Clinical trial NCT03681951
Conditions: Neoplasms, Pancreatic
Keywords: Anticancer Agents FTIH Pembrolizumab Rip1K GSK3145095 Dose Escalation Immunotherapy resistance Dose Expansion RECIST 1.1 Advanced solid tumors Innate immunity
Sponsor: GlaxoSmithKline
Start date: 2018-11-16; Completion date: 2019-08-13
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
In an unbiased CRISPR screen, RIPK1 was identified as a top gene contributing to immunotherapy resistance. In addition, RIPK1 has been reported to drive pancreatic oncogenesis. In murine models, inhibition of RIPK1 kinase activity in the pancreatic tumor microenvironment leads to the replacement of tumor-permissive myeloid infiltrates with innate cells that promote an effective antitumor response by adaptive cells. The investigators hypothesize that inhibition of RIPK1 in human pancreatic cancer subjects will modulate the immune infiltrate to sensitize tumors to checkpoint blockade.

Detailed description:
Study 205013 is a Phase 1 FTIH study of GSK3145095 alone and in combination with other anticancer agents including pembrolizumab in subjects with pancreatic ductal adenocarcinoma (PDAC) and other selected tumors. The study includes up to 4 parts: Part 1 dose escalation will be conducted in approximately 30 adult subjects with advanced or metastatic PDAC using escalating doses of GSK3145095 as monotherapy only. Part 2 will combine escalating doses of GSK3145095 with 200 milligram (mg) pembrolizumab. Dose escalation of GSK3145095 will begin at least one level below the highest dose shown to have an acceptable toxicity profile in at least 3 subjects in Part 1. Part 2 may be conducted in a broader population of selected solid tumors using a combination of escalating doses of GSK3145095 and 200 mg pembrolizumab. Part 3 will enroll subjects treated with one or more dose levels of GSK3145095 in combination with 200 mg pembrolizumab. Part 4 will investigate the combination of additional anticancer agents with one or more doses of GSK3145095 identified as safe in Part 1. Up to approximately 220 subjects will be treated in the study. Parts 1 and 2 will each treat up to approximately 30 subjects. Parts 3 and 4 will treat up to approximately 160 subjects (up to 80 subjects in each Part). The total duration of the study is expected to last up to 2 years.

Arms: arm 1: In Part 1, advanced or metastatic PDAC will be enrolled. Part 1 will be using escalating doses of GSK3145095 (total daily dose of 100 mg, 200 mg, 400 mg, 800 mg, and 1600 mg) orally as monotherapy for up to 2 years. For each dose level, subjects will receive a single dose of half the total daily dose on Day 1; and as BID (total daily dose divided in two equal doses) starting from Day 2. arm 2: In Part 2, subjects with selected solid tumors, including but not limited to, PDAC, NSCLC, TNBC and/or melanoma will be enrolled. Part 2 will be using GSK3145095 combination escalation to start at least one dose level below the highest dose of GSK3145095 shown to be safe in Part 1, orally BID for up to 2 years along with pembrolizumab 200 mg intravenous (IV) every 3 weeks (Q3W) for up to 2 years. arm 3: In Part 3, subjects with selected solid tumors will be enrolled. Part 3 will be using GSK3145095 at one or two dose levels shown to be tolerable in Part 2 orally BID for up to 2 years along with pembrolizumab 200 mg IV Q3W for up to 2 years. arm 4: In Part 4, subjects with selected solid tumors will be enrolled. Part 4 will be using GSK3145095 at one or two dose levels shown to be tolerable in Part 2 orally BID for up to 2 years along with combination of additional anticancer agents.
Interventions: intervention 1: GSK3145095 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water. intervention 2: Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).

Protocol documents:
Prot_000.pdf: 
2017N343207_03
CONFIDENTIAL
GlaxoSmithKline group of companies
205013
1
TITLE PAGE
Protocol Title: A Phase I/II, Open-Label Study to Investigate the Safety, Clinical 
Activity, Pharmacokinetics, and Pharmacodynamics of GSK3145095 Administered 
Alone and in Combination with Anticancer Agents Including Pembrolizumab in Adult 
Participants with Selected Advanced Solid Tumors
Protocol Number: 205013 / Amendment 01
Study Phase: I/II
Short Title: First-time-in-human study of GSK3145095 alone and in combination with 
other anticancer agents in adults with advanced solid tumors
Compound 
Number:
GSK3145095
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information [will be provided separately OR can 
be found in the Study Reference Manual]
Regulatory Agency Identifying Number(s): IND138899
Approval Date: 25-OCT-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.
 
2019N419040_00


 
 
 
2019N419040_00
PPD
PPD


2017N343207_03
CONFIDENTIAL
205013
3
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1
25-OCT-2018
2017N343207_03
Original Protocol (republished) 
06Aug2018
2017N343207_02
Original Protocol (republished)
28Jun2018
2017N343207_01
Original Protocol 
22Jun2018
2017N343207_00
Amendment 1: 25-OCT-2018
Overall Rationale for the Amendment: Protocol Amendment 1 is an administrative amendment only which 
includes the summary of changes information, as well as a change in the title of the protocol (i.e. 
“Amendment 01”).  The changes listed below were previously made in the 06Aug18 republished version of 
the original protocol in response to FDA feedback from the initial FDA IND Application 138899 (original 
republished protocol dated 28Jun2018) submitted on 2 July 2018.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
4
Section # and 
Name
Description of Change
Brief Rationale
Synopsis (table)
Added dose proportionality/time invariance 
to Parts 1/2 secondary endpoints
Added exploratory PK endpoint (relationship 
between GSK3145095 exposure and 
safety/QTcF parameters) 
FDA requested changes from IND 
submission
1.Synopsis
Treatment 
Groups/Duration
Change to starting dose (100mg) and 
change in dose levels (100, 200, 400, 800, 
and 1600 mg per day)
FDA requested changes (modification 
of starting dose and dose intervals) 
from IND submission
2.Schedule of 
Activities
Addition of Genetics (PGx) sample to Mono 
and Combo tables
Item inadvertently omitted from 
previous protocol version
3.2.1. GSK3145095
Change starting dose from 50mg to 100mg 
and corresponding increase in level of Rip1 
inhibition 
FDA requested change (modification 
of starting dose)
3.3.1.1. 
GSK3145095 risk 
assessment
Hepatox in vivo data inadvertently placed in 
wrong section (cardiac); moved to correct 
section (hepatotox)
Administrative change 
3.3.2 benefit 
assessment
Change starting dose from 50mg to 100mg 
and corresponding increase in level of Rip1 
inhibition
FDA requested change (modification 
of starting dose)
4. Objectives and 
Endpoints
Added dose proportionality/time invariance 
to Parts 1/2 secondary endpoints
Added exploratory PK endpoint (relationship 
between GSK3145095 exposure and 
safety/QTcF parameters)
FDA requested changes from IND 
submission
5.1.1.1. 
Monotherapy Dose 
Escalation
revision of dosing language, DLT, and 
statistical language, and grammatical 
corrections
FDA requested changes from IND 
submission
5.1.1.3 Dose 
Limiting Toxicity
Change CTCAE version to 5.0
GSK administrative change
Table 1 (DLT)
Add tox language to definitions (<80% 
doses)
FDA requested changes from IND 
submission
5.1.1.4 Max Dose 
Increment
Change to language regarding dose 
levels/increments
FDA requested changes from IND 
submission
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
5
Section # and 
Name
Description of Change
Brief Rationale
5.1.1.5 Planned 
Dose Levels
Change to language regarding dose 
levels/increments
FDA requested changes from IND 
submission
5.1.1.7 Alternative 
Dosing Schedules 
for GSK3145095
Clarification of wording in section 
GSK administrative change
5.7 Justification for 
Starting Dose
Change to language regarding starting dose 
and pharmacology
FDA requested changes from IND 
submission
6.1 Inclusion 
Criteria #3
Revision of eligibility criteria to include only 
patients who have received prior therapy 
(not include those who have refused prior)
FDA requested changes from IND 
submission
7.2 Toxicity 
Management 
Guidelines
Section 7.2 has been edited to clarify that 
guidelines in Section 7.2.1 are intended for 
management of immune-related adverse 
events associated with pembrolizumab use; 
revised reference to CTCAE 5.0
FDA requested changes from IND 
submission
7.2.1 General 
Guidelines for 
Immune-Related 
Adverse Events 
(irAEs)
Clarify language that an irAE is defined as a 
clinically significant AE of any organ that is 
associated with pembrolizumab exposure
FDA requested changes from IND 
submission
7.2.1.1 Overview 
of Management 
of irAEs
Clarify language that patients who 
experience a life-threatening adverse event 
should discontinue study treatment.
FDA requested changes from IND 
submission
7.2.1.2 General 
Principles of 
Immune-Related 
Adverse Events 
Identification and 
Evaluation
Clarify that AESIs are subset of irAEs
GSK administrative change
Table 4 Dose 
Mod/Tox Mgmt 
Guidelines irAEs
Change to CTCAE v.05
FDA requested change from IND 
submission 
7.2.2. General 
Guidelines 
Addition of language (last paragraph) to 
provide guidance on permanent 
discontinuation of subjects and life-
threatening AEs
FDA requested changes from IND 
submission, and GSK administrative 
changes
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
6
Section # and 
Name
Description of Change
Brief Rationale
Table 5 Dose 
Mod/Tox Mgmt 
Guidelines
Revision to criteria (Grades 2-4), including 
clarify that patients with Grade 2 toxicities 
lasting > 7 days should interrupt study
treatment
FDA requested changes from IND 
submission
7.7.2 Prohibited 
Medications
Addition of drugs that are strong inducers of 
CYP3A4, removal of multivitamins
FDA requested changes from IND 
submission, GSK administrative 
changes
8.1 
Discontinuation 
of Study 
Treatment
Addition of 12-week language, clarification 
of language 
FDA requested changes from IND 
submission, GSK administrative 
changes
9.9 
Immunogenicity 
assessments 
Clarification of wording that samples may be 
collected
GSK administrative change
10.4.1 
Revision to NCRM language, dose levels, 
scenarios/simulations
GSK administrative changes
10.6.2.2 Adverse 
Events
Change to CTCAE v.05
FDA requested changes from IND 
submission
10.6.2.3 Clinical 
Lab Evaluations
Change to CTCAE v.05
FDA requested changes from IND 
submission
10.6.3.2 PK/PD 
Analyses
Language added regarding additional 
exploratory endpoint
FDA requested changes from IND 
submission
12.2.3 Dose 
Escalation 
Committee
Revision of wording regarding collection of 
data from minimum 3 subjects
GSK administrative change
12.4 Appendix 4: 
Adverse Events
Change to CTCAE v.05
FDA requested changes from IND 
submission
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
7
TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................11
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................17
3.
INTRODUCTION....................................................................................................31
3.1.
Study Rationale ..........................................................................................31
3.2.
Background ................................................................................................31
3.2.1.
GSK3145095...............................................................................33
3.2.2.
Pembrolizumab............................................................................33
3.2.3.
Rationale for Combining GSK3145095 and 
Pembrolizumab............................................................................34
3.3.
Benefit/Risk Assessment ............................................................................35
3.3.1.
Risk Assessment .........................................................................36
3.3.1.1.
GSK314095 Risk Assessment....................................36
3.3.1.2.
Pembrolizumab Risk Assessment ..............................42
3.3.2.
Benefit Assessment.....................................................................43
3.3.3.
Overall Benefit:Risk Conclusion...................................................43
4.
OBJECTIVES AND ENDPOINTS...........................................................................43
5.
STUDY DESIGN ....................................................................................................46
5.1.
Overall Design ............................................................................................46
5.1.1.
Dose Escalation...........................................................................47
5.1.1.1.
Monotherapy Dose Escalation....................................47
5.1.1.2.
Combination Therapy Dose Escalation.......................48
5.1.1.3.
Dose-Limiting Toxicity ................................................50
5.1.1.4.
Maximum Dose Increment..........................................51
5.1.1.5.
Planned Dose Levels..................................................52
5.1.1.6.
Dose Escalation Decisions .........................................52
5.1.1.7.
Alternative Dosing Schedules for GSK3145095..........52
5.1.2.
Dose Expansion...........................................................................53
5.1.3.
Intra-Participant Dose Escalation and/or Therapy Switch.............54
5.1.4.
Treatment Duration......................................................................54
5.2.
Number of Participants ...............................................................................55
5.3.
Participant and Study Completion...............................................................55
5.4.
Scientific Rationale for Study Design ..........................................................55
5.5.
Human PK Prediction..................................................................................56
5.6.
Potential Efficacious Dose ..........................................................................57
5.7.
Justification for Starting Dose .....................................................................57
6.
STUDY POPULATION...........................................................................................58
6.1.
Inclusion Criteria.........................................................................................58
6.2.
Exclusion Criteria........................................................................................61
6.3.
Lifestyle Restrictions...................................................................................63
6.3.1.
Meals and Dietary Restrictions ....................................................63
6.4.
Screen Failures...........................................................................................64
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
8
7.
TREATMENTS.......................................................................................................64
7.1.
Treatments Administered............................................................................64
7.1.1.
Transition of Study Treatment from Capsules to Tablets..............65
7.2.
Toxicity Management Guidelines ................................................................65
7.2.1.
General Guidelines for Immune-Related Adverse Events 
(irAEs) .........................................................................................66
7.2.1.1.
Overview of Management of irAEs .............................66
7.2.1.2.
General Principles of Immune-Related Adverse 
Events Identification and Evaluation...........................67
7.2.2.
General Guidelines for Clinically Significant Toxicities Not 
Otherwise Specified.....................................................................70
7.3.
Method of Treatment Assignment ...............................................................71
7.4.
Blinding.......................................................................................................72
7.5.
Preparation/Handling/Storage/Accountability..............................................72
7.6.
Treatment Compliance................................................................................72
7.7.
Concomitant Therapy..................................................................................73
7.7.1.
Permitted Medications and Non-Drug Therapies..........................73
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................74
7.8.
Treatment after the End of Study Therapy ..................................................75
8.
DISCONTINUATION CRITERIA.............................................................................75
8.1.
Discontinuation of Study Treatment ............................................................75
8.1.1.
Liver Chemistry Stopping Criteria ................................................77
8.1.2.
QTc Stopping Criteria ..................................................................80
8.1.3.
Clinical Deterioration Stopping Criteria ........................................80
8.2.
Withdrawal from the Study..........................................................................81
8.3.
Lost to Follow Up........................................................................................82
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................83
9.1.
Study Visits.................................................................................................83
9.1.1.
Visit Types...................................................................................83
9.1.2.
Visit Windows ..............................................................................83
9.2.
Assessments ..............................................................................................84
9.2.1.
Screening and Critical Baseline Assessments .............................84
9.2.2.
Demographic and Baseline Assessments....................................85
9.2.2.1.
Critical Baseline Assessments....................................85
9.2.3.
Baseline Documentation of Target and Non-Target 
Lesions ........................................................................................85
9.2.4.
Disease Assessments..................................................................86
9.3.
Adverse Events...........................................................................................87
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................87
9.3.2.
Method of Detecting AEs and SAEs.............................................88
9.3.3.
Follow-up of AEs and SAEs.........................................................88
9.3.4.
Regulatory Reporting Requirements for SAEs .............................88
9.3.5.
Cardiovascular and Death Events................................................88
9.3.6.
Pregnancy ...................................................................................89
9.4.
Treatment of Overdose...............................................................................89
9.4.1.
GSK3145095 Overdose...............................................................89
9.4.2.
Pembrolizumab Overdose ...........................................................90
9.5.
Other Safety Assessments .........................................................................90
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
9
9.5.1.
Physical Examinations and Performance Status 
Evaluations..................................................................................90
9.5.2.
Vital Signs....................................................................................91
9.5.3.
Electrocardiograms......................................................................91
9.5.4.
Clinical Safety Laboratory Assessments ......................................91
9.6.
Pharmacokinetics .......................................................................................93
9.6.1.
Blood Sample Collection..............................................................93
9.6.2.
Blood Sample Processing for GSK3145095.................................94
9.6.3.
Sample Analysis ..........................................................................94
9.6.4.
Tumor Tissue Biopsy for Pharmacokinetic Assay ........................94
9.6.5.
Tissue Sample Analysis...............................................................95
9.6.6.
Assessment of CYP3A4 Enzyme Activity.....................................95
9.6.6.1.
Plasma Analysis .........................................................95
9.6.6.2.
Urine Sample Collection and Analysis ........................95
9.7.
Pharmacodynamics ....................................................................................96
9.7.1.
Blood Biomarkers ........................................................................96
9.7.2.
Tumor Tissue...............................................................................96
9.8.
Genetics .....................................................................................................97
9.9.
Immunogenicity Assessments.....................................................................97
9.10.
Health-Related Quality of Life .....................................................................97
10. STATISTICAL CONSIDERATIONS........................................................................98
10.1.
Sample Size Determination ........................................................................98
10.2.
Populations for Analyses ............................................................................98
10.3.
Hypotheses.................................................................................................98
10.3.1.
Dose Escalation (GSK3145095) ..................................................98
10.3.2.
Dose Expansion (GSK3145095)..................................................98
10.4.
Statistical Considerations for Dose Escalation ............................................99
10.4.1.
NCRM for Monotherapy Dose Escalation.....................................99
10.4.2.
mTPI for Combination Therapy Dose Escalation........................101
10.5.
Statistical Considerations for Dose Expansion..........................................101
10.6.
Statistical Analyses...................................................................................101
10.6.1.
Efficacy Analyses.......................................................................102
10.6.2.
Safety Analyses.........................................................................102
10.6.2.1.
Extent of Exposure ...................................................102
10.6.2.2.
Adverse Events ........................................................103
10.6.2.3.
Clinical Laboratory Evaluations ................................103
10.6.2.4.
Other Safety Measures.............................................103
10.6.3.
Other Analyses ..........................................................................103
10.6.3.1.
Pharmacokinetic Parameters and Analyses .............103
10.6.3.2.
Pharmacokinetic/Pharmacodynamic Analyses .........105
10.6.3.3.
Translational Research Analyses .............................105
10.6.3.4.
Novel Biomarker(s) Analyses ...................................105
10.6.3.5.
Longitudinal Tumor Size Modeling............................105
10.6.3.6.
Pharmacogenetic Analyses ......................................105
10.6.4.
Interim Analyses ........................................................................105
11. REFERENCES.....................................................................................................107
12. APPENDICES......................................................................................................110
12.1.
Appendix 1: Abbreviations and Trademarks..............................................110
12.2.
Appendix 2: Study Governance Considerations........................................116
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
10
12.2.1.
Posting of Information on Publicly Available Clinical Trial 
Registers ...................................................................................116
12.2.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process ........................................................116
12.2.3.
Dose Escalation Committee.......................................................117
12.2.4.
Quality Assurance......................................................................117
12.2.5.
Study and Site Closure ..............................................................118
12.2.6.
Records Retention.....................................................................118
12.2.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication ..........................................................................119
12.3.
Appendix 3: Liver Safety and Study Treatment Restart Guidelines ...........120
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................122
12.5.
Appendix 5: Adverse Events of Special Interest........................................128
12.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................130
12.7.
Appendix 7: Genetics................................................................................135
12.8.
Appendix 8: NYHA Functional Classification System for Heart 
Failure ......................................................................................................138
12.9.
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST version 
1.1 ............................................................................................................139
12.9.1.
Assessment Guidelines by RECIST 1.1.....................................139
12.9.2.
Evaluation of Response by iRECIST ..............................................140
12.10. Appendix 10: ECOG Performance Status .................................................147
12.11. Appendix 11: Protocol Amendment History...............................................148
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
11
1.
SYNOPSIS
Protocol Title: A Phase I/II, Open-Label Study to Investigate the Safety, Clinical 
Activity, Pharmacokinetics, and Pharmacodynamics of GSK3145095 Administered 
Alone and in Combination with Anticancer Agents Including Pembrolizumab in Adult 
Participants with Selected Advanced Solid Tumors
Short Title: First-time-in-human study of GSK3145095 alone and in combination with 
other anticancer agents in adults with advanced solid tumors
Rationale:
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths 
worldwide with a 5-year survival rate of less than 5%. A major therapeutic barrier for 
PDAC is the highly immunosuppressive myeloid infiltrate that is a hallmark of the 
pancreatic tumor microenvironment (TME). This immunosuppressive innate infiltrate is
largely responsible for PDAC resistance to current immunotherapies that target the 
adaptive immune system. To overcome this barrier, the next generation of 
immunotherapies for pancreatic cancer and other tumors with a similar cellular 
phenotype will need to modulate the innate infiltrate to increase sensitivity to T cell 
checkpoint inhibitors. 
Nonclinical evidence suggests that there is therapeutic potential for inhibition of receptor 
interacting protein 1 (RIP1), encoded by the RIPK1 gene, across multiple therapeutic 
areas, including oncology. RIP1 kinase activity in pancreatic oncogenesis reveals that 
within the pancreatic TME, RIP1 inhibition leads to the replacement of tumor-permissive 
myeloid infiltrates with innate cells that promote an effective anti-tumor response by the 
adaptive immune system (Seifert, 2016). Furthermore, in an unbiased screen, RIPK1 was 
identified as a top gene contributing to resistance to immunotherapy (Manguso, 2017). 
These data suggest that the small molecule RIP1 inhibitor GSK3145095 may have 
therapeutic potential in multiple tumor types. 
Study 205013 is a Phase 1 first-time-in-human (FTIH) study of GSK3145095 alone and 
in combination with other anticancer agents including pembrolizumab in participants 
with PDAC and other selected tumors, e.g. non-small cell lung cancer (NSCLC), triple-
negative breast cancer, or melanoma. These tumor types were chosen based on preclinical 
evidence supporting a role for RIP1 kinase activity promoting oncogenesis and/or their 
phenotypic similarity to PDAC characterized by high infiltrates of immunosuppressive 
innate infiltrates (Seifert, 2016; Manguso, 2017; Santoni, 2018; Liu, 2015; Lievense,
2013; Hartwig, 2017). The study includes up to 4 parts: Parts 1 and 2 will be conducted 
as dose escalation as monotherapy and in combination with pembrolizumab), Part 3 will
explore dose expansion with pembrolizumab, and Part 4 will explore dose expansion of 
GSK3145095 in combination with other anticancer therapies. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
12
Objectives and Endpoints:
In the following tables, primary and secondary objectives are presented separately for 
Dose Escalation (Parts 1 and 2) and Dose Expansion (Parts 3 and 4), while exploratory 
objectives are presented together for all parts.
Parts 1 & 2: Dose Escalation
Objectives
Endpoints
Primary
To evaluate the safety and tolerability and 
identify the maximum tolerated dose (MTD) 
or the maximum administered dose (MAD) of 
GSK3145095 administered orally alone and 
in combination with other agents such as 
pembrolizumab to participants with selected 
advanced or recurrent solid tumors.
Frequency and severity of adverse events 
including frequency of dose-limiting toxicities 
(DLTs).
Secondary
To evaluate the antitumor activity of 
GSK3145095 alone and in combination with 
other agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Best overall response based on RECIST 1.1 
criteria
To characterize the pharmacokinetics (PK) 
of GSK3145095 alone and in combination 
with other agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Derived PK parameters for GSK3145095 
including area under the plasma drug 
concentration versus time curve (AUC(0-t), 
AUC(0-)), maximum observed plasma drug 
concentration (Cmax), minimum observed 
plasma drug concentration (Cmin), time to 
maximum observed plasma drug 
concentration (tmax), clearance (CL/F), volume 
of distribution (V/F) and terminal half-life (t1/2) 
following single and repeat doses, and 
evaluation of dose proportionality, 
accumulation ratio and time invariance where 
data allow
To characterize the pharmacokinetics (PK) 
of pembrolizumab when administered in 
combination with GSK3145095.
Serum pembrolizumab concentrations and 
PK parameters including Cmax, AUC(0-), and 
Cmin.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
13
Parts 3 & 4: Dose Expansion
Objectives
Endpoints
Primary
To evaluate the antitumor activity of 
GSK3145095 in combination with other 
agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Overall Response Rate (ORR; % of 
participants achieving CR or PR) based on 
RECIST 1.1 criteria.
Secondary
To further evaluate the safety and tolerability 
of GSK3145095 administered orally in 
combination with other agents such as 
pembrolizumab to participants with selected 
advanced or recurrent solid tumors.
Frequency and severity of adverse events.
To further evaluate the antitumor activity of 
GSK3145095 in combination with other 
agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Progression-Free Survival and Overall 
Survival.
To characterize the PK of GSK3145095 in 
combination with other agents such as 
pembrolizumab in participants with selected 
advanced or recurrent solid tumors.
Derived PK parameters for GSK3145095 and 
combination agent including AUC(0-t), AUC(0-), 
Cmax, tmax, and t1/2 following single and repeat 
doses, and evaluation of dose proportionality, 
accumulation ratio and time invariance where 
data allow
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
14
Parts 1, 2, 3, & 4: Exploratory Objectives
Objectives
Endpoints
To explore the inter-relationship between 
antitumor activity, PK parameters, 
pharmacodynamic activity, and other 
participant characteristics
Assessment of antitumor activity (CR, PR, SD, progressive 
disease [PD]), tumor kinetic/PK parameters, pharmacodynamic 
activity, and other participant characteristics
To evaluate the pharmacokinetic and 
pharmacodynamic activity of 
GSK3145095 in the periphery and the 
tumor microenvironment
Assessment of GSK3145095 tumor penetration, RIP1 target 
engagement, activation, and pathway inhibition may be 
explored.
To evaluate the relationship between 
GSK3145095 and safety parameters, 
including QTcF following single and 
repeated administration.
Relationship between GSK3145095 exposure (e.g. 
concentration, Cmax, AUC) and safety parameters including 
change from baseline QTcF.
To explore the effect of RIP1 inhibition on 
the tumor microenvironment and the 
immune response within the tumor and
periphery
May include assessment of:

Tumor biopsies via immunohistochemistry (IHC)

Changes in gene expression (ribonucleic acid [RNA] and 
protein), T cell receptor [TCR] diversity, tumor 
microenvironment or mutational load (genomic 
deoxyribonucleic acid [DNA]) 

Measures of immune function in peripheral blood 
mononuclear cells (PBMCs)

