A Phase I First Time in Human Open Label Study of GSK3745417 Administered With and Without Anticancer Agents in Participants With Advanced Solid Tumors
Phase: PHASE1
Conditions: Neoplasms
Sponsor: GlaxoSmithKline

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GSK group of companies 
 
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TITLE PAGE 
Protocol Title: A Phase I First Time in Human Open Label Study of GSK3745417 
administered with and without Anticancer Agents in Participants with Advanced Solid 
Tumors 
Protocol Number: 208850/07 
Short Title: Phase 1 First Time in Human, open label study of GSK3745417 
administered to participants with advanced solid tumors 
Compound 
Number: 
GSK3745417  
 
Sponsor Name and Legal Registered Address:  
GSK Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual  
Regulatory Agency Identifying Number(s):  
Investigational New Drug Number: 139899 
European Drug Regulatory Authorities Clinical Trials Number: 2018-001924-20 
Approval Date: 04 Aug 2023 
 
 
 
 
 
 
Copyright 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 
Amendment 7 
04 Aug 2023 
Amendment 6/JPN-1 
07-Apr-2022 
Amendment 6 
19-Jan-2022 
Amendment 5/NET-1 (country amendment) 
19-JUL-2021 
Amendment 4 
21-APR-2021 
Amendment 3 
16-OCT-2020 
Amendment 2 
27-AUG-2020 
Amendment 1 
12-DEC-2018 
Original Protocol 
12-SEP-2018 
 
Amendment 7: 04 Aug 2023 
This amendment is considered to be substantial  based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
 
Overall Rationale for the Amendment:  
 
 
 
 
  
In line with GSK’s decision, this protocol has been amended to provide updated 
instructions for study conduct of participants currently on study who are continuing to 
receive study GSK3745417 monotherapy or GSK3745417 in combination with 
dostarlimab, those in survival follow-up for any participants receiving treatment under 
post analysis continued treatment (PACT) phase. 
 
 
  
The correction of errors in Protocol Amendment 6. 
A table of key changes from Protocol Amendment 6 to Amendment 7 is shown below:  
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Section Number and 
Name 
Description of Change 
Brief Rationale 
1 Protocol Summary  
 
1.1 Synopsis 
• 
Removed Objectives & Endpoints 
 
 
. 
• 
 
 
. 
• 
Updated safety follow up period to 90 
days after last dose or until start of 
subsequent anticancer treatment, 
whichever is earlier.  
• 
 
• 
A 90-day safety follow-up after 
last dose of study drug is 
appropriate based on the half-
life of GSK3741417 and 
dostarlimab (for dostarlimab 
consistent with other 
protocols). 
• 
 
 
 
 
1.1.1 Schema 
1.2 Schedule of Activities 
• 
The updated and revised SoA for further 
conduct of the study, is provided under 
Section 1.2.1 Revised Schedule of 
Activities; and and 
 
 
• 
 
 
• 
For easy readability and 
conduct of study in participants 
receiving study treatment. 
• 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
2. Introduction 
3. Objectives and 
Endpoints 
• 
Removed Objectives & Endpoints 
 
 
 
• 
 
4.1 Overall Design 
• 
Updated to reflect no enrollment in the 
planned dose expansion phase (Parts 1B 
and 2B). 
• 
Addition of 90-day safety follow up period  
• 
 
• 
Added language on the possibility of 
post-assessment continued treatment 
(PACT) phase 
• 
 
 
 
• 
A 90-day safety follow-up after 
last dose of study drug is 
appropriate considering the 
half-life of GSK3741417 and 
dostarlimab.A 90-day safety 
follow-up after last dose of 
study drug is appropriate based 
on the half-life of GSK3741417 
and dostarlimab. 
• 
PACT language added to 
enable the continued treatment 
with study drugs for any 
participants who may continue 
to benefit from continued 
treatment beyond 2 years. 
4.1.1 Dose Escalation 
4.1.2 Dose Limiting 
Toxicity 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
• 
 
  
4.1.6 Study Duration 
• 
Updated study duration language in view 
of PACT language addition 
• 
PACT - Updated based on the 
recent program level wording 
4.2 Number of 
Participants 
• 
Updated to reflect the actual number of 
enrolled participants  
• 
Further enrollment ceased in 
this study 
4.3 Participant and Study 
Completion 
• 
Language updated on definition of study 
completion and safety follow up of 90 
days after last dose 
• 
For more clarity following 
addition fo PACT language 
4.6 End of Study 
Definition 
• 
Added language on PACT and End of 
Study  
• 
Added for more clarity 
6.6 Dose Modification 
• 
 
 
 
• 
Table 15 on guidelines for immune-
related AEs, updated with 
 
 
  
• 
 
 
 
• 
 
 
  
6.6.1  Management of 
Infusion Reactions 
or Severe Cytokine 
Release Syndrome 
(sCRS) 
• 
 
• 
Added a note above Table 16 Biomarker 
panel, that samples will no longer be 
collected at the time of a CRS event 
• 
Instruction added pertaining to dose 
reduction for CRS 
• 
As adequate 
chemokine/cytokine and PK 
samples for characterization of 
CRS have been obtained 
further sampling not required, 
and reducing.  burden for 
ongoing participants, 
• 
Dose modification for CRS also 
added to this section for clarity. 
6.6.1.1. Cardiac 
Monitoring and 
Dose Modification 
Guidelines 
• 
Updated to reflect preference of local 
troponin testing over central testing 
(same frequency); with Troponin I 
preferred 
• 
Preference for troponin I over 
troponin T at localf lab, based 
on emerging evidence that 
former may be more 
informative. 
6.8. Continued Access to 
Study Intervention 
after the End of the 
Study 
• 
Updated with PACT language 
• 
Added a subsection 6.8.1 on 
Continued Access to Study 
Intervention After Data Cut-off prior 
to EOS 
• 
PACT added to enable the 
continued access to study 
treatment (s) for participant 
who may continue to benefit 
from continued treatment 
beyond 2 years 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
7.1 Discontinuation of 
Study Intervention 
• 
Deleted redundant information related to 
End of Study  
• 
The following information has been 
added: “Participants will be followed up 
for safety until 90 days after last dose, 
until start of subsequent anticancer 
therapy or until death, whichever comes 
first.” 
• 
To align with PACT language 
• 
In alignment with the current 
updates 
7.2. Participant 
Discontinuation/ 
Withdrawal from the 
Study 
• 
The term “withdrawl of consent” has been 
added in the first paragraph for better 
clarity. 
• 
Added for more clarity 
8. Study Assessments 
And Procedures 
• 
Reference added to the Revised SoA in 
Section 1.2.1 
• 
PK related information on blood volume 
collection deleted 
• 
In alignment with the current 
updates 
8.1. Efficacy Assessments 
8.2.8. Chest Imaging 
(Japan cohort Only) 
• 
Added reference to revised SoA tables in 
Section 1.2.1  
• 
 
 
 
 
 
 
 
 
• 
Added for more clarity 
8.3.1. Time Period and 
Frequency for 
Collecting AE and 
SAE Information 
• 
Updated to reflect the revised SoA 
• 
Added PACT language 
• 
Added for more clarity on 
PACT phase 
8.5. Pharmacokinetics – 
Blood and Urine 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
8.7. Pharmacodynamics/ 
Biomarkers 
9.1. Statistical Hypotheses 
9.2. Sample Size 
Determination 
9.2.3 Dose Escalation 
 
 
9.3. Populations for 
Analyses 
9.4.1. Efficacy Analyses 
9.4.2.2 Adverse Events 
• 
Summaries of AEs to focus on TEAEs as 
defined in RAP 
• 
Updated according to RAP 
9.5. Interim Analyses 
• 
Updated language on potential additional 
interim analysis requirements 
• 
Any review of aggregate 
unblinded data is counted as 
an interim analysis (even if the 
study is open-label). 
• 
Wording added to cover 
potential future analyses 
11.2. Appendix 2: Clinical 
Laboratory Tests 
• 
In this amendment, any tests conducted 
in a clinical laboratory will no longer be 
performed; instead, it will be performed 
by the local laboratory 
• 
In alignment with the current 
updates 
11.3.5. Reporting of SAE 
to GSK 
• 
A note added that during the PACT 
phase, all SAEs and pregnancies will be 
reported via paper CRFs. 
• 
To align with PACT language 
11.15. Appendix 15: 
Imaging Sub-study 
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Section Number and 
Name 
Description of Change 
Brief Rationale 
11.17 Appendix 17: 
Protocol 
Amendment History 
• 
Moved the Amendment 6: 19-JAN-2022 
Summary of changes to Appendix 17 
• 
Minor formatting edits 
 
Additional changes were made for typos and other minor clarifications throughout the 
text. 

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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SUMMARY ........................................................................................ 20 
1.1. 
Synopsis ..................................................................................................... 20 
1.1.1. 
Schema ....................................................................................... 25 
1.2. 
Schedule of Activities (SoA) ........................................................................ 25 
1.2.1. 
Revised Schedule of Assessments .............................................. 79 
2. 
INTRODUCTION .................................................................................................. 110 
2.1. 
Study Rationale ........................................................................................ 110 
2.2. 
Background .............................................................................................. 111 
2.2.1. 
GSK3745417 ............................................................................. 111 
2.2.2. 
Clinical Safety of GSK3745417 .................................................. 113 
2.2.3. 
Dostarlimab ............................................................................... 113 
2.2.4. 
GSK3745417 and Dostarlimab Combination Background .......... 113 
2.3. 
Benefit/Risk Assessment .......................................................................... 114 
2.3.1. 
Risk Assessment ....................................................................... 115 
2.3.2. 
Overall Benefit: Risk Conclusion ................................................ 119 
3. 
OBJECTIVES AND ENDPOINTS ......................................................................... 119 
4. 
STUDY DESIGN .................................................................................................. 121 
4.1. 
Overall Design .......................................................................................... 121 
4.1.1. 
Dose Escalation ......................................................................... 124 
4.1.2. 
Dose-Limiting Toxicity ................................................................ 128 
4.1.3. 
Dose Escalation Committee ....................................................... 130 
4.1.4. 
Tumor Types Enrolled During Parts 1A and 2A.......................... 131 
4.1.5. 
Participant Re-Treatment ........................................................... 131 
4.1.6. 
Study Duration ........................................................................... 131 
4.2. 
Number of Participants ............................................................................. 132 
4.3. 
Participant and Study Completion ............................................................. 132 
4.4. 
Scientific Rationale for Study Design ........................................................ 133 
4.5. 
Justification for Dose ................................................................................ 134 
4.5.1. 
Human PK Prediction................................................................. 134 
4.5.2. 
Justification of Starting Dose...................................................... 134 
4.5.3. 
Dostarlimab Dose Rationale ...................................................... 137 
4.6. 
End of Study definition .............................................................................. 138 
5. 
STUDY POPULATION ......................................................................................... 138 
5.1. 
Inclusion Criteria ....................................................................................... 139 
5.2. 
Exclusion Criteria ...................................................................................... 141 
5.3. 
Lifestyle Considerations ............................................................................ 144 
5.3.1. 
Meals and Dietary Restrictions .................................................. 144 
5.3.2. 
Caffeine, Alcohol, and Tobacco ................................................. 144 
5.3.3. 
Activity ....................................................................................... 145 
5.4. 
Screen Failures......................................................................................... 145 
6. 
STUDY INTERVENTION ...................................................................................... 145 
6.1. 
Study Intervention(s) Administered ........................................................... 145 
6.2. 
Preparation/Handling/Storage/Accountability ............................................ 148 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ......................... 148 

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6.4. 
Study Intervention Compliance ................................................................. 149 
6.5. 
Concomitant Therapy................................................................................ 149 
6.5.1. 
Permitted Medications and Non-Drug Therapies ........................ 149 
6.5.2. 
Prohibited Medications and Non-Drug Therapies ....................... 150 
6.6. 
Dose Modification ..................................................................................... 151 
6.6.1. 
Management of Infusion Reactions or Severe Cytokine 
Release Syndrome (sCRS) ........................................................ 158 
6.6.2. 
Management of Renal Events .................................................... 166 
6.6.3. 
Management of Thrombophlebitis .............................................. 166 
6.7. 
Dose Delay ............................................................................................... 166 
6.8. 
Continued Access to Study Intervention after the End of the Study .......... 167 
6.8.1. 
Continued Access to Study Intervention After Data Cut-off 
prior to EOS ............................................................................... 167 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................... 168 
7.1. 
Discontinuation of Study Intervention ........................................................ 168 
7.1.1. 
Liver Chemistry Stopping Criteria .............................................. 169 
7.1.2. 
QTc Stopping Criteria ................................................................ 171 
7.1.3. 
Stopping Rules for Clinical Deterioration .................................... 171 
7.2. 
Participant Discontinuation/Withdrawal from the Study ............................. 172 
7.3. 
Lost to Follow Up ...................................................................................... 173 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 173 
8.1. 
Efficacy Assessments ............................................................................... 174 
8.2. 
Safety Assessments ................................................................................. 175 
8.2.1. 
Physical Examinations ............................................................... 175 
8.2.2. 
Vital Signs .................................................................................. 176 
8.2.3. 
Electrocardiograms .................................................................... 176 
8.2.4. 
Holter Monitoring for QT Assessment ........................................ 176 
8.2.5. 
Neurological Assessments ......................................................... 177 
8.2.6. 
Follow-Up Phone Call ................................................................ 177 
8.2.7. 
Clinical Safety Laboratory Assessments .................................... 177 
8.3. 
Adverse Events and Serious Adverse Events ........................................... 178 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................. 178 
8.3.2. 
Method of Detecting AEs and SAEs ........................................... 179 
8.3.3. 
Follow-up of AEs and SAEs ....................................................... 179 
8.3.4. 
Regulatory Reporting Requirements for SAEs ........................... 179 
8.3.5. 
Pregnancy ................................................................................. 179 
8.3.6. 
Cardiovascular and Death Events .............................................. 180 
8.3.7. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs............................................. 180 
8.3.8. 
Guidelines for Events of Special Interest ................................... 180 
8.4. 
Treatment of Overdose ............................................................................. 181 
8.5. 
Pharmacokinetics – Blood and Urine ........................................................ 181 
8.6. 
Anti-Drug Antibodies ................................................................................. 182 
8.7. 
Pharmacodynamics/Biomarkers ............................................................... 182 
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8.8. 
Genetics ................................................................................................... 185 
9. 
STATISTICAL CONSIDERATIONS ...................................................................... 186 
9.1. 
Statistical Hypotheses............................................................................... 186 
9.2. 
Sample Size Determination ...................................................................... 186 
9.2.1. 
Dose Escalation (Part 1A) .......................................................... 186 
9.2.2. 
Dose Escalation (Part 2A) .......................................................... 192 
9.2.3. 
Dose Escalation 
............................. 196 
9.3. 
Populations for Analyses .......................................................................... 196 
9.4. 
Statistical Analyses ................................................................................... 197 
9.4.1. 
Efficacy Analyses ....................................................................... 197 
9.4.2. 
Safety Analyses ......................................................................... 198 
9.4.3. 
Other Analyses .......................................................................... 199 
9.5. 
Interim Analyses ....................................................................................... 200 
10. REFERENCES ..................................................................................................... 202 
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................. 206 
11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations .......................................................................................... 206 
11.1.1. 
Regulatory and Ethical Considerations ...................................... 206 
11.1.2. 
Financial Disclosure ................................................................... 206 
11.1.3. 
Informed Consent Process ........................................................ 207 
11.1.4. 
Data Protection .......................................................................... 207 
11.1.5. 
Dissemination of Clinical Study Data ......................................... 207 
11.1.6. 
Data Quality Assurance ............................................................. 208 
11.1.7. 
Source Documents .................................................................... 209 
11.1.8. 
Study and Site Closure .............................................................. 209 
11.1.9. 
Publication Policy ....................................................................... 209 
11.2. 
Appendix 2: Clinical Laboratory Tests ....................................................... 211 
11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ..................................... 213 
11.3.1. 
Definition of AE .......................................................................... 213 
11.3.2. 
Definition of SAE ........................................................................ 214 
11.3.3. 
Definition of Cardiovascular Events ........................................... 215 
11.3.4. 
Recording and Follow-Up of AE and SAE .................................. 216 
11.3.5. 
Reporting of SAE to GSK ........................................................... 217 
11.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information ................................................................................................ 219 
11.4.1. 
Definitions .................................................................................. 219 
11.4.2. 
Contraception Guidance ............................................................ 220 
11.4.3. 
Collection of Pregnancy Information .......................................... 221 
11.5. 
Appendix 5: Genetics ................................................................................ 222 
11.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge Guidelines .................. 223 
11.6.1. 
Study Treatment Restart or Rechallenge ................................... 224 
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11.6.2. 
Restart Following Transient Resolving Liver Stopping 
Events Not Related to Study Treatment ..................................... 225 
11.7. 
Appendix 7: Estimated Glomerular Filtration Rate ..................................... 227 
11.8. 
Appendix 8: NYHA Functional Classification System for Heart 
Failure ...................................................................................................... 228 
11.9. 
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST version ....... 229 
11.9.1. 
RECIST 1.1 Guidelines .............................................................. 229 
11.9.2. 
Guidelines for Evaluation of Disease ......................................... 230 
11.9.3. 
Measurable and Non-Measurable Definitions ............................ 230 
11.9.4. 
iRECIST Guidelines ................................................................... 231 
11.10. Appendix 10: ECOG Performance Statusa ................................................ 238 
11.11. Appendix 11: Adverse Events of Special Interest ...................................... 239 
11.12. Appendix 12: Management Guidelines for CRSa ....................................... 241 
11.13. Appendix 13: IRR/CRS Prophylaxis Regimen ........................................... 242 
11.14. Appendix 14: Statistical Simulation Dose Levels ....................................... 243 
11.15. Appendix 15: Imaging Sub-study .............................................................. 244 
11.15.1. Part A – [18F]F-AraG Study ........................................................ 244 
11.15.2. Part B – [11C]GSK3745417 Study .............................................. 250 
11.15.3. Positron Emission Tomography (PET) Scans ............................ 254 
11.15.4. Study Population ........................................................................ 256 
11.15.5. Study Interventions in the Imaging Sub-study (Parts A and 
B) ............................................................................................... 256 
11.15.6. Preparation/Handling/Storage/Accountability ............................. 256 
11.15.7. Discontinuation from the Imaging Sub-study (Parts A and 
B) ............................................................................................... 257 
11.15.8. Study Assessments and Procedures ......................................... 257 
11.15.9. Statistical Considerations Imaging Sub-study Analyses ............. 283 
11.15.10. References Specific to Imaging Sub-study ................................. 285 
11.16. Appendix 16: Radiation Dose .................................................................... 287 
11.17. Appendix 17: Protocol Amendment History ............................................... 289 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF TABLES 
PAGE 
Table 1 
Schedule of Assessments 
 
 
Table 2 
Schedule of Assessments 
 
 
Table 3 
Schedule of Assessments 
 
 
Table 4 
Schedule of Assessments 
 
 
Table 5 
Schedule of Assessments 
 
 
Table 1-1 
Schedule of Assessments 
 
 
Table 2-1 
Schedule of Assessments 
 
 
Table 3-1 
Schedule of Assessments 
 
 
Table 4-1 
Schedule of Assessments 
 
 
Table 5-1 
Schedule of Assessments 
 
 
Table 6 
Dosing Schedule for GSK3745417 Monotherapy (Part 1) .................... 125 
Table 7 
Dosing Schedule for GSK3745417 Combination with Dostarlimab 
(Part 2) ................................................................................................. 125 
Table 8 
3+3 Dose-Escalation Guidelines .......................................................... 127 
Table 9 
Dose-Limiting Toxicity Criteria .............................................................. 128 
Table 10 
Study Treatments ................................................................................. 132 
Table 11 
Predicted human starting dose based on ex vivo cytokine 
response in monkey and human whole blood, corrected to 
plasma ................................................................................................. 136 
Table 12 
Predicted human starting dose based on in vivo cytokine 
response in cynomolgus monkey ......................................................... 136 
Table 13 
Organ Function .................................................................................... 140 
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Table 14 
Investigational Product Dosage/Administration .................................... 147 
Table 15 
Dose Modification and Toxicity Management Guidelines for 
Immune-Related AEs ........................................................................... 153 
Table 16 
Biomarker Panel................................................................................... 159 
Table 17 
Management Guidelines for Cytokine Release Syndrome .................... 159 
Table 18 
GSK3745417  Dostarlimab Infusion Reaction Dose Modification 
and Treatment Guidelines .................................................................... 161 
Table 19 
ICE-Encephalopathy Assessment Tool for Grading of ICANS .............. 163 
Table 20 
Grading of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) .............................................................................. 164 
Table 21 
Guidelines for Dose Modification and Management of Renal 
Events .................................................................................................. 166 
Table 22 
Simulation Results Under Various Scenarios 
 
 
Table 23 
Simulation Results Under Various Scenarios 
 
 
Table 24 
Simulation Results Under Various Scenarios 
 
 
Table 25 
Simulation Results Under Various Scenarios 
 
 
Table 26 
Protocol-Required Safety Laboratory Assessments ............................. 212 
Table 27 
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease ............................................................................ 236 
Table 28 
Table 29 
Table 30 
Table 30-1 
Table 31 
Table 32 
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Table 33 
Table 34 
 
 
LIST OF FIGURES 
PAGE 
Figure 1 
Study Design ........................................................................................ 122 
Figure 2 
Liver Stopping and Monitoring Event Algorithm .................................... 170 
Figure 3 
Graphical Display of the Prior Distribution for the Probability of 
DLT Given Dose (Median with 90% Credible Interval) .......................... 187 
Figure 4 
Virtual subject response - Toxicity - Scenario 1: 
 
Figure 5 
Virtual subject response - Toxicity - Scenario 2: Intermediate 
DLT ...................................................................................................... 188 
Figure 6 
Virtual subject response - Toxicity - Scenario 3: Late DLT ................... 189 
Figure 7 
 
 
Figure 8 
Virtual subject response - Toxicity - Scenario 1: 
 
Figure 9 
Virtual subject response - Toxicity - Scenario 2:
 
 
Figure 10 
Virtual subject response - Toxicity - Scenario 3: Late DLT ................... 192 
Figure 11 
 
 
Figure 12 
Decision-Making Flow Diagram for the 
 
Figure 13 
Figure 14 
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LIST OF ABBREVIATIONS AND TRADEMARKS 
Abbreviations 
ADA 
Antidrug antibody 
AE 
Adverse event(s) 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AraG 
Arabinofuranosyl guanine 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC0-t 
Area under the concentration-time curve from time zero to time  
AUC(0-inf) 
Area under the concentration-time curve from time zero to infinity 
BLRM 
Bayesian Logistic Regression Model 
BPND 
Binding Potential 
BNP 
B-type Natriuretic Peptide 
CBC 
Complete blood count 
cfDNA 
Circulating free DNA 
cGAS 
Cyclic GMP-AMP synthase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
CL 
Clearance 
CrCl 
Calculated creatinine clearance 
Cmax 
Maximum observed concentration 
CNS 
Central nervous system 
CPMS 
Clinical Pharmacology Modeling and Simulation 
CR 
Complete response 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine Release Syndrome 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen 4 
CV 
Cardiovascular 
CYP 
Cytochrome p450 
DC 
Dendritic cell 
DEC 
Dose Escalation Committee 
DILI 
Drug-induced liver injury 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
EC10 
Ten percent effect concentration 
ECG 
Electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
EORTC-QLQ 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 

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eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
F-18 
Fluorine-18 
FACT GP5 
Functional Assessment of Cancer Therapy – General Physical Well Being Form Item 5 
FACTS 
Fixed and Adaptive Clinical Trial Simulator 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-positron-emission tomography 
FOV 
Field of View 
FSH 
Follicle stimulating hormone 
FTIH 
First time in human 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GMP 
Good Manufacturing Practice 
GSK 
GlaxoSmithKline 
h 
Hour(s) 
HPLC 
High performance liquid chromatography 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICE 
Immune Effector Cell-associated Encephalopathy (ICE) 
ICH 
International Council on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
ICF 
Informed consent form 
iCPD 
Immune-confirmed progressive disease 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHC 
Immunohistochemistry 
IL-6 
Interleukin 6 
IL-10 
Interleukin 10 
ILD 
Interstitial lung disease 
INR 
International normalized ratio 
irAE 
Immune-related adverse event(s) 
IRB 
Institutional Review Board(s) 
iRECIST 
Immune-related RECIST 
IRR 
Infusion related reaction 
IV 
Intravenous 
IVIVE 
In vitro to in vivo extrapolation 
kg 
Kilogram(s) 
L 
Liter 
g 
Microgram 
MABEL 
Minimally anticipated biologic effect level 
MBq 
Megabecquerel 

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mCi 
Millicurie 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
min 
Minute(s) 
mL 
Milliliter(s) 
MRI 
Magnetic resonance imaging 
MSS CRC 
Microsatellite stable colorectal cancer 
mSv 
Millisievert 
MTD 
Maximum tolerated dose 
mTPI 
Modified Toxicity Probability Interval 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
N-CRM 
Neuenschwander-Continuous Reassessment Method 
NOAEL 
No-observed-adverse-effect level 
NTproBNP 
N-terminal-pro hormone BNP 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PACT 
Post-Analysis Continued Treatment 
PBMC 
Peripheral blood mononuclear cell 
PD-1 
Programmed death receptor-1 
PD 
Progressive disease 
PET 
Positron Emission Tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance status 
QLQ 
Quality of life questionnaire 
QTc 
Corrected QT interval duration 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase 2 dose 
SAE 
Serious adverse event(s) 
SC 
Subcutaneous 
SD 
Stable disease 
SRM 
Study Reference Manual 
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STING 
STimulator of INterferon Genes 
SUV 
Standardized Uptake Value 
TCR 
T-cell receptor 
t½ 
Apparent terminal phase half-life 
TDV 
Treatment discontinuation visit 
TGI 
Tumor growth inhibition 
TLC 
Thin layer chromatography 
TNF 
Tumor necrosis factor 
ULN 
Upper limit of normal 
VT 
Volume of Distribution 
WOCBP 
Women of childbearing potential 
 
Trademark Information 
Trademarks of the GSK group of 
companies 
 
Trademarks not owned by the GSK 
group of companies 
NONE 
 
MedDRA 
 
 
OLINDA 
 
 
 
 

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1. 
PROTOCOL SUMMARY 
With this Amendment, the study sponsor GSK 
 
 
 
 
 
 
 
 
In line with GSK’s decision, this protocol has been amended to provide updated 
instructions for study conduct of participants currently on study who are continuing to 
receive study GSK3745417 monotherapy or GSK3745417 in combination with 
dostarlimab. 
 
 
  
Following the DCO (data cut-off) date for the final analysis, study 208850 may move 
into a post analysis continued treatment (PACT) phase where the study remains open 
only to provide continued access to treatment for study participants who are continuing to 
derive clinical benefit in the opinion of the treating physician. During PACT only SAEs, 
AEs leading to treatment discontinuation, overdose and pregnancy cases will be reported 
directly to GSK. The end of study is defined as the date of the last visit of the last 
participant in the study (e.g. last dose plus 90 days safety reporting period) or last 
scheduled procedure shown in the SoA for the last participant in the study.  
1.1. Synopsis 
Protocol Title: A Phase I Open Label Study of GSK3745417 in Combination with 
Anticancer Agents in Participants with Advanced Solid Tumors. 
Short Title: PH1 FTIH, OL study of GSK3745417 administered to participants with 
advanced solid tumors. 
Rationale: The concept of cancer immune surveillance has been well established. The 
key tenet of this concept is that the immune system plays a critical role in protecting the 
body from neoplastic disease. Consistent with this concept, the immune checkpoint 
inhibitors anti-PD(L)-1 and anti-CTLA-4 have demonstrated therapeutic benefit across 
multiple tumor types, yielding durable responses in some patients. However, a majority 
of patients do not respond to monotherapy with checkpoint inhibitors, at least in part due 
to the non-inflamed nature of the tumor. Therefore, strategies to increase the tumor 
immunogenicity are being actively explored. 
STimulator of INterferon Genes (STING) is the key adaptor molecule in the 
cGAS--STING-TBK1 pathway that mediates the sensing of cytosolic DNA. Activation of 
STING generates a distinctive set of type I interferons (IFNα and β) and 
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pro-inflammatory cytokines that instigate T-cell dependent tumor immunity and 
tumor-vascular collapse. The pre-clinical data strongly suggest that the STING pathway 
is the intrinsic tumor sensing pathway of the immune system. Therefore, activation of the 
STING pathway has the potential to boost tumor antigen presentation and the tumor 
immunogenicity. Potent and durable anti-tumor response has been demonstrated in the 
syngeneic murine tumor models with STING agonist treatment. 
In addition, the effect of STING activation in boosting tumor antigen presentation 
suggests potential combination benefit with immune check point modulators. Given their 
non-overlapping mechanisms of action, the combination of the two could simultaneously 
accelerate separate steps in the cancer-immunity cycle, i.e., the tumor antigen 
presentation process and the T-cell activation process, therefore generating synergistic 
anti-tumor effect.  
GSK3745417 is a synthetic STING agonist that is being developed by GlaxoSmithKline 
as an immune stimulatory agent for the treatment of cancer. This study will be the first 
time in human (FTIH) study of GSK3745417 to assess the safety, pharmacokinetic (PK), 
 of GSK3745417 administered alone 
and in combination with other immunotherapies to participants with advanced solid 
tumors. The initial combination partner is dostarlimab, based on mechanisms of action 
targeting complementary modes of the cancer-immunity cycle and compelling antitumor 
activity observed in preclinical models. Subsequent combination partners and/or 
additional routes of administration may be evaluated (following protocol amendment/s) 
based on biologic rationale, nonclinical data, and/or emerging clinical data. 
This open label, dose escalation study will assess the safety, PK, 
 
 
 
  
With this Amendment, the study sponsor GSK 
 
 
 
 
 
 
 
 
In line with GSK’s decision, this protocol has been amended to provide updated 
instructions for study conduct of participants current on study who are continuing to 
receive study GSK3745417 monotherapy or GSK3745417 in combination with 
dostarlimab. 
 
