during the course of the study based on newly available data. 
Table 30 
Schedule of Activities – Screening Arm 4: GSK4428859A and Dostarlimab Combination 
Screening Study Assessments 
Screening1  
Notes 
Visit Window 
≤4 Wks 
 
Informed Consent1 
X 
1. All screening assessments must be performed within 4 weeks (28 days) prior to first dose of study treatment 
unless otherwise specified. The informed consent may be signed within 45 days prior to first dose. 
Participant Registration2 
X 
2. Participants will be registered in RAMOS NG at screening. 
Inclusion/Exclusion Criteria 
X 
Review eligibility prior to randomization. 
Demographics, Medical History (including 
alcohol and tobacco use), Prior Medications, 
Disease History12 
X 
12. All known mutations should be entered in the eCRF as disease history. 
Prior Anticancer Treatment, Radiotherapy 
X 
 
Screening Safety 
AE/SAE/AESI Assessment3 
X 
3. Any AESI or SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time 
a participant consents to participate in the study. After the initial AE/SAE report, the investigator is required to 
proactively follow each participant at subsequent visits/contacts. Refer to Section 9.4 for further details.  
ECOG PS 
X 
 
Physical Examination 
X 
 
Vital Signs, Height and Weight4 
X 
4. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. Height is recorded 
at Screening only. Record weight in kilograms. 
12-lead ECG 
X 
Consider cardiologist or locally appropriate specialist review for participants with potentially significant ECG 
abnormalities such as AV block (except for first degree), new cardiac arrhythmias, or frequent PVCs. Please inform 
the Sponsor regarding these participants.  
Echocardiogram or MUGA scan5 
X 
5. ECHO required at Screening within 28 days prior to first dose of study treatment, and during treatment phase if 
clinically indicated. MUGA scan may be used if ECHO not feasible.  
Screening Local Laboratory Assessments (Safety) 
Hepatitis B and C6 
X 
 
Serum β-hCG (for women of childbearing 
potential) 
≤3d 
 


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Screening Study Assessments 
Screening1  
Notes 
Visit Window 
≤4 Wks 
 
Clinical Chemistry6, Coagulation6, 
Hematology6, Thyroid function6 
X 
6. Refer to Appendix 3 for a complete list of required assessments. Required within 7 days of randomization day. 
Not required to be tested on Day 1 if screening labs are within 72 hours from time of scheduled first dose. Must be 
drawn predose or up to 3 days prior to dosing. If Hepatitis B and C was performed within 3 months prior to first dose 
of study intervention or SoC, repeat testing at screening is not required; otherwise, this testing is mandatory. 
Calculated CrCl7 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. See Appendix 9. 
Urinalysis6 
X 
 
Screening Other Laboratory Assessments 
PD-L1 expression by IHC8 
X 
8. PD-L1 expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, Dako 28-8, or Dako 
22C3) must be recorded in the eCRF, if known. Note: Test is not required to be performed by the site if not 
previously performed. 
Screening Disease Assessments 
 
Tumor Imaging9 
X 
9. Diagnostic quality CT scan of chest and abdomen with contrast must be obtained within 28 days of first dose. 
Baseline brain scan (MRI with and without IV gadolinium) should be obtained within 6 weeks of first dose if history of 
CNS disease or if clinically indicated. Bone scan should be obtained within 6 weeks of first dose if clinically 
indicated. See additional information regarding bone scans in Section 9.3.1. 
Pre-Baseline scans for Tumor Growth 
Kinetics10 
X 
10. Upon participant consent, up to 3 pre-baseline scans (within 12 months before the baseline scan) will be 
collected to assess tumor growth rate to support exploratory investigation of tumor growth kinetics (See Section 
9.3.2 for details on images for submission). 
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Screening Study Assessments 
Screening1  
Notes 
Visit Window 
≤4 Wks 
 
Screening Tumor Biopsies 
Fresh tumor tissue sample and Archival 
tumor11 
X 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; β-hCG = β -human chorionic gonadotropin; BNP = B-type natriuretic peptide; CKD-EPI = chronic 
kidney disease epidemiology collaboration; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG PS = Eastern 
Cooperative Oncology Group performance status; eCRF = electronic case report form; IHC = Immunohistochemistry; IWRS = interactive web response system; MRI = magnetic 
resonance imaging; MUGA = multi-gated acquisition; NT-pro-BNP = N-terminal pro-hormone BNP; SAE = serious adverse event.  
 
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Table 31 
 Schedule of Activities – Treatment Period Experimental Arm 4: GSK4428859A (Anti-TIGIT) and Dostarlimab (Anti-
PD-1) Combination 
On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
1. Once determined to be eligible, 
participants must be randomized via IWRS. 
Drug shipments will be managed via IWRS. 
Sites must allow up to 7 business days for 
shipment of study drug. Randomization can 
be done prior to Day 1, but no more than 3 
days prior to Day 1. (Refer to SRM). 
Study treatments1 
Administer Dostarlimab2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
 
 
 
  
 
 
Refer to Section 5.2 for maximum duration 
of study treatment. 
On Treatment Safety 
AE/SAE/AESI 
Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3. After the initial AE/SAE report, the 
investigator is required to proactively follow 
each participant at subsequent 
visits/contacts. Refer to Section 9.4.1 for 
further details.  
ECOG PS** 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from 
Week 25 (i.e. the first Q6W visit is Week 31, 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
then Week 37, etc.) unless more frequent 
assessments are clinically indicated. 
Physical Examination** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
** Physical examinations and ECOG may be 
performed within 24 hours prior to dosing 
(i.e., as opposed to the day of dosing), if 
necessary. 
Vital Signs and Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Vital signs include blood pressure, 
temperature, pulse, respiratory rate, and 
oxygen saturation. Weight is to be recorded 
at every other treatment visit in kilograms. 
Vital signs are to be performed predose on 
treatment days. Refer to Section 9.5.3. 
If a participant experiences an infusion-
related reaction, refer to Section 12.1.4.11.1 
for guidance on vital signs monitoring.  
12-lead ECG* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
* Perform at every dosing visit (may be 
performed within 24 hours prior to dosing). 
Results must be reviewed before  dosing 
Cardiologist or locally appropriate specialist 
review may be required if abnormal results 
are obtained and confirmed as described in 
Table 34 . 
 
On Treatment Local Laboratory Assessments (Safety) – assessments may be performed up to 3 days prior to treatment 
Serum β-hCG (for 
women of childbearing 
potential)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5. Monthly urine pregnancy testing may also 
be performed as consistent with local 
standards however if a urine test is positive 
or borderline, or in the event of a missed 
menstrual period or suspicion of pregnancy, 
a serum β-hCG test will be required. 
Clinical Chemistry, 
Hematology, 
Coagulation6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6. Refer to Appendix 3 for a complete list of 
required assessments. Laboratory testing 
may be performed one day prior to dosing if 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
1 if screening labs are within 72 hours from 
time of scheduled first dose.  
 
 
Thyroid function tests 
 
 
X 
 
X 
 
X 
 
X* 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from 
Week 25 (i.e. the first Q6W visit is Week 31, 
then Week 37, etc.). 
Calculated CrCl7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7. CrCl is calculated by the CKD-EPI or 
Cockcroft-Gault formula. Either formula is 
acceptable and must be consistently utilized 
for each participant throughout the study. 
See Appendix 9. 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
On Treatment Disease Assessments 
Tumor 
Imaging/Response 
Assessment8 
 
 
X 
 
X 
 
X 
 
X 
X8 
8. Diagnostic quality CT scan of chest and 
abdomen with contrast is required every 6 
weeks (±1 week) until Week 49 and every 
12 weeks thereafter. Imaging/clinical 
assessments should be performed as 
indicated in Section 9.2. The same method 
of assessment is required throughout the 
study. Brain scan (MRI with and without IV 
gadolinium) and bone scan to be performed 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
as clinically indicated during the treatment 
period. If a participant has achieved a PD, 
CR, or PR in the previous radiologic 
assessment, a repeat scan should be 
performed after at least 4 weeks to confirm 
the response.  
On Treatment Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Biomarkers 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Tumor biopsies 
Fresh tumor tissue 
sample13 
 
 
X13 
 
 
 
X19 
 
 
 
 
On Treatment Pharmacokinetics and Anti-Drug Antibodies (ADA) 
GSK4428859A PK*14 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
 
 
 
 
 
 
 
 
 
 
 
17. Assessment required in participant 
experiencing anaphylaxis, serious 
hypersensitivity, or in the occurrence of an 
infusion reaction/CRS of any grade. 
Samples should be drawn during the 
occurrence of the event. Only if not possible 
to collect at the occurrence of the event, 
samples should be drawn as soon as 
possible after the event and within 24 hours 
(Refer to Section 7.2.1.2).Refer to Table 3 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
for list of analytes. Predose analysis will be 
performed on the serum sample collected 
for GSK4428859A and/or dostarlimab 
immunogenicity assessments. 
On Treatment Pharmacogenetics 
Genetic research18 
X 
 
 
 
 
 
 
 
 
 
 
18. Informed consent for optional genetic 
research must be obtained before collecting 
this sample. It is recommended that the 
optional research sample be taken at the 
first opportunity after a participant has met 
all eligibility requirements before Day 1 or on 
Day 1. 
 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; BNP = B-type natriuretic 
peptide; CKD-EPI = Chronic kidney disease epidemiology collaboration; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events; ECG = Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = End of infusion; 
 
 IRR = infusion related reaction; 
 
; NT-pro-BNP = N-terminal pro-hormone BNP; 
; PD = Progressive Disease; 
 
; PR = Partial response; Pre =Predose; 
 
 SAE = Serious adverse event. 
Pre: predose sample to be collected prior to dosing per institutional guidance, as long as it is collected prior to dosing of the corresponding agent; EOI: End of infusion sample is in 
reference to EOI of the corresponding agent. 
 
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Table 32 
Schedule of Activities – Treatment Discontinuation Visit and Follow-Up Arm 4: GSK4428859A (Anti-TIGIT) and 
Dostarlimab (Anti-PD-1) Combination 
TDV and Follow Up 
Assessments 
Treatment 
Discontinuation 
Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
within 30 days 
of study 
treatment 
discontinuation  
 
 
Anticancer Treatment 
 
Q12W* 
*If the participant dies before the first follow up, any subsequent anticancer therapy or radiotherapy should be 
recorded in the eCRF. 
 
 
Concomitant Medications 
X 
 
 
TDV and Follow Up Safety 
AE/SAE/AESI Assessment2 
X 
 
2. After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. Refer to Section 9.4.1 and Section 9.4.3 for further details. 
ECOG PS 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs and Weight3 
X 
 
3. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. 
TDV and Follow Up Local Laboratory Assessments 
Clinical Chemistry  
X 
X^ 
 
Serum β-hCG (for women of 
childbearing potential) 
X 
 
 Refer to Appendix 3 for a complete list of required laboratory assessments. 
^Safety laboratory assessments should be collected at TDV (within 30 days of last dose of study treatment) 
and at 60 and 90 days after last dose of study treatment, unless the participant has started a new anti-cancer 
therapy within the 90 day follow-up period, in which case safety laboratory assessments are not applicable. 
Hematology 
X 
X^ 
Coagulation 
X 
 
Thyroid function tests 
X 
X^ 
Calculated CrCl 
X 
 
Urinalysis 
X 
 
 
 
12-lead ECGa 
X 
 
TDV and Follow Up Disease Assessments 
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TDV and Follow Up 
Assessments 
Treatment 
Discontinuation 
Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
within 30 days 
of study 
treatment 
discontinuation  
 
 
Tumor Imaging/Response 
Assessment4 
X 
 
4. At the TDV, CT scan is required only if the last disease assessment did not show confirmed PD and was 
performed ≥6 weeks before TDV. For participants who discontinue study treatment without documented 
disease progression, every effort should be made to continue monitoring disease status by tumor imaging 
using the same imaging schedule used while on treatment until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. 
See additional information in Section 9.3.1 
Telephone call for survival status1a 
 
Q12W 
 
TDV and Follow Up Tumor Biopsies 
Fresh tumor tissue sample 
X5 
 
5. If possible, obtain an optional tumor tissue sample at time of confirmed PR or PD. 
TDV and Follow Up Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY  
 
 
 
 
 
 
 
 
 
 
 
TDV and Follow Up Biomarkers 
TDV and Follow Up Pharmacokinetics and Anti-Drug Antibodies (ADA) 
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Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; BNP = B-type natriuretic 
peptide; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events;ECG = 
Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = Electronic case report form; 
 
 
; NT-pro-BNP = N-terminal pro-hormone BNP; PBMC = 
peripheral mononuclear cells; PD = Progressive Disease; 
; 
 
; SAE = Serious adverse event; TDV = Treatment Discontinuation Visit 
1. The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to the 
start of subsequent anticancer therapy. If participant attends clinic for scheduled visit and decision is made to discontinue treatment, site can use this visit as the TDV and complete 
all assessments.  
1a. Survival Follow-Up is the Observational Phase of the study. Participants will be followed for survival and subsequent anticancer therapy every 12 weeks after the last dose of study 
treatment, via telephone contact. Participants will be contacted every 12 weeks (±7 days) until death or participant’s withdrawal from further contact. Subsequent anticancer 
treatment and death date will be documented in the eCRF 
.
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12.1.4.3. 
Rationale for the GSK4428859A (Anti-TIGIT) and Dostarlimab (Anti-PD-
1) Combination 
Multiple immune checkpoints in addition to PD-(L)1 may regulate T cell anergy and 
modulate antitumor immunity [Topalian, 2011; Mellman, 2011]. Co-regulatory receptors 
expressed on T cells can induce stimulatory or inhibitory signaling cascades that 
modulate T cell proliferation, cytokine production, and cytotoxic T cell activation. 
Proteins of the nectin and nectin-like (Necl1) family, including TIGIT (T cell 
immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain), PVRIG 
(Poliovirus Receptor-related Immunoglobulin Domain Containing), and CD96, have 
emerged as immune-suppressing candidates that may prevent immune reactivation after 
PD-(L)1 blockade. These co-regulatory receptors modulate the CD226 immune 
checkpoint, which is one of the major activating receptors for natural killer (NK) cells. 
TIGIT interaction with the ligand CD155 downregulates cytotoxic T and NK cells and is 
a critical regulator of antitumor T cell immunity [Harjunpää, 2020]. TIGIT may regulate 
antitumor immunity through a variety of mechanisms: by inhibiting NK cells from 
releasing tumor antigens, impairing T cell priming by dendritic cells, or inhibiting CD8+ 
effector tumor cell killing [Harjunpää, 2020; Johnston, 2014; Joller, 2014]. The 
interaction of TIGIT with its complementary costimulatory receptor, CD226, is 
analogous to the interaction of CTLA-4 and CD28. TIGIT competes with CD226 for its 
main ligand, CD155 [Stengel, 2012; Johnston, 2014], modulating antitumor immunity 
through multiple mechanisms. Binding of TIGIT on T cells with CD155 ligand on 
dendritic cells impairs CD4+ T cell function [Chauvin, 2020]. In addition, binding of 
TIGIT prevents homodimerization and activation of CD226 on CD8+ T cells [Johnston, 
2014]. TIGIT also interacts weakly with other co-regulatory inhibitors of the CD226 
pathway including CD112, CD113, and CD114. 
TIGIT is highly expressed on murine and human tumor infiltrating T cells [Johnston, 
2014]. In human tumor specimens from the Cancer Genome Atlas (TCGA [NCI, 2021]), 
TIGIT expression is upregulated in a broad range of solid tumors [Johnston, 2014]. 
TIGIT is upregulated on tumor infiltrating CD8+ T cells and a population of infiltrating 
CD4+ T cells in solid tumors in comparison to peripheral T cells from patients and 
normal donors. CD8+ and CD4+ TIGIT-expressing T cells also co-express PD-1. 
In NSCLC, TIGIT was expressed in tumor-infiltrating CD8+ and CD4+ T cells and was 
co-expressed with PD-1 [Johnston, 2014]. Peripheral CD8+ and CD4+ T cells from 
NSCLC tumor donors had higher levels of TIGIT compared with healthy donors. In 
addition, in patients with NSCLC, the expression of PD-1 was higher in TIGIT+ cells 
than in TIGIT- cells in both circulating CD8+ T cells and tumor infiltrating CD8+ T cells 
[Hu, 2020]. TIGIT could act as a checkpoint inhibitor in exhausted tumor-infiltrating T 
cells. 
 
EOS884448 (also known as EOS-448; hereafter referred to as GSK4428859A) is a fully 
human IgG1 mAb that prevents TIGIT-ligand binding. As an IgG1, GSK4428859A also 
displays a potent affinity for the FcγRs with the potential to mediate antibody-dependent 
cellular cytotoxicity/phagocytosis (ADCC/P) against TIGIT expressing cells. Binding of 
GSK4428859A to TIGIT was shown to increase T cell activation by competing with 


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TIGIT ligands. GSK4428859A (or its mouse surrogate for rodent studies) mediates 
ADCC/P of immunosuppressive cells by preferentially targeting immunosuppressive 
Tregs that express a high level of TIGIT relative to cytotoxic CD8 or NK cells, resulting 
in an increased ratio of effector CD8+/immunosuppressive Treg cells. Moreover, this 
effect was abrogated in mice lacking FcγRs, further suggesting the requirement for an 
ADCC/P effect to fully induce tumor growth inhibition. Overall, these data demonstrate 
that GSK4428859A restores antitumor immunity by preventing the activation of TIGIT 
by its natural ligands, PVR/CD155 and Nectin2/CD112, and induces a strong immune 
response mediated by Treg depletion and ADCC/P [Preillon, 2021]. 
Dostarlimab (formerly referred to as TSR-042) is an IgG4-k humanized monoclonal 
antibody that binds with high affinity to PD-1 resulting in inhibition of binding to PD-L1 
and PD-L2. This antibody was generated based on a proprietary platform that utilizes 
affinity maturation to select antibodies with desired functional characteristics. The 
functional antagonist activity of dostarlimab was confirmed in an MLR demonstrating 
enhanced interleukin-2 production upon addition of dostarlimab. Dostarlimab is an anti-
PD1 agent so nonclinical safety data is expected to be similar to a large extent to what 
was seen with data supporting pembrolizumab combinations. To support combination 
with dostarlimab, the principal nonclinical toxicology findings associated with 
dostarlimab were reviewed. A toxicology program including single-dose and repeat-dose 
IV toxicity studies in cynomolgus monkeys for up to 13 weeks indicated that dostarlimab 
was well tolerated with no signs of adverse effects, except for potential immune-related 
reactions in tissues, such as the skin, heart, liver, and kidney. 
Pharmacological inhibition of TIGIT with antagonist antibodies inhibits tumor growth in 
murine tumor models, either alone or in combination with immune checkpoint inhibitors 
like anti-PD-(L)1 [Johnston, 2014; Zhang, 2018; Hung, 2018; Guillerey, 2018; Dixon, 
2018; Minnie, 2018; Minnie, 2019]. Activation of PD-1 signaling dephosphorylates and 
inactivates CD226 via an intracellular SH2-containing protein tyrosine phosphatase 2 
domain. Combined blockade of TIGIT and PD-1 can synergize to promote antitumor 
immune response and overcome resistance to immunotherapy in a variety of tumor types 
in nonclinical model systems. In a nonclinical mouse model system of CT26 CRC, anti-
TIGIT or anti-PD-L1 antibodies alone were insufficient to decrease tumor burden, 
however the combination of anti-PD-1 and anti-TIGIT blocking antibodies caused tumor 
regression with the majority of mice achieving a complete response [Johnston, 2014]. 
Mice bearing CT26 tumors treated with anti-TIGIT and anti-PD-L1 agents in 
combination had improved survival compared with control or monotherapy treated mice. 
Combined TIGIT and PD-1 blockade in mice with established MC38 CRC demonstrated 
tumor regression and tumor clearance compared with monotherapy and control treatment 
[Dixon, 2018]. Combination treatment with anti-TIGIT and anti-PD-1 agents resulted in 
increased production of inflammatory cytokines including IL-2, IFN, and TNF by 
CD4+ and CD8+ tumor infiltrating lymphocytes compared with either therapy alone, 
suggesting that combined blockade of TIGIT and PD-1 enhances TIL function and 
associated OS. These findings suggest the potential for synergy between anti-PD-(L)1 
and anti-TIGIT agents to overcome T cell anergy and stimulate antitumor immunity. 
 