Expression of circulating soluble factors
To investigate the mechanism of action 
and indicators of sensitivity and resistance 
to GSK3145095 alone or in combination 
with other agents such as pembrolizumab
Assessment of DNA, RNA, and/or protein markers in tumor or 
periphery and their association with anti-tumor activity for 
potential use in the development of a predictive biomarker 
and/or diagnostic test
To characterize the metabolite profile of 
GSK3145095 after single or repeated oral 
dosing in some participants
Identification and quantitative estimates of parent 
GSK3145095 and metabolites in plasma and/or urine following 
single or repeat doses
To assess potential effect of repeat doses 
of GSK3145095 on Cytochrome P450 
3A4 (CYP3A4) enzyme activity in some 
participants
Plasma 4βhydroxycholesterol to cholesterol ratio pretreatment 
and following repeat dosing of GSK3145095
To evaluate disease and treatment related 
symptoms and impact on function and 
health-related quality-of-life (Parts 3 & 4 
only)
Qualitative telephone interview(s)
To investigate the relationship between 
genetic variants in candidate genes, PK, 
and safety profile of GSK3145095 alone 
or in combination with other agents such 
as pembrolizumab
Pharmacogenomic (PGx) study using blood samples
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
15
Overall Design:
This is a FTIH, open-label, non-randomized, multicenter study designed to evaluate the 
safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of 
GSK3145095 orally administered twice daily (BID) to participants with selected 
advanced or recurrent solid tumors. 
The study will utilize a staged approach consisting of at least four parts. In Part 1, 
GSK3145095 monotherapy will be assessed in escalating doses in participants with
advanced or metastatic pancreatic cancer. Part 2 will assess escalating doses of 
GSK3145095 in combination with a fixed dose of pembrolizumab in participants with 
selected solid tumors that may include PDAC, NSCLC, triple-negative breast cancer, 
and/or melanoma. Initiation of Part 2 will occur after emerging data from Part 1 
demonstrate the safety of GSK3145095 monotherapy. Part 2 will begin with a 
GSK3145095 dose below the highest Part 1 dose shown to have an acceptable toxicity 
profile in at least 3 participants. Part 3 may evaluate the combination of one or more 
doses of GSK3145095 and pembrolizumab in disease-specific expansion cohorts via 
protocol amendment. All available safety, pharmacodynamic, PK, and efficacy data will 
be used to select 1 or more doses of GSK3145095 to evaluate in Part 3. The population of 
participants selected for Part 3 will also be determined by data emerging from Part 2. The 
protocol may be amended to include investigation of additional anticancer agent 
combinations with GSK3145095 in Part 4. 
All participants in Parts 1 and 2 must be willing to undergo mandatory fresh biopsy 
collection at baseline, on treatment, and if feasible at the time of disease progression.
Exploration of lower dose levels (or expansion of a previously tested dose level) will be 
allowed if agreed upon by the Medical Monitor and treating investigators. The 
Neuenschwander Continual Reassessment Method (NCRM) (Neuenschwander, 2008)
will be used to guide dose escalation for monotherapy and the modified Toxicity 
Probability Interval (mTPI) procedure (Ji, 2013) will be used for combination therapy. 
The final dose escalation decision will be made by the study team based on all available 
data, including biomarker and PK data and the safety profile of prior cohorts. 
Dose-escalation decisions will be documented in writing with copies maintained at each 
site and in the study files.
Criteria that may be considered in the determination of which dose level(s) to expand and 
which tumor types to enroll in Parts 3 and 4 may include target engagement and 
pharmacodynamic activity, tolerability, and clinical activity, including stable disease of at 
least 12 weeks.
Unless otherwise specified, all response endpoints will be assessed by Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1; iRECIST will be used to determine 
treatment decisions.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
16
Number of Participants:
The study will enroll up to approximately 220 participants (Parts 1 and 2 [approximately 
30 participants each], Parts 3 and 4 [approximately 80 each]) with tumor types that may 
include PDAC, NSCLC, triple-negative breast cancer, and/or melanoma.
Treatment Groups and Duration:
The study includes a screening period, a treatment period, and a follow-up period. 
Participants will be screened for eligibility beginning approximately 21 days before the 
start of treatment. The maximum duration of treatment with GSK3145095 alone and 
GSK3145095 plus pembrolizumab will be 2 years. The follow-up period for safety 
assessments will be a minimum of 3 months from the date of the last dose of any study 
drug. The post-treatment follow-up period includes disease assessments every 12 weeks 
until documented PD, initiation of another anticancer therapy, or death. Following PD or 
initiation of another anticancer therapy, participants will be contacted every 12 weeks to 
assess survival status until death occurs. 
Participants with confirmed PR or CR will be followed for response duration and may be 
eligible for additional treatment with GSK3145095 at the time of relapse/progression. 
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.
In Part 1, dose escalation for GSK3145095 monotherapy will begin with a total daily 
dose of 100 mg GSK3145095 administered by mouth in two equally divided doses 
(50 mg po BID). Planned dose levels are 100, 200, 400, 800, and 1600 mg per day but 
intermediate doses or schedules other than BID may be explored if exposure differs 
significantly from that predicted, if there is excessive toxicity, or if further evaluation of 
pharmacodynamic markers to aid dose selection is warranted. Dose escalation of 
GSK3145095 in combination with 200 mg pembrolizumab (Part 2) will begin with a 
GSK3145095 dose below the highest Part 1 dose shown to have acceptable toxicity 
profile in at least 3 participants.
Analyses:
No formal statistical hypothesis will be tested in the dose escalation phase.  
For the combination therapy, in the dose expansion phase, the anti-tumor activity of 
combination therapy will be tested using the predictive probability design of Lee and Liu 
(Lee 2008). The response rates to be tested for null and alternative hypotheses for the 
secondary endpoint of overall response rate (ORR) will be specified prior to initiation of 
the expansion phase. These rates will depend on the target tumor type and the choice of 
anti-cancer agent.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
17
2.
SCHEDULE OF ACTIVITIES (SOA)
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Office Visit
X
X1
X1
X
X
X
X
X
X
X2
X
X
Visit Types/Windows - see Section 9.1
1 On Week 1, Day 3, sites will call participants to 
assess AEs.
2After the first 6 weeks, office visits to occur 
every 3 weeks
Inclusion/ Exclusion
X
X
I/E checked prior to first dose on Day 1
See Section 6.1 and Section 6.2 re: I/E criteria
Screening
X
Participant Registration, IC, Demographics, 
MHx, Prior Medications
Refer to the Study Reference Manual (SRM)
Anti-Cancer Treatment
X
X
X
Any anti-cancer treatments administered prior to 
signing consent and/or during study follow-up 
periods will be collected. 
Administer GSK3145095 
See notes
Day 1 – single morning dose only; Day 2 –
begin BID schedule.  See Section 7.1 for 
treatment schedule.  Dosing may be delayed 
due to toxicity (Section 7.2). See Section 8 for 
treatment discontinuation criteria. GSK3145095 
will be dosed for a maximum of 2 years.
Con Meds
See notes
Concomitant medications to be collected at all 
office visits (Day 1 through Response Follow 
Up). See Section 9.1 and Section 9.3 for more 
details.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
18
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
AE/SAE Assessment
See notes
On Week 1, Day 3, sites will call participants to 
assess AEs. All other AE assessments will be 
done at office visits (weekly for the first 6 weeks 
and then q3wks).
AEs: Dose 1 – EOT. 
SAEs: Consent - 90d post last dose
AESIs: Dose 1 – 90d post last dose. 
See Section 9.1 and Section 9.3 for more 
details.
PS, PE, VS, Weight
X
X
X
X
X
X
X
X
X
Weekly for first 6 wks, then every 3 wks and at 
EOT visit; see Section 9.5.1 and Section 9.5.2
for more details.
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
Days 1,2,8,15,16,22, and 36: triplicate 12-lead 
ECGs to coincide with PK timepoints. Other 
days: single 12-lead ECGs. PK samples will be 
collected directly after ECG, not during the 
recordings.
HIV, HCV, HBVAb, UA 
X
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
19
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Pregnancy Test
X
X
X
X
X
Women of child bearing potential only. Serum 
test is required at screening & EOT visits. Urine 
pregnancy test is adequate at other visits. Day 1 
test should be done within 24 hours before the 
first dose of any study drug. If a urine test 
cannot be confirmed as negative (e.g., an 
ambiguous result), a serum pregnancy test is 
required. After starting study treatment, 
participants will undergo urine pregnancy testing 
every 3 weeks and whenever a menstrual cycle 
is missed or when pregnancy is otherwise 
suspected. If the participant hasn’t been on an 
acceptable method of contraception for at least 
2 weeks prior to start of therapy, pregnancy 
testing must be done weekly for the first month 
of treatment.
CBC, Chemistry, LFT
X
X
X
X
X
X
X
X
X
Weekly for the first 6 weeks, then q3wks, and at 
the EOT visit.  See Table 9 for more details 
regarding Clinical Safety Laboratory 
Assessments.
TFT
X
X
X
At screening, q6wk and as clinically indicated.  
See Table 9 for more details regarding Clinical
Safety Laboratory Assessments.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
20
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Disease 
Assessment/Imaging
X
X
X
X
Screening: within 28 days before the first dose
Treatment: every 6 weeks for the first 24 weeks, 
then every 12 weeks until disease progression 
confirmed by iRECIST (see Section 9.2.4 and 
Section 12.9.2) ; disease assessment 
(Section 9.2) must be performed after biopsy
(See Section 9.1.2 for visit windows); 
EOT: required if the last disease assessment 
did not show progressive disease & was 
performed 6 weeks before EOT.
Follow-up: every 12 weeks in the absence of 
progression or starting another anticancer 
therapy.
Fresh tumor tissue
X1
X1
X2
X3
X3
1 Two fresh tumor biopsy samples are required 
in Part 1, the first during screening and the 
second after 5 weeks of study treatment.
Please refer to Section 9.7.2. 
2 With participant consent & agreement by the 
PI & GSK Medical Monitor, additional optional 
fresh biopsies may be obtained during the 
study. See Section 9.7.2.
3 Optional fresh tumor biopsy should be 
attempted at disease progression (EOT or 
during follow-up). PK & PD blood samples
should be obtained within approximately 1h of 
tumor biopsy.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
21
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Blood PD
X1
X2
X2,3
X4,5,6
X
X7
1 Pre-dose, 1.5h, and 8h after dosing
2 Pre-dose
3 After 5 weeks of study treatment, on the day 
of the fresh tumor biopsy collection. If no on-
treatment biopsy, the blood PD sample must 
still be taken.
4 Obtain sample on day of first tumor imaging, 
before administration of any IV contrast
5 If participant consents to additional biopsies, 
the blood PD sample must be taken at the 
time of collection of the additional biopsy. 
6 With participant consent & agreement by the 
PI & GSK Medical Monitor, additional optional 
blood samples may be obtained during the 
study. See Section 9.7.1.
7 If a tumor biopsy is taken at the time of 
disease progression at EOT or during 
follow-up, then a PD blood sample must be 
taken within approximately 1h of tumor 
biopsy.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
22
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Plasma PK
X1
X1
X2
X3
X3
X2
X2
X4
X4
1 Day 1 (single dose PK): Pre-dose (within 1h 
prior to dosing) & 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 
8h, 10h, and 24h (before Day 2 morning dose). 
The 10-hour collection is optional
2 Pre-dose and 1.5h post dose (morning dose 
only).
3 Day 15: Pre-dose & 0.5h, 1h, 1.5h, 2h, 3h, 4h, 
6h, 8h, 10h (before evening dose), & 24h 
(before Day 16 morning dose). The 10-hour 
collection is optional. If possible after the 
Day 15 evening dose: 0.5h, 1h, 2h, 3h, 6h, & 
8h (in addition to the pre-dose sample on Day 
16). 
4 If a tumor biopsy is taken at the time of 
disease progression at EOT or during followup, 
then a PK blood sample should be taken within 
approximately 1h of tumor biopsy.
The number and sampling times may be 
adjusted based on the emerging PK data 
available. Refer to SRM for additional details.
4β-HC/Cholesterol
Plasma
X
X
X
Part 1 only, all dose levels. Day 1 predose, 
Day 15 predose and Day 36 predose
Metabolite Plasma
X
X
X
X
Part 1 only, all dose levels. Day 1 to coincide 
with all PK timepoints.  Day 2 predose, Day 15
to coincide with all PK timepoints, Day 16 
predose.  See SRM for additional details.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
23
Monotherapy Schedule
Visit Week 
Visit Day
SCR
1
2
3
4
5
6
7+
EOT
Follow Up
Notes
1
2
8
15
16
22
29
36
43+
Response
Survival
Urine Metabolite
X
X
Part 1 only, all dose levels. To be taken pre-
dose, 0-24h on Day 1 and 0-24h on Day 15. The 
024h urine volume will be measured, and 200 
mL will be aliquoted for metabolite identification 
purposes.
Genetics (PGx) sample
X
See Appendix 7 for more details
Follow-up telephone call
X
Survival status: See Section 9.1 for more details 
regarding follow-up visit types. Participants 
should be contacted every 12±2 weeks after 
documented disease progression (or after 
initiation of another anticancer treatment) until 
death.
Abbreviations: AE=adverse event; AESI=AE of special interest; BID=twice daily; CBC=complete blood count; Con Meds=concomitant medications; CrCl=calculated creatinine clearance; 
ECG=electrocardiogram; EOT=end of treatment; HBVAb=hepatitis B virus antibody; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IC=informed consent; I/E=inclusion/exclusion;
iRECIST = modified RECIST 1.1 for immune-based therapeutics; LFT=liver function test; MHx=medical history; PD=pharmacodynamics (or progressive disease, depending on context); 
PE=physical examination; PK=pharmacokinetic(s); PS=performance status; q#wks=every # weeks; SAE=serious AE; SRM=study reference manual; TFT=thyroid function test; UA=urinalysis; 
VS=vital signs; wks=weeks.
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
24
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Office Visit
X
X1
X
X
X
X
X
X
X
X2
X
X
Visit Types/Windows – see Section 9.1
1 On Week 1, Day 3, sites will call participants 
to assess AEs.
2 After the first 6 weeks, office visits to occur 
every 3 weeks.
Inclusion/Exclusion
X
X
I/E checked prior to first dose on Day 1
See Section 6.1 and Section 6.2 re: I/E criteria
Screening
X
Participant Registration, IC, Demographics, 
MHx, Prior Medications
Refer to the Study Reference Manual (SRM)
Anti-Cancer Treatment
X
X
X
Any anti-cancer treatments administered prior 
to signing consent and/or during study 
followup periods will be collected.
Administer 
Pembrolizumab
See notes
See Section 7.1 for dosing schedule. Dosing 
may be delayed due to toxicity (Section 7.2). 
See Section 8 for treatment discontinuation 
criteria. GSK3145095 alone or in combination 
with pembrolizumab will be dosed for a 
maximum of 2 years.
For GSK3145095, BID from Day 1. If the half-
life is found to be more than 5 hours in 
monotherapy, the Day 1 evening dose will be 
omitted.
Administer GSK3145095 
See notes
Con Meds
See notes
Concomitant medications to be collected at all 
office visits (Day 1 through Response 
Follow-up). See Section 9.1 and Section 9.3
for more details.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
25
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
AE/SAE Assessment
See notes
On Week 1, Day 3, sites will call participants 
to assess AEs. All other AE assessments will 
be done at office visits (weekly for the first 
6 weeks and then q3wks).
AEs: Dose 1 – EOT. 
SAEs: Consent - 90d post last dose
AESIs: Dose 1 – 90d post last dose. 
See Section 9.1 and Section 9.3 for more 
details
PS, PE, VS, Weight
X
X
X
X
X
X
X
X
X
Weekly for first 6 wks, then every 3 wks and at 
EOT visit; see Section 9.5.1 and Section 9.5.2
for more details.
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
Days 1, 2, 8, 15, 16, 22, and 36: triplicate 
12-lead ECGs to coincide with PK timepoints 
(GSK3145095 and pembrolizumab). Other 
days: single 12-lead ECGs. PK samples will 
be collected directly after ECG, not during the 
recordings
HIV, HCV, HBVAb, UA 
X
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
26
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Pregnancy Test
X
X
X
X
X
Women of child bearing potential only. Serum 
test is required at screening & EOT visits. 
Urine pregnancy test is adequate at other 
visits. Day 1 test should be done within 
24 hours before the first dose of any study 
drug. If a urine test cannot be confirmed as 
negative (e.g., an ambiguous result), a serum 
pregnancy test is required. After starting study 
treatment, participants will undergo urine 
pregnancy testing every 3 weeks and 
whenever a menstrual cycle is missed or 
when pregnancy is otherwise suspected. If the 
participant hasn’t been on an acceptable 
method of contraception for at least 2 weeks 
prior to start of therapy, pregnancy testing 
must be done weekly for the first month of 
treatment.
CBC, Chemistry, LFT
X
X
X
X
X
X
X
X
X
Weekly for the first 6 weeks, then q3wks, and 
at the EOT visit.  See Table 9 for more details 
regarding Clinical Safety Laboratory 
Assessments.
TFT, Cortisol
X1
X2
X1
X1
1TFTs at screening, q6wks, and as clinically 
indicated.
2Day 1: baseline a.m. cortisol only (no TFTs); 
to be collected before 1st dose, and then as 
clinically indicated.  See Table 9 for more 
details regarding Clinical Safety Laboratory 
Assessments.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
27
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Disease Assessment 
and Tumor Imaging
X
X
X
X
Screening: within 28 days before the first dose
Treatment: every 6 weeks for the first 
24 weeks, then every 12 weeks until disease 
progression confirmed by iRECIST; disease 
assessment must be performed after biopsy; 
see Section 9.2.
EOT: required if the last disease assessment 
did not show progressive disease and was 
performed 6 weeks before EOT.
Follow-up: every 12 weeks in the absence of 
progression or starting another anticancer 
therapy.
Fresh Tumor Tissue
X1
X1
X2
X3
X3
1 Two fresh tumor biopsy samples are 
required in Part 2, the first during screening 
and the second after 5 weeks of study 
treatment. Disease assessment must be 
performed after biopsy. Please refer to 
Section 9.7.2. 
2 With participant consent & agreement by 
the PI & GSK Medical Monitor, additional 
optional fresh biopsies may be obtained 
during the study. See Section 9.7.2.
3   Optional fresh tumor biopsy should be 
attempted at disease progression (EOT or 
during follow-up). PK & PD blood samples
must be obtained within approximately 1h of 
tumor biopsy.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
28
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Blood PD
X1
X2
X2,3
X4,5,6
X
X7
1 Pre-dose, 1.5h, and 8h after dosing 
GSK3145095
2 Pre-dose relative to GSK3145095
3 After 5 weeks of study treatment, on the day 
of the fresh tumor biopsy collection. If no 
on-treatment biopsy, the blood PD sample 
must still be taken.
4 Obtain sample on day of first tumor imaging, 
before administration of any IV contrast
5 If participant consents to a
tional biopsies, the blood PD sample should 
be taken at the time of collection of the 
additional biopsy.
6 With participant consent & agreement by 
the PI & GSK Medical Monitor, additional 
optional blood samples may be obtained 
during the study. See Section 9.7.1.
7 If a tumor biopsy is taken at the time of 
disease progression at EOT or during 
follow-up, then a PD blood sample must be 
taken within approximately 1h of tumor 
biopsy.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
29
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Plasma PK for 
GSK3145095
X1
X1
X2
X3
X3
X2
X2
X4
X4
1 Day 1 (single dose PK): pre-dose (within 1h 
prior to dosing) & 0.5h, 1h, 1.5h, 2h, 3h, 4h, 
6h, 8h, 10h, and 24h (before Day 2 morning 
dose). The 10 hour collection is optional. 
2 Pre-dose and 1.5h post dose (morning dose 
only, relative to GSK3145095 dose).
3 Day 15: pre-dose & 0.5h, 1h, 1.5h, 2h, 3h, 
4h, 6h, 8h, 10h (before evening dose), & 
24h (before Day 16 morning dose). The 10 
hour collection is optional. If possible after 
the Day 15 evening dose: 0.5h, 1h, 2h, 3h, 
6h, & 8h (in addition to the pre-dose sample 
on Day 16).
4 If a tumor biopsy is taken at the time of 
disease progression at EOT or during 
follow-up, then a PK blood sample must be 
taken within approximately 1h of tumor 
biopsy.
The number and sampling times may be 
adjusted based on the emerging PK data 
available. Refer to SRM for additional details.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
30
Combination Therapy Schedule
Visit Week 
Visit Day (if applicable)
SCR
1
2
3
4
5
6
7+
EOT
Follow-Up
Notes
1
2
8
15
16
22
29
36
43+
Respon
se
Survival
Pembrolizumab
PK
X1
X2
X2
X3
X3
X2
1 Cycle 1 Day 1: pre-dose (within 1 hour 
before the start of infusion) and 0.5 h (within 
30 minutes after the end of infusion) and 24h 
(±4h) after the end of infusion. 
2 Anytime during visit
3 Day 1 of all subsequent cycles: pre-dose 
(within 1 hour before the start of infusion)
The number and sampling times may be 
adjusted based on the emerging PK data 
available. Refer to SRM for additional details.
Refer to SRM for additional details.
Genetics (PGx) sample
X
See Appendix 7 for more details
Follow-up telephone call 
X
Survival status: See Section 9.1 for more 
details regarding followup- visit types. 
Participants should be contacted every 
12±2 weeks after documented disease 
progression (or after initiation of another 
anticancer treatment) until death.
Abbreviations: AE=adverse event; AESI=AE of special interest; BID=twice daily; CBC=complete blood count; Con Meds=concomitant medications; CrCl=calculated creatinine clearance; 
ECG=electrocardiogram; EOT=end of treatment; HBVAb=hepatitis B virus antibody; HCV=hepatitis C virus; HIV=human immunodeficiency virus; IC=informed consent; I/E=inclusion/exclusion;
iRECIST = Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; LFT=liver function test; MHx=medical history; PD=pharmacodynamics (or 
progressive disease, depending on context); PE=physical examination; PK=pharmacokinetic(s); PS=performance status; q#wks=every # weeks; SAE=serious AE; SRM=study reference 
manual; TFT=thyroid function test; UA=urinalysis; VS=vital signs; wks=weeks.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
31
3.
INTRODUCTION
3.1.
Study Rationale
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer deaths 
worldwide with a 5-year survival rate of less than 5%. A major therapeutic barrier for 
PDAC is the highly immunosuppressive myeloid infiltrate that is a hallmark of the 
pancreatic tumor microenvironment (TME). This immunosuppressive innate infiltrate is 
largely responsible for PDAC resistance to current immunotherapies that target the 
adaptive immune system. To overcome this barrier, the next generation of 
immunotherapies for pancreatic cancer and other tumors with a similar cellular 
phenotype will need to modulate the innate infiltrate to increase sensitivity to T cell 
checkpoint inhibitors. 
Nonclinical evidence suggests that there is therapeutic potential for inhibition of receptor 
interacting protein 1 (RIP1), encoded by the RIPK1 gene, across multiple therapeutic 
areas, including oncology. Increased RIPK1 protein expression has been reported in 
human pancreatic (Seifert, 2016), hepatocellular (Wang, 2016), melanoma (Liu, 2015), 
and gallbladder (Zhu, 2014) cancer biopsies, as well as gliomas from resected brain 
tumors (Park, 2009). In each of these studies, RIPK1 expression correlated with a worse 
patient prognosis. In murine models, RIP1 kinase activity has been reported to drive 
pancreatic oncogenesis. Inhibition of kinase activity in the pancreatic TME leads to the 
replacement of tumor-permissive myeloid infiltrates with innate cells that promote an 
effective anti-tumor response by the adaptive immune system (Seifert, 2016). 
Furthermore, in an unbiased screen, RIPK1 was identified as a top gene contributing to 
resistance to immunotherapy (Manguso, 2017). These data suggest that the small 
molecule RIP1 inhibitor GSK3145095 may have therapeutic potential in multiple tumor 
types.  
Study 205013 is a Phase 1 first-time-in-human (FTIH) study of GSK3145095 alone and 
in combination with other anticancer agents including pembrolizumab, in participants 
with PDAC, non-small cell lung cancer, triple-negative breast cancer, or melanoma. 
These tumor types were chosen based on preclinical evidence supporting a role for RIP1 
kinase activity promoting oncogenesis and/or their phenotypic similarity to PDAC 
characterized by high infiltrates of immunosuppressive innate infiltrates (Seifert 2016; 
Manguso, 2017; Santoni, 2018; Liu, 2015; Lievense, 2013; Hartwig, 2017). The study 
includes up to 4 parts: Parts 1 and 2 (Dose Escalation) and Parts 3 and 4 (Dose 
Expansion) The hypothesis being tested in this study is that GSK3145095 can be safely 
administered to participants with selected advanced or recurrent solid tumors at doses at 
which target engagement and pharmacodynamic effects can be demonstrated. No formal 
statistical hypotheses will be tested; analyses will be descriptive and exploratory.
3.2.
Background
Inflammation and cell death are intimately linked, and an appropriate balance between 
the two is essential for maintaining tissue homeostasis. Tumorigenesis represents one of 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
32
the best examples of the pathological consequences of a disruption in this balance, as 
dysregulated cross-talk between cell death and immune signaling in the tumor promotes 
immunosuppression and tissue-regeneration. To circumvent this miscommunication, 
much work has been done to develop immuno-therapies that directly activate the adaptive 
immune system to induce cytotoxicity and tumor regression. However, therapeutics that 
block immune checkpoints in T cells are only able to eradicate malignant cells if the T 
cells can infiltrate the tumor and effectively interact with proinflammatory innate 
immune cells (Garrido-Laguna, 2015). 
The lack of efficacy of T cell based immuno-therapies in pancreatic ductal 
adenocarcinoma (Garrido-Laguna, 2015) underscores the importance of targeting 
additional immunoregulatory pathways. Hallmarks of PDAC that contribute to this 
therapeutic barrier include the vast infiltrate of myeloid cells, and impenetrable 
desmoplasia (Scarlett, 2013, Garrido-Laguna, 2015, Engblom, 2016). Tumor infiltrated 
myeloid cells often correlate with a worse patient prognosis and are increasingly 
recognized as key drivers of an immunosuppressive tumor microenvironment 
contributing to therapeutic resistance. For these reasons, immunomodulation of the 
myeloid cell population within tumors is an attractive target for next-generation 
therapeutics in PDAC (Scarlett, 2013).
Recent work demonstrates a novel role for RIP1 kinase activity in recruiting 
immunosuppressive myeloid cells in PDAC (Seifert, 2016). RIP1 is a ubiquitous kinase 
but is only active upon homeostatic disruptions. In its ubiquinated form, RIP1 provides a 
scaffolding function essential to pro-survival NF-κB signaling that is required for vitality. 
Inhibition of cIAP proteins prevent RIP1 ubiquitination, and in the absence of pro-
apoptotic caspase activity, will lead to a RIP1 kinase dependent, pro-inflammatory 
programmed cell death termed necroptosis (Ofengeim, 2013). Initially it was thought that 
inducing necroptosis in tumor cells could serve as a novel treatment for tumors resistant 
to apoptosis. However, increasing evidence reveals a detrimental effect of danger 
associated molecular patterns (DAMPs) released following necrosis or necroptosis within 
solid tumors (Lofti, 2016), and necroptosis in endothelial cells promotes metastasis 
(Strilic, 2016). 
It is increasingly clear that there are a variety of RIP1 driven processes that are 
independent of cell death including cytokine secretion (Najjar, 2016), cell differentiation 
(Xin, 2017), DNA stability (Chen, 2014, Park, 2009), extravasation (Hänggi, 2018), and 
anchorage independent cell growth (Liu, 2016). Given these additional roles for RIP1 
kinase activity, combined with the negative effects of necroptosis in solid tumors, it is not 
surprising that recent in vivo work shows a role for RIP1 in promoting oncogenesis that 
contradicts earlier in vitro studies. Recent work from the Miller lab, for example, showed 
that RIP1 kinase activity leads to the recruitment of myeloid derived suppressor cells 
(MDSCs), tumor associated macrophages (TAMs) and IL-10 expressing T cells in a 
CXCL1 and SAP130 dependent manner to promote pancreatic oncogenesis (Seifert,
2016). This work has been expanded internally to show that therapeutic blockade of RIP1 
kinase activity retarded tumor progression and decreased fibrosis within the remaining 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
33
pancreatic tumor. Preclinical PDAC models support the clinical hypothesis. The first 
models tested were the orthotopic KPC and transgenic KC models. In the former model, 
tumors are derived from a mouse harboring the same Kras and p53 mutations present in 
>90% of pancreatic cancer cases. In the latter, pancreatic intraepithelial (PanIN) lesions 
develop spontaneously due to a Kras mutation. Similar to human tumors, these tumors 
are fibrotic in nature and resistant to anti-PD1. In both models, maintenance of >90% 
inhibition of RIP1 in the periphery led to an approximate 50% decrease in tumor size. 
Concomitant with this efficacy, there was a significant decrease in the number of M2-like 
TAMS. Macrophages present in the tumor after RIP1 inhibition were polarized to a more 
M1-like anti-tumor phenotype (Seifert, 2016, and unpublished data). Furthermore, RIP1 
inhibition markedly upregulated T-cell infiltration and PD-1 expression on the T cells in 
the TME. Functionally, this sensitized tumors to checkpoint blockade with anti-PD1. In a 
third subcutaneous model using pan02 cells, inhibiting RIP1 >90% in the periphery also 
led to an approximate 50% reduction in tumor size. Similarly, the addition of anti-PD1 
increased the efficacy in this model.
3.2.1.
GSK3145095
GSK3145095 is a compound which is structurally similar to the lead RIP1 inhibitor 
GSK2982772, which is currently in Phase 2 clinical development. Results from healthy 
volunteer study with GSK2982772 have been published (Weisel, 2017). GSK3145095 
demonstrates consistent pharmacology across all the assays in the RIP1 critical path. 
GSK3145095 is a high-quality candidate with desirable physiochemical properties which 
result in excellent pharmacokinetic and safety profiles. Please refer to Section 5.7 for 
details on selection of the starting dose, and the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2017N334332_00] for additional details.
In vivo efficacy for GSK3145095 could not be evaluated because it is not selective for 
non-primate RIP1. This necessitated the use of the tool compound GSK3540547A, a 
potent mouse RIP1 inhibitor for evaluation of anti-tumor activity in the pancreatic tumor 
model. One dose was evaluated in the form of food-based dosing which resulted in 
approximately 50% tumor growth inhibition with blood concentration maintained above 
90% RIP1 inhibition during the entire dosing period. A dose of 100 mg when 
administered as 50 mg BID is anticipated to provide 97.4% RIP1 inhibition in the blood 
over the dosing interval in 50% of participants. The actual level of RIP1 inhibition 
required for anti-tumor activity in humans is not known.
GSK3145095 has not yet been studied in humans.
3.2.2.
Pembrolizumab
Immunotherapy has emerged as a transformative anticancer therapeutic strategy over the 
past few years.  In particular, the inhibition of negative T cell regulatory pathways with 
the checkpoint inhibitors has been very successful, first in the treatment of melanoma 
and, more recently, expanding to additional indications, including NSCLC. Ipilimumab 
and pembrolizumab are examples of these initial checkpoint inhibitors, which are mAbs 
that block the activity of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
34
PD-1 pathways, respectively, thereby freeing the T cell priming and T cell effector 
functions from their negative regulatory effects.  
Pembrolizumab, a humanized monoclonal antibody against the PD-1 protein, has been 
developed by Merck & Co for the treatment of patients with cancer. Pembrolizumab is 
approved for treatment of patients with melanoma in several countries; in the US and EU 
it is approved for the treatment of patients with advanced (unresectable or metastatic) 
melanoma in adults. Pembrolizumab has also been approved for treatment of patients 
with NSCLC in several countries; in the US it is indicated for the treatment of patients 
with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-
approved test and who have disease progression on or after platinum-containing 
chemotherapy. Patients with NSCLC and EGFR or ALK genomic tumor aberrations 
should also have disease progression on FDA-approved therapy for these aberrations 
prior to receiving pembrolizumab. In the US, pembrolizumab is also approved for the 
treatment of patients with recurrent or metastatic squamous cell carcinoma of the head 
and neck with disease progression on or after platinum-containing chemotherapy.
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy 
trials in participants with non-small cell lung cancer, head and neck squamous cell 
carcinoma, urothelial cancer, gastric cancer, triple negative breast cancer and Hodgkin’s 
Lymphoma as determined by response rate. Ongoing clinical trials are being conducted in 
advanced melanoma, NSCLC, head and neck cancer, urothelial cancer, gastric cancer, 
TNBC, Hodgkin’s lymphoma and a number of other advanced solid tumor indications 
and hematologic malignancies.  For study details please refer to the IB [Merck Sharp & 
Dohme Corp, 2015].  
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W.
3.2.3.
Rationale for Combining GSK3145095 and Pembrolizumab
The anticancer immune response is a multistep process that includes antigen processing 
and presentation, T-cell priming and activation, tumor infiltration, and subsequent 
destruction by activated effector T cells (Chen, 2013). Each of these steps can be 
negatively regulated, which provides the malignant tumor with redundant mechanisms by 
which to block an anticancer immune response. In some cases, tumors will be highly 
dependent on a single mechanism, and in these cases, there is the potential to achieve 
significant clinical activity with a single immunomodulatory therapy. However, it is 
expected that tumors will often utilize redundant mechanisms to block the antitumor 
immune response. In these instances, combination therapies will likely be required. 
Current immunotherapies such as the anti-PD1 checkpoint inhibitor pembrolizumab 
target the latter of these processes to release pathways negatively regulating T-cell 
activation. While these therapies have revolutionized cancer patient care in certain 
indications, they are not approved for pancreatic cancer. In order to complement T-cell 
checkpoint inhibitors and sensitize resistant tumors, one approach for the next generation 
of immuno-therapeutics is to target the innate immune system. This clinical study aims to 
release the immuno-suppressive mechanisms imposed on the adaptive system from M2-
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
35
like TAMs to sensitize tumors to checkpoint blockade. The preclinical data described 
above supports this hypothesis
RIP1 has also been implicated in promoting oncogenesis in hepatocellular, melanoma, 
and breast tumor models. Furthermore, in an unbiased screen, RIP1 was identified as a 
top gene contributing to resistance to immunotherapy (Manguso, 2017). These data 
suggest that the small molecule RIP1 inhibitor GSK3145095 may have therapeutic 
potential when combined with immunotherapy such as pembrolizumab in multiple tumor 
types. 
3.3.
Benefit/Risk Assessment
To date, GSK3145095 has not been administered to human participants; therefore, no
clinical data are available. Th is is the first dose escalation study proposed in human 
participants with GSK3145095. GlaxoSmithKline is not aware of any compound
targeting RIP1 for oncology having previously been administered in humans.  The risk 
assessment of GSK3145095 is based on the nonclinical studies conducted to date. 
Summaries of findings from nonclinical studies conducted with GSK3145095 can be 
found in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2017N334332_00].  
Details of these risks and the proposed strategy to mitigate/monitor these risks are 
detailed in Section 3.3.1. The proposed risk assessment and management plan for the 
study has been developed in accordance with the tenets of European Medicines Agency 
(EMA) guideline on strategies to identify and mitigate risks for first time in human 
(FTiH) clinical trials with investigational medicinal products [European Medicines 
Evaluation Agency (EMEA)/ Committee for Medicinal Products for Human Use 
(CHMP)/SWP/28367/07]. GlaxoSmithKline (GSK) has assessed this study for any risks 
that may be posed to participants taking part. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
36
3.3.1.
Risk Assessment
3.3.1.1.
GSK314095 Risk Assessment
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity
Non-clinical data:
In vitro

BSEP inhibition in vitro (IC50=25 uM). BSEP 
risk prediction (i.e., Cmax/BSEP IC50 ≥0.05) 
suggests GSK3145095 could be a BSEP 
inhibitor in vivo at ≥150 mg per day dose 
(Cmax = 0.75 µg/mL; 1.8 µM)

Glutathione adduct formation: A trace 
oxidative, defluorinated glutathione 
conjugate was detected in human liver 
microsomal incubates as well as at trace 
levels in rat and monkey hepatocytes, but 
not in human hepatocytes (however 
cryopreserved human hepatocytes might 
express low glutathione-S-transferase). 