 
  
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Following the DCO (data cut-off) date for the final analysis, study 208850 may move 
into a post analysis continued treatment (PACT) phase where the study remains open 
only to provide continued access to treatment for study participants who are continuing to 
derive clinical benefit in the opinion of the treating physician. During PACT only SAEs, 
AEs leading to treatment discontinuation, overdose and pregnancy cases will be reported 
directly to GSK.  The end of study is defined as the date of the last visit of the last 
participant in the study (e.g. last dose plus 90 days safety reporting period) or last 
scheduled procedure shown in the SoA for the last participant in the study.  
 
Objectives and Endpoints (Dose Escalation, Part 1A and Part 2A): 
Objective 
Endpoint 
Primary 
• 
To determine the safety, tolerability, and the 
recommended phase 2 dose (RP2D) of 
GSK3745417 alone or in combination with 
dostarlimab administered intravenously to 
participants with selected advanced/recurrent 
solid tumors.  
 
• 
Incidence of DLT 
• 
Incidence and severity of adverse events  
Secondary 
• 
To characterize the PK properties of 
GSK3745417 alone or in combination with 
dostarlimab 
 
• 
GSK3745417 concentrations in plasma and PK 
parameters  
Exploratory 
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Objective 
Endpoint 
 
Overall Design: This is a Phase I, FTIH, open-label, repeat-dose, non-randomized, 
multicenter, multi-country study to evaluate the safety, tolerability, and 
 
 and establish a recommended dose of GSK3745417 administered 
 or in combination with dostarlimab (Part 2A) in 
participants with refractory/relapsed solid tumors. Both Part 1A and Part 2A consist of a 
dose escalation phase only. 
 
 
 
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Disclosure Statement: This is an open label interventional study.  
 
Intervention Groups and Duration: Participants will initially receive GSK3745417 as 
monotherapy during dose escalation in Part 1A. Escalating doses of GSK3745417 will be 
evaluated as guided by the Bayesian Logistic Regression Model (BLRM) approach. In 
Part 2A, escalating doses of GSK3745417 in combination with dostarlimab 
 
 will be evaluated as guided by the 
BLRM approach. 
 
 
 
 
.  
The study includes a screening period, a treatment period, and a follow-up period. 
Participants will be screened for eligibility beginning 4 weeks before the start of 
treatment. The duration of study intervention is expected to be up to 2 years. Ongoing 
participants will be followed up for safety until 90 days after the last dose or until start of 
subsequent anticancer treatment, whichever is earlier. Participants who have already 
progressed will no longer be followed for survival. 
Data Monitoring Committee: No. 
 
 
 
 
 
 
 
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1.2. Schedule of Activities (SoA) 
Note: In this protocol amendment, participants receiving study treatments should 
follow Schedule of Assessment according to their cohort assignment as outlined in 
Section 1.2.1, and in the Imaging Sub-study (Appendix 15, Section 11.15, Table 30-1). 
The timing and number of planned study assessments, including safety, laboratory, 
, pharmacokinetic (PK), and 
 
assessments included in the tables below may be altered during the course of the study 
based on newly available data (e.g., to obtain data closer to the time of peak plasma 
concentrations) to ensure appropriate monitoring.  
 
For the PACT Phase: Participants who continue to receive study treatment during the 
PACT phase will be monitored and will receive follow-up care in accordance with 
standard local clinical practice. Assessments will revert to the standard of care at a 
participant’s particular study site and only SAEs, AEs leading to discontinuation of study 
treatment, overdoses, and pregnancy cases, will be reported directly to the Sponsor via 
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paper forms (see Section 11.3.5). For participants discontinuing treatment under PACT,  
a +90days Safety Follow-up visit is required. 
Any changes in the timing or addition of time points for any planned study assessments 
must be documented and approved by the sponsor and then archived in the sponsor and 
site study files but will not constitute a protocol amendment. The Institutional Review 
Board (IRB)/ Independent Ethics Committees (IEC) will be informed of any safety issues 
that require alteration of the safety monitoring scheme or amendment of the informed 
consent form (ICF). The changes will be approved by the IEC/IRB before 
implementation. 
 

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NOTE: For Study participants receiving study treatment and in post-treatment survival follow-up, follow the Schedule of 
Assessment tables as outlined in Section 1.2.1 
Table 1 
Schedule of Assessments (Part 1A, Arm A1: GSK3745417 Monotherapy 
 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Informed consent 
X 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
 
 
 
 
 
Demographics, 
Medical History, 
Prior Medications, 
Disease 
Characteristics 
X 
 
 
 
 
Include use of antibiotics and probiotics taken 
up to 60 days prior to study intervention. 
Anticancer Therapy 
X 
 
 
 
 
 
Participant 
Registration 
X 
 
 
 
 
Source document only. 
Safety Assessments 
24 Hour In-House 
Monitoring 
 
Day 1 only 
 
 
 
During the first study intervention participants 
should be monitored in a medically qualified 
unit/clinic/hospital for at least 24 hours following 
the administration of GSK3745417. This 
requirement may be eliminated as safety data 
emerge. At all other visits, participants should 
stay for an 8-hour observation following dosing 
with GSK3745417. Participants may be 
released after a 6-hour observation period if, in 
the opinion of the investigator, it is safe to do 
so, and there is no protocol mandated 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
assessment after this time. However, on 
Weeks 2 and 3, sites encouraged to observe for 
8h to allow for collection of 
8h PK 
and biomarker samples. Additional in-house 
monitoring should be considered for 8-24 hrs 
post-dose as clinically indicated. 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical examination 
details. At screening, a complete physical exam 
including height and weight is required, at 
subsequent visits, brief or targeted physical 
exams are acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On 
 (i.e. during 24-hour in-house 
monitoring), vital signs should be collected pre-
dose 
 
  
 
 On all other visits that do not require 24-
hour in-house monitoring, vital signs must be 
collected pre-dose 
 
 
Weight 
X 
X 
 
 
Echocardiogram 
X 
 
 
  
(or when 
clinically 
indicated) 
X 
 
If available, a 3D ECHO is preferred, otherwise 
a 2D ECHO may be performed. Where the 
quality of the ECHO examination is sub-optimal 
or ECHO is not available, MUGA scans may be 
used. The modality used at baseline should be 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
repeated throughout the study to ensure 
comparison to baseline.  
ECHO/MUGA obtained within a -4-day window 
pre-dose, and at TDV (unless performed in the 
previous 4 weeks). 
12-lead ECG 
X 
X 
 
Triplicate ECGs will be obtained at screening. 
Single ECGs should be obtained prior to 
GSK3745417 dosing,
, and 
within 2 hours prior to completion of clinic visit. 
Post Week 6, next ECG should be on Week 9, 
then 
 thereafter.  Patients with new onset 
symptoms consistent with immune-mediated 
pericarditis or myocarditis should have 
additional ECGs as clinically indicated. 
Holter Monitoring 
 
Day 1 
 
 
 
12-lead Holter monitoring will be conducted on 
Day 1 and must start at least -2h (pre-dose), 
followed by normal activity (ambulatory) until -
30 min predose, when participant will be lying 
supine until time 0. Holter monitoring will end at 
24h for all participants after the first study 
intervention. Holter will remain with the 
participant until the end of Day 1 and will be 
removed prior to end of clinic visit. If heart rate 
is increased or based on emerging data, 
hospitalization time might be extended. The 
requirement for Holter monitoring may be 
waived by study sponsor based on emerging 
data. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Neurological 
Assessment 
including ICE 
scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs to be collected until 90 days after the last 
dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from time of informed 
consent. 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow Up Phone 
Call 
 
 
 
 
After each of the first 6 doses of study 
intervention, participants should be contacted 
by phone 24-72 hours following discharge from 
clinic to assess for any AEs or cytokine related 
events. 
Safety Laboratory Assessments 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
Pregnancy Test  
X 
(urine) 
Week 4 (pre-dose urine) 
  
(pre-dose 
urine) 
X 
X 
Negative serum pregnancy test required within 
72 hours prior to date of first dose of study 
treatment on Day 1 for WOCBP; predose urine 
pregnancy test conducted every 3 weeks for 
duration of study, on last day of treatment (if 
possible), at TDV, and at the Follow-Up visits. 
≤72 hours (serum) of first dose 
 
CBC with 
differentiald 
X 
X 
 
Sample collection times: Predose, EOI+4h and 
. If a participant experiences cytokine 
release syndrome, perform CBC with differential 
at 
8h too. The 
 sample is only 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
required if participant remains in the clinic for 
either 24-hour monitoring, or other purposes. 
Clinical Chemistryd 
Xe 
X 
 
Sample collection time: Predose. See Section 
11.2 for complete list of required laboratory 
assessments. Additional clinical chemistry 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
X 
 
Sample collection times: Predose, 
 
 
 sample collections are only required if 
participant remains in the clinic for either 8 - 24-
hour monitoring, or other purposes. 
Additional C-Reactive Protein samples should 
be collected in the event of CRS (see Section 
6.6.1) 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should be 
done at 
 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for 
Troponin T for central lab, and T or I for local 
lab, to be collected pre-dose and result 
available before dosing. Samples will be 
collected every
weeks. On weeks where 
ECHO is required, pre-dose Troponin can also 
be obtained during the 4 days leading up to 
dose day.  
BNP (or 
NTproBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of 
cardiac events (Section 6.6.1.1) 
eGFR 
X 
 
 
 
 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening and 
starting at 
. Additional 
coagulation samples should be collected in the 
event of CRS (see Section 6.6.1)  
Laboratory Assessments for HBV/HCV Populations 
HBV DNAd 
X 
Week 4 
X 
 
Sample collection time: Predose starting on 
 
 
This test to be performed in participants 
diagnosed with hepatocellular carcinoma (HCC) 
and positive for HBV on screening. 
Quantitative 
HBsAgd 
X 
 
X 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
HCV antibody, HCV 
RNA 
X 
 
 
 
This test to be performed in participants 
diagnosed with HCC and positive for HCV on 
screening. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Efficacy Assessments 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Archival tumor 
tissue 
X 
 
 
 
 
Fresh tumor biopsy 
X 
Week 5 (required)  
(preferred within 48h window 
post dose) 
Week 13 
(optional) 
 
X  
(at disease 
progression, 
optional) 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
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a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 6 weekly study interventions, unless otherwise specified 
c. 
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 
 
 
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified.  
e. 
Baseline ALT in Participants with HCC and positive for HBV or positive for HCV should be determined by taking the mean value of the screening ALT and the pre-dose Day 1 ALT. 
f. 
 
 
 
 
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Table 2 
Schedule of Assessments (Part 1A, Arm A2: 
 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
Demographics, Medical 
History, Prior 
Medications, Disease 
Characteristics 
X 
 
 
 
 
Include use of antibiotics and probiotics taken 60 
days prior to study intervention. 
Anticancer Therapy 
X 
 
 
 
 
 
Participant Registration 
X 
 
 
 
 
Source document only. 
Safety Assessments 
24 Hour In-House 
Monitoring 
 
Day 1 only 
 
 
 
During the first study intervention, participants should 
be monitored in a medically qualified 
unit/clinic/hospital for at least 24 hours following the 
administration of GSK3745417. This requirement 
may be eliminated as safety data emerge. At all other 
visits, participants should stay for an 8-hour 
observation following dosing with GSK3745417. 
Participants may be released after a 6-hour 
observation period if, in the opinion of the 
investigator, it is safe to do so, and there is no 
protocol mandated assessment after this time. 
However, on Weeks 4 and 7, sites encouraged to 
observe for EOI+8h to allow for collection of EOI+8h 
PK and biomarker samples.  In-house monitoring 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
should be considered for 8-24 h post-dose as 
clinically indicated.  
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical examination 
details. At screening, a complete physical exam 
including height and weight is required, at 
subsequent visits, brief or targeted physical exams 
are acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On Weeks 1 through 16 (i.e., during 24 hour in-house 
monitoring), vital signs should be collected pre-dose 
GSK3745417 and at the following times after the end 
of infusion 
 
. On all other 
visits that do not require 24-hour in-house monitoring, 
vital signs must be collected pre-dose GSK3745417 
and 2 hours following the infusion. 
Weight 
X 
X 
 
 
Echocardiogram 
X 
X 
 
If available, a 3D ECHO is preferred, otherwise a 2D 
ECHO may be performed. Where the quality of the 
ECHO examination is sub-optimal or ECHO is not 
available, MUGA scans may be used. The modality 
used at baseline should be repeated throughout the 
study to ensure comparison to baseline.  
ECHO/MUGA obtained within a -4-day window pre-
dose, and at TDV (unless performed in the previous 
4 weeks). 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
12-lead ECG 
X 
X 
 
Triplicate ECGs will be obtained at screening 
Single ECGs should be obtained prior to 
GSK3745417 dosing, 
 
 prior to completion of clinic visit.  
Patients with new onset symptoms consistent with 
immune-mediated pericarditis or myocarditis should 
have additional ECGs as clinically indicated. 
Holter Monitoring 
 
Day 1 
 
 
 
12-lead Holter monitoring will be conducted on Day 1 
and must start at least -2h (pre-dose), followed by 
normal activity (ambulatory) until 
, 
when participant will be lying supine until time 0. 
Holter monitoring will end at 24h for all participants 
after the first study intervention. Holter will remain 
with the participant until the end of Day 1 and will be 
removed prior to end of clinic visit. If heart rate is 
increased or based on emerging data, hospitalization 
time might be extended. The requirement for Holter 
monitoring may be waived for individual participants 
upon approval from GSK. 
Neurological 
Assessment including 
ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological assessment 
details. 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs collected to be collected until 90 days 
after the last dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from 
time of informed consent. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow Up Phone Call 
 
 
 
 
After the first 6 doses of study intervention, 
participants should be contacted by phone 24-72 
hours following discharge from clinic to assess for 
any AEs or cytokine related events. 
Safety Laboratory Assessments 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
Pregnancy Test  
X 
(urine) 
X 
X 
Negative serum pregnancy test required within 72 
hours prior to date of first dose of study treatment on 
Day 1 for females of childbearing potential; predose 
urine pregnancy test conducted every 3 weeks for 
duration of study, on last day of treatment (if 
possible), at TDV, and at the Follow-Up visits 
≤72 hours (serum) of first dose 
CBC with differentiald 
X 
X 
 
Sample collection times: Predose, 
 and 
 If a participant experiences cytokine 
release syndrome, perform CBC with differential at 
 too. The 
sample is only required if 
participant remains in the clinic for either 24-hour 
monitoring, or other purposes. 
Clinical Chemistryd 
Xe 
X 
 
Additional clinical chemistry samples should be 
collected in the event of CRS (see Section 6.6.1) 
Sample collection time: Predose. See Section 11.2 
for complete list of required laboratory assessments. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
C-Reactive Protein 
X 
X 
 
Sample collection times: Predose, 
 
 sample 
collections are only required if participant remains in 
the clinic for either 8 - 24-hour monitoring, or other 
purposes. 
Additional C-Reactive Protein samples should be 
collected in the event of CRS (see Section 6.6.1) 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should be done at 
 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for Troponin 
T for central lab, and T or I for local lab, to be 
collected pre-dose and result available before dosing. 
Samples will be collected every 3 weeks. On weeks 
when ECHO is required, pre-dose Troponin can also 
be obtained during the 4 days leading up to dose 
day. 
BNP (or NTproBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of cardiac 
events (Section 6.6.1.1) 
eGFR 
X 
 
 
 
 
 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy should be 
performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening starting at 
 thereafter. Additional coagulation 
samples should be collected in the event of CRS 
(see Section 6.6.1) 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Laboratory Assessments for HBV/HCV Populations 
Liver Function Testd 
X 
X 
 
After 
, etc. 
unless ALT is ≥8x ULN, or ≥5x ULN and increasing, 
in which case continue weekly LFTs 
This test to be performed in participants testing 
positive for HBV or HCVf at Screening. Note: On visit 
days where pre-dose Clinical Chemistry is 
performed, LFTs do not have to be performed as a 
separate test. 
HBV DNAd 
X 
X 
 
 
 
These tests to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening.  
Quantitative HBsAgd 
X 
X 
 
Tests to be performed in participants diagnosed with 
Hepatocellular carcinoma (HCC) and positive for 
HBV on screening. 
HCV antibody, HCV 
RNA  
X 
 
 
 
 
These tests to be performed in participants 
diagnosed with HCC and positive for HCV on 
screening. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Efficacy Assessments 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
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Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 6 study interventions, unless otherwise specified 
c. 
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 
 
. 
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
Baseline ALT in Participants with HCC and positive for HBV or positive for HCV should be determined by taking the mean value of the screening ALT and the pre-dose day 1 ALT. 
f. 
When LFT and clinical chemistry collection time points coincide, samples for clinical chemistry only will be collected as the clinical chemistry panel includes LFT.  
g. 
 
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Table 3 
Schedule of Assessments 
 
 
Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
Demographics, Medical 
History, Prior Medications, 
Disease Characteristics 
X 
 
 
 
 
Include use of antibiotics and probiotics taken 
60 days prior to study intervention. 
Anticancer Therapy 
X 
 
 
 
 
 
Participant Registration 
X 
 
 
 
 
Source document only. 
Safety Assessments 
 
 
24-Hour In-House 
Monitoring 
 
 
 
24-hour In-house monitoring is required on 
 The requirement for the 24-
hour stays may be eliminated as safety data 
emerge. At all visits, participants should be 
monitored in a medically qualified 
unit/clinic/hospital for minimum of 30 min pre-
dose and for an 8-hour observation following 
dosing with GSK3745417 or GSK3745417 and 
dostarlimab. Participants may be released after 
a 6-hour observation period if, in the opinion of 
the investigator, it is safe to do so. Additional in-
house monitoring should be considered for 8-24 
h post-dose as clinically indicated.  
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical examination 
details. At screening, a complete physical exam 
is required, at subsequent visits, brief or 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
targeted physical exams are acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On Weeks 
 and
vital signs 
should be collected predose GSK3745417 and 
at the following times after the end of infusion 
 
 measurement is 
collected if subject is in the clinic at this time for 
observation or other reason. On all other visits, 
vital signs will be collected predose 
 
 
Weight 
X 
X 
 
 
Echocardiogram 
X 
X 
 
If available, a 3D ECHO is preferred, otherwise 
a 2D ECHO may be performed. Where the 
quality of the ECHO examination is sub-optimal 
or ECHO is not available, MUGA scans may be 
used. The modality used at baseline should be 
repeated throughout the study to ensure 
comparison to baseline. 
ECHO/MUGA obtained within a -4-day window 
pre-dose, and at TDV (unless performed in the 
previous 4 weeks). 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
12-lead ECG 
X 
X 
 
Triplicate ECGs will be obtained at screening. 
Single ECGs should be obtained prior to 
GSK3745417 dosing, 
 
 to completion of clinic visit. 
Post Week 6, next ECG should be on Week9 
and then
 thereafter. 
Patients with new onset symptoms consistent 
with immune-mediated pericarditis or 
myocarditis should have additional ECGs as 
clinically indicated.   
Neurological Assessment 
including ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs collected to be collected until 90 
days after the last dose or until start of subsequent anticancer treatment. SAEs related to study participation are 
collected from time of informed consent. 
Concomitant Medication 
Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone Call 
 
 
 
 
Participants should be contacted by phone 24-
72 hours following discharge from clinic to 
assess for any AEs or cytokine related events.  
Safety Laboratory Assessments 
 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Pregnancy Test 
X 
(urine) 
 
X 
X 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of 
first dose of study treatments on Day 1 for 
females of childbearing potential; predose urine 
pregnancy test conducted every 3 weeks for 
duration of study, on last day of treatment (if 
possible), at TDV, and at the Follow-Up visits. 
≤72 hours (serum) of first 
dose 
CBC with differentiald 
X 
X 
 
Sample collection times: 
 and 
. If a participant experiences cytokine 
release syndrome, perform CBC with differential 
at 
 too. The 
 sample is only 
required if participant remains in the clinic for 
either 24-hour monitoring, or other purposes. 
 
 
administered. 
Clinical Chemistryd 
Xe 
X 
 
Sample collection time: Predose. See Section 
11.2 for complete list of required laboratory 
assessments. Additional clinical chemistry 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
X 
 
Sample collection times: Predose, 
 
 and 
. When both study drugs 
are given, 
 
 sample 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
collections are only required if participant 
remains in the clinic for 8 - 24 hours of 
monitoring, or other purposes. 
Additional C-Reactive Protein samples should 
be collected in the event of CRS (see Section 
6.6.1) 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should be 
done at 
 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for 
Troponin T for central lab, and T or I for local 
lab, to be collected pre-dose and result 
available before dosing. Samples will be 
collected 
 On weeks when 
ECHO is required, pre-dose Troponin can also 
be obtained during the 4 days leading up to 
dose day. 
 
BNP (or NTproBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in Cardiac Effects 
(Section 2.3.1) and management of cardiac 
events (Section 6.6.1.1) 
eGFR 
X 
 
 
 
 
See Section 6.6.2 for management of renal 
events (if needed). 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening starting 
at 
 thereafter. Additional 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
coagulation samples should be collected in the 
event of CRS (see Section 6.6.1) 
Laboratory Assessments for HBV/HCV Populations 
HBV DNAd 
X 
X 
 
Sample collection time: Predose.  
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Quantitative HBsAgd 
X 
X 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
HCV antibody, HCV RNA 
X 
 
 
 
 
This test to be performed in participants 
diagnosed with HCC and positive for HCV on 
screening. 
Study Intervention 
 
 
 
Study Intervention must be administered within 
±1 day of scheduled visit unless otherwise 
indicated. Subsequent doses should be 
administered at least 5 days apart. Infuse 
GSK3745417 over 2 minutes.  When overnight 
stays are not required, participants should be 
observed for 8 hours, but can released at 
 
 hours if in the opinion of the investigator it is 
safe to do so. See Section 4.1.6 for maximum 
duration of study intervention.f 
 
 
Dostarlimab will be started on Week 1, 
 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Note: For participants in 
Japan, dostarlimab dosing 
will be dosed at 500 mg 
 throughout the 
treatment period. 
Dostarlimab should be administered via an IV 
infusion over 30 minutes (-5 minute and +15 
minute) with a post-dostarlimab infusion 
observation period of 2 hours. See Section 6.1 
Efficacy Assessments 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Pharmacokinetics (PK), 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Dostarlimab Serum PK 
 
Week 1  
and 4 
Weeks 13, 19, and then 
Q18W 
X 
W12 
Dostarlimab PK Sampling Schedule: Predose-
dose (within 1h prior to the start of the 
dostarlimab infusion) and 1 hour following the 
EOI of dostarlimab. One sample should be 
obtained 12 weeks after the last dose. 
Dostarlimab Serum ADA 
 
 Week 1 
and 4 
Weeks 13, 19, and then 
Q18W 
X 
W12 
Dostarlimab antidrug antibody (ADA) samples 
should be collected within 1h prior to the start of 
the dostarlimab infusion. One sample should be 
obtained 12 weeks after the last dose. 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
 
 
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a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 12 weekly study interventions, unless otherwise specified 
c. 
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 
 
 
d. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
Baseline ALT in Participants with HCC and positive for HBV or positive for HCV should be determined by taking the mean value of the screening ALT and the pre-dose Day 1 ALT. 
f. 
 
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Table 4 
Schedule of Assessments 
 
 
Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
Demographics, Medical 
History, Prior 
Medications, Disease 
Characteristics 
X 
 
 
 
 
Include use of antibiotics and probiotics taken 
60 days prior to study intervention. 
Anticancer Therapy 
X 
 
 
 
 
 
Participant Registration 
X 
 
 
 
 
Source document only. 
Safety Assessments 
24-Hour In-House 
Monitoring 
 
 
 
 
24-Hour In-House monitoring are required on 
. The requirement for the 24-
hour stays may be eliminated as safety data 
emerge. At all visits, participants should be 
monitored in a medically qualified 
unit/clinic/hospital for 30 minutes pre-dose and 
stay for an 8 h observation following dosing 
with GSK3745417 and dostarlimab. 
Participants may be released after a 6-hour 
observation period if, in the opinion of the 
investigator, it is safe to do so.  Additional in-
house monitoring should be considered for 8-
24 h post-dose as clinically indicated. 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical 
examination details. At screening, a complete 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
physical exam is required, at subsequent 
visits, brief or targeted physical exams are 
acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On Weeks 
 vital signs 
should be collected predose GSK3745417 
and at the following times after the 
 
 
 
measurement is collected if subject is in the 
clinic at this time for observation or other 
reason. On all other visits, vital signs will be 
collected 
 
 
Weight 
X 
X 
 
 
Echocardiogram 
X 
X 
 
If available, a 3D ECHO is preferred, 
otherwise a 2D ECHO may be performed. 
Where the quality of the ECHO examination is 
sub-optimal or ECHO is not available, MUGA 
scans may be used. The modality used at 
baseline should be repeated throughout the 
study to ensure comparison to baseline.  
ECHO/MUGA obtained within a -4-day 
window pre-dose, and at TDV (unless 
performed in the previous 4 weeks). 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
12-lead ECG 
X 
X  
 
Triplicate ECGs will be obtained at screening. 
Single ECGs should be obtained prior to 
GSK3745417 dosing, within 
 and 
within 2 hours prior to completion of clinic visit.  
Patients with new onset symptoms consistent 
with immune-mediated pericarditis or 
myocarditis should have additional ECGs as 
clinically indicated. 
Neurological 
Assessment including 
ICE scoring 
X 
 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs to be collected until 90 days after the 
last dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from time of 
informed consent. 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
Follow-Up Phone Call 
 
 
 
Participants should be contacted by phone 24-
72 hours following discharge from clinic to 
assess for any AEs or cytokine related events. 
Safety Laboratory Assessments 
Hepatitis B and C 
screening 
X 
 
 
 
 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Pregnancy Test  
X 
(urine) 
 (pre-dose urine) 
  
(pre-dose 
urine)  
X (urine) 
 
X (urine) 
 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of 
first dose of combination treatment on Day 1 
for females of childbearing potential; predose 
urine pregnancy test conducted 
 
for duration of study, on last day of treatment 
(if possible), at TDV, and at the Follow-Up 
visits. 
≤72 hours (serum) of first dose 
CBC with differentiald 
X 
X  
 
Sample collection times: Predose, 
 
  
If a participant experiences cytokine release 
syndrome, perform CBC with differential at 
 sample is only 
required if participant remains in the clinic for 
either 24-hour monitoring, or other purposes. 
Note that 
 of 
dostarlimab on days when both study drugs 
are administered. 
Clinical Chemistryd 
Xe 
X  
 
Sample collection time: Predose; see Section 
11.2 for complete list of required laboratory 
assessments. Additional clinical chemistry 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
 X 
 
Sample collection times: Predose, 
 
 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
sample collections are only required if 
participant remains in the clinic for 8 - 24 
hours of monitoring, or other purposes 
Additional C-Reactive Protein samples should 
be collected in the event of CRS (see Section 
6.6.1) 
Thyroid functiond 
X 
X  
 
After Screening, first assessment should be 
done at 
. 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for 
Troponin T for central lab, and T or I for local 
lab, to be collected pre-dose and result 
available before dosing Samples will be 
collected every 3 weeks. On weeks when 
ECHO is required, pre-dose Troponin can also 
be obtained during the 4 days leading up to 
dose day. 
BNP (or NTproBNP) 
X 
Repeat as clinically indicated 
 
 
Repeat test as outlined in management of 
cardiac events (Section 6.6.1.1) 
eGFR 
X 
 
 
 
 
See Section 6.6.2 for management of renal 
events (if needed).  
Urinalysisd 
X 
 X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening, and 
starting at 
 
and 
thereafter. Additional coagulation 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
Laboratory Assessments for HBV/HCV Populations 
Liver Function Testd  
Xe 
 X 
 
After Week 13, LFTs will be evaluated 
 
the next LFT evaluation will be at Week 13, 
16, etc., unless ALT is ≥8xULN, or ≥5x ULN 
and increasing, in which case continue weekly 
LFTs. 
This test to be performed in participants 
testing positive for HBV or HCVf at Screening. 
Note: On visit days where pre-dose Clinical 
Chemistry is performed, LFTs do not have to 
be collected as a separate test since they will 
be part of clinical chemistry. 
HBV DNAd 
X 
X  
 
Sample collection time: Predose.  
 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Quantitative HBsAgd 
X 
X  
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
HCV antibody, HCV 
RNA 
X 
 
 
 
 
This test to be performed in participants 
diagnosed with HCC and positive for HCV on 
screening. 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Study Intervention 
 
 
Study Intervention 
 
.  When overnight stays are not 
required, participants should be observed 
 
 if in 
the opinion of the investigator it is safe to do 
so. 
 
 
Dostarlimab will be started on Week 1, one 
hour after completion of the 
 
 Dostarlimab should be administered 
via an IV infusion over 30 minutes (a -5/+15 
minute window is permitted).  Patients will be 
observed for 2 hours post-dostarlimab 
infusion.  See Section 6.1 
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Screeninga 
Study Intervention Period 
 
Follow-
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Efficacy Assessments 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Pharmacokinetics (PK), 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Plasma 
 
 
 
 
 
Dostarlimab Serum PK 
 
Week 1 and 4 
 X 
W12 
Dostarlimab PK Sampling Schedule: Predose 
(within 1h prior to the start of the dostarlimab 
infusion), and 1 hour following the EOI of 
dostarlimab. One sample should be obtained 
12 weeks from the last dose. 
Dostarlimab Serum 
ADA 
 
Dostarlimab antidrug antibody (ADA) samples 
should be collected within 1h prior to the start 
of the dostarlimab infusion. One sample 
should be obtained 12 weeks from the last 
dose. 
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Screeninga 
Study Intervention Period 
 
Follow-
Up 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
; SAE=serious adverse event; W=week; TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
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a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all study interventions, unless otherwise specified. 
c. 
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 
 
 
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
Baseline ALT in participants with HCC and positive for HBV or positive for HCV should be determined by taking the mean value of the screening ALT and the pre-dose Day 1 ALT. 
f. 
When LFT and clinical chemistry collection time points coincide, samples for clinical chemistry only will be collected as the clinical chemistry panel includes LFT.  
g. 
. 
 