 


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To support combination with GSK4428859A, the principal nonclinical toxicology 
findings associated with GSK4428859A were reviewed. A program including a battery of 
nonclinical toxicity studies was completed to evaluate the potential repeat-dose toxicities, 
immunotoxicity, potential for cytokine release, tissue cross-reactivity and safety 
pharmacology. All studies, including single-dose and repeat-dose IV toxicity studies in 
cynomolgus monkeys for up to 4 weeks indicated that GSK4428859A was well tolerated 
with no signs of adverse effects, and a NOAEL that was the highest tested dose of 
mg/kg. 
 
12.1.4.4. 
 Clinical Safety Summary 
12.1.4.4.1.  GSK4428859A 
Several mAbs targeting TIGIT are in various stages of clinical development. These 
agents include tiragolumab, vibostolimab, domvanalimab, etigilimab, and 
GSK4428859A, among  an increasing number of others. 
A Phase 1b study of vibostolimab monotherapy in participants with advanced solid tumor 
types previously treated with anti-PD-(L)1 therapy reported a 3% ORR and 35% DCR 
[Golan, 2018]. In a Phase 1a/Phase 1b study of tiragolumab as a single agent and in 
combination with atezolizumab in advanced solid tumors, there were no objective 
responses in 24 participants treated with tiragolumab monotherapy [Bendell, 2020]. The 
24 participants enrolled in the tiragolumab monotherapy arm included primary cancer 
history types such as colon, rectum, breast, ovarian, endometrial, melanoma, and other 
cancer diagnosis [Bendell, 2020]. The ORR for etigilimab in the dose-escalation phase 
was 0%, with a DCR of 30% in a Phase 1a/Phase 1b study of etigilimab in participants 
with advanced solid tumors [Sharma, 2018]. A Phase 1 dose-finding study of 
GSK4428859A, monotherapy demonstrated favorable tolerability and modest 
preliminary efficacy in 20 participants with advanced solid tumors, with an ORR of 5% 
[Van den Mooter, 2021]. 
The safety profile of anti-TIGIT mAbs has been tolerable and comparable to that of other 
single-agent immune checkpoint inhibitors. In the vibostolimab Phase 1b study of 
immune checkpoint inhibitor-experienced participants, 59% of participants experienced 
any treatment-related adverse event (TRAE) with Grade ≥3 TRAEs in 15% of 
participants in the vibostolimab monotherapy arm. The most common TRAEs reported 
were fatigue (22%) and rash (20%). One participant (2%) had a TRAE that led to 
discontinuation and none experienced a fatal TRAE [Golan, 2018]. In the Phase 1a 
dose-escalation phase of the tiragolumab study in 24 patients, there were no DLTs 
[Bendell, 2020]. TRAEs occurred in 67% of participants, Grade 3 TRAEs in 4% (Grade 
3 blood creatinine increase) and the most common AE reported was fatigue (38%). There 
were 6 SAEs reported (25%) with no AEs leading to study withdrawal or death [Bendell, 
2020].  
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12.1.4.4.2. Dostarlimab 
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• 
Treatment-emergent SAEs regardless of causality were reported in
% of 
participants; the most frequently reported 
% of participants) were 
abdominal pain 
%), pneumonia 
%), and dyspnoea 
%). Treatment-
related SAEs were reported in 8.5% of participants; the most frequently 
reported 
% of participants) were pneumonitis 
%), adrenal 
insufficiency 
%), and pyrexia 
%). 
• 
TEAEs leading to treatment discontinuation regardless of causality were 
reported in 
% of participants; the most frequently reported
% of 
participants) were alanine aminotransferase increased 
%), aspartate 
aminotransferase increased 
%), pneumonitis 
%), and transaminases 
increased
%). Treatment-related events leading to discontinuation were 
reported in
% of participants; the most frequently reported 
% of 
participants) were alanine aminotransferase increased
%), aspartate 
aminotransferase increased
%), pneumonitis 
%), and transaminases 
increased
%). 
• 
TEAEs leading to death regardless of causality were reported in
% of 
participants with respiratory failure the only event reported in >1 participant 
participants 
%]); 
% of the deaths were due to treatment-related 
TEAEs (completed suicide, hepatic ischaemia). 
Of the
participants,
% who received dostarlimab monotherapy experienced at 
least 1 immune-related TEAE (irAE). The most frequent 
%) irAEs were 
hypothyroidism, diarrhea, alanine aminotransferase increased, aspartate aminotransferase 
increased, blood creatinine increased, hyperglycemia and amylase increased. 
 
participants 
%) who received dostarlimab monotherapy experienced at least 1 irAE 
with severity of ≥Grade 3. For
 participants with ≥Grade 3 irAEs, the AE was 
assessed as study drug related by investigators. 
The safety profile of monotherapy dostarlimab in participants with advanced or recurrent 
solid tumors was generally similar to the reported safety profiles of other mAbs blocking 
the PD-1 interactions (KEYTRUDA USPI, 2021; KEYTRUDA, SmPC, 2021; OPDIVO 
USPI, 2021; OPDIVO, SmPC, 2021).  
12.1.4.5.  Anti-TIGIT and Anti-PD-1/PD-L1 Monoclonal Antibody Combinations in 
Clinical Studies 
Combinations with anti-TIGIT mAbs and anti-PD-1/PD-L1 mAbs have demonstrated 
improved antitumor efficacy while preserving acceptable side effect profiles. The 
combination of vibostolimab with pembrolizumab (an anti-PD-1 mAb) demonstrated a 
confirmed ORR of 24%, DCR of 36%, and a median DOR that was not reached 
(95% CI: 4 to 17+ months) in participants with a variety of advanced solid tumors who 
were naïve to anti-PD-(L)1 therapy [Niu, 2020]. Notably, even in participants who had 
previously received anti-PD-(L)1 therapy, the DCR was 50%, driven mostly by disease 
stabilization [Ahn, 2020]. In a Phase 1b dose-escalation study, the combination of 
tiragolumab with atezolizumab (an anti-PD-L1 mAb) showed an ORR of 9% in 
participants with advanced solid tumors. In an expansion cohort of anti-PD(L)1-naïve 
participants with PD-L1+ NSCLC, an ORR of 46% and a DCR of 85% were observed 
[Bendell, 2020].  
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The results from the aforementioned Phase 1b study led to the Phase 2 CITYSCAPE 
study, a randomized, double-blind study of tiragolumab plus atezolizumab versus placebo 
plus atezolizumab in participants with PD-L1+ (TPS ≥1%), treatment-naïve, locally 
advanced or metastatic NSCLC. In the CITYSCAPE study, a confirmed ORR of 37% for 
the combination arm compared with 21% for the placebo/atezolizumab arm in the intent-
to-treat population (n=135) was reported [Rodríguez-Abreu, 2020]. Median PFS was 
improved from 3.88 months (range: 2.73 to 4.53 months) with atezolizumab to 5.5 
months (range: 4.2 to 10.4 months; HR: 0.58, 95% CI: 0.38, 0.89) for the combination. In 
58 participants with PD-L1-high (TPS ≥50%) tumors, the confirmed ORR was 66% for 
the combination compared with 24% in the atezolizumab arm. The median PFS was not 
reached with the combination (95% CI: 5.49 to not evaluable [NE]) compared with 
4.11 months (95% CI: 2.07, 4.73) for the atezolizumab arm (HR for PFS: 0.3; 
95% CI: 0.15. 0.61). For participants with PD-L1 TPS 1-49%, the ORR and PFS were 
similar across both arms (ORR: 18% with atezolizumab vs 16% with tiragolumab and 
atezolizumab; PFS: 3.58 months and 4.04 months, respectively [HR:0.89; 
95% CI: 0.53, 1.49]). The rates of TEAEs (99% vs 96%), Grade 3 AEs (48% vs 44%), 
Grade 5 AEs (5% vs 7%), SAEs (37% vs 35%), and AEs leading to treatment withdrawal 
(10% vs 9%) were all similar between the combination and placebo/atezolizumab arms, 
respectively; there was a modest increase in AEs leading to dose modification in the 
combination arm (40% vs 28%). The overall rate of immune-mediated AEs (69% vs 
47%) and Grade 3 or 4 immune-mediated AEs (18% vs 13%) were higher in the 
combination arm [Rodríguez-Abreu, 2020]. 
Similar results have been observed with other anti-TIGIT mAbs and anti-PD-(L)1 
combinations, suggesting anti-TIGIT mAbs promote enhanced antitumor immune 
responses without a substantial increased risk of toxicity over single-agent immune 
checkpoint blockade [Niu, 2020]. Vibostolimab in combination with pembrolizumab has 
demonstrated responses in participants with advanced NSCLC naïve to anti-PD-(L)1 
therapy both with and without PD-L1 expression [Niu, 2020]. As a result, multiple 
Phase 3 clinical studies are underway evaluating anti-TIGT and anti-PD(L)1 combination 
therapy in PD-L1+ NSCLC (NCT04738487; NCT04746924; NCT04262856; 
NCT04294810; NCT04736173). 
The combination of GSK4428859A and dostarlimab is supported by the reported clinical 
safety profiles of similar TIGIT-targeting agents administered alone or in combination 
with anti-PD-(L)1 agents. In the dose-escalation phase, tiragolumab (an anti-TIGIT mAb) 
was administered at 2, 8, 30, 100, 400, 600, 1200 mg Q3W in combination with the anti-
PD-L1 agent, atezolizumab (1200 mg Q3W). No DLTs were observed across all doses 
(N=49). TRAEs occurred in 59% of participants and the most frequently reported TRAEs 
were Grade 1 pruritus, Grade 1-2 fatigue, Grade 1-2 rash, Grade 1 diarrhea, and Grade 1 
arthralgia. Two Grade 3 TRAEs were reported in the combination: 1 hyperlipasemia and 
1 lymphocyte count decreased. Infusion reactions were seen in 8% of participants, most 
were Grade 1/2. A higher rate of immune-related AEs (irAEs) was observed with the 
combination than with tiragolumab monotherapy [Bendell, 2020]. In the Phase 2 
CITYSCAPE study, the addition of tiragolumab at 600 mg Q3W to first-line 
atezolizumab at 1200 mg Q3W in PD-L1–selected metastatic NSCLC demonstrated good 
tolerability with a safety profile similar to placebo plus atezolizumab [Rodríguez-Abreu, 
2020]. Vibostolimab (an anti-TIGIT mAb) demonstrated a tolerable safety profile across 


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the various doses tested alone and in combination with pembrolizumab (anti-PD-1, 200 
mg Q3W) in the Phase 1b study (see Rationale Section 12.1.4.3 for further details). 
12.1.4.6. Dose Justification 
12.1.4.6.1. GSK4428859A Pharmacokinetics and Pharmacodynamics  
12.1.4.6.2.  GSK4428859A Dose Rationale (Arm 4) 
The GSK4428859A RP2D of
mg
is based on the preliminary safety, PK/PD, 
and efficacy data available from the Phase 1/Phase 2a clinical Study IO-002 
(NCT04335253), as well as observations from other clinical studies evaluating anti-
TIGIT mAbs which generally have similar properties [Bendell, 2020; Rodríguez-Abreu, 
2020; Niu, 2020]. Additionally, Study TIG-006 is currently evaluating the safety, 
tolerability, PK, PD, and anti-tumor activity of GSK4428859A in combination with 
pembrolizumab in participants with advanced solid tumors. The starting dose level of 
GSK4428859A will be
 mg 
 in combination with pembrolizumab. 
The doses of GSK4428859A under evaluation in the FTIH Study IO-002 ranged from 
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In vitro evaluation shows that GSK4428859A competes with CD155 for TIGIT binding 
with a saturating effect noted at 4.22 to 133 nM (0.623 to 20.0 µg/mL) [Refer to Section 
5.1.1.1.4  of the iTeos EOS884448 [EOS-448] IB, 2021]. This target level has been 
confirmed in multiple functional assays, including ADCC, and translates to in vivo 
mouse studies [Refer to Section 5.1.1.1.8 and Section 5.1.1.2.3 of the iTeos EOS884448 
[EOS-448] IB, 2021]. Assuming a tumor tissue dilution of 20-fold [Shah, 2013] and 
dosing,
µg/mL would result in tumor 
concentrations that would saturate TIGIT binding in the tumor. A preliminary population 
PK analysis of GSK4428859A FTIH data was conducted and simulations were 
performed to evaluate a variety of GSK4428859A doses and regimens for future studies. 
The simulated minimum serum concentration after the first dose and at steady state 
following
mg
is
µg/mL and
µg/mL, respectively  [Refer to Table 16 
of the iTeos EOS884448 [EOS-448] IB, 2021], both of which are within the range 
estimated to result in tumor concentrations that would saturate TIGIT binding. 
 
Based on these data, GSK4428859A
mg is considered an appropriate starting dose to 
combine with dostarlimab to minimize the risk of unacceptable toxicity and maximize the 
potential benefit to participants with NSCLC. Moreover, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12.1.4.6.3. Dostarlimab Dose Rationale 
No reduction in dostarlimab dose is allowed given that the safety and efficacy profile of 
the included dose regimen for dostarlimab is considered acceptable, whereas the efficacy 
of lower doses is not fully characterized.  
12.1.4.7. 
Study Treatments 
Table 33 
Description and Administration of Arm 4 GSK4428859A plus 
Dostarlimab (Anti-PD-1) Study Treatments 
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 (see 
pharmacy manual for administration instructions).  
All participants should remain under observation at the study site after the completion of 
study treatment administration (refer to SRM for details). Section 12.1.4.11, Table 35 for 
details on the management of participants experiencing infusion reactions. Refer to 
Section 5.2 for information on the duration of study treatment. 
The date and time of administration will be documented in the source documents and 
reported in the eCRF. For drug administered by an investigator or designee, the dose of 
study treatment and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
treatment. The specific time of study treatment administration (e.g., time of the week for 
first administration; time of the day for each administration) should take into 
consideration PK sampling time points, study visit procedures, and the post-infusion 
observation time interval. Infusions may be administered up to 72 hours before or after 
the planned date of treatment for administrative reasons only (e.g., scheduling an infusion 
around a holiday). Both drugs should be administered on the same day. The 72-hour 
window does not apply to completion of study treatment administration interrupted by an 
infusion reaction. Refer to Section 7.2.1.4 for criteria governing dose interruptions or 
delays. 
Details on preparation and administration of GSK4428859A and dostarlimab are 
described in the pharmacy manual.  
12.1.4.8. 
Concomitant Therapy 
Please refer to Section 7.7 
12.1.4.9. 
Treatment of Overdose 
12.1.4.9.1. GSK4428859A Overdose 
An overdose of GSK4428859A is defined as administration of a dose that is above 
mg.  
In the event of an overdose, the investigator must: 
1 Contact the Medical Monitor immediately. 
2 Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 120 days. 
3 Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).  
4 Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
 
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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 the experimental treatments being 
evaluated in this study. 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.  
12.1.4.9.2. Dostarlimab Overdose 
Human data on overdose are not available. There is no known antidote for dostarlimab.  
 
An overdose of dostarlimab is defined as any dose that is ≥20% than 
mg
 
In the event of an overdose, the investigator must: 
1 Contact the Medical Monitor immediately. 
2 Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 120 days. 
3 Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).  
4 Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.  
 
There is no specific antidote for overdose with the experimental treatments being 
evaluated in this study. 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.  
 
12.1.4.10. Treatment Duration for GSK4428859A and Dostarlimab  
Participants enrolled will be treated until disease progression, intolerable toxicity, 
informed consent withdrawal or death. Combination study treatment will continue to be 
administered at the indicated schedule for a maximum duration of up to 35 treatment 
visits or approximately 2 years, whichever comes first. Refer to Section 5.2 for additional 
details regarding follow up after discontinuation of study treatment. 
 
12.1.4.11. Dose modification and Management Guidelines 
No dose reductions are allowed for dostarlimab. No dose reductions are allowed for 
GSK4428859A at the participant level. Dose modification guidelines for immune related 
adverse events are listed in Table 34. If study drugs must be held or discontinued for any 
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toxicity, all study drugs must be held or discontinued, unless discussed otherwise with 
Medical Monitor. 
 
In case of any unforeseen toxicities for GSK4428859A occurring at the
mg
dose cohort in combination, de-escalation to
mg or a lower dose
 may be 
considered at the cohort level, if needed. 
 
In addition to the immune-related adverse events listed in Table 34, immunotherapy may 
be associated with other irAEs, including events which may be less commonly associated 
with PD-(L)1 inhibitors but can similarly result from activation of cellular immune 
response. For these events, most current professional guidelines (e.g.: National 
Comprehensive Cancer Network [NCCN], National Comprehensive Cancer Network 
[SITC]) should be considered. Patients should receive appropriate supportive care 
measures as deemed necessary by the treating Investigator, including but not limited to 
the items outlined below: 
 
Table 34 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs 
General instructions: 
• 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
• 
For situations where immunotherapy treatment has been withheld, treatment can be resumed after AE 
has been reduced to Grade 1 or resolved and corticosteroid has been tapered. Immunotherapy treatment 
should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
• 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Respiratory 
Pneumonitis  
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Gastrointestinal 
Diarrhea / colitis 
Hepatobiliary 
Hepatitis with no tumor 
involvement of the liver 
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Hepatitis with tumor 
involvement of the liver** 
Endocrine 
Type 1 diabetes mellitus 
(T1DM) or Hyperglycemia 
 
Endocrinopathies (e.g. 
hypophysitis, hypo-
/hyperthyroidism, adrenal 
insufficiency) 
Renal 
Nephritis with renal 
dysfunction 
Cardiovascular 
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Cardiac Investigations 
i) ECG changes and/or ii) 
troponin and/ or NT-
proBNP/BNP elevations 
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Myocarditis 
Other 
Neurological Events 
(myasthenia gravis, Guillain-
Barré syndrome, encephalitis, 
transverse myelitis) 
All other immune-related 
AEs 
Skin Toxicities1 
Rash 
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Pruritis 
Exfoliative dermatologic 
conditions (e.g. SJS, TEN, 
DRESS) 
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Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
NOTES:  
*Resume in patients with complete resolution or partial resolution  to Grade 1 after corticosteroid taper. Permanently 
discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone 
to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids. 
 