CYP3A induction – In vitro human pregnane 
X receptor (hPxr) activation.
In vivo

There was no evidence of hepatotoxicity in 
the 4-week rat or monkey studies.  There 
was a small increase in liver weight and 
serum cholesterol after 1 month at high 
dose (300 mg/kg/day) in female rats and a 
small increase in liver weight and 4beta-
hydroxycholesterol for 1 female monkey 
after 1 month of dosing at high dose 
(60 mg/kg/day), suggesting CYP3A 
induction.
Inclusion criteria:
Hepatic
Total bilirubin
For participants with Gilbert’s Syndrome 
(only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
AST
ALT
≤2.5xULN
2.5xULN 
Exclusion criteria:  

Current active liver or biliary disease (except for Gilbert’s syndrome or 
asymptomatic gallstones, liver metastasis, or otherwise stable chronic liver 
disease per investigator assessment).  
NOTE: Stable chronic liver disease should generally be defined by the 
absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, persistent jaundice, or cirrhosis. 

Known current drug or alcohol abuse.
Permitted Medications: 

Acetaminophen: Due to potential risk of liver toxicity when combining 
acetaminophen with GSK3145095, acetaminophen dosage is 
restricted to no more than 2g per day. 
Participant Monitoring:

Chemistry laboratory tests reflecting liver function are readily 
obtainable in the clinic and will be monitored weekly for the first 6 
weeks, then q3wk and at the EOT visit.

Plasma and urine will be screened for reactive metabolite formation.

Liver Chemistry Stopping Criteria are included in the clinical protocol.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
37
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Increases in Heart rate, Decreases in 
blood pressure and effects on QT 
interval
Nonclinical data: 

Increases in heart rate observed in both the 
4-week toxicology study and the single 
dose safety pharmacology monkey study 
were transient and reversible and seem to 
correlate with systemic drug exposure 
levels

There were apparent increases in QTc in 
both sexes given 60 mg/kg/day 
GSK3145095 during Week 4; however, the 
relationship to test item cannot be 
determined due to the test item related 
changes in heart rate.  

In a cardiovascular study in monkeys, a 
single oral dose of 60 mg/kg produced a 
reversible increase in HR (up to 59 beats 
per minute or 45%), and a reversible 
decrease in mean arterial pressure (up to 
22 mmHg or 24%), systolic blood pressure 
(up to 21 mmHg or 20%), diastolic blood 
pressure (up to 20 mmHg or 27%), and QT 
interval (up to 38 milliseconds or 16%).  
Since the effects of QT were inconsistent 
between the single dose CV study and the 
4-week study, there was an uncertain 
relationship to drug,
Inclusion criteria:

QTcF >450 msec (or QTcF >480 msec for participants with bundle 
branch block)
Exclusion Criteria:
History or evidence of cardiovascular risk including any of the 
following:

Recent (within the past 6 months) history of serious uncontrolled 
cardiac arrhythmia or clinically significant electrocardiogram (ECG) 
abnormalities including second degree (Type II) or third degree 
atrioventricular block.  

Documented cardiomyopathy, myocardial infarction, acute coronary 
syndromes (including unstable angina pectoris), coronary angioplasty, 
stenting, or bypass grafting within the past 6 months before beginning 
screening.  

Documented congestive heart failure (Class II, III, or IV) as defined by 
the New York Heart Association functional classification system.  

Recent (within the past 6 months) history of symptomatic pericarditis.  
Participant Monitoring: 

Standard ECG monitoring for QT effect (i.e., intermittent PK matched 
timepoints to assess QTc)
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
38
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Bone marrow effects/lymph node 
enlargement
Nonclinical data: 

Sternal bone marrow necrosis or lymph 
node necrosis was present in 2 female 
monkeys given 60 mg/kg/day. Test item-
related clinical pathology findings at 60 
mg/kg/day were characterized by 
decreased reticulocyte (up to 0.23X Pretest) 
and platelet counts (up to 0.55X Pretest), 
and red cell mass (up to 0.64X Pretest) as 
measured by hemoglobin, hematocrit, and 
RBC counts in males and females, 
increased total white blood cells (up to 
2.39X Pretest).  GSK3145095-related 
microscopic changes were increased 
generalized cellularity or increased 
inflammatory cell infiltrates in various 
organs including the spleen (minimal to 
moderate), lymph nodes (minimal to 
marked) and bone marrow (slight to 
marked) in animals given 20 mg/kg/day, 
most notably at 60 mg/kg/day
Inclusion criteria:
Hematologic
ANC
≥1.5x109/L
Lymphocyte count
>1000/mm3
Hemoglobin
≥9 g/dL
Platelets
≥100x109/L
Participant Monitoring: 

CBC weekly for the first 6 weeks, then 
q3wks and at the EOT visit

Physical exams (weekly for first 6 wks, 
then q3wks and at the EOT visit) and 
imaging (see Schedules of Activities, 
Section 2) to include monitoring for 
lymphadenopathy
Immunomodulation and/or risk of 
infection
Although there were no signs of infections observed 
preclinically, the possibility of immune modulation 
including an increase in the frequency and/or severity 
of infections may result from the intended 
pharmacologic effect of GSK3145095. 
Immune-compromised conditions such as 
malignancies and immunosuppressive cancer 
treatment may compound this risk.
Infections may include, but are not limited to, Herpes 
Zoster. Herpes Zoster is relatively common, with a 
Exclusion criteria: 

Concurrent medical condition requiring the use of systemic 
immunosuppressive medications within 28 days before the first dose of 
study treatment. Physiologic doses of corticosteroids for treatment of 
endocrinopathies or steroids with minimal systemic absorption, including 
topical, inhaled, or intranasal corticosteroids, may be continued if the 
participant is on a stable dose.  

Active infection (including active herpes zoster infection), known human 
immunodeficiency virus infection, or positive test for hepatitis B surface 
antigen or hepatitis C.  
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
39
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
lifetime risk between 25% and 30% and overall 
incidence between 3 to 5 cases per 1000 person-
years in the general population.
Participant Monitoring: 

Participants will undergo routine physical examinations at regular 
intervals while on study.
Vaccinations 
There is a theoretical risk that GSK3145095 could 
alter an individual’s immune response to vaccines or 
allow symptoms to develop following vaccination with 
a live vaccine when administered while on therapy.
Exclusion criteria: 

Receipt of any live vaccine within 4 weeks before starting study 
treatment.
Study Restriction:

Receipt of any live vaccine within 5 half-lives of GSK3145095 plus 
30 days after discontinuation of GSK3145095.
Participant management: 

Attenuated or live vaccines should not be administered to participants 
from 30 days prior to the first dose of GSK3145095, during the study and 
for 5 half-lives plus 30 days (total 32 days) after GSK3145095 is 
discontinued. 

If indicated, non-live vaccines (e.g. inactivated influenza vaccines) may 
be administered while receiving GSK3145095 based on a treating 
physician’s assessment of the benefit:risk (e.g., risk of theoretical 
decreased responsiveness). 
Investigators will be expected to have followed local and/or national guidelines 
with respect to vaccinations, including against influenza and pneumococcus.
Drug-drug Interactions: 
Victim Interaction: with potent inhibitors 
of Pgp, resulting in potential increased 
exposure of GSK3145095 if fraction 
absorbed (Fa) is low (<50%)
Perpetrator Interaction:
with narrow therapeutic index (NTI) 
CYP3A4 substrates such as the anti-
rejection drugs cyclosporine, sirolimus, 
Nonclinical data:
GSK3145095 was a P-gp substrate in vitro with an 
efflux ratio of >100. In vivo bioavailability (F) was high 
(≥78%) in all species tested except mouse, for which 
F= 26%, suggesting it may be high in human.
In vitro human pregnane X receptor (hPxr) activation 
suggests potential for CYP3A4 induction in vivo; 
however in monkey 4 week study, no observed 
increase in 4β-hydroxycholesterol (4β-HC; biomarker 
for CYP3A activity) at NOAEL (20 mg/kg/day; Cmax = 
Subject Selections:

Subjects who are taking concomitant medications known to inhibit Pgp or 
are CYP3A4 narrow therapeutic index (NTI) substrates or are sensitive 
substrates of OATP1B1 or OATP1B3 transporters will be excluded from 
the study.
Subject Monitoring:

Subjects’ concomitant medication usage will be reviewed prior to 
inclusion and monitored throughout the study.

Subjects should be monitored throughout the study for potential effects 
of interaction between GSK3145095 and other concomitant medications.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
40
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and tacrolimus, resulting in potential 
loss of exposure and thus efficacy.
Via weak inhibition of CYP2C9, 
perpetrator risk for NTI CYP2C9 
substrates (i.e., warfarin and phenytoin) 
only at highest dose of 800 mg BID.
Via weak inhibition of uptake 
transporters, OATP1B1 and OATP1B3, 
perpetrator risk for sensitive OATP 
substrates, including but not limited to 
Grazoprevir, Eluxadoline, Paritaprevir, 
Rosuvastatin, Pitavastatin and 
Pravastatin  
No DDI risk is predicted for co-
administration of GSK3145095 with 
pembrolizumab
9.58 g/mL) and <2-fold increase in 4β-HC at highest 
dose (60 mg/kg/day; Cmax = 24 g/mL). 
In vitro CYP2C9 inhibition in human liver microsomes 
IC50 = 78 µM
In vitro inhibition of uptake transporters, OATP1B1 
and OATP1B3 [IC50 = 38.0 and 43.9 µM, 
respectively, corrected for nonspecific binding]
Literature review:
Clearance of mAbs is through lysosomal degradation 
or endocytosis. Absorption is dependent on 
physiological parameters not related to enzymes or 
transporters and distribution is dependent on 
extravasation in tissue and distribution in the 
interstitial space. Thus no known mechanistic 
opportunity for a DDI with an NCE such as 
GSK3145095.
Patient urine will be pooled and analyzed for parent and metabolites to provide 
information on fraction absorbed.
The 4β-HC to cholesterol ratio will be measured in patient plasma pre-dose and 
after repeat dosing to assess potential changes in hepatic CYP3A4 activity.
Advise caution at GSK2982772 plasma Cmax ≥ 8 g/mL, predicted for 1600 mg 
daily (800 mg BID), only with NTI CYP2C9 substrates.
Reproductive toxicity
Since EFD studies have not been completed, the 
reproductive toxicity is not known.  GSK3145095 was 
not mutagenic.  Induction of CYP3A4 in humans 
could lead to a potential DDI with oral contraceptives; 
as substrates, their exposure and thus effectiveness 
could decrease.
Participant Selection:

Male and female participants of childbearing potential will be included in 
this study only if they agree to use highly effective methods of 
contraception and avoid conception for defined periods of time before 
first administration of study drug until 15 days (males/females – Part 1) 
and 120 days (males/females – Parts 2-4) after the last administration of 
study drug 

Females of childbearing potential will undergo serum pregnancy test at 
screening. After starting study treatment, participants will undergo urine 
pregnancy testing every 3 weeks and whenever a menstrual cycle is 
missed or when pregnancy is otherwise suspected. If the participant 
hasn’t been on an acceptable method of contraception for at least 2 
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
41
GSK314095 Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
weeks prior to start of therapy, pregnancy testing must be done weekly 
for the first month of treatment.

Pregnant and lactating females are not eligible for inclusion in the study.
Withdrawal Criteria:
If a female participant should become pregnant during the study, study 
medication should be discontinued. The participant will be followed to determine 
the outcome of the pregnancy. Any pregnancy complication or elective 
termination of a pregnancy will be reported as an AE or SAE.
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
42
3.3.1.2.
Pembrolizumab Risk Assessment
Pembrolizumab Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Immune related reactions  

Pneumonitis 

Colitis 

Nephritis 

Neuritis 

Hepatitis 

Skin inflammation

Endocrinopathies
Identified risks caused by an 
excessive T-cell immune activation 
and potential expansion and 
activation of T-cell clones against 
normal tissues
Please refer to the KEYTRUDA prescribing information and Section 7.2
(Management of Immune Related SAEs)
Infusion reaction 
(pembrolizumab)
Identified risk associated with 
pembrolizumab infusion
Please refer to the KEYTRUDA prescribing information
Reproductive toxicity
Participant Selection:

Male and female participants of childbearing potential will be included in this study only if they 
agree to use highly effective methods of contraception and avoid conception for defined periods of 
time before first administration of study drug until 15 days (Part 1) for males/females, and 120 
days (Parts 2-4) for males/females after the last administration of study drug 

Females of childbearing potential will undergo serum pregnancy test at screening and then urine 
pregnancy testing at regular intervals during the study. 

Pregnant and lactating females are not eligible for inclusion in the study.
Withdrawal Criteria:
If a female participant should become pregnant during the study, study medication should be discontinued. 
The participant will be followed to determine the outcome of the pregnancy. Any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.
No DDI risk is predicted for co-
administration of GSK3145095 
with pembrolizumab
 
 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
43
3.3.2.
Benefit Assessment
In vivo efficacy for GSK3145095 could not be evaluated because it is not selective for 
non-primate RIP1. This necessitated the use of the tool compound GSK3540547A, a 
potent mouse RIP1 inhibitor for evaluation of anti-tumor activity in the pancreatic tumor 
model. Only one dose was evaluated in the form of food-based dosing which resulted in 
approximately 50% tumor growth inhibition with blood concentration maintained above 
the IC90 for RIP1 inhibition during the entire dosing period. A dose of 100 mg when 
administered as 50 mg BID is anticipated to provide 97.4% RIP1 inhibition in the blood 
over the dosing interval in 50% of participants. The actual level of RIP1 inhibition which 
would translate into efficacy in humans is not known.  
3.3.3.
Overall Benefit:Risk Conclusion
This is an open-label, dose escalation study and the FTIH study of this agent to be 
conducted in participants with relapsed/refractory solid tumors for which no standard 
therapies are anticipated to result in a durable remission. GSK3145095 has nonclinical 
activity in vivo, however it is unknown whether GSK3145095 will have clinical activity, 
thus any potential beneficial effect for an individual participant attributable to 
GSK3145095 is unknown. Data obtained in this study may help identify individuals more 
likely to benefit or have side effects from GSK3145095. Study participants may benefit 
from the medical tests and screening performed during the study.  
4.
OBJECTIVES AND ENDPOINTS
In the following tables, primary and secondary objectives are presented separately for 
Parts 1 & 2 (monotherapy and combination escalation) and Parts 3 & 4 (expansion), 
while exploratory objectives are presented together for all parts.
Parts 1 & 2: Dose Escalation
Objectives
Endpoints
Primary
To evaluate the safety and tolerability and 
identify the maximum tolerated dose (MTD) or 
the maximum administered dose (MAD) of 
GSK3145095 administered orally alone and in 
combination with other agents such as 
pembrolizumab to participants with selected 
advanced or recurrent solid tumors.
Frequency and severity of adverse events 
including frequency of DLTs.
Secondary
To evaluate the antitumor activity of 
GSK3145095 alone and in combination with 
other agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Best overall response based on 
RECIST 1.1 criteria
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
44
Parts 1 & 2: Dose Escalation
Objectives
Endpoints
To characterize the pharmacokinetics (PK) of
GSK3145095 alone and in combination with 
other agents such as pembrolizumab in 
participants with selected advanced or 
recurrent solid tumors.
Derived PK parameters for GSK3145095 
including area under the plasma drug 
concentration versus time curve (AUC(0-t), 
AUC(0-)), maximum observed plasma drug 
concentration (Cmax), minimum observed 
plasma drug concentration (Cmin), time to 
maximum observed plasma drug 
concentration (tmax), clearance (CL/F), 
volume of distribution (V/F) and terminal 
half-life (t1/2) following single and repeat 
doses, and evaluation of dose 
proportionality, accumulation ratio and time 
invariance where data allow
To characterize the pharmacokinetics (PK) of 
pembrolizumab when administered in 
combination with GSK3145095.
Serum pembrolizumab concentrations and 
PK parameters including Cmax, AUC(0-), 
and Cmin.
Parts 3 & 4: Dose Expansion
Objectives
Endpoints
Primary
To evaluate the antitumor activity of 
GSK3145095 in combination with other agents 
such as pembrolizumab in participants with 
selected advanced or recurrent solid tumors.
ORR (% of participants achieving CR or 
PR) based on RECIST 1.1 criteria.
Secondary
To further evaluate the safety and tolerability 
of GSK3145095 administered orally in 
combination with other agents such as 
pembrolizumab to participants with selected 
advanced or recurrent solid tumors.
Frequency and severity of adverse events.
To further evaluate the antitumor activity of 
GSK3145095 in combination with other agents 
such as pembrolizumab in participants with 
selected advanced or recurrent solid tumors.
Progression-Free Survival and Overall 
Survival.
To characterize the PK of GSK3145095 in 
combination with other agents such as 
pembrolizumab in participants with selected 
advanced or recurrent solid tumors.
Derived PK parameters for GSK3145095 
and combination agent including AUC(0-t), 
AUC(0-), Cmax, tmax, and t1/2 following single 
and repeat doses, and evaluation of dose 
proportionality, accumulation ratio and time 
invariance where data allow
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
45
Parts 1, 2, 3, & 4: Exploratory Objectives
Objectives
Endpoints
To explore the inter-relationship between 
antitumor activity, PK parameters, 
pharmacodynamic activity, and other 
participant characteristics
Assessment of antitumor activity (CR, PR, SD, progressive 
disease [PD]), tumor kinetic/PK parameters, pharmacodynamic 
activity, and other participant characteristics
To evaluate the pharmacokinetic and 
pharmacodynamic activity of 
GSK3145095 in the periphery and the 
tumor microenvironment
Assessment of GSK3145095 tumor penetration, RIP1 target 
engagement, activation, and pathway inhibition may be 
explored.
To evaluate the relationship between 
GSK3145095 and safety parameters, 
including QTcF following single and 
repeated administration.
Relationship between GSK3145095 exposure (e.g. 
concentration, Cmax, AUC) and safety parameters including 
change from baseline QTcF.
To explore the effect of RIP1 inhibition on 
the tumor microenvironment and the 
immune response within the tumor and
periphery
May include assessment of:

Tumor biopsies via immunohistochemistry (IHC)

Changes in gene expression (ribonucleic acid [RNA] and 
protein), T cell receptor [TCR] diversity, tumor 
microenvironment or mutational load (genomic 
deoxyribonucleic acid [DNA]) 

Measures of immune function in peripheral blood 
mononuclear cells (PBMCs)

Expression of circulating soluble factors
To investigate the mechanism of action 
and indicators of sensitivity and resistance 
to GSK3145095 alone or in combination 
with other agents such as pembrolizumab
Assessment of DNA, RNA, and/or protein markers in tumor or 
periphery and their association with anti-tumor activity for 
potential use in the development of a predictive biomarker 
and/or diagnostic test
To characterize the metabolite profile of 
GSK3145095 after single or repeated oral 
dosing in some participants
Identification and quantitative estimates of parent 
GSK3145095 and metabolites in plasma and/or urine following 
single or repeat doses 
To assess potential effect of repeat doses 
of GSK3145095 on Cytochrome P450 
3A4 (CYP3A4) enzyme activity in some 
participants
Plasma 4βhydroxycholesterol to cholesterol ratio pretreatment 
and following repeat dosing of GSK3145095
To evaluate disease and treatment related 
symptoms and impact on function and 
health-related quality-of-life (Parts 3 & 4 
only)
Qualitative telephone interview(s)
To investigate the relationship between 
genetic variants in candidate genes, PK, 
and safety profile of GSK3145095 alone 
or in combination with other agents such 
as pembrolizumab
Pharmacogenomic (PGx) study using blood samples
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
46
5.
STUDY DESIGN
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Schedule of Activities (Section 2) 
are essential.
5.1.
Overall Design
This is a FTIH, open-label, non-randomized, multicenter study designed to evaluate the 
safety, tolerability, PK, pharmacodynamics, and preliminary clinical activity of 
GSK3145095 orally administered twice daily (BID) to participants with selected 
advanced or recurrent solid tumors. 
The study will be conducted in a staged approach consisting of at least 4 parts, as shown 
in Figure 1. Parts 1 and 2 represent dose escalation while Parts 3 and 4 represent dose 
expansion. Parts 2, 3, and 4 will be opened via protocol amendment. Part 1 dose 
escalation will be conducted in approximately 30 adult participants with advanced or 
metastatic pancreatic ductal adenocarcinoma (PDAC) using escalating doses of 
GSK3145095 as monotherapy only. The protocol may be amended to include one or 
more biomarker cohorts. 
Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab. Dose 
escalation of GSK3145095 will begin at least one level below the highest dose shown to 
have an acceptable toxicity profile in at least 3 participants in Part 1. Part 2 may be 
conducted in a broader population of selected solid tumors, including but not limited to,
PDAC, NSCLC, triple-negative breast cancer (TNBC), and/or melanoma using a 
combination of escalating doses of GSK3145095 and 200 mg pembrolizumab. 
Part 3 may enroll participants treated with one or more dose levels of GSK3145095 in 
combination with 200 mg pembrolizumab. Cohorts in Part 3 may be defined by 
indication or biomarker.
Part 4 may investigate the combination of additional anticancer agent(s) with one or more 
doses of GSK3145095 identified as safe in Part 1.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
47
Figure 1
Study Design
5.1.1.
Dose Escalation
5.1.1.1.
Monotherapy Dose Escalation
In Part 1, dose level 1, a single 50 mg dose of GSK3145095 will be administered to each 
participant in that cohort on the first day of treatment. Blood samples will be taken before 
and after the first dose to assess PK parameters (see Schedules of Activities, Section 2). 
On study Day 2, participants will then continue to receive 50 mg of GSK3145095 BID.
The first 3 participants treated at Part 1 dose level 1 will begin treatment at least 1 week 
apart to allow assessment of initial safety data between the enrolment of each participant.
Evaluation of the available PK and safety data over the first 4 weeks of treatment (DLT 
period) is required from at least 3 participants before a decision is made regarding 
whether to enroll additional participants at the same or the next higher dose level. 
Participants who do not experience a DLT and withdraw from the study before the 
completion of the DLT period may be replaced if they have not received at least 80% of 
GSK3145095 (all participants) and/or 2 doses of pembrolizumab (for combination 
therapy participants). All data from the replaced subjects who received less than 80% of 
GSK3145095 because of low grade toxicity not constituting a DLT will still be taken into 
consideration for dose-escalation and determination of the recommended Phase 2 dose 
(RP2D).
After a minimum of 3 participants in Part 1 dose level 1 have completed the DLT 
evaluation period (i.e., first 28 days), subsequent dose levels may initially enroll up to 4 
participants with participants beginning treatment at least one calendar day apart. A 
minimum of 3 participants will be enrolled in each subsequent cohort until the maximum 
tolerated dose (MTD) or maximum administered dose (MAD) is defined. 
The Neuenschwander Continual Reassessment Method (NCRM) (Neuenschwander,
2008) will be used to guide dose escalation decisions for monotherapy. At the time of 
each dose escalation decision, the Fixed and Adaptive Clinical Trial Simulator (FACTS) 
will be used to obtain, for each potential dose, the posterior probabilities that the DLT 
rate for that dose lies in each of four toxicity intervals (underdosing, target toxicity range, 
3
1
4
5
Part 1: Pancreatic 
cancer
GSK3145095 
monotherapy 
2
Part 3: Selected 
solid tumors 
Indication 1
Indication 2
RP2D GSK3145095 + 
pembrolizumab
Indication 3
Part 4: Selected 
solid tumors
Indication 1
Indication 2
Indication 3
RP2D GSK3145095 + 
other anticancer therapy
Part 2: Selected 
solid 
tumors
GSK3145095 + 
pembrolizumab
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
48
excessive toxicity, and unacceptable toxicity). The four DLT toxicity intervals are 
defined as follows: 

[0%,16%)=Underdosing; 

[16%,33%)=Target toxicity range; 

[33%,60%)=Excessive toxicity; 

[60%,100%)=Unacceptable toxicity.  
The recommended dose will be 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%. An updated estimate of the toxicity curve will be 
provided at the time of each dose escalation meeting. Statistical properties of NCRM are 
described in Section 10. 
Exploration of lower dose levels than the NCRM-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 from previous dose levels.  This includes the 
NCRM-recommended dose as described earlier in this section, Section 5.1.1.6 and 
Section 10.4.1, and all safety and PK data. Safety data includes, but is not limited to, 
dose limiting toxicities and toxicities regardless of grade that result in dose reductions or 
delays. All dose escalation decisions will be assessed by the Dose Escalation Committee
(DEC, see Section 12.2.3). The DEC is comprised of study investigators and the GSK 
study team (GSK Medical Monitor, pharmacokineticist, biomarker scientist, and 
statisticians).
Criteria that may be considered in the determination of which dose level(s) to expand and 
which tumor types to enroll in Parts 3 and 4 may include safety, target engagement,
pharmacodynamic activity, and clinical activity.
5.1.1.2.
Combination Therapy Dose Escalation
The DEC will make the decision of whether to start Part 2 as described in Section 12.2.3:
Dose escalation of GSK3145095 in combination with 200 mg pembrolizumab (Part 2) 
will target 3 participants up to a target maximum of 6 at each dose level and will begin 
with a GSK3145095 dose below the highest Part 1 (monotherapy) dose shown to have an 
acceptable toxicity profile in at least 3 participants. GSK3145095 dose levels used in 
combination therapy may be the same dose levels as for monotherapy. The dose of 
pembrolizumab will remain fixed at 200 mg administered IV once every three weeks
(Q3W). 
Fewer doses in combination therapy (compared to monotherapy) are expected to be 
studied for dose escalation; therefore, the modified Toxicity Probability Interval (mTPI) 
procedure (Ji, 2013) (and not NCRM) will be used to identify the MTD or the MAD of 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
49
GSK3145095 in combination with pembrolizumab (or other anticancer therapy) and 
determine the recommended dose to be used in the dose expansion phase (Parts 3 and 4).
Dose escalation will proceed until the MTD or MAD for GSK3145095 in combination 
with 200 mg Q3W pembrolizumab is determined. Dose escalation decisions will be based 
on all available PK, pharmacodynamic, and safety data of ongoing and prior cohorts. This 
data will be reviewed by the (DEC). The dose-escalation decision for the subsequent 
cohort and rationale will be documented in writing with copies maintained at each site 
and the study files.
The rules guiding dose escalation based on the mTPI procedure are provided in Figure 2. 
Columns provide the numbers of participants treated at the current dose level, and rows 
provide the corresponding numbers of participants experiencing toxicity. The 
recommended decision (E = escalate to next higher dose, S = stay at current dose, 
D = de-escalate, DU = unacceptably toxic dose) is determined by taking the row showing 
the total number of participants with DLT at the current dose and finding the cell that 
corresponds to the column showing total number of participants in the current dose level.
For example, when one of three participants experiences DLT at the current dose, the 
decision can be located at row indicating 1 and column indicating 3, which is S (to stay at 
the current dose level). All dose escalation decisions will be assessed by the DEC (See 
Section 12.2.3).
Figure 2
Rules Guiding Dose Escalation (mTPI Procedure)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
D
S
S
S
S
E
E
E
E
E
E
E
E
E
E
2
DU
D
S
S
S
S
S
S
S
E
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
S
8
DU
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
DU
12
DU
DU
DU
DU
13
DU
DU
DU
14
DU
DU
15
DU
No. of Participants Treated at Current Dose
No. of Dose-Limiting Toxicities
The spreadsheet was generated based on a beta/binomial model and precalculated before 
trial initiation. The letters in different colors are computed based on the decision rules 
under the mTPI method and represent different dose-finding actions. In addition to 
actions de-escalate the dose (D), stay at the same dose (S), and escalate the dose (E), the 
E
= Escalate to the next higher dose
S
= Stay at the current dose
D = De-escalate to the next lower dose
DU = Unacceptably toxic dose
Target Toxicity Rate (Interval):
30% (25%, 35%)
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
50
table includes action unacceptable toxicity (DU), which is defined as the execution of the 
dose-exclusion rule in mTPI.
5.1.1.3.
Dose-Limiting Toxicity
All toxicities will be graded using National Cancer Institute - Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE) (version 5.0).  
An AE is considered a DLT if it occurs during the first 28 days of treatment, is 
considered by the investigator to be clinically relevant, and meets one of the following 
criteria listed in Table 1, unless it can be clearly established that the event is unrelated to 
treatment. As described in Section 5.1.1.1, participants unable to receive at least 80% of 
scheduled doses for reasons other than toxicity (e.g., acute illness, disease progression) 
will not be evaluable for DLT purposes and will be replaced in the cohort. If an AE is 
considered related to the underlying disease, it is not a DLT. For Part 2 and Part 3, 
Grade 3 toxicities that are known to occur with pembrolizumab and are controlled 
within 2 weeks using the recommended supportive measures (see Section 7.2) may not be 
considered dose-limiting.  
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Section 7.2 and is based on the experience of management of immune-related 
adverse events (irAEs) since the development of ipilimumab and PD-1 inhibitors such as 
pembrolizumab.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
51
Table 1
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Febrile neutropenia of any duration

Grade 4 neutropenia of >7 days’ duration or requiring G-CSF

Grade 4 anemia of any duration

Grade 4 thrombocytopenia of any duration or Grade 3 thrombocytopenia with 
bleeding
Non-
hematologic

Grade 4 toxicity

Grade 3 toxicity that does not downgrade to Grade 1 or baseline within 3 days 
despite optimal supportive carea

Any Grade 2 ocular toxicity requiring systemic steroids, or any ≥ Grade 3 ocular 
toxicity
Other

Toxicity that results in permanent discontinuation of GSK3145095 or GSK3145095 
and pembrolizumab during the first 4 weeks of treatment

Toxicity attributed to treatment resulting in administration of <80% of scheduled 
GSK3145095 doses.