 
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Table 5 
Schedule of Assessments 
 
 
 
Pre
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Informed consent 
X 
 
Participant signs informed consent for Part 2A 
Inclusion/Exclusion 
X 
 
 
Participant Registration 
X 
 
Source document only 
Safety Assessments 
24-Hour In-House 
Monitoring 
 
 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
 
Physical Exam 
X 
Refer to Section 8.2.1 for physical examination details. At pre-
crossover baseline, a complete physical exam is required, at 
subsequent visits, brief or targeted physical exams are acceptable. 
ECOG PS 
X 
 
Vital Signs 
X 
 
Weight 
X 
 
Oxygen saturation 
Applies only to participants in Japan cohort. Chest CT scan 
(preferred) or chest x-ray. If tumor imaging for a given participant is 
conducted via chest CT scan or chest x-ray, the same imaging may 
be used for ILD assessment (Section 8.2.8) 
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Pre-
 a 
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Echocardiogram 
ECHO/MUGA performed if 
not conducted within 4 
weeks prior to start of 
combination treatment 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
If available, a 3D ECHO is preferred, otherwise a 2D ECHO may be 
performed. Where the quality of the ECHO examination is sub-
optimal or ECHO is not available, MUGA scans may be used. The 
modality used at baseline should be repeated throughout the study 
to ensure comparison to baseline. 
 
12-lead ECG 
X 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
 
Triplicate ECGs will be obtained at pre-combination baseline.  
Neurological Assessment 
including ICE scoring 
X 
Refer to Section 8.2.5. for neurological assessment details. 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first monotherapy dose 
until the combination TDV.  For AESI and SAEs collected until 90 
days after the last combination dose or until start of subsequent 
anticancer treatment. SAEs related to study participation are 
collected from informed consent for monotherapy. 
Concomitant Medication 
Review 
Continuous: Assess at each 
visit from first dose of study 
intervention 
 
Safety Laboratory Assessments 
Pregnancy Test 
≤72 hours (serum) of first 
combination dose 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
See Section 6.6.1 
CBC with differential 
X 
Clinical Chemistry 
X  
C-Reactive Protein 
X 
See Section 6.6.1 
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Pre-
 a 
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Thyroid function 
If not performed within 7 
days prior to first 
combination dose 
 
Troponin I, T 
Samples for Troponin T for 
central lab, and T or I for 
local lab, collected pre-dose 
and result available before 
first combination dose 
See Section 6.6.1.1 
BNP (or NTproBNP) 
X 
 
eGFR 
X 
See Section 6.6.2 for management of renal events (if needed). 
Urinalysis 
X 
If urinalysis is abnormal, a microscopy should be performed. 
Coagulation 
X 
Coagulation test required at pre-combination baseline  
Laboratory Assessments for HBV/HCV Populations 
HBV DNA 
Repeat If not performed 
within prior 3 weeks of Day 
1 of combination 
 
 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
This test to be performed in participants diagnosed with HCC and 
positive for HBV on initial screening in monotherapy. 
Quantitative HBsAg 
X 
This test to be performed in participants diagnosed with HCC and 
positive for HBV on initial screening in monotherapy. 
Study Intervention 
Administer GSK3745417 
 
 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
 
Administer Dostarlimab 
 
 
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Pre
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Pharmacokinetics (PK), 
 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
 
 
X = Anytime during visit (sampling date/time should be recorded) 
a. 
Assessments to be repeated at pre-combination baseline if assessment has not been performed within 7 days prior to first combination dose unless otherwise specified. 
 
 
 
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1.2.1. 
Revised Schedule of Assessments  
Table 1-1 
Schedule of Assessments 
 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Safety Assessments 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical 
examination details. At screening, a 
complete physical exam including height 
and weight is required, at subsequent 
visits, brief or targeted physical exams are 
acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
Vital signs must be collected pre-dose 
GSK3745417 and +2h 
 
 
: pulse oximetry will 
be part of vitals. 
Weight 
X 
X 
 
 
Oxygen saturation 
X 
X 
 
Applies only to participants in 
 
only. (Section 8.2.2) 
Echocardiogram 
X 
 
 
If available, a 3D ECHO is preferred, 
otherwise a 2D ECHO may be performed. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Where the quality of the ECHO 
examination is sub-optimal or ECHO is not 
available, MUGA scans may be used. The 
modality used at baseline should be 
repeated throughout the study to ensure 
comparison to baseline.  
ECHO/MUGA obtained within a -4-day 
window pre-dose 
12-lead ECG 
X 
X 
 
Triple ECGs will be obtained at Screening. 
Single ECGs should be obtained prior to 
GSK3745417 dosing, 
 
 
. Post 
Week 4, ECGs should be on Week 7, then 
 thereafter.  Patients with new onset 
symptoms consistent with immune-
mediated pericarditis or myocarditis should 
have additional ECGs as clinically 
indicated. 
Neurological 
Assessment 
including ICE 
scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
Follow Up Phone 
Call 
 
 
X 
Participant contacted at +90 days from end 
of treatment for Safety Follow-up 
assessment of AESIs and SAEs (below) 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs to be collected until 90 days after the last 
dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from time of informed 
consent. 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
 
Safety Laboratory Assessments 
Pregnancy Test  
X 
(urine) 
 (pre-dose urine) 
  
(pre-dose 
urine) 
X 
 
Negative serum pregnancy test required 
within 72 hours prior to date of first dose of 
study treatment on Day 1 for WOCBP; 
predose urine pregnancy test conducted 
every 3 weeks for duration of study, on last 
day of treatment (if possible), at TDV, and 
at the Follow-Up visits. 
≤72 hours (serum) of first dose 
 
CBC with 
differentiald 
X 
X 
 
Sample collection times: 
 
and 
. If a participant experiences 
cytokine release syndrome, perform CBC 
with differential at 
 too. The 
 sample is only required if 
participant remains in the clinic for either 
24-hour monitoring, or other purposes. 
Clinical Chemistryd 
X 
X 
 
Sample collection time: Predose. See 
Section 11.2 for complete list of required 
laboratory assessments. Additional clinical 
chemistry samples should be collected in 
the event of CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
X 
 
Sample collection times: Predose, EOI+ 
4h, EOI+8h and EOI+24h. The EOI+8h 
and EOI+24h sample collections are only 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
required if participant remains in the clinic 
for either 8 - 24-hour monitoring, or other 
purposes. 
Additional C-Reactive Protein samples 
should be collected in the event of CRS 
(see Section 6.6.1) 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples 
for Troponin at local lab (for local lab 
Troponin I is preferred), to be collected 
pre-dose and result available before 
dosing. Samples will be collected 
 
. On weeks where ECHO is 
required, pre-dose troponin can also be 
obtained during the 4 days leading up to 
dose day. The same local laboratory test 
(troponin I or troponin T) should be used 
consistently for an individual subject 
throughout the study. 
Note: Samples for troponin at central 
lab no longer required. 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should 
be done at 
. 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy 
should be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening and 
starting at 
. Additional 
coagulation samples should be collected in 
the event of CRS (see Section 6.6.1)  
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Laboratory Assessments for HBV/HCV Populations 
HBV DNAd 
X 
X 
 
Sample collection time: Predose starting 
on 
 and continue 
. 
This test to be performed in participants 
diagnosed with hepatocellular carcinoma 
(HCC) and positive for HBV on screening. 
Quantitative HBsAgd 
X 
X 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV 
on screening. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
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a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 6 weekly study interventions, unless otherwise specified 
c. 
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 anti-cancer therapy; the window for this visit is +10 days.  
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified.  
e. 
+90 day Safety Follow-up assessment must be completed within 90 days from the date study treatment was discontinued. The window for this visit is +/-10 days 
 
 
Table 2-1 
Schedule of Assessments (Part 1A, Arm A2: GSK3745417 Monotherapy Every 3 Weeks Dosing Schedule) 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Safety Assessments 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical examination 
details. At screening, a complete physical exam 
including height and weight is required, at 
subsequent visits, brief or targeted physical exams 
are acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
Vital signs must be collected pre-dose GSK3745417 
and 2 hours 
 
 pulse oximetry will be part of vitals. 
Weight 
X 
X 
 
 
Echocardiogram 
X 
 
 
If available, a 3D ECHO is preferred, otherwise a 2D 
ECHO may be performed. Where the quality of the 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
(and when clinically indicated for 
elevated biomarkers or cardiovascular 
symptoms) 
ECHO examination is sub-optimal or ECHO is not 
available, MUGA scans may be used. The modality 
used at baseline should be repeated throughout the 
study to ensure comparison to baseline.  
ECHO/MUGA obtained within a -4-day window pre-
dose. 
12-lead ECG 
X 
X 
 
Triplicate ECGs will be obtained at screening 
Single ECGs should be obtained prior to 
GSK3745417 dosing, 
 
  
Patients with new onset symptoms consistent with 
immune-mediated pericarditis or myocarditis should 
have additional ECGs as clinically indicated. 
Neurological 
Assessment including 
ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological assessment 
details. 
Follow Up Phone Call 
 
 
X 
Participant contacted at +90 days from end of 
treatment for Safety Follow-up assessment of AESIs 
and SAEs (below) 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs to be collected until 90 days after the 
last dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from time of 
informed consent. 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study 
intervention 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Safety Laboratory Assessments 
Pregnancy Test  
X 
(urine) 
X 
 
Negative serum pregnancy test required within 72 
hours prior to date of first dose of study treatment on 
Day 1 for females of childbearing potential; predose 
urine pregnancy test conducted every 
 for 
duration of study, on last day of treatment (if 
possible), at TDV, and at the Follow-Up visits 
≤72 hours (serum) of first dose 
CBC with differentiald 
X 
X 
 
Sample collection times: 
 
 If a participant experiences cytokine 
release syndrome, perform CBC with differential at 
 too. 
 
 
 
Clinical Chemistryd 
Xe 
X 
 
Additional clinical chemistry samples should be 
collected in the event of CRS (see Section 6.6.1) 
Sample collection time: Predose. See Section 11.2 
for complete list of required laboratory assessments. 
C-Reactive Protein 
X 
X 
 
Sample collection times: 
 
 sample 
collections are only required if participant remains in 
the clinic for either 8 - 24-hour monitoring, or other 
purposes. 
Additional C-Reactive Protein samples should be 
collected in the event of CRS (see Section 6.6.1) 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should be done at 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for Troponin 
T or I at local lab (for local lab Troponin I is 
preferred), to be collected pre-dose and result 
available before dosing. Samples will be collected 
. On weeks when ECHO is required, 
pre-dose Troponin can also be obtained during the 4 
days leading up to dose day. 
Note: Samples for Troponin at central lab no 
longer required. 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy should be 
performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening starting at 
 thereafter. Additional coagulation 
samples should be collected in the event of CRS 
(see Section 6.6.1) 
Laboratory Assessments for HBV/HCV Populations 
Liver Function Testd 
X 
X 
 
After 
, etc. 
unless ALT is ≥8x ULN, or ≥5x ULN and increasing, 
in which case continue weekly LFTs 
This test to be performed in participants testing 
positive for HBV or HCVf at Screening. Note: On visit 
days where pre-dose Clinical Chemistry is 
performed, LFTs do not have to be performed as a 
separate test. 
HBV DNAd 
X 
X 
 
Sample collection time: Predose starting on 
 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
These tests to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening.  
Quantitative HBsAgd 
X 
X 
 
Tests to be performed in participants diagnosed with 
Hepatocellular carcinoma (HCC) and positive for 
HBV on screening. 
Study Intervention 
Administer 
GSK3745417 
 
 
 
 
 
 
 
  When 
overnight stays are not required, participants should 
be observed for 8 hours, but can released at 
 
hours if in the opinion of the investigator it is safe to 
do so. 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
 
 
Day 
28 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
; PBMC = peripheral blood mononuclear cells RECIST=response evaluation criteria in solid tumors; 
 
; SAE=serious adverse event; W=week; TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 6 study interventions, unless otherwise specified 
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c. 
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 
 
 
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
+90 day Safety Follow-up assessment must be completed within 90 days from the date study treatment was discontinued. The window for this visit is +/-10 days 
 
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Table 3-1 
Schedule of Assessments 
 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Safety Assessments 
 
 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical examination 
details. At screening, a complete physical exam 
is required, at subsequent visits, brief or 
targeted physical exams are acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On Weeks 
 and
vital signs 
should be collected predose GSK3745417 and 
at the following times after the 
 
 
 measurement is 
collected if subject is in the clinic at this time for 
observation or other reason. On all other visits, 
vital signs will be collected predose 
GSK3745417 and 2 hours 
 
 
 
 
 
Weight 
X 
X 
 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Echocardiogram 
X 
 
 
  
(and when clinically 
indicated for elevated 
biomarkers or 
cardiovascular symptoms) 
 
 
If available, a 3D ECHO is preferred, otherwise 
a 2D ECHO may be performed. Where the 
quality of the ECHO examination is sub-optimal 
or ECHO is not available, MUGA scans may be 
used. The modality used at baseline should be 
repeated throughout the study to ensure 
comparison to baseline. 
ECHO/MUGA obtained within a -4-day window 
pre-dose. 
12-lead ECG 
X 
X 
 
Triplicate ECGs will be obtained at screening. 
Single ECGs should be obtained prior to 
GSK3745417 dosing, 
, and 
 prior to completion of clinic visit. 
Post Week 6, next ECG should be on Week9 
and then 
 thereafter. 
Patients with new onset symptoms consistent 
with immune-mediated pericarditis or 
myocarditis should have additional ECGs as 
clinically indicated.   
Neurological Assessment 
including ICE scoring 
X 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
Follow Up Phone Call 
 
 
X 
Participant contacted at +90 days from end of 
treatment for Safety Follow-up assessment of 
AESIs and SAEs (below) 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs collected to be collected until 90 
days after the last dose or until start of subsequent anticancer treatment. SAEs related to study participation are 
collected from time of informed consent. 
Concomitant Medication 
Review 
 
Continuous: Assess at each visit from first dose of study 
intervention 
 
Safety Laboratory Assessments 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
(urine) 
X 
 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of 
first dose of study treatments on Day 1 for 
females of childbearing potential; predose urine 
pregnancy test conducted every 3 weeks for 
duration of study, on last day of treatment (if 
possible), at TDV, and at the Follow-Up visits. 
≤72 hours (serum) of first 
dose 
CBC with differentiald 
X 
X 
 
Sample collection times: 
 
 If a participant experiences cytokine 
release syndrome, perform CBC with differential 
 too. The EOI+24h sample is only 
required if participant remains in the clinic for 
either 24-hour monitoring, or other purposes. 
Note that 
 of dostarlimab 
on days when both study drugs are 
administered. 
Clinical Chemistryd 
Xe 
X 
 
Sample collection time: Predose. See Section 
11.2 for complete list of required laboratory 
assessments. Additional clinical chemistry 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
X 
 
Sample collection times: 
 
. When both study drugs 
are given, 
 
 
collections are only required if participant 
remains in the clinic for 8 - 24 hours of 
monitoring, or other purposes. 
Additional C-Reactive Protein samples should 
be collected in the event of CRS (see Section 
6.6.1) 
Thyroid functiond 
X 
X 
 
After Screening, first assessment should be 
done at 
. 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for 
troponin T or I at local lab (for local lab, troponin 
I is preferred), to be collected pre-dose and 
result available before dosing. Samples will be 
collected 
. On weeks when 
ECHO is required, pre-dose troponin can also 
be obtained during the 4 days leading up to 
dose day. 
Note: Samples for troponin for central lab no 
longer required. 
Urinalysisd 
X 
X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening starting 
at 
 thereafter. Additional 
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Study Intervention Period 
 
 
 
Study Procedure 
 
GSK3745417 Weekly+ Dostarlimab 
TDVc 
Safety 
F-U 
Notes 
Week 
≤4 
1-12b 
13-104 
+4 
 
 
Day 
28 
1 - 78 
85 - 722 
+30d 
+90de 
 
coagulation samples should be collected in the 
event of CRS (see Section 6.6.1) 
 
HBV DNAd 
X 
X 
 
Sample collection time: Predose.  
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Quantitative HBsAgd 
X 
X 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Study Intervention 
 
Administer GSK3745417 
 
Administer Dostarlimab 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Efficacy Assessments 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
; SAE=serious adverse event; W=week; TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
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a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all 12 weekly study interventions, unless otherwise specified 
c. 
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 
 
 
d. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
+90 day Safety Follow-up assessment must be completed within 90 days from the date study treatment was discontinued. The window for this visit is +/-10 days 
 
  
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Table 4-1 
Schedule of Assessments 
 
 
Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Safety Assessments 
Physical Exam 
X 
X 
 
Refer to Section 8.2.1 for physical 
examination details. At screening, a complete 
physical exam is required, at subsequent 
visits, brief or targeted physical exams are 
acceptable. 
ECOG PSd 
X 
X 
 
 
Vital Signs 
X 
X 
 
On 
, vital signs 
should be collected predose GSK3745417 
and at the following times after the end of 
infusion 
 
 
measurement is collected if subject is in the 
clinic at this time for observation or other 
reason.On all other visits, vital signs will be 
collected predose GSK3745417 and 2 h 
Weight 
X 
X 
 
 
Echocardiogram 
X 
 
 
If available, a 3D ECHO is preferred, 
otherwise a 2D ECHO may be performed. 
Where the quality of the ECHO examination is 
sub-optimal or ECHO is not available, MUGA 
scans may be used. The modality used at 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
baseline should be repeated throughout the 
study to ensure comparison to baseline.  
ECHO/MUGA obtained within a -4-day 
window pre-dose. 
12-lead ECG 
X 
X  
 
Triplicate ECGs will be obtained at screening. 
Single ECGs should be obtained prior to 
 
  
Patients with new onset symptoms consistent 
with immune-mediated pericarditis or 
myocarditis should have additional ECGs as 
clinically indicated. 
Neurological 
Assessment including 
ICE scoring 
X 
 
Conduct if clinically indicated 
 
Refer to Section 8.2.5. for neurological 
assessment details. 
Follow Up Phone Call 
 
 
X 
Participant contacted at +90 days from end of 
treatment for Safety Follow-up assessment of 
AESIs and SAEs (below) 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first dose until the TDV. AESIs and SAEs to be collected until 90 days after the 
last dose or until start of subsequent anticancer treatment. SAEs related to study participation are collected from time of 
informed consent. 
Concomitant 
Medication Review 
 
Continuous: Assess at each visit from first dose of study intervention 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Safety Laboratory Assessments 
Pregnancy Test  
X 
(urine) 
 
 
Negative serum pregnancy test required at 
screening and within 72 hours prior to date of 
first dose of combination treatment on Day 1 
for females of childbearing potential; predose 
urine pregnancy test conducted every 3 weeks 
for duration of study, on last day of treatment 
(if possible), at TDV, and at the Follow-Up 
visits. 
≤72 hours (serum) of first dose 
CBC with differentiald 
X 
X  
 
Sample collection times: 
 
  
If a participant experiences cytokine release 
syndrome, perform CBC with differential at 
 sample is only 
required if participant 
 for 
either 24-hour monitoring, or other purposes. 
Note that EOI here refers to EOI of 
dostarlimab on days when both study drugs 
are administered. 
Clinical Chemistryd 
Xe 
X  
 
Sample collection time: Predose; see Section 
11.2 for complete list of required laboratory 
assessments. Additional clinical chemistry 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
C-Reactive Protein 
X 
 X 
 
Sample collection times: 
 
 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
sample collections are only required if 
participant 
 
 or other purposes 
Additional C-Reactive Protein samples should 
be collected in the event of CRS (see Section 
6.6.1) 
Thyroid functiond 
X 
X  
 
After Screening, first assessment should be 
done at 
. 
Troponin I, T 
X 
X 
 
See Section 6.6.1.1 for details. Samples for 
troponin T or I at local lab (for local lab 
troponin I is preferred), to be collected pre-
dose and result available before dosing 
Samples will be collected 
. On 
weeks when ECHO is required, pre-dose 
troponin can also be obtained during the 4 
days leading up to dose day. 
Note: Samples for troponin for central lab 
no longer required. 
Urinalysisd 
X 
 X 
 
If urinalysis is abnormal, a microscopy should 
be performed. 
Coagulationd 
X 
 
 
Coagulation test required at screening, and 
starting at 
 
. Additional coagulation 
samples should be collected in the event of 
CRS (see Section 6.6.1) 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Laboratory Assessments for HBV/HCV Populations 
Liver Function Testd  
Xe 
 X 
 
After Week 13, LFTs will be evaluated 
 
the next LFT evaluation will be at Week 13, 
16, etc., unless ALT is ≥8xULN, or ≥5x ULN 
and increasing, in which case continue weekly 
LFTs. 
This test to be performed in participants 
testing positive for HBV or HCVf at Screening. 
Note: On visit days where pre-dose Clinical 
Chemistry is performed, LFTs do not have to 
be collected as a separate test since they will 
be part of clinical chemistry. 
HBV DNAd 
X 
X  
 
Sample collection time: Predose.  
 
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Quantitative HBsAgd 
X 
X  
 
This test to be performed in participants 
diagnosed with HCC and positive for HBV on 
screening. 
Study Intervention 
Administer 
GSK3745417 
 
 
 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
GSK3745417 Every 3 Weeks + Dostarlimab 
 
TDVc 
Safety  
F-U 
Notes 
Week 
≤4 
1, 4, 7, and 10 b 
13-104 
+4 
 
 
Day 
28 
1, 22, 43, and 64 
85 - 722 
+30d 
+90de 
 
Administer Dostarlimab 
 
 
 
Efficacy Assessments 
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Screeninga 
Study Intervention Period 
 
 
 
Study Procedure 
 
Notes 
Week 
≤4 
 
Day 
28 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
; SAE=serious adverse event; W=week; TDV=treatment discontinuation visit 
Timepoint Definitions for assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
a. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
b. 
Procedures should be performed at all study interventions, unless otherwise specified. 
c. 
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 
 
 
d. 
Procedures scheduled pre-dose on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
e. 
+90 day Safety Follow-up assessment must be completed within 90 days from the date study treatment was discontinued. The window for this visit is +/-10 day 
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Table 5-1 
Schedule of Assessments 
 
 
 
Pre-Crossover Baseline a 
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Informed consent 
X 
 
Participant signs informed consent for Part 2A 
Inclusion/Exclusion 
X 
 
 
Participant Registration 
X 
 
Source document only 
Safety Assessments 
24-Hour In-House 
Monitoring 
 
 
Follow SoA for A3 (Table 3) or A4 
(Table 4) at crossover, as assigned 
 
Physical Exam 
X 
 
Refer to Section 8.2.1 for physical examination details. At pre-
crossover baseline, a complete physical exam is required, at 
subsequent visits, brief or targeted physical exams are acceptable. 
ECOG PS 
X 
 
 
Vital Signs 
X 
 
 
Weight 
X 
 
 
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Pre-Crossover Baseline a 
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
Echocardiogram 
ECHO/MUGA performed if 
not conducted within 4 
weeks prior to start of 
combination treatment 
Follow SoA for A3 (Table 3-1) or A4 
(Table 4-1) at crossover, as assigned 
If available, a 3D ECHO is preferred, otherwise a 2D ECHO may be 
performed. Where the quality of the ECHO examination is sub-
optimal or ECHO is not available, MUGA scans may be used. The 
modality used at baseline should be repeated throughout the study 
to ensure comparison to baseline. 
 
 
 
 
 
12-lead ECG 
X 
Follow SoA for A3 (Table 3-1) or A4 
(Table 4-1) at crossover, as assigned 
 
Triplicate ECGs will be obtained at pre-combination baseline.  
Neurological Assessment 
including ICE scoring 
X 
 
Follow-up phone call 
 
Participant contacted at +90 days from end of treatment for Safety 
Follow-up assessment of AESIs and SAEs (below) 
AE/SAE Review 
 
Continuous: Assess AEs at each visit from first monotherapy dose 
until the combination TDV.  For AESI and SAEs collected until 90 
days after the last combination dose or until start of subsequent 
anticancer treatment. SAEs related to study participation are 
collected from informed consent for monotherapy. 
Concomitant Medication 
Review 
Continuous: Assess at each 
visit from first dose of study 
intervention 
 
Safety Laboratory Assessments 
Pregnancy Test 
≤72 hours (serum) of first 
combination dose 
Follow SoA for A3 (Table 3-1) or A4 
(Table 4-1) at crossover, as assigned 
 
 
See Section 6.6.1 
CBC with differential 
X 
Clinical Chemistry 
X  
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Pre-Crossover Baseline a 
Study Intervention 
Notes 
Study Procedure 
 
Week (in combination) 
≤1 (unless indicated) 
Day (in combination) 
≤7 day (unless indicated) 
C-Reactive Protein 
X 
 
 
 
 
 
 
Follow SoA for A3 (Table 3-1) or A4 
(Table 4-1) at crossover, as assigned 
See Section 6.6.1 
Thyroid function 
If not performed within 7 
days prior to first 
combination dose 
 
Troponin I, T 
Samples for Troponin I for 
central lab, and T or I for 
local lab (Troponin I at local 
lab is preferred), collected 
pre-dose and result 
available before first 
combination dose 
See Section 6.6.1.1 
BNP (or NTproBNP) 
X 
 
eGFR 
X 
See Section 6.6.2 for management of renal events (if needed). 
Urinalysis 
X 
If urinalysis is abnormal, a microscopy should be performed. 
Coagulation 
X 
Coagulation test required at pre-combination baseline  
Laboratory Assessments for HBV/HCV Populations 
HBV DNA 
Repeat If not performed 
within prior 3 weeks of Day 
1 of combination 
 
 
Follow SoA for A3 (Table 3-1) or A4 
(Table 4-1) at crossover, as assigned 
This test to be performed in participants diagnosed with HCC and 
positive for HBV on initial screening in monotherapy. 
Quantitative HBsAg 
X 
This test to be performed in participants diagnosed with HCC and 
positive for HBV on initial screening in monotherapy. 
Study Intervention 
Administer GSK3745417 
 
 
Administer Dostarlimab 
 
 
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Pre-Crossover Baseline a 
Study Intervention 
Notes 
Study Procedure 
 
GSK3745417 Weekly or 3 Weekly + 
Dostarlimab 
Week (in combination) 
≤1 (unless indicated) 
1-104 
Day (in combination) 
≤7 day (unless indicated) 
1-722 
Efficacy Assessments 
 
 
 
Abbreviations: AE= adverse event; AESI=adverse events of special interest; CBC=Complete blood count; d=day; ECG=electrocardiogram; ECHO=echocardiography; ECOG 
PS=Eastern Cooperative Oncology Group Performance Score; eGFR= Estimated glomerular filtration rate; EOI=end of infusion; h=hour; ICF=informed consent form; m=min; 
 
; SAE=serious adverse event; W=week; TDV=treatment discontinuation visit Timepoint Definitions for 
assessments: 
X = Anytime during visit (sampling date/time should be recorded) 
a. 
Assessments to be repeated at pre-combination baseline if assessment has not been performed within 7 days prior to first combination dose unless otherwise specified. 
 
 
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2. 
INTRODUCTION 
2.1. Study Rationale 
The concept of cancer immune surveillance has been well established. The key tenet of 
this concept is that the immune system plays a critical role in protecting the body from 
neoplastic disease. Consistent with this concept, the immune checkpoint inhibitors 
anti-PD(L)-1 and anti-CTLA-4 have demonstrated therapeutic benefit across multiple 
tumor types, yielding durable responses in some patients. However, a majority of patients 
do not respond to monotherapy with checkpoint inhibitors, at least in part due to the 
non-inflamed nature of the tumor. Therefore, strategies to increase the tumor 
immunogenicity are being actively explored. 
STimulator of INterferon Genes (STING) is the key adaptor molecule in the 
cGAS--STING-TBK1 pathway that mediates the sensing of cytosolic DNA [Chen, 2016; 
Sun, 2013]. Activation of STING generates a distinctive set of type I interferons (IFNα 
and β) and pro-inflammatory cytokines that instigate T-cell dependent tumor immunity 
and tumor-vascular collapse [Ishikawa, 2009; Woo, 2014; Mahadevan, 1990]. Innate 
immune sensing of the cytosolic DNA, and the subsequent type I interferon production, 
has been demonstrated to be crucial for tumor antigen-specific CD8 cytotoxic T-cell 
priming mediated via the activation of dendritic cell (DC) subsets. Given the prominent 
role of STING in cytosolic DNA sensing and type I IFN production, it is believed that 
STING is a central player in triggering body’s spontaneous sensing of tumor by 
activating dendritic cells. The pre-clinical data strongly suggest that the STING pathway 
is the intrinsic tumor sensing pathway of the immune system. Therefore, activation of the 
STING pathway has the potential to boost tumor antigen presentation and the tumor 
immunogenicity. Potent and durable anti-tumor response has been demonstrated in the 
syngeneic murine tumor models with STING agonist treatment [Corrales, 2015; Sivick, 
2018; Woo, 2014]. 
In addition, the effect of STING activation in boosting tumor antigen presentation 
suggests potential combination benefit with immune check point modulators. Given their 
non-overlapping mechanisms of action, the combination of the two could simultaneously 
accelerate separate steps in the cancer-immunity cycle, i.e., the tumor antigen 
presentation process and the T-cell activation process, therefore generating synergistic 
anti-tumor effect. The enhanced anti-tumor activity with the combination of STING 
activation and PD(L)1 blockade in preclinical murine models has been demonstrated 
[Moore, 2016; Wang, 2017]. In addition, checkpoint inhibitors (anti-PD-L1/anti-CTLA4) 
have diminished efficacy in STING deficient mice [Woo, 2014].  
GSK3745417 is a synthetic STING agonist that is being developed by GlaxoSmithKline 
as an immune stimulatory agent for the treatment of cancer. This study will be the first 
time in human study (FTIH) of GSK3745417 to assess the safety, pharmacokinetic (PK), 
pharmacodynamics, and preliminary clinical activity of GSK3745417 administered alone 
and in combination with other immunotherapies to participants with advanced solid 
tumors. The planned initial combination partner is dostarlimab, a PD-1 antagonist that 
abrogates the PD-1/PD-L1 signalling pathway to regain an anti-tumor immune response. 