**If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or 
permanently discontinue based on recommendations for hepatitis with no liver involvement. 
***Abnormal troponin and proNTBNP/BNP at screening is defined as any value >ULN at screening 
 
1. For any grade skin toxicities, recent alcohol intake or other potentially related concomitant exposures per 
Investigator assessment, should be recorded in the eCRF. Please refer to SRM for additional details. 
Abbreviations: BNP = B-type natriuretic peptide; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; 
DRESS = drug reaction with eosinophilia and systemic symptoms. 
12.1.4.11.1. 
Dose Modification and Toxicity Management of Infusion-Reactions 
Related to Immunotherapy Treatment 
Table 35 
Immunotherapy Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
Please refer to the pharmacy manual for 
administration details.  
Participant may be premedicated 
1h (± 30 minutes) prior to infusion 
of study drugs with: 
Diphenhydramine 50 mg (or 
equivalent dose of antihistamine) 
and/or acetaminophen 325-1000 
mg (or equivalent dose of 
analgesic) 
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. 
Participant may be premedicated 
1h (± 30 minutes) prior to infusion 
of study drugs with: 
Diphenhydramine 50 mg (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg (or 
equivalent dose of analgesic). 
If necessary, corticosteroids (up 
to 25mg of hydrocortisone or 
equivalent) may be used and 
adaptation of the infusion rate 
should be discussed with Medical 
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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
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), unless otherwise specified in the 
pharmacy manual. Otherwise dosing will 
be held until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose. 
 
Participants who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
study drug treatment. 
 
Please refer to the pharmacy manual for 
administration details. 
Monitor. 
 
Grades 3 or 4 
Grade 3: 
Prolonged (e.g. not rapidly 
responsive to symptomatic 
medication and/or 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. 
 
Please refer to the pharmacy manual for 
administration details. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
Abbreviations: NSAIDs = non-steroidal anti-inflammatory drugs. 
If a participant has an infusion related reaction, vital signs will be obtained every 15 
minutes (± 5 minutes) at the start of symptoms until the participant is deemed medically 
stable in the opinion of the investigator; pulse oximetry should be performed in 
conjunction with vital signs. 
 
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Refer to Section 7.2.1.1 for details. In addition, for AESIs of immune related cutaneous 
toxicities of any grade, recent alcohol intake or other potentially related concomitant 
exposures per Investigator assessment, should be recorded in the eCRF. Please refer to 
SRM for additional details. 
12.1.4.12. Safety Evaluation 
If a participant withdraws from the study before the completion of the 21-day DLT 
evaluation period for reasons other than DLT or becomes non-evaluable during the DLT 
period, then the participant may be replaced to achieve the three-participant required 
minimum. The decision to declare the combination tolerable will occur following review 
of the safety, PK and PD data (if available) and joint discussion by the GSK Medical 
Monitor and investigators. Membership, roles and accountabilities, and the process for 
safety review and meeting frequency is outlined in the Study Reference Manual.  
The mTPI design assumptions include the following: 
(i) 
(ii) 
The monitoring rules guiding dose decision are provided in Table 36. The tolerability 
decision framework using the mTPI method were generated based on a beta/binomial 
model and pre-calculated before study initiation. The rules in Table 36 utilize the mTPI 
method along with additional rules as following: 
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. 
12.1.4.14. Dose Limiting Toxicity 
The severity of all toxicities will be graded using National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 5.0) [NCI, 2017]. The 
DLT observation period is 21 days in length and begins on the day study treatment is first 
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administrated to the participant. 
A DLT is defined as an AE that meets at least one of the criteria listed in Table 37 and is 
considered by the investigator to be clinically relevant and attributed (probably, or 
possibly) to the study treatment during the 21-day DLT observation period. An AE 
considered related to the underlying disease under study it is not defined as a DLT. A 
safety event can still be included for DLT consideration after the 21 day window. See 
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Table 37 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition (Grading per CTCAE v5) 
Hematologic 
• 
Grade 4 neutropenia of any duration or febrile neutropenia  
• 
Grade 4 anemia of any duration 
• 
Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with bleeding 
Non- hematologic 
• Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to G1 severity or requires systemic treatment.  
• Grade 2 colitis or diarrhea that persists without resolution to ≤ Grade 1 for ≥ 7 days 
despite adequate immunosuppressive therapy  
• Grade 3 diarrhea/colitis lasting ≥72h regardless of medical intervention or G4 
diarrhea/colitis    
• Grade 3 pneumonitis  
• Grade 3 rash if no resolution to ≤Grade 2 or baseline within 2 weeks with use of systemic 
steroids or anti-inflammatory agents per standard of care  
• Grade 3 hypersensitivity or IRR   
• ALT ≥ 3x ULN plus bilirubin ≥ 2x ULN (>35% direct) or plus INR >1.5, if measureda 
(possible Hy’s Law) 
• Grade 3 toxicity that does not resolve to ≤Grade 1 or baseline within 3 days despite optimal 
supportive careb or any Grade 4 toxicity  
• Following events are not considered DLTs 
o 
≥ Grade 3 electrolyte abnormalities that are corrected to ≤ Grade 1 or 
baseline within 72 hours without clinical sequelae 
o 
Grade 3 nausea or vomiting that resolves to ≤Grade 1 or baseline within 7 
days 
o 
≥Grade 3 fatigue ≤7 days  
o 
≥Grade 3 lymphopenia  
o 
Grade 3 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis  
Other 
• Toxicity that results in permanent discontinuation of either agent in combination  
• Any other toxicity considered to be dose-limiting that occurs after the completion of the DLT 
observation period will be considered in the selection of the dose to recommend for 
expansion cohorts 
• Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT 
a. Not applicable to participants taking anticoagulants.  
b. Suggested toxicity management guidelines as described in Section 12.1.4.11 may include systemic 
corticosteroids for immune-related toxicities; if systemic corticosteroids use delays administration of the 
second dose of study treatment and the event does not otherwise meet the DLT criteria for non- hematologic 
toxicity, the dose delay will not be considered a DLT. 
CTCAE=Common Toxicity Criteria for Adverse Events; DLT = Dose-limiting toxicity; G-CSF =Granulocyte 
colony-stimulating factor; GSK =GlaxoSmithKline; IRR=infusion related reaction 
 
If a participant experiences a DLT during the DLT observation period, the participant 
may resume dosing provided the toxicity did not meet study treatment discontinuation 
criteria and following approval by the Sponsor. 


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Toxicity management and dose modification guidelines provided in Section 12.1.4.11 are 
directed for those AEs of special interest that, although not observed in nonclinical 
studies, may be expected with the administration of immune directed therapies. 
 
Guidance for the identification, evaluation, and the established algorithms for the 
treatment management of immune-related adverse events (irAEs) including dose 
modification algorithms are provided in Section 12.1.4.11. These guidelines are based on 
the experience of irAE management following the development of immune check-point 
inhibitors such as ipilimumab and pembrolizumab. Guidelines are also provided for 
infusion reactions or severe cytokine release (Section 12.1.4.11.1). The joint ASCO and 
NCCN guidelines for the diagnosis and management of irAEs treated with immune 
checkpoint inhibitor therapy may be used as a supplement to the guidance provided in 
Section 12.1.4.11. 
 
If there is a delay in administration of study treatment, refer to Section 12.1.4.11 for 
guidance on planning of subsequent study visits. 
 
12.1.4.15. Risk-Benefit Assessment of GSK4428859A and Dostarlimab combined   
Table 38 
Risk Assessment and Mitigation Strategy: Dostarlimab and 
GSK4428859A 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immune-related AEs 
(irAEs) 
 
 
 
• Inflammatory AEs such as diarrhea/colitis, 
pneumonitis, nephritis, myocarditis and 
hepatotoxicity are well established as 
treatment emergent AEs with immune-
modulating agents, and are consistent 
with the immune-stimulatory mechanism 
of action of these agents.  
• An anti-PD-1 checkpoint inhibitor 
(dostarlimab) will be used in combination 
with an anti-TIGIT mAb (GSK4428859A).  
• Based on the safety profile of anti PD-1 
antibodies, administered alone or in 
combination, the anticipated adverse 
reactions may be primarily immune 
mediated. Based on emerging data from 
anti-TIGIT mAbs, administered alone or in 
combination, the anticipated adverse 
reactions are similarly immune mediated. 
 
• Participants with the following 
medical history are ineligible for this 
study 
o Toxicity (≥Grade 3) related to 
prior immunotherapy leading to 
study treatment discontinuation  
o Active autoimmune disease (refer 
to Section 6.2 exclusion criterion 
6) 
o Severe hypersensitivity to another 
mAb 
• Established management algorithms 
for immune-related adverse events 
(irAEs)  
• Refer to Section 12.1.4.11 for further 
details on the identification, 
evaluation, and management of 
toxicities with a potential immune 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Infusion and 
hypersensitivity 
reactions and potential 
CRS 
• 
Risk for infusion reactions and 
hypersensitivity is inherent to many 
mAbs [Brennan, 2010]  
Dostarlimab: 
• 
The frequency of IRRs with dostarlimab 
is labelled as common 
 
 
 GSK4428859A 
• 
 
See Investigator’s Brochures for dostarlimab, 
and GSK4428859A [iTeos EOS884448 
[EOS-448] IB, 2021] for details. 
• 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 12.1.4.11 for further 
details on management and 
monitoring of infusion reactions.  
• Refer to Section 12.1.4.11 for further 
details on management of CRS 
• Refer to Protocol Section 7.2.1.2; 
Table 3 for details of blood panel 
collection for all participants 
experiencing any grade of infusion 
reaction or CRS  
• For severe (Grade 3) or 
life-threatening (Grade 4) IRRs 
associated with GSK4428859A or 
dostarlimab, infusion should be 
stopped, and treatment should be 
permanently discontinued. 
ADA and Immune 
complex disease 
• Immune complex deposition may cause 
clinical symptoms, most commonly renal, 
skin, or vasculitis pathology. 
• For nonclinical immune complex formation 
and deposition findings (refer to individual 
product Investigator’s Brochure [IBs]) 
• GSK4428859A is a fully human IgG1 mAb 
with a wild-type Fc domain. Based on the 
characteristics of the molecules and 
active pharmaceutical ingredients, the risk 
of immunogenicity in humans is 
considered to be low and similar to other 
mAbs. 
• Clinical laboratory safety 
assessments and immunogenicity 
testing  
Reproductive toxicity 
• Animal studies assessing reproductive 
toxicity have not yet been conducted. 
• Immune-checkpoint inhibitors (such as 
dostarlimab) have been shown to have 
potential to disrupt maternal-fetal 
tolerance leading to failure of 
implantation or spontaneous abortion. A 
similar risk will be assumed for 
GSK4428859A. 
• 
Inclusion of contraception guidelines 
for WOCBP (Section 6.1). 
• 
Exclusion of lactating or pregnant 
women (Section 6.2). 
• 
Pregnancy testing for WOCBP 
during Screening and throughout the 
Treatment period, as specified in the 
SoA (Section 12.1.4.1). 
Abbreviations: AE = adverse event; IB = Investigator’s Brochure; irAEs= immune-related adverse events; IRR= 
infusion-related reactions; mAb = monoclonal antibody. 
 
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12.1.4.16. Additional Study Population Criteria: Arm 4  
12.1.4.16.1. 
Additional Inclusion Criteria: Arm 4 
1. Male contraception is not required for this arm.  
12.1.4.16.2. 
Additional Exclusion Criteria: Arm 4 
1. Known hypersensitivity to dostarlimab and/or GSK4428859A components or 
excipients. 
2. Has received prior antibodies or drugs targeting TIGIT, CD96, PVRIG, or other 
therapies targeting the CD226 axis pathway. 
 


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12.1.4.17. References 
Ahn MJ, Niu J, Kim D, Rasco D, Mileham KF, Chung HC, et al. Vibostolimab, an 
anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in 
anti-PD-1/PD-L1-refractory NSCLC. Ann Oncol. 2020;31(Suppl 4):S754-S840. 
Bendell JC, Bedard P, Bang YJ, LoRusso P, Hodi S, Gordon M, et al. Abstract CT302: 
Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single 
agent and in combination with atezolizumab in patients with advanced solid tumors. 
Cancer Res. 2020;80(Suppl 16):CT302. 
Beyrend, G., et al., PD-L1 blockade engages tumor-infiltrating lymphocytes to co-
express targetable activating and inhibitory receptors. J Immunother Cancer, 2019. 7(1): 
p. 217. 
Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 
2020;8(2):e000957. 
Dixon KO, Schorer M, Nevin J, Etminan Y, Amoozgar Z, Kondo T, et al. Functional 
Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor 
Immunity. J Immunol. 2018;200(8):3000-3007. 
Golan T, Bauer T, Jimeno A, Perets R, Niu J, Lee J, et al. Phase 1 dose-finding study of 
the anti-TIGIT antibody MK-7684 as monotherapy and in combination with 
pembrolizumab in patients with advanced solid tumors. J Immunother Cancer. 
2018;6(suppl 1): O25. 
Gros, A., et al., PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire 
infiltrating human tumors. J Clin Invest, 2014. 124(5): p. 2246-59. 
GSK Document Number TMF-11850520. Analysis of PD-1 receptor modulation by 
dostarlimab (TSR-042) using ex vivo IL2 stimulation ratio. Effective Date: 
22 August 2019. 
GSK Document Number RPS-SA-1628635. Population pharmacokinetic analysis and 
exploratory exposure-response analysis of dostarlimab (TSR-042) (Study 4010-01-001 
GARNET). Effective Date: 09 November 2020. 
Guillerey C, Harjunpää H, Carrié N, Kassem S, Teo T, Miles K, et al. TIGIT immune 
checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma. Blood. 
2018;132(16):1689-1694. 
Harjunpää H, Guillery C. TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 
2020;200(2):108-119. 
Hu F, Wang W, Fang C, Bai C. TIGIT presents earlier expression dynamic than PD-1 in 
activated CD8+ T cells and is upregulated in non-small cell lung cancer patients. Exp 
Cell Res. 2020;396(1):112260.  


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Hung AL, Maxwell R, Theodros D, Belcaid Z, Mathios D, Luksik AS, et al. TIGIT and 
PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. 
Oncoimmunology. 2018;7(8):e1466769. 
iTeos Investigator’s Brochure for EOS884448 (EOS-448) Edition 2.0 02 April 2021. 
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The 
immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. 
Cancer Cell. 2014;26(6):923-937. 
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the 
coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell 
responses. Immunity. 2014; 40(4):569-581. 
Kamphorst, A.O., et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-
1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A, 2017. 114(19): p. 
4993-4998. 
KEYTRUDA [package insert]. Whitehouse Station, NJ. Merck Sharp & Dohme 
Corporation; 2021.  
KEYTRUDA [Summary of Product Characteristics]. Merck Sharp & Dohme B.V., 2021.  
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011; 
480(7378):480-489. 
Mimura, K., The JL, Okayama H, et al.. PD-L1 expression is mainly regulated by 
interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 
2018; 109: 43-53. 
Minnie SA, Kuns RD, Gartlan KH, Zhang P, Wilkinson AN, Samson L, et al. Myeloma 
escape after stem cell transplantation is a consequence of T-cell exhaustion and is 
prevented by TIGIT blockade. Blood. 2018;132(16):1675-1688. 
Minnie SA, Kuns RD, Gartlan KH, Zhang P, Wilkinson AN, Samson L, et al. Myeloma 
escape after stem cell transplantation is a consequence of T-cell exhaustion and is 
prevented by TIGIT blockade. Blood. 2019; 134(21):1878. 
National Cancer Institute (NCI). The Cancer Genome Atlas. 
https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga. 
Accessed 04 June 2021. 
Niu J, Nagrial A, Voskoboynik M, Chung HC, Lee DH, Ahn M, et al. Safety and efficacy 
of vibostolimab, an anti-TIGIT antibody, plus pembrolizumab in patients with 
anti-PD-1/PD-L1-naive NSCLC. Ann Oncol. 2020;31(suppl 4): S754-S840. 
OPDIVO [package insert]. Princeton, NJ. Bristol-Myers Squibb Company; 2021. 
OPDIVO [Summary of Product Characteristics]. Bristol-Myers Squibb Pharma EEIG; 
2021.  


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Preillon J, Cuende J, Rabolli V, Garnero L, Mercier M, Wald N, et al. Restoration of 
T-cell effector function, depletion of Tregs, and direct killing of tumor cells: the multiple 
mechanisms of action of a-TIGIT antagonist antibodies. Mol Cancer Ther. 2021;20(1), 
121–131. 
Rodríguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, et al. 
Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT 
antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as 
first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin 
Oncol. 2020;38(15_suppl):9503. 
Shah DK, Betts AM. Antibody biodistribution coefficients: inferring tissue 
concentrations of monoclonal antibodies based on the plasma concentrations in several 
preclinical species and human. MAbs. 2013;5(2):297-305. 
 
Sharma S, Moore K, Mettu N, Garrido-Laguna I, Ulahannan SV, Khemka V, et al. Initial 
results from a Phase 1a/b study of etigilimab (OMP-313M32), an anti-T cell 
immunoreceptor with Ig and ITIM domains (TIGIT) antibody, in advanced solid tumors. 
J Immunother Cancer. 2018;6(suppl 1):P289. 
 
Stengel KF, Harden-Bowles K, Yu X, Rouge L, Yin J, Comps-Agrar L, et al. Structure of 
TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and 
signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci USA. 
2012;109(14):5399-5404. 
TESARO Investigator’s Brochure for Dostarlimab Edition 6.0 19 April 2021. 
Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin 
Oncol. 2011;29(36):4828-4836. 
Van den Mooter TFA, Migeotte A, Jungles C, Delafontaine BR, Nguyen TLA, et al. 
Preliminary data from Phase I first-in-human study of EOS884448, a novel potent anti-
TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of 
clinical activity in immune-resistant advanced cancers. Cancer Res. 2021;81(13_Suppl): 
Abstract CT118. 
Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint 
receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat 
Immunol. 2018;19 (7):723-732. 
 