Any other toxicity considered to be dose-limiting that occurs beyond 4 weeks will be 
considered in the selection of the dose for expansion cohorts

Any other event which in the judgment of the investigator and GSK Medical Monitor is 
considered a DLT
a.
Suggested management guidelines are described in Section 7.2 for toxicity and may include systemic 
corticosteroids for immune-related toxicities; if use of systemic corticosteroids delays administration of the second 
dose of study treatment, but the event does not otherwise meet the DLT criteria for non-hematologic toxicity, the 
dose delay will not be considered a DLT. 
DLT = Dose-limiting toxicity; G-CSF = Granulocyte colony-stimulating factor; AST = Aspartate aminotransferase; 
ALT = Alanine aminotransferase; ULN = Upper limit of normal; GSK = GlaxoSmithKline
Table 1 provides a list of protocol-defined DLTs; it does not provide guidelines for 
management of these toxicities. In appropriate clinical circumstances, resumed dosing 
after a DLT (at a reduced dose level) may be considered after discussion between the 
investigator, medical monitor, and GSK medical governance (as necessary). For 
management of liver toxicity, please refer to Section 8.1.1. For management of cardiac 
toxicity, see Section 8.1.2. For management of all other toxicities, see Section 7.2.
5.1.1.4.
Maximum Dose Increment
Built-in safety constraints are in place to prevent exposing participants to undue risk of 
toxicity. The dose levels described in Section 5.1.1.5 represent protocol-defined 
maximum dose increments; investigators and the GSK medical monitor will include the 
data from all prior dose levels (Section 5.1.1.6) in the selection of the next dose level, and 
a smaller increment may be used based on the totality of the available data. 
For each individual dose escalation step, if no grade ≥ 2 non-hematologic non-disease-
related toxicity is observed at the current dose, the dose increment will be no more than 
100% of the current dose.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
52
5.1.1.5.
Planned Dose Levels
Projected total daily dose levels of GSK3145095 are 100 mg, 200 mg, 400 mg, 800 mg, 
and 1600 mg. These doses will be administered twice daily in equally divided doses. For 
example, participants in the 100 mg dose level will receive 50 mg GSK3145095 by 
mouth twice daily. Please refer to Table 3 at the beginning of Section 7.1 for additional
details of GSK3145095 administration. Doses intermediate to these or alternate schedules 
may be explored based on emerging safety, PK, and PD data. See Section 5.1.1.7 for 
discussion of alternate schedules. 
5.1.1.6.
Dose Escalation Decisions
The DEC will be responsible for determining whether dose escalation should continue as
recommended by NCRM (Part 1) or mTPI procedure (Part 2). Prior to the dose escalation 
decision, the DEC will review critical safety data defined in the Dose Escalation Plan, 
including data on all adverse events including non-DLT toxicities, laboratory assessments 
and other safety evaluations, as well as PK and PD data. The quality review of critical 
safety data will be described in the Dose Escalation Plan, which includes ongoing study 
monitoring visits along with data review of the clinical database.  See Section 12.2.3 for 
more details. 
The dose-escalation decision and rationale for each cohort will be discussed with 
investigators during teleconference(s) and documented in writing with copies maintained 
at each study site and in the master study files at GlaxoSmithKline (GSK).
5.1.1.7.
Alternative Dosing Schedules for GSK3145095
Alterations may be made to the schedule of GSK3145095 administration and/or PK/PD 
sampling schedule based on the results of emerging PK and safety data. Schedules of 
GSK3145095 administration that incorporate a recovery period may be explored (e.g., 3 
weeks on, 1 week off). This approach will be considered if the safety and PK data suggest 
that a therapeutic exposure of GSK3145095 cannot be achieved using the initial schedule 
without excessive toxicity. Escalation of GSK3145095 using an alternate schedule will 
begin at or below the highest dose level with the initial schedule shown to be safe in at 
least 3 participants (and not to exceed the MTD, if identified). Escalation of 
GSK3145095 using the alternate schedule will then proceed as described in Section 
5.1.1.1 through Section 5.1.1.6.
Schedules of GSK3145095 that use a different daily regimen (e.g., once daily [QD] or 
three times daily [TID] dosing) may also be explored. This approach will be considered if 
the safety, PK, and PD data suggest that a sufficient therapeutic exposure of 
GSK3145095 cannot be achieved using the initial schedule. If an alternate schedule of 
GSK3145095 with a shorter recovery period (for example, TID dosing) is used, 
escalation of GSK3145095 will begin with a dose that is 50% of the highest dose level 
shown to be safe in at least 3 participants with the initial schedule (and not to exceed the 
MTD, if identified). Escalation of GSK3145095 using the alternate schedule will then 
proceed as described in Section 5.1.1.1 through Section 5.1.1.6. If TID dosing is to be 
utilized, a study events table specific for TID dosing will be distributed to all sites.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
53
The dosing schedule of GSK3145095 may also be adjusted to expand a prior dose cohort 
to further evaluate safety, pharmacokinetic and/or pharmacodynamic findings at a given 
dose level, or to add cohorts to evaluate additional dose levels. The study procedures for 
these additional participant(s) or cohort(s) will be the same as that described for other 
study participants.
Any changes to the dosing schedule may be made only after review of all available data
and clearance by the GSK medical monitor. Any planned changes will apply to a cohort
of participants and not an individual participant. Changes will be communicated to the 
site in writing along with justification and data supporting the change. A modified SRM,
including updated Schedules of Activities, will be provided to the sites prior to initiation
of the alternative regimen.
5.1.2.
Dose Expansion
Any dose level(s) established as safe in Parts 1 or 2 may be selected for cohort expansion 
in Parts 3 or 4 to collect additional data on safety, PK, pharmacodynamic activity, and 
clinical activity. Each expansion cohort will enroll up to approximately 30 participants 
with the same tumor type. 
Additional expansion cohorts may enroll up to approximately 20 participants per cohort
to further explore pharmacodynamic activity. 
Part 3 will evaluate GSK3145095 in combination with 200 mg pembrolizumab. Selection 
of tumor indications will be based in part on data generated in Parts 1 and 2, respectively. 
The GSK study team will review the available preliminary safety, PK, pharmacodynamic, 
and clinical activity data with investigators and site staff before selecting the dose level 
indications for all expansion cohorts. Criteria that may be considered in the determination 
of which dose level(s) to expand and which tumor types to select for cohort expansion 
may include:
•
Target engagement and pharmacodynamic activity
•
Tolerability: The frequency and severity of AEs and DLT.  
•
Clinical activity: Evidence of clinical response, including SD of at least 12 weeks 
and/or minor responses.  
After 10 participants have been enrolled at a given dose level, continued accrual in the
expansion cohort up to a total of approximately 20 to 30 participants may occur based on 
emerging anti-tumor and pharmacodynamic data. While it is anticipated that the 
additional 10 to 20 participants in each cohort will be treated at the same dose level as the 
initial 10 participants, exploration of a different dose level based on emerging data is also 
possible. 
The selection of dose level(s) and tumor types selected for Part 3 will be communicated 
to the sites in writing.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
54
The protocol may be amended to include investigation of additional anticancer agent 
combinations with GSK3145095 in Part 4.
5.1.3.
Intra-Participant Dose Escalation and/or Therapy Switch
There will be no intra-participant dose escalation.
Participants in Part 1 may be eligible for crossover into Parts 3 or 4 (once these Parts 
have been opened at a dose of GSK3145095 previously shown to be safe in Part 1) upon 
disease progression and with discussion and approval from the GSK Medical Monitor.
5.1.4.
Treatment Duration
The study includes a screening period, a treatment period, and a follow-up period (visit 
windows for these periods are in Section 9.1.2). Participants will be screened for 
eligibility beginning approximately 4 weeks before the start of treatment. The maximum 
duration of treatment with GSK3145095 with or without pembrolizumab will be 2 years 
(Table 2) or 35 cycles (each cycle is 21 days), whichever comes first. The follow-up 
period for safety assessments will be a minimum of 3 months from the date of the last 
dose of any study drug. The post-treatment follow-up period includes disease assessments 
every 12 weeks until documented progressive disease (PD), initiation of other anticancer 
therapy, or death. Following PD or initiation of other anticancer therapy, participants will 
be contacted every 12 weeks to assess survival status. 
Participants with confirmed partial response (PR) or complete response (CR) will be 
followed for response duration and may be eligible for additional treatment with 
GSK3145095 with or without pembrolizumab at the time of relapse/progression. 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.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
55
Table 2
Study Treatments
Part 1: Dose Escalation – GSK3145095 monotherapy
GSK3145095 PO BIDa for up to 2 years
Part 2: Dose Escalation – GSK3145095 + pembrolizumab
GSK3145095 PO BIDb for up to 2 years
Pembrolizumab 200 mg IV Q3W for up to 2 years
Part 3: Dose Expansion – GSK3145095 + pembrolizumab
GSK3145095 PO BIDc for up to 2 years
Pembrolizumab 200 mg IV Q3W for up to 2 years
Part 4: Dose Expansion – GSK3145095 + anticancer agent
GSK3145095 PO BIDc for up to 2 years
Combination Partner to be communicated by amendment
Note: Participants will receive a single dose of GSK3145095 on Day 1 with the BID schedule starting on 
Day 2.
a: For dose levels, see Section 5.1.1.5.
b: Combination escalation to start at least one dose level below the highest dose of GSK3145095 shown to 
be safe in Part 1.
c: At one or two dose levels shown to be tolerable in Part 2. 
PO = by mouth; BID = twice daily; IV = Intravenous; Q3W = Every 3 weeks
5.2.
Number of Participants
Up to approximately 220 participants will be treated in the study. Parts 1 and 2 will each 
treat up to approximately 30 participants will be treated. Parts 3 and 4 may treat up to 
approximately 160 participants (up to 80 participants in each Part).
5.3.
Participant and Study Completion
Because participants will be followed for survival in this study, only when a participant 
dies is he/she considered to have completed the study; consequently “death” is not listed 
as a reason for withdrawal from the study. Furthermore, disease progression, 
discontinuation of study treatment, and AEs are not by themselves reasons for withdrawal 
from the study as follow-up for overall survival (OS) is desired. If a participant dies, a 
copy of the death certificate should be available for review, if possible, and the cause of 
death should be evaluated and documented.
The end of the study is defined as the last participant’s last visit/contact.
5.4.
Scientific Rationale for Study Design
The study will utilize a staged approach consisting of at least four parts. In Part 1, 
GSK3145095 monotherapy will be assessed in escalating doses in participants with 
advanced or metastatic pancreatic cancer. Part 2 will assess escalating doses of 
GSK3145095 in combination with a fixed dose of pembrolizumab in participants with 
selected solid tumors that may include PDAC, NSCLC, triple-negative breast cancer, 
and/or melanoma. Initiation of Part 2 will occur after emerging data from Part 1 
demonstrates the safety and pharmacodynamic activity of GSK3145095 monotherapy. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
56
Part 2 will begin with a GSK3145095 dose below the highest Part 1 dose shown to be 
safe in at least 3 participants. Part 3 may evaluate the combination one or more doses of 
GSK3145095 and pembrolizumab in disease-specific expansion cohorts via protocol 
amendment. All available safety, pharmacodynamic, PK, and efficacy data will be used 
to select 1 or more doses of GSK3145095 to evaluate in Part 3. The population of 
participants selected for Part 3 will also be determined by data emerging from Part 2. The 
protocol may be amended to include investigation of additional anticancer agent 
combinations with GSK3145095 in Part 4. 
To ensure sufficient safety and pharmacodynamic data are available before beginning 
enrollment in Part 2 of the study, available clinical data from Part 1 of the study, 
including safety, PK, pharmacodynamics, and efficacy, will be reviewed. The decision to 
initiate Part 2 will be documented and reported to all participating PIs and IRBs/IECs.
In the dose escalation phase (Parts 1 and 2), participants will be enrolled with selected 
solid tumors that are likely to respond to RIP1 inhibition therapy (e.g., indications 
previously reported to have a response to immunotherapies, predicted immunogenicity, 
and/or expression of RIP1). The tumor types to be evaluated in dose escalation may 
include the following: PDAC, NSCLC, triple negative breast cancer, and/or melanoma.
The inclusion of the combination with pembrolizumab is based on the preference to 
identify potential transformational activity early in development. GSK3145095 is not 
expected to have significant clinical activity as a monotherapy, and the full potential of 
the molecule is likely to be discovered in combination with other agents, particularly 
immunotherapies because RIP1 was identified as a top gene contributing to resistance to 
immunotherapy (Manguso, 2017). Pembrolizumab is an ideal combination partner for 
GSK3145095 because it targets a different aspect of the cancer-immunity cycle, has a 
toxicity profile of mainly Grade 1 or 2 events, and preclinical data strongly supports the 
potential for synergy.
Recently reported data show that within the pancreatic TME, RIP1 inhibition leads to the 
replacement of tumor-permissive myeloid infiltrates with innate cells that promote an 
effective anti-tumor response by the adaptive immune system (Seifert, 2016). To better 
understand dose-response and variables that may influence clinical response to treatment 
with GSK3145095 alone or in combination with pembrolizumab, it is critical that 
immune biomarkers in the TME are assessed in this study across a range of doses and, if 
feasible, correlated with clinical response. Thus, pharmacodynamic markers will be 
evaluated in Parts 1 and 2 to aid dose selection. 
5.5.
Human PK Prediction
Several methods were used to predict the PK of GSK3145095 in humans based on 
nonclinical PK data from various species (mouse, rat, dog, and cynomolgus monkey) and 
in vitro studies conducted with human liver microsomes and hepatocytes. Population PK 
analysis using data delivered from Dedrick transformation allowed prediction of 
compartmental IV PK parameters with predicted human blood clearance of 14.3 L/h/70 
kg, central volume of distribution of 46.6 L/70 kg, peripheral volume of distribution of 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
57
66.4 L/70 kg and intercompartmental clearance of 7.76 L/h/70 kg. Oral bioavailability is 
calculated as 79% based on average in nonclinical species. Linear PK of GSK3145095 is 
assumed for human PK prediction.
5.6.
Potential Efficacious Dose
In vivo efficacy for GSK3145095 could not be evaluated because it is not selective for 
nonprimate RIP1 (IC90 range from 4503 -14239 ng/mL). This necessitated the use of tool 
compound GSK3540547A, a potent mouse RIP1 inhibitor for evaluation of anti-tumor 
activity in the pancreatic tumor model. One dose level of the tool molecule (administered 
in the diet) was evaluated which resulted in approximately 50% tumor growth inhibition,
with blood concentrations maintained at approximately IC98 for RIP1 inhibition during 
the entire dosing period. A dose of 140 mg GSK3145095 (when administered as 70 mg 
BID) is anticipated to provide 98% RIP1 inhibition in the blood over the dosing interval 
in 50% of participants. When between-subject variability in PK parameters and IC50 are 
accounted for, assuming the variability between subjects with respect to PK parameters
and IC50 is similar for GSK3145095 and the RIP1 inhibitor lead (GSK2982772), a dose 
of 400 mg GSK3145095 administered as 200 mg BID is anticipated to provide 98% RIP1
inhibition in the blood over the dosing interval in 90% of participants. The level of RIP1
inhibition which would translate into efficacy in humans is not known and the anticipated 
efficacious dose could be greater than a total daily dose of 400 mg and higher.
5.7.
Justification for Starting Dose 
The proposed starting dose of GSK3145095 is 100 mg (50 mg twice daily) based on the 
ICH S9 guidance which allows for the human starting dose in advanced cancer patients to 
be 1/6 of the HNSTD (highest non-severely toxic dose) in non-rodent or 1/10 the STD10 
(severely toxic dose to 10%) in rodents based on body surface area scaling of dose.  
Monkey was considered as the more relevant species for determining the starting dose 
based on RIP1 potency in monkeys being similar to human for GSK3145095.  The 
NOAEL in monkeys was 20 mg/kg/day (240 mg/m2) and the HNSTD was determined to 
be 60 mg/kg/day (720 mg/m2) While a 194-mg total daily starting dose of GSK3145095 
is the human equivalent dose of 1/6 of the HNSTD in the monkey GLP toxicity study, the 
actual total daily starting dose for this study is 100 mg. Details of the rat and monkey 
studies are summarized below.
GSK3145095 was given to rats at once daily oral doses of 20, 60, and 300 mg/kg/day for 
up to 4 weeks. The no observed adverse effect level (NOAEL) in this study was 300 
mg/kg (1800 mg/m2) (AUC of 349 µg.h/mL and Cmax of 37.8 µg.h/mL). As an STD10 was 
not determined in the 4-week rat study, the NOAEL was used to conservatively define 
the STD10. A starting dose based on 1/10 of the rat NOAEL translates to a starting dose in 
a human of 292 mg, assuming a 60-kg adult with a surface area of 1.62 m2.
GSK3145095 was given to monkeys at once daily oral doses of 6, 20, and 60 mg/kg/day 
for up to 4 weeks. The NOAEL in this study was 20 mg/kg (240 mg/m2) (AUC of 52.2 
µg.h/mL and Cmax of 9.58 µg.h/mL). The HNSTD was determined to be 60 mg/kg/day 
(720 mg/m2) based on the nature and demonstrated, or predicted, reversibility of the 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
58
hematologic, inflammatory and heart rate findings. A 194-mg (approximately 200 mg) 
total daily starting dose is the human equivalent dose of 1/6 of the HNSTD in the monkey 
GLP toxicity study.
MABEL (Minimum Anticipated Biological Effect Level) approach was also considered 
similar to what was used for the healthy volunteer FTIH study of GSK2982772, a RIP1
inhibitor which shares similar chemical structure and selectivity profile compared to 
GSK3145095. For GSK2982772, the MABEL dose was estimated to be provide 
approximately 30% RIP1 inhibition in the blood at Cmax. Based on this approach, a total 
daily starting dose of 0.15 mg (0.075 mg twice daily) of GSK3145095 is estimated to 
provide approximately 30% RIP1 inhibition in the blood at Cmax in 50% of participants. 
GSK2982772 has demonstrated safety and tolerability in Phase I healthy volunteer study 
with single and repeated doses having RIP1 inhibition in blood greater than 90% over a 
24-hour period. Although the starting dose for GSK3145095 is predicted to have a high 
level of target engagement in the blood, this measure may not directly translate to 
predicting anti-tumor activity. It is unclear what level of exposure in the blood is required 
to achieve changes in the tumor, which is especially hard to penetrate due to its fibrous 
outer layer. Since participants with pancreatic cancer have a short life expectancy, an 
initial dose of 100 mg (50 mg twice daily) was selected with the goal of administering a 
therapeutically relevant dose that is also anticipated to be safe to use, in accordance with 
ICH S9.
The starting dose of 100 mg (50 mg twice daily) has a predicted total exposure AUC of 
5.52 µg.h/mL with a Cmax of 0.5 µg/mL and provides mean 97.4% inhibition of target 
engagement at predicted trough concentration (Ctrough; 74.6 ng/mL). These human 
predicted exposures are 19.2- and 9.45-fold lower than the monkey plasma Cmax and 
AUC(0-t) values at the NOAEL providing sufficient safety margin.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
1. Participant must provide signed, written informed consent.  
2. Male and female participants, age 18 years (at the time consent is obtained). 
a.
Male participants are eligible to participate if they agree to the following during 
the study treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-
4) after the last dose of study treatment:

Refrain from donating sperm
PLUS either:
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
59

Be abstinent from heterosexual or homosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long term and persistent 
basis) and agree to remain abstinent 
OR

Must agree to use contraception/barrier: male condom and female partner 
to use an additional highly effective contraceptive method with a failure 
rate of <1% per year as described in Appendix 6.
b. 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

Is a WOCBP and using a contraceptive method that is highly effective 
(with a failure rate of <1% per year), with low user dependency, as 
described in Appendix 6 during the study treatment period and for at least
15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study 
treatment and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. The investigator should evaluate the 
effectiveness of the contraceptive method in relationship to the first dose 
of study treatment.  Hormonal contraception may be susceptible to 
interaction with the study drug, which may reduce the efficacy of the 
contraceptive method. Therefore, a barrier method is also required for 
participants using a hormonal option (including hormonal IUD, oral 
contraceptive pills/ patch/ vaginal inserts, and hormonal implants) and 
both highly effective methods of contraception should be utilized during 
the treatment period and for at least 15 days (Part 1) and 120 days (Parts 
2-4) after the last dose of study treatment. If a highly effective non-
hormonal method is used, then only one method of contraception is 
required during the treatment period and for at least 15 days (Part 1) and 
120 days (Parts 2-4) after the last dose of study treatment.
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum)
as required by local regulations) within 24 hours before the first dose of study 
intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. If the 
participant hasn’t been on an acceptable method of contraception for at least 2 
weeks prior to start of therapy, pregnancy testing must be done weekly for the 
first month of treatment.
Additional requirements for pregnancy testing during and after study treatment
are described in Appendix 6.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
60
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
3. Histological documentation of locally advanced, recurrent or metastatic pancreatic 
ductal adenocarcinoma (PDAC) (Part 1), non-small cell lung cancer (NSCLC), triple-
negative breast cancer, or melanoma (Part 2) that has progressed after standard 
therapy appropriate for the specific tumor type, or for which standard therapy has 
proven to be ineffective, intolerable, or is considered inappropriate. Participants 
should have received at least one, but not more than 2 prior lines of therapy for 
advanced disease including both standards of care and investigational therapies.
Participants whose cancers harbor molecular alterations for which targeted therapy is 
standard of care should have received health authority-approved appropriate targeted 
therapy for their tumor types before enrollment.
4. All participants in Parts 1 and 2 must consent to provide a fresh biopsy during 
screening of a primary tumor lesion or from other metastases (e.g. liver, lung, etc.),
and a second biopsy after approximately 5 weeks of treatment. Please refer to Section 
9.7.2.
5. Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable 
by radiologic or photographic evaluations may not be utilized as the only measurable 
lesion. Participants are encouraged to provide a pre-baseline scan (within 24 weeks 
before the baseline scan) to support exploratory investigation of tumor growth 
kinetics.
6.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.  
7.
Life expectancy of at least 12 weeks.  
8.
Adequate organ function (see Table below):
System
Laboratory Test
Laboratory Values
Hematologic
ANC
≥1.5x109/L
Lymphocyte count
1000/mm3
Hemoglobin
≥9 g/dL
Platelets
≥100x109/L
Hepatic
Total bilirubin
For participants with Gilbert’s Syndrome (only if direct bilirubin ≤35%)
≤1.5xULN
≤3.0xULN
AST
ALT
≤2.5xULN
2.5xULN 
Serum Albumin
3.0 g/dL
Renal
Serum Creatinine OR
Calculated CrCla
≤1.5xULN
>50 mL/min
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
61
NC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; TSH = thyroid-
stimulating hormone; ULN = upper limit of normal; WNL = within normal limits
a.
Estimated CrCl should be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
formula or per institutional standard.
b.
If TSH is not within normal limits at baseline, the participant may still be eligible if total T3 or free T3 and free T4 
are within the normal limits.
9.
QTcF <450 msec (or QTcF <480 msec for participants with bundle branch block)*
* QTcF = QT duration corrected for heart rate by Fridericia’s formula
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Prior treatment with the following agents: 

Agents affecting tumor associated macrophage function or number, including but 
not limited to inhibitors of RIP1, RIP3, CSFR-1, CCR2, and CD40.
NOTE: Participants treated in monotherapy with GSK3145095 may be eligible 
for crossover into combination therapy upon disease progression and upon 
discussion and approval from the GSK Medical Monitor.

Other anticancer therapy, including chemotherapy, targeted therapy, and 
biological therapy, within 14 days or 5 half-lives (from last dose of prior 
treatment to first dose of GSK3145095), whichever is shorter. Prior radiation 
therapy is permissible if at least one non-irradiated measurable lesion is available 
for assessment via RECIST version 1.1. No washout after palliative radiation is 
required.

Subjects who are currently taking concomitant medications known to inhibit Pgp,
CYP3A4 narrow therapeutic index (NTI) substrates, or sensitive substrates of 
OATP1B1 and OATP1B3 transporters within 14 days or 5 half-lives (from last 
dose of prior treatment to first dose of GSK3145095), whichever is shorter.

Investigational therapy within 14 days or 5 half-lives (from last dose of prior 
treatment to first dose of GSK3145095), whichever is shorter. 
2.
Prior allogeneic or autologous bone marrow transplantation or other solid organ 
transplantation.  
3.
Toxicity from previous treatment:

Participants whose toxicity related to prior treatment has not resolved to Grade 1 
(except alopecia, hearing loss, Grade 2 neuropathy or endocrinopathy managed 
with replacement therapy) are not eligible.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
62
4.
Malignancy other than disease under study, except as noted below:

Participant with any other malignancy from which the participant has been 
disease-free for more than 2 years and, in the opinion of the principal 
investigators and GSK Medical Monitor, will not affect the evaluation of the 
effects of this clinical trial treatment on currently targeted malignancy, can be 
included in this clinical trial.  
5.
Major surgery 4 weeks before the first dose of study treatment. Participants must 
have also fully recovered from any surgery (major or minor) and/or its complications 
before initiating study treatment.  
6.
Active autoimmune disease that has required systemic treatment within the last 
2 years (i.e., with use of disease-modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.
7.
Concurrent medical condition requiring the use of systemic immunosuppressive 
medications within 28 days before the first dose of study treatment. Physiologic 
doses of corticosteroids for treatment of endocrinopathies or steroids with minimal 
systemic absorption, including topical, inhaled, or intranasal corticosteroids, may be 
continued if the participant is on a stable dose.  
8.
Active infection (including active herpes zoster infection), known human 
immunodeficiency virus infection, or positive test for hepatitis B surface antigen or 
hepatitis C.  
9.
Current active liver or biliary disease (except for Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease 
per investigator assessment).  

NOTE: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric 
varices, persistent jaundice, or cirrhosis. 
10. Known current drug or alcohol abuse.
11. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel 
disease, intra-abdominal abscess, or gastrointestinal obstruction.
12. Receipt of any live vaccine within 4 weeks before starting study treatment.
13. Recent history of allergen desensitization therapy within 4 weeks before starting 
study treatment (applies to participants enrolled in Parts 2 and 3 only)
14. History or evidence of cardiovascular risk including any of the following:

Recent (within the past 6 months) history of serious uncontrolled cardiac 
arrhythmia or clinically significant electrocardiogram (ECG) abnormalities 
including second degree (Type II) or third degree atrioventricular block.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
63

Documented cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting, or bypass 
grafting within the past 6 months before beginning screening.  

Documented congestive heart failure (Class II, III, or IV) as defined by the New 
York Heart Association functional classification system.  