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Dostarlimab is marketed for dMMR, endometrial and solid tumors and is being evaluated 
clinically as an immunotherapy for advanced malignancies.  
Subsequent combination partners and/or additional routes of administration may be 
evaluated (following protocol amendment/s) based on biologic rationale, nonclinical data, 
and/or emerging clinical data. 
This FTIH, open label, dose escalation study will assess the safety, PK, 
 in participants with 
advanced or recurrent solid tumors as monotherapy (Part 1A), in combination with 
dostarlimab (Part 2A), and potentially in combination with additional therapies. 
However, the study sponsor decided 
 
 
. Subsequently, the planned 
monotherapy cohort expansion (Part 1B) and the combination with dostarlimab cohort 
expansion (Part 2B) arms 
 
2.2. Background 
2.2.1. 
GSK3745417  
An overview of GSK3745417 is provided below. Detailed information concerning the 
biology, pharmacology, PK, and safety characteristics can be found in the Investigators’ 
Brochure (IB) for GSK3745417. 
GSK3745417 is a novel, first-in-class, non-CDN (cyclic dinucleotide, natural ligand of 
STING) STING agonist belonging to a dimeric 2-amidobenzimidazole (ABZI) scaffold 
that is active against all known haplotypes of human STING. 
 
 
 
 
 
 
 
 
 
 
 
2.2.1.1. 
GSK3745417 Nonclinical Studies 
2.2.1.1.1. Pharmacology 
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2.2.1.1.2. Toxicology 
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2.2.2. 
Clinical Safety of GSK3745417 
The first  clinical study evaluating GSK3745417 is this first time in human study 208850. 
In this study, 
. 
A summary of adverse events (AEs) and dose limiting toxicities (DLTs) is included in the 
GSK3745417 Investigator’s Brochure. 
For this ongoing study of GSK3745417 advanced solid tumors, data are summarized for 
 that have been dosed with GSK3745417 monotherapy as of the cut-off 
date of 
 
Upon review of the clinical safety data received during the period of this report 
 
 
. 
2.2.3. 
Dostarlimab 
Detailed information concerning the biology, pharmacology, PK, and safety 
characteristics can be found in the IB for dostarlimab. 
2.2.4. 
GSK3745417 and Dostarlimab Combination Background 
The rationale for combining a STING agonist with an anti-PD-1 agent such as 
dostarlimab is because these two agents target different steps in the cancer-immunity 
cycle and may result in synergistic anti-tumor activity. Administration of GSK3745417 in 
advance of dostarlimab is expected to increase the priming/activation of antitumor T-cells 
while the anti-PD-1 agent dostarlimab prevents the inhibitory effect of the PD-1/PD-L1 
pathway on effector T-cells in the tumor.  
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Administration of GSK3745417 in combination with an anti-PD1 antibody 
 
 
 
 
 
 
 
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of GSK3745417 in the form of summaries of 
findings from nonclinical studies conducted may be found in the IB.  
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dostarlimab in the form of summaries of findings from nonclinical 
studies conducted may be found in the IB for dostarlimab.  
The following section outlines the risk assessment and mitigation strategy for this 
protocol. 
 
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2.3.1. 
Risk Assessment 
Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Investigational Product (IP) GSK3745417 (GSK417) and dostarlimab (where noted) 
Infusion related 
reactions (IRR) 
including cytokine 
release syndrome 
(CRS) 
General Measures: 
• 
Sites selected based on CRS management capabilities (i.e. 
ICU proximity, staff experience, resuscitation measures, 
central line placement and medication administration 
capability). CRS events are categorized as Adverse Events of 
Special interest (AESIs) which must be reported to the 
Medical Monitor within 24 hours regardless of study drug 
relationship. 
Monitoring: 
Careful observation with 24hr hospital observation post- dosing.  
Mitigation: 
• 
 
 
 
• 
Dose staggering of participants for previously uncleared dose 
levels to allow assessment initial safety data before enrolling 
next participant. 
• 
Guidelines on the management of CRS symptoms is provided 
in Table 17 and dose modifications in Section 6.6. 
• 
 
Anemia 
Monitoring 
• 
Frequent monitoring of complete blood count and differential 
 
 
Mitigation 
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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• 
Anemia has been included as an expected event in the 
reference safety information of the IBs both GSK417 and 
dostarlimab. 
• 
Inclusion of patients with hemoglobin >9 g/dL 
• 
All grade 4 anemias are reported as AESIs1 within 24 hours to 
medical monitor 
• 
Grade 3 anemia requiring transfusion or Grade 4 anemia 
reports are DLTs with discontinuation of study treatment. 
Reproductive toxicity 
 
Mitigation: 
• 
Contraception guidelines will be included as inclusion criteria 
for females.  
• 
Exclusion of lactating and pregnant women (See Section 5.1). 
 
• 
Patients who are women of childbearing potential (WOCBP) 
will be informed that taking dostarlimab or GSK417 may 
involve unknown risks to the fetus if pregnancy occurs during 
the study. To participate in the study, women of child bearing 
potential in heterosexual relationships must adhere to the 
contraception guideline (defined in Section 11.4.2) during the 
study and through 150 days after the last dose of dostarlimab 
or 7 days after last dose of GSK417 in monotherapy patients.  
Immune-related AEs 
General 
• 
AEs are categorized as AESIs which must be reported to the 
Medical Monitor within 24 hours regardless of study drug 
relationship. 
Mitigation:  
• 
Exclusion of patients with active immune disease or 
unresolved immune-related toxicity from prior treatment as 
per Section 5.2 
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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Guidelines on the management of potential immune-related 
AEs is provided in Section 6.6 and Table 15. 
Renal toxicity 
Monitoring 
• 
Frequent monitoring of clinical chemistry including serum 
creatinine and eGFR as per schedule of activities (SOA), 
Section 1.2.1. 
 
Mitigation 
• 
Inclusion criteria for eGFR  60 mL/min/1.73 m2  
• 
Specific renal stopping criteria and management guidelines 
are defined in the protocol (See Section 6.6.2). 
• 
Manage immune-mediated events with dostarlimab treatment 
modifications and corticosteroids, as outlined in Section 
11.11. 
Cardiac effects 
Monitoring 
• 
Frequent study cardiac monitoring with ECG, ECHO, and 
troponin (see SOA and Section 6.6.1.1. cardiac monitoring). 
• 
Holter monitoring per SOA. 
 
Mitigation 
• 
Inclusion of those with adequate LF function (Section 5.1) 
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Potential Risk of 
Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
• 
Exclusion of patients with a history or evidence of 
cardiovascular risk including a history of immune myocarditis 
and/or pericarditis (Section 5.2). 
Specific dose modification and management guidelines, 
including when cardiac consult needed outlined in Section 
7.1.2 
Hepatic toxicity 
• 
Inclusion criteria for ALT≤2.5x ULN and bilirubin≤1.5x ULN 
Mitigation Strategy 
• 
Inclusion criteria for ALT 2.5x ULN and bilirubin 1.5x ULN. 
• 
Standard phase 1 oncology Liver Chemistry Stopping Criteria. 
(See Section 7.1.1). 
• 
Guidelines on the management of potential immune-related 
hepatic AEs is provided in Section 6.6 and Table 15. 
 
1AESI: Adverse event of special interest 
 
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2.3.2. 
Overall Benefit: Risk Conclusion 
In this FTIH study, only participants with advanced stage solid tumors will be enrolled. 
All participants in this study will have exhausted all approved and effective therapies 
prior to receiving GSK3745417. The study protocol has been specifically designed to 
carefully monitor all participants and thereby, minimize the clinical risk of intervention 
related toxicities. 
Consistent with other Phase 1 trials for the treatment of cancer, a target DLT rate has 
been set as 16-33%, and a Bayesian adaptive dose escalation design is employed to 
efficiently determine the dose(s) associated with this DLT rate. Overall, the benefit:risk is 
typical of a Phase I study of participants with advanced cancer. 
Considering the novel and very relevant mode-of-action, the anti-tumor activity observed 
in pre-clinical tumor models, and the clinical monitoring measures incorporated into this 
study protocol, the sponsor believes that the potential clinical benefit associated with 
GSK3745417 study intervention outweighs the risk of severe, intervention-emergent 
toxicities. 
3. 
OBJECTIVES AND ENDPOINTS 
Dose Escalation (Part 1A GSK3745417 Monotherapy and Part 2A Combination GSK3745417 and 
Dostarlimab) 
Objective 
Endpoint 
Primary 
• 
To determine the safety, tolerability, and the 
recommended phase 2 dose (RP2D) of 
GSK3745417 alone or in combination with 
dostarlimab administered intravenously to 
participants with advanced/recurrent solid 
tumors.  
• 
Incidence of DLT 
• 
Incidence and severity of adverse events  
Secondary 
• 
To characterize the PK properties of 
GSK3745417 alone or in combination with 
dostarlimab 
• 
GSK3745417 concentrations in plasma and PK 
parameters  
Exploratoryb 
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Dose Escalation (Part 1A GSK3745417 Monotherapy and Part 2A Combination GSK3745417 and 
Dostarlimab) 
Objective 
Endpoint 
a) 
b) 
Objectives and endpoints for the Imaging Sub-study are described in Appendix 15. 
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4. 
STUDY DESIGN 
4.1. Overall Design 
This is a Phase I, FTIH, open-label, repeat-dose, non-randomized, multicenter, 
multicountry study to evaluate the safety, tolerability, and preliminary clinical activity 
and establish a recommended dose of GSK3745417 administered intravenously (IV) 
alone (Part 1A) or in combination with dostarlimab (Part 2A) in participants with 
refractory/relapsed solid tumors. Both Part 1A and Part 2A consist of a dose escalation 
phase only; dose expansion phases (Part 1B and 2B) will not be conducted following 
sponsor’s decision to cease further enrolment into the study. 
 
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• Part 1A: The safety and tolerability of escalating doses of GSK3745417 
 
 will be evaluated according to a Bayesian Logistic 
Regression Model (BLRM) design [Neuenschwander, 2014] (see Section 4.1.1).  
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Each part of the study includes a screening period, a treatment period, and a follow-up 
period. Participants will be screened for eligibility beginning 4 weeks (or 28 days) before 
the start of treatment. The duration of study treatment will be up to 2 years. Ongoing 
participants will be followed up for safety until 90 days after the last dose or until start of 
subsequent anticancer treatment, whichever is earlier. 
 
 
 
 
. The decision 
whether a participant will receive additional treatment will be discussed and agreed upon 
by the treating investigator and the Sponsor/Medical Monitor on a case-by-case basis. 
Participants receiving study treatment at the time of the final analysis data cut-off date 
may continue to receive it, if in the opinion of their treating physician, they are benefiting 
from continued treatment, and they do not meet any protocol-defined treatment 
discontinuation criteria (see Section 7.1). Study treatment will continue until a study 
treatment discontinuation criterion (see Protocol Section 7.1), as assessed by the 
investigator, has been met.  
Participants who continue study treatment in the PACT phase will be cared for in 
accordance with local standard clinical practice. Participants will continue to be 
monitored for all SAEs, AEs leading to treatment discontinuation, overdoses, pregnancy 
cases while receiving study treatment. Information relating to participant care will be 
recorded on participant medical records, except for SAEs, AEs leading to treatment 
discontinuation, overdoses, pregnancy cases that must continue to be reported to GSK. 
Investigators must report all SAEs, AEs leading to treatment discontinuation, overdose 
and pregnancy cases until 90 days after the participant’s last dose of study treatment in 
accordance with Section 11.3.5 (Reporting of Serious Adverse Events). 
.  
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4.1.1. 
 
Part 1A Starting Dose: Dose escalation for GSK3745417 monotherapy will begin with a 
starting dose of 
  
Dose escalation for GSK3745417 monotherapy subjects will be conducted in Arm A1 
. Alternative 
dosing schedules may be explored based on emerging data. 
: Once a dose of GSK3745417 has been identified that is both 
tolerable and demonstrates 
, enrolment in Part 2A may begin. 
Dose escalation for GSK3745417 in combination with dostarlimab will begin with a 
starting dose of 
  
Dose Schedule: 
• Part 1A: 
 
Following discussion with the sponsor Medical Monitor, and if in the best interest 
of and in agreement with the study participant, the dosing frequency may be 
changed from 
 to reduce the burden to the 
participant. 
• 
 There will be two arms in Part 2A: combination of 
 
 
. Dostarlimab will be added to this regimen starting at 
 
 
 
 This dostarlimab regimen may be 
extended to participants receiving combination therapy outside of 
 The first 
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3 participants in each dose level will begin treatment ≥48 hours apart to allow 
assessment of initial safety data in each participant before beginning the next 
participant’s treatment. All evaluable participants in the dose level cohort must 
complete the 
 observation period and the available safety data must 
be reviewed before a decision is made on whether to proceed to the next dose 
level. Once a 
 observation period has been completed, BLRM 
analysis will be performed to guide the dose level to which the next 3 participants 
will be assigned based on the posterior probability of the DLT rate (Section 9.2). 
If a participant withdraws from the study before completion of the 29-day DLT 
period for reasons other than DLT, the participant will not be counted as DLT 
evaluable and will be replaced. 
• Following discussion with the sponsor Medical Monitor, and if in the best interest 
of and in agreement with the study participant, the dosing frequency may be 
changed from 
 
 
 
 
Dose Escalation (Part 1A and Part 2A): After each dose cohort, BLRM will be used to 
guide dose escalation decisions for monotherapy and combination therapy. At the time of 
each dose escalation decision, BLRM will be used to obtain, for each potential dose, an 
updated estimate of the toxicity curve and the posterior probabilities that the DLT rate for 
that dose lies in each of four toxicity intervals (underdosing, target toxicity range, 
excessive toxicity, and unacceptable toxicity). The four DLT toxicity intervals are 
defined as follows:  
• (0%, 16%] =Underdosing range;  
• (16%, 33%] =Target toxicity range;  
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• (33%, 50%] =Excessive toxicity range;  
• (50%, 100%] =Unacceptable toxicity range.   
The dose with the highest posterior probability of lying in the Target Toxicity range will 
be the model-recommended dose for the next cohort. Additionally, the following 
constraints for the recommended dose will be maintained:  
• 
The posterior probability of the DLT rate lying in the Excessive Toxicity or 
Unacceptable Toxicity range is less than 25%. 
• 
The recommended dose is no more than two-fold (100%) of the previous dose. 
Note that de-escalation as well as escalation is possible using this method. Statistical 
properties of BLRM design are described in Section 9.  
Dose escalation will continue until: 
i. An MTD is found: 
At least 9 participants have been treated at the current target dose  
AND 
The posterior probability that the DLT rate for the current dose lies in either the 
excessive toxicity or unacceptable toxicity range is less than 25%. 
AND 
The posterior probability that the DLT rate for the next higher dose lies in either 
the excessive toxicity or unacceptable toxicity range is greater than or equal to 
25%.  
OR 
ii. The maximum administered dose has been reached and at least 9 participants 
have been dosed at that dose level. 
OR 
iii. All doses have a posterior probability of lying in either the excessive toxicity or 
unacceptable toxicity range of greater than or equal to 25%  
AND 
At least two DLTs have been observed. 
All available data, including safety, PK and 
 data from current and 
prior cohorts will be reviewed at the dose escalation meeting. Although the BLRM design 
will be used to recommend the next dosing level, clinical judgment by the Medical 
Monitor, recommendation from GSK clinical pharmacologist, GSK scientist and GSK 
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statistician, and in consultation with the investigators can halt dose escalation or reduce 
the recommended dose as deemed appropriate at any time during the trial.  
Maximum-tolerated Dose: The MTD will be defined as the dose with the highest 
posterior probability of lying in the target toxicity range with the additional requirement 
that the sum of the posterior probabilities of the DLT rate lying in the excessive toxicity 
range or unacceptable toxicity range is less than 25%. 
Table 8 
3+3 Dose-Escalation Guidelines 
Number of Participants with DLT at a Given 
Dose Level 
Action 
0 of 3 
Escalate to the next dose level 
1 of 3 
Accrue 3 additional participants at current dose 
level for a total of 6 evaluable participants 
• 
If 0 of the additional 3 participants 
experience a DLT, escalate to next dose 
level 
• 
If 1 of the additional 3 participants 
experiences a DLT, stop dose escalation 
1 of 6 
Escalate to the next dose level 
2 of up to 6 
Stop dose escalation 
 
All dose escalation/de-escalation decisions will be made by the DEC. Although the 3+3 
dose escalation procedure will be used to recommend the next dosing decision, clinical 
judgment by the Medical Monitor with input from the sponsor study team, and in 
consultation with the investigators, can halt dose escalation or reduce the recommended 
dose as deemed appropriate at any time during the trial. 
 dose escalation cohort will be analyzed 
separately from the monotherapy dose escalation study conducted outside 
 
 
 
Recommended Phase 2 Dose: RP2D of GSK3745417 will be determined after review of 
all available safety, PK, pharmacodynamics, and clinical efficacy data in accordance with 
the BLRM design. The RP2D will be equivalent with the MTD or a lower GSK3745417 
dose that provides adequate PK exposure and biologic activity with superior tolerability. 
Exploration of lower or intermediate dose levels than the BLRM recommended dose (or 
expansion of a previously tested dose level) will be allowed if agreed upon by the 
Medical Monitor and treating investigators. The progression from one dose level to 
another will be made based on the assessment of all the available data (even outside of 
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DLT criteria) from previous dose levels, including the BLRM recommended dose as 
described in Section 9.2. All dose escalation decisions will be assessed by the Dose 
Escalation Committee. 
 
 
 
 
 
 
  
Cohorts permitted IRR/CRS prophylaxis: At the discretion of the DEC, cohorts may 
be opened which explore the effects of IRR/CRS prophylaxis in designated dose levels.  
4.1.2. 
Dose-Limiting Toxicity 
All toxicities will be graded using National Cancer Institute - Common Toxicity Criteria 
for AEs (NCI-CTCAE), version 5.0.   
An AE is considered to be a DLT if it is considered by the investigator to be clinically 
relevant and attributed (definitely, probably, or possibly) to the study intervention and 
meets at least 1 of the criteria listed in Table 9. If an AE is considered related to the 
underlying disease, it is not a DLT. 
Table 9 
Dose-Limiting Toxicity Criteria 
DLT Criteria for Non-hematologic Toxicitya, c 
Cytokine Release 
Syndromeb 
• 
Grade 3 or Grade 4 (See Appendix 12) 
Liver Toxicityd 
• 
ALT 3x upper limit of normal (ULN), plus bilirubin 2x ULN (>35% direct) 
or plus international normalized ration (INR)>1.5 (Possible Hy’s law) 
OR 
• 
Both ALT 5x ULN and 2x baseline value (in participants with liver 
metastases/tumor infiltration or HCC at baseline) 
Any other 
• 
Grade 3 non-hematologic toxicity of any duration with the following 
exceptions: 
o Transient (≤72 hours) abnormal laboratory value without 
associated clinically significant signs or symptoms  
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DLT Criteria for Non-hematologic Toxicitya, c 
o Individual parameters of cytokine release syndrome (CRS) which 
collectively constitute < Grade 3 CRS  
o Diarrhea adequately controlled with supportive care within 48 
hours 
o Nausea and vomiting resolving to Grade ≤1 within 48 hours 
o Alopecia of any grade 
o Grade 3 fatigue with duration <7 days  
o Grade 3 headache which resolves with supportive treatment to ≤ 
Grade 2 within 24 hours 
• 
Grade 3 immune-related toxicity that does not resolve to  Gr1 or 
baseline within 8 days despite adequate immune suppressive therapy 
• 
Grade ≥3 infusion-related reactions 
• 
Any treatment-related non-hematologic toxicity specifically defined as: 
o Grade ≥2 uveitis, eye pain, or blurred vision that does not resolve 
with topical therapy within 2 weeks 
o Grade ≥2 immune-related endocrine toxicity that requires 
hormone replacement (except Grade 2 thyroiditis or thyroid 
dysfunction)  
o Grade 2 colitis or diarrhea that persists without resolution to 
Grade ≤1 for ≥7 days despite adequate steroid therapy 
• 
Grade ≥2 Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
• 
Any other event which in the judgment of the investigator and GSK Medical 
Monitor is considered to be a DLT 
DLT Criteria for Hematologic Toxicitya, c 
Neutropenia 
• 
Grade 4 neutropenia of ≥7 days duration or Grade 3 or 4 associated with 
infection or febrile neutropenia  
Thrombocytopenia 
• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding or 
requiring platelet transfusion 
Anemia 
• 
Grade 4 anemia or Grade 3 requiring blood transfusion 
Hematologic Events 
• 
Any other hematologic event which, in the judgment of the investigator and 
GSK Medical Monitor, is considered to be a DLT 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BSC=best supportive care; DLT=dose limiting toxicity; NCI 
CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events; ULN=upper limit of normal 
aToxicity graded according to the NCI-CTCAE, Version 5.0 [NCI, 2017] 
bGrading according to Lee, 2019 
cThe following event is not considered as a DLT: Changes in leukocyte parameters within 48 hours of GSK3745417 administration 
 
Participants unable to receive at least 80% of scheduled doses for reasons other than 
toxicity (e.g., acute illness, disease progression) will be replaced in the cohort, however 
any low-grade toxicity not constituting a DLT will be taken into consideration for dose 
escalation decisions. If an AE is considered related to the underlying disease, it is not a 
DLT.   
Participants who withdraw from the study before completing DLT period for reasons 
other than DLT may be replaced. If a participant experiences a DLT during the DLT 
period of treatment, the participant will be discontinued from study treatment unless the 
investigator considers it in the best interest of the participant to continue on study (e.g., in 
case of tumor regression, symptomatic disease improvement, and/or if the DLT is viewed 
as preventable in subsequent doses/visits, etc.) and the sponsor approves of the decision.  

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Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 6.6. 
4.1.3. 
Dose Escalation Committee 
The Dose Escalation Committee (DEC) will be established by GSK to monitor 
intervention-emergent data on an ongoing basis throughout study conduct for the purpose 
of ensuring the continued safety of participants enrolled in this study as described in the 
Dose Escalation Plan. The DEC will be chaired by the GSK medical monitor and 
membership will include a GSK scientist, GSK pharmacovigilance physician, GSK 
statistician, GSK clinical pharmacologist, along with additional GSK staff as appropriate 
and all participating investigators.  
In Part 1A, the DEC will review relevant safety, PK, and PD data generated immediately 
after all participants treated in the same dose cohort have passed the DLT period. 
Although the escalation of the GSK3745417 dose will be guided by the BLRM and 3+3 
dose escalation procedure for Japan monotherapy participants, the DEC can override this 
recommendation.  
Participants will be enrolled in this study as described in the Dose Escalation Plan. 
In addition, throughout the conduct of the study the DEC may decide to: 
1. Modify the dose escalation of GSK3745417 proposed by the BLRM/3+3 dose 
escalation procedure based on clinical judgment. Note: GSK3745417 dose steps 
which will not exceed two-fold (100%) increments 
2. Investigate alternative dosing regimens  
3. Modify the timing, frequency, and/or type of safety assessments performed during 
study conduct  
4. Approve continuation of GSK3745417 study therapy in participants who have 
experienced DLT provided the toxicity did not meet study discontinuation criteria 
and has resolved at the time of re-start.  
5. Request intervention of additional participants at previously completed dose 
levels for the purpose of obtaining additional safety, PK, PD, metabolite, or 
biomarker data. 
6. Recommend intra-participant dose escalation allowing participants to be moved 
from a lower to a higher GSK3745417 dose not exceeding the MTD if the DEC 
has declared the next dose cohort as acceptable safety profile. 
7. Decide on intervention beyond initial evidence of disease progression in 
participants who receive clinical benefit (i.e., stable Eastern Cooperative 
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8. Halt enrollment into any cohorts as deemed appropriate based on emerging 
clinical data at any time during the trial. 
During Part 1A and Part 2A of the study, the DEC will meet at least after each dose 
cohort is fully recruited and all participants have completed the DLT evaluation 
period. The schedule of dose escalation meetings will depend on the frequency of 
DLT and when an RP2D is determined.  
Documentation of DEC meeting outcomes will be maintained by GSK. Decisions 
with potential impact on the safety of study participants (i.e., unfavorable change in 
risk/benefit assessment) will be promptly communicated to regulatory authorities and 
study sites as appropriate. 
4.1.4. 
Tumor Types Enrolled During Parts 1A and 2A 
Participants with advanced solid tumors will be enrolled. 
4.1.5. 
Participant Re-Treatment 
Upon initiation of Part 2A combination therapy with dostarlimab, participants in Part 1A 
monotherapy may be considered on a case-to-case basis and when required criteria are 
met (below) to transition to a cleared combination dose/frequency regimen as tested in 
Part 2A.  
Participants must have completed at least 1 treatment period of GSK3745417 
monotherapy without the occurrence of drug-related Grade ≥3 AEs or serious adverse 
events (SAEs) of any severity Grade in the first 21 days (for those in Arm A1, Q1W 
regimen) or 29 days (for those in Arm A2, Q3W regimen) of treatment and meet disease 
progression criteria (i.e., only confirmed radiologic progression as defined by iRECIST) 
at the current dose.  
A participant who upon disease progression is permitted to re-start treatment and receive 
GSK3745417 in combination with dostarlimab will be reconsented, and follow the 
Schedule of Assessments as outlined in Table 5-1. 
Additionally, the GSK medical monitor must be consulted and approve the decision 
before re-treatment is permitted.  
For participants who 
 
 the data prior to crossover will 
be considered for analysis in the monotherapy arm and data after crossover will be 
analyzed in a different treatment group (i.e. Crossover GSK3745417 + dostarlimab). 
Additional safety assessments or PK sampling may be specified at the time of dose 
escalation or schedule modification based on the safety profile in previous participants at 
the higher dose level.  
4.1.6. 
Study Duration 
In this study, participants will receive GSK3745417 monotherapy or combination therapy 
with GSK3745417 and dostarlimab. Participants will be screened for eligibility beginning 
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approximately 4 weeks before the start of treatment. Following the screening phase, 
participants will initiate the treatment phase of the study. The duration of treatment with 
GSK3745417 monotherapy or in combination with dostarlimab is expected to be 2 years. 
Participants will continue study therapy until one of the following events occurs: disease 
progression, death, unacceptable toxicity including meeting stopping criteria for liver 
chemistry or withdrawal of consent.   
The decision whether a participant will receive additional treatment beyond two years 
will be discussed and agreed upon by the treating investigator and the Sponsor/Medical 
Monitor on a case-by-case basis.  
Following discontinuation of the treatment phase, participants will enter the follow-up 
phase of the study. During the follow-up phase, participants will complete clinic visits for 
assessments of safety and for AESI and SAEs until 90 days after the last dose of study 
treatment or until the start of subsequent anti-cancer treatment.  
 
 
4.2. Number of Participants 
It is estimated that approximately 
 will be enrolled in the escalation arms 
of this study. In addition,
 will be enrolled into a 
 
 
  
4.3. Participant and Study Completion 
Participants will be considered to have completed the DLT portion of the study if they 
complete screening assessments and receive at least 1 study treatment and experience a 
DLT during the 21- or 29-day DLT observation period or complete the DLT observation 
period. 
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Under this amendment, participants will be considered to have completed the study if 
they complete the safety follow-up until 90 days after last dose, start subsequent therapy 
or die. Participants who are in follow-up at the time of this amendment and have been 
followed for at least 90 days are considered as having completed the study. The end of 
study visit will be used to capture study completion. 
A participant will be considered to have withdrawn from the study if the participant has 
not died and is lost to follow-up, has withdrawn consent, at the investigator’s discretion is 
no longer being followed or if the study is closed/terminated. Disease progression, 
discontinuation of study treatment, and AEs, are not by themselves reasons for 
withdrawal from the study. 
4.4. Scientific Rationale for Study Design 
Given the high unmet medical need of relapsed/refractory advanced solid tumors, this 
two-part Phase I study is proposed. This study evaluates the safety, tolerability, 
pharmacology, and 
 of GSK3745417 alone or 
co--administered with dostarlimab. The study comprises a dose escalation phase to 
identify the MTD/ RP2D [GSK Document Number 2020N357563_04]. 
Blood, urine, 
 
 
Eligibility criteria require that participants have progressed after standard therapies or are 
otherwise unsuitable for standard therapies, and the criteria are intended to minimize the 
risk of adverse reactions to treatment with immunotherapies. 
Dose escalation of GSK3745417 alone or in combination with dostarlimab will be 
performed using a BLRM approach used to optimize the allocation of participants to dose 
levels with a 
. The DLT criteria are based on typical oncology rules 
with additional modifications for toxicities expected for the study treatments. 
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4.5. Justification for Dose 
4.5.1. 
Human PK Prediction 
Two methods were used to predict the PK of GSK3745417 in humans using data from in 
vitro studies conducted with liver microsomes and hepatocytes and from 
concentration-time data following IV administration of GSK3745417 to various species 
(mouse, rat, and cynomolgus monkey). 
4.5.1.1. 
In-vitro-to-in-vivo Extrapolation 
There was good in vitro-in vivo correlation between clearance (CL) estimates from 
mouse, rat, monkey, liver microsomes and fresh hepatocytes and CL estimates from in 
vivo IV plasma PK profiles in mouse, rat, monkey. The hepatic blood clearance of 
GSK3745417 was predicted to be 13 mL/min/kg or 6 mL/min/kg by in vitro to in vivo 
extrapolation (IVIVE) using human microsomes or hepatocytes, respectively, assuming a 
well stirred model. The plasma CL of GSK3745417 was calculated using the scaled up 
hepatic blood CL values and experimental blood to plasma ratio of 0.59 to be 
8 mL/min/kg or 3 mL/min/kg, respectively, from human microsomes or hepatocytes. The 
predicted CL values for mouse, rat and monkey were within 2.5-fold of the observed in 
vivo mean plasma clearance values using IVIVE from microsomes or hepatocytes 
suggesting a good in vitro to in vivo correlation. 
4.5.1.2. 
Allometry 
Clearance and Vd values obtained from mouse, rat, and monkey administered 
GSK3745417 IV were used for allometric scaling. The allometric exponent for the 
log-log CL to body weight relationship was >0.75; hence, maximum lifespan potential 
(MLP) correction factor was used to predict human CL; the predicted human CL value 
using this method was 7.2 mL/min/kg. The geometric mean of these human predicted 
plasma clearance values (5.6 mL/min/kg = 23372 ml/h for a 70 kg human) was used for 
human dose and exposure predictions. A low human volume of distribution of 0.17 L/kg 
was predicted, suggesting distribution in the extracellular fluid. The rat Vd of 0.1 L/kg 
was used for the most conservative estimate. 
Linear PK of GSK3745417 is assumed for human dose predictions as well as for animal 
PK. 
 