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12.1.5. 
Arm 5: GSK4428859A (Anti-TIGIT) plus Dostarlimab (Anti-PD-1) 
plus GSK6097608 (Anti-CD96) Combination 
12.1.5.1. 
Protocol Amendment 9 Summary of Changes Specific to GSK4428859A 
and Dostarlimab and GSK6097608 Arm 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.5.2 
(Table 30, Table 40 
and Table 41) 
Dose modification and 
Management 
Guidelines (Section 
12.1.5.11 and Table 
34) 
 
 
 
 
 
 
 
 
 
 
Addition of text to clarify 
that the following 
investigations will require a 
Cardiologist or locally 
appropriate specialist 
review;  
Addition of text to clarify 
that the Sponsor will need to 
be informed regarding these 
participants 
Addition of text to clarify 
that investigators are 
required to review all safety 
laboratory assessments 
before dosing..  
 
Section 12.1.5.15 and 
Table 50 
 
 
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Protocol Amendment 8 Summary of Changes Specific to GSK4428859A and 
Dostarlimab and GSK6097608 Arm 
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.5.2 
(Table 39, Table 40 
and Table 41) 
Schedule of Activities 
Section 12.1.5.2 
(Table 40 and Table 
41) 
 
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Protocol Amendment 7 Summary of Changes Specific to GSK4428859A and 
Dostarlimab and GSK6097608 Arm  
Section # and Name 
Description of Change 
Brief Rationale 
Schedule of Activities 
Section 12.1.5.2 
(Table 40 and Table 
41)  
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Schedule of Activities Specific to the GSK4428859A (Anti-TIGIT) plus Dostarlimab (Anti-PD-1) plus GSK6097608 
(Anti-CD96) Combination 
The timing and number of planned study assessments (including safety, pharmacokinetic, ADA, biomarker or other assessments) may 
be altered during the course of the study based on newly available data. 
Table 39 
Schedule of Activities – Screening: Arm 5: GSK4428859A (Anti-TIGIT) plus Dostarlimab (Anti-PD-1) plus 
GSK6097608 (Anti-CD96) Combination 
Screening Study Assessments 
Screening1  
Notes 
Visit Window 
≤4 Wks 
 
Informed Consent1 
X 
1. All screening assessments must be performed within 4 weeks (28 days) prior to first dose of study treatment 
unless otherwise specified. The informed consent may be signed within 45 days prior to first dose. 
Participant Registration2 
X 
2. Participants will be registered in RAMOS NG at screening. 
Inclusion/Exclusion Criteria 
X 
Review eligibility prior to randomization. 
Demographics, Medical History (including 
alcohol and tobacco use), Prior Medications, 
Disease History12 
X 
12. All known mutations should be entered in the eCRF as disease history. 
Prior Anticancer Treatment, Radiotherapy 
X 
 
Screening Safety 
AE/SAE/AESI Assessment3 
X 
3. Any AESI or SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product will be recorded from the time 
a participant consents to participate in the study. After the initial AE/SAE report, the investigator is required to 
proactively follow each participant at subsequent visits/contacts. Refer to Section 9.4 for further details.  
ECOG PS 
X 
 
Physical Examination 
X 
 
Vital Signs, Height and Weight4 
X 
4. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. Height is recorded 
at Screening only. Record weight in kilograms. 
12-lead ECG 
X 
Consider cardiologist or locally appropriate specialist review for participants with potentially significant ECG 
abnormalities such as AV block (except for first degree), new cardiac arrhythmias, or frequent PVCs. Please inform 
the Sponsor regarding these participants.   
Echocardiogram or MUGA scan5 
X 
5. ECHO required at Screening within 28 days prior to first dose of study treatment, and during treatment phase if 
clinically indicated. MUGA scan may be used if ECHO not feasible.  
Screening Local Laboratory Assessments (Safety) 
Hepatitis B and C6 
X 
 


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Screening1  
Notes 
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≤4 Wks 
 
Serum β-hCG (for women of childbearing 
potential) 
≤3d 
Clinical Chemistry6, Coagulation6, 
Hematology6, Thyroid function6 
X 
6. Refer to Appendix 3 for a complete list of required assessments. Required within 7 days of randomization day. 
Not required to be tested on Day 1 if screening labs are within 72 hours from time of scheduled first dose. Must be 
drawn predose or up to 3 days prior to dosing. If Hepatitis B and C was performed within 3 months prior to first dose 
of study intervention or SoC, repeat testing at screening is not required; otherwise, this testing is mandatory. 
Calculated CrCl7 
X 
7. CrCl is calculated by the CKD-EPI or Cockcroft-Gault formula. See Appendix 9. 
Urinalysis6 
X 
 
Screening Other Laboratory Assessments 
PD-L1 expression by IHC8 
X 
8. PD-L1 expression by IHC and type of assay utilized (i.e., Ventana SP263, Ventana SP142, Dako 28-8, or Dako 
22C3) must be recorded in the eCRF, if known. Note: Test is not required to be performed by the site if not 
previously performed. 
Screening Disease Assessments 
 
Tumor Imaging9 
X 
9. Diagnostic quality CT scan of chest and abdomen with contrast must be obtained within 28 days of first dose. 
Baseline brain scan (MRI with and without IV gadolinium) should be obtained within 6 weeks of first dose if history of 
CNS disease or if clinically indicated. Bone scan should be obtained within 6 weeks of first dose if clinically 
indicated. See additional information regarding bone scans in Section 9.3.1. 
Pre-Baseline scans for Tumor Growth 
Kinetics10 
X 
10. Upon participant consent, up to 3 pre-baseline scans (within 12 months before the baseline scan) will be 
collected to assess tumor growth rate to support exploratory investigation of tumor growth kinetics (See Section 
9.3.2 for details on images for submission). 
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Screening1  
Notes 
Visit Window 
≤4 Wks 
 
Screening Tumor Biopsies 
Fresh tumor tissue sample and Archival 
tumor11 
X 
 
Abbreviations: AE = adverse event; AESI = adverse events of special interest; β-hCG = β -human chorionic gonadotropin; BNP = B-type natriuretic peptide CKD-EPI = chronic 
kidney disease epidemiology collaboration; CrCl = creatinine clearance; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiography; ECOG PS = Eastern 
Cooperative Oncology Group performance status; eCRF = electronic case report form; IHC = Immunohistochemistry; IWRS = interactive web response system; MRI = magnetic 
resonance imaging; MUGA = multi-gated acquisition; NT-pro-BNP = N-terminal pro-hormone BNP ;SAE = serious adverse event.  
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Table 40 
 Schedule of Activities – Treatment Period Experimental Arm 5: GSK4428859A (Anti-TIGIT) plus Dostarlimab 
(Anti-PD-1) plus GSK6097608 (Anti-CD96) Combination 
On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant 
Randomization1 
X 
 
 
 
 
 
 
 
 
 
 
1. Once determined to be eligible, 
participants must be randomized via IWRS. 
Drug shipments will be managed via IWRS. 
Sites must allow up to 7 business days for 
shipment of study drug. Randomization can 
be done prior to Day 1, but no more than 3 
days prior to Day 1. (Refer to SRM). 
Study treatments1 
Administer Dostarlimab2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3W 
On Treatment Safety 
AE/SAE/AESI 
Assessment3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3. After the initial AE/SAE report, the 
investigator is required to proactively follow 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
each participant at subsequent 
visits/contacts. Refer to Section 9.4.1 for 
further details.  
ECOG PS** 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from 
Week 25 (i.e. the first Q6W visit is Week 31, 
then Week 37, etc.) unless more frequent 
assessments are clinically indicated. 
Physical Examination** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q6W* 
Q6W* 
** Physical examinations and ECOG may be 
performed within 24 hours prior to dosing 
(i.e., as opposed to the day of dosing), if 
necessary. 
Vital Signs and Weight4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4. Vital signs include blood pressure, 
temperature, pulse, respiratory rate, and 
oxygen saturation. Weight is to be recorded 
at every other treatment visit in kilograms. 
Vital signs are to be performed predose on 
treatment days. Refer to Section 9.5.3. 
If a participant experiences an infusion-
related reaction, refer to Section 12.1.4.11.1 
for guidance on vital signs monitoring.  
12-lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X* 
*Perform at every dosing visit (may be 
performed within 24 hours prior to dosing). 
Results must be reviewed before  dosing 
Cardiologist or locally appropriate specialist 
review may be required if abnormal results 
are obtained and confirmed as described in 
Table 46. 
On Treatment Local Laboratory Assessments (Safety) – assessments may be performed up to 3 days prior to treatment 
Serum β-hCG (for 
women of childbearing 
potential)5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
5. Monthly urine pregnancy testing may also 
be performed as consistent with local 
standards however if a urine test is positive 
or borderline, or in the event of a missed 
menstrual period or suspicion of pregnancy, 
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Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
Clinical Chemistry, 
Hematology, 
Coagulation6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6. Refer to Appendix 3 for a complete list of 
required assessments. Laboratory testing 
may be performed one day prior to dosing if 
necessary. Not required to be tested on Day 
1 if screening labs are within 72 hours from 
time of scheduled first dose.  
Thyroid function tests 
 
 
X 
 
X 
 
X 
 
X* 
Q6W* 
Q6W* 
*Q6W procedures are counted starting from 
Week 25 (i.e. the first Q6W visit is Week 31, 
then Week 37, etc.). 
Calculated CrCl7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
7. CrCl is calculated by the CKD-EPI or 
Cockcroft-Gault formula. Either formula is 
acceptable and must be consistently utilized 
for each participant throughout the study. 
See Appendix 9. 
Urinalysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
On Treatment Disease Assessments 
Tumor 
Imaging/Response 
Assessment8 
 
 
X 
 
X 
 
X 
 
X 
X8 
8. Diagnostic quality CT scan of chest and 
abdomen with contrast is required every 6 
weeks (±1 week) until Week 49 and every 
12 weeks thereafter. Imaging/clinical 
assessments should be performed as 
indicated in Section 9.2. The same method 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
of assessment is required throughout the 
study. Brain scan (MRI with and without IV 
gadolinium) and bone scan to be performed 
as clinically indicated during the treatment 
period. If a participant has achieved a PD, 
CR, or PR in the previous radiologic 
assessment, a repeat scan should be 
performed after at least 4 weeks to confirm 
the response.  
On Treatment Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY 
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On Treatment Study 
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Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Biomarkers 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Tumor biopsies 
Fresh tumor tissue 
sample13 
 
 
X13 
 
 
 
X19 
 
 
 
 
On Treatment Pharmacokinetics and Anti-Drug Antibodies (ADA) 
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On Treatment Study 
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Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
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On Treatment Study 
Assessments 
 
Notes 
Week 
1 
4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
21. To be collected at Week 25 and every 
12 weeks thereafter. 
Serum: IRR lab panel17 
 
 
 
 
 
 
 
 
 
 
 
17. Assessment required in participant 
experiencing anaphylaxis, serious 
hypersensitivity, or in the occurrence of an 
infusion reaction/CRS of any grade. 
Samples should be drawn during the 
occurrence of the event. Only if not possible 
to collect at the occurrence of the event, 
samples should be drawn as soon as 
possible after the event and within 24 hours 
(Refer to Section 7.2.1.2). Refer to Table 3 
for list of analytes. Predose analysis will be 
performed on the serum sample collected 
for GSK4428859A and/or dostarlimab 
and/or GSK6097608 immunogenicity 
assessments. 
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Notes 
Week 
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4 
7 
10 
13 
16 
19 
22 
25 
28 - 49 
52 - 106 
 
Day 
1 
22 
43 
64 
85 
106 
127 
148 
169 
190 - 
337 
358 - 
736 
 
Visit Window 
±3-day window on treatment days (Visits occur once every 3 weeks during treatment period) 
On Treatment Pharmacogenetics 
Genetic research18 
X 
 
 
 
 
 
 
 
 
 
 
18. Informed consent for optional genetic 
research must be obtained before collecting 
this sample. It is recommended that the 
optional research sample be taken at the 
first opportunity after a participant has met 
all eligibility requirements before Day 1 or on 
Day 1. 
 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; BNP = B-type natriuretic 
peptide ; CKD-EPI = Chronic kidney disease epidemiology collaboration; CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common 
Terminology Criteria for Adverse Events;ECG = Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = End of infusion;
 
 IRR = infusion related reaction; 
 
; NT-pro-BNP = N-terminal pro-hormone BNP; PBMC = peripheral mononuclear cells; PD = Progressive Disease; 
 
; PR = Partial response; Pre =Predose; 
 
 – Physical Function; SAE = Serious adverse event. 
Pre: predose sample to be collected prior to dosing per institutional guidance, as long as it is collected prior to dosing of the corresponding agent; EOI: End of infusion sample is in 
reference to EOI of the corresponding agent. 
 
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Table 41 
Schedule of Activities – Treatment Discontinuation Visit and Follow-Up Arm 5: GSK4428859A (Anti-TIGIT) plus 
Dostarlimab (Anti-PD-1) plus GSK6097608 (Anti-CD96) Combination 
TDV and Follow Up 
Assessments 
Treatment 
Discontinuation 
Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
within 30 days 
of study 
treatment 
discontinuation 
 
 
Anticancer Treatment 
 
Q12W* 
*If the participant dies before the first follow up, any subsequent anticancer therapy or radiotherapy should be 
recorded in the eCRF. 
 
 
Concomitant Medications 
X 
 
 
TDV and Follow Up Safety 
AE/SAE/AESI Assessment2 
X 
 
2. After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. Refer to Section 9.4.1 and Section 9.4.3 for further details. 
ECOG PS 
X 
 
 
Physical Examination 
X 
 
 
Vital Signs and Weight3 
X 
 
3. Vital signs include blood pressure, temperature, pulse, respiratory rate, and oxygen saturation. 
TDV and Follow Up Local Laboratory Assessments 
Clinical Chemistry  
X 
X^ 
 
Serum β-hCG (for women of 
childbearing potential) 
X 
 
 Refer to Appendix 3 for a complete list of required laboratory assessments. 
^Safety laboratory assessments should be collected at TDV (within 30 days of last dose of study treatment) 
and at 60 and 90 days after last dose of study treatment, unless the participant has started a new anti-cancer 
therapy within the 90 day follow-up period, in which case safety laboratory assessments are not applicable. 
Refer to Appendix 3 for the specific laboratory assessments.   
 
Hematology 
X 
X^ 
Coagulation 
X 
 
Thyroid function tests 
X 
X^ 
Calculated CrCl 
X 
 
Urinalysis 
X 
 
 
 
12-lead ECGa 
X 
 
TDV and Follow Up Disease Assessments 
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TDV and Follow Up 
Assessments 
Treatment 
Discontinuation 
Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
within 30 days 
of study 
treatment 
discontinuation 
 
 
Tumor Imaging/Response 
Assessment4 
X 
 
4. At the TDV, CT scan is required only if the last disease assessment did not show confirmed PD and was 
performed ≥6 weeks before TDV. For participants who discontinue study treatment without documented 
disease progression, every effort should be made to continue monitoring disease status by tumor imaging 
using the same imaging schedule used while on treatment until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first. 
See additional information in Section 9.3.1 
Telephone call for survival status1a 
 
Q12W 
 
TDV and Follow Up Tumor Biopsies 
Fresh tumor tissue sample 
X5 
 
5. If possible, obtain an optional tumor tissue sample at time of confirmed PR or PD. 
TDV and Follow Up Patient-Reported Outcomes/Health-Related Quality of Life: Part 2 ONLY  
 
 
 
 
 
 
 
 
 
 
 
TDV and Follow Up Biomarkers 
TDV and Follow Up Pharmacokinetics and Anti-Drug Antibodies (ADA) 
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Treatment 
Discontinuation 
Visit1 
 
Survival 
Follow-
Up1a 
Notes 
Visit Window 
within 30 days 
of study 
treatment 
discontinuation 
 
 
Abbreviations: ADA = Anti-drug antibody; AE = Adverse event; AESI = Adverse events of special interest; β-hCG = Beta-human chorionic gonadotropin; BNP = B-type natriuretic 
peptide CR = complete response; CrCl = Creatinine clearance; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events;ECG = 
Electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = Electronic case report form; 
 
 
; NT- pro- BNP =N-terminal pro-hormone BNP 
 
; PD = Progressive Disease; 
; PR = Partial response; 
 
 SAE = Serious adverse event; TDV = Treatment Discontinuation Visit. 
 