Recent (within the past 6 months) history of symptomatic pericarditis.  
15. Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or 
organizing pneumonia. Note: Post-radiation changes in the lung related to prior 
radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring 
treatment may be permitted if agreed by the investigator and GSK Medical Monitor.
16. History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
17. Recent history (within 14 days) of ascites or pleural effusions requiring drainage.  
18. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other 
condition that could interfere with the participant’s safety, obtaining informed 
consent, or compliance to the study procedures.  
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective Institutional Review Board (IRB) approval (by chair or designee) 
is given allowing exception to this criterion for a specific participant.
6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions
GSK3145095 will be administered under fasting conditions, with no food or antacids for 
1 hour before and 2 hours after each dose. Fasting will consist of avoiding the oral 
ingestion of calorie-containing products; however, ingestion of water is permitted. 
Participants will be instructed to record the time and date of study treatments and meals 
in relation to dosing in the supplied GSK dosing diary. 
On serial PK sampling days, participants should fast overnight (i.e., nothing by mouth 
apart from water and other medications for at least 8 hours) and should continue fasting 
until at least 2 hours after administration of the morning dose. Fasting is required for 1 
hour before and 2 hours after administration of the evening dose. Also, participants will 
abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-containing 
products (e.g. coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing 
until collection of the final pharmacokinetic and/or pharmacodynamic sample during 
each serial PK/PD session.
If a participant vomits after taking study medication, the participant should be instructed 
not to retake the dose and should take the next scheduled dose. Requirements for fasting 
before and after dosing may be modified based on emerging PK, pharmacodynamic, and 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
64
safety data. Any change in fasting requirements will be communicated to each 
investigator and site staff in a future protocol amendment. 
Participants should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment through the last dose of study drug.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered into 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 serious adverse 
events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Rescreened participants will be assigned a new screening number.
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.
7.1.
Treatments Administered
Table 3
Study Drug Characteristics
Characteristic
Study Treatments
Product name:
GSK3145095
Pembrolizumab
Dosage form:
Capsule or Tablet
Solution for infusion 
Unit dose 
strength(s)
GSK3145095 Size ‘1’ capsule: Opaque 
white HPMC capsule containing 5 mg – 25 
mg GSK3145095.
GSK3145095 Size ‘00’ capsule: Opaque 
white HPMC capsule containing above 25 
mg – 75 mg GSK3154095.
25 mg GSK3145095 tablet: White to 
slightly colored round coated tablet.
50 mg GSK3145095 tablet: White to 
slightly colored round coated tablet.
200 mg GSK3145095 tablet: White to 
slightly colored oval-shaped coated 
tablet  
100 mg/4 mL solution 
Dose: 200 mg
Route of 
Administration
Oral
IV infusion – 30 mina
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
65
Characteristic
Study Treatments
Treatment 
Schedule
Day 1 – single dose only.  Participants will 
start receiving twice daily (BID) in two equal 
doses starting on Day 2.
Q3W
Dosing 
instructions:
Participants must take their doses fasted (i.e. 
with no food or antacids for 1 hour before and 
2 hours after each dose.) with approximately 
200 mL of water. On extensive PK sampling 
days, participants must fast overnight and 
2 hours post dose.
Make every effort to target infusion 
duration to be as close to 30 min as 
possible. However, given the 
variability of infusion pumps from site 
to site, a window of -5 min and 
+10 min is permitted (i.e., infusion time 
is 25 to 40 min).
Manufacturer/ 
source of 
procurement
GSK
Merck
a.
Infusions may be prolonged in the event of an infusion reaction. If multiple participants experience clinically 
significant infusion reactions, the infusion rate may be slowed for all future administrations of study drug(s) for all 
participants. Should this global change in infusion rate be required, it will be communicated to the sites in writing.
7.1.1.
Transition of Study Treatment from Capsules to Tablets
Participants will initially receive API capsules (size “00/1”, 5 mg to 75 mg) until the 
tablet formulation (25 mg/50 mg/200 mg) of the study treatment is manufactured and 
ready for distribution. The dose level at which this transition will occur will be 
designated the “transition” dose level. At the transition dose level, the safety of capsules 
compared with tablets will be assessed as follows. Three subjects will be dosed with
capsules and evaluated for DLT, as described in Section 5.1.1.3. After the transition dose 
has met criteria for dose escalation with capsules as per the N-CRM method, an 
additional three participants will receive the same transition dose with tablets and will be 
evaluated for DLT. Once the safety of the transition dose has been established in tablets 
as per the N-CRM method, all participants still receiving capsules (including those 
receiving capsules at lower dose levels) will begin receiving tablets.
7.2.
Toxicity Management Guidelines
Distinct safety management guidelines, including dose modification algorithms, are 
provided in Section 7.2.1 for the management of AEs associated with pembrolizumab 
exposure; these AEs are defined as immune-related AEs (irAEs) as the etiology may be 
immune mediated. General safety management guidelines for GSK3145095 are provided 
in Section 7.2.2.  Refer to Section 3.3.1.1 for the Risk/Benefit Assessment for 
GSK3145095 based on preclinical data with GSK3145095, and Section 8.1 for a 
discussion of criteria for discontinuation of study treatment(s). Please note that in 
instances where the investigator is directed to permanently discontinue study treatment 
(single agent or combination), these instructions are mandatory as described in the 
sections mentioned above.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
66
All AEs will be graded according to NCI-CTCAE (version 5.0) (http://ctep.cancer.gov). 
All dose modifications and the reason(s) for the dose modification must be documented 
in the eCRF.
7.2.1.
General Guidelines for Immune-Related Adverse Events (irAEs)
An irAE is defined as a clinically significant AE of any organ that is associated with 
pembrolizumab exposure, is of unknown etiology, and is consistent with an immune-
related mechanism. Special attention should be paid to AEs that may be suggestive of 
potential irAEs. An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.  
Early recognition of irAEs and initiation of treatment are critical to reduce the risk of 
complications, since the majority of irAEs are reversible with the use of steroids and 
other immune suppressants [Pardoll, 2012; Weber, 2012]. If an irAE is suspected, the 
participant should return to the study site as soon as possible instead of waiting for 
his/her next scheduled visit. Participants who experience a new or worsening irAE should 
be contacted and/or evaluated at the study site more frequently.  
If an irAE is suspected, a thorough evaluation should be conducted in an effort to 
possibly rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes before 
diagnosing an irAE. Serological, immunological, and histological (biopsy) data should be 
considered to support the diagnosis of an immune-related toxicity. Consultation with the 
appropriate medical specialist should be considered when investigating a possible irAE.  
Organs most frequently affected by irAEs include the skin and the colon due to their 
rapid regeneration rate. Less frequently affected tissues are lung, liver, and the pituitary 
and thyroid glands. Mild irAEs are usually treated symptomatically and do not require 
dosing delays or discontinuation. Higher grade and persistent lower grade irAEs typically 
necessitate interrupting or discontinuing treatment and administration of systemic 
steroids or other immunosuppressive agents (such as TNF blockers) when systemic 
steroids are not effective. Dose modification and toxicity management guidelines for 
irAEs associated with study drug(s) are provided in Table 4 .
7.2.1.1.
Overview of Management of irAEs
Please refer to Table 4 for details.
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and 
continue to taper over at least 4 weeks.
2. For situations where study drug(s) has been withheld, study drug(s) can be 
resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been 
tapered. Study drug(s) should be permanently discontinued if AE does not resolve 
within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg 
prednisone or equivalent per day within 12 weeks. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
67
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.
The decision to withhold or permanently discontinue study drug(s) is at the discretion of 
the investigator or treating physician.  However, study treatment should be permanently 
discontinued for life-threatening adverse events.  In cases where discontinuation of study 
treatment is not mandated in Section 8.1, continuation of study treatment may be 
considered on a case by case basis after discussion between the GSK medical monitor 
and treating physician, and after a participant has recovered to baseline from the event.
For participants with Grade 3 or 4 immune-related endocrinopathy where withholding 
study drug(s) is required, study drug(s) may be resumed when AE resolves to ≤ Grade 2 
and is controlled with hormonal replacement therapy or achieved metabolic control (in 
case of Type 1 diabetes mellitus [T1DM]).  
7.2.1.2.
General Principles of Immune-Related Adverse Events Identification 
and Evaluation
Before administration of study treatment, investigators are to review a participant's AEs, 
concomitant medications, and clinical evaluation results e.g., vital signs, lab results, 
ECGs, ECOG PS, physical exam findings, responses, etc. (as outlined in Schedule of 
Activities, Section 2) to monitor for new or worsening irAEs and ensure continued dosing 
is appropriate.  
AESI (See Appendix 5) are a subset of irAEs. Such events recently reported after 
treatment with other immune modulatory therapy include, but are not limited to Grade 2 
colitis, uveitis, hepatitis, pneumonitis, Grade 3 diarrhea, endocrine disorders, and 
specific cutaneous toxicities, as well as other events that may be immune mediated, 
including but not limited to demyelinating polyneuropathy, myasthenia gravis-like 
syndrome, non-infectious myocarditis, or non-infectious pericarditis.
For participants who experience signs or symptoms that may be consistent with an AESI, 
sites are strongly encouraged to immediately notify the GSK Medical Monitor of the 
event via email and/or phone. Documentation of events potentially qualifying for AESI 
should occur after discussion between the investigator and the Sponsor/Medical Monitor. 
Even events without clear confirmation of their immunologic etiology may qualify for 
AESI.  Many of these events may also qualify as an SAE. See the SRM for details.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
68
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs
Event
Grade 
(CTCAE v5.0)
Action:
study 
drug(s)
Management 
Follow-up
Pneumonitis 
Grade 2
Withhold 
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
Withhold
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 
gastrointestinal (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
Aspartate 
and/or alanine 
transaminase 
(AST / ALT) 
elevation or 
increased 
bilirubin
Grade 2
Withhold
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
Grade 3 or 4 
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
methylprednisolone 
or equivalent) 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
69
Event
Grade 
(CTCAE v5.0)
Action:
study 
drug(s)
Management 
Follow-up
followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell failure
Withhold
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.
Grade 3 or 4 
Withhold or 
permanently 
discontinue
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency) 
Hyperthyroidism Grade 2
Continue 
Treat with non-
selective beta-
blockers (e.g.,
propranolol) or 
thionamides as 
appropriate 
Monitor for signs and 
symptoms of thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue
Hypothyroidism
Grade 2 to 4
Continue 
Initiate thyroid 
replacement 
hormones (e.g.,
levothyroxine or 
liothyroinine) per 
standard of care
Monitor for signs and 
symptoms of thyroid disorders. 
Nephritis and 
renal 
dysfunction
Grade 2
Withhold 
Administer 
corticosteroids 
(methylprednisolone 
1-2 mg/kg or 
equivalent) followed 
by taper.
Monitor changes of renal 
function
Grade 3 or 4 
Permanently 
discontinue
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
70
Event
Grade 
(CTCAE v5.0)
Action:
study 
drug(s)
Management 
Follow-up
All other 
immune-related 
AEs
Grade 3, or 
intolerable/ 
persistent 
Grade 2
Withhold
Based on severity 
of AE administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude 
other causes
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
7.2.2.
General Guidelines for Clinically Significant Toxicities Not 
Otherwise Specified
While specific guidance is provided for AESI, it is possible that other clinically 
significant drug-related toxicities that are not specifically described may occur and 
warrant dose modification. Table 5 provides general guidance for the management of 
clinically significant toxicities that are not otherwise specifically described in Table 4 or 
in subsections of Section 8.1.
Investigators must contact the GSK Medical Monitor for all Grade 3 or greater clinically 
significant non-hematological drug-related toxicities where interruption or permanent 
discontinuation of study treatment may be warranted according to the guidelines provided 
in this section. Otherwise, investigators are encouraged to contact the GSK Medical 
Monitor as needed to discuss any case that warrants separate discussion outside of the 
scope of current guidelines.  
In case toxicity does not resolve to Grade 0 to 1 within 12 weeks after the last infusion, 
study treatment should be permanently discontinued after consultation with the Sponsor. 
With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 
2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.  
For participants who experience a recurrence of the same AE(s) at the same grade or 
greater with restart of study treatment, a consultation between the GSK Medical Monitor 
and investigator should occur to determine whether the participant should continue in the 
study.  Recurrence of an SAE at the same grade or greater with restart of study treatment 
must result in permanent discontinuation of the study treatment.  
The decision to withhold or permanently discontinue study drug(s) is at the discretion of 
the investigator or treating physician.  However, study treatment should be permanently 
discontinued for life-threatening adverse events. In cases where discontinuation of study 
treatment is not mandated in Section 8.1, continuation of study treatment may be 
considered on a case by case basis after discussion between the GSK medical monitor 
and treating physician, and after a participant has recovered to baseline from the event.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
71
Table 5
Dose Modification and Toxicity Management Guidelines for Other 
Adverse Events Not Otherwise Specified
Severity
Management
Follow-up
Grade 1

Administer symptomatic 
treatment as appropriate

Continue study drug(s)a
Symptoms resolve to baseline within 7 days:

Provide close follow-up to evaluate for increased 
severity
Symptoms ongoing >7 days:

Consider following algorithm for Grade 2 events
Grade 2

Administer symptomatic 
treatment

Investigate etiology

Consider consulting 
subspecialist, biopsy, 
and/or diagnostic procedure

Discuss with 
Sponsor/Medical Monitor
Symptoms ongoing >7 days or worsening

Interrupt study drug(s)a
o Resume study drug(s) at the same dose if 
symptoms have improved to Grade 1 and, if 
applicable, steroid dose is 10 mg prednisone/day 
or less

Consider starting 
moderate dose systemic corticosteroids (e.g., 0.5 
mg/kg/day of prednisone or equivalent) if clinically 
indicated OR if toxicity is considered 
pembrolizumab-related 
o Continue steroids until improvement to Grade 1 or 
resolution; taper steroids as medically appropriate

If symptoms continue or worsen to Grade 3-4, see 
below
Grade 3-
4

Interrupt study drug(s)a

Consult subspecialist

Administer 1-2 mg/kg/day 
IV methylprednisolone if 
clinically indicated OR if 
toxicity is pembrolizumab-
related 

Discuss with 
Sponsor/Medical Monitor
Symptoms improve to Grade 2:

If applicable, continue steroids until improvement to 
≤Grade 1 or baseline; taper steroids over at least 1 
month, then if symptoms have improved to Grade 1 
and steroid dose is 10 mg prednisone/day or less, 
consider resumption of study drug(s) at the next 
lower dose level
Symptoms ongoing: 

Discuss further management with consultant and 
Sponsor/Medical Monitor

Discontinue study drug permanently for Grade 3 or 
Grade 4 symptoms persisting for 21 days (see 
Section 8.1). 

Consider alternative immunosuppressive therapy if 
indicated/applicable
a.
If multiple study drugs are administered per protocol, guidance may apply to one or more study agents; 
discuss management on a case-by-case basis with the Sponsor/Medical Monitor.  
7.3.
Method of Treatment Assignment
Participants will be identified by a unique participant number that will remain consistent 
for the duration of the study.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
72
Upon completion of all the required screening assessments, eligible participants will be 
registered into a GSK designated registration and medication ordering system, by the 
investigator or authorized site staff.  
Participants will be assigned to study treatment in the order in which they complete 
screening assessments (i.e., the study is not randomized).  
7.4.
Blinding
Not applicable to this open-label study.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).  
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.  
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye 
or skin contact and the generation of aerosols or mists. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor, and/or GSK study contact.
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.
7.6.
Treatment Compliance
For GSK3145095, compliance will be assessed by querying the participant at study visits 
and counting the number of tablets dispensed and returned. A record of the number of 
GSK3145095 tablets dispensed to and taken by each participant must be maintained and 
reconciled with study treatment and compliance records. Treatment start and stop dates, 
including dates for treatment delays and/or dose reductions, will also be recorded in the 
electronic case report form (eCRF).
Pembrolizumab will be intravenously administered to participants at the site.  
Administration will be documented in the source documents and reported in the eCRF.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
73
7.7.
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 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 will be recorded.  
Additionally, a complete list of all prior anticancer therapies will be recorded in the 
eCRF.  
Medications or vaccinations specifically prohibited (see Section 7.7.2) are not allowed 
during the ongoing trial. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the participant's primary physician. However, the 
decision to continue the participant on trial therapy or vaccination schedule requires the 
mutual agreement of the investigator, the Sponsor, and the participant.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.  
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter.  
7.7.1.
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 
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:  The use of growth factors, RANK-L inhibitors, 
and bisphosphonates (if on a stable dose for at least 4 weeks) is permitted while 
participating in this study. 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.
Steroids:  Use of steroids 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. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
74
Warfarin and Phenytoin:  GSK3145095 at doses of ≥1600 mg daily (800 mg BID) may 
inhibit CYP2C9. A potential risk for drug-drug interaction (DDI) exists for CYP2C9 
narrow therapeutic index (NTI) substrates such as warfarin and phenytoin. Therefore, 
caution is advised to monitor for higher levels of these agents when co-administered with
GSK3145095 doses ≥1600 mg daily.  
Acetaminophen: due to potential risk of liver toxicity when combining acetaminophen 
with GSK3145095, acetaminophen dosage is restricted to no more than 2g per day. 
7.7.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited before the first dose of study treatment (see 
Section 6.2 Exclusion Criteria for specific time requirements) and while on treatment in 
this study:

Any investigational drug(s).

Other non-study related anticancer therapy (chemotherapy, radiation therapy 
[unless administered palliatively], immunotherapy, biologic therapy, or hormone 
therapy other than for replacement). 

Live vaccines such as intra-nasal flu vaccine. Attenuated or live vaccines should 
not be administered to participants from 30 days prior to the first dose of 
GSK3145095, during the study, and for 5 half-lives plus 30 days (total 32 days) 
after GSK3145095 is discontinued.
o
If indicated, non-live vaccines (e.g., inactivated influenza vaccines) may 
be administered while receiving GSK3145095 based on a treating 
physician’s assessment of the benefit:risk (e.g., risk of theoretical 
decreased responsiveness). 
o
Investigators will be expected to have followed local and/or national 
guidelines with respect to vaccinations, including against influenza and 
pneumococcus.

Drugs that are CYP3A substrates:  Narrow therapeutic index (NTI) CYP3A4 
substrates (examples include alfentanil, astemizole, cisapride, cyclosporine, 
dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, and terfenadine) are prohibited.  Please refer to the FDA website for 
more information: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm

Drugs that are strong inducers of CYP3A4: examples include avasimibe, 
carbamazepine, phenytoin, rifampin, and St. John’s wort.

Drugs that are inhibitors of PgP: examples include amiodarone, carvedilol, 
clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
75
propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, 
tipranavir and ritonavir, and verapamil. Please refer to the FDA website for more 
information: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm#table5-2

Drugs that are sensitive substrates of OATP1B1 and OATP1B3 transporters:
including but not limited to grazoprevir, eluxadoline, paritaprevir, rosuvastatin, 
pitavastatin and pravastatin 

Over the counter medications, including but not limited to, dietary supplements 
(such as biotin or St. John’s Wort).
7.8.
Treatment after the End of Study Therapy
The investigator is responsible for ensuring that consideration has been given to the post-
study therapy care of the participant’s medical condition.
Refer to Section 5.1.4 for follow-up assessments of participants for disease progression
and/or survival after they permanently discontinue from study treatment.  
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants will receive study treatment for the scheduled time period (up to 2 years or 
35 cycles, whichever occurs first), unless one of the following occurs earlier: disease 
progression (as determined by iRECIST), death, or unacceptable toxicity. 
Events that may lead to permanent discontinuation of study treatment include, but are not 
limited to, the following:

Major deviation(s) from the protocol

Request of the participant or proxy (withdrawal of consent by participant or 
proxy)

Investigator’s discretion

Participant is lost to follow-up 

Study is closed or terminated

Toxicity attributed to study treatment and resulting in interruption of study 
treatment that does not resolve to Grade 0 to 1 within 12 weeks after the last dose 
of study treatment.

Intercurrent illness that prevents further administration of study treatment(s)

Criteria for discontinuation of study drug(s) as described in Section 7.2 have been 
met
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
76

Criteria described in Section 8.1.1 (Liver Chemistry Stopping Criteria) have been 
met

Criteria described in Section 8.1.2 (QTcF Stopping Criteria) have been met

Criteria described in Section 8.1.3 (Clinical Deterioration Stopping Criteria) have 
been met

Confirmed CR. A participant with a complete response (CR) requires 
confirmation of response via imaging at least 4 weeks after the first imaging 
showed a CR. Early discontinuation of GSK3145095 and/or pembrolizumab may 
be considered for participants who have attained a confirmed complete response 
per RECIST 1.1 that have been treated for at least 6 months and had at least two 
cycles beyond the date when the initial CR was declared.
The primary reason study treatment was permanently discontinued must be documented 
in the participant’s medical records and eCRF.  
Note: Participants who require permanent discontinuation of one of the study treatments 
due to toxicity in a given treatment combination must permanently discontinue both 
treatments (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 end-of-treatment (EOT) visit should be 
conducted within 30 days (+10 days) of the decision to discontinue study drug(s).
All participants who permanently discontinue study treatment without disease 
progression will be followed for disease progression according to the protocol schedule 
until one of the following occurs:

New anticancer therapy is initiated

Disease progression (as determined by iRECIST)

Death
Participants permanently discontinuing study intervention after progression by RECIST 
1.1 but prior to confirmed progression by iRECIST should be followed to confirm 
progression (see Table 11). Once progression has been confirmed by iRECIST, 
participants may continue study treatment(s) on a case by case basis if agreed by the 
treating investigator and Sponsor/Medical Monitor.
Once a participant has permanently discontinued from study treatment, the participant 
will not be allowed to be re-treated, except as described in Appendix 3 and in the 
following scenario. Re-treatment of participants who progress after a best overall 
response of PR or CR may be considered on a case-by-case basis for up to 1 year after 
discussion between the treating investigator and the Sponsor/Medical Monitor if:

No cancer treatment was administered since the last dose of GSK3145095 
pembrolizumab.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
77

The participant meets the safety parameters listed in the Inclusion/Exclusion 
criteria.

The study is open.  
Participants allowed to resume study therapy will do so at the same regimen, dose, and 
schedule that they were taking at the time of initial study treatment discontinuation. 
Response or progression in this Second Course Phase will not count towards the primary 
efficacy endpoint in this study.
The follow-up period for safety assessments will be a minimum of 3 months from the 
date of the last dose. The post treatment follow-up period includes disease assessments 
every 12 weeks until documented PD, initiation of other anticancer therapy, or death. 
Following PD or initiation of other anticancer therapy, participants will be contacted 
every 12 weeks to assess survival status. 
If the participant voluntarily discontinues from treatment due to toxicity, ‘AE’ will be 
recorded as the primary reason for permanent discontinuation on the eCRF.  
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 
Schedules of Activities (Section 2).  
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the Food and Drug 
Administration [FDA] pre-marketing clinical liver safety guidance 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf). 
If any of the criteria in this section (Table 6 ) are met, study treatment must be 
discontinued.
If a participant meets liver chemistry stopping criteria, do not restart the participant with 
study treatment unless:
•
GSK Medical Governance approval is granted
•
Ethics and/or IRB approval is obtained, if required, and
•
Separate consent for treatment restart is signed by the participant
Please refer to Appendix 3 for guidelines on study treatment restart. 
Please refer to Table 7 for liver chemistry monitoring criteria after restart.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
78
Table 6
Liver Chemistry Stopping Criteria – Liver Stopping Event
Liver Chemistry Stopping Criteria –Liver Stopping Event
ALT Absolute
ALT 5xULN
ALT Increase
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1,2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related to 
liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immediately discontinue study treatment 
Report the event to GSK within 24 hours
Complete the liver event CRF and complete SAE 
data collection tool if the event also meets the 
criteria for an SAE2
Perform liver event follow up assessments 
Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline (see 
MONITORING below)
Do not restart participant with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (refer to 
Appendix 3) 
If restart is not allowed per protocol or not 
granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria:
Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within 24 hrs
Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline
A specialist or hepatology consultation is 
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 24 hours after last dose6
Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin2xULN
Obtain complete blood count with differential to 
assess eosinophilia
Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications
Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins)
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
79
recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within 24-72 hrs 
Monitor participants weekly until liver chemistries 
resolve, stabilize or return to within baseline
liver injury in participants with definite or likely 
acetaminophen use in the preceding week
[James, 2009]). 
Liver imaging (ultrasound, magnetic resonance, or 
computerized tomography [CT]) and /or liver 
biopsy to evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that participant if ALT 
3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement 
is not required and the threshold value stated will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to 
hypersensitivity (such as fever, rash or eosinophilia)
4.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or 
if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D 
RNA virus (where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK 
comparator treatments.)  Record the date/time of the PK blood sample draw and the date/time of 
the last dose of study treatment prior to blood sample draw on the CRF. If the date or time of the 
last dose is unclear, provide the participant’s best approximation. If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated above, 
do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
80
Table 7
Liver Chemistry Monitoring Criteria after Study Treatment Restart
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT ≥3x ULN and ≥1.5x baseline value but
ALT <5x ULN and <2x baseline value and
bilirubin <2xULN, without symptoms believed to 
be related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks
Notify the medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety. 
Participant can continue study treatment.
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize, or return to 
within baseline 
If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above.
If, after 4 weeks of monitoring, ALT <3xULN and 
<1.5x baseline value, and bilirubin <2xULN, monitor 
participants twice monthly until liver chemistries 
normalize or return to within baseline.
8.1.2.
QTc Stopping Criteria
The QT duration corrected for heart rate by Fridericia’s formula (QTcF) 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.
The QTcF should be based on single or averaged QTcF values of triplicate ECGs 
obtained over a brief (e.g., 5 to 10 minute) recording period (i.e., single QTcF is used 
when a single ECG is performed, and averaged QTcF is used when triplicate ECGs are 
performed).
If a participant meets either of the following criteria, they must be discontinued.  
•
QTcF >500 msec
OR
•
Change from baseline of QTcF >60 msec
For participants with underlying bundle branch block, follow the discontinuation 
criteria listed below:
Baseline QTcF with Bundle Branch Block
Discontinuation QTcF with Bundle Branch Block
<450 msec
500 msec
450 – 480 msec
530 msec
QTcF = QT duration corrected for heart rate by Fridericia’s formula
8.1.3.
Clinical Deterioration Stopping Criteria
Accumulating clinical evidence indicates that the emergence of objective responses to 
agents that activate antitumor immune responses may follow delayed kinetics of weeks or 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
81
months and can be preceded by initial apparent progression with appearance of new 
lesions or some enlarging lesions while certain index lesions are regressing (“mixed 
response”). To adequately assess the antitumor effect of immunotherapeutic agents, it is 
reasonable to allow participants experiencing apparent progression as defined by RECIST 
1.1 guidelines to continue to receive treatment until progression is confirmed at the next 
imaging assessment at least 4 weeks later as indicated by iRECIST guidelines. Please 
refer to Appendix 9 for additional details. These considerations should be balanced by 
clinical judgment as to whether the participant is clinically deteriorating and unlikely to 
receive any benefit from continued treatment.  
Such deterioration will be assessed to have occurred after a clinical event that, in the 
investigator’s opinion, is attributable to disease progression, is unlikely to reverse with 
continued study treatment and therefore indicates that the participant is not benefiting 
from study treatment and cannot be managed by the addition of supportive care (e.g., 
bisphosphonates and/or bone directed radiotherapy, thoracentesis, or paracentesis for 
accumulating effusions). 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 include, but are not limited to, the following:
•
ECOG PS decrease of at least 2 points from baseline
•
Skeletal related events defined by the following:
o
Pathologic bone fracture in the region of cancer involvement,
o
Cancer related surgery to bone, and/or
o
Spinal cord or nerve root compression.
•
Development of new central nervous system (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 events
8.2.
Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
Refer to the Schedules of Activities (Section 2) for data to be collected at the time study 
discontinuation and any further evaluations that need to be completed.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
82
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:
•
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain 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. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
83
9.
STUDY ASSESSMENTS AND PROCEDURES
9.1.
Study Visits
9.1.1.
Visit Types
Screening: All screening assessments should be completed within 21 days prior to dosing 
start. Pregnancy testing must be completed 7 days prior to dosing start and checked again 
on Day 1 within 24 hours before the first dose of study drug. Screening assessments can 
be done over multiple office visits as needed.
Treatment: While on study drug(s), participants should have office visits per the Schedule 
of Activities (Section 2) and within the visit windows specified in Section 9.1.2. One 
cycle is 21 days in length.
End of Treatment (EOT): The end-of-treatment (EOT) visit should be conducted within 
30 days (+10 days) of the decision to discontinue study drug(s).
Follow up (see also Section 8.1 and Schedules of Activities [Section 2]):

Response Follow-up (RFU): If study treatment has been permanently 
discontinued in the absence of progressive disease, participants still in the study 
must have a RFU office visit every 12 weeks until disease progression, initiation 
of another anticancer treatment, or death. 

AEs and Concomitant Medications: All AEs and concurrent medications will be
collected until at least 30 days after the last dose of study treatment (i.e., AEs and 
Concomitant Medications: All AEs and concurrent medications will be collected
from study day 1 until at least 30 days after the last dose of study treatment (i.e., at 
least through the EOT visit). AESIs will be collected starting day 1, while SAEs 
will be recorded from the time a participant consents to participate in the study. 
All AESIs and SAEs and any concurrent medications relevant to the reported 
AESIs and SAEs will be collected until at least 90 days after the last dose of 
study treatment. If another anticancer agent is started during the 90-day reporting 
period, only AESI and SAEs that occur within 30 days from the last dose of 
study drug(s) should be recorded.