4.5.2. 
Justification of Starting Dose 
 
 The minimally anticipated biologic effect level (MABEL) approach was 
used as the basis for this starting dose for use in cancer patients with advanced tumors to 
provide the most conservative estimate of starting dose for this STING agonist. In 
addition, 1/10 STD10 (Severely Toxic Dose in 10% rodent species) and 1/6 HNSTD 
(highest non-severely toxic dose in a non-rodent species) were considered for starting 
dose estimates. The approaches used are in consideration of the International Council on 
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Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) S9 guidance on selection of starting dose for a molecule with immune 
agonistic properties. The starting dose for the study was determined after consideration of 
relevant in vitro and in vivo preclinical data as described below. 
In order to provide the most conservative systemic exposure estimate, the lowest 
predicted CL value of 3 mL/min/kg (12600 mL/h, for a 70 kg human) and lowest Vd 
estimate of 0.1 L/kg (7000 mL, for a 70 kg human) were used to calculate exposures 
following a 
 
 
 
 
 
4.5.2.1. 
Calculation of MABEL (Minimally Anticipated Biological Effect Level) 
A panel of cytokines (IFN, IL-1, IL-6, TNF, IP-10, MIP-1, MIP-1, IL-8) from 
human and monkey ex vivo assays and monkey in vivo studies was evaluated. Of these, 
the response of cytokines IL-6 and IP-10 in relation to GSK3745417 concentration were 
considered the most sensitive and were used as the basis for MABEL dose estimation. 
This relationship was investigated in both ex vivo assays in monkey and human whole 
blood and in the in vivo monkey GLP toxicology study.   
MABEL based on ex vivo cytokine response in whole blood assays, cynomolgus 
monkey and human 
Monkey whole blood and human whole blood was spiked with GSK3745417 ranging in 
concentration from 0.04 to 30 M (n=8 donors per concentration level) and cytokine 
concentrations were measured 4 hours later.   
An Emax model was fit to concentration-response curves for IL-6 and IP-10. The ten 
percent effect concentration (EC10) corrected to plasma (human blood-to-plasma ratio of 
0.59) was calculated and related to the predicted plasma human Cmax using the predicted 
human Vd of 11900 mL (based on 70 kg human and predicted Vd of 0.17 L/kg).   
A summary of the range of predicted human starting dose for IL-6 and IP-10 based on the 
ex vivo whole blood assay in monkey and human is shown in Table 11. 
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Table 11 
Predicted human starting dose based on ex vivo cytokine response 
in monkey and human whole blood, corrected to plasma 
Cytokine 
Species 
Plasma EC10 (ng/mL) 
Predicted human starting dose 
range (mg) 
IL-6 
Monkey 
349 
Human 
1409 
IP-10 
Monkey 
114 
Human 
338 
 
MABEL based on in vivo cytokine response, cynomolgus monkey 
Activation of the STING pathway in the cytosol drives a downstream signal transduction 
cascade leading to transcriptional changes and production of type I IFNs and 
proinflammatory cytokines. To approximate this indirect relationship, the relationship 
between each cytokine and PK was examined using the following parameters: 1) cytokine 
AUC vs. GSK3745417 AUC, 2) cytokine Cmax vs. GSK3745417 AUC, and 3) cytokine 
Cmax vs. GSK3745417 Cmax. An Emax model was fit for each IL-6 and IP-10 to 
GSK3745417 relationship. The ten percent effect AUC (E(AUC)10) or maximal 
concentration (E(Cmax)10) was calculated. The dose of GSK3745417 estimated to achieve 
a AUC or Cmax approximating E(AUC)10 or E(Cmax)10, respectively, was calculated using 
the predicted human PK parameters described in Section 4.5.2.  
For IL-6, the estimated starting dose range is 
. For IP-10, the estimated 
starting dose range is 
. A summary of the range of predicted human starting 
dose for IL-6 and IP-10 is shown in Table 12. 
Table 12 
Predicted human starting dose based on in vivo cytokine response 
in cynomolgus monkey 
Cytokine 
Cytokine to 
PK 
relationship 
Target exposure 
parameter and estimate 
Relate to human 
parameter 
IL-6 
AUC vs. AUC 
E(AUC)10 = 125 ng.h/mL 
AUC1 
Cmax vs. AUC 
E(AUC)10 = 157 ng.h/mL 
AUC1 
Cmax vs. Cmax 
E(Cmax)10= 967 ng/mL 
Cmax2 
IP-10 
AUC vs. AUC 
E(AUC)10 = 64 ng.h/mL 
AUC1 
Cmax vs. AUC 
E(AUC)10 = 48 ng.h/mL 
AUC1 
Cmax vs. Cmax 
E(Cmax)10= 457 ng/mL 
Cmax2 
1Using human predicted CL = 5.6 ml/min/kg  23372 mL/h (based on 70 kg human) 
2Using human predicted V = 0.17 L/kg  11900 mL (based on 70 kg human) 
 
As a good correlation between monkey ex vivo and in vivo cytokine response is observed 
for IL-6 and IP-10, a similar correlation is anticipated in human. Therefore, ex vivo 
human EC10 values for IL-6 and IP-10 were considered appropriate to use to estimate the 
MABEL. A dose of 
 was considered as the most conservative estimate per the 
MABEL approach. 
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4.5.2.2. 
Starting dose based on ICH S9 guidance 
Data from the GLP toxicology studies, allowed calculation of starting dose based on 1/10 
STD10 (Severely Toxic Dose in 10% rodent species) and 1/6 HNSTD (highest 
non-severely toxic dose in a non-rodent species) per the ICH S9 guidance. 
The STD10 in mouse was 3 mg/kg administered IV once weekly for 4 weeks. A starting 
dose based on this STD10, assuming a 60 kg human with BSA of 1.62 m2, and taking 
1/10 of this value, translates to a dose of 
. 
The HNSTD in cynomolgus monkey was 0.03 mg/kg IV once weekly for 4 weeks, a 
human equivalent dose of 1/6 HNSTD of 100 mcg IV given once weekly. Monkey is the 
more sensitive nonclinical species. 
4.5.2.3. 
Potential therapeutic dose 
Anti-tumor efficacy in BALB/c mice inoculated with CT-26 cells was investigated upon 
IV administration of GSK3745417 with doses of 
 
Treatment with 
 resulted in complete tumor regression in 50% of mice 
(5/10); treatment with 
 resulted in complete tumor regression in 100% of 
mice (9/9). The mouse exposure area under the concentration-time curve from time zero 
to infinity [AUC(0-inf)] for a 
 was estimated to be 958 ng.h/mL 
and 3194 ng.h/mL, using mouse plasma concentration profiles observed in the GLP 
toxicology study where GSK3745417 IV was administered and assuming linear PK. A 
predicted human dose range of 
 would deliver a similar exposure range 
that was shown to be efficacious in 50% to 100% mice based on predicted human PK 
parameters. However, the actual exposure of GSK3745417 in humans that would 
translate into efficacy in humans is not known and the 
 
   
The anticipated IL-6 and IP-10 response in human following a 
, at which a 
predicted Cmax is 1849 ng/mL, are approximately 30 pg/mL and 2110 pg/mL, 
respectively, based on the PK/pharmacodynamic relationship observed in the ex vivo 
whole blood assay, when corrected to plasma. Given the adverse event profiles which 
were consistent with an inflammatory/cytokine response at the explored monotherapy 
dose levels of 
 weekly, and where there is incomplete and exploratory 
biomarker data available for a small number of subjects, 
 
 
 
4.5.3. 
Dostarlimab Dose Rationale 
The recommended clinical dose and regimen of dostarlimab is 500 mg 
 for 4 doses 
followed by 1000 mg 
 This regimen was determined from the results of the Phase 
1/2 study 4010-01-001, where the PK, efficacy and safety were evaluated over 3 parts: 
• 
• 
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• 
 
 
A two-compartment model with no effect of body weight on dostarlimab clearance 
described the observed PK data well. Full PD1 receptor occupancy in peripheral blood 
cells was observed with drug concentrations of 
 The predicted arithmetic 
mean (90% CI) trough concentrations at steady state for the 
 
 
The two regimens maintained trough concentrations at least 
 
concentration of 
, considering the lower bounds of the 90% CI’s. Further 
exposure-response analyses determined 
 
 
 
 
 
  
 
4.6. End of Study definition 
A final data cut-off representing the end of data collection, prior to the end of study 
(EOS), is defined as the data cut-off date for the primary/final analysis. Following the 
final data cut-off date, the study may move into the PACT phase and the clinical study 
database will be closed to new data. Participants who are receiving study treatment may 
continue to receive study treatment if they are gaining clinical benefit as assessed by the 
investigator until they meet any protocol-defined treatment discontinuation criteria. 
Although the clinical study database will be closed at the time of the final data cut-off 
date, the study remains open until all participants discontinue study treatment (and 
complete the 90-day safety follow-up) and the EOS definition is reached.The end of 
study is defined as the date of the last visit of the last participant receiving study 
treatment in the study (i.e. last dose plus 90 days safety reporting period) or last 
scheduled procedure shown in the SoA for the last participant in the study.  
 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
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may impact participant eligibility is provided in the IBs/IB supplements. Deviations from 
inclusion and exclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or participant safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.   
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Participant must be 18 years of age at the time of signing the informed consent. 
Participants in the Republic of Korea must be 19 years of age at the time of signing 
the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants with advanced/recurrent solid tumors, with disease progression on, 
intolerance of, or ineligible for, all available therapies for which clinical benefit has 
been established. 
3. Histological or cytological documentation of an advanced solid tumor. 
4. 
5. Participants must provide a fresh biopsy of a tumor lesion not previously irradiated 
during the screening period.  
6. Measurable disease per Response Evaluation Criteria in Solid Tumors 
(RECIST version 1.1). 
 
 
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. 
8. 
9. 
10.
11.
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Sex 
12. Male or female 
a) Female Participants are eligible to participate if they are not either pregnant or 
breastfeeding, and at least one of the following conditions applies: 
• Is not a woman of childbearing potential (WOCBP)  
OR 
• 
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• 
• 
• 
Informed Consent 
13. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. 
2. 
3. Active autoimmune disease that has required systemic disease modifying or 
immunosuppressive treatment within the last 2 years. 
 
 
4. Concurrent medical condition requiring the use of systemic immunosuppressive 
treatment within 28 days before the first dose of study treatment. 
 
 
 
 
5. Current unstable liver or biliary disease 
 
 
  
 
 
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6. History of vasculitis at any time prior to study treatment. 
7. Evidence or history of significant active bleeding or coagulation disorder.  
8. Active infection requiring systemic treatment, known human immunodeficiency virus 
infection, or positive test for hepatitis B surface antigen or hepatitis C. 
 
 
9. QTcF >450 msec or QTcF >480 msec for participants with bundle branch block.  
 
 
10. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel 
disease, intra-abdominal abscess, or gastrointestinal obstruction.  
11. Recent history of allergen desensitization therapy within 4 weeks of starting study 
treatment.   
12. History or evidence of cardiovascular (CV) risk including any of the following: 
• 
• 
 
• 
• Recent (within the past 6 months) history of any grade of 
 
 or pericarditis. 
13. History of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing 
pneumonia, or evidence of active, non-infectious pneumonitis. 
 
 
 
14. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
15. Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural 
effusions. 
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16.
 
 
   
17. 
 
 
 
 
Prior/Concomitant Therapy 
18. Prior treatment with the following agents:  
• 
STING agonist at any time. 
o 
NOTE: Does not apply to participants treated in Part 
1A/monotherapy with GSK3745417 who move to combination with 
dostarlimab upon radiologically confirmed disease progression 
following discussion and approval from the GSK Medical Monitor. 
• 
Anticancer therapy or investigational therapy or used an investigational device 
within 28 days or 5 half-lives of the drug, whichever is shorter. 
• 
Checkpoint inhibitors, including PD-1, PD-L1, PD-L2 and CTLA-4 inhibitors 
within 28 days. 
• 
Prior radiation therapy: permissible if at least 1 non-irradiated measurable 
lesion is available for assessment according to RECIST version 1.1 or if a 
solitary measurable lesion was irradiated, objective progression is documented. 
 
 
 
 
 
 
19.
 
. 
20. Receipt of any live vaccine within 30 days of the start of study treatment. 
21. Prior allogeneic or autologous bone marrow transplantation or other solid organ 
transplantation.   
22.
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23.
24.
Other Exclusions 
25. Major surgery 28 days before the first dose of study treatment. Participants must 
have also fully recovered from any surgery (major or minor) and/or its complications 
before initiating study treatment.   
26.
 
27. Participants with signs/symptoms suggestive of COVID-19 within 14 days of study 
entry, or with known exposure to COVID-19 within 14 days prior to study entry 
 
Exclusions Only for participants in Part 2A, participants crossing over to 
combination therapy, and participants in Imaging Sub-study: 
 
In addition to the criteria listed above, participants are excluded from Part 2A of the 
study, participants crossing over to combination, and Imaging Sub-study if the following 
criterion applies: 
28. Known hypersensitivity to any of the study interventions or any of their excipients. 
 
5.3. Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
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5.3.3. 
Activity 
Participants will abstain from strenuous exercise for 8 hours before each blood collection 
for clinical laboratory tests. Participants may participate in light recreational activities 
during studies (e.g., watching television, reading) and be ambulatory when possible. 
5.4. Screen Failures 
A screen failure is defined as a participant who consents to participate in the clinical 
study but is not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. This includes retesting specific vital sign measurements, 
laboratory assessments, etc. that may not have met eligibility criteria. 
6. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study intervention’ is used throughout the protocol to 
describe any combination of products received by the participant as per the protocol 
design.   
6.1. Study Intervention(s) Administered 
Following administration of GSK3745417 monotherapy or GSK3745417 in combination 
with dostarlimab, assessments should be performed as noted in the SOA, Section 1.2.1. 
Cytokine-related AEs including changes in vital signs may begin within several hours of 
administration of GSK3745417. In Arm A1 and Arm A2, participants must be monitored 
 
 
 
, however, participants may be released after a 6-hour observation period if 
in the opinion of the investigator if it is safe to do so; and longer at all visits if clinically 
indicated. In case of the combination therapy 
 
 
On other treatment visits, participants be monitored for 30 minutes 
 
, however, participants may be released 
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after a 6-hour observation period if in the opinion of the investigator if it is safe to do so, 
and at least 2 hours after administration of dostarlimab. Guidelines for monitoring 
cytokine-related AEs are summarized in Section 6.6.1. 
GSK3745417 
 alone or in combination with dostarlimab will be 
administered to participants at each study site under medical supervision of an 
investigator or designee. When both study interventions are to be administered in Part 
2A, the following order of administration should be followed: 
 
 
 
 
 
 
Note: Dostarlimab will be administered at the dose of 
 for the first 
4 doses, followed by 1000 mg 
 for subsequent doses. Participants in Japan 
will receive dostarlimab at a dose and schedule of 
 throughout the 
dosing period. 
The date and time of administration will be recorded in the source documents and 
reported in the eCRF.    
In Part 2A, if a participant experiences an 
, 
associated AEs should resolve before dostarlimab is administered. 
 
 
. 
The specific time of study treatment administration (e.g., time of the week for first 
administration; time of the day for each administration) should take into consideration PK 
sampling time points and study visit procedures. Depending on the dosing schedule 
 
 
 (e.g., scheduling an 
infusion around a holiday). 
 
 However, such changes from the planned date should not 
result in changes to consecutive doses of GSK3745417  dostarlimab (i.e., participant 
should return to initial schedule). Subsequent doses should be administered at least 5 days 
apart in both 
 
The Study Reference Manual (SRM) contains specific instructions for the preparation 
and administration of GSK3745417 and dostarlimab.  
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Table 14 
Investigational Product Dosage/Administration 
Intervention Name 
GSK3745417 Dostarlimab 
Type  
Small 
molecule 
Monoclonal 
antibody IgG4 
Dose Formulation 
See SRM for 
details 
See SRM for 
details 
Dosage Form 
Unit Dose Strength(s) 
Dosage Level(s) 
Route of Administration 
Reconstitution 
See SRM for 
details 
See SRM for 
details 
IMP 
GSK3745417 GSK4057190A 
Sourcing 
Provided 
centrally by 
the sponsor 
Provided 
centrally by 
the sponsor 
Packaging and Labelling 
 
Study 
Intervention 
will be 
 
 
 Each 
vial and 
carton will be 
labelled as 
required per 
country 
requirement. 
Study 
intervention 
will be 
 
 
. Each 
vial and carton 
will be labelled 
as required 
per country 
requirement. 
[Current/Former Name(s) or Alias(es)] 
N/A 
Dostarlimab 
 
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6.2. Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study interventions 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
the investigator and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study intervention 
are provided in the SRM.  
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK. 
6.3. Measures to Minimize Bias: Randomization and Blinding 
This is an open-label study. All screened participants will be identified by a unique 
participant number that will remain consistent for the duration of the study. Upon 
completion of all the required screening assessments, eligible participants will be 
registered into the study by the investigator or authorized site staff. See SRM for 
additional information on screening and enrollment procedures. 
One to nine participants may be enrolled at a particular dose level in each treatment arm. 
Each eligible participant entering the study will be allocated into the next available 
treatment arm, rotating through the list of currently open treatment arms at that time in 
the order 
 
 
 
1) Enrollment at a particular dose level of combination therapy will only begin if 
that dose level DLT period has been cleared in the corresponding monotherapy 
arm. This rule will not apply to any dose level below the highest dose with an 
acceptable safety profile in monotherapy. 
In case multiple participants are available simultaneously, they will be enrolled in order 
of their availability for the targeted dosing day.  
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At a minimum, the first 3 participants in the first 4 dose levels in each arm will receive 
study treatment ≥48 hours apart to allow assessment of initial safety data in each 
participant before beginning the next participant’s treatment. (e.g., if a participant is 
dosed on Monday, the earliest the next participant could be dosed is Thursday). 
6.4. Study Intervention Compliance 
GSK3745417 alone or in combination with dostarlimab 
 
 
 
 Administration will be documented in the source documents and reported in 
the eCRF. 
6.5. Concomitant Therapy 
Participants will be instructed to inform the investigator before starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including antibiotic and probiotic use 
within 60 days prior to first dose, non-prescription medication(s), and herbal product(s), 
taken during the study will be recorded in the eCRF. The minimum requirement is that 
drug name, dose, and the dates of administration are to be recorded. Additionally, a 
complete list of all prior anticancer therapies will be recorded in the eCRF.   
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.   
If future changes are made to the permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter.   
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded in the eCRF along with: 
• 
reason for use 
• 
dates of administration including start and end dates 
• 
dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.5.1. 
Permitted Medications and Non-Drug Therapies 
Supportive Care: Participants should receive full supportive care during 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. Intra-nasal flu vaccine is excluded. Elective surgery or 
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palliative radiation may be permitted on a case-by-case basis in agreement with the 
Medical Monitor, if these do not include any "target" lesions. 
Growth Factors and Bisphosphonates: Bisphosphonates and receptor activator of 
nuclear factor-kappaB ligand (RANKL) inhibitors (e.g., denosumab): permitted for 
treatment of bone metastasis or other indicated conditions such as hypercalcemia 
provided participants have been on a stable dose for at least 4 weeks prior to enrolment 
date. Note: prophylactic use in participants without evidence or history of bone 
metastasis is not permitted, except for the treatment of osteoporosis. However, the 
initiation of growth factors and bisphosphonates is not allowed during the first 4 weeks of 
study treatment, unless used in the management of toxicity and agreed upon by the 
investigator and Medical Monitor. 
Prophylaxis of cytokine-related symptoms: The DEC may authorise the opening of a 
separate cohort of subjects to determine the effect of prophylaxis with certain 
medications (including anti-pyretics, antihistamines and steroids) on efficacy and 
tolerability. For these participants only, the Investigator (in consultation with the Medical 
Monitor) may consider giving anti-pyretics, anti-histamines and steroids prior to the first, 
or subsequent doses (see Appendix 13 for suggested CRS prophylaxis regimen).  
For subjects in other cohorts, prophylaxis with steroid may be used outside of DLT 
period for repeated Grade 2 and above CRS at investigator’s discretion following 
consultation with GSK Medical Monitor. Subjects in all cohorts may receive 
antihistamines and antipyretics prior to dosing with GSK3745417 at the investigator’s 
discretion following consultation with GSK Medical Monitor. 
For all cohorts, use of steroids is also permitted for treatment of AEs (as per Section 6.6) 
while the participant is undergoing treatment on this study. 
IL-6/TNF Inhibitors: Use of IL-6 and TNF inhibitors is permitted for treatment of 
AEs while the participant is undergoing treatment on this study. 
Participants with conditions pre-existing before study enrollment requiring steroids are 
permitted to continue taking up to a maximum of 10 mg of prednisone or equivalent 
provided that the participant has been on a stable dose for at least 4 weeks before 
enrollment. 
Participants considered to have an increased risk of thrombosis (e.g., history of catheter-
related clots, DVT) can be considered for prophylactic anticoagulation per local practice 
and/or clinical judgement. 
6.5.2. 
Prohibited Medications and Non-Drug Therapies 
The following medications are prohibited before the first dose of study treatment (see 
Section 5.2 for specific time requirements) and while on treatment in this study: 
• 
 
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6.6. Dose Modification 
AEs associated with treatment with GSK3745417  dostarlimab exposure may be 
immune-mediated. These immune-related AEs (irAEs) may occur shortly after the first 
dose or several months after the last dose of GSK3745417  dostarlimab treatment, or 
anywhere in between, 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 
GSK3745417  dostarlimab and administer corticosteroids.  
In study 208850 examining GSK3745417 in participants with advanced solid tumors,
Dose modification and toxicity management guidelines for irAEs associated with 
GSK3745417 or dostarlimab are provided in Table 15. The recent joint American Society 
of Clinical Oncology and National Comprehensive Cancer Network guidelines for the 
diagnosis and management of irAEs treated with immune checkpoint inhibitor therapy 
may be used as a supplement to Table 15 (Schneider, 2021).  
In case a dose reduction is necessary, the dose level of GSK3745417 may be 
changed/stopped as determined by the investigator and sponsor. Participants in 
combination arms may not discontinue only 1 study treatment. If either study treatment is 
deemed intolerable and requires discontinuation despite optimal management, as 
described in Table 15, the participant must be discontinued from both study treatments. 
, if study treatment administration is delayed or withheld due to 
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non-immune-related adverse event(s) during the DLT-evaluation period, the timing of 
restart of study treatment should be discussed with GSK Medical Monitor when the 
adverse events are resolved to Grade 1 or baseline. If Grade 2 symptom(s) persist or 
worsen to Grade 3 or greater, study investigator should contact GSK Medical Monitor to 
discuss further treatment, discontinuation, and restart of study treatment. 

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Table 15 
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs  
General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
Toxicity grade 
or conditions 
(ASCO 2018) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Restart dosing when toxicity resolves to Grade 1. If 
Grade 2 recurs, permanently discontinue. 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone or 
equivalent) followed by taper 
• 
Monitor participants for signs and symptoms of 
pneumonitis 
• 
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic antibiotics for opportunistic 
infections 
Grade 3 or 4, or 
recurrent grade 2 
Permanently discontinue 
Diarrhea / colitis  
Grade 2 or 3 
Restart dosing when toxicity resolves to Grade 0-1. 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone or 
equivalent) followed by taper 
• 
Monitor participants for signs and symptoms of 
enterocolitis (i.e. diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (i.e. peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
Grade 4 
Permanently discontinue 
AST / ALT elevation or 
increased bilirubin* 
Grade 2 
Restart dosing when toxicity resolves to Grade 1. 
• Administer corticosteroids (initial dose of 
0.5- 1 mg/kg methylprednisolone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable 
• 
See Section 11.6 for additional details on Liver 
Event Follow-Up Assessments 
Grade 3 or 4  
Permanently discontinue1 
• Administer corticosteroids (initial dose of 
1-2 mg/kg methylprednisolone or 
equivalent) followed by taper 
Type 1 diabetes mellitus 
(T1DM) or Hyperglycemia 
Grade 3 to 4 
hyperglycemia or 
T1DM 
(associated with 
metabolic 
acidosis or 
ketonuria) 
Restart dosing in appropriately managed, clinically, 
and metabolically stable patients; insulin 
replacement therapy is required. 
• Initiate insulin replacement therapy for 
participants with T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
• 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes. 

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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
Toxicity grade 
or conditions 
(ASCO 2018) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Hypophysitis 
Grade 2, 3 or 4 
For Grade 2-3, hold until administration of 
hormonal therapy results in return to adequate 
hormone levels based on laboratory values and 
restart dosing when toxicity 
resolves to Grade 1. For recurrence or worsening 
of ≥ Grade 2 hypophysitis after steroid taper has 
been completed and patient is on adequate 
hormone replacement therapy, permanently 
discontinue. 
• 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated.   
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)  
Hyperthyroidism  
Grade 3 or 4 
Grade 3 or 4– Hold until returns to adequate 
hormone levels based on laboratory values and 
restart dosing when toxicity resolves to Grade 1. 
• Treat with non-selective beta-blockers 
(e.g. propranolol) or thionamides as 
appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Hypothyroidism 
Grade 3 or 4 
Hold until administration of hormonal therapy 
results in return to adequate hormone levels based 
on laboratory values and restart dosing when 
toxicity resolves to Grade 1. 
• 
Initiate thyroid replacement hormones 
(e.g. levothyroxine or liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
• 
Monitor TFTs 
• 
Ensure adequate evaluation (e.g., endocrine 
consultation) 
• 
Exclude concomitant adrenal insufficiency (AM 
cortisol level) 
In Japan Participants 
only: 
Myocarditis or pericarditis 
(Also refer to Section 
6.6.1.1. for further details) 
Grade 1 
(including Grade 
1 cardiac 
troponin 
elevation) 
Discuss with GSK medical monitor regarding 
option to withhold or discontinue dosing 
• 
As required as outlined below for Grade 2 
and higher 
• 
As agreed with GSK medical monitor 

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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
Toxicity grade 
or conditions 
(ASCO 2018) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Myocarditis or pericarditis 
Grade 2, 3 or 4 
Permanently discontinue  
• 
 Administer high dose corticosteroids (1 
g/day of IV methylprednisolone) for 3 to 5 
days, followed by oral prednisone taper 
over 4 to 6 weeks based on improvement 
in cardiac function and biomarkers. 
• 
If no improvement in 24 hours, consider 
adding other potent immunosuppressive 
agents 
• 
Ensure adequate evaluation (e.g. Urgent 
cardiology consultation) to confirm etiology 
and/or exclude other causes 
Adrenal insufficiency 
Grade 2, 3 or 4 
Hold until administration of hormonal therapy results 
in return to adequate hormone levels based on 
laboratory values and restart dosing when toxicity 
resolves to Grade 1. 
For recurrent or worsening ≥ Grade 2 adrenal 
insufficiency while adequate hormonal replacement is 
continuing, permanently discontinue study drug. 
• Start treatment with corticosteroids before 
other hormone replacement to avoid adrenal 
crisis (hydrocortisone slowly titrating doses 
down according to symptoms OR prednisone 
and fludrocortisone titrating up or down 
based on BP, other symptoms and labs); 
patient with severe symptoms may require 
additional fluids (e.g., saline >2 L). 
• Monitor for cortisol level (AM), comprehensive 
metabolic panel (Na, K, CO2, glucose) and renin. 
• Ensure adequate endocrine evaluation (e.g. 
Endocrine consultation)   
Uveitis 
Grade 2 to 4 
Withhold 
• Urgent ophthalmology consultation 
• Administer treatment with ophthalmic and 
systemic prednisone/methylprednisolone 
• Ensure adequate evaluation (e.g., urgent 
ophthalmology consultation)  
 
Immune-related 
Encephalitis 
Any grade  
Permanently discontinue 
• Consider IV acyclovir until PCR results 
obtained 
• Trial with methylprednisolone; if severe, 
treatment with methylprednisolone 
• If positive for autoimmune encephalopathy 
antibody or no improvement after 7-14 days, 
consider rituximab  
• Ensure adequate evaluation to confirm etiology 
and/or exclude other causes. 
Severe neurologic events 
(myasthenic 
syndrome/myasthenia 
gravis, Guillain Barré 
Syndrome, transverse 
myelitis) 
Grade 2, 3 or 4 
Permanently discontinue 
Consider high dose corticosteroids and other 
therapies as needed. 
• It is highly recommended that Investigators 
discuss any AEs with the sponsor before 
using infliximab. 
Ensure adequate evaluation (e.g., neurology 
consultation). 
Consider MRI of brain and/or spine depending on 
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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
Toxicity grade 
or conditions 
(ASCO 2018) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
• Consider inpatient management as clinically 
indicated. 
Rash/ Skin reactions 
Grade 3 or 
Suspected DRESS, 
SJS or TEN   
Withhold 
• Treat with high potency topical steroids to 
affected areas 
• Treat with prednisone 
• Ensure adequate evaluation (e.g., urgent 
dermatology consultation) to confirm etiology and/or 
exclude other causes. 
 