1. The assessments required at the study treatment discontinuation visit must be completed within 30 days from the date study treatment was discontinued and must occur prior to the 
start of subsequent anticancer therapy. If participant attends clinic for scheduled visit and decision is made to discontinue treatment, site can use this visit as the TDV and complete all 
assessments. See Section 9.4.1 for details on collecting AE and SAE information.  
1a. Survival Follow-Up is the Observational Phase of the study. Participants will be followed for survival and subsequent anticancer therapy every 12 weeks after the last dose of study 
treatment, via telephone contact. Participants will be contacted every 12 weeks (±7 days) until death or participant’s withdrawal from further contact. Subsequent anticancer treatment 
and death date will be documented in the eCRF. 
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12.1.5.3. 
Study Design Arm 5: GSK4428859A (Anti-TIGIT) plus Dostarlimab 
(Anti-PD-1) plus GSK6097608 (Anti-CD96) Combination 
 
GSK4428859A will be evaluated at a 
 
 
 
 
, in accordance to the mTPI dose decision rules 
presented in Table 48 Section 12.1.5.12 (see Figure 9). A maximum of 9 evaluable 
participants will be assigned to DLT cohorts for each dose combination per mTPI. 
Further evaluation of a combination dose demonstrated to result in unacceptable toxicity 
as described in Table 48 will be stopped.  
After the combinations mentioned above are determined to be tolerated per the mTPI 
rules in Section 12.1.5.12 (Table 48), there is an option to open PK/PD cohorts to further 
evaluate safety and PK/PD. If PK/PD cohorts are opened, 
 
 
 
 
 
   
 
12.1.5.4. 
Rationale for the GSK4428859A (Anti-TIGIT) plus Dostarlimab (Anti-PD-
1) plus GSK6097608 (Anti-CD96) Combination 
Anti-TIGIT and Anti-PD-1/PD-L1 Monoclonal Antibody Combinations in Clinical 
Studies 
Combinations with anti-TIGIT mAbs and anti-PD-1/PD-L1 mAbs have demonstrated 
improved antitumor efficacy while preserving acceptable side effect profiles. The 
combination of vibostolimab (an anti-TIGIT mAb) with pembrolizumab (an anti-PD-1 
mAb) demonstrated a confirmed ORR of 24%, DCR of 36%, and a median DOR that was 
not reached (95% CI: 4 to 17+ months) in participants with a variety of advanced solid 
tumors who were naïve to anti-PD-(L)1 therapy [Niu, 2020]. Notably, even in 
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participants who had previously received anti-PD-(L)1 therapy, the DCR was 50%, 
driven mostly by disease stabilization [Ahn, 2020]. Vibostolimab demonstrated a 
tolerable safety profile across the various doses tested alone and in combination with 
pembrolizumab (anti-PD-1, 200 mg Q3W) in the Phase 1b study (see Rationale Section 
12.1.5.3 for further details). 
In the dose escalation phase, tiragolumab (an anti-TIGIT mAb) was administered at 2, 8, 
30, 100, 400, 600, 1200 mg Q3W in combination with the anti-PDL1 agent, atezolizumab 
(1200 mg Q3W). No DLTs were observed across all doses (N=49). TRAEs occurred in 
59% of participants and the most frequently reported TRAEs were Grade 1 pruritus, 
Grade 1 to 2 fatigue, Grade 1 to 2 rash, Grade 1 diarrhea, and Grade 1 arthralgia. Two 
Grade 3 TRAEs were reported in the combination: 1 hyperlipasemia and 1 lymphocyte 
count decreased. Infusion reactions were seen in 8% of participants, most were 
Grade 1/2. A higher rate of immune-related AEs (irAEs) was observed with the 
combination than with tiragolumab monotherapy [Bendell, 2020]. In a Phase 1b dose 
escalation study, the combination of tiragolumab with atezolizumab (an anti-PD-L1 
mAb) showed an ORR of 9% in participants with advanced solid tumors. In an expansion 
cohort of anti-PD(L)1naïve participants with PD-L1+ NSCLC, an ORR of 46% and a 
DCR of 85% were observed [Bendell, 2020]. The results from the aforementioned Phase 
1b study led to the Phase 2 CITYSCAPE study, a randomized, double-blind study of 
tiragolumab plus atezolizumab versus placebo plus atezolizumab in participants with 
PD-L1+ (TPS ≥1%), treatment-naïve, locally advanced or metastatic NSCLC. In the 
CITYSCAPE study, a confirmed ORR of 37% for the combination arm compared with 
21% for the placebo/atezolizumab arm in the intent-to-treat population (n=135) was 
reported [Rodríguez-Abreu, 2020]. Median PFS was improved from 3.88 months (range: 
2.73 to 4.53 months) with atezolizumab to 5.5 months (range: 4.2 to 10.4 months; 
HR: 0.58, 95% CI: 0.38, 0.89) for the combination. In 58 participants with PD-L1 high 
(TPS ≥50%) tumors, the confirmed ORR was 66% for the combination compared with 
24% in the atezolizumab arm. The median PFS was not reached with the combination 
(95% CI: 5.49 to not evaluable [NE]) compared with 4.11 months (95% CI: 2.07, 4.73) 
for the atezolizumab arm (HR for PFS: 0.3; 95% CI: 0.15. 0.61). For participants with 
PD-L1 TPS 1-49%, the ORR and PFS were similar across both arms (ORR: 18% with 
atezolizumab vs 16% with tiragolumab and atezolizumab; PFS: 3.58 months and 4.04 
months, respectively [HR:0.89; 95% CI: 0.53, 1.49]). The rates of TEAEs (99% vs 96%), 
Grade 3 AEs (48% vs 44%), Grade 5 AEs (5% vs 7%), SAEs (37% vs 35%), and AEs 
leading to treatment withdrawal (10% vs 9%) were all similar between the combination 
and placebo/atezolizumab arms, respectively; there was a modest increase in AEs leading 
to dose modification in the combination arm (40% vs 28%). The overall rate of immune-
mediated AEs (69% vs 47%) and Grade 3 or 4 immune mediated AEs (18% vs 13%) 
were higher in the combination arm [Rodríguez-Abreu, 2020]. 
As a result, multiple Phase 3 clinical studies are underway evaluating anti-TIGIT and 
anti-PD(L)1 combination therapy in PD-L1+ NSCLC (NCT04738487; NCT04746924; 
NCT04262856; NCT04294810; NCT04736173). 
 
 


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Triplet Combination of GSK4428859A plus Dostarlimab plus GSK6097608  
Multiple immune checkpoints in addition to PD-(L)1 may regulate T cell anergy and 
modulate antitumor immunity [Topalian, 2011; Mellman, 2011]. Co-regulatory receptors 
expressed on T cells can induce stimulatory or inhibitory signaling cascades that 
modulate T cell proliferation, cytokine production, and cytotoxic T cell activation. 
Proteins of the nectin and nectin-like (Necl1) family, including TIGIT, PVRIG 
(poliovirus receptor-related immunoglobulin domain), and CD96, have emerged as 
immune-suppressing candidates that may prevent immune reactivation after PD(L)1 
blockade. These co-regulatory receptors modulate the CD226 immune checkpoint, which 
is one of the major activating receptors for NK cells.  
CD96, TIGIT and CD226 (DNAM-1) are cell-surface receptors in the Ig superfamily and 
are known to interact with nectin and nectin-like ligands. CD155 is the primary ligand for 
all 3 receptors (CD96, TIGIT, and CD226). CD226 has been reported to potentiate 
NK-cell cytotoxicity against cancer cells, and is critical for tumor immunosurveillance 
[Gilfillan, 2008; Iguchi-Manaka , 2008; Lakshmikanth, 2009; Chan, 2010]. Conversely, 
both CD96 [Chan , 2014] and TIGIT [Li , 2018] 
[Lozano , 2012] are known to dampen immune responses through inhibition of 
NK- and/or T-cell function. Binding of CD96 and TIGIT with CD155 prevents 
homodimerization and activation of CD226 on CD8+ T cells [Johnston, 2014].  
In the tumor microenvironment, CD96 is expressed by NK cells, effector T cells, and 
regulatory T cells (Tregs). TIGIT is highly expressed on murine and human tumor 
infiltrating T cells [Johnston, 2014]. In human tumor specimens from the Cancer Genome 
Atlas (TCGA [NCI, 2021]), TIGIT expression is upregulated in a broad range of solid 
tumors [Johnston, 2014]. TIGIT is upregulated on tumor infiltrating CD8+ T cells and a 
population of infiltrating CD4+ T cells in solid tumors in comparison to peripheral 
T cells from patients and normal donors. CD8+ and CD4+ TIGIT-expressing T cells also 
co-express PD-1. 
 
 
 
 [GSK Document Number 2019N420882_00]. In NSCLC, TIGIT 
was expressed in tumor-infiltrating CD8+ and CD4+ T cells and was co-expressed with 
PD-1 [Johnston, 2014]. Peripheral CD8+ and CD4+ T cells from NSCLC tumor donors 
had higher levels of TIGIT compared with healthy donors. In addition, in patients with 
NSCLC, the expression of PD-1 was higher in TIGIT+ cells than in TIGIT-negative cells 
in both circulating CD8+ T cells and tumor-infiltrating CD8+ T cells [Hu, 2020]. TIGIT 
could act as a checkpoint inhibitor in exhausted tumor-infiltrating T cells. 
CD96 and TIGIT represent novel immune checkpoint receptor targets. As depicted 
schematically in Figure 10, engagement of CD96 and TIGIT with CD155 functions as an 
‘off switch,’ or immune checkpoint, to downregulate immune responses.  
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Figure 10 
Mechanism of Action for CD226 Axis 
 
Abbreviations: APC = antigen-presenting cell; CD = cluster of differentiation; NK = natural killer; TIGIT = T-cell 
immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain. 
 
EOS884448 (also known as EOS-448; hereafter referred to as GSK4428859A) is a fully 
human IgG1 mAb that prevents TIGIT-ligand binding. As an IgG1, GSK4428859A also 
displays a potent affinity for the fragment crystallizable (Fc) gamma receptors (FcγRs) 
with the potential to mediate ADCC/P against TIGIT expressing cells. Binding of 
GSK4428859A to TIGIT was shown to increase T cell activation by competing with 
TIGIT ligands. GSK4428859A (or its mouse surrogate for rodent studies) mediates 
ADCC/P of immunosuppressive cells by preferentially targeting immunosuppressive 
regulatory T cells that express a high level of TIGIT relative to cytotoxic CD8 or NK 
cells, resulting in an increased ratio of effector CD8+/immunosuppressive regulatory T 
cell cells. Moreover, this effect was abrogated in mice lacking FcγRs, further suggesting 
the requirement for an ADCC/P effect to fully induce tumor growth inhibition. Overall, 
these data demonstrate that GSK4428859A restores antitumor immunity by preventing 
the activation of TIGIT by its natural ligands, PVR/CD155 and Nectin2/CD112, and 
induces a strong immune response mediated by regulatory T cell depletion and ADCC/P 
[Preillon, 2021]. 
GSK6097608 is a fully human IgG1 mAb checkpoint inhibitor designed to modulate this 
axis by forming a high-affinity complex with CD96, disrupting CD96 binding to CD155, 
and subsequently redirecting CD155-mediated costimulatory signaling through the 
activating receptor CD226 to increase T‑cell and NK-cell antitumor activity. Modulation 


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of this axis via inhibition or deletion of CD96 has resulted in antitumor activity in mouse 
tumor models both alone and in combination with PD‑1 inhibition [Blake, 2016; 
Harjunpää, 2018]. 
Dostarlimab (formerly referred to as TSR-042) is an IgG4-k humanized monoclonal 
antibody that binds with high affinity to PD-1 resulting in inhibition of binding to PD-L1 
and PD-L2. This antibody was generated based on a proprietary platform that utilizes 
affinity maturation to select antibodies with desired functional characteristics. The 
functional antagonist activity of dostarlimab was confirmed in an MLR demonstrating 
enhanced interleukin-2 production upon addition of dostarlimab. Dostarlimab is an anti-
PD1 agent so nonclinical safety data is expected to be similar to a large extent to what 
was seen with data supporting pembrolizumab combinations. To support combination 
with dostarlimab, the principal nonclinical toxicology findings associated with 
dostarlimab were reviewed. 
 
 
 
. 
As a proof of concept, co-inhibition of CD96 and PD-(L)1 has proven efficacious in 
several nonclinical tumor models. For example, dual genetic ablation of CD96 and Pdcd1 
(PD-1) significantly suppressed SM1WT1 (melanoma) tumor growth in mice relative to 
single knockout approaches (i.e., CD96-/- or Pdcd1-/-) without overt perturbations in 
immune homeostasis beyond what has been reported for PD-1-deficient mice [Harjunpää, 
2018]. Combinations of anti-CD96 antibodies with anti-CTLA-4 or anti-PD-1 antibodies 
have also been shown to be more effective than anti-CD96 alone with regards to mouse 
survival [Blake, 2016]. Similar improvements in antitumor responses have been observed 
in mice following antibody-mediated co-blockade of CD96 and PD-1 or PD-L1 [Blake, 
2016; Li, 2018; Mittal, 2019]. Likewise, in nonclinical models, the combination of anti-
PD-L1 and anti-TIGIT agents synergistically improved tumor control over either 
antibody alone [Johnston, 2014]. Finally, and most importantly, triple combination of 
anti-CD96, -TIGIT, and -PD-1 has been shown to further improve antitumor responses in 
multiple tumor models [Mittal, 2019]. Therefore, approaches that block the binding of 
both CD96 and TIGIT to CD155 could have therapeutic benefit. Thus, combined 
blockade of CD96 and TIGIT may potentiate the activity of dostarlimab.  
 
 
 
. Monoclonal 
antibodies, such as GSK6097608 and dostarlimab, are not substrates for cytochrome 
P450 or drug transporters. Although treatments are checkpoint inhibitors and are not 
expected to increase the potential for CRS based on in vitro cytokine release assays 
(CRAs) and toxicology studies of each individual inhibitor, a combination CRA is being 
conducted and the data will be available to support dosing of the triplet. For additional 
nonclinical toxicology data for GSK6097608, dostarlimab, and GSK4428859A refer to 
the individual Investigator Brochures[see the iTeos EOS884448 [EOS-448] IB, 2021; 
Dostarlimab IB, 2021; GSK6097608 IB, 2021].  
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12.1.5.5. 
Clinical Safety Summary 
12.1.5.5.1. GSK4428859A 
Several mAbs targeting TIGIT are in various stages of clinical development. These 
agents include tiragolumab, vibostolimab, domvanalimab, etigilimab, and 
GSK4428859A, among an increasing number of others. 
A Phase 1b study of vibostolimab monotherapy in participants with advanced solid tumor 
types previously treated with anti-PD-(L)1 therapy reported a 3% ORR and 35% DCR 
[Golan, 2018]. In a Phase 1a/Phase 1b study of tiragolumab as a single agent and in 
combination with atezolizumab in advanced solid tumors, there were no objective 
responses in 24 participants treated with tiragolumab monotherapy [Bendell, 2020]. The 
24 participants enrolled in the tiragolumab monotherapy arm included primary cancer 
history types such as colon, rectum, breast, ovarian, endometrial, melanoma, and other 
cancer diagnosis [Bendell, 2020]. The ORR for etigilimab in the dose-escalation phase 
was 0%, with a DCR of 30% in a Phase 1a/Phase 1b study of etigilimab in participants 
with advanced solid tumors [Sharma, 2018]. A Phase 1 dose-finding study of 
GSK4428859A, monotherapy demonstrated favorable tolerability and modest 
preliminary efficacy in 20 participants with advanced solid tumors, with an ORR of 5% 
[Van den Mooter, 2021]. 
The safety profile of anti-TIGIT mAbs has been tolerable and comparable to that of other 
single-agent immune checkpoint inhibitors. In the vibostolimab Phase 1b study of 
immune checkpoint inhibitor-experienced participants, 59% of participants experienced 
any treatment-related adverse event (TRAE) with Grade ≥3 TRAEs in 15% of 
participants in the vibostolimab monotherapy arm. The most common TRAEs reported 
were fatigue (22%) and rash (20%). One participant (2%) had a TRAE that led to 
discontinuation and none experienced a fatal TRAE [Golan, 2018]. In the Phase 1a 
dose-escalation phase of the tiragolumab study in 24 patients, there were no DLTs 
[Bendell, 2020]. TRAEs occurred in 67% of participants, Grade3 TRAEs in 4% 
(Grade 3 blood creatinine increase) and the most common AE reported was fatigue 
(38%). There were 6 SAEs reported (25%) with no AEs leading to study withdrawal or 
death [Bendell, 2020].  
 
 
 
 
 
 
 
 
 
 There were no AEs that led to 
treatment discontinuations or any TEAEs leading to death. TRAEs were reported by
% 
of participants, with % of participants having Grade ≥3 TRAEs, and % having serious 
TRAEs. The most frequent TRAEs included pruritus (n=
%]), infusion-related 
reaction (n=
%]), fatigue (n=
%]), and pyrexia (n=
%]); at least
skin 
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disorder (all confounded) was reported in
participants (for additional details, see the 
iTeos EOS884448 [EOS-448] IB, 2021). 
Overall, the early data from this Phase 1 study 
 
.  
12.1.5.5.2. Dostarlimab 
A total of 
participants with advanced or recurrent solid tumors received at least one 
dose of monotherapy dostarlimab 
 
prior to the data cut-off date of 1 November 2020 in study 4010-01-001 (GARNET). 
The data from participants treated with monotherapy dostarlimab in Study 4010-01-001 
demonstrated an acceptable safety profile with manageable toxicity in participants with 
advanced or recurrent solid tumors:  
• 
Treatment-emergent adverse events (TEAEs) regardless of causality were 
reported in
% of participants, and 
% of participants had treatment 
related events. The most common reported TEAEs 
%) were anemia 
%), fatigue
0%), nausea 
%), and diarrhea 
%). 
• 
Grade ≥3 TEAEs regardless of causality were reported in
% of 
participants; the most frequently reported 
% of participants) were anaemia 
%), dyspnoea 
%), abdominal pain 
%), and hyponatraemia 
%). 
Treatment-related Grade 3 events were reported in 
% of participants; 
the most frequently reported
% of participants) were anaemia 
%), 
fatigue 
%), alanine aminotransferase increased (
%), and lipase 
increased 
%). 
• 
Treatment-emergent SAEs regardless of causality were reported in
% of 
participants; the most frequently reported 
% of participants) were 
abdominal pain
%), pneumonia
%), and dyspnoea 
%). Treatment-
related SAEs were reported in
% of participants; the most frequently 
reported 
% of participants) were pneumonitis
%), adrenal 
insufficiency 
%), and pyrexia
%). 
• 
TEAEs leading to treatment discontinuation regardless of causality were 
reported in
% of participants; the most frequently reported
% of 
participants) were alanine aminotransferase increased 
%), aspartate 
aminotransferase increased 
%), pneumonitis 
%), and transaminases 
increased
%). Treatment-related events leading to discontinuation were 
reported in
% of participants; the most frequently reported 
% of 
participants) were alanine aminotransferase increased
%), aspartate 
aminotransferase increased 
%), pneumonitis
%), and transaminases 
increased 
%). 
• 
TEAEs leading to death regardless of causality were reported in
% of 
participants with respiratory failure the only event reported in >1 participant 
 participants
%]); 
% of the deaths were due to treatment-related 
TEAEs (completed suicide, hepatic ischaemia). 
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Of the
 participants, 
% who received dostarlimab monotherapy experienced at 
least 1 immune-related TEAE (irAE). The most frequent
%) irAEs were 
hypothyroidism, diarrhea, alanine aminotransferase increased, aspartate aminotransferase 
increased, blood creatinine increased, hyperglycemia and amylase increased. 
 