Survival Follow-up (SFU): The SFU telephone call should be completed every 12 
weeks after documented disease progression or after initiation of another 
anticancer treatment. All participants still in the study should be contacted every 
12 weeks (±2 weeks) until death occurs.  
9.1.2.
Visit Windows
All screening assessments should be completed within 21 days prior to dosing start. 
Pregnancy testing for screening must be completed 7 days prior to dosing start and 
checked again on Day 1 within 24 hours before the first dose of study drug. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
84
Week 1: Visits for Week 1 Days 1 and 2 must be performed on the day indicated.
Telephone call on Week 1 Day 3 must be performed on the day indicated.
Week 2 through Week 7: Based on participant and clinic schedule, assessments can be ±3
days.
The Week 3 Day 1 PK collection is timed to permit evaluation of GSK3145095 PK at
steady-state dosing. If a participant is not receiving drug on Week 3 Day 1 (either as a
consequence of a planned drug holiday or due to toxicity), then this PK collection should
be rescheduled for a later timepoint when the participant is again being dosed at steady 
state, and the alternate collection date noted in the eCRF. 
Visits at Week 8 and beyond will be allowed to have a ±3-days window. 
The EOT visit should be completed within 30 days (+10 days) after the last dose of study 
drug(s).
9.2.
Assessments
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Schedules of Activities (Section 2).
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 draws to occur at the exact 
nominal time.  
The timing and number of planned study assessments may be altered during 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, pharmacodynamic/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 Sponsor 
study 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.  
Protocol waivers or exemptions are not allowed except for immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the 
Schedules of Activities (Section 2), are essential and required for study conduct.  
9.2.1.
Screening and Critical Baseline Assessments
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. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
85
9.2.2.
Demographic and Baseline Assessments
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 6.  
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
counts, ECG, and scans) and obtained prior to signing of the ICF may be utilized for 
screening or baseline purposes provided the procedure meets the protocol-defined criteria 
and has been performed in the timeframe specified by the Schedules of Activities 
(Section 2).  
9.2.2.1.
Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the eCRF) will be assessed at 
screening.  
9.2.3.
Baseline Documentation of Target and Non-Target Lesions
All baseline lesion assessments must be performed within 21 days before the first dose. 
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).
•
Lymph nodes that have a short axis of <10 mm are considered non-pathological 
and should not be recorded or followed.  
•
Pathological lymph nodes with short axis 10 mm but <15 mm are considered 
nonmeasurable-.
•
Pathological lymph nodes with short axis 15 mm 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.  
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by computed tomography (CT) or magnetic 
resonance imaging (MRI) can be considered measurable. Bone scans, 
fluorodeoxyglucose-positron-emission tomography (FDG-PET) scans or X-rays 
are not considered adequate imaging techniques to measure bone lesions.  
•
All other lesions (or sites of disease) should be identified as non-target and should 
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 should be noted throughout follow-up.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
86
Note: Cystic lesions thought to represent cystic metastases should 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 should not be considered as target lesions. 
The following are required at baseline: A CT scan with contrast of the chest, abdomen, 
and pelvis, and other areas as indicated by the participant’s underlying disease, and 
clinical disease assessment for palpable lesions. For participants with head and neck 
cancer, a CT or MRI of the head and neck area is required. At each post-baseline 
assessment, evaluations of the sites of disease identified by these scans are required.  
NOTE: Although CT scan is preferred, MRI may be used as an alternative method of 
baseline disease assessment, especially for participants for whom a CT scan is 
contraindicated due to allergy to contrast agent, provided that the method used to 
document baseline status is used consistently throughout study treatment to facilitate 
direct comparison.
Confirmation of CR and PR are required per protocol. Confirmation assessments must be 
performed at least 4 weeks after the criteria for response were met initially and may be 
performed at the next protocol scheduled assessment. If a confirmation assessment is 
performed prior to the next protocol schedule assessment, the next protocol scheduled 
evaluation is still required (e.g., evaluations must occur at each protocol scheduled time 
point regardless of unscheduled assessments).  
9.2.4.
Disease Assessments
A participant’s disease status and determination of disease progression at postbaseline 
visits will be evaluated by the local investigators’ assessments of radiology by RECIST 
v1.1 (Eisenhauer, 2009) and iRECIST (Seymour, 2017). A decision to discontinue 
treatment due to disease progression will be based upon iRECIST and the primary 
endpoint analysis will use RECIST. Scans will be collected and stored to allow for the 
option of central radiologic audit or review.  See Appendix 9 for more details.
Disease assessment modalities may include imaging (e.g., CT scan, MRI, bone scan, 
plain radiography) and physical examination (as indicated for palpable/superficial 
lesions).  
The baseline disease assessment will be completed within 21 days prior to the first dose 
of GSK3145095. Post-baseline disease assessments must be performed after the 
mandatory biopsies per the Schedule of Activities Section 2).  
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays.  
For post-baseline assessments, a window of 7 days is permitted to allow for flexible 
scheduling. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
87
Participants whose disease responds (either CR or PR) should have a confirmatory 
disease assessment performed at least 4 weeks after the date of assessment during which 
the response was first demonstrated. 
Participants whose disease progresses (PD) must have a confirmatory scan performed at 
least 4 weeks after the date of assessment during which the first indication of PD was 
demonstrated.  See Appendix 9 for more details.  If the last radiographic assessment was 
more than 12 weeks prior to the participant’s withdrawal from study and PD has not been 
documented, a disease assessment should be obtained at the time of withdrawal from the 
study.  
To ensure comparability between the baseline and subsequent assessments, the same 
method of assessment and the same technique will be used when assessing response
throughout the study.  
9.3.
Adverse Events
The definitions of an adverse event (AE) or serious adverse event (SAE) can be found in
Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue study treatment. 
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information
All AEs and concurrent medications will be collected until at least 30 days after the last
dose of study treatment (i.e., through the EOT visit). All AESIs and SAEs and any 
concurrent medications relevant to the reported AESIs and SAEs will be collected until at 
least 90 days after the last dose of study treatment. If another anticancer agent is started 
during the 90-day reporting period, only AESI and SAEs that occur within 30 days from 
the last dose of study drug(s) should be recorded. SAEs must be reported within 24 hours 
to the Sponsor either by electronic media or paper.
Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the eCRF.
All AESIs and SAEs will be recorded and reported to GSK within 24 hours, as indicated 
in Appendix 4.  
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event reasonably 
related to the study treatment or study participation, the investigator must promptly notify 
GSK.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
88
NOTE: The method of recording, evaluating, and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.  
9.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
•
“How are you feeling?”
•
“Have you had any (other) medical problems since your last visit/contact?”
•
“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”
9.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each
participant at subsequent visits/contacts. All SAEs and non-serious AESIs (defined in 
Appendix 5), will be followed until the event is resolved, stabilized, otherwise explained, 
or the participant is lost to follow-up (as defined in Section 8.3). Further information on 
follow-up procedures is given in Appendix 4.
9.3.4.
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 treatment 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 treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to all investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.3.5.
Cardiovascular and Death Events
For any cardiovascular events (Table 8) and all deaths, whether or not they are 
considered SAEs, specific CV and Death sections of the eCRF will be required to be 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
89
completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death. 
The CV eCRFs are presented as queries in response to the reporting of certain CV 
Medical Dictionary for Regulatory Activities (MedDRA) terms. The CV information 
should be recorded in the specific CV section of the eCRF within one week of receipt of 
a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
Table 8
Definition of Cardiovascular Event
A cardiovascular (CV) event is defined as follows:
•
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
9.3.6.
Pregnancy
Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of dosing until 120 days after the last dose of study 
medication.
If a pregnancy is reported, then the investigator must inform GSK within 24 hours of 
learning of the pregnancy and must follow the procedures outlined in Appendix 6.  
9.4.
Treatment of Overdose
9.4.1.
GSK3145095 Overdose
An overdose is defined as administration of a dose that is at least 50% greater than the 
intended dose. In the event of an overdose, the investigator should:
•
Contact the Medical Monitor immediately.  
•
Closely monitor the participant for AEs/SAEs and laboratory abnormalities for at 
least 130 days. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
90
•
Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study treatment if requested by the Medical Monitor (determined on a 
case-by-case basis).  
•
Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.  
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant. 
There is no specific antidote for overdose with GSK3145095. 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.
9.4.2.
Pembrolizumab Overdose
An overdose of pembrolizumab will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the participant should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any overdose of pembrolizumab, or follow up to an 
overdose, must be reported within 5 days to GSK as an AESI, either by electronic media 
or paper.
9.5.
Other Safety Assessments
Planned time points for all other safety assessments are provided in the Schedules of 
Activities (Section 2).
9.5.1.
Physical Examinations and Performance Status Evaluations
A complete physical examination will be done at screening and will include assessments 
of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
and weight will also be measured and recorded.  
A brief, targeted physical examination will be done at all other timepoints, unless 
physician’s judgement requires a full exam. 
All physical examinations should also include an evaluation of organ systems described 
in Section 3.3.1, including an assessment for lymphadenopathy.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.  
For participants with melanoma, a full body dermatological examination will be 
performed by a dermatologist (or suitably qualified physician) to identify abnormal skin 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
91
lesions within the 28-day screening period. All findings will be photographed and 
identified during screening. Subsequently, brief skin examinations will be included in all 
physical exams per the Schedules of Activities (Section 2) or more frequently as 
necessitated. Wherever possible, the same physician should perform these examinations. 
Follow-up skin examinations by a referral dermatologist should be conducted if clinically 
indicated.  
Participant performance status will be assessed using the ECOG scale (Appendix 10) as 
specified in the Schedules of Activities (Section 2).
9.5.2.
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 pulse rate. 
Vital signs will be measured more frequently if warranted by the clinical condition of the 
participant. On days on which vital signs are measured multiple times, temperature does 
not need to be repeated unless clinically indicated.  
9.5.3.
Electrocardiograms
The 12-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 8.1.2 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.
The ECG measurements will be performed in triplicate at specified times (Section 2, 
including footnotes), and will coincide with PK assessments as specified in the Schedules 
of Activities. 
9.5.4.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 9 , must be conducted 
in accordance with the SRM and the Schedule of Activities (Section 2). Laboratory 
requisition forms must be completed and samples must be clearly labeled with the 
participant number, protocol number, site/center number, and visit date. Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the SRM. Reference ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), the results must be recorded in the eCRF.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
92
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.  
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Hematology

Clinical Chemistry, including cortisol

Hepatitis B and C

Pregnancy Test

Urinalysis, calculated creatinine clearance (CrCl)

Thyroid Function Tests

The results of each test must be entered into the eCRF.
Table 9
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistrya
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Calculated creatinine clearance (CrCl)
Chloride
Carbon Dioxide
Thyroid function 
Thyroid stimulating hormoneb, free T4, free T3, cortisolb
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Serum or urine -hCG Pregnancy test (as needed for women of child bearing potential) 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
93
a.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.1.
b.
At screening only
RBC = red blood cells; WBC = white blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular 
hemoglobin; BUN = blood urea nitrogen; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
HBsAg = Hepatitis B surface antigen; -hCG = beta-human chorionic gonadotropin.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline. If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the Sponsor notified.  
9.6.
Pharmacokinetics
9.6.1.
Blood Sample Collection
Blood samples for PK analysis of GSK3145095 and pembrolizumab will be collected at 
the time points described in Section 2, Schedule of Activities. 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.  
The sampling scheme is based on a BID dosing regimen. The number and sampling times 
may be adjusted once the human PK data are available.
Blood samples (1 mL) for analysis of plasma GSK3145095 concentrations will be 
collected from all participants at the times indicated in Section 2. In Part 1, an additional 
blood sample (2 mL) will be collected for metabolite profiling at the timepoints described 
in Section 2, as well as an additional blood sample (1 mL) for analysis of 
4β-hydroxycholesterol and cholesterol as a marker for CYP3A4 activity at the timepoints 
described in Section 2. 
Blood samples (approximately 3 mL) for possible analysis of pembrolizumab 
concentrations (blood processing details to be included in the SRM) will be collected 
from all participants at the times indicated in Section 2.
Processing, storage, and shipping procedures are provided in the SRM.  
Permissible time windows for PK sampling are as follows:

Up to ≤1 hour post-dose: ±5 minutes

More than 1 hour but <24 hours post-dose: ±15 minutes

More than 24 hours post-dose: ±2 hour and before the next dose administration.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
94
9.6.2.
Blood Sample Processing for GSK3145095
Blood will be collected into EDTA tubes and processed to plasma for PK analysis of 
GSK3145095 at the time points indicated in Section 2. The actual date and time (24-hour 
clock time) of each blood sample collection will be recorded. The timing of PK samples 
may be altered and/or PK samples may be obtained at additional time points to ensure 
thorough PK monitoring.  
Blood will be collected into EDTA tubes and processed to plasma for 
4β-hydroxycholesterol and cholesterol. This will be collected at the time points indicated 
in Section 2. The actual date and time of each blood sample collection will be recorded. 
Details of blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
9.6.3.
Sample Analysis
Plasma analysis will be performed under the control of Platform Technology and Science 
In Vitro/In Vivo Translation (PTS IVIVT) and Third Party Resource, 
GlaxoSmithKline. Concentrations of GSK3145095 will be determined in plasma samples 
using the currently approved bioanalytical methodology. The original raw data, report 
and any amendments will be held under the control of the US/UK GSK R&D GLP 
archives, where they will be managed in accordance with the applicable GSK procedures, 
including GSK Global Records Retention Schedule.
Once the plasma sample has been analyzed for GSK3145095, any remaining plasma 
sample may be analyzed for any compound-related material and the results may be 
reported as part of this study or under a separate PTS GlaxoSmithKline protocol.
Serum bioanalysis for pembrolizumab will be performed under the control of Merck 
Sharp & Dohme Corp the details of which will be included in the SRM. Concentrations 
of pembrolizumab may be determined in select PK serum samples, using the currently 
approved bioanalytical methodology. The original raw data, report and any amendments
will be held under the control of Merck Sharp & Dohme Corp. Once the serum has been 
analyzed for pembrolizumab, any remaining sample may be analyzed for other 
compound-related metabolites and the results reported under a separate Merck Sharp & 
Dohme protocol.  
9.6.4.
Tumor Tissue Biopsy for Pharmacokinetic Assay
See Section 9.7.2 for details on tumor tissue biopsies.  Select tumor tissue biopsy samples 
may be analyzed to measure the concentration of GSK3145095 in the tumor tissue.  
Information on processing the biopsies for the tumor tissue pharmacokinetic assay will be 
provided in the SRM.
Once the tumor tissue has been analyzed for GSK3145095, any remaining tissue may be 
analyzed for other compound-related material and the results reported under a separate 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
95
Platform Technology and Science In Vitro/In Vivo Translation (PTS IVIVT), 
GlaxoSmithKline protocol.
9.6.5.
Tissue Sample Analysis
Tumor tissue biopsy sample analysis will be performed under the control of PTS-IVIVT, 
GlaxoSmithKline.  An exploratory analysis will be conducted to assess concentrations of 
GSK3145095 in tumor tissue if available.
9.6.6.
Assessment of CYP3A4 Enzyme Activity
9.6.6.1.
Plasma Analysis
Plasma derived from select PK blood samples in Part 1, will be analyzed for 
4βhydroxycholesterol and cholesterol as a potential in vivo marker of CYP3A4 enzyme 
activity. Samples collected pre-treatment and at steady-state will be compared to evaluate 
this potential marker.
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SRM.
Baseline, Day 15, and Day 36 plasma samples will be analyzed using a validated, 
specific, and sensitive liquid chromatography–mass spectrometry (LC-MS/MS) method 
to determine concentrations of 4βhydroxycholesterol and total cholesterol. A comparison 
will be made between the ratio of 4βhydroxycholesterol: cholesterol at baseline and on 
Days 15 and 36 to assess potential changes in CYP3A4 enzyme activity following 
GSK3145095 treatment.
Analysis will be performed at a bioanalytical site (to be detailed in the SRM) under the 
control of PTS-IVIVT and Third Party Resource, GlaxoSmithKline.
9.6.6.2.
Urine Sample Collection and Analysis
Urine samples for analysis of GSK3145095 and any metabolites will be collected at the 
time points listed in the Schedules of Activities in Section 2.
Prior to dosing on Day 1, each participant will be instructed to void their bladder and no 
more than 40 mL of this urine sample will be retained as a control. Urine samples will be 
collected during the first 24 hours after dosing (a list of time points may be found in the 
Schedule of Activities). Urine samples will be shipped to GSK and may be analyzed for 
GSK3145095 and any compound-related metabolites. Results will be reported under a 
separate PTS GlaxoSmithKline protocol. Processing, storage and shipping procedures are 
provided in the SRM. The original urine raw data, report and any amendments will be 
held under the control of GSK.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
96
9.7.
Pharmacodynamics
9.7.1.
Blood Biomarkers
Blood samples will be collected to evaluate peripheral PD at the time points indicated in 
the Schedule of Assessment tables in Section 2.
Peripheral PD measurements may include, but are not limited to, target engagement of 
the RIP1 protein by compound, detection of circulating tumor DNA (ctDNA) using 
genetic analysis techniques, detection of circulating tumor antigens CA19-9 and CEA, 
and detection of circulating cytokines and chemokines in plasma or serum.
Blood samples and PBMCs may also be collected and used or stored for other 
exploratory analyses. These include, but are not limited to, flow cytometry to determine 
effects of GSK3145095 on peripheral immune cell numbers and phenotype or by using 
genetic analysis techniques to evaluate genomic or transcriptomic signatures (using 
isolated DNA or RNA). Plasma and serum samples may also be used for analysis of 
circulating factors including, but not limited to, tumor-derived exosomes or serum 
proteomic signature. Refer to SRM for full details on PD measurements.  
With participant consent and agreement by the PI and GSK Medical Monitor, additional 
PD samples may be obtained during the study. Examples of when this may be considered 
is at subsequent tumor imaging scans or when a mixed response occurs and tumor 
biomarker data are anticipated to inform why some lesions are, and some are not, 
responding to the treatment.
9.7.2.
Tumor Tissue
Participants in Part 1 and Part 2 are required to provide at least two fresh biopsies from 
their primary tumor or from other metastases (e.g. liver, lung, etc). One fresh biopsy must 
be obtained before beginning study treatment, and a second must be obtained at the week
6 visit (i.e., after completion of 5 weeks of treatment), which must be collected 1 week 
prior to tumor imaging. Additional optional fresh biopsies may be obtained during the 
study, as described below. All participants will be encouraged to provide an archival 
tumor sample prior to starting study drug. Fresh biopsies will be evaluated by IHC for 
expression of phenotypic and functional immune cell markers on tumor infiltrating 
myeloid cells and lymphocytes as well as immune signaling markers on the surface of 
tumor cells (e.g. including, but not limited to PD-L1) to understand antitumor immune 
responses. Inhibition of RIP-1 pathway activation by IHC may be assessed. Gene 
expression signatures in pre- and on-treatment biopsies will be evaluated for changes 
using genetic analysis techniques of RNA. Additionally, tumor tissue may be sequenced 
to assess T-cell receptor diversity or tumor mutation burden as well as evaluated for any 
DNA/RNA/protein changes correlating with response. Archival tissue may also be 
assessed as described above.
It is strongly encouraged that paired fresh pre- and on-treatment tumor biopsies are 
obtained from the same tumor lesion.  If it is not possible to obtain the on-treatment 
biopsy from the same lesion the pre-treatment biopsy was obtained from, it is strongly 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
97
encouraged that the on-treatment biopsy is obtained from the same organ as the pre-
treatment biopsy. The tumor site chosen for biopsy must not be the one used as an 
indicator lesion for assessment of disease unless otherwise discussed and agreed upon 
with the GSK medical monitor.
With participant consent and agreement by the PI and GSK Medical Monitor, additional 
optional fresh biopsies may be obtained during the study. One example of when this may 
be considered is when a mixed response occurs and tumor biomarker data are anticipated 
to inform why some lesions are, and some are not, responding to the treatment. In this 
case, the additional biopsies are not required to be obtained from the same lesion or organ 
as the pre-treatment biopsy. 
Other biomarkers may be evaluated as determined by additional data, including but not 
limited to measurements of protein changes, genetic analysis techniques of DNA or 
RNA, or percent target engagement of RIP1 by compound. Details for sample collection, 
processing, storage, and shipment will be provided in the SRM.  
Blood and tumor samples may be used for purposes related to the quality assurance of the 
laboratory tests described in this protocol or for the development of a diagnostic assay.
9.8.
Genetics
Information regarding genetic research is included in Appendix 7.
9.9.
Immunogenicity Assessments
Serum samples may be collected and tested for the presence of antibodies that bind to 
pembrolizumab, or other select anti-cancer agents administered in combination with 
GSK3145095, as described in the Schedule of Activities (Section 2). The actual date and 
time of each blood sample collection will be recorded. Details of blood sample collection 
(including volume to be collected), processing, storage, and shipping procedures are 
provided in the SRM.
The timing and number of planned immunogenicity samples may be altered during the 
course of the study, based on newly-available data to ensure appropriate safety 
monitoring. In the event of a hypersensitivity reaction that is either 1) clinically-
significant in the opinion of the investigator, or 2) leads to the participant withdrawing 
from the study, blood samples should be taken from the participant for immunogenicity 
testing at the time of the event and again 30 days, 12 weeks, and 24 weeks after. For 
participants who prematurely withdraw from the study, immunogenicity testing will 
occur at withdrawal and at follow-up 30 days, 12 weeks, and 24 weeks after the last dose.
9.10.
Health-Related Quality of Life
To further evaluate disease and treatment related symptoms and associated impacts on 
function and health-related quality of life, participants will participate in qualitative 
interviews (Parts 3 and 4) conducted via telephone. The interview will be conducted by a 
trained interviewer in the participant’s native language and will be audio recorded for 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
98
transcription and analysis. Please refer to the SRM for further details on these 
assessments.  
The telephone interview should be conducted within 21 days following completion of 
Weeks 12 and 52 and/or the EOT Visit, unless the participant has already completed an 
interview within the prior 30 days.
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
The planned sample size for each part of the study was chosen to allow adequate 
characterization of safety, clinical activity, PK, and pharmacodynamic profile based on 
the objectives of each part of the study. 
For dose escalation, the total sample size will depend on the number needed to 
adequately characterize the DLT profile and determine the MTD.
For the dose expansion phase, approximately 30 participants will be targeted for each 
tumor type and treatment combination.
10.2.
Populations for Analyses
The All-Treated Population is defined as all participants who receive at least one dose of 
GSK3145095.  Safety and anticancer activity will be evaluated based on this analysis 
population.  
The PK Population will consist of all participants from the All-Treated Population for 
whom a PK sample is obtained and analyzed.
The Pharmacodynamic Population will consist of all participants from the All-Treated 
Population who contribute Pharmacodynamic/Biomarker sample(s).
10.3.
Hypotheses
10.3.1.
Dose Escalation (GSK3145095)
No formal statistical hypothesis will be tested in the dose escalation phase.  
10.3.2.
Dose Expansion (GSK3145095)
The antitumor activity of GSK3145095 in combination with pembrolizumab or another 
anticancer agent will be tested using the predictive probability design by Lee and Liu
(Lee, 2008).  The null and alternative hypotheses are as follows:
H0: p≤P0
HA: p>PA.   
The response rates to be tested, P0 and PA (P0 < PA) will depend on the tumor type chosen 
for the expansion part as well as the choice of anticancer agent used in combination with 
GSK3145095.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
99
10.4.
Statistical Considerations for Dose Escalation
The NCRM dose-escalation procedure will be implemented for monotherapy and the 
mTPI procedure will be used for combination therapy. 
10.4.1.
NCRM for Monotherapy Dose Escalation
Dose escalation for monotherapy will use NCRM.  This method utilizes a 2-parameter 
logistic model, with parameters and , to describe the relationship between DLT and 
dose (100, 200, 400, 800, and 1600 mg per day). NCRM uses a Bayesian framework 
where the parameters and are assumed to have a bivariate normal prior distribution. 
Using the FACTS software version 6.1, the parameters (mean[sd]) of the bivariate normal 
prior for (, ln()) were derived, using the ‘Scenarios’ option, as: = -1.7451[1.5665], 
ln() = -0.1671[0.2087], and correlation = -0.969, with median dose as reference and 
independent variable as log(dose/reference dose)  
Simulations were conducted to understand the statistical properties of NCRM in this 
study, including the average sample size and percentage of times each planned dose is 
selected as MTD. Three scenarios were considered for this simulation: scenario 1 
representing toxicity at high dose has toxicity based on Emax with ED50=1200 mg/day and 
maximum toxicity of 0.60; scenario 2 representing toxicity at middle dose has toxicity 
based on Emax with ED50=800 mg/day and maximum toxicity of 0.70; scenario 3 
representing toxicity at low dose has toxicity based on Emax with ED50=200 mg/day and 
maximum toxicity of 0.75; scenario 4 representing no toxicity up to the high dose has 
toxicity based on logistic model with ED50=1600 mg/day and maximum toxicity of 0.60. 
In scenario 1, the DLT rate exceeds 0.33 (the upper limit of the target) at high dose 
starting around 1500 mg/day. In scenario 2, the DLT rate exceeds 0.33 starting around 
800 mg/day. In scenario 3, the DLT rate exceeds 0.33 at low dose starting around 150 
mg/day. The toxicity curves for these 4 scenarios are shown below.
Scenario 1: Toxic at high dose.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
100
Scenario 2: Toxic at middle dose.
Scenario 3: Toxic at low dose.
Scenario 4: No toxicity up to high dose.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
101
For each of these scenarios, 10,000 clinical trials were simulated and the table below 
shows the percent of times the various dose levels are selected as MTD in these 
simulations.
Simulation Results Under Various Scenarios:
Dose 
(mg/day)
Scenario 1
Toxic at high 
dose.
Scenario 2
Toxic at middle 
dose.
Scenario 3
Toxic at low dose.
Scenario 4
No toxicity up to 
the high dose.
True 
DLT 
Rate
Percent 
of Trials 
Selecting 
Dose as 
MTD
True 
DLT 
Rate
Percent 
of Trials 
Selecting 
Dose as 
MTD
True 
DLT 
Rate
Percent 
of Trials 
Selecting 
Dose as 
MTD
True 
DLT 
Rate
Percent 
of Trials 
Selecting 
Dose as 
MTD
100
0.05
2.3%
0.08
8.7%
0.25
80.5%
0
0.0%
200
0.09
4.2%
0.14
19.2%
0.38
16.9%
0
0.0%
400
0.15
28.2%
0.23
45.8%
0.50
2.5%
0
0.0%
800
0.24
46.0%
0.35
23.4%
0.60
0.1%
0
19.6%
1600
0.34
19.3%
0.47
3.0%
0.67
0.0%
0.30
80.4%
Based on these simulations, the average sample sizes are 24, 23, 14, and 24 for scenarios 
1, 2, 3, and 4, respectively, assuming the maximum number of cohorts is 8 and each 
cohort has 3 subjects.
10.4.2.
mTPI for Combination Therapy Dose Escalation
The number of dose levels that will be used for dose escalation for combination therapy 
is expected to be fewer than the number of levels in monotherapy. This is the key 
rationale for the choice of mTPI rather than NCRM for dose escalation for combination 
therapy.  
10.5.
Statistical Considerations for Dose Expansion
Up to 30 participants per cohort (tumor type and treatment combination) will be targeted 
for the dose expansion phase. Futility assessment will be performed after approximately 
10 participants and then with each additional participant, allowing the study to stop for 
futility but not efficacy. The type 1 error rate, power and other statistical properties will 
depend on the rates to be tested. Dose-escalation participants who took the same 
treatment (dose and anticancer agent combination) selected for the expansion phase will 
be included in the dose expansion analysis.
10.6.
Statistical Analyses
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
102
(RAP). Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
10.6.1.
Efficacy Analyses
The All Treated Population will be used for anticancer activity analyses. Since this is a 
Phase I/II study, anticancer activity will be evaluated based on clinical evidence and 
response criteria.  If data warrant, the response data will be summarized by dose level.
RECIST v1.1 guidelines are used for disease measurements.  iRECIST will be used by 
the Investigator to assess tumor response and progression and make treatment decisions. 
A description of the adaptations and iRECIST process is provided in Appendix 9 and 
Seymour, 2017. A summary of imaging and treatment requirements after first radiologic
evidence of progression is provided in Table 11 and illustrated as a flowchart in Figure 3
in Appendix 9. 
If the data warrant, ORR, PFS and OS will be calculated and listed for each participant. 
ORR is defined as the percentage of participants with a best overall confirmed CR or PR 
at any time as per disease-specific criteria (refer to Appendix 9). DCR is defined as the 
percentage of participants with a confirmed CR + PR at any time, plus SD 12 weeks.
PFS is defined as time from the date of first dose to the date of disease progression 
according to clinical or radiological assessment or death due to any cause, whichever 
occurs earliest. For the analysis of PFS, if the participant received subsequent anti-cancer 
therapy prior to the date of documented events, PFS will be censored at the last adequate 
assessment (e.g., assessment where visit level response is CR, PR, or SD) prior to the 
initiation of therapy. Otherwise, if the participant does not have a documented date of 
event, PFS will be censored at the date of the last adequate assessment.
OS is defined as the interval from the first dose of study treatment to the date of death, 
irrespective of the cause of death. If a participant does not have a documented date of 
death, time of death will be censored at the date of last contact.  
Further details on rules of censoring will be provided in the RAP. PFS and OS will be 
summarized using the Kaplan-Meier method if the data warrant.
10.6.2.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP.
10.6.2.1.
Extent of Exposure
The number of participants administered study treatment will be summarized according 
to the duration of therapy.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
103
10.6.2.2.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE (version 5.0).  
Events will be summarized by frequency and proportion of total participants, by system 
organ class and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, SAEs and AEs leading to discontinuation of study treatment. AEs, if listed 
in the NCI-CTCAE (version 5.0) will be summarized by the maximum grade. Otherwise, 
the AEs will be summarized by maximum intensity.  
Characteristics (e.g., number of occurrences, action taken, grade, etc) of AESI will be 
summarized separately.  
The incidence of deaths and the primary cause of death will be summarized.  
10.6.2.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (version 5.0). Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criteria will be summarized 
using proportions. Further details will be provided in the RAP.  
10.6.2.4.
Other Safety Measures
Data for vital signs and ECGs will be summarized based on pre-determined criteria 
identified to be of potential clinical concern. Further details will be provided in the RAP.  
10.6.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses 
may be presented separately from the main clinical study report (CSR). 
10.6.3.1.
Pharmacokinetic Parameters and Analyses
Bioanalysis of GSK3145095 and pembrolizumab will be the responsibility of GSK and 
Merck Sharp and Dohme Corp respectively.
PK analysis of drug concentration-time data of both GSK3145095 and pembrolizumab 
will be conducted by non-compartmental methods under the direction of CPMS, 
Quantitative Sciences, GSK.  The following PK parameters will be determined if data 
permit:  

Cmax

time to Cmax (tmax)