Grade 4 or 
Confirmed DRESS, 
SJS or TEN 
Permanently discontinue 
Administer 1 to 2 mg/kg/day IV 
methylprednisolone and taper steroid when 
dermatitis is controlled 
Renal failure or nephritis 
Grade 2 with 
creatinine >1.5 to 
≤3×ULN 
. 
. Restart dosing when toxicity resolves to Grade 1. 
• Start treatment with prednisone; if persistent 
G2 beyond 1 week, 
prednisone/methylprednisone 
 
• Monitor participants for signs and symptoms, 
including monitoring of creatinine and urine protein 
every 3-7 days. 
• Ensure adequate evaluation (e.g., nephrology 
consultation) to confirm etiology and/or exclude other 
causes. 
Grade 3 or 4 with 
creatinine >3×ULN 
Permanently discontinue 
• Start treatment with prednisone; if persistent 
G2 beyond 1 week, 
prednisone/methylprednisone 
• Consider adding one of the following after 1 
week of steroids: azathioprine, cyclosporine, 
cyclophosphamide, infliximab, 
mycophenolate 
• Ensure adequate evaluation (e.g., nephrology 
consultation, renal biopsy) to confirm etiology and/or 
exclude other causes. 
• Consider inpatient care  
Hemophagocytic 
lymphohistiocytosis 
Any grade 
Permanently discontinue 
 
 
Other irARs 
Based on severity 
and type of reaction 
(Grade 2 or 3) 
Restart dosing when toxicity resolves to Grade 1 
Based on severity of AE, administer 
corticosteroids. When controlled, taper 
steroid. 
Ensure adequate evaluation to confirm etiology and 
exclude other causes 
Grade 4 or recurrent 
Grade 3 
Permanently discontinue 
 
 
Grade 1 or 2 
Withhold 

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General instructions: 
1. 
Corticosteroid taper may be initiated upon AE improving to Grade 1 or less as per investigator judgement and institutional treatment guidelines 
2. 
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 
Toxicity grade 
or conditions 
(ASCO 2018) 
Action taken 
irAE management with corticosteroid 
and/or other therapies  
Monitor and follow-up  
Recurrence of AEs after 
resolution to ≤Grade 1 
Grade 3 or 4 
Permanently discontinue 
• Based on severity of AEs, administer 
appropriate treatment until symptoms 
improve to ≤Grade 2 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; HRT=hormone replacement therapy; irAR=immune related adverse 
reaction; DRESS= Drug reaction with eosinophilia and systemic symptoms; PD-1=programmed cell death protein 1; SJS=Stevens Johnson syndrome; T1DM=Type 1 
diabetes mellitus; TEN=toxic epidermal necrolysis. 
NOTES:  
1. 
*For participants with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by ≥50% relative to baseline and lasts for at least 1 week, then the participant should be 
discontinued 
*For endocrine associated conditions, ASCO guidelines suggest consideration can be given to restarting drug in those with Grade 4 events once the condition is stabilised with hormone therapy; for study 208850, 
which only permits missing 3 doses of GSK3745417, stabilisation of a Grade 4 condition is unlikely to be achieved in the protocol defined timeframe and therefore participants with Grade 4 events should 
permanently discontinue study drug. 
 

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6.6.1. 
Management of Infusion Reactions or Severe Cytokine Release 
Syndrome (sCRS) 
Infusion reactions typically develop within 30 minutes to two hours after initiation of 
drug infusion, although symptoms may be delayed for up to 48 hours. There are multiple 
mechanisms known to lead to infusion-related reactions including both IgE-dependant 
anaphylactic and non-IgE dependent anaphylactoid hypersensitivities. Cytokine release 
syndrome, and when severe, cytokine “storm”, has been identified as a sequelae of 
immune system activation associated with infusion reactions. 
Infusion Reaction 
Infusion reactions may affect any organ system in the body. Most are mild in severity, 
although severe and fatal reactions can occur. As a group, infusion reactions (including 
both cytokine mediated and allergic) usually occur during or within a few hours of drug 
infusion. Occasionally, a reaction may occur one to two days after administration. The 
NCI-CTCAE (version 5.0) [NCI, 2017] for grading adverse reactions during the infusion 
of a pharmacological or biological substance has a term for grading the severity of 
infusion reactions and separate terms for grading allergic reactions, anaphylaxis, and 
cytokine release syndrome. The use of these separate terms in grading severity of the 
event may be useful for classifying the nature of an infusion reaction for research 
purposes; they are less useful for clinical care, since it may not be obvious if the 
participant is having an allergic infusion reaction or a non-allergic infusion reaction. 
Clinically, infusion reactions may present with fever, chills, flushing, itching, urticaria, 
and/or angioedema, repetitive cough, sudden nasal congestion, shortness of breath, chest 
tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality, 
faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss 
of consciousness, nausea, vomiting, abdominal cramping, and/or diarrhea, sense of 
impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, and pelvic 
pain. 
Cytokine Release Syndrome 
Table 17 provides the recommended management of CRS according to grade, which has 
been further adapted from CTCAE for use with immunotherapy and should be 
implemented in accordance with institutional guidelines. Symptoms can mimic those 
seen with infection. The diagnosis of CRS is clinical and is supported by the exclusion of 
infection as well as the presence of increased cytokine levels and other biomarkers. 
Assessment and treatment guidelines are provided below in alignment with (the Society 
for Immunotherapy of Cancer SITC) guidelines [Maus, 2020]. 
If CRS is suspected, in addition to assessment for infection, the following tests should be 
conducted every day for the first week and approximately every other day thereafter until 
symptoms are improving or an alternative diagnosis is confirmed: 
- 
Local tests: 

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o Clinical chemistry including LFTs, hematology, ferritin, tryptase and 
coagulation, as well as C-reactive protein (CRP) labs; 
o In addition, troponin, and N-terminal pro B-type natriuretic peptide (NT-
proBNP) / BNP tests should be monitored for participants with CRS grade 
≥2 as clinically indicated; 
- 
Central tests:  
o Central testing of samples will no longer be conducted.When CRS is 
suspected, obtain blood for the following tests: See Table 16 below for 
local testing: 
Table 16 
Biomarker Panel 
Note: With this amendment, samples for cytokines/chemokines and PK will no 
longer be taken at the time of CRS event 
Biomarker 
Relationship to Adverse Event 
Serum tryptasea 
IgE-related infusion reaction 
(Allergic/anaphylaxis) [Schwartz, 2006] 
Serum ferritina 
Elevated in CRS [Lee, 2019] 
Serum cytokine/chemokine panelb 
(IFNγ*, TNFα*, IL-2*, IL-4, IL-6*, IL-8, IL-10*, IL-12p70, 
IL-13, IL-1*, IP-10, MCP-1, MIP-1, MIP-1, IFNβ  
*Reported to be elevated in CRS [Lee, 2019] 
GSK3745417 plasma PKc 
To be determined 
Abbreviations: CRS= Cytokine Release Syndrome; IFN = Interferon gamma; TNF = Tumor necrosis factor alpha; 
IgE: immunoglobulin E; IL = Interleukin 
a. 
Performed by investigator designated local laboratory if available; otherwise performed by GSK designated 
laboratory 
b. 
With this Amendment, samples for central testing of cytokines and chemokines will no longer be collected. 
c. 
With this Amendment, a sample for central testing of plasma PK will no longer be collected.. 
 
Assessment and management of neurological signs and symptoms associated with CRS 
should include consideration of concurrent occurrence of Immune-effector cell-associated 
neurotoxicity syndrome (ICANS). See Section 6.6.1.2 for further details. 
Table 17 
Management Guidelines for Cytokine Release Syndrome 
Grade 
Clinical Presentation for Grading Assessment1,2 
Management Guidelines 
1 
Temperature ≥38.0 °C 
Vigilant supportive care4 
Assess for infection and treat5 
2 
Temperature ≥38.0°C with hypotension not 
requiring vasopressors and/or hypoxia requiring the 
use of oxygen delivered by low-flow nasal cannula 
(≤6 L/minute) or blow-by. 
Monitor cardiac and other organ function 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid  
Administer O2 for hypoxia6 
Consider administering tocilizumab ± 
corticosteroids7  
3 
Temperature ≥38.0°C with hypotension requiring a 
vasopressor with or without vasopressin and/or 
hypoxia requiring high-flow nasal cannula 
Monitor participant very closely for cardiac and 
other organ dysfunction. Most likely will require 
monitoring in an intensive care unit (ICU). 
Vigilant supportive care4 

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Grade 
Clinical Presentation for Grading Assessment1,2 
Management Guidelines 
(>6 L/minute), facemask, non-rebreather mask, or 
venturi mask not attributable to any other cause3 
Assess for infection and treat5 
Treat hypotension with fluid and pressors6. 
Administer O2 for hypoxia. 
Administer tocilizumab ± corticosteroids7 
4 
Temperature ≥38.0°C with hypotension requiring 
multiple vasopressors (excluding vasopressin) 
and/or hypoxia requiring positive pressure (e.g.: 
CPAP, BiPAP, intubation and mechanical 
ventilation)8 
Manage participant in ICU 
Intensive supportive care including mechanical 
ventilation, fluids, pressors, antibiotics and 
other measures as required6 
Administer tocilizumab ± corticosteroids7 
5 
Death9 
 
 
1. Fever is defined as temperature 38°C not attributable to any other cause. The constitutional symptoms of CRS, 
such as myalgia, arthralgia, and malaise, are by themselves nonspecific; however, when coincident with fever in 
the expected timeframe, the etiology of CRS is more likely. In patients who have CRS then receive antipyretic or 
anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS 
severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2. CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
3. Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
4. Supportive care includes monitor fluid balance, maintain adequate hydration and blood pressure  
5. Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever and 
neutropenia as per institutional practice; and antipyretics, analgesics as needed.  
6. Given that prolonged fluid resuscitation without pressor use is associated with worse outcome and because early 
and aggressive supportive care, early use of vasopressors, and timely anti-cytokine therapy are paramount to 
mitigating life-threatening CRS. 
7. Other immunosuppressor agents may be used, including TNFα and IL-1R inhibitors.  
8. Intubation of a patient without hypoxia for the possible neurologic compromise of a patent airway alone or for a 
procedure is not, by definition, grade 4 CRS. By extension, a patient experiencing seizures in which a 
compromised airway affects oxygenation and intubation reverses such deficits is not considered to have grade 4 
CRS, because the seizure rather than CRS is the cause of the hypoxia. Furthermore, a patient who remains 
intubated for a neurologic cause is not considered to have CRS when the other signs of CRS have resolved. 
9. Grade 5 CRS is defined as death due to CRS in which another cause is not the principle factor leading to this 
outcome. 
Source: Lee, 2019 
 
In the event of an infusion reaction following administration of dostarlimab, the 
subsequent doses of dostarlimab should be delayed for 6 to 24 hours 
 
 
Dose reduction for CRS 
In the event of Grade 2 CRS outside the DLT period, further dosing can be given with 
prophylaxis against CRS with steroids, paracetamol/acetaminophen and antihistamines 
(as agreed between investigator and MM). Patients with more than one episode of 
Grade 2 CRS within the same cycle despite prophylaxis should be dose reduced to the 
next dose level down once dosing resumes. Participants will come off study if more than 
2 dose reductions required, or if they require dose reduction below the lowest study dose 
of 0.1 mg. 
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Table 18 
GSK3745417  Dostarlimab Infusion Reaction Dose Modification and 
Treatment Guidelines 
NCI CTCAE Gradea 
Treatmentb 
Premedication at 
Subsequent Dosing 
(Dostarlimab Only) 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hr 
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
 
 
 
 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 
intervention. 
Participant may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of dostarlimab 
with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic).c  
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
a. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
b. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
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c. 
Administration should be omitted if previously administered as per prophylaxis for GSK3745417 (Appendix 13). 
6.6.1.1. 
Cardiac Monitoring and Dose Modification Guidelines  
In study 208850 examining GSK3745417 in participants with advanced solid organ 
tumours, one case of immune-mediated perimyocarditis has been observed, with a likely 
causal relationship to GSK3745417. On-study monitoring of troponins and cardiac 
function (using ECHO or MUGA) is required.  
BNP (or NTproBNP) should be measured at screening and then on study as clinically 
indicated.  
Troponin should be measured at baseline and then every 3 weeks on study as per the 
revised SoA (Section 1.2.1). As of this Amendment, Troponin testing at a central 
laboratory will no longer be required. A troponin sample will continue to be assessed at a 
local laboratory for purposes of subject management. Whenever possible, troponin I will 
be assayed by the local laboratory. However, the same local laboratory test (troponin I or 
troponin T) should be used consistently for an individual subject throughout the study.  
Participants should receive a screening ECHO which should be a 3D ECHO if available. 
If not, a 2D ECHO should be used, and MUGA may be used where ECHO is considered 
sub-optimal e.g. large body habitus. The same modality should then be used throughout 
the study to enable comparison to baseline and be evaluated by the same reader at study 
centre.  
All ECHO/MUGA data will be transferred and reviewed centrally by an independent 
cardiologist.  
GSK3745417 should be withheld, and participant referred for cardiology consult if: 
• 
Troponin is elevated ≥2x ULN 
• 
patient experiences symptoms consistent with pericarditis or myocarditis 
• 
ECHO - on-study decrease in left ventricular ejection fraction ≥ 10% AND falling 
below the LLN, OR 
• 
Absolute decrease in left ventricular ejection fraction ≥ 15%, even if LVEF remains 
in the normal range for the institution 
Elevation of troponin ≥2x ULN without symptoms requires withholding GSK3745417 
while awaiting repeat troponin value. A repeat troponin ≥2x ULN requires withholding 
GSK3745417 and awaiting cardiology consult. It is likely that additional cardiac imaging 
will be required to fully determine the nature of the event; the cardiology consult should 
guide the choice of imaging. In participants with asymptomatic troponin elevations, 
GSK417 may be restarted in discussion with Medical monitor, depending on benefit / 
risk. 
Participants with suspected myocarditis should be diagnosed and managed in line with 
institutional guidelines and cardiology advice. For a detailed review of diagnosis and 
management of myocarditis, and to guide treatment principles, the ASCO guidelines 

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(Schneider, 2021) and a recent review of myocarditis in patients treated with checkpoint 
inhibitors (Palaskas, 2020) may be used, which include treatment principles around use of 
high dose steroids with a slow, monitored taper.  
6.6.1.2. 
Neurological Adverse Events on Study 
Neurological DLTs (including severe headache, confusion, and hallucinations) 
considered possibly related to cytokine release as a result of study drug have been 
observed in the FTIH solid tumor Study 208850. Given that GSK3745417 is an immune-
stimulatory agent, there may be potential for Immune Effector Cell-Associated 
Neurotoxicity Syndrome (ICANS). Although ICANS has not been observed in the 
development programme to date, all participants should have baseline brain imaging and 
full neurological assessment prior to starting study. Baseline assessment should also 
include use of the ICE-Encephalopathy Assessment Tool for Grading of ICANS (see 
below). In the event of mental state changes on study, or any new neurological symptoms 
potentially consistent with ICANS, additional regular testing with the ICE-
encephalopathy assessment tool should be used based in investigator judgement and 
institutional guidelines. A specialist neurology consult (and further neurological imaging) 
should also be obtained in the event of new neurological symptoms or mental state 
changes on study  
ICANS is a disorder characterized by a pathologic process involving the central nervous 
system following any immune therapy that results in the activation or engagement of 
endogenous or infused T-cells and/or other immune effector cells. Symptoms or signs of 
ICANS can be progressive and may include aphasia, altered level of consciousness, 
impairment of cognitive skills, motor weakness, seizures, and cerebral edema. However, 
ICANS-like symptoms in cancer patients may be due to other causes ranging from mild 
to moderate somnolence and confusion as a result of sedating medications, to seizures in 
relation to CNS tumors. The possible contribution of other medications, underlying 
disease and/or co-morbidities should be evaluated when considering a diagnosis of 
ICANS. A neurological consult and appropriate imaging should be considered in order to 
exclude other causes.  
6.6.1.3. 
Grading of ICANS 
Lee et al. [Lee, 2019] have developed a new grading system for ICANS which 
incorporates the use of a modified version of the CARTOX 10-point neurological 
assessment tool termed Immune Effector Cell-Associated Encephalopathy (ICE) (Table 
19). Points are assigned for each of the tasks in Table 19, which are performed correctly. 
Normal cognitive function is defined by an overall score of 10. The ICE should be used 
to monitor all participants for ICANS. 
Table 19 
ICE-Encephalopathy Assessment Tool for Grading of ICANS 
Task 
ICE Points 
Orientation to: year, month, city, hospital 
Total of 4 points (one point for each) 
Name three objects, for example point to: clock, 
pen, button 
Total of 3 points (one point for each) 

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Task 
ICE Points 
Follow simple commands (for example, “Show me 2 
fingers” or “Close your eyes and stick out your 
tongue” 
1 point 
Write a standard sentence, e.g. ‘our national bird is 
the bald eagle’ 
1 point 
Count backwards from 100 in tens 
1 point 
Abbreviation: ICE = Immune Effector Cell-Associated Encephalopathy; ICANS= Immune Effector Cell-Associated 
Neurotoxicity Syndrome. 
Scoring: 10, no impairment; 7-9; grade 1 ICANS; 3-6, grade 2 ICANS; 0-2, grade 3 ICANS; 0 due to patient 
unarousable and unable to perform ICE assessment, grade 4 ICANS 
 
The ICE score is used in grading of ICANS in adults as presented in Table 20.   
Table 20 
Grading of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS)  
Neurotoxicity 
Domain  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score1 
7 to 9  
3 to 6  
0 to 2  
0 (Participant is unarousable and 
unable to perform ICE) 
Depressed level of 
consiousness2 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Patient is unarousable or requires 
vigorous or repetitive 
tactile stimuli to arouse. Stupor or 
coma 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging4 
Diffuse cerebral edema on 
neuroimaging; decerebrate 
or decorticate posturing; or cranial 
nerve VI palsy; or papilledema3; 
or Cushing's triad 
Motor findings5 
N/A 
N/A 
N/A 
Deep focal motor weakness such 
as hemiparesis or 
paraparesis 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly 
or 
nonconvulsive 
seizures on EEG 
that resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or electrical 
seizures without 
return to Baseline in between 
Abbreviations:  ICANS= Immune Effector Cell-Associated Neurotoxicity Syndrome; ICE = Immune Effector Cell-
Associated Encephalopathy; CSF = cerebrospinal fluid; ICP = Intracranial Pressure; N/A = not applicable. 
1. See Table 19 for ICE. A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global 
aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
2. Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medication) 
3. Papilloedema grading is performed according to the modified Frisén scale. 
4. Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is 
excluded from ICANS grading.  
5. Tremors and myoclonus associated with immune effector cell therapies do not influence ICANS grading 
This table is based on Lee, 2019. 
 
 

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6.6.1.4. 
Monitoring for Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) 
The ICE score must be obtained at baseline prior to dosing with GSK3745417, and then 
on study as clinically indicated in patients experiencing new neurological symptoms or 
mental state changes.  
6.6.1.5. 
Management of ICANS 
A neurology consultation should be obtained for all participants with ICANS for 
thorough neurological evaluation, and recommendations for further testing such as 
electroencephalogram (EEG) and neuroimaging as indicated.  
The following tests should be conducted every day for the first week and approximately 
every other day thereafter until symptoms are improving or an alternative diagnosis is 
confirmed: 
- 
Local tests: 
o chemistry, hematology, ferritin and coagulation, as well as C-reactive 
protein (CRP) labs. 
Grade 1 ICANS is primarily managed with supportive care. Across several trials, 
tocilizumab has failed to resolve symptoms of ICANS, despite alleviating severe CRS 
(Maus, 2020). It remains to be determined whether targeting IL-6R in isolation during 
established CRS is insufficient to prevent subsequent neurotoxicity or if the lack of 
efficacy is due to tocilizumab’s inability to cross the blood–brain barrier. It has been 
postulated that tocilizumab may worsen ICANS and therefore an assessment of treatment 
priority may be required between the severity of CRS and ICANS. Alternative IL-6 
blockade such as siltuximab or the IL-1 antagonist, anakinra, have been proposed as 
potential alternatives, but data are lacking on their safety and efficacy. 
Corticosteroids have been successfully used for the management of ICANS and seizure 
prophylaxis has been implemented in some studies, but the ideal dose and duration have 
not yet been determined (Maus, 2020).  
In the event of ICANS, Investigators should follow institutional guidelines for symptom 
management, or refer to the SITC guidelines (Maus, 2020). Additional guidance on 
assessment and grading of ICANS can also be found in Lee 2019, (Lee, 2019). 

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6.6.2. 
Management of Renal Events 
Table 21 
Guidelines for Dose Modification and Management of Renal Events 
Adverse Event 
Management 
Serum Creatinine Increase 
by >0.3 mg/dL or 26.5 
mol/L Compared to 
Baseline 
• 
Hold Study Treatment 
• 
Repeat serum creatinine levels every 24 hours 
• 
Perform diagnostics to identify root cause 
• 
Discuss with Sponsor/Medical Monitor 
• 
If serum creatinine returns to baseline level within one week, or 
cause found not attributable to study intervention, resume study 
treatment 
• 
If serum creatinine remains elevated more than one week without a 
known cause, permanently discontinue treatment 
• 
Nephrology consultation is highly recommended 
Abnormal urinalysis 
findings, including 
hematuria 
• 
Perform diagnostics to identify root cause 
• 
Nephrology consultation is highly recommended if cause is not 
known 
 
6.6.3. 
Management of Thrombophlebitis 
 
 
  
6.7. Dose Delay 
.  
During the GSK3745417 
 (monotherapy or combination), if 
there is a dose delay between 1 and 3 days, the procedures at the original scheduled visit 
(including dosing) should be performed as soon as possible. If the delay is >3 days, the 
visit and dose(s) will be considered missed.   
During the GSK3745417 
 dosing schedules (monotherapy or combination), if there 
is a dose delay between 1 and 7 days, the procedures at the original scheduled visit 
(including dosing) should be performed as soon as possible. If the delay is >7 days, the 
visit and dose(s) will be considered missed.  
During all the dosing schedules, subsequent doses should be administered at least 5 days 
apart. 
Dosing delays or omissions are permitted in the case of medical/surgical events or for 
logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical 
events, participant vacation, and/or holidays, but not for participants’ decision to delay or 
omit treatment). If a dose (visit) is missed, participant should wait for the next scheduled 
dose to resume treatment. In individual cases, where in the judgement of an investigator 
waiting a full cycle to resume treatment after delay (skipping dose) related to toxicity 
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which has resolved would be detrimental to patient’s health, the PI should contact 
Medical Monitor to discuss an earlier re-start. 
The reason for any dose delay must be documented in the participant's eCRF and clinic 
record. 
Participants with infusion delays equivalent to 3 consecutive missed doses should 
discontinue study treatment(s) unless the treating investigator and sponsor agree there is 
strong evidence supporting continued treatment. 
6.8. Continued Access to Study Intervention after the End of the 
Study 
 
Study participants who continue to benefit from study intervention beyond the data cut-
off date will continue to have access to study intervention until the EOS as defined in 
Section 4.3 and Section 4.6. There is no planned intervention following the EOS. The 
investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition. 
New therapy should be documented on the CRF (if applicable). Every effort should be 
made to complete the required discontinuation of study treatment and follow up 
evaluations prior to initiating further therapy or dosing of an investigational agent  
6.8.1. 
Continued Access to Study Intervention After Data Cut-off prior 
to EOS 
Participants receiving study treatment at the time of the final analysis data cut-off date 
may continue to receive GSK3745417 and/or dostarlimab, if in the opinion of their 
treating physician, they are benefiting from continued treatment, and they do not meet 
any protocol-defined treatment discontinuation criteria (see Section 7.1). Study treatment 
will continue until a study treatment discontinuation criterion (see Section 7.1), as 
assessed by the investigator, has been met.  
Participants who continue study treatment in the PACT phase will be cared for in 
accordance with local standard clinical practice. Additional guidance on treatment with 
the study drug and participant management is provided in the SRM. Participants will 
continue to be monitored for all SAEs, AEs leading to treatment discontinuation, 
overdoses, and pregnancy cases while receiving study treatment. Information relating to 
participant care will be recorded on participant medical records, with the exception of 
SAEs, AEs leading to treatment discontinuation, overdoses and pregnancy cases that 
must continue to be reported to GSK. Investigators must report all SAEs, AEs leading to 
treatment discontinuation, overdose and pregnancy cases until 90 days after the 
participant’s last dose of study treatment in accordance with Section 11.3.5 (Reporting of 
Serious Adverse Events). Post final analysis data cut-off date, reporting and follow up of 
SAEs, overdose and pregnancy cases will be done via paper forms (see SRM for details). 
For dispensing of study treatment and maintaining study drug accountability in the PACT 

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phase please refer to the SRM. All other assessments will revert to standard of care at 
their site. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Participants will receive study intervention for the scheduled time period, unless 1 of the 
following occurs earlier: disease progression (as determined by iRECIST), death, 
unacceptable toxicity or stopping criteria are met. 
7.1. Discontinuation of Study Intervention 
In addition to the above, study intervention might be permanently discontinued for any of 
the following reasons: 
• Deviation(s) from the protocol 
• Withdrawal of consent by participant or proxy 
• Discretion of the investigator  
• Participant loss to follow-up by the investigative site 
• Closure or termination of the study  
• Criteria described in Section 6.7 (Dose Delay) 
• Female participant who becomes pregnant while on study treatment 
• Criteria for discontinuation of study treatment(s) as described in Section 6.6 
(Dose Modification Guidelines) have been met 
• Criteria described in Section 7.1.2 (QTcF Stopping Criteria) have been met 
• Criteria described in Section 7.1.3 (Stopping Rules for Clinical Deterioration) 
have been met 
Note: Participants enrolled in Part 2A combination therapy of GSK3745417 with 
dostarlimab who require permanent discontinuation of one of the study 
interventions due to toxicity in a given treatment combination must permanently 
discontinue both interventions (unless continued treatment with the remaining 
agent is agreed upon by the treating investigator and Sponsor/Medical Monitor) 
in that combination and the reason for discontinuation must be recorded. The 
TDV should be conducted within 30 days of the last dose of study treatment(s). 
The primary reason for discontinuation must be documented in the participant’s medical 
records and eCRF. If the participant voluntarily discontinues from treatment due to 
toxicity, ‘AE’ will be recorded as the primary reason for permanent discontinuation on 
the eCRF.  
Participants discontinuing from GSK3745417 monotherapy due to confirmed radiological 
disease progression will be allowed to transition to GSK3745417 combination with 
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The assessments required at the TDV should be completed within 30 days of the last dose 
of study intervention(s). 
All participants who discontinue from study treatment will undergo safety assessments at 
the time of discontinuation and during post-study treatment follow-up as specified in the 
SoA (Section 1.2.1). Participants will be followed up for safety until 90 days after last 
dose, until start of subsequent anticancer therapy or until death, whichever comes first. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
• 
Discontinuation of study intervention for abnormal liver tests is required when a 
participant meets one of the conditions outlined in Figure 2.  
OR 
• 
In the presence of abnormal liver chemistry not meeting protocol-specified stopping 
rules, if the Investigator believes that it is in the best interest of the participant. 
 
Participants with HCC and positive for HBV: Participants with ALT elevations ≥1.5x 
baseline, or an increase in ALT deemed clinically significant by the investigator, should 
have additional HBsAg and HBV DNA tests performed as clinically indicated to exclude 
a viral flare. These Participants should also have liver imaging to determine whether an 
increase in tumor size, or increase in liver metastases if present, may be contributing to 
the ALT elevation. 

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Figure 2 
Liver Stopping and Monitoring Event Algorithm 
 
 
Refer to Appendix 6 for required Liver Safety Actions and Follow up Assessments. 
7.1.1.1. 
Study Intervention Restart or Rechallenge after Liver Stopping Criteria 
Met 
If participant meets liver chemistry stopping criteria, do not restart/rechallenge 
participant with study intervention unless all of the following occurs:  
• GSK Medical Governance approval is granted 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for intervention restart/rechallenge is signed by the participant 
Note: If study treatment was interrupted for suspected drug-induced liver injury, the 
participant should be informed of the risk of death, liver transplantation, 
hospitalization, and jaundice and re-consented before resumption of dosing. 
Refer to Appendix 6 for details on the restart/rechallenge process.  
Continue Study Treatment 
Discontinue Study Treatment 
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5*
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5*
Possible
Hy’s Law
ALT≥3xULN
Both
ALT≥5xULN 
and ≥2X 
baseline 
value
Both 
ALT≥3xULN 
and ≥1.5X 
baseline value  
Plus
Symptoms of 
liver injury or 
hypersensitivity
Both
ALT≥3xULN 
and ≥1.5X 
baseline 
value but 
able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
Both
ALT≥3xULN
and ≥1.5X 
baseline value 
persist for
4 weeks or 
other stopping 
criteria met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
➢If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix

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If GSK Medical Governance approval to restart/rechallenge participant with study 
intervention is not granted, then participant must permanently discontinue study 
intervention and may continue in the study for protocol-specified follow up assessments. 
7.1.2. 
QTc Stopping Criteria 
The QTcF correction formula must be used for each individual participant to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the participant has been enrolled. If an ECG demonstrates a prolonged 
QTcF interval, then obtain 2 more ECGs over a brief period of time and then use the 
averaged QTcF values of the 3 ECGs to determine whether the participant should be 
discontinued from the study. 
If a participant meets either of the following criteria, they must be discontinued from 
study treatment.   
• QTcF >500 msec 
OR 
• Change from baseline of QTcF >60 msec 
For participants with underlying bundle branch block, proceed with the following 
discontinuation criteria: 
Baseline QTcF with Bundle Branch Block 
Discontinuation QTcF with Bundle Branch Block 
<450 msec 
500 msec 
450 – 480 msec 
530 msec 
QTcF = QT duration corrected for heart rate by Fridericia’s formula 
 
See the SoA (Section 1.2.1) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. 
7.1.3. 
Stopping Rules for Clinical Deterioration 
As indicated in Appendix 9, in order to adequately assess the antitumor effect of 
immunotherapeutic agents, participants experiencing apparent progression as defined by 
RECIST version 1.1 guidelines may continue to receive treatment until progression is 
confirmed at a subsequent imaging assessment at least 4 weeks later as indicated by 
iRECIST guidelines. These considerations should be balanced by clinical judgment as to 
whether the participant is clinically deteriorating and unlikely to receive benefit from 
continued study treatment. The following parameters should be considered by the 
Investigator prior to treating participants beyond confirmed progression as defined by 
iRECIST: 
• Disease progression is not rapid as assessed by the Investigator 
• Participant continues to meet all eligibility criteria as assessed by the Investigator 
• Participant is tolerating study intervention 
• Participant has stable performance status (ECOG PS 0-1) 

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• Treatment beyond progression will not delay an imminent intervention to prevent 
serious complications of disease progression (e.g. CNS metastases) 
• Participant has provided written informed consent prior to receiving additional 
study drug. 
In cases where deterioration was assessed in the investigator’s opinion to have occurred 
after a clinical event and is attributable to disease progression, is unlikely to reverse with 
continued study treatment or managed by supportive care (e.g., bisphosphonates and/or 
bone directed radiotherapy, thoracentesis, or paracentesis for accumulating effusions), 
study treatment should be discontinued. The decision to stop treatment should be 
discussed with the Sponsor’s Medical Monitor. Examples of events that may, in the 
investigator’s opinion, indicate a lack of clinical benefit and should result in the 
discontinuation of study drug include, but are not limited to, the following at the time of 
progression: 
• ECOG PS decrease of at least 2 points from baseline, or a decrease considered 
clinically significant 
• Clinically relevant worsening of laboratory values 
• Skeletal related events defined by the following: 
• pathologic bone fracture in the region of cancer involvement 
• cancer related surgery to bone, and/or 
• spinal cord or nerve root compression 
• Rapid progression of disease at critical anatomical sites requiring urgent medical 
intervention 
• Development of new CNS metastases 
• Any setting where the initiation of new antineoplastic therapy has been deemed 
beneficial to the participant even in the absence of any such documented clinical 
event. 
7.2. Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request 
(withdrawal of consent) or may be withdrawn at any time at the discretion of the 
investigator for safety, behavioral, compliance or administrative reasons. 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA (Section 1.2.1) for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
If a 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. 