participants
%) who received dostarlimab monotherapy experienced at least 1 irAE 
with severity of ≥Grade 3. For
participants with ≥Grade 3 irAEs, the AE was 
assessed as study drug related by investigators. 
The safety profile of monotherapy dostarlimab in participants with advanced or recurrent 
solid tumors was generally similar to the reported safety profiles of other mAbs blocking 
the PD-1 interactions (KEYTRUDA USPI, 2021; KEYTRUDA, SmPC, 2021; OPDIVO 
USPI, 2021; OPDIVO, SmPC, 2021).  
12.1.5.5.3. GSK6097608 
An ongoing Phase 1 FTIH study (Study 212214; NCT04446351) in advanced solid 
tumors is assessing the safety, tolerability, PK, PD, and preliminary anticancer activity of 
GSK6097608. The study design allows for the assessment of GSK6097608 as 
monotherapy and in combination with dostarlimab.  
Arm A consists of dose escalation to determine the RP2D of GSK6097608 as a single 
agent, and Arm B consists of dose escalation in combination with dostarlimab. Results 
from Arm A and Arm B will be used to establish the RP2Ds for monotherapy and 
combination therapy. 
As of the preliminary data cut-off date of 05 November 2021,
participants have 
received GSK6097608 in Study 212214. 
 participants have received at 
least 1 dose of GSK6097608 monotherapy (Arm A) and
participants have received at 
least 1 dose of GSK6097608 in combination with dostarlimab (Arm B). Participants in 
the Arm A population (GSK6097608 monotherapy; n
 were enrolled at the following 
dose levels: 
 mg (n=
mg (n=
 mg (n=
mg (n
 mg (n=
mg 
(n=
and
 mg (n=
Participants in the Arm B population (GSK6097608 in 
combination with dostarlimab; n
were enrolled in dose-escalation cohorts and 
received GSK6097608 at the
mg (n=
mg (n=
and 
mg (n=
and 
mg 
(n=
dose levels. In the study,
deaths were reported; 
deaths were considered 
treatment-related. 
Arm A (GKS6097608 Monotherapy) – Ongoing:  
%) participants 
have experienced at least 1 treatment-emergent AE (TEAE). The most frequently 
reported TEAEs (n>2) across all dose levels were fatigue (n=
%); nausea (n=
%); constipation (n=
%); diarrhoea (n=
%); chills, vomiting (n=
%] 
each); dizziness, anaemia, and anorexia  (n=
%] each). Of the
participants 
enrolled acros
dose level
participants experienced
SAEs 
event [urinary tract 
infection] at
mg
vents [disease progression and cerebrovascular accident] a
mg, 
event [failure to thrive] at 
mg;
events [pulmonary hemorrhage and hypovolemic 
shock] at
mg; and
event [pneumonia] at 
mg). No SAEs were noted as treatment 
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related. Of the TRAEs reported as of 05 November 2021 (Table 42), the majority 
 
%) Grade 1 or Grade 2 events. 
 DLTs have been observed to date.  
Arm B (GSK6097608 in Combination with Dostarlimab) – Ongoing: 
 
participants
%) have experienced at least 1 TEAE. Table 43 presents TRAEs for Arm 
B as of the 05 November 2021. 
 participants experienced 4 serious adverse 
events (hyponatremia, tumor hemorrhage, meningitis and CNS necrosis) as a result of 
disease progression.
 DLTs have been reported. Of the TRAEs reported
were 
Grade 1 or 2 events. 
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12.1.5.6. Dose Justification 
12.1.5.6.1. GSK4428859A Pharmacokinetics and Pharmacodynamics  
 
 
 
 
 
 
 
 
 
 
 
. PK data 
obtained at Cycle 1 are summarized in the iTeos EOS884448 [EOS-448] IB, 2021.  
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12.1.5.6.2. GSK4428859A Dose Rationale (Arm 5) 
The GSK4428859A RP2D of
mg 
 is based on the preliminary safety, PK/PD, 
and efficacy data available from the Phase 1/Phase 2a clinical Study IO-002 
(NCT04335253), as well as observations from other clinical studies evaluating anti-
TIGIT mAbs which generally have similar properties [Bendell, 2020; Rodríguez-Abreu, 
2020; Niu, 2020]. Additionally, Study TIG-006 is currently evaluating the safety, 
tolerability, PK, PD, and anti-tumor activity of GSK4428859A in combination with 
pembrolizumab in participants with advanced solid tumors. The starting dose level of 
GSK4428859A is
mg
in combination with pembrolizumab in study IO-006 
(NCT05060432). Furthermore, GSK4428859A 
 mg
will also be tested in 
combination with dostarlimab in Arm 4 of this platform study and will inform the 
safety/tolerability profile of this doublet (see Section 12.1.4).  
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TRAEs were Grade 1 pruritus, Grade 1-2 fatigue, Grade 1-2 rash, 
diarrhea, and arthralgia. Two Grade 3 TRAEs were reported in the group receiving 
combination treatment: 1 event of hyperlipasemia and 1 event of lymphocyte count 
decreased. Infusion reactions were seen in 8% of participants. A higher rate of irAEs was 
observed with the combination than with tiragolumab monotherapy [Bendell, 2020]. In 
the Phase 2 CITYSCAPE study, the addition of tiragolumab at 600 mg Q3W to first-line 
atezolizumab at 1200 mg Q3W in PD-L1–selected metastatic NSCLC demonstrated good 
tolerability, with a safety profile similar to placebo plus atezolizumab [Rodríguez-Abreu, 
2020]. Vibostolimab (an anti-TIGIT mAb) has also demonstrated a good safety and 
tolerability profile across the various doses tested alone and in combination with 
pembrolizumab (an anti-PD-1 mAb, 200 mg Q3W) in the Phase 1b study [Ahn, 2020; 
Niu, 2020]. 
12.1.5.6.3. Dostarlimab Dose Rationale 
The anti-PD-1 mAb dostarlimab will be administered in combination with 
GSK4428859A and GSK6097608 as a flat dose of 
 mg
Dostarlimab has been approved in the US and the EU for the treatment of adult patients 
with dMMR/MSI-H (the latter in the EU only) recurrent or advanced endometrial cancer 
that has progressed on or following prior treatment with a platinum-containing regimen. 
As determined in the GARNET study, the recommended clinical dose of dostarlimab 
deemed safe and effective is
mg 
 for 4 cycles, followed by 
mg 
To facilitate combination with the other study intervention regimens of this study, 
dostarlimab dosing 
 
 
 
 
 
 
 
 
 
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No reduction in dostarlimab dose is allowed given that the safety and efficacy profile of 
the included dose regimen for dostarlimab is considered acceptable, whereas the efficacy 
of lower doses is not fully characterized. 
12.1.5.6.4. GSK6097608 Pharmacokinetics and Pharmacodynamics  
 
 
 
 
 
 
 
 
 
 Preliminary pharmacokinetic summary statistics are 
presented in Table 44 below.  
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12.1.5.6.5. GSK6097608 Dose Rationale 
See associated text under Section 12.1.5.6.4 and Section  12.1.5.5.3 for details regarding 
preliminary pharmacokinetic and clinical safety data from the FTIH Study. 
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12.1.5.7. 
Study Treatments 
Table 45 
Description and Administration of Arm 5 GSK4428859A plus 
Dostarlimab plus GSK6097608 Study Treatments 
Name 
Dostarlimab 
GSK4428859A 
GSK6097608 
 
In the  dostarlimab + GSK4428859A +  GSK6097608 combination arm, dostarlimab 
mg will be administered first as an IV infusion
 GSK4428859A
mg will be 
administered as an IV infusion 
after completion of dostarlimab infusion. Lastly (3rd 
agent to be infused), GSK6097608 
mg, 
mg or
mg will be administered as 
an IV infusion 
after completion of GSK4428859A infusion (see pharmacy manual 
for administration instructions).  
All participants should remain under observation at the study site after the completion of 
study treatment administration (refer to SRM for details). Section 12.1.5.11, Table 47 for 
details on the management of participants experiencing infusion reactions. Refer to 
Section 5.2 for information on the duration of study treatment. 
The date and time of administration will be documented in the source documents and 
reported in the eCRF. For drug administered by an investigator or designee, the dose of 
study treatment and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
treatment. The specific time of study treatment administration (e.g., time of the week for 
first administration; time of the day for each administration) should take into 
consideration PK sampling time points, study visit procedures, and the post-infusion 
observation time interval. Infusions may be administered up to 72 hours before or after 
the planned date of treatment for administrative reasons only (e.g., scheduling an infusion 
around a holiday). All drugs should be administered on the same day. The 72-hour 
window does not apply to completion of study treatment administration interrupted by an 
infusion reaction. Refer to Section 7.2.1.4 for criteria governing dose interruptions or 
delays. 
Details on preparation and administration of GSK4428859A, dostarlimab, and 
GSK6097608 are described in the pharmacy manual.  
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12.1.5.8. 
Concomitant Therapy 
Refer to Section 7.7. 
12.1.5.9. 
Treatment of Overdose 
12.1.5.9.1. GSK4428859A Overdose 
An overdose of GSK4428859A is defined as administration of a dose that is above 
mg.  
In the event of an overdose, the investigator must: 
1 Contact the Medical Monitor immediately. 
2 Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 120 days. 
3 Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).  
4 Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.  
There is no specific antidote for overdose with the experimental treatments being 
evaluated in this study. 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.  
12.1.5.9.2. Dostarlimab Overdose 
Human data on overdose are not available. There is no known antidote for dostarlimab.  
 
An overdose of dostarlimab is defined as any dose that is ≥20% than
mg
 
In the event of an overdose, the investigator must: 
1 Contact the Medical Monitor immediately. 
2 Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 120 days. 
3 Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).  
4 Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
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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 the experimental treatments being 
evaluated in this study. 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. 
12.1.5.9.3. GSK6097608 Overdose 
There is no specific information on overdose of GSK6097608. GSK does not recommend 
specific treatment for an overdose of GSK6097608. An overdose of GSK6097608 is 
defined as administration of more than the protocol-specified dose. 
In the event of an overdose, the investigator must: 
1 Contact the Medical Monitor immediately. 
2 Closely monitor the participant for adverse events and laboratory abnormalities 
for at least 120 days. 
3 Obtain a sample for PK analysis within 28 days from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).  
4 Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
There is no specific antidote for overdose with the experimental treatments being 
evaluated in this study. 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. 
12.1.5.10. Treatment Duration for GSK4428859A, Dostarlimab, and GSK6097608 
Participants enrolled will be treated until disease progression, intolerable toxicity, 
informed consent withdrawal or death. Combination study treatment will continue to be 
administered at the indicated schedule for a maximum duration of up to 35 treatment 
visits or approximately 2 years, whichever comes first. Refer to Section 5.2 for additional 
details regarding follow up after discontinuation of study treatment. 
12.1.5.11. Dose modification and Management Guidelines 
No dose reductions are allowed for GSK4428859A, dostarlimab, or GSK6097608 at the 
participant level. Dose modification guidelines for immune related adverse events are 
listed in Table 46. If study treatment must be held or discontinued for any toxicity, all 


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three study drugs must be held or discontinued, unless discussed otherwise with Medical 
Monitor. 
In addition to the immune-related adverse events listed in Table 46, immunotherapy may 
be associated with other irAEs, including events which may be less commonly associated 
with PD-(L)1 inhibitors but can similarly result from activation of cellular immune 
response. For these events, most current professional guidelines (e.g.: NCCN, SITC) 
should be considered. Patients should receive appropriate supportive care measures as 
deemed necessary by the treating Investigator, including but not limited to the items 
outlined below: 
 
Table 46 
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs 
General instructions: 
• 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
• 
For situations where immunotherapy treatment has been withheld, treatment can be resumed after AE 
has been reduced to Grade 1 or resolved and corticosteroid has been tapered. Immunotherapy treatment 
should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
• 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
Immune-related AEs 
Severity 
grade or 
conditions 
(CTCAEv5.0) 
Action taken  
irAE management with 
corticosteroid and/or 
other therapies  
Monitor and 
follow-up  
Respiratory 
Pneumonitis  
Gastrointestinal 
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Diarrhea / colitis 
Hepatobiliary 
Hepatitis with no tumor 
involvement of the liver 
Hepatitis with tumor 
involvement of the liver** 
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Endocrine 
Type 1 diabetes mellitus 
(T1DM) or Hyperglycemia 
 
Endocrinopathies (e.g. 
hypophysitis, hypo-
/hyperthyroidism, adrenal 
insufficiency) 
Renal 
Nephritis with renal 
dysfunction 
Cardiovascular 
 
 
 
 
 
 
 
Cardiac Investigations 
i) ECG changes and/or ii) 
troponin and/ or NT-
proBNP/BNP elevations 
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Myocarditis 
Other 
Neurological Events 
(myasthenia gravis, Guillain-
Barré syndrome, encephalitis, 
transverse myelitis) 
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All other immune-related 
AEs 
Skin Toxicities1 
Rash 
Pruritis 
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Exfoliative dermatologic 
conditions (e.g. SJS, TEN, 
DRESS) 
NOTES:  
*Resume in patients with complete resolution or partial resolution  to Grade 1 after corticosteroid taper. Permanently 
discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone 
to less than 10 mg/day (or equivalent) within 12 weeks of initiating steroids. 
 
**If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or 
permanently discontinue based on recommendations for hepatitis with no liver involvement. 
***Abnormal troponin and proNTBNP/BNP at screening is defined as any value >ULN at screening 
 
1. For any grade skin toxicities, recent alcohol intake or other potentially related concomitant exposures per 
Investigator assessment, should be recorded in the eCRF. Please refer to SRM for additional details. 
 
Abbreviations: BNP = B-type natriuretic peptide; NT-pro-BNP = N-terminal pro-hormone BNP; SJS = Stevens-Johnson 
syndrome; TEN = toxic epidermal necrolysis; DRESS = drug reaction with eosinophilia and systemic symptoms. 
 
 
;  
 
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12.1.5.11.1. 
Dose Modification and Toxicity Management of Infusion-Reactions 
Related to Immunotherapy Treatment 
Table 47 
Immunotherapy Infusion Reaction Dose Modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
Please refer to the pharmacy manual for 
administration details.  
Participant may be premedicated 
1h (± 30 minutes) prior to infusion 
of study drugs with: 
Diphenhydramine 50 mg (or 
equivalent dose of antihistamine) 
and/or acetaminophen 325-1000 
mg (or equivalent dose of 
analgesic) 
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), unless otherwise specified in 
the pharmacy manual. Otherwise dosing 
will be held until symptoms resolve and 
the participant should be premedicated 
for the next scheduled dose. 
 
Participants who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
study drug treatment. 
 
Please refer to the pharmacy manual for 
administration details. 
Participant may be premedicated 
1h (± 30 minutes) prior to infusion 
of study drugs with: 
Diphenhydramine 50 mg (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg (or 
equivalent dose of analgesic). 
If necessary, corticosteroids (up 
to 25 mg of hydrocortisone or 
equivalent) may be used and 
adaptation of the infusion rate 
should be discussed with Medical 
Monitor. 
 
Grades 3 or 4 
Grade 3: 
Prolonged (e.g. not rapidly 
responsive to symptomatic 
medication and/or interruption of 
infusion; recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
impairment, pulmonary 
infiltrates)) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
 
Please refer to the pharmacy manual for 
administration details. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
Abbreviations: NSAIDs = non-steroidal anti-inflammatory drugs. 
If a participant has an infusion related reaction, vital signs will be obtained every 
15 minutes (± 5 minutes) at the start of symptoms until the participant is deemed 
medically stable in the opinion of the investigator; pulse oximetry should be performed in 
conjunction with vital signs. 
 
Adverse Events of Special Interest (AESI) 
Refer to Section 7.2.1.1 for details. In addition, for AESIs of immune related cutaneous 
toxicities of any grade, recent alcohol intake or other potentially related concomitant 
exposures per Investigator assessment, should be recorded in the eCRF. Please refer to 
SRM for additional details. 
 
12.1.5.12. Safety Evaluation 
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If a participant withdraws from the study before the completion of the 21-day DLT 
evaluation period for reasons other than DLT or becomes non-evaluable during the DLT 
period, then the participant may be replaced to achieve the three-participant required 
minimum. The decision to declare the combination tolerable will occur following review 
of the safety, PK and PD data (if available) and joint discussion by the GSK Medical 
Monitor and investigators. Membership, roles and accountabilities, and the process for 
safety review and meeting frequency is outlined in the Study Reference Manual.  
The mTPI design assumptions include the following: 
(iii) 
(iv) 
The monitoring rules guiding dose decision are provided in Table 48. The tolerability 
decision framework using the mTPI method were generated based on a beta/binomial 
model and pre-calculated before study initiation. The rules in Table 48 utilize the mTPI 
method along with additional rules as following: 
• A maximum of
DLT evaluable participants will be enrolled for DLT evaluation 
for each dose combination. 
• To avoid exposing participants to excessive toxicities, if or more DLTs occur at 
a dose combination, that dose combination will stop enrolling more participants 
and will de-escalate to lower dose combination (where applicable). 
• Re-escalate to a dose combination is not allowed if that dose has been evaluated 
and the mTPI rule indicates “D” or “DU”. 
The entries in the dose decision rules in Table 48 below represent dose-finding decision 
points at which a determination is made whether the combination remains safe for 
continued testing using the data generated in the cohort of interest. These points are often 
denoted as “E”, “S”, “D” and “DU”, denoting the thresholds governing escalating the 
dose, staying at the same dose, de-escalating the dose, or de-escalating and no longer re-
visit, respectively. To note, there is no “D” in Table 48 due to the above additional rules 
that re-escalation is not allowed. If a dose combination is not tolerated per Table 48, 
further evaluation of that dose combination will be stopped.  
 
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additional participants experience DLTs, the rule indicates "DU" so this combination will 
not be considered acceptable and no additional participants will be treated with this 
combination because of unacceptable toxicity. However, if none of these additional 
participants experience DLTs, the rule indicates "S" with a DLT rate of 
% 
DLTs out 
of participants), hence the combination will be considered tolerated.  
 
If a combination is considered tolerated and the observed DLT rate is
%, additional 
participants may be enrolled to further evaluate safety and PK/PD. No formal evaluation 
of DLTs will be performed after the 21 day period, however other measures of safety will 
continue to be monitored. 
 
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12.1.5.14. Dose Limiting Toxicity 
The severity of all toxicities will be graded using National Cancer Institute - Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) (version 5.0) [NCI, 2017]. The 
DLT observation period is 21 days in length and begins on the day study treatment is first 
administrated to the participant. 
 