Cmin

area under the plasma concentration-time curve (AUC(0-t), AUC(0-τ) [repeat dosing] 
and/or AUC(0-) [single dose])
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
104

apparent terminal phase elimination rate constant (z) (single dose)

apparent terminal phase half-life (t½) (single dose)

systemic clearance of parent drug (CL/F)

volume of distribution (V/F)

time invariance (TI) and accumulation ratio (AR) as calculated by the following 
equations:
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK.
Drug concentration-time data will be listed for each participant and summarized by 
descriptive statistics at each time point by cohort. PK parameter data will be listed for 
each participant and summarized by descriptive statistics by cohort. 
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) will be plotted as a 
function of the dose administered and data from all available Parts may be combined. If 
more than 2 dose levels are evaluated, dose proportionality of AUC and Cmax for 
GSK3145095 following single dose administration and AUC(0-) and Cmax following 
repeat dose administration will be assessed graphically and using the power model as 
described below:
log (pharmacokinetic parameter) = a + b * log(dose)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed. Both the intercept and slope will be fitted as fixed effects. If there is 
sufficient data, the model may also be fit with the intercept and/or slope as random 
effects depending on the ability of the model to converge and on estimation of variance 
covariance matrix. The mean slope and corresponding 90% confidence interval will be 
estimated from the power model.
The data from this study may be combined with the data from other studies for a 
population PK analysis, which will be reported separately.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
105
10.6.3.2.
Pharmacokinetic/Pharmacodynamic Analyses
Data obtained from the pharmacodynamic samples will be descriptively and/or 
graphically summarized, and if warranted, exploratory PK/Pharmacodynamic analyses 
will be conducted to inform dose selection decisions.
In addition, exposure-response relationship between GSK3145095 exposure (e.g. dose, 
concentration, Cmax or AUC) and clinical activity or safety including change from 
baseline QTcF may be explored.
Further details on the analyses will be addressed in the RAP.
10.6.3.3.
Translational Research Analyses
The results of translational research investigations may be reported in the CSR. All 
endpoints of interest from all comparisons will be descriptively and/or graphically 
summarized as appropriate to the data.
Further details on the translational research analyses will be addressed in the RAP.  
10.6.3.4.
Novel Biomarker(s) Analyses
The results of these biomarker investigations may be reported separately from the main 
clinical study report. All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.  
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.  
10.6.3.5.
Longitudinal Tumor Size Modeling
Longitudinal tumor size data will be analyzed using a non-linear mixed effects model to 
determine tumor kinetic constants. These parameters may be related to other participant
characteristics, such as dose group, GSK3145095 exposure, or biomarkers.
10.6.3.6.
Pharmacogenetic Analyses
Further details on PGx analyses will be addressed in Appendix 7 and the PGx RAP.  
10.6.4.
Interim Analyses
No formal interim analyses will be performed using the data generated from dose 
escalation cohorts. Preliminary safety and available PK/PD data will be performed and 
reviewed by study team (to include at minimum, the GSK medical monitor and 
investigator) after completion of each dose cohort. This review will support the decision 
on the dose level in the next dose cohort. Dose escalation decisions making will be based 
on the rules as described in Section 10.4. 
For each dose expansion cohort, continuous assessment of futility and safety will be 
performed after approximately 10 participants with available unconfirmed Overall 
Response data. Safety and efficacy will be monitored by study investigators and staff, as 
well as GSK team members (including the GSK medical monitor, safety physician, 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
106
statistician, pharmacokineticist, biomarker scientist, and other staff) following the futility 
rules for expansion cohorts described in Section 10.4.1.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
107
11.
REFERENCES
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009; 8:709-714.
Chen D, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 
2013;39(1):1-10.
Chen W, Wang Q, Bai L, Chen W, Wang X, Tellez CS, et al. RIP1maintains DNA 
integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative 
phosphorylation and glycolysis. Cell Death Differ. 2014;21(7):1061-1070.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors: Revised RECIST guidelines (version 1.1). 
Eur J Cancer. 2009; 45:228-247.
Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat 
Rev Cancer. 2016;16(7):447-462. 
Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to 
promising novel therapies. Nat Rev Clin Oncol. 2015;12(6):319-334.
GlaxoSmithKline Document Number 2017N334332_00.; for GSK3145095, effective 
date 12-Jun-2018. 
Hänggi, Kay et al. “RIPK1/RIPK3 Promotes Vascular Permeability to Allow Tumor Cell 
Extravasation Independent of Its Necroptotic Function.” Cell Death & Disease 8.2 
(2017): e2588–. PMC. Web. 23 May 2018.
Hartwig T, Montinaro A, von Karstedt S, Sevko A, Surinova S, Chakravarthy A, et al. 
The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune 
Microenvironment via CCR2. Mol Cell. 2017;65(4):730-742 e735.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010; 
52:2216-2222.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Ji Y, Wang SJ. Modified toxicity probability interval design: A safer and more reliable 
method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31:1785-
1791.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
108
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clin 
Trials. 2008; 5:93-106.
Lievense LA, Bezemer K, Aerts JG, Hegmans JP. Tumor-associated macrophages in 
thoracic malignancies. Lung Cancer. 2013;80(3):256-262.
Liu X, Zhou M, Mei L, Ruan J, Hu Q, Peng J, et al. Key roles of necroptotic factors in 
promoting tumor growth. Oncotarget. 2016;7(16):22219-22233.
Liu XY, Lai F, Yan XG, Jiang CC, Guo ST, Wang CY, et al. RIP1 kinase is an oncogenic 
driver in melanoma. Cancer Res. 2015;75(8):1736-1748.
Lofti R, Kaltenmeier C, Lotze MT, Bergmann C. Until death do us part: necrosis and 
oxidation promote the tumor microenvironment. Transfus Med Hemother 
2016;43(2):120-132.
Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, et al. In vivo 
CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 
2017;547(7664):413-418.
Merck Sharp & Dohme Corp. Investigator’s Brochure for Pembrolizumab. 31-Aug-2015.
Najjar M, Saleh D, Zelic M, Nogusa S, Shah S, Tai A, et al. RIPK1 and RIPK3 kinases 
promotes cell-death-independent inflammation by toll-like receptor 4. Immunity. 
2016;45(1):46-59.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stats Med. 2008;27:2420-2439.
NYHA: The Criteria Committee of the New York Heart Association (NYHA). 
Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th Ed. 
Boston, Mass: Little, Brown & Co.; 1994:253-256.
Ofengeim D, Yuan J. Regulation of RIP1 kinase signalling at the crossroads of 
inflammation and cell death. Nature Reviews Molecular Cell Biology. 2013;14(11):727 
736.
Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982; 5:649-655.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al.  Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009; 54:84-90.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev 
Cancer. 2012; 12:252-264.
Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM, et al. The receptor 
interacting protein (RIP1) inhibits p53 induction through NF-κB activation and confers a 
worse prognosis in glioblastoma. Cancer Res. 2009;69(7):2809-2816.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
109
Santoni M, Romagnoli E, Saladino T, Foghini L, Guarino S, Capponi M, et al. Triple 
negative breast cancer: Key role of Tumor-Associated Macrophages in regulating the 
activity of anti-PD-1/PD-L1 agents. Biochim Biophys Acta. 2018;1869(1):78-84.
Scarlett CJ. Contribution of bone marrow derived cells to the pancreatic tumour 
microenvironment. Front Physiol. 2013;4:56.
Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, et al. The 
necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune 
suppression. Nature. 2016;532(7598):245-249. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST:
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 
2017; 18: e143-52.
Strilic B, Yang L, Albarran-Juarez J, Wachsmuth J, Han K, Muller UC, et al. Tumour-
cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. 
Nature. 2016;536(7615):215-218.
Wang C, Yao B, Xu M, Zheng X. RIP1 upregulation promoted tumor progression by 
activating AKT/Bcl-2/BAX signaling and predicted poor postsurgical prognosis in HCC. 
Tumour Biol 2016; 37:15305-15313
Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and 
kinetics of response with ipilimumab. J Clin Oncol. 2012; 30:2691-2697.
Weisel K, Scott NE, Tompson DJ, Votta BJ, Madhavan S, Povey K, Wolstenholme A, 
Simeoni M, Rudo T, Richards-Peterson L, Sahota T, Wang JG, Lich J, Finger J, 
Verticelli A, Reilly M, Gough PJ, Harris PA, Bertin J, Wang ML. Randomized clinical 
study of safety, pharmacokinetics, and pharmacodynamics of RIPK1 inhibitor 
GSK2982772 in healthy volunteers. Pharmacol Res Perspect. 2017 Dec;5(6). 
Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response 
Criteria. Clin Cancer Res 2009;15(23): 7412-20.
Xin J, You D, Breslin P, Li J, Zhang J, Wei W, et al. Sensitizing acute myeloid leukemia 
cells to induced differentiation by inhibitin the RIP1/RIP3 pathway. Leukemia. 
2017;31(5):1154-1165.
Zamarin D, Postow MA. Immune checkpoint modulation: Rational design of 
combination strategies. Pharmacol Ther. 2015;150:23-32.
Zhu G, Chen X, Wang X, Li X, Du Q, Hong H, et al. Expression of the RIP-1 Gene and 
its Role in Growth and Invasion of Human Gallbladder Carcinoma. Cell Physiol Biochem 
2014; 34: 1152-65
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
110
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACT
Adoptive cell transfer
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event(s)
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC(0-t)
Area under the plasma concentration-time curve from time 0 
to the time of the last quantifiable concentration)
AUC(0-)
Area under the concentration-time curve over the dosing 
interval
BAL
Bronchoalveolar lavage
-hCG
Beta-human chorionic gonadotropin
BUN
Blood urea nitrogen
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration 
CL
Systemic clearance of parent drug
CrCl
Calculated creatinine clearance
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modeling and Simulation
CR
Complete response
CRM
Continual reassessment method
CRP
C-reactive protein
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
111
CRS
Cytokine release syndrome
CSR
Clinical Study Report
CT
Computed tomography
CTC
Circulating Tumor Cell
CTLA-4
Cytotoxic T-lymphocyte-associated antigen 4
CV
Cardiovascular
DCR
Disease Control Rate
DFS
Disease-free survival
DFSFU
Disease-free survival follow-up
DILI
Drug-induced liver injury
dL
Deciliter
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DRE
Disease-related event
ECG
Electrocardiogram(s)
ECOG
Eastern Cooperative Oncology Group
EOI
End of infusion
EOPI
End of pembrolizumab infusion
eCRF
Electronic case report form
FACTS
Fixed and Adaptive Clinical Trial Simulator
FcR
Antibody receptor crystalizable fragments gamma
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron-emission tomography
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
FTIH
First time in human
GCP
Good Clinical Practice
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
112
G-CSF
Granulocyte colony-stimulating factor
GITR
Glucocorticoid-induced TNFR family related gene
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GSK
GlaxoSmithKline
HED
Human equivalent dose
HNSTD
Highest non-severely toxic dose
HPLC
High-performance liquid chromatography
h
Hour(s)
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL-10
Interleukin 10
INR
International normalized ratio
IP
Intraperitoneal
irAE
Immune-related adverse event(s)
IRB
Institutional Review Board(s)
iRECIST
modified RECIST 1.1 for immune-based therapeutics
ITIM
Immunoreceptor tyrosine-based inhibition motif
ITSM
Immunoreceptor tyrosine-based switch motif
IV
Intravenous
Kd
Equilibrium dissociation constant
kg
Kilogram(s)
L
Liter
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
113
LDH
Lactate dehydrogenase
LFT
Liver function Tests
g
Microgram
mAb
Monoclonal antibody
MABEL
Minimum anticipated biological effect level
MAD
Maximum administered dose
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
min
Minute(s)
mL
Milliliter(s)
mmHg
Millimeters of mercury
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
MSI CRC
Colorectal carcinoma displaying microsatellite instability
MTD
Maximum tolerated dose
mTPI
modified Toxicity Probability Interval
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria 
for Adverse Events
NK
Natural killer
NOAEL
No observed adverse effect level
NCRM
Neuenschwander Continual Reassessment Method
NSCLC
Non-small cell lung cancer
nTregs
Natural Tregs
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
114
PBMC
Peripheral blood mononuclear cell
PD-1
Programmed death receptor-1
PD
Progressive disease
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
PGx
Pharmacogenetics
PI
Principal investigator
PK
Pharmacokinetic(s)
PR
Partial response
PS
Performance status
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QTc
Corrected QT interval duration
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RANKL
Receptor activator of nuclear factor-kappaB ligand
RBC
Red blood cells
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event(s)
SCCHN
Squamous cell carcinoma of the head and neck
sCRS
Severe cytokine release syndrome
SD
Stable disease
SFU
Survival follow-up
SLD
Sum of the longest diameters
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
115
SRM
Study Reference Manual
TCR
T-cell receptor
TILs
Tumor infiltrating lymphocytes
TNBC
Triple-negative breast cancer
TNF
Tumor necrosis factor
TNFR
Tumor necrosis factor receptor
Tregs
Regulatory T cells
Tr1
Type 1 regulatory
TSH
Thyroid stimulating hormone
TTR
Time to Response
ULN
Upper limit of normal
WBC
White blood cells
WNL
Within normal limits
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
Keytruda
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
116
12.2.
Appendix 2: Study Governance Considerations
12.2.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of participants begins.  
12.2.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH GCP, all applicable participant
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable.  

Obtaining signed informed consent.  

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC).  

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.  

Signed informed consent must be obtained for each participant prior to 
participation in the study.  

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.  

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK designated monitors will contact the site prior to the start of the study to 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
117
review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement, and documentation of data items for which the eCRF 
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of participants are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.  
12.2.3.
Dose Escalation Committee
The Dose Escalation Committee (DEC) will make the decision to proceed to the next 
dose level of GSK3358699 at the end of each monotherapy and combination therapy 
cohort in Parts 1 and 2; along with making the decision to move into Part 2 of the study.
The decision will be based on:

All available data (including, but not limited to PK, PD, safety, dose 
reductions/delays) from a minimum of 3 participants who have received a 
dose of GSK3145095 at the current dose level and have been followed for 
at least 48 hours post dose.

All available data accumulated from preceding dose levels.
Safety stopping criteria will be strictly applied. Details of these criteria are in Section 8.
Although the escalation of the GSK3145095 monotherapy dose will be guided by the 
NCRM and escalation of the GSK3145095 dose in combination with pembrolizumab will 
be guided by the mTPI, the DEC can override this recommendation.
DEC members and requirements are provided in the Dose Escalation Plan.
12.2.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  
In the event of an assessment, audit, or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
118
the study, any findings/relevant issues, and to implement any corrective and/or 
preventative actions to address any findings/issues identified.  
12.2.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK designated monitor 
will conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP and GSK Standard Operating 
Procedures.  
GSK reserves the right to temporarily suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance. For multicenter studies, this can occur at one or more or at all sites.  
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action.  
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.  
12.2.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including regenerating 
a hard copy, if required.  Furthermore, the investigator must ensure there is an acceptable 
back-up of these reproductions and that an acceptable quality control process exists for 
making these reproductions.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
119
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, GSK standards/procedures, and/or institutional
requirements.  
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator is no longer associated with the site.  
12.2.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables and relevant reports and will have the opportunity to 
review the complete study results at a GSK site or other mutually-agreeable location.  
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate.  
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
120
12.3.
Appendix 3: Liver Safety and Study Treatment Restart 
Guidelines
If a participant meets liver chemistry stopping criteria detailed in Section 8.1.1, 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 is signed by the participant
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.  
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, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has a 
human leukocyte antigen (HLA) genetic marker associated with liver injury (e.g., 
lapatinib, abacavir, amoxicillin/clavulanate) are reviewed and excluded.  

Ethics Committee or IRB approval of study treatment restart must be obtained, as 
required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
participant must be provided with a clear description of the possible benefits and 
risks of study treatment administration, including the possibility of recurrent, more 
severe liver injury or death.  

The participant must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
121

Participants approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume as 
per protocol. 

If after study treatment re-start, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or IRB as required, must be 
informed of the participant’s outcome following study treatment restart. 

GSK to be notified of any AEs, as per Appendix 4. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
122
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
123
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 (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE: If an event is not an AE per definition above, then it cannot be an 
SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires in-patient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
124
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 (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AEs and SAEs
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 eCRF.

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.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
125
Follow-up of AEs and SAEs

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 be asked to provide GSK with a copy of any post-
mortem findings, including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will grade it according to the NCI- CTCAE v5.0.:
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
126
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
127
Reporting of SAEs 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 for greater than 24 hours, the site will use the 
paper SAE data collection tool and email to 
 or fax to 
 
 Site will enter the SAE data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, the site can report this information to the Medical Monitor by 
telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N419040_00
PPD
PPD
PPD


2017N343207_03
CONFIDENTIAL
205013
128
12.5.
Appendix 5: Adverse Events of Special Interest
The list of terms and reporting requirements for GSK AESI are provided below.  These 
are selected SAEs and non-serious AEs that must be reported to GSK within 24 hours 
regardless of relationship to study treatment.  Any event that meets the criteria described 
below must be reported within 24 hours 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.
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
Cytokine release syndrome
Serum sickness
Infusion reactions
Infusion-like reactions
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
129
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
Pembrolizumab-specific events of clinical interest for this trial include:

An overdose of pembrolizumab, as defined in Section 9.4.2, that is not 
associated with clinical symptoms or abnormal laboratory results. 

An elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
130
12.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:
•
Documented hysterectomy
•
Documented bilateral salpingectomy
•
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female
•
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
•
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
Contraception Guidance
Male participants
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following from first administration of study drug 
until 15 days (Part 1) and 120 days (Parts 2-4) after the last administration of study drug:
•
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
131
•
Agree to use a male condom plus an additional method of contraception with a 
failure rate of <1% per year as described in Table 10 when having penile-vaginal 
intercourse with a WOCBP.
Also, men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration from first administration of study drug until 15 days (Part 1) and 120 days 
(Parts 2-4) after the last administration of study drug.
In addition, male participants must refrain from donating sperm for duration of study and 
for 15 days (Part 1) and 120 days (Parts 2-4) after the last dose.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in
Table 10. Female participants of childbearing potential must use highly effective methods 
of contraception and avoid conception for defined periods of time before first 
administration of study drug until 15 days (Part 1) and 120 days (Parts 2-4) after the last 
administration of study drug.  
Hormonal contraception may be susceptible to interaction with the study drug, which 
may reduce the efficacy of the contraceptive method. Therefore, a barrier method is also 
required for participants using a hormonal option (including hormonal IUD, oral 
contraceptive pills/ patch/ vaginal inserts, and hormonal implants) and both highly 
effective methods of contraception should be utilized during the treatment period and for 
at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment. If 
a highly effective non-hormonal method is used, then only one method of contraception 
is required during the treatment period and for at least 15 days (Part 1) and 120 days 
(Parts 2-4) after the last dose of study treatment
In addition, women must agree not to donate eggs (ova, oocytes) for the purposes of 
reproduction during the treatment period and for at least 15 days (Part 1) and 120 days 
(Parts 2-4) after the last dose of study treatment.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
132
Table 10
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. Therefore, a barrier method is also required for participants using a hormonal option
and both highly effective methods of contraception should be utilized during the treatment period and for at least 
15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment. If a highly effective non-hormonal 
method is used, then only one method of contraception is required during the treatment period and for at least 15 
days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment.
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive pregnancy test (urine 
or serum) as required by local regulations) within 24 hours before the first dose of study 
treatment. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
Additional pregnancy testing should be performed per Schedules of Activities (Section 
2).
Pregnancy testing will be performed every 3 weeks and whenever a menstrual cycle is 
missed or when pregnancy is otherwise suspected. If the participant hasn’t been on an 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
133
acceptable method of contraception for at least 2 weeks prior to start of therapy,
pregnancy testing must be done weekly for the first month of treatment.
Pregnancy testing (serum and/or urine β-hCG) will be performed by the certified local 
laboratory.
Action to be taken if pregnancy occurs

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on mother and infant, which will be 
forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to GSK. 
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.  
Action to be taken if pregnancy occurs in a female partner of a male study 
participant

Investigator will attempt to collect pregnancy information on any female partner of a 
male study participant who becomes pregnant while participating in this study. This 
applies only to participants who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
134
Any female participant who becomes pregnant while participating

Will discontinue study medication or be withdrawn from the study.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
135
12.7.
Appendix 7: Genetics
Variable response to therapy may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis.
Genetic Research Objectives and Analyses
The objectives of the genetic research are as follows:

To investigate the relationship between genetic variants and: 
Response to medicine, including GSK3145095 or pembrolizumab or any 
concomitant medicines;
PDAC or other selected solid tumors, susceptibility, severity, progression, and 
related conditions 

To develop tests/assays including diagnostic tests) related to GSK3145095 and 
PDAC and other selected solid tumors.
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Note that the analyses may be part of a multi-study assessment of genetic factors 
involved in the response of PDAC and other selected solid tumors to GSK3145095 or 
RIP1 inhibitors.
Study Population
Any participant who is enrolled in the study (except for those who have received an 
allogeneic bone marrow transplant) may participate in the genetic research component of 
the study.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
136

A 6 mL blood sample will be taken for deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the participant has met all 
eligibility requirements and provided informed consent for genetic research. 
Instructions for collection and shipping of the genetic sample are described in the 
laboratory manual. The DNA from the blood sample may undergo quality control 
analyses to confirm the integrity of the sample. If there are concerns regarding the 
quality of the sample, then the sample may be destroyed. The blood sample is 
taken on a single occasion unless a duplicate sample is required due to an inability 
to utilize the original sample.  
The genetic sample is labeled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the participant by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely with adequate measures to protect confidentiality and 
may be kept for up to 15 years after the last participant completes the study, or GSK may 
destroy the samples sooner.  GSK or those working with GSK (for example, other 
researchers) will only use samples collected from the study for the purpose stated in this 
protocol and in the informed consent form.  Samples may be used as part of the 
development of a companion diagnostic to support the GSK medicinal product.
Participants can request their sample to be destroyed at any time.
Informed Consent
Participants who do not wish to participate in the genetic research may still participate in 
the study.  Genetic informed consent must be obtained prior to any blood sample for 
genetic research being taken.
Participant Withdrawal from Study
If a participant who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the participant will be 
given a choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a participant withdraws consent for genetic research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
137

If a participant withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the 
participant does not meet the entry criteria for participation in the study, then the 
investigator should instruct the participant that their genetic sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Provision of Study Results and Confidentiality of Participant’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the 
participant, family members, insurers, or employers of individual genotyping results that 
are not known to be relevant to the participant’s medical care at the time of the study, 
unless required by law. This is because the information generated from genetic studies is 
generally preliminary in nature, and therefore the significance and scientific validity of 
the results are undetermined.  Further, data generated in a research laboratory may not 
meet regulatory requirements for inclusion in clinical care.  
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
138
12.8.
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.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
139
12.9.
Appendix 9: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 
version 1.1
12.9.1.
Assessment Guidelines by RECIST 1.1
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.

All measurements should 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 should be noted as CT on the eCRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required.
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should 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 should be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible, the same 
scanner should be used.
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
140
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.  
Guidelines for Evaluation of Disease
Measurable and Non-measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm. If 
the slice thickness is greater than 5 mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest X-ray.

Additionally, lymph nodes can be considered pathologically enlarged and 
measurable if 15 mm in the short axis when assessed by CT or MRI (slice 
thickness recommended to be no more than 5 mm). At baseline and follow-up, 
only the short axis will be measured.
Non-measurable lesion: 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques 
Measurable disease: The presence of at least one measurable lesion. Palpable lesions that 
are not measurable by radiologic or photographic evaluations may not be utilized as the 
only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 
Note: non-measurable only disease is not allowed per protocol.  
12.9.2.
Evaluation of Response by iRECIST
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs. iRECIST will be used to assess tumor response and 
progression, and make treatment decisions. When clinically stable, participants should 
not be discontinued until progression is confirmed according to the rules described 
below. This allowance to continue treatment despite initial radiologic PD takes into 
account the observation that some participants can have a transient tumor flare in the first 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
141
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
Any participant deemed clinically unstable may be discontinued from study intervention 
at site-assessed first radiologic evidence of PD. It is strongly preferred to obtain the 
repeat tumor imaging, when feasible, for confirmation of PD by iRECIST. 
In a clinically unstable participant, if the Investigator decides to continue treatment, 
following consultation with the Sponsor medical monitor, the participant may continue to 
receive study intervention. The tumor assessment should be repeated at least 4 weeks and 
up to 8 weeks later to confirm PD by iRECIST. 
If repeat imaging does not confirm PD per iRECIST and the participant continues to be 
clinically stable, study intervention may continue and follow the regular imaging 
schedule or as clinically indicated; see Section 2 SOA for more details. If PD is 
confirmed, participants will be discontinued from study intervention.
If a participant has confirmed radiographic progression (iCPD) as defined below, study 
intervention should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, continuation of study intervention may be considered following 
consultation with the Sponsor. In this case, if study intervention is continued, tumor 
imaging should follow the regular imaging schedule or as clinically indicated; see Section 
2 SOA for more details.
Description of the iRECIST Process for Assessment of Disease Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct 
iRECIST assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 the Investigator 
will decide whether to continue a participant on study intervention until repeat imaging is 
obtained (using iRECIST for participant management (see Table 11 and Figure 3). This
decision should be based on the participant’s overall clinical condition. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 
1.1, including:
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
142

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% 
and ≥5 mm from nadir
o Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable 
new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions –
Target. The sum of diameters of these lesions will be calculated, and kept distinct from 
the sum of diameters for target lesions at baseline. All other new lesions will be followed 
qualitatively as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
At the confirmatory imaging visit assessment, the participant will be classified as 
progression confirmed (with an overall response of iCPD), or as showing persistent 
unconfirmed progression (with an overall response of iUPD), or as showing disease 
stability or response (iSD/iPR/iCR). Timing of confirmatory imaging is described in 
Section 9.2.4.
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 
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
143

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen. This may correspond to the next visit in the original visit 
schedule. The assessment of the subsequent confirmation imaging proceeds in an 
identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows 
radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, 
and the confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and 
the participant continues to be clinically stable, study intervention may continue and 
follow the regular imaging schedule. If PD is confirmed, participants will be discontinued 
from study intervention.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, 
but the participant is achieving a clinically meaningful benefit, continuation of study 
intervention may be considered following consultation with the Sponsor. In this case, if 
study intervention is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 2.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
144
Detection of Progression at Visits After Pseudo-Progression Resolves
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is 
indicated by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, doing so for the 
first-time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the 
confirmatory imaging the burden of new lesions has increased from its smallest value (for 
new target lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD 
cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion 
burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication 
[Seymour, 2017].
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
145
Table 11
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at 
4 to 8 weeks to 
confirm PD.
May continue study 
intervention at the 
Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment
No additional 
imaging required.
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled imaging 
visit.
Continue study 
intervention at the 
Investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only.
Discontinue treatment
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
Investigator 
assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study 
intervention at the 
Investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if condition 
has improved and/or 
clinically stable per 
Investigator’s discretion. 
Next tumor imaging 
should occur according 
to the regular imaging 
schedule.
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = 
iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors 1.1.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
146
Figure 3
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
147
12.10.
Appendix 10: ECOG Performance Status
Grade
Descriptions
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care.  
Totally confined to bed or chair.
5
Dead.
Oken, 1982.
 
2019N419040_00


2017N343207_03
CONFIDENTIAL
205013
148
12.11.
Appendix 11: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
 
2019N419040_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205013
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP) 
Title
:
Reporting and Analysis Plan for A Phase I/II, Open-Label Study 
to Investigate the Safety, Clinical Activity, Pharmacokinetics, 
and Pharmacodynamics of GSK3145095 Administered Alone 
and in Combination with Anticancer Agents Including 
Pembrolizumab in Adult Participants with Selected Advanced 
Solid Tumors
Compound Number 
:
GSK3145095
Effective Date 
:
18-OCT-2019
Description:

The purpose of this RAP is to describe the planned analyses and outputs to be included 
in the Synoptic Clinical Study Report for Protocol 205013.

This RAP will be provided to the study team members to convey the content of the Part 
1 Statistical Analysis Complete (SAC) deliverable. Due to early termination of the 
study, Part 2, Part 3 and Part 4 were not initiated. This document will only include the 
reporting plan for subjects enrolled in the study. 

Only the primary and secondary objectives are to be analysed due to the early 
termination. 
Author
Date
Approval Method
15-OCT-2019
N/A
Associate Statistician, Biostatistics
Principal Statistician, Biostatistics
15-OCT-2019
N/A
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N419040_00
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205013
2
RAP Team Approvals:
Approver
Date
Approval Method
10-SEP-2019
Email
Principal Programmer, Oncology Clinical 
Programming
Director, Clinical Development
12-SEP-2019
Email
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
 
Director Statistics, Biostatistics
15-OCT-2019
eSignature
Programming Manager, Biostatistics
18-OCT-2019
eSignature
 
2019N419040_00
PPD
PPD
PPD
PPD


CONFIDENTIAL
205013
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment .........................................................................................13
5.2.
Baseline Definitions ....................................................................................13
5.3.
Multicentre Studies .....................................................................................13
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
7.
EFFICACY ANALYSES..........................................................................................16
7.1.
Primary Efficacy Analyses ..........................................................................16
7.2.
Secondary Efficacy Analysis.......................................................................16
7.2.1.
Endpoint/Variables.......................................................................16
7.2.2.
Summary Measure ......................................................................16
8.
SAFETY ANALYSES .............................................................................................17
8.1.
Adverse Events Analyses ...........................................................................17
8.1.1.
Deaths and Serious Adverse Events............................................17
8.1.2.
Dose Limiting Toxicity..................................................................18
8.2.
Clinical Laboratory Analyses.......................................................................18
8.3.
Other Safety Assessments .........................................................................19
8.3.1.
Pregnancies.................................................................................19
8.3.2.
Physical Examinations and Performance Status 
Evaluations..................................................................................19
8.3.3.
Vital Signs....................................................................................19
8.3.4.
Electrocardiograms......................................................................19
8.3.5.
Liver Events.................................................................................19
9.
PHARMACOKINETIC ANALYSES.........................................................................20
9.1.
Primary Pharmacokinetic Analyses.............................................................20
9.2.
Secondary Pharmacokinetic Analyses........................................................20
 
2019N419040_00


CONFIDENTIAL
205013
4
9.2.1.
Endpoint / Variables.....................................................................20
9.2.1.1.
Drug Concentration Measures....................................20
9.2.1.2.
Derived Pharmacokinetic Parameters.........................20
9.2.2.
Summary Measure ......................................................................21
9.2.3.
Population of Interest...................................................................21
9.2.4.
Statistical Analyses / Methods .....................................................21
10. REFERENCES.......................................................................................................22
11. APPENDICES........................................................................................................23
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................23
11.1.1.
Exclusions from Per Protocol Population .....................................23
11.2.
Appendix 2: Schedule of Activities ..............................................................24
11.2.1.
Protocol Defined Schedule of Events...........................................24
11.3.
Appendix 3: Assessment Windows .............................................................25
11.3.1.
Definition of Assessment Windows for Analyses..........................25
11.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................26
11.4.1.
Study Phases ..............................................................................26
11.4.1.1.
Study Phases for Concomitant Medication .................26
11.4.1.2.
Study Phases for [Vital signs, ECG and 
Laboratory Values] .....................................................26
11.4.1.3.
Treatment Emergent Flag for Adverse Events............26
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................27
11.5.1.
Reporting Process .......................................................................27
11.5.2.
Reporting Standards....................................................................27
11.5.3.
Reporting Standards for Pharmacokinetic Parameters.................28
11.6.
Appendix 6: Derived and Transformed Data ...............................................29
11.6.1.
General........................................................................................29
11.6.2.
Study Population..........................................................................30
11.6.3.
Efficacy........................................................................................31
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................32
11.7.1.
Premature Withdrawals................................................................32
11.7.2.
Handling of Missing Data.............................................................32
11.7.2.1.
Handling of Missing and Partial Dates ........................32
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................34
11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................36
11.9.1.
Abbreviations...............................................................................36
11.9.2.
Trademarks .................................................................................37
11.10. Appendix 10: List of Data Displays..............................................................38
11.10.1. Data Display Numbering..............................................................38
11.10.2. Mock Example Shell Referencing ................................................38
11.10.3. Deliverables.................................................................................38
11.10.4. Study Population Tables..............................................................39
11.10.5. Efficacy Tables ............................................................................40
11.10.6. Safety Tables...............................................................................41
11.10.7. Pharmacokinetic Tables...............................................................42
11.10.8. Pharmacokinetic Figures .............................................................43
11.10.9. ICH Listings .................................................................................44
11.10.10.Non-ICH Listing ...........................................................................47
11.11. Appendix 11: Example Mock Shells for Data Displays ................................48
 
2019N419040_00


CONFIDENTIAL
205013
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Insert revision chronology as detailed within the protocol.
Revision Chronology:
2017N343207_00
22-JUN-2018
Original Protocol
2017N343207_01
28-JUN-2018
Original Protocol (republished)
2017N343207_02
06-AUG-2018
Original Protocol (republished)
2013N343207_03
25-OCT-2018
Amendment 1 incorporates summary of changes to the 
protocol as requested by the United States Food and 
Drug Administration (FDA).
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Due to the early termination of the study 205013 during part 1, this RAP is developed for 
a synoptic CSR. Subsequent parts were not initiated prior to study closure; therefore, no 
statistical outputs will be produced for Part 2, Part 3 and Part 4.
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

No changes or deviations
specified in the protocol 
amendment 1 (Dated: 
25/OCT/2018).

No Statistical Analysis or 
outputs to be generated for 
Part 2, Part 3 and Part 4

Part 2, Part 3 and Part 4
were not implemented

Full CSR

Synoptic CSR

Early study termination 
during part 1.
 
2019N419040_00


CONFIDENTIAL
205013
6
2.2.
Study Objective(s) and Endpoint(s)
Parts 1 & 2: Dose Escalation 
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and tolerability 
and identify the maximum tolerated 
dose (MTD) or the maximum 
acceptable dose (MAD) of 
GSK3145095 administered orally 
alone and in combination with other 
agents such as pembrolizumab to 
participants with selected advanced or 
recurrent solid tumors. 

Frequency and severity of adverse events including 
frequency of DLTs. 
Secondary Objectives
Secondary Endpoints

To evaluate the antitumor activity of 
GSK3145095 alone and in 
combination with other agents such as 
pembrolizumab in participants with 
selected advanced or recurrent solid 
tumors. 

Best overall response based on RECIST 1.1 criteria. 