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If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record. 
• 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. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.2). Under this 
amendment, study procedures and their timing are summarised in SoAs in Section 1.2.1.  
Protocol waivers or exemptions are not allowed.  
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the time frame defined in the SoA. 

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If assessments are scheduled for the same nominal time, it is recommended that the 
assessments should occur in the following order: 12-lead ECG, vital signs, and blood 
draws. The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.   
The timing and number of planned study assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the following assessments: 
safety, PK, pharmacodynamics/biomarker, or other assessments.   
The change in timing or addition of time points for any planned study assessments must 
be approved by the relevant GSK study team member and then archived in the study 
Sponsor and site study files, but this will not constitute a protocol amendment.   
The IRB/ IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form.   
 
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the SoAs (Section 1.2).   
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8.1.2. 
Tumor Growth Kinetics 
8.2. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1. 
Physical Examinations 
A complete physical examination will be done at screening and TDV and will include 
assessments of the CV, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded. 
A brief physical examination will be done at all other time points and will include 
assessments of the skin, lungs, CV system, and abdomen (liver and spleen).  
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
For melanoma participants, a full body dermatological examination will be performed by 
a dermatologist (or suitably qualified physician) to identify abnormal skin lesions within 
the 28-day screening period. All findings will be photographed and identified during 
screening. Brief skin examinations will be performed as indicated in the SoA 
(Section 1.2.1) or more frequently as necessitated. Wherever possible, the same physician 
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should perform these examinations. Follow-up skin examinations by a referral 
dermatologist should be conducted if clinically indicated by the ECOG PS.   
The PS will be assessed using the ECOG scale (Section 11.10) as specified in the SoA 
(Section 1.2.1). 
8.2.2. 
Vital Signs 
Vital sign measurements to be measured in semi-supine position after 5 minutes rest will 
include temperature, systolic and diastolic blood pressure, and heart rate. For study 
participants in Japan only, pulse oximetry for oxygen saturation will also be conducted as 
part of vitals as outlined in Table 5.  
Vital signs will be measured more frequently on dosing days of GSK3745417 and 
dostarlimab. See Section 1.2.1 for details. 
If a participant develops a fever, refer to Section 6.6 for fever management guidelines. 
8.2.3. 
Electrocardiograms 
Twelve-lead ECGs will be obtained at each planned ECG assessment during the study 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals. Refer to Section 7.1.2 for QTcF stopping criteria and 
additional QTcF readings that may be necessary.   
Before each ECG test, the participant should be at rest for approximately 10 minutes. The 
participant should be in the semi-recumbent or supine position; the same position must be 
used for all subsequent ECG tests. 
ECG measurements will be performed in triplicate at Screening (all within a 5-minute 
time period), then as single ECG measurements. If QTc interval prolongation is observed 
during the study, triplicate ECG measurements will be performed. 
8.2.4. 
Holter Monitoring for QT Assessment 
Digital Holter ECG data will be obtained from 12-lead continuous Holter monitoring 
device supplied by the sponsor. ECG acquisition via the Holter monitoring device will be 
performed at planned time points indicated in the SoA (Section 1.2). Holter monitoring 
may be waived for individual participants upon approval from GSK. 
Holter monitoring will not be conducted in participants in the combination dose 
escalation (Part 2A). 
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and may be manually over-read by an external central 
validated ECG laboratory. 
Refer to the Study Reference Manual (SRM) for details regarding Holter monitoring 
procedures. 

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8.2.5. 
Neurological Assessments 
In the event of neurological symptoms and/or signs, treating physician may consider 
serial neurological examinations (i.e., Immune Effector Cell-Associated Encephalopathy 
[ICE]), neurological consultation and appropriate imaging. These are described in more 
detail in Section 6.6.1.2. 
All participants who experience neurological AEs will be graded according to CTCAE 
(version 5.0); any participants with ICANs will be graded according to the grading 
system described in Section 6.6.1.3.  
8.2.6. 
Follow-Up Phone Call 
After the first 6 doses of study intervention (monotherapy and combination), participants 
should be contacted between 24 hours and 72 hours following discharge from the 
clinic/hospital. The purpose of this phone-call is to assess for any AEs or cytokine related 
symptoms. 
8.2.7. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA Section 1.2.1 and Appendix 15 for the timing and frequency.  
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
significantly abnormal by the investigator or medical monitor.  
If such values do not return to normal/baseline within a period of time judged reasonable 
by the investigator, the etiology should be identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA Section 1.2.1.  
8.2.8. 
Chest Imaging (Japan cohort Only) 
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8.3. Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. All toxicities will be 
graded using National Cancer Institute - Common Toxicity Criteria for AEs (NCI-
CTCAE), version 5.0 and as outlined in Section 4.1.2. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see 
Section 4.3).  
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All SAEs that are deemed related to study participation will be collected from the time of 
consent until the time points specified in the SoA (Section 1.2.1). Therefore, any SAEs 
assessed as related to study participation (including protocol-mandated procedures, 
invasive tests, or change in existing therapy) as well as those related to study drugs will 
be recorded from the time a participant consents to participate in the study. 
AEs will be assessed and documented at each visit from first dose until the TDV. AESIs 
and SAEs will be collected until 90 days after the last dose or until start of subsequent 
anticancer treatment, whichever comes first (Section 1.2.1).  
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion of the 
study participation. However, if the investigator learns of any SAE or death, at any time 
after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator 
must promptly notify the sponsor. 
For participants in the PACT phase of the study, GSK will continue to collect safety 
information including SAEs, AEs leading to treatment discontinuation, overdose and 
pregnancy cases via paper forms which will be reported directly to GSK. SAEs, AEs 
leading to treatment discontinuation, overdose and pregnancy cases will be reported 
during the PACT treatment period and for up to 90 days after last dose. Additionally, any 
SAEs that are ongoing at the time of the final data cut-off must be followed up to 
resolution unless the event is considered by the investigator unlikely to resolve, or the 
participant is lost to follow-up. Updates to these events will also occur via paper forms 
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directly to GSK. GSK retains the right to request additional information for any 
participant with ongoing AE(s)/SAE(s) at EOS, if judged necessary.  
 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Appendix 3), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 150 days following the last dose of study intervention. 
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
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Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered an SAE. 
8.3.6. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.   
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.  
8.3.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. 
Death due to disease under study is to be recorded on the death eCRF form. 
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the participant, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol 
design/procedures and the disease progression, then this must be reported as a SAE. 
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as a SAE (instead of a disease-related event): 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or 
• 
The investigator considers that there is a reasonable possibility that the event 
was related to treatment with study treatment(s). 
8.3.8. 
Guidelines for Events of Special Interest 
The severity of AEs will be graded utilizing the NCI-CTCAE, version 5.0. Guidelines for 
dose modifications and interruptions for management of common toxicities associated 
with the study treatment(s) are provided in Section 6.6. 
Please also refer to Appendix 11 for AEs of Special Interest. 

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8.4. Treatment of Overdose 
For this study, any dose of GSK3745417 greater than 50% within a 24-hour time period 
will be considered an overdose. 
There is no specific antidote for overdose with GSK3745417. In the event of a suspected 
overdose, it is recommended that the appropriate supportive clinical care should be 
instituted, as dictated by the participant’s clinical status.  
An overdose of dostarlimab is defined as any dose that is ≥20% than 1000 mg Q6W.  
In the event of an overdose, the investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the participant for AE/SAE and laboratory abnormalities until 
study intervention can no longer be detected systemically (at least 48 hours). 
• Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF. 
• Obtain a blood sample for PK analysis as soon as possible following the study 
intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
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. 
8.5. Pharmacokinetics – Blood and Urine 
Blood samples for PK analysis of GSK3745417, dostarlimab and ADA will be collected 
at the time points described in the SoA (Section 1.2). The actual date and time of each 
blood sample collection will be recorded in the eCRF. The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring. Details on PK blood sample collection, processing, storage, and shipping 
procedures are provided in the SRM. Plasma samples may be analyzed for other 
compound-related metabolites and the results reported under a separate DMPK, 
GlaxoSmithKline protocol. ADAs will be analyzed in a tiered approach using 
electrochemiluminescence (i.e., screening, confirmation, titer, and neutralizing antibody 
assay), if appropriate. 
Collection of urine 
 should enable a quantitative 
assessment of parent drug GSK3745417 and qualitative or quantitative assessment of 
drug metabolites in this matrix. Metabolite-related results may be reported under a 
separate DMPK, GlaxoSmithKline protocol. The pre-dose collection will be a single 
voiding. For post-dose collection intervals, the actual start and stop time and date for each 
urine sample collection interval will be recorded. The volume pre-dose and during each 
collection intervals will also be recorded. The timing of the urine samples may be altered 
and/or urine samples may be obtained at additional time points to ensure thorough urine 
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PK monitoring. Details on PK urine sample collection, processing, storage, and shipping 
procedures are provided in the SRM. 
PK, ADA and urine sample collection may be terminated when sufficient data have been 
collected. 
8.6. Anti-Drug Antibodies 
Serum samples will be collected for the presence of antibodies that bind to dostarlimab. 
See Section 1.2.1 for the timing of sample collection. The actual date and time of each 
blood sample collection will be recorded in the eCRF. The timing of immunogenicity 
samples may be altered and/or may be obtained at additional time points to ensure 
thorough immunogenicity monitoring. The collected immunogenicity blood samples will 
be held and processed in the future, as necessary.  
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10. 
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Jensen RE, Moinpour CM, Potosky AL, et al. Responsiveness of 8 Patient-Reported 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
11.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
• Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Notify significant/major protocol deviations to the EC/IRB, as well as 
findings of internal Quality Audits and CAPA’s. 
• 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 
 
11.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 

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11.1.3. 
Informed Consent Process 
The investigator or his/her representative will explain the nature of the study including 
the risk and benefits, to the participant or his/her legally authorized representative and 
answer all questions regarding the study.  
Participants must be informed that their participation is voluntary and that they can 
withdraw their consent to participate for any reason or no reason at all.  Participants or 
their legally authorized representative must be informed that they are free to take the 
Informed Consent home to discuss participation with members of their family or personal 
medical physician. 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, the date the written consent was 
obtained, and which persons were present when the study was explained to the potential 
participant or their legally authorized representative. The authorized person obtaining the 
informed consent must also sign the ICF. 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
11.1.4. 
Data Protection 
Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant.  
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
11.1.5. 
Dissemination of Clinical Study Data 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 

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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 protocol and results summary and 
for development of a manuscript for publication for this study will be in accordance with 
GSK Policy. 
GSK intends to make anonymized patient-level data from this trial available to external 
researchers for scientific analyses or to conduct further research that can help advance 
medical science or improve patient care. This helps ensure the data provided by trial 
participants are used to maximum effect in the creation of knowledge and understanding. 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge. 
11.1.6. 
Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan. 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
The sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  

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Records and documents, including signed ICF’s, 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.  
11.1.7. 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
Definition of what constitutes source data can be found in The Monitoring Plan. 
11.1.8. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
11.1.9. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.  
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 

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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

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11.2. 
Appendix 2: Clinical Laboratory Tests 
Note: In this amendment, any tests conducted in a clinical laboratory will no 
longer be performed.  Table 26 has been updated to reflect this change and 
now details the tests which will be performed by the local laboratory 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 4.6. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator (e.g. for suspected CRS) or required by local 
regulations. 
• 
Pregnancy Testing  
• 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• 
Negative serum pregnancy test is required within 72 hours prior to date of 
first dose of GSK3745417 on Day 1 and first dose of dostarlimab on Day 8 
for females of childbearing potential; predose urine pregnancy test is required 
every 3 weeks for monotherapy arms with GSK3745417 and every 3 weeks 
for combination arms with GSK3745417 in co-administration with 
dostarlimab for the duration of the study, on the last day of treatment (if 
possible), at TDV, and at the Follow-Up visits. 

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Table 26 
Protocol-Required Safety Laboratory Assessments 
Local Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Clinical 
Chemistry1 
BUN 
Creatinine 
Glucose 
Potassium 
Sodium 
Calcium 
AST (SGOT) 
ALT (SGPT) 
Alkaline Phosphatase 
eGFR 
 
Total Protein 
Albumin 
Total and direct bilirubin 
 
Liver Function 
Test 
AST (SGOT), ALT (SGPT), Alkaline Phosphatase, Total and direct bilirubin, Total 
Protein, Albumin in HCC and underlying HBV or HCV (see Section 1.2) 
 
Thyroid 
Function 
Thyroid Stimulating Hormone, free T4, free T3 
Cardiac 
Function 
Troponin I and/or T, BNP/NTproBNP 
Routine 
Urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones by dipstick 
Microscopic examination (if blood or protein is abnormal)  
HBV monitoring 
for participants 
with HBV and 
HCC 
HBV DNA 
Coagulation 
PTT (or INR), PT/INR 
Other Screening 
Tests 
Hepatitis B (HBsAg), HBe Antigen 
Quantitative HBsAg 
Hepatitis C (Hep C antibody) 
Serum Pregnancy test (as needed for WOCBP) 
For participants positive for HBV or HCV at Screening: HBV DNA, HBsAg, and HCV 
RNA 
Hematology, C-
Reactive 
Protein, Ferritin, 
Coagulation, 
Tryptase 
To be also conducted locally if CRS is suspected (Section 6.6.1) 
Hematology 
Platelet Count 
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Other 
C-Reactive Protein 
NOTES: 
1. Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1.1 and Appendix 6. All events of ALT ≥3 × upper limit of normal 
(ULN) and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized ratio (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). 
 
 

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11.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
11.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil 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. 
 
11.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
o Results in death 
o Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils 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 at baseline (prior to 
first dose of study drug) that did not worsen from baseline is not considered an AE. 

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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. 
Is a congenital anomaly/birth defect 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, 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. 
 
11.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization (stent or CABG) 
 

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11.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the CRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page. 
• 
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 assess severity for each AE and SAE reported during the study 
and will grade it according to the NCI-CTCAE v 5.0. Other measures to evaluate AE 
and SAE may be utilized (e.g., National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE).   
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 
For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 

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important that the investigator always assess 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 may 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. 
 
11.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the Study Reference Manual. 
 

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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. 
• 
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 Study Reference Manual. 
Note: During the PACT phase, all SAEs and pregnancies will be reported via paper 
CRFs. 
 
 

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11.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
11.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the 
participant’s medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
• 
A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement >40 IU/L or mIU/mL is required.  
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
 

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11.4.2. 
Contraception Guidance 
• 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
• 
Note: Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
• 
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
• 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure with friction) 
 

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11.4.3. 
Collection of Pregnancy Information 
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.   
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the investigator, will be reported to 
GSK as described in Appendix 3. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
Any female participant who becomes pregnant while participating will discontinue study 
intervention. 
 
 

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11.5. 
 
 
CCI
CCI

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11.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study Intervention Rechallenge 
Guidelines 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
ALT absolute 
Both ALT  5xULN and 2x baseline value 
ALT Increase 
Both ALT ≥3xULN and ≥ 1.5x baseline value that persists for ≥4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5 
Cannot Monitor 
Both ALT ≥3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 
weeks 
Symptomatic3 
Both ALT  3xULN and ≥ 1.5x baseline value associated with symptoms (new 
or worsening) believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• Immediately discontinue study treatment  
• Report the event to GSK within 24 hours 
• Complete the liver event 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 (refer to 
Appendix 6) 
• If restart/rechallenge not allowed per protocol or 
not granted, permanently discontinue study 
treatment, and may continue participant in the 
study for any protocol specified follow up 
assessments MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, and INR) and 
perform liver event follow up assessments within 
24 hr 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend 
• Blood sample for pharmacokinetic (PK) 
analysis, obtained within 48h of the last dose6 
• Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin2xULN 
• Obtain complete blood count with differential to 
assess eosinophilia 
• Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form 
• Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over 
the counter medications 
• Record alcohol use on the liver event alcohol 
intake case report form 

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• Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to within 
baseline 
• A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, and INR) and 
perform liver event follow up assessments within 
24-72 hr 
• Monitor participants weekly until liver chemistries 
resolve, stabilize, or return to within baseline 
 
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 computerized tomography) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
CRF forms 
 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, which 
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the threshold value stated will not apply to participants receiving anticoagulants 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash, or 
eosinophilia) 
4. 
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 
 
  
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. Not required for single-dose studies 
 
11.6.1. 
Study Treatment Restart or Rechallenge 
If participant meets liver chemistry stopping criteria do not restart participant with study 
treatment unless: 
• GSK Medical Governance approval is granted (as described below), 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for treatment restart/rechallenge is signed by the 
participant 
CCI

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If GSK Medical Governance approval to restart 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.  
11.6.2. 
Restart Following Transient Resolving Liver Stopping Events Not 
Related to Study Treatment 
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcoholic hepatitis. 
Approval by GSK for study treatment restart can be considered where: 
• 
Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN). 
• 
Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 11.6.2 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 
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.  

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• 
If after study treatment re-start, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 
• 
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart.  
• 
GSK to be notified of any adverse events, as per Section 11.3.  
 

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11.7. 
Appendix 7: Estimated Glomerular Filtration Rate 
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] x 0.813 [if Japanese] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
 

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11.8. 
Appendix 8: NYHA Functional Classification System for 
Heart Failure 
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994] 
provides a simple way of classifying the extent of heart failure. It places participants in 
one of four categories based on the level of limitation experienced during physical 
activity: 
Class 
Symptoms 
Class I 
(Mild) 
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath). 
Class II 
(Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea. 
Class III 
(Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea. 
Class IV 
(Severe) 
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased. 
 
 
 

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11.9. 
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 
version  
11.9.1. 
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. [Eisenhauer, 2009] 
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. [Eisenhauer, 2009] 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray. [Eisenhauer, 2009] 
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 

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11.9.2. 
Guidelines for Evaluation of Disease 
Evaluation of Anticancer 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. 
11.9.3. 
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. [Eisenhauer, 2009] 
Non-measurable lesion: 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009]. 
Measurable disease: The presence of at least 1 measurable lesion. Palpable lesions that 
are not measurable by radiologic or photographic evaluations may not be utilized as the 
only measurable lesion. 
Non-Measurable only disease: The presence of only non-measurable lesions.  
Note: non-measurable only disease is not allowed per protocol. 
11.9.4. 
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, participants should not 
be discontinued until progression is confirmed according to the rules described below. 
This allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some participants can have a transient tumor flare in the first few months 
after the start of immunotherapy, and then experience subsequent disease response. These 
data will be captured in the clinical database. 
Clinical stability is defined as meeting all of the following:  
• 
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 

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Any participant deemed clinically unstable may be discontinued from study treatment at 
site-assessed first radiologic evidence of PD. It is strongly preferred to obtain the repeat 
tumor imaging, when feasible, for confirmation of PD by iRECIST.  
In a clinically unstable participant, if the investigator decides to continue treatment, 
following consultation with the sponsor medical monitor, the participant may continue to 
receive study treatment. 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 into 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, participants will be discontinued from study treatment. 
If a participant has confirmed radiographic progression (iCPD) as defined below, study 
treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, continuation of study treatment may be considered following 
consultation with the sponsor. In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 8.1 and 
submitted to the central imaging vendor.  
Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic disease progression based on RECIST 1.1, there is no distinct 
iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
For participants who show evidence of radiological PD by RECIST 1.1 the investigator 
will decide whether to continue a participant on study treatment until repeat imaging is 
obtained (using iRECIST for participant management (see Table 27 and Figure 11). This 
decision should be based on the participant’s overall clinical condition (See discussion of 
clinical stability in Section 11.9.1).  
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 

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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 
Table 27. 
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) 

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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen. This may correspond to the next visit in the original visit 
schedule. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows 
radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, 
and the confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and 
the participant continues to be clinically stable, study treatment may continue and follow 
the regular imaging schedule. If PD is confirmed, participants will be discontinued from 
study treatment or for participants in monotherapy dose escalation and eligible, crossover 
to receive combination therapy. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, 
but the participant is achieving a clinically meaningful benefit, continuation of study 
treatment may be considered following consultation with the Sponsor. In this case, if 
study treatment is continued, tumor imaging should continue to be performed following 
the intervals as outlined in Section 3 and submitted to the central imaging vendor. 
Detection of Progression at Visits after Pseudo-Progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is 
indicated by any of the following events: 
• 
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 

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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 27 
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 while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST. 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD 
per 
investigator’s 
discretion 
only. 
Discontinue 
treatment 
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST per 
investigator 
assessment 
No additional 
imaging 
required. 
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
sponsor). 
No additional 
imaging 
required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
investigator 
assessment 
Repeat 
imaging at 4 
to 8 weeks to 
confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
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. 
May restart study 
treatment 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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11.10. 
Appendix 10: ECOG Performance Statusa 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
a. 
Oken, 1982. 
 
 
 

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11.11. 
Appendix 11: Adverse Events of Special Interest 
The list of terms and reporting requirements for AESI are provided below. These are 
selected non-serious AEs and SAEs that must be reported to the GSK medical monitor 
within 24 hours regardless of relationship to study treatment. Any event that meets the 
criteria described below must be reported regardless of investigator-determined 
relationship to study treatment or if considered immune-related (unless otherwise 
specified). Investigators/study coordinators/designated site personnel are required to 
record these experiences in the eCRF (as described in the eCRF completion guidance 
document) and to provide supplemental information (such as medical history, 
concomitant medications, investigations, etc.) about the event. 
Cytokine-related AEs 
Cardiopulmonary or hemodynamic toxicity starting within 24 hours of study treatment 
that requires >40% FiO2, vasopressor administration, antiarrhythmic agent, or other 
significant medical intervention. Asystole, as measured by ECG, or bradycardia that is 
symptomatic and requires medical intervention. 
Immune-related AEs 
Pneumonitis (reported as AESI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as AESI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as AESI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA) 
Endocrine (reported as AESI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as AESI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Autoimmune hemolytic anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura (ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Hemolytic Uremic Syndrome 
(HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as AESI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations 
(ALT and/or AST) 
Infusion Reactions (reported as AESI for any grade) 
Allergic reaction 
Anaphylaxis 
CRS 

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Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as AESI for any grade) 
Autoimmune neuropathy 
Guillain-Barré syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as AESI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as AESI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as AESI if ≥Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin (reported as AESI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as AESI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as AESI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
Any grade of hemophagocytic lymphohistiocytosis 
 
 
 

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11.12. 
Appendix 12: Management Guidelines for CRSa 
Grade 
Clinical Presentation for Grading 
Assessment1,2 
Management Guidelines 
1 
Temperature ≥38.0 °C 
Vigilant supportive care4 
Assess for infection and treat5 
2 
Temperature ≥38.0 °C with hypotension not 
requiring vasopressors and/or hypoxia 
requiring the use of oxygen delivered by low-
flow nasal cannula (≤6 L/minute) or blow-by. 
Monitor cardiac and other organ function 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid 
Administer O2 for hypoxia6 
Consider administering tocilizumab ± 
corticosteroids7  
3 
Temperature ≥38.0 °C with hypotension 
requiring a vasopressor with or without 
vasopressin and/or hypoxia requiring high-flow 
nasal cannula (>6 L/minute), facemask, non-
rebreather mask, or venturi mask not 
attributable to any other cause3 
Monitor participant very closely for cardiac 
and other organ dysfunction. Most likely 
will require monitoring in an intensive care 
unit (ICU). 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid and pressors6. 
Administer O2 for hypoxia. 
Administer tocilizumab ± corticosteroids7 
4 
Temperature ≥38.0 °C with hypotension 
requiring multiple vasopressors (excluding 
vasopressin) and/or hypoxia requiring positive 
pressure (e.g.: Continuous Airway Positive 
Pressure (CPAP), Bilevel Airway Positive 
Pressure BiPAP, intubation and mechanical 
ventilation) 
Manage participant in ICU 
Intensive supportive care including 
mechanical ventilation, fluids, pressors, 
antibiotics and other measures as 
required6 
Administer tocilizumab ± corticosteroids7 
5 
Death 
 
1. 
Fever is defined as temperature 38°C not attributable to any other cause. In patients who have CRS then 
receive antipyretic or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2. CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
3. Low-flow nasal cannula is defined as oxygen delivered at 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
4. Supportive care includes monitor fluid balance, maintain adequate hydration and blood pressure  
5. Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever and 
neutropenia as per institutional practice; and antipyretics, analgesics as needed.  
6. Given that prolonged fluid resuscitation without pressor use is associated with worse outcome and because early 
and aggressive supportive care, early use of vasopressors, and timely anti-cytokine therapy are paramount to 
mitigating life-threatening CRS. 
7. Other immunosuppressor agents may be used, including TNFα and IL-1R inhibitors.  
a.  Lee, 2019 

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11.13. 
Appendix 13: IRR/CRS Prophylaxis Regimen 
Pre-medication 
Dose 
Administration 
Action 
Corticosteroid Medication 
Note: Administer full (8 mg) dose of dexamethasone (or equivalent) noted below for first treatment dose. If no 
cytokine related reactions are observed then administer half (i.e.., 4 mg) the corticosteroid dose for second 
treatment dose. If no reactions after second dose, then administer half (i.e.., 2 mg) the corticosteroid dose for 
third treatment dose. If no reactions after the third dose, no further corticosteroids are required. 
Prophylactic corticosteroids may also be restarted as needed if cytokine related reactions of any grade occur 
and at a dose level at the discretion of the investigator after consultation with and approval by the sponsor.   
Glucocorticoid 
dexamethasone (8 mg) 
or equivalent 
IV - administer approximately 30-60 
minutes prior to the infusion 
Requireda – 
see above 
Glucocorticoid 
dexamethasone (4 mg) 
or equivalent 
IV - administer approximately 30-60 
minutes prior to the infusion 
Requireda – 
see above 
Glucocorticoid 
dexamethasone (2 mg) 
or equivalent 
IV - administer approximately 30-60 
minutes prior to the infusion 
Requireda – 
see above 
Other Medications 
Antihistamine 
diphenhydramine (50 
mg) or equivalent 
Oral - administer at least 1 hour (±15 
minutes) prior to study drug 
or 
IV - start infusion approximately 15 to 
30 minutes prior to study drug 
Required 
Antipyretic 
acetaminophen (650 
mg) or equivalent 
Oral or IV- administer approximately 15 to 
30 minutes prior to study drug 
Required 
H2-antagonist 
ranitidine (50 mg) or 
equivalent  
IV - start infusion 30 (±15) minutes prior to 
study drug 
Optional 
Antiemetic 
ondansetron (16 mg) or 
equivalent  
IV - start infusion approximately 15 to 
30 minutes prior to study drug 
Optional 
Abbreviations: CRS=cytokine release syndrome; IRR=infusion-related reaction; IV=intravenous. 
a. 
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Timepoint Definitions for assessments: 
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Timepoint Definitions for assessments: 
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g. 
All assessments performed at Screening must be performed within 28 days prior to first dose unless otherwise specified.  
h. 
Procedures should be performed at all 6 weekly study interventions, unless otherwise specified 
i. 
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 
 
. 
j. 
Procedures scheduled on study treatment administration days can be performed within 3 days prior to dosing day, unless otherwise specified. 
k. 
Baseline ALT in Participants with HCC and positive for HBV or positive for HCV should be determined by taking the mean value of the screening ALT and the pre-dose Day 1 ALT. 
l. 
 
 
 
 
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11.17. 
Appendix 17: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Amendment 1 (12-Dec-2018) 
Section # and Name Description of Change 
Brief Rationale 
Section 3: Objectives 
and Endpoints 
Section 4.1: Study 
Design 
Added wording that Parts 1B, 2A 
and 2B will start upon amendment 
only. 
Updated study design to remove 
MSS CRC expansion cohort. 
Updated dose escalation intervals 
not to exceed two-fold increments.  
Cohort size updated to be 
consistent with Appendix 13 
Section 4.1.2: Dose 
Limiting Toxicity 
Specific criteria for Cytokine 
Release Syndrome (CRS) and non-
hematologic toxicities were updated. 
Section 5.1: Inclusion 
Criteria 
Clarified disease characteristics for 
advanced/recurrent solid tumors.  
Expanded population from selected 
solid tumors to all solid tumors. 
Section 7.1.3: 
Stopping Rules for 
Clinical Deterioration 
Added considerations for treating 
participants beyond disease 
progression. 
Section 9.2.1: Dose 
Escalation 
Updated with revised Bayesian prior 
and operating characteristics. 
Section 11.14: 
Appendix 14 
Dose levels updated. 
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Section # and Name Description of Change 
Brief Rationale 
Whole Document 
Minor typographical errors and 
inconsistencies corrected. 
 
 
Amendment 2 (27-Aug-2020) 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1. 
Synopsis 
Text related to pembrolizumab 
replaced with dostarlimab. 
A stipulation was added that, based on 
emerging data, addition of other 
combination partners or dose 
expansion cohorts could be added by 
protocol amendment. 
Deleted objectives and endpoints 
associated with dose expansion cohort 
Number of participants were clarified 
so that approximately 140 participants 
will be in four dose escalation arms. 
The reference to cohorts was changed 
to refer to arms. 
Section 1.2. 
Schema 
Schema was updated 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3: 
Schedule of 
Activities (SoA) 
Text related to pembrolizumab 
replaced with dostarlimab. 
Removed dose expansion cohort 
(including patient reported outcomes) 
details. 
Additional text added to clarify in-
house monitoring duration for all 
visits. 
Additional text added for 12-lead 
ECG and Holter Monitoring. 
 