A DLT is defined as an AE that meets at least one of the criteria listed in Table 49 and is 
considered by the investigator to be clinically relevant and attributed (probably, or 
possibly) to the study treatment during the 21-day DLT observation period. An AE 
considered related to the underlying disease under study it is not defined as a DLT. A 
safety event can still be included for DLT consideration after the 21 day window. See 
Section 10.4 for the definition of a DLT evaluable participant.  
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Table 49 
Dose-Limiting Toxicity Criteria 
Toxicity 
DLT Definition (Grading per CTCAE v5) 
Hematologic 
• 
Grade 4 neutropenia of any duration or febrile neutropenia  
• 
Grade 4 anemia of any duration 
• 
Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with bleeding 
Non- hematologic 
• Grade 2 uveitis, episcleritis, iritis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to G1 severity or requires systemic treatment.  
• Grade 2 colitis or diarrhea that persists without resolution to ≤ Grade 1 for ≥7 days 
despite adequate immunosuppressive therapy  
• Grade 3 diarrhea/colitis lasting ≥72h regardless of medical intervention or G4 
diarrhea/colitis    
• Grade 3 pneumonitis  
• Grade 3 rash if no resolution to ≤Grade 2 or baseline within 2 weeks with use of systemic 
steroids or anti-inflammatory agents per standard of care  
• Grade 3 hypersensitivity or IRR   
• ALT ≥ 3x ULN plus bilirubin ≥ 2x ULN (>35% direct) or plus INR >1.5, if measureda 
(possible Hy’s Law) 
• Grade 3 toxicity that does not resolve to ≤Grade 1 or baseline within 3 days despite optimal 
supportive careb or any Grade 4 toxicity  
• Following events are not considered DLTs 
o 
≥ Grade 3 electrolyte abnormalities that are corrected to ≤ Grade 1 or 
baseline within 72 hours without clinical sequelae 
o 
Grade 3 nausea or vomiting that resolves to ≤Grade 1 or baseline within 7 
days 
o 
≥Grade 3 fatigue ≤7 days  
o 
≥Grade 3 lymphopenia  
o 
Grade 3 elevation of amylase or lipase not associated with clinical or 
radiographic evidence of pancreatitis  
Other 
• Toxicity that results in permanent discontinuation of any agent in combination  
• Any other toxicity considered to be dose-limiting that occurs after the completion of the DLT 
observation period will be considered in the selection of the dose to recommend for 
expansion cohorts 
• Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT 
a. Not applicable to participants taking anticoagulants.  
b. Suggested toxicity management guidelines as described in Section 12.1.5.12 may include systemic 
corticosteroids for immune-related toxicities; if systemic corticosteroids use delays administration of the 
second dose of study treatment and the event does not otherwise meet the DLT criteria for non- hematologic 
toxicity, the dose delay will not be considered a DLT. 
CTCAE=Common Toxicity Criteria for Adverse Events; DLT = Dose-limiting toxicity; G-CSF =Granulocyte 
colony-stimulating factor; GSK =GlaxoSmithKline; IRR=infusion related reaction 
 
If a participant experiences a DLT during the DLT observation period, the participant 
may resume dosing provided the toxicity did not meet study treatment discontinuation 
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Toxicity management and dose modification guidelines provided in Section 12.1.5.11 are 
directed for those AEs of special interest that, although not observed in nonclinical 
studies, may be expected with the administration of immune directed therapies. 
 
Guidance for the identification, evaluation, and the established algorithms for the 
treatment management of immune-related adverse events (irAEs) including dose 
modification algorithms are provided in Section 12.1.5.11. These guidelines are based on 
the experience of irAE management following the development of immune check-point 
inhibitors such as ipilimumab and pembrolizumab. Guidelines are also provided for 
infusion reactions or severe cytokine release (Section12.1.5.11.1). The joint ASCO and 
NCCN guidelines for the diagnosis and management of irAEs treated with immune 
checkpoint inhibitor therapy may be used as a supplement to the guidance provided in 
Section 12.1.5.11. 
 
If there is a delay in administration of study treatment, refer to Section 12.1.5.11 for 
guidance on planning of subsequent study visits. 
 
12.1.5.15. Risk-Benefit Assessment of GSK4428859A, GSK6097608 and 
Dostarlimab combined   
Table 50 
Risk Assessment and Mitigation Strategy: GSK4428859A, 
GSK6097608 and Dostarlimab 
Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immune-related AEs 
(irAEs) 
 
 
 
• Inflammatory AEs such as diarrhea/colitis, 
pneumonitis, nephritis, myocarditis  and 
hepatotoxicity are well established as 
treatment emergent AEs with immune-
modulating agents, and are consistent 
with the immune-stimulatory mechanism 
of action of these agents.  
• An anti-PD-1 checkpoint inhibitor 
(dostarlimab) will be used in combination 
with an anti-TIGIT mAb (GSK4428859A) 
and anti-CD96 (GSK6097608).  
• Based on the safety profile of anti PD-1 
antibodies, administered alone or in 
combination, the anticipated adverse 
reactions may be primarily immune 
mediated. Based on emerging data from 
anti-TIGIT mAbs, administered alone or in 
combination, the anticipated adverse 
reactions are similarly immune mediated. 
 
• Participants with the following 
medical history are ineligible for this 
study 
o Toxicity (≥Grade 3) related to 
prior immunotherapy leading to 
study treatment discontinuation  
o Active autoimmune disease (refer 
to Section 6.2 exclusion criterion 
6) 
o Severe hypersensitivity to another 
mAb 
• Established management algorithms 
for immune-related adverse events 
(irAEs)  
• Refer to Section 12.1.5.12 for further 
details on the identification, 
evaluation, and management of 
toxicities with a potential immune 
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Potential Risk of 
Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Infusion and 
hypersensitivity 
reactions and potential 
CRS 
• 
Risk for infusion reactions and 
hypersensitivity is inherent to many 
mAbs [Brennan, 2010]  
 
GSK6097608: 
• 
Manageable infusion reactions have 
been observed with GSK6097608 in the 
ongoing Phase 1 clinical study. 
 
Dostarlimab: 
• 
The frequency of IRRs with dostarlimab 
is labelled as common 
 
 
 
 GSK4428859A: 
• 
 
See Investigator’s Brochures for dostarlimab, 
GSK6097608 and GSK4428859A [iTeos 
EOS884448 [EOS-448] IB, 2021] for details. 
• 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 12.1.5.12 for further 
details on management and 
monitoring of infusion reactions.  
• Refer to Section 12.1.5.12 for further 
details on management of CRS 
• Refer to Protocol Section 7.2.1.2; 
Table 3 for details of blood panel 
collection for all participants 
experiencing any grade of infusion 
reaction or CRS 
• For severe (Grade 3) or 
life-threatening (Grade 4) IRRs 
associated with GSK6097608, 
GSK4428859A or dostarlimab, 
infusion should be stopped, and 
treatment should be permanently 
discontinued. 
ADA and Immune 
complex disease 
• Immune complex deposition may cause 
clinical symptoms, most commonly renal, 
skin, or vasculitis pathology. 
• For nonclinical immune complex formation 
and deposition findings (refer to individual 
product Investigator’s Brochure [IBs]) 
• GSK4428859A and GSK6097608 are fully 
human IgG1 mAb with a wild-type Fc 
domain. Based on the characteristics of 
the molecules and active pharmaceutical 
ingredients, the risk of immunogenicity in 
humans is considered to be low and 
similar to other mAbs. 
• Clinical laboratory safety 
assessments and immunogenicity 
testing  
Reproductive toxicity 
• 
• Immune-checkpoint inhibitors (such as 
dostarlimab) have been shown to have 
potential to disrupt maternal-fetal 
tolerance leading to failure of 
implantation or spontaneous abortion. A 
similar risk will be assumed for 
GSK6097608 and GSK4428859A. 
• 
Inclusion of contraception guidelines 
for WOCBP (Section 6.1). 
• 
Exclusion of lactating or pregnant 
women (Section 6.2). 
• 
Pregnancy testing for WOCBP 
during Screening and throughout the 
Treatment period, as specified in the 
SoA (Section 12.1.4.2 and Section  
12.1.5.2). 
Abbreviations: AE = adverse event; IB = Investigator’s Brochure; irAEs= immune-related adverse events; IRR= 
infusion-related reactions; mAb = monoclonal antibody. 
 
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12.1.5.16. Additional Study Population Criteria: Arm 5 
12.1.5.16.1. 
Additional Inclusion Criteria: Arm 5 
1. Male contraception is not required for this arm.  
12.1.5.16.2. 
Additional Exclusion Criteria: Arm 5 
1. Known hypersensitivity to components or excipients of dostarlimab, GSK6097608, 
and/or GSK4428859A . 
2. Has received prior antibodies or drugs targeting TIGIT, CD96, PVRIG, or other 
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12.1.5.17. References 
Ahn MJ, Niu J, Kim D, Rasco D, Mileham KF, Chung HC, et al. Vibostolimab, an 
anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in 
anti-PD-1/PD-L1-refractory NSCLC. Ann Oncol. 2020;31(Suppl 4):S754-S840. 
Bendell JC, Bedard P, Bang YJ, LoRusso P, Hodi S, Gordon M, et al. Abstract CT302: 
Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single 
agent and in combination with atezolizumab in patients with advanced solid tumors. 
Cancer Res. 2020;80(Suppl 16):CT302. 
Beyrend, G., et al., PD-L1 blockade engages tumor-infiltrating lymphocytes to co-
express targetable activating and inhibitory receptors. J Immunother Cancer, 
2019;7(1):217. 
Blake SJ, Stannard K, Liu J, Allen S, Yong MC, Mittal D, et al. Suppression of 
metastases using a new lymphocyte checkpoint target for cancer immunotherapy. Cancer 
Discov. 2016;6(4):446-459. 
Chan CJ, Andrews DM, McLaughlin NM, Yagita H, Gilfillan S, Colonna M, et al. 
DNAM-1/CD155 interactions promote cytokine and NK cell-mediated suppression of 
poorly immunogenic melanoma metastases. J Immunol. 2010;184(2):902-911. 
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Anti-TIGIT Antibodies Regulate Development of Autoimmunity and Antitumor 
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Gros A, et al. PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire 
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GSK Document Number 2019N420882_00. Expression of CD96, TIGIT, and related 
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GSK Document Number TMF-11850520. Analysis of PD-1 receptor modulation by 
dostarlimab (TSR-042) using ex vivo IL2 stimulation ratio. Effective Date: 
22 August 2019. 
GSK Document Number RPS-SA-1628635. Population pharmacokinetic analysis and 
exploratory exposure-response analysis of dostarlimab (TSR-042) (Study 4010-01-001 
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GSK Document Number RPS-CLIN-014254. GSK6097608 Investigator's Brochure. 
Effective Date: 09 June 2021. 
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checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma. Blood. 
2018;132(16):1689-1694. 
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and PD-1 or TIGIT enhances tumor immunity without significantly compromising 
immune homeostasis. Oncoimmunology. 2018;7(7):e1445949. 
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2020;200(2):108-119. 
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activated CD8+ T cells and is upregulated in non-small cell lung cancer patients. Exp 
Cell Res. 2020;396(1):112260.  
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PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. 
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iTeos Investigator’s Brochure for EOS884448 (EOS-448) Edition 2.0 02 April 2021. 
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The 
immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. 
Cancer Cell. 2014;26(6):923-937. 
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the 
coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell 
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Kamphorst, A.O., et al., Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-
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KEYTRUDA [package insert]. Whitehouse Station, NJ. Merck Sharp & Dohme 
Corporation; 2021.  
KEYTRUDA [Summary of Product Characteristics]. Merck Sharp & Dohme B.V., 2021.  
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lines in vitro and in vivo. J Clin Invest. 2009;119(5):1251-1263. 
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regulates human T cell function. J Immunol. 2012;188(8):3869–3875. 
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escape after stem cell transplantation is a consequence of T-cell exhaustion and is 
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Rodríguez-Abreu D, Johnson ML, Hussein MA, Cobo M, Patel AJ, Secen NM, et al. 
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Immunol. 2018;19 (7):723-732. 


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12.2. 
Appendix 2: Abbreviations and Trademarks 
Abbreviation 
Definition 
-hCG 
Beta-human chorionic gonadotropin 
ADA 
Anti-drug antibodies 
ADCC/P 
Antibody-dependent cellular cytotoxicity/phagocytosis 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AKT 
V-AKT murine thymoma viral oncogene 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration time curve 
AUC(0-) 
Area under the concentration-time curve over the dosing interval 
BAL 
Bronchoalveolar lavage 
BARC 
Breast Cancer gene 
BCG 
Bacillus calmette-guérin 
BNP 
B-type natriuretic peptide 
cfDNA 
Cell-free DNA 
CHO 
Chinese hamster ovary 
CIOMS 
Council for international organizations of medical sciences 
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 
CPK 
Creatine phosphokinase 
CPMS 
Clinical pharmacology modeling and simulation 
CR 
Complete response 
CRA 
Cytokine release assays 
CRC 
Colorectal carcinoma 
CrCl 
Calculated creatinine clearance 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
ct-DNA 
Circulating tumor DNA 
CTLA-4 
Cytotoxic t-lymphocyte-associated protein 4 
CV 
Cardiovascular 
DCR 
Disease control rate 
DILI 
Drug-induced liver injury 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
EC 
Effective concentration 
ECG 
Electrocardiogram(s) 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EOI 
End of infusion 


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Abbreviation 
Definition 
Fc 
Fragment crystallizable 
FcR 
Fc-gamma receptor 
FcR 
Fc region receptor 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FSH 
Follicle stimulating hormone 
FTIH 
First-time-in-human 
GCP 
Good clinical practice 
%GCV 
Percent geometric coefficient of variation 
G-CSF 
Granulocyte colony-stimulating factor 
GI 
Gastrointestinal 
GM 
Geometric mean 
GSK 
GlaxoSmithKline 
HIPAA 
Health insurance portability and accountability act 
HLA 
Human leukocyte antigen 
HPLC 
High performance liquid chromatography 
HR 
Hazard ratio 
HRD 
Homologous recombination deficiency 
HRQL 
Health related quality of life 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International council on harmonization of technical requirements for registration of 
pharmaceuticals for human use 
ICOS 
Inducible t-cell costimulator 
iCPD 
iRECIST Confirmed disease progression  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committees 
IFN 
Interferon, gamma 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL 
Interleukin 
INR 
International normalized ratio 
IO 
Immunotherapy 
irAE 
Immune-related adverse event 
IRB 
Institutional review board 
iRECIST 
Modified RECIST 1.1 for immune-based therapeutics 
IRR 
Infusion-related reactions 
ITT 
Intent to treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
L 
Litre 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LLOQ 
Lower limit of quantitation 
LPS 
Lipopolysaccharide 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
CCI


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Abbreviation 
Definition 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MLR 
Mixed lymphocyte reaction 
mmol 
Millimolar 
MRI 
Magnetic resonance imaging 
MRSA 
Methicillin-resistant Staphylococcus Aureus 
MTD 
Maximum tolerated dose 
mTPI 
Modified toxicity probability interval 
MUGA 
Multigated acquisition scan 
NA 
Not applicable 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
NCCN 
National Comprehensive Cancer Network 
NE 
Not evaluable 
NIH 
National Institutes for Health 
NK 
Natural killer 
nM 
Nanomolar(s) 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
NT-pro-BNP 
N-terminal pro-hormone BNP 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
OTC 
Over the counter 
PARP 
Poly(ADP-ribose) polymerase 
PBMC 
Peripheral blood mononuclear cells 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed cell death ligand 1  
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PoS 
Predictive probability of success 
PR 
Partial response 
PRO 
Patient-reported outcome 
PS 
Performance status 
PVRIG 
Poliovirus Receptor-related Immunoglobulin Domain Containing 
Q1W 
Every 1 week 
Q2W 
Every 2 weeks 
Q3W 
Every 3 weeks 
QLQ 
Quality of life questionnaire 
QoL 
Quality of life 
QTc 
Corrected QT interval duration 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RANKL 
Receptor activator of nuclear factor-kappaB ligand 
RAP 
Reporting and analysis plan 
CCI
CCI
CCI


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Abbreviation 
Definition 
RECIST 
Response evaluation criteria in solid tumors 
RNA 
Ribonucleic acid 
RO 
Receptor occupancy 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event 
SCCHN 
Squamous cell carcinoma of head and neck 
SD 
Stable disease 
SGPT 
Serum glutamic pyruvic transaminase 
SITC 
Society for Immunotherapy of Cancer 
SJS 
Stevens-Johnson syndrome 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SoC 
Standard of care 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
T1DM 
Type 1 Diabetes Mellitus 
TCR 
T-cell receptor 
TDV 
Treatment discontinuation visit 
TEAE 
Treatment emergent adverse events 
TEN 
Toxic epidermal necrolysis 
TIGIT 
T-cell immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain 
TIL 
Tumor infiltrating lymphocytes 
TIM-3 
T cell immunoglobulin and mucin-domain containing-3 
TMDD 
Target-mediated drug disposition 
TNF 
Tumor necrosis factor 
TPS 
Tumor proportion score 
TRAE 
Treatment related adverse event 
Tregs 
Regulatory t-cells 
TSH 
Thyroid stimulating hormone 
TTR 
Time to response 
ULN 
Upper limit of normal 
UPM 
Unit probability mass 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
FluMist 
 
 
Keytruda 
 
 
Opdivo 
 
 
Taxotere 
 
 
Yervoy (ipilimumab) 
 
 


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12.3. 
Appendix 3: Clinical Laboratory Tests 
Table 51 
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 
Amylase 
Lipase 
 
Coagulationd 
PT/INR 
PTT/aPTT 
Cardiac Function 
Troponin I or Troponin T (Troponin I is preferred over Troponin T. High 
sensitivity assays are preferred where available)  
BNP or NT-pro-BNP (NT-pro-BNP is preferred) 
Thyroid Function 
Thyroid stimulating hormone 
Free T4 
Free T3 (when clinically indicated) 
Routine Urinalysis 
Specific gravity 
pH, glucose, protein, blood and ketones by dipstick (Note: routine urinalysis 
by method other than dipstick is acceptable, in accordance with local 
practice). 
Other Screening Tests 
Hepatitis B surface antigen (HBsAg) 
Hepatitis C (Hep C antibody)c 
Serum -hCG Pregnancy test (for women of child bearing potential) 
 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; -hCG = beta-human chorionic 
BNP = B-type natriuretic peptide; 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 = triiodothyronine; T4 = thyroxine; WBC = white blood cells; INR = International Normalized Ratio; NT-pro-BNP = N-
terminal pro-hormone BNP; 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 9. 
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. 
d.   Coagulation factors (PT/INR and aPTT/PTT) should be tested per the SOA under each study arm in Section 12.1 
for all participants. Any participant receiving anticoagulant therapy should have coagulation factors monitored closely 
throughout the study. 
 


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12.4. 
Appendix 4: Study Governance Considerations 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable 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 
 
Financial Disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  


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• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
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. 
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. 
Committees Structure 
As indicated in Section 5.5.1, a Steering Committee will convene to provide 
recommendations at key decision points during the conduct of the study. Details 
describing the administrative structure for the Steering Committee are located in the 
Steering Committee Charter.  
As indicated in Section 5.1, an IDMC will convene for review of efficacy and safety 
results at appropriate intervals. Additional details of the IA will be provided in an IDMC 
Charter.  


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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. 
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-agreeable location. 
• 
GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate. 
• 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
• 
The Sponsor will comply with the requirements for publication of study results 
and will publish the results of each substudy within 12 months of the primary 
completion date (last participant last visit date). 
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.  
• 
The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  


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• 
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.  
• 
Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify 
systematic issues that can impact participant reliability of study results. These 
pre-defined parameters will be monitored during and at the end of the study and 
all deviations from the QTLs and remedial actions taken will be summarized in 
the clinical study report. 
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. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development. 


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12.5. 
Appendix 5: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered 
related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE.  
 
 
 


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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 


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d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
 Revascularization 
 


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Recording AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Severity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign a grade according to the NCI-CTCAE v5.0 [NCI, 
2017].  
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 


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important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• 
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide GSK with a copy of any post-
mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the Medical Monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM on the Sponsor/Medical 
Monitor Contact Information page.  


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SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the SAE coordinator to OAX37649@gsk.com. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• 
Contacts for SAE reporting can be found in the SRM. 


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12.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Contraception Guidance 
Male participants (if required) 
• 
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 6.1:  
• 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 52 when having 
penile-vaginal intercourse with a woman of childbearing potential  


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• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for the duration of the study and for at least 120 days after the 
last dose of study treatment. 
• 
In addition, male participants must refrain from donating sperm for duration of 
study and for at least 120 days after the last dose of study treatment. 
• 
If the participant is randomized to the SoC regimen only, then the duration of 
contraception is at least 3 days after the last dose of study treatment (or per 
institutional standard).  
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 52.  
Table 52 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
• oral 
• intravaginal  
• transdermal  
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
• injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
Vasectomized partner  
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)  


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Highly Effective Methods That Are User Independent 
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. 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. Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies.  
b. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. In this case 2 highly effective methods of contraception should be utilized during the treatment 
period and for at least 120 days after the last dose of study treatment. However, if the participant is randomized to the 
SoC regimen only, then the duration of contraception is at least 3 days after the last dose of study treatment.  
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum β-hCG test  
• 
Additional pregnancy testing should be performed at monthly intervals as indicated 
in the SoA during the treatment period and at for at least 120 days after the last dose 
of study treatment and as required locally. If the participant is randomized to the SoC 
regimen only, then the duration of contraception is at least 3 days after the last dose 
of study treatment.  
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. Pregnancy testing (serum β-hCG) will be 
performed by the certified local laboratory.  
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 participants who receive study treatment. 
• 
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.  
• 
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 treatment by the investigator, will be reported to GSK 
as described in Appendix 5. 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 be discontinued 
from study treatment.  
 
 


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12.7. 
Appendix 7: Genetics 
CCI


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12.8. 
Appendix 8: ECOG Performance Status 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
1. [Oken, 1982] 
 
 


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12.9. 
Appendix 9: CKD-EPI and Cockcroft-Gault Formulas 
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. 
Cockcroft-Gault Formula 
The Cockcroft-Gault formula is a commonly-used surrogate marker for actual creatinine 
clearance (CrCl) and employs creatinine measurements and a participant’s weight (kg) to 
predict the clearance.  
If the participant is obese (>30% over ideal body weight), use ideal body weight in 
calculation of estimate CrCl. 
If the participant is below ideal body weight, use actual body weight in calculation of 
estimate CrCl. 


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Cockcroft-Gault Formula for serum creatinine in mmol/L 
 
 
 
CrCl (mL/min)= 
Q X (140-age [years]) X ideal body weight (kg)a 
 
72 X serum creatinine (mmol/L) 
Q=0.85 for females 
Q=1.0 for males 
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974] 
Male participants: 
 
 
 
50.0 kg + (2.3 kg X each inch over 5 feet) 
or 
50.0 kg + (0.906 kg X each cm over 152.4 cm) 
Female participants: 
 
 
 
45.5 kg + (2.3 kg X each inch over 5 feet) 
or 
45.5 kg + (0.906 kg X each cm over 152.4 cm)  
 
 
Cockcroft-Gault Formula for serum creatinine in mg/dL 
 
 
For example: 
For a male participant with actual body weight = 90.0 kg and height = 68 inches, the 
calculation would be as follows: 
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg 
This 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. 
 


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12.10. 
Appendix 10: Liver Safety: Required Actions and Follow-up 
Assessments and Study Treatment Rechallenge Guidelines 
Phase 2 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology. 
12.10.1. 
For Participants with ALT up to 2.5 X ULN at Baseline: 
Phase 2 Liver Chemistry Stopping Criteria and Required Follow-Up Assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT - absolute 
ALT  5xULN 
ALT Increase 
ALT  3xULN persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot Monitor 
ALT  3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
ALT  3xULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity 
Required Actions and Follow-up Assessments Following ANY Liver Stopping Event* 
Actions 
Follow-Up Assessments 
• Immediately discontinue study treatment 
 
• Report the event to GSK within 24 hours 
• Complete the liver event CRF and complete SAE 
data collection tool if the event also meets the 
criteria for an SAE2 
• Perform liver event follow-up assessments  
• Monitor the participant until liver chemistries resolve, 
stabilize, or return to within baseline (see 
MONITORING below) 
• Do not restart/rechallenge participant with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted  
• 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: 
• 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 


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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 
 
• Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the AE 
report form 
• Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications 
• Record alcohol use on the liver event alcohol intake 
case report form 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG or gamma 
globulins) 
• Serum acetaminophen adduct HPLC assay (quantifies 
potential acetaminophen contribution to liver injury in 
participants with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: not 
required in China  
• Liver imaging (ultrasound, magnetic resonance, or 
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, 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 
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. 
*Study drugs refer to all drugs that comprise a study treatment arm. Refer to the central laboratory manual for 
instructions on sample requirements for follow-up tests performed at central laboratory. 
 


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12.10.2. 
For Participants with Documented Liver Metastases and ALT up 
to 5 X ULN at Baseline: 
Phase 2 Liver Chemistry Stopping Criteria and Required Follow-Up Assessments  
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, if INR measured 
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 CRF and complete SAE 
data collection tool if the event also meets the 
criteria for an SAE2 
• Perform liver event follow-up assessments  
• Monitor the participant until liver chemistries resolve, 
stabilize, or return to within baseline (see 
MONITORING below) 
• Do not restart/rechallenge participant with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted  
• 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 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 


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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 perform liver event 
follow-up assessments within 24-72 hrs  
• Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline 
 
• 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]). NOTE: not 
required in China  
• 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, 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 
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.  
*Study drugs refer to all drugs that comprise a study treatment arm. Refer to the central laboratory manual for 
instructions on sample requirements for follow-up tests performed at central laboratory. 
 


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12.10.3. 
Phase 2 Liver Chemistry Increased Monitoring Criteria with 
Continued Therapy 
In the event a participant has an increase in ALT, bilirubin, and/or INR that does not 
require stopping of study intervention (does not meet liver chemistry stopping criteria as 
noted in Section 12.10.1 and Section 12.10.2), the following guidance for monitoring of 
the increase in ALT, bilirubin, and/or INR should be followed as noted below.   
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Participant with entry criteria ALT≤2.5x 
ULN 
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 
Participant with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN 
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value 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 treatment 
• 
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline  
• 
If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above 
For participants with entry criteria ALT≤2.5 x ULN 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
For participants with documented liver 
metastases/tumor infiltration at baseline AND entry 
criteria ALT>2.5 x ULN but ≤5 x ULN 
• 
If, after 4 weeks of monitoring, ALT <3xULN and 
<1.5x baseline value, and bilirubin <2xULN, 
monitor participants twice monthly until liver 
chemistries normalize or return to within baseline 
 


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12.10.4. 
Liver Safety Drug Restart or Rechallenge Guidelines 
12.10.4.1. Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment 
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within 1 month of 
initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  
Risk factors for a fatal drug rechallenge outcome include: 
• 
Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia)  
• 
jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total) 
• 
participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5 
• 
serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009; Hunt, 2010] 
• 
evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010]) 
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a participant for whom there is compelling evidence of benefit from a 
critical or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favorable. 
Approval by GSK for rechallenge with study treatment can be considered where: 
• 
Investigator requests consideration of rechallenge with study treatment for a 
participant who is receiving compelling benefit (partial response or complete 
response) with study treatment that exceeds risk, and no effective alternative therapy 
is available.  
• 
The ALT at the time of rechallenge is <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. 
• 
Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.   
• 
If the rechallenge is approved by GSK Medical Governance in writing, the 
participant must be provided with a clear description of the possible benefits and 
risks of study treatment administration, including the possibility of recurrent, more 
severe liver injury or death.  


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• 
The participant must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart.  
• 
Study treatment must be administered at the dose specified by GSK. 
• 
Participants approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol. 
• 
If after study treatment rechallenge, participant meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued.  
• 
Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
rechallenge.  
• 
GSK must be notified of any AEs as per Section 9.4.4. 
 
12.10.4.2. Rechallenge Following Transient Liver Stopping Events Not Related to 
Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, and acute viral hepatitis). Furthermore, there should be 
no evidence of alcoholic hepatitis or hypersensitivity 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• 
Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g. lapatinib, abacavir, and 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 12.10.4.1 will apply. 
• 
There is no evidence of alcoholic hepatitis. 
• 
Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required. 
• 
If restart of study treatment is approved by GSK Medical Governance in writing, the 
participant must be provided with a clear description of the possible benefits and 


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risks of study treatment administration, including the possibility of recurrent, more 
severe liver injury or death.  
• 
The participant must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study 
chart.  
• 
Study treatment must be administered at the dose specified by GSK. 
• 
Participants approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume as 
per protocol.  
• 
If after study treatment re-start, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 
• 
Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart.  
• 
GSK must be notified of any AEs, as per Section 9.4 
 


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12.11. 
Appendix 11: Country-Specific Requirements 
Korea: Section 6.1, Inclusion Criteria #2: Participants in Korea must be age 19 years or 
older at the time consent is obtained.  
 
 


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12.12. 
Appendix 12: Guidelines for Assessment of Disease, 
Disease Progression and Response Criteria 
12.12.1. 
RECIST 1.1 Guidelines 
Please note the following: 
• 
The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines. 
• 
All measurements must be taken and recorded in millimeters (mm), using a ruler 
or calipers. 
• 
Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required. 
• 
Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments 
of disease. However, FDG-PET can be useful in confirming new sites of disease 
where a positive FDG-PET scans correlates with the new site of disease present 
on CT/MRI or when a baseline FDG-PET was previously negative for the site of 
the new lesion. FDG-PET may also be used in lieu of a standard bone scan 
providing coverage allows interrogation of all likely sites of bone disease and 
FDG-PET is performed at all assessments. 
• 
If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast. The method of 
assessment must be noted as CT on the eCRF. 
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required. 
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended. 
Minimum size of a measurable baseline lesion must be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences must be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible, the same 
scanner should be used. 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray. 
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 


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Guidelines for Evaluation of Disease 
Evaluation of Anti-Cancer Activity 
• 
RECIST version 1.1 guidelines will be used to determine the overall tumor burden at 
Screening, select target and non-target lesions, and in the disease assessments 
through the duration of the study [Eisenhauer, 2009]. 
• 
As indicated in RECIST version 1.1 guidelines: 
o Lymph nodes that have a short axis of <10 mm are considered non-
pathological and must not be recorded or followed. 
o Pathological lymph nodes with <15 mm, but 10 mm short axis are 
considered non-measurable. 
o Pathological lymph nodes with 15 mm short axis are considered measurable 
and can be selected as target lesions; however, lymph nodes should not be 
selected as target lesions when other suitable target lesions are available. 
o Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target 
lesions, and recorded and measured at baseline. These lesions should be 
selected based on their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques 
or clinically). 
Note: Cystic lesions thought to represent cystic metastases must not be selected as target 
lesions when other suitable target lesions are available. 
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation must not be considered as target lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by CT or MRI) can be considered measurable. Bone scans, FDG-
PET scans or X-rays are not considered adequate imaging techniques to measure bone 
lesions. 
• All other lesions (or sites of disease) must be identified as non-target and must 
also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each must be noted throughout follow-up. 
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 


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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 1 measurable lesion. Palpable lesions that 
are not measurable by radiologic or photographic evaluations may not be utilized as the 
only measurable lesion. 
Non-Measurable only disease: The presence of only non-measurable lesions.  
Note: non-measurable only disease is not allowed per protocol. 
Response Criteria 
Evaluation of target lesions: 
Definitions for assessment of response for target lesion(s) are as follows: 
• 
Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis. 
• 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline). 
• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm. 
• 
Not Applicable (NA): No target lesions at baseline. 
• 
Not Evaluable (NE): Cannot be classified by one of the five preceding definitions. 


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Note: 
• 
If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions).  When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression. 
• 
If at a given assessment time point all target lesions identified at baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments.  However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented.  If an assessment of 
PD cannot be made, the response assessment should be NE. 
• 
All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported. 
• 
If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured.  The response at the time when the lesion reappears will depend upon 
the status of the other lesions.  For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance.  However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir. 
Evaluation of non-target lesions: 
Definitions for assessment of response for non-target lesions are as follows: 
• 
Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. <10 
mm short axis). 
• 
Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥ 10 mm short axis. 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
• 
Not Applicable (NA):  No non-target lesions at baseline. 
• 
Not Evaluable (NE):  Cannot be classified by one of the four preceding definitions. 
Note: 
• 
In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 


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• 
Sites of non-target lesions, which are not assessed at a particular timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable").  
New lesions: 
New malignancies denoting disease progression must be unequivocal.  Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions. 
Any equivocal new lesions should continue to be followed.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented. 
Evaluation of overall response: 
Table 53 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline. 
Table 53 
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/Non-PD or NE 
No 
PR 
PR 
Non-PD or NA or NE 
No 
PR 
SD 
Non-PD or NA or NE 
No 
SD 
NE 
Non-PD or NA or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, 
and NE=Not Evaluable 
 
Note: 
• 
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.   
• 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the CR. 


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Evaluation of best overall response: 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point.  
Confirmation Criteria: 
• 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met. 
 
12.12.2. 
iRECIST Guidelines 
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 and upon approval from 
the Medical Monitor and separate written consent of the participant (See Section 8.1), 
participants may continue treatment 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:  
• 
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 
• 
Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites (e.g., CNS metastasis, respiratory failure due to tumor compression, or spinal 
cord compression) requiring urgent alternative medical intervention 
• 
No significant, unacceptable, or irreversible toxicities related to study treatment 
Any participant deemed clinically unstable should be discontinued from study treatment 
at site-assessed radiologic evidence of PD. It is required to obtain the repeat tumor imaging, 
when feasible, for confirmation of PD by iRECIST. 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 treatment may continue and follow the regular imaging schedule. If 
PD is confirmed (iCPD), the participant will be discontinued from study treatment. 
 


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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 in consultation with the Medical Monitor whether to continue a participant on 
study treatment until repeat imaging is obtained (using iRECIST for participant 
management (see Table 54 and Figure 11). This decision should be based on the 
participant’s overall clinical condition (See discussion of clinical stability in Section 
12.12.1 above). The investigator must obtain approval from the Medical Monitor and 
separate consent from the participant prior to continuing treatment.  
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 
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 9.3.1. 


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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 
• 
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 


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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 treatment may continue and follow 
the regular imaging schedule. If PD is confirmed, participants will be discontinued from 
study treatment. 
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: 
• 
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 trial, 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 54 
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 
treatment at the 
investigator’s 
discretion, with 
Medical Monitor 
approval and 
participant consent, 
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 
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 
treatment 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 
treatment at the 
investigator’s 
discretion. 
Continue regularly 
scheduled 
imaging 
assessments. 
If clinically unstable, 
hold treatment 
 
May consider restarting 
study treatment only 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 11 
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator 
 
 


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12.14. 
Appendix 14: Immune-Related Diseases 
Table 56 
Potential Immune-Mediated Diseases 
Neuroinflammatory disorders 
Musculoskeletal disorders 
Skin disorders 
• 
Cranial nerve disorders, 
including 
paralyses/paresis (e.g. 
Bell’s palsy) 
• 
Optic neuritis 
• 
Multiple sclerosis  
• 
Transverse myelitis 
• 
Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other 
variants 
• 
Acute disseminated 
encephalomyelitis, 
including site specific 
variants: e.g. non-
infectious encephalitis, 
encephalomyelitis, 
myelitis, 
myeloradiculoneuritis 
• 
Myasthenia gravis, 
including Lambert-Eaton 
myasthenic syndrome  
• 
Immune-mediated 
peripheral neuropathies 
and plexopathies, 
(including chronic 
inflammatory 
demyelinating 
polyneuropathy, 
multifocal motor 
neuropathy and 
polyneuropathies 
associated with 
monoclonal 
gammopathy). 
• 
Narcolepsy 
• 
Systemic lupus 
erythematosus and 
associated conditions 
• 
Systemic Scleroderma 
(Systemic sclerosis), 
including diffuse 
systemic form and 
CREST syndrome 
• 
Idiopathic inflammatory 
myopathies, including 
Dermatomyositis, 
Polymyositis, 
• 
Antisynthetase 
syndrome 
• 
Rheumatoid arthritis and 
associated conditions 
including Juvenile 
chronic arthritis and 
Still’s disease) 
• 
Polymyalgia rheumatica  
• 
Spondyloarthritis, 
including ankylosing 
spondylitis, reactive 
arthritis (Reiter's 
Syndrome) and 
undifferentiated 
spondyloarthritis 
• 
Psoriatic arthropathy 
• 
Relapsing polychondritis 
• 
Mixed connective tissue 
disorder 
• 
Psoriasis 
• 
Vitiligo 
• 
Erythema nodosum 
• 
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis) 
• 
Alopecia areata 
• 
Lichen planus 
• 
Sweet’s syndrome 
• 
Localized Scleroderma 
(Morphoea) 
Liver disorders 
Gastrointestinal disorders 
Endocrine disorders 
• 
Autoimmune hepatitis 
• 
Primary biliary cirrhosis 
• 
Primary sclerosing 
cholangitis 
• 
Autoimmune cholangitis. 
• 
Inflammatory Bowel 
disease, including 
Crohn’s disease, 
ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis 
• 
Celiac disease 
• 
Autoimmune pancreatitis 
• 
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis) 
• 
Grave's or Basedow’s 
disease 
• 
Diabetes mellitus type I 
• 
Addison’s disease 
• 
Polyglandular autoimmune 
syndrome 
• 
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Vasculitides 
Blood disorders 
Others 
• 
Large vessels vasculitis 
including: giant cell 
arteritis such as 
Takayasu's arteritis and 
temporal arteritis.  
• 
Medium sized and/or 
small vessels vasculitis 
including: polyarteritis 
nodosa, Kawasaki's 
disease, microscopic 
polyangiitis, Wegener's 
granulomatosis, Churg–
Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s 
disease (thromboangiitis 
obliterans), necrotizing 
vasculitis and anti-
neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type 
unspecified), Henoch-
Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic 
vasculitis. 
• 
Autoimmune hemolytic 
anemia 
• 
Autoimmune 
thrombocytopenia 
• 
Antiphospholipid 
syndrome 
• 
Pernicious anemia 
• 
Autoimmune aplastic 
anemia 
• 
Autoimmune 
neutropenia  
• 
Autoimmune 
pancytopenia 
• 
Autoimmune 
glomerulonephritis (including 
IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis) 
• 
Ocular autoimmune 
diseases (including 
autoimmune uveitis and 
autoimmune retinopathy) 
• 
Autoimmune 
myocarditis/cardiomyopathy 
• 
Sarcoidosis 
• 
Stevens-Johnson syndrome 
• 
Sjögren’s syndrome 
• 
Idiopathic pulmonary fibrosis 
• 
Goodpasture syndrome 
• 
Raynaud’s phenomenon 
 


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12.15. 
Appendix 15: Protocol Amendment History 
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