 
 
Updated consideration for follow-up 
call between 24- and 72-hours 
following discharge from the 
clinic/hospital. 
Safety laboratory assessment text 
updated to include HBV DNA, 
HBsAg sample timepoints and HCV 
antibody, and HCV RNA sample 
timepoints. 
Notes updated for Hepatitis B and C 
screening, pregnancy test, thyroid 
function, GSK3745417 
, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
 
 
Schedule for 
 
 
Footnote added to clarify that Baseline 
ALT in participants with HCC and 
historic/current HBV or historic HCV 
should be determined by taking the 
mean value of the screening ALT and 
the pre-dose Day 1 ALT.  
 
 
 
 
 
 
 
Section 2.1: Study 
Rationale 
Combination partner changed from 
pembrolizumab to dostarlimab. 
Dose escalation Part 1 changed to Part 
1A and Part 2 changed to Part 2A. 
Dose expansion Part 2 changed to Part 
2B. 
Timing was updated for various 
assessments and time points.  
Section 2.2.1: 
GSK3745417 
Combination partner changed from 
pembrolizumab to dostarlimab. 
Added wording that Parts 1B and 2B 
will start upon amendment based on 
emerging data. 
Section 2.2.2: 
Clinical Safety of 
GSK3745417 
New Section with GSK3745417 
newly emerging clinical safety data 
Section 2.2.3: 
Dostarlimab 
New Section with dostarlimab use as 
an investigational drug added. 
Dostarlimab IB cross reference added. 
Dostarlimab IB edition updated. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 2.3: 
Benefit/Risk 
Assessment 
Benefits, risks, and reasonably 
expected AEs of dostarlimab added. 
Section 3: 
Objectives and 
Endpoints 
Deleted objectives and endpoints 
associated with dose expansion cohort 
Section 4.1: 
Overall Design 
Dose escalation Part 1 changed to Part 
1A and Part 2 changed to Part 2A. 
Two treatment arms changed to 4 
treatment arms. 
 
 
 
 
 
 
  
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Section # and 
Name 
Description of Change 
Brief Rationale 
Updated study design to remove dose 
expansion cohort and 
. 
Cohort size updated to be consistent 
with Appendix 13. 
Section 4.1.1: Dose 
Escalation 
Presentation of dose escalation for 
 
 
Dose escalation criteria and dosing 
schedule updated for all the 4 
treatment arms. 
Pharmacokinetic/
 
 
Footnote added to Table 6.  
 
 
 
 
 
Cohorts permitted IRR/CRS 
prophylaxis added. 
Section 4.1.2: Dose 
Limiting Toxicity 
DLT text added for Monotherapy 
Arm A1 and Arm A2 and for 
combination therapy Arm A3 and 
Arm A4. 
DLT criteria for non-hematologic 
toxicity added with specifications: 
DLT criteria updated for any other 
non-hematologic toxicity:  
Grade ≥2 uveitis, eye pain, or blurred 
vision that does not resolve with 
topical therapy within 2 weeks 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Grade ≥2 immune-related endocrine 
toxicity that requires hormone 
replacement 
Grade ≥2 colitis or diarrhea that 
persists without resolution to Grade 
≤1 for ≥7 days despite adequate 
steroid therapy 
 
DLT criteria for hematologic toxicity 
added with specifications.  
Section 4.1.3: Dose 
Escalation 
Committee 
Text related to dose expansion 
monitoring deleted. 
Section 4.1.4: 
Tumor Types 
Enrolled During 
Parts 1A and 2A 
Text related to dose expansion 
enrolment deleted. 
Section 4.1.5: 
Participant Re-
Treatment 
Added considerations for additional 
arms. 
Text updated to explain that 
participants must have completed at 
least 1 treatment period of 
GSK3745417 monotherapy without 
the occurrence of drug-related Grade 
≥3 AE or serious adverse events 
(SAEs) of any severity Grade in the 
first 21 days of treatment. 
Clarification added that the GSK 
medical monitor must be consulted 
and approve the decision before 
crossover is permitted. 
Section 4.1.6: 
Study Duration 
Study treatments table updated to 
include additional treatment arms. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 4.2: 
Number of 
Participants 
Text related to participants in 
expansion cohorts, 
pharmacokinetic/
 
 
 
Number of participants were clarified 
so that approximately 
 
 
Section 4.3: 
Participant and 
Study Completion 
 
  
Section 4.4: 
Scientific Rationale 
for Study Design 
Text added for dostarlimab. 
Expansion cohort deleted. 
 
 
Section 4.5.2: 
Justification of 
starting dose 
Presentation of dose escalation for 
 
 
 
Section 4.5.3: 
Dostarlimab Dose 
Rationale 
Dostarlimab dose rationale added. 
Section 5.1: 
Inclusion Criteria 
Inclusion criteria added for 
participants with hepatocellular 
carcinoma (HCC) and historic/current 
HBV or historic HCV. 
One additional on-treatment biopsy 
criterion removed. 
Organ function table updated to 
include activated partial 
thromboplastin time and participants 
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Section # and 
Name 
Description of Change 
Brief Rationale 
with HCC and historic/current HBV 
or historic HCV. 
Contraceptive method duration for 
participants receiving dostarlimab 
added. 
Urine pregnancy test removed, and 
duration of serum pregnancy test 
updated to 72 hours before the first 
dose of study intervention. 
 
 
 
 
 
 
Section 5.2: 
Exclusion Criteria 
Exclusion criteria added for 
participants with hepatocellular 
carcinoma (HCC) and historic/current 
HBV or historic HCV. 
Prior treatment with checkpoint 
inhibitor PD-L2 added. 
Transfusion of blood products within 
3 weeks per dostarlimab added. 
Exclusions only for Part 2A added to 
include known hypersensitivity to 
dostarlimab or associated excipients. 
Section 6.1: Study 
Intervention(s) 
Administered 
Text updated to include Arm A1, Arm 
A2, Arm A3, and Arm A4. 
Added combination therapy 
monitoring. 
Dostarlimab dosing administration 
schedule added. 
Investigational product 
dosage/administration table updated. 
Section 6.3 
Measures to 
Minimize Bias: 
Randomization and 
Blinding 
Added allocation description per 
treatment arm. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.5.1: 
Permitted 
Medications and 
Non-Drug 
Therapies 
Text updated to add prophylaxis of 
cytokine-related symptoms.  
 
Text updated to add non-mandatory 
prophylactic treatment of thrombosis. 
Section 6.5.2: 
Prohibited 
Medications and 
Non-Drug 
Therapies 
Added considerations for additional 
prohibited medications. 
Section 6.6: Dose 
Modification 
Added considerations for dose 
reduction. 
Dose modification and toxicity 
management guidelines for immune- 
related AEs table updated. Text added 
for adrenal insufficiency, uveitis, 
immune-related encephalitis, rash, 
renal failure or nephritis, and 
recurrence of AEs after resolution to 
≤Grade 1. Line item added for 
Infusion-related reaction guidance and 
cross-referenced with Table 15. 
Biomarker panel table updated. 
Section 6.7: Dose 
Delay 
Clarification added that during all the 
dosing schedules, subsequent doses 
should be administered at least 5 days 
apart. 
Conditions added for dosing delays or 
omissions. 
Section 7.1: 
Discontinuation of 
Study Intervention 
Clarification added that participants 
discontinuing from GSK3745417 
monotherapy will be allowed to 
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Section # and 
Name 
Description of Change 
Brief Rationale 
crossover to GSK3745417 plus 
dostarlimab combination. 
Section 7.1.1: Liver 
Chemistry 
Stopping Criteria 
Consideration added for participants 
with HCC and historic/current HBV. 
Section 8.1: 
Efficacy 
Assessments 
Explanation added that in case if a 
fresh tumor tissue biopsy cannot be 
obtained, the reason for missed biopsy 
must be documented in the medical 
record.  
 
Section 8.2.3: 
Electrocardiograms 
Explanation added that if QTc interval 
is prolonged during the study, 
triplicate ECG measurements will be 
performed. 
 
Section 8.2.5: 
Telemetry 
Telemetry is only required for 
 
monotherapy arm. 
Section 8.2.6 
Neurological 
Assessments 
Text updated to add neurological 
examinations if clinically significant. 
Section 8.2.7: 
Follow-Up Phone 
Call 
Updated consideration for follow-up 
call between 24- and 72-hours 
following discharge from the 
clinic/hospital. 
Section 8.4: 
Treatment of 
Overdose 
Definition of dostarlimab overdose 
added. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.5. 
Pharmacokinetics 
Added text associated with analysis of 
plasma samples. 
Section 8.6: Anti-
Drug Antibodies 
Consideration added for possession 
and processing of collected 
immunogenicity blood samples. 
Section 8.7.2: 
Tumor Tissue 
Consideration added for biopsy 
schedule. 
Section 9: 
Statistical 
Considerations 
Section revision due to addition of 
two arms and updated sample size. 
 
Section 9.2.1: Dose 
Escalation (Part 
1A) 
Updated with revised Bayesian prior 
and operating characteristics. 
Section 9.2.1: Dose 
Escalation 
Text updated with simulation results 
under various scenarios. 
Section 9.2.2: Dose 
Escalation (Part 
2A) 
Added dose escalation plan in the 
combination arms. 
Deleted dose expansion plan. 
Section 9.4.1 
Efficacy Analyses 
Added description of exploratory 
efficacy endpoints. 
Deleted description of PFS, OS and 
TTR as exploratory efficacy 
endpoints. 
Section 11.2: 
Appendix 2: 
Clinical Laboratory 
Tests 
Text updated for pregnancy testing 
and participants with HCC.  
Section 11.12: 
Appendix 12: 
Management 
Guidelines for CRS 
Appendix revised according to the 
updated Cytokine Release Syndrome 
(CRS) management guidelines (Lee, 
2019). 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 11.13: 
Appendix 13: 
IRR/CRS 
Prophylaxis 
Regimen 
Appendix includes list of 
premedications and regimen. 
Section 11.14: 
Appendix 14 
Statistical 
Simulation Dose 
Levels 
Dose levels and number of 
participants per dose cohort updated. 
Whole Document 
Combination partner changed from 
pembrolizumab to dostarlimab. 
Pembrolizumab information deleted. 
Additional treatment arms added. 
Processes during dose expansion 
cohort deleted. 
Patient reported outcomes deleted. 
Minor typographical errors and 
inconsistencies corrected. 
Amendment 3 (16-OCT-2020) 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3: 
Schedule of 
Activities (SoA) 
Schedule for coagulation testing 
added to Table 1 and Table 2. 
Clarification of coagulation 
testing timepoints added in Table 
3 and Table 4. 
Timepoint definition in footnotes 
– typos corrected (Table 1, Table 
2, Table 3, Table 4).  
Section 4.1.1: Dose 
Escalation 
Upper limit of target toxicity 
range changed from 35% to 33% 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 4.4: 
Scientific Rationale 
for Study Design 
Upper limit of target toxicity 
range changed from 35% to 33% 
Section 5.1: 
Inclusion Criteria 
Addition of minimal age of study 
inclusion in South Korea as ≥ 19 
years. 
Simplification of Table 11 with 
respect to PT/INR and PTT 
measurements. Addition of 
APTT. 
Section 5.2: 
Exclusion Criteria 
Removed of option to enrol 
participants treated in 
 
 
. 
Section 6.1: Study 
Intervention(s) 
Administered 
Table 12. Dostarlimab dosage 
form: Supplied only as solution 
for infusion. 
Section 7.1.3. 
Stopping Rules for 
Clinical 
Deterioration 
 
  
Section 9.2.1: Dose 
Escalation (Part 1A) 
Section 9.2.2: Dose 
Escalation (Part 2A) 
Section 11.2: 
Appendix 2: 
Clinical Laboratory 
Tests 
LFT at local lab for HCC 
subjects. 
PTT and PT/INR conducted at 
local lab. 
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Amendment 4 (21-APR-2021) 
Section Number 
Description of Change 
Brief Rationale 
1.3.Synopsis Objectives  
Section 3. Objectives  
Synopsis  
• Added clarification that 
the objectives presented 
are applicable to Part 
1A/2A only 
1.3. SoA – Tables 1-5 
Safety assessments 
8.2.3 Electrocardiogram 
• 12-Lead ECG at Screening 
to be taken in triplicate 
1.3. SoA – Tables 1-5 
Safety assessments 
 
• BNP or NTproBNP 
measurement added to 
Safety assessments at 
Baseline 
1.3 SoA – Tables 1-5 
Safety assessments 
 
• Periodic echocardiograms 
performed whist on 
treatment  
1.3. SoA – Tables 1-5 
Safety assessments 
 
• Troponin assessments 
modified for frequent 
monitoring. 
1.3. SoA – Tables 1-5 
Safety assessments 
 
• Additional clinical 
chemistry, CBC with 
differential and 
coagulation samples to be 
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Brief Rationale 
collected in the event of a 
CRS 
1.3. SoA – Tables 1-5 
Efficacy assessments 
1.3. SoA – Table 1-5 
PK and Biomarkers 
• Sample collection 
schedules modified with 
additional collections   
1.3. SoA – Table 1-5 
Safety assessments  
• Neurological assessment 
modified to include ICE 
monitoring 
1.2 Table 1 
8.5 Pharmacokinetics 
• Urine collection schedule 
added for GSK3745417 
metabolite measurement 
1.3 SoA – Table 1 
• Telemetry 
1.3 SoA – Table 3-5 
Safety Assessments 
• 24-hr In-house monitoring 
schedule modified 
1.3 SoA – Table 3-5 
Safety Assessments 
8.2.4 Holter monitoring 
• Holter monitoring deleted 
1.3.New SoA table, 
Table 5. 
4.1 Overall Design 
• New SoA table for 
subjects from Part 1A that 
cross to combination 
treatment 
1.3 SoA – Tables 3-5, 
Section 4.1.1 Table 7 
• 
 
 
monotherapy removed. 
Dosing starts with 
combination. Timing of 
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many assessments have 
been amended accordingly 
1.3 SoA – Table 3 
• Dosing day allowable 
window is ± 1 day 
2.3.1 Risk Assessment 
• Cardiac effects updated 
based on event of 
perimyocarditis 
Section 4.1.2 Table 8  
• Additional term of 
‘hematologic events’ 
added to the existing DLT 
criteria for anemia, 
neutropenia and 
thrombocytopenia.   
Section 4.1.5. 
Participant retreatment 
• Clarification re. allowing 
Part1A participants to 
crossover to combination 
added. 
Section 5.2 Excl 
Criteria 
• Expanded neurological 
exclusion criteria to any 
CNS metastases 
(symptomatic or 
asymptomatic) located in 
the brainstem. 
Section 5.2 Excl 
Criteria 
• Prior treatment with 
STING agonist criteria 
modified  
Section 5.2 Excl 
Criteria 
• Participants with 
signs/symptoms suggestive 
of COVID-19 within 14 
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Brief Rationale 
days of study entry, or 
with known exposure to 
COVID-19 within 14 days 
prior to study entry 
1.3 SoA Tables 3-5, 
Section 6.1 Study 
intervention 
administered 
• Monitoring time before 
combination therapy 
administration shortened to 
30 mins (from 2 hours) 
• Clarification of monitoring 
time after dostarlimab 
therapy to at least 2 hours 
6.5.1 Permitted 
Medications and Non-
Drug Therapies 
 
• Addition of language to 
allow subjects in non-
prophylaxis cohorts to be 
receive prophylaxis with 
steroid post DLT period 
for repeated Grade 2 and 
above CRS  
6.6. Dose Modification 
Table 15 
• Language related to dose 
modification and toxicity 
management modified  
6.6.1 CRS Section and 
Table 16 
• Language related to CRS 
management clarified. A 
new Table has been added 
for monitoring guidelines 
for CRS management 
6.6.1.1 Cardiac 
monitoring 
• 
A new Section 6.6.1.1 
Cardiac monitoring and 
dose modification 
guidelines added  
6.6.1.2 Neurological 
monitoring 
• 
A new Section 6.6.1.2 
Neurological Adverse 
Events On Study added 
6.6.1.3 Grading 
Immune Effector 
Cell-Associated 
• 
A new Section 6.6.1.3 for 
grading ICANS added 
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Brief Rationale 
Neurotoxicity 
Syndrome 
(ICANS) 
6.6.1.4. Monitoring 
ICANS 
• 
A new Section 6.6.1.4 for 
monitoring ICANS added 
6.6.1.5. Management of 
ICANS 
• 
A new Section 6.6.1.5 for 
managing ICANS added 
8.1.2. Tumor Growth 
Kinetics 
• 
A new Section 8.1.2 
added for tumor growth 
kinetics 
9.4.3.2. 
Immunogenicity 
Analyses 
• 
A new Section 9.4.3.2 
added for immunogenicity 
analyses 
11.9.4 iRECIST 
Guidelines  
• 
Figure 11 updated 
Amendment 5/NET-1: 19-JUL-2021 
Overall Rationale for the Amendment:  
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Brief Rationale 
• 
Table 3: removed pregnancy test 
on Day 8 
• 
Table 3: Changed vital signs from 
Week 8, 11, and 14, to Week 7, 
10, and 13 
• 
Table 1: Added sample for C-
reactive protein at EOI+4 h 
• 
Table 5: CBC with Differential 
added: “If a participant 
experiences cytokine release 
syndrome, perform CBC with 
differential at EOI+8h too” 
4.1 Overall Design and 
Synopsis 
Added definition of “enrolled” 
5.4 Screen Failure 
Modified wording to define screen failre 
to exactly match boilerplate 
8.8 Genetics 
Add boilerplate text on genetic samples 
9.1. Statistical Hypotheses 
 
 
 
11.1.3 Informed Consent 
Process 
Added “Including the risk and benefits” 
Required per GSK template updates 
11.3.5 Reporting to GSK via 
Electronic Data Collection 
Tool 
Removed paragraph that starts “The 
investigator or…” 
Required per GSK template V16 
11.15. Appendix 15: Imaging 
Sub-study 
This appendix describes the objectives, 
and all procedures specific to the 
Imaging Sub-study that will be 
conducted in Netherlands only 
All procedures for the conduct of the 
Imaging Sub-study are described. 
11.16 Appendix 16: Radiation 
Dose 
New Appendix that describes how to 
estimate radiation dose 
Appendix needed to support 
Imaging Sub-study 
 
Amendment 6: 19-JAN-2022 
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This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
A table of key changes from Protocol Amendment 4 to Amendment 6 is shown below:  
 
Section Number and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
• 
Additional text added to 
Overall Design referring to the 
inclusion of a 
 
 
1.2. Schedule of Activities 
(SoA)  
• 
 
activities are described in 
Appendix 15 
• 
Table 1- Table 5: 24 Hour In-
House Monitoring: Added 
“Participants may be released 
after a 6-hour observation 
period… PK and 
 
 
• 
Table 1- Table 5, AE/SAE 
Review revised 
• 
 
 
• 
 
 
 
• 
Table 1- Table 5: Added 
“predose” to urine pregnancy 
test and ≤72 h serum prior to 
first dose 
• 
Table 1: Added sample for C-
reactive protein at 
 
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Section Number and Name 
Description of Change 
Brief Rationale 
• 
Table 1- Table 5: change 
 
 
• 
Table 1 - Table 5, Table 29 – 
added timeframe for 
 
 
 
• 
Table 1- Table 2: First on-
treatment fresh 
 
 
 
 
• 
Table 1 – Table 5: 
 
 
• 
Table 1 – 5: additional 
timepoints 
 
 
• 
Table 1 -3, 5: added changes 
 
 
• 
Table 1- 2: changes added to 
GSK3745417 plasma PK 
timepoints collection 
• 
 
 
 
 
• 
Table 1- Table 5: revised 
definition of 
 
 
• 
Table 3: 12-lead ECG changed 
from 
 after the 
 
• 
Table 1- Table 5, added 
clarifications for 
 
  
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Section Number and Name 
Description of Change 
Brief Rationale 
• 
Table 3: 
 
 
 
• 
Table 3: removed pregnancy 
test on Day 8 
• 
Table 3: Changed vital signs 
from 
 
 
• 
Table 2 and 4: additional text 
added to the timepoints for 
liver function test (LFT) 
• 
 
 
 
2. Introduction 
Updated Study Rationale, Background 
2.3.1 Risk Assessment 
Updated table of rationale for risks and 
mitigation strategies  
2.3.2 Overall Benefit:Risk 
Conclusion 
Removed first two paragraphs  
3 Objectives and Endpoints 
Added footnote about 
 
 
 
4.1 Overall design 
Added additional text for 
 
 
4.1.1. Dose Escalation and 
Synopsis 
Added Dose escalation for GSK3745417 
monotherapy in 
 
 
 
 
 
  
Reduced time between first 3 
participants to 48 hours (was 72) 
Descriptions added to Dose Schedule 
and new section under subhead: 
 
 
  
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Section Number and Name 
Description of Change 
Brief Rationale 
4.1.3 Dose Escalation 
Committee 
Added item 6: defining the role of DEC in 
deciding dose escalation  
4.1.5. Participant Re-treatment 
Removed requirement for new 
participant number 
4.2. Number of participants 
Added numbers of participants for 
 
 
4.4. Scientific Rationale for 
Study Design 
Added “
 
 
 
 
4.5.2. Dostarlimab Dose 
Rationale 
Added clarification for 
 
 
5.1 Inclusion Criteria 
Added Inclusion Criterion #10: “
 
 
 
 
Update Table 12 eGFR cut-off 
5.2 Exclusion Criteria 
Revised exclusion 12 to include #13 
Revised Exclusion 28 (was 29): Known 
hypersensitivity to any of the study 
interventions or any of their exipients 
6.1. Study Intervention(s) 
Administered 
Additional text added for observation 
period to allow less than 8 hours 
monitoring 
Table 13 updated 
6.3 Measures to minimize bias: 
Randomization and Blinding 
Deleted: “The first dose level of Arm A4 
will open only after that dose level of 
 
 
Reduced time between first 3 
participants to 48 hours (was 72)  
6.5.1. Permitted medications 
and Non-Drug Therapies 
Added additional text to the second 
paragraph “Growth Factors and 
Bisphosphonates”  
6.6. Dose Modification 
Updated language 
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Section Number and Name 
Description of Change 
Brief Rationale 
Table 14 for guidelines for immune-
related AEs updated 
6.6.1 Management of Infusion 
Reactions or Severe 
Cytokine Release 
Syndrome 
Table16 removed “and pressors”  
Added “If patient experiences symptoms 
consistent with pericarditis or 
myocarditis” 
6.6.1.4 Monitoring for Immune 
Effector Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
 
Removed:” Brain MRI (or CT Scan if MRI 
not feasible) should be obtained for all 
participants at the time of Screening.   
6.7. Dose Delay 
Removed Paragraph 6: “If a dose is 
missed, participant should perform all 
assessments indicated for the missed 
dose after 6th dose” 
7.1.1 Liver Chemistry Stopping 
Criteria 
 
7.1.1.1 Study Intervention 
Restart or Rechallenge after 
Liver Stopping Criteria Met 
 
Added “• In the presence of abnormal 
liver chemistry not meeting protocol 
specified stopping rules, if the 
Investigator believes that it is in the best 
interest of the participant.” 
Added “Note: If study treatment was 
interrupted for suspected drug-induced 
liver injury, the participant should be 
informed of the risk of death, liver 
transplantation, hospitalization, and 
jaundice and re-consented before 
resumption of dosing.” 
8.1 
 
Added Paragraph 2 
8.2.2 Vital Signs 
Added pulse oximetry for oxygen 
saturation” 
8.2.5. Telemetry  
Removed telemetry for the Part 1A, 
 
monotherapy 
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information 
Revised Paragraph 2: “AEs at each 
visit….Until start of subsequent 
anticancer treatment (Section 1.3).” 
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Section Number and Name 
Description of Change 
Brief Rationale 
9.3 Populations for Analysis 
Added DLT Evaluable (Part 1A and 2A) 
and 
 populations 
 
9.5 Interim Analysis 
Deleted “The Reporting and Analysis 
Plan will describe the planned interim 
analyses and subgroups in greater 
detail. 
…Any additional decision rules will be 
documented in RAP before the interim 
analysis.” 
11.1.1 Regulatory and Ethical 
Consideration 
Added next to last bullet:” • Notify 
significant/major protocol 
deviations to the EC/IRB, as well 
as findings of internal Quality 
Audits and CAPA’s.” 
11.1.3 Informed Consent 
Process 
Added “Including the risk and benefits” 
Added in Paragraph 2: “and that they 
can withdraw their consent to participate 
for any reason or no reason at all.  
Participants or their legally authorized 
representative must be informed that 
they are free to take the Informed 
Consent home to discuss participation 
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Section Number and Name 
Description of Change 
Brief Rationale 
with members of their family or personal 
medical physician.” 
Added in Paragraph 3: “and which 
persons were present when the study 
was explained to the potential participant 
or their legally authorized 
representative.” 
11.2 Appendix 2: Clinical 
Laboratory Tests 
Revised first paragraph language 
Table 25:Added HBe antigen and 
Tryptase, and revised hepatitis test 
language 
11.3.5 Reporting of SAE to 
GSK  
Removed paragraph that starts “The 
investigator or…” 
11.7 CKD-EPI Formula 
Revised Title to Estimated Glomerular 
Filtration Rate 
Added factor for participants in Japan 
This appendix describes the objectives, 
and all procedures specific to the 
 
 
11.16 Appendix 16: Radiation 
Dose 
New Appendix that 
 
 
 
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Signature Page for  208850 TMF-16209529 v1.0
Signature Page for TMF-16209529 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 04-Aug-2023 13:42:07 GMT+0000
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Effective Date 27-JAN-2022 
11.18.  
FRENCH-SPECIFIC REQUIREMENTS 
 
This appendix includes all applicable requirements of French Public Health Code / specific local 
GSK requirements and identifies, item per item, the mandatory modifications or additional 
information to the study protocol. 
1. Concerning the « SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA»  
 
The following vulnerable subject populations will be excluded: minors, protected subjects, adult 
subjects not in condition to express their consent, subjects deprived of liberty, subjects receiving 
psychiatric cares, subjects hospitalized in a Health and Social Establishment for other purpose 
than the participation to the study. 
 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or beneficiary of 
a social security category (French Public Health Code Law L.1121-8-1). (Exception for a 
participant to a non-interventional study or to a participant to an interventional study if authorised 
by the Ethics Committee). 
It is the investigator’s responsibility to ensure and to document (in the source document - subject 
notes) that the subject: 
- 
is either affiliated to or beneficiary of a social security category.  
- 
has got an authorisation by the Ethics Committee. 
 
2. 
Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
• In section “Regulatory and Ethical Considerations, including the Informed Consent 
Process” of study protocol 
 Concerning the process for informing the subject and/or his/her legally authorized 
representative, the following text is added:  
French Patient Informed Consent is a document which summarizes the main features of the 
study and allows collection of the subject and/or his/her legally authorized representative 
written consent. It also contains a reference to the authorisation of ANSM and the approval 
from the French Ethics Committee. 
 
 Concerning the management of the Patient Informed Consent Forms, the following text 
is added: 
French Patient Informed Consent Form is in duplicate (triplicate for minor subject). 
The first page of the Patient Informed Consent Form is given to the investigator. The copy 
is kept by the patient or legally authorized representative. 
 
• NOTIFICATION TO THE HOSPITAL DIRECTOR 
In accordance with Article L1123-13 of the French Public Health Code, the Hospital Director is 
informed of the commitment to the trial in her/his establishment. The Hospital Director is 
supplied with the protocol and any information needed for the financial disposition, the name 
of the investigator(s), the number of sites involved in his establishment and the estimated time 
schedule of the trial (R.1123-69). 
 

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Effective Date 27-JAN-2022 
• INFORMATION TO THE HOSPITAL PHARMACIST 
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The Pharmacist 
is supplied with a copy of the protocol (which allows her/him to dispense the drug(s) of the trial 
according to the trial methodology), all information concerning the product(s) of the trial (e.g. 
included in the IB), the name of the investigator(s), the number of sites involved in her/his 
establishment and the estimated time schedule of the trial. 
 
• Ethnic Origin 
In accordance with the data privacy regulation, the ethnic origin, as any personal data, can 
only be collected if the collection of this data is strictly necessary and relevant for the purpose 
of the study. 
 
• TESTING OF BIOLOGICAL SAMPLES 
In accordance with the French Public Health Code Law – article L1211-2, a biological sample 
without identified purpose at the time of the sample and subject’s preliminary information is not 
authorized. 
3. Concerning the “DATA MANAGEMENT” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the investigators and/or 
co-investigators and/or the pharmacists if applicable, involved in this clinical trial, and data 
regarding the subjects recruited in this clinical trial (subject number, treatment number, 
subjects status with respect to the clinical trial, dates of visit, medical data) will be collected 
and computerized in GSK data bases by GSK or on its behalf, for reasons of follow up, clinical 
trial management and using the results of said clinical trial. According to the data privacy 
regulation, each of these people aforesaid has a right of access, correction and opposition on 
their own data through GSK (Clinical Operations Department). 
4. Concerning Data Privacy 
In accordance with the applicable data privacy regulation, personal data are processed in a 
manner that ensures appropriate security, including protection against unauthorized or 
unlawful processing and against accidental loss, destruction or damage, using appropriate 
technical or organizational measures. The processing is whether deemed to be compliant with 
one of the methodologies of reference (MR-001) or has been the subject of a request for 
authorization to the CNIL. The Investigator has, regarding the processing data related to 
her/him, a right of access, of rectification, erasure and of opposition with GSK in accordance 
with the legal provisions. 
 
5. Investigational Product Accountability, Reconciliation, and Destruction 
In specific situations where institutional practices dictate that the site disposes of and/or 
destroys IP prior to allowing the “monitor’ to verify and document IP accountability, the 
following applies: 
“During the conduct of the Study, Investigational Product (IP) will be destroyed by the 
Institution prior to a GSK “monitor” conducting final investigational product accountability. 
Institution agrees that such destruction will comply with Institution’s investigational product 
accountability procedures and will provide GSK with investigational product accountability 
logs and supporting documentation to verify adherence to ‘Bonnes Pratiques Cliniques’ 
(decision dated on the 24th of November 2006).