To characterize the pharmacokinetics 
(PK) of GSK3145095 alone and in 
combination with other agents such as 
pembrolizumab in participants with 
selected advanced or recurrent solid 
tumors. 

Derived PK parameters for GSK3145095 including area 
under the plasma drug concentration versus time curve 
(AUC(0-t), AUC(0- τ )), maximum observed plasma drug 
concentration (Cmax), minimum observed plasma drug 
concentration (Cmin), time to maximum observed plasma 
drug concentration (tmax), clearance (CL/F), volume of 
distribution (V/F) and terminal half-life (t1/2) following 
single and repeat doses, and evaluation of dose 
proportionality, accumulation ratio and time invariance 
where data allow 

To characterize the pharmacokinetics 
(PK) of pembrolizumab when 
administered in combination with 
GSK3145095. 

Serum pembrolizumab concentrations and PK 
parameters including Cmax, AUC(0-τ), and Cmin. 
Parts 3 & 4: Dose Expansion
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the antitumor activity of 
GSK3145095 in combination with 
other agents such as pembrolizumab 
in participants with selected advanced 
or recurrent solid tumors.

Overall Response Rate (ORR; % of participants achieving 
CR or PR) based on RECIST 1.1 criteria.
 
2019N419040_00


CONFIDENTIAL
205013
7
Secondary Objectives
Secondary Endpoints

To further evaluate the safety and 
tolerability of GSK3145095 
administered orally in combination 
with other agents such as 
pembrolizumab to participants with 
selected advanced or recurrent solid 
tumors.

Frequency and severity of adverse events.

To further evaluate the antitumor
activity of GSK3145095 in 
combination with other agents such as 
pembrolizumab in participants with 
selected advanced or recurrent solid 
tumors.

Progression-Free Survival and Overall Survival.

To characterize the PK of 
GSK3145095 in combination with 
other agents such as pembrolizumab 
in participants with selected advanced 
or recurrent solid tumors.

Derived PK parameters for GSK3145095 and 
combination agent including AUC(0-t), AUC(0-τ), Cmax, 
tmax, and t1/2 following single and repeat doses, and 
evaluation of dose proportionality, accumulation ratio and 
time invariance estimation of an accumulation ratio where 
data allow
Parts 1, 2,3, & 4: Exploratory Objectives
Exploratory Objectives
Exploratory Endpoints

To explore the inter-relationship 
between antitumor activity, PK 
parameters, pharmacodynamic 
activity, and other participant 
characteristics 

Assessment of antitumor activity (CR, PR, SD, 
progressive disease [PD]), tumor kinetic/PK parameters, 
pharmacodynamic activity, and other participant 
characteristics 

To evaluate the pharmacokinetic and 
pharmacodynamic activity of 
GSK3145095 in the periphery and the 
tumor microenvironment 

Assessment of GSK3145095 tumor penetration, RIP1 
target engagement, activation, and pathway inhibition 
may be explored. 

To evaluate the relationship between 
GSK3145095 and safety parameters, 
including QTcB following single and 
repeated administration.

Relationship between GSK3145095 exposure (e.g. 
concentration, Cmax, AUC) and safety parameters 
including change from baseline QTcF.

To explore the effect of RIP1 inhibition 
on the tumor microenvironment and 
the immune response within the tumor 
and periphery 
May include assessment of: 

Tumor biopsies via immunohistochemistry (IHC) 

Changes in gene expression (ribonucleic acid [RNA] and 
protein), T cell receptor [TCR] diversity, tumor 
microenvironment or mutational load (genomic 
deoxyribonucleic acid [DNA]) 

Measures of immune function in peripheral blood 
mononuclear cells (PBMCs) 

Expression of circulating soluble factors 
 
2019N419040_00


CONFIDENTIAL
205013
8

To investigate the mechanism of 
action and indicators of sensitivity and 
resistance to GSK3145095 alone or in 
combination with other agents such as 
pembrolizumab 

Assessment of DNA, RNA, and/or protein markers in 
tumor or periphery and their association with anti-tumor 
activity for potential use in the development of a 
predictive biomarker and/or diagnostic test 

To characterize the metabolite profile 
of GSK3145095 after single or 
repeated oral dosing in some 
participants 

Identification and quantitative estimates of parent 
GSK3145095 and metabolites in plasma and/or urine 
following single or repeat doses 

To assess potential effect of repeat 
doses of GSK3145095 on 
Cytochrome P450 3A4 (CYP3A4) 
enzyme activity in some participants 

Plasma 4βhydroxycholesterol to cholesterol ratio pre-
treatment and following repeat dosing of GSK3145095 

To evaluate disease and treatment 
related symptoms and impact on 
function and health-related quality-of-
life (Parts 3 & 4 only) 

Qualitative telephone interview(s) 

To investigate the relationship 
between genetic variants in candidate 
genes, PK, and safety profile of 
GSK3145095 alone or in combination 
with other agents such as 
pembrolizumab 

Pharmacogenomic (PGx) study using blood samples 
Note that ECGs, vitals, labs (chem, haem and urinalysis), liver events are also incorporated in the safety 
reporting. 
 
2019N419040_00


CONFIDENTIAL
205013
9
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

This study consists of 4 parts; Parts 1 and 2 represent dose escalation while Parts 3 and
4 represent dose expansion.

Part 1 is designed to evaluate safety and tolerability of escalating doses of GSK3145095
alone in participants with advanced or metastatic pancreatic ductal adenocarcinoma
(PDAC) using Neuenschwander-Continual Reassessment Method (N-CRM) design
[Neuenschwander, 2008] to identify a dose for evaluation in Part 2. PK samples will be
obtained to evaluate PK parameters. Initiation of Part 2 will occur after emerging data
from Part 1 demonstrates the safety of GSK3145095 monotherapy.

Part 2 combines escalating doses of GSK3145095 with 200 mg pembrolizumab (fixed
dose). Modified Toxicity Probability Interval (mTPI) (Ji 2013) will be used to identify the
MTD of GSK3145095 in combination with pembrolizumab and determine the
recommended dose for the dose expansion phase (Parts 3 and 4).  Following protocol
amendment, a broader population of selected solid tumours may be enrolled in part 2.
These tumor types include PDAC, NSCLC, triple-negative breast cancer, and/or
melanoma. Part 2 will begin with a GSK3145095 dose below the highest Part 1 dose
shown to have an acceptable toxicity profile in at least 3 participants.

Part 3 dose expansion is designed to evaluate safety, PK, pharmacodynamic activity, and
clinical activity of one or more doses of GSK3145095 in combination with 200 mg
pembrolizumab. Any dose level(s) established as safe in Parts 1 or 2 may be selected for
cohort expansion. All available safety, pharmacodynamic, PK, and efficacy data will be
used to select one or more doses of GSK3145095 for cohort expansion. Part 3 will be
opened via a protocol amendment

Part 4 dose expansion will investigate the combination of additional anticancer agent(s)
with one or more doses of GSK3145095 identified as safe in Part 1. Part 4 will be opened
via a protocol amendment.
3
1
4
5
Part 1: Pancreatic 
cancer
GSK3145095 
monotherapy 
2
Part 3: Selected solid 
tumours  
Indication 1
Indication 2
RP2D GSK3145095 + 
pembrolizumab
Indication 3
Part 4: Selected solid 
tumours 
Indication 1
Indication 2
Indication 3
RP2D GSK3145095 + 
other anticancer therapy
Part 2: Selected 
solid 
tumours 
GSK3145095 + 
pembrolizumab
2019N419040_00


CONFIDENTIAL
205013
10
Overview of Study Design and Key Features
Dosing

Part 1 will involve dose escalation of GSK3145095 starting with a 50mg dose
administered orally (PO) twice daily (BID). Participants will receive a single dose of
GSK3145095 PO on Day 1 with the BID schedule starting on Day 2. Four additional dose
levels (ranging from 200 to 1600 mg) are planned.

Part 2 will involve dose escalation of GSK3145095 in combination with  pembrolizumab
beginning with a GSK3145095 dose below the highest Part 1 (monotherapy) dose shown
to have an acceptable toxicity profile in at least 3 participants. The dose of
pembrolizumab will remain fixed at 200 mg administered IV once every three weeks
(Q3W). Part 2 will be opened by protocol amendment.

Part 3 will further explore GSK3145095 combined with pembrolizumab in one or more
expansion cohorts. Selection of the dose of GSK3145095 and tumor types to be explored
in Parts 3 will be guided by data generated in Parts 1 & 2. Part 3 will be opened by
protocol amendment.

Following an amendment, Part 4 will involve dose expansion cohort(s) of GSK3145095
administered with additional anticancer agent combinations. The dose and indication will
be determined based on data from Parts 1 & 2.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

This is a FTIH, open-label, non-randomized study.
Interim 
Analysis

No formal interim analyses will be performed using the data generated from dose
escalation cohorts (parts 1 & 2). However, data may be summarized at the completion of
part 1 to determine the RP2D of GSK3145095 for part 2 and at the completion of part 2 to
determine the RP2D of GSK3145095+pembrolizumab for part 3.

For Parts 3 & 4 cohort expansions, the predictive probability design by Lee and Liu will be
used to assess futility.  The details will be determined once the base and target response
rates are specified (through an amendment).  These rates will depend on the tumor-type
and for part 4, the anti-cancer agent used in the combination therapy Approximately 80
participants will be enrolled in each part (3 & 4).
Note:
Due to the early study termination, Parts 2, 3 and 4 were not implemented. As a result, 
the remainder of this document contains no content related to Parts 2, 3 and 4, and will 
only provide information related to Part 1. 
2.4.
Statistical Hypotheses
Part 1 Dose Escalation
Due to limited enrolment in part 1, analyses for this part will be restricted to a descriptive 
summary of the study population and primary and secondary endpoints. 
2019N419040_00


CONFIDENTIAL
205013
11
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analyses were conducted as study was terminated early during Part 1.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants at the time of termination of study have completed the study as 
defined in the protocol (see protocol Section 5.3). 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
 
2019N419040_00


CONFIDENTIAL
205013
12
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses 
Screened

All participants screened for eligibility for trial entry

Study population
All Treated

All participants who receive at least 1 dose of 
GSK3145095.  

Clinical Activity

Safety

Study Population
PK 

The PK Population will consist of all participants from 
the All-Treated Population for whom a PK sample is 
obtained and analyzed.

PK
4.1.
Protocol Deviations
Major protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed as described in 11.10.4. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
with the Protocol Deviation Specifications developed by PAREXEL.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
There is no Per-Protocol Population for this study. Protocol deviations will not be used to 
determine membership in any study population for this study.
 
2019N419040_00


CONFIDENTIAL
205013
13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value, including those from unscheduled 
visits. If time is not collected, Day 1 assessments are assumed to be taken prior to first 
dose and used as baseline. For laboratory data, baseline will be the latest non-missing 
pre-dose value from central lab. If no central lab value is available, the latest non-missing 
pre-dose value from local lab will be used. If there are multiple assessments on the same 
day, the mean will be used as the baseline value. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. The baseline definition will be footnoted on all change 
from baseline displays.
In general, the derived baseline values (e.g. disease assessments, vital signs, ECOG, 
physical examination, mean 12-lead ECG (from triplicate measurements), laboratory 
assessments) in summary tables and displays is the last available value prior to treatment.
5.3.
Multicentre Studies
Due to early termination of the study, subject accrual will be spread thinly across centres
and summaries of data by centre would be unlikely to be informative and will not, 
therefore, be provided. 
Treatment Group Descriptions
Overall
Data Displays for Reporting
Code
General description
Description
Order in 
TLF 
Part 1
50 mg BID GSK3145095
50 mg BID GSK3145095
1
 
2019N419040_00


CONFIDENTIAL
205013
14
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
 
2019N419040_00


CONFIDENTIAL
205013
15
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the All Treated Subjects population, 
unless otherwise specified.
Summaries of participants’ disposition, protocol deviations, demographic and baseline 
characteristics, exposure will be based on GSK Core and Oncology Data Standards. 
Details of the planned displays are presented in Appendix 10: List of Data Displays.
 
2019N419040_00


CONFIDENTIAL
205013
16
7.
EFFICACY ANALYSES
The All Treated Population will be used for anticancer efficacy analyses. Since only Part 
1 was treated, the efficacy analysis is part of the secondary objective and the endpoint is 
Best Overall Response (BOR) based on RECIST 1.1 criteria.
7.1.
Primary Efficacy Analyses 
There are no primary efficacy endpoints or analyses. 
7.2.
Secondary Efficacy Analysis
7.2.1.
Endpoint/Variables
The Part 1 efficacy analysis is based on Best Overall Response (BOR). This is defined as 
the best unconfirmed response (Complete Response [CR] > Partial Response [PR] > 
Stable Disease [SD] [or non-CR/non-PD] > Progressive Disease [PD] > Not Evaluable 
[NE]) from treatment start date until disease progression or initiation of new anti-cancer 
therapy, whichever is earlier, as assessed by the investigator per RECIST 1.1 Criteria. 
The BOR rate is defined as the percentage of participants with each best unconfirmed 
response category (CR, PR, SD, PD, or NE).
7.2.2.
Summary Measure
The summary measures for the endpoints for the secondary analyses are provided in the 
table below.
Table 2
Summary of Summary Measures for Secondary Efficacy Analysis
Endpoint
Summary Measure
Best Overall Response (BOR) Rate 
(Part 1)
The number and percentage of participants with 
the BOR in the following response categories will 
be summarized: CR, PR, SD, PD and NE. 
Participants with unknown or missing responses 
will be treated as non-responders, i.e., these 
participants will be included in the denominator 
when calculating percentages of response.
 
2019N419040_00


CONFIDENTIAL
205013
17
8.
SAFETY ANALYSES
The safety analyses will be based on the All Treated population, unless otherwise 
specified.
All details of the planned displays are provided in Appendix 10: List of Data Displays. 
Unless otherwise specified, endpoints / variables will be summarised using descriptive 
statistics and listed.
8.1.
Adverse Events Analyses
Reporting of adverse events (AEs), Serious (SAEs) and other significant AEs will be 
based on GSK Core Data Standards. The details of the planned displays are provided in 
full study RAP. Details on treatment emergent AEs are provided in Section 11.4.1.3 Dose 
Limiting Toxicity (DLT) [for GSK3145095 alone] will  be and listed according to GSK 
Oncology Data Standards. The details of the planned displays are provided in Appendix 
10: List of Data Displays.
AEs will be coded to the preferred term (PT) level using the Medical Dictionary for 
Regulatory Affairs (MedDRA) V22.0.AEs will be graded by the investigator according to 
the NCI-CTCAE (version 5.0).
A summary of non-serious AEs that occurred in strictly 20% of the participants or above 
will be provided (no rounding for the percentage will be used in terms of 20% threshold, 
e.g. events with 19.9% incidence rate should not be included in this table). 
A summary of number and percentage of participants with any adverse event by 
maximum grade will be produced. AEs will be sorted by PT in descending order of total 
incidence. The summary will use the following algorithms for counting the participant:

Preferred term row: Participants experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade.

Any event row: Each participant with at least one adverse event will be counted 
only once at the maximum grade no matter how many events they have.
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced. 
AEs with missing date of onset will be considered treatment-emergent.
8.1.1.
Deaths and Serious Adverse Events
A supportive listing will be generated to provide participant-specific details on 
participants who died. 
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”. A worst-case scenario approach will be 
taken to handle missing data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. 
 
2019N419040_00


CONFIDENTIAL
205013
18
SAEs are included in the listing of all adverse events. Separate supportive listings with 
participant-level details will be generated for

Fatal SAEs 

Non-Fatal SAEs.
8.1.2.
Dose Limiting Toxicity
A listing of adverse events recorded as dose-limiting toxicities will be provided. 
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. 
The assessment of laboratory toxicities will examine the following laboratory tests 
performed by local laboratories: 
Table 3
Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistrya
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin32
Calculated creatinine clearance (CrCl)
Chloride
Carbon Dioxide
Thyroid function 
Thyroid stimulating hormone, free T4, free T3
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Serum or urine -hCG Pregnancy test (as needed for women of child bearing potential) 
a.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Protocol Section 8.1.1.
RBC = red blood cells; WBC = white blood cells; MCV = mean corpuscular volume; MCH = mean corpuscular 
hemoglobin; BUN = blood urea nitrogen; AST = aspartate aminotransferase; ALT = alanine aminotransferase; 
HBsAg = Hepatitis B surface antigen; -hCG = beta-human chorionic gonadotropin.
 
2019N419040_00


CONFIDENTIAL
205013
19
Laboratory grades will be reported using the Common Terminology Criteria for Adverse 
Events (CTCAE v5.0).
The summary of lab values and change from baseline are required for late phase 
studies.The summary of lab data by max grade is normally only used for the early phase 
studies and there is an exemption for early phase studies to not produce the summary of 
lab values and change from baseline when this summary is produced.
Separate summary tables for change from baseline in grade for haematology and 
chemistry laboratory tests will be produced.
A listing for participants with any values of potential clinical importance for all 
laboratory data and urinalysis data will be produced separately. 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of participants with non-missing value at each visit.
8.3.
Other Safety Assessments
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. Performance status will 
be summarized and listed based on GSK Oncology Data Standard. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
8.3.1.
Pregnancies
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE as described in the protocol. If the participant or 
participant’s partner become pregnant while on the study, the information will be 
included in the narratives and no separate table or listing will be produced.
8.3.2.
Physical Examinations and Performance Status Evaluations
A listing for  Eastern Cooperative Oncology Group (ECOG) performance status will be 
produced.
8.3.3.
Vital Signs
Change in vital signs from baseline will be summarized by scheduled visit using mean, 
median, standard deviation, minimum and maximum. The vital signs measurements of 
interest include temperature, systolic and diastolic blood pressure, and pulse rate.
8.3.4.
Electrocardiograms
A summary of maximum QTc values post-baseline relative to baseline by category will 
be displayed. ECG values are collected in triplicates as per protocol Section 7.4.6. 
Average of these triplicate values will be used for all ECG reporting. Listing of ECG for 
participants with any value of potential clinical importance values will be produced. 
8.3.5.
Liver Events
The number of events does not support a summary, so only listings will be produced for 
medical conditions for participants with liver events.
 
2019N419040_00


CONFIDENTIAL
205013
20
9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
There are no primary PK endpoints or analyses. All PK analyses are secondary or 
exploratory.
9.2.
Secondary Pharmacokinetic Analyses
9.2.1.
Endpoint / Variables
9.2.1.1.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions. Plasma drug 
concentrations will be listed. descriptively summarised and plotted over time for 
individual subjects.
(Section 11.5.3 Reporting Standards for Pharmacokinetic)
9.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters for GSK3145095 alone for only Part 1 will be calculated by 
standard non-compartmental analysis according to current working practices and using 
the currently supported version of WinNonlin.
Analysis procedures will follow GSK GUI_51487 (Version 5.0) unless otherwise noted 
below. All calculations of non-compartmental parameters will be based on actual 
sampling times. 
The parameters listed in Table 4 will be calculated (if data permit) for GSK3145095.
Table 4
Summary of PK parameters calculated for GSK3145095
Parameter
Parameter Description
AUC (0-
)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
AUC(0-t)
Area under the concentration-time curve from time 0 to the time of last quantifiable 
concentration will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid. 
AUC (0-)
Area under the concentration-time curve over the dosing interval, calculated from time zero 
(predose) to predose of the next dose. 
Cmax
Maximum observed plasma concentration determined directly from the concentration-time 
data. 
Tmax
Time to Cmax.
t1/2
Apparent terminal phase half-life (single dose)
Cmin
Minimum observed plasma concentration. 
Clearance 
Apparent oral clearance of parent drug. 
 
2019N419040_00


CONFIDENTIAL
205013
21
Parameter
Parameter Description
(CL/F)
Volume of 
distribution 
(V/F)
Apparent Volume of distribution. 
9.2.2.
Summary Measure

Part 1 for GSK3145095: 
o
AUC (0-
), AUC (0-t), AUC (0-), Cmax, Cmin, tmax, CL/F, V/F, t1/2
9.2.3.
Population of Interest 
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
9.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. Analysis procedures will follow GSK GUI_51487 (Version 5.0) and GSK PK 
Display Standards unless otherwise noted.
GSK3145095 plasma concentration-time data will be listed by study part, dose level, 
study day, and nominal time, and will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) if n for that level of 
summarization is ≥ 3 (if n = 2 only minimum and maximum will be reported; if n = 1 
only n will be reported). Individual plasma concentration-time figure will be produced. 
GSK3145095 plasma PK parameters will be listed by study part, dose level, and study 
day and will be summarized using descriptive statistics (n, mean, standard deviation, 
median, minimum, maximum, geometric mean, and geometric CV%) if n for that level of 
summarization is ≥ 3 (if n = 2 only minimum and maximum will be reported; if n = 1 
only n will be reported). 
 
2019N419040_00


CONFIDENTIAL
205013
22
10.
REFERENCES
GlaxoSmithKline Document Number 2017N343207_03 Study ID 205013: A Phase I/II, 
Open-Label Study to Investigate the Safety, Clinical Activity, Pharmacokinetics, and 
Pharmacodynamics of GSK3145095 Administered Alone and in Combination with 
Anticancer Agents Including Pembrolizumab in Adult Participants with Selected 
Advanced Solid Tumors. 25-OCT-2018.
Ji Y, Wang SJ. Modified toxicity probability interval design: A safer and more reliable 
method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013;31:1785-
1791.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Stats Med. 2008;27:2420-2439.
 
2019N419040_00


CONFIDENTIAL
205013
23
11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from Per Protocol Population
There are no planned exclusions from the per protocol population in this study.
 
2019N419040_00


CONFIDENTIAL
205013
24
11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Refer to Protocol Amendment 3 (2017N343207_03) Section 2, Schedule of Activities 
(SOA) for detailed schedule of activities for each part.
 
2019N419040_00


CONFIDENTIAL
205013
25
11.3.
Appendix 3: Assessment Windows
11.3.1.
Definition of Assessment Windows for Analyses
The visit assigned to the assessment as entered in the CRF (nominal visit) will be used for 
reporting.
 
2019N419040_00


CONFIDENTIAL
205013
26
11.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
11.4.1.
Study Phases
Study Phase
Definition
Part 1 
Dose Escalation: GSK3145095 monotherapy
11.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to earliest screening 
visit
Concomitant
If the medication is not Prior.
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is missing.
11.4.1.2.
Study Phases for [Vital signs, ECG and Laboratory Values]
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date 
11.4.1.3.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent
In general, all AEs with a start date after treatment are considered emergent 
regardless of AE start date is before or after treatment stop date. 

If AE onset date is on or after treatment start date & on or before treatment stop 
date + lag time on or before treatment stop date. (plus washout or protocol-
specified time limit (e.g. half-life of drug, certain number of days, etc.).]
o
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date [+ 
Lag Time].
o
AE Start Date is missing

For studies with greater than one treatment period, if AE onset is during one 
period and worsens during a later period it would be counted in both periods. For 
the initial period the logic would be as above. For the later period the logic would 
use the treatment dates associated with the later period:
o
Treatment Period Start Date ≤ AE Worsening Date ≤ Study Treatment Stop 
Date [+ Lag Time].

Missing AE Start Date will be imputed following rules in Section 11.7.2.1 for 
determining Treatment Emergent AEs. 
NOTES: 

[If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.]

Time of study treatment dosing and start time of AEs should be considered, if collected.

Lag time = 90 days if not additional anticancer agent started; 30 days if another anticancer agent is started within 
90 days
 
2019N419040_00


CONFIDENTIAL
205013
27
11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Compound
: Compound: GSK3145095, study: 205013, reporting effort: final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1].
Generation of RTF Files

RTF files will be generated for SAC.
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless otherwise 
stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All participant 
level listings should be located in the modular appendices as ICH or non-ICH listings

All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects CDISC and GSK 
Data Display Standards terminology
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:
o
Planned time relative to dosing will be used in figures, summaries, statistical analyses and calculation 
of any derived parameters, unless otherwise stated.
o
The impact of any major deviation from the planned assessment times and/or scheduled visit days on 
the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 
o
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).
o
Unscheduled or unplanned readings will be presented within the participant’s listings. 
 
2019N419040_00


CONFIDENTIAL
205013
28
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures. All unscheduled visits will be 
included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.    
11.5.3.
Reporting Standards for Pharmacokinetic Parameters
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[Insert document name]. 
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to [Standards for Handling NQ Impacted PK Parameters].
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to GUI_51487 
 
2019N419040_00


CONFIDENTIAL
205013
29
11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:
o
Ref Date = Missing              → Study Day = Missing 
o
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date
o
Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Change from Baseline

Change from Baseline = Post-Baseline Visit Value – Baseline

If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change 
from Baseline is set to missing
Date of Response

For post-baseline disease assessments, the date of response (PR or better) is assigned to the latest 
date of disease assessments; for other response categories ([MR,] SD [or Non-CR/Non-PD], NE, PD), 
the date of response is assigned to the earliest date of disease assessments.   
 
2019N419040_00


CONFIDENTIAL
205013
30
11.6.2.
Study Population
Treatment Compliance
For oral drugs only

Treatment compliance will be calculated based on the formula:  
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency)

Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated.
Extent of Exposure

Missing treatment stop date will be imputed following rules specified in Section 11.7.2.1.

Daily Oral Drugs  
o
Number of days of exposure (duration on study treatment) to study drug will be calculated based 
on the formula:  
Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1
o
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 
o
The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)
o
If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
Actual Treatment

Participant’s actual treatment will be derived from exposure data and/or study treatment data provided 
by Clinical Operations. If a participant’s actual treatment is the same as assigned treatment, actual 
treatment is the assigned treatment; if a participant received treatment different from assigned treatment 
for the entire duration of treatment, actual treatment is different from assigned treatment.
Time since Initial Diagnosis
To report in months, divide the number of days by 30.4375; to report in weeks divide the number of days by 
7; to report in years divide the number of days by 365.25.

Calculated as the number of Days from the Date of Initial Diagnosis:
o
First Dose Date = Missing           → Elapse Time = Missing 
o
Date of Initial Diagnosis = Completely/partially Missing       → Elapse Time = Missing 
o
Otherwise       → Elapse Time = First Dose Date – Date of Initial Diagnosis + 1           
 
2019N419040_00


CONFIDENTIAL 
205013 
31 
11.6.3. 
Efficacy 
Efficacy Endpoints 
Best Overall Response (BOR) is defined as the best unconfirmed response (Complete Response [CR] > 
Partial Response [PR] > Stable Disease [SD] [or non-CR/non-PD] > Progressive Disease [PD] > Not 
Evaluable [NE]) from treatment start date until disease progression or initiation of new anti-cancer therapy, 
whichever is earlier, as assessed by the investigator per RECIST 1.1 Criteria.  
The BOR rate is defined as the percentage of participants with each best unconfirmed response category 
 
2019N419040_00


CONFIDENTIAL
205013
32
11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as follows 
- For Part 1, participants were considered to have completed the study if they complete 
screening assessments and receive at least 1 study treatment and experience a DLT or 
completed the 4-week DLT observation period, and the treatment discontinuation visit 
(TDV). 

A participant will be considered to have withdrawn from the study if (1) the participant 
has not died and is lost to follow-up, (2) the participant has withdrawn consent, (3) at 
the investigator’s discretion is no longer being followed, or (4) the study is 
closed/terminated.

Withdrawn participants who discontinue before completing the 4-week DLT observation 
period and did not receive at least 80% of GSK3145095 (all participants) may be 
replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 

Withdrawal visits will be summarised as withdrawal visits.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant listing displays. However, 
where necessary, display macros may impute dates as temporary variables for 
sorting data in listings only. In addition, partial dates may be imputed for ‘slotting’ 
data to study phases or for specific analysis purposes as outlined below.

Imputed partial dates will not be used to derive study day, duration (e.g., duration 
of adverse events), or elapsed time variables (e.g., time since diagnosis). In 
addition, imputed dates are not used for deriving the last contact date in overall 
survival analysis dataset.

With the exception of new anti-cancer therapy start date in the time to event 
analysis dataset and exposure end date in the exposure analysis dataset, imputed 
dates will not be stored on datasets.
 
2019N419040_00


CONFIDENTIAL
205013
33
Element
Reporting Detail
Adverse Events

Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings.

The eCRF allows for the possibility of partial dates (e.g., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will be 
used. 
o
Missing Start Month and Day: First of January will be used unless AE stop 
date is after treatment start date, in this case treatment start date will be used

Completely missing start dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.

Completely or partially missing end dates will remain missing, with no imputation 
applied. Consequently, duration of such events will be missing.
Concomitant 
Medications/ 
Blood Supportive 
Products

Completely missing start dates will not be imputed

Partial start dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If day and month are missing:
‒
If treatment start date is missing (i.e., participant did not start study 
treatment), a '01' will be used for the day and 'Jan' will be used for the 
month;
‒
If treatment start date is not missing 

If year of start date = year of study treatment start date
If stop date contains a full date which is earlier than the treatment 
start date, a '01' will be used for the day and 'Jan' will be used for 
the month;
else study treatment start date will be used

else a ‘01’ will be used for the day and ‘Jan’ will be used for the 
month
o
If day is missing:
‒
If treatment start date is missing (i.e., participant did not start study 
treatment), a '01' will be used for the day;
‒
If treatment start date is not missing 

If year and month of start date = year and month of study treatment 
start date
If stop date contains a full date which is earlier than the treatment 
start date, a '01' will be used for the day;
else study treatment start date will be used

else a ‘01’ will be used for the day and ‘Jan’ will be used for the 
month

Completely missing end dates will not be imputed

Partial end dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If day and month are missing
‒
Earliest of (Dec 31st, date of last contact) will be used 
o
If day is missing
‒
Earliest of (last day of the month, date of last contact) will be used
 
2019N419040_00


CONFIDENTIAL
205013
34
Element
Reporting Detail
New Anti-Cancer 
Therapy/ 
Radiotherapy/
Surgical 
Procedures for 
Efficacy 
Evaluation (e.g., 
response rate, 
time to event)
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be imputed in order to define event and 
censoring rules for progression-free survival, response rate, or duration of response 
(i.e. start date for new anti-cancer therapy). Dates will only be imputed when a month 
and year are available but the day is missing. The following rules will be used to 
impute the date when partial start dates are present on anti-cancer therapy, 
radiotherapy, and/or surgical procedures dataset[s]:

Completely missing start dates will remain missing, with no imputation applied;

Partial start dates will be imputed using the following convention:

If both month and day are missing, no imputation will be applied;

If only day is missing: 
o
If the month of partial date is the same as the month of last dosing date, 
minimum of (last dosing date + 1, last day of the month) will be used for 
the day;
o
If the month of partial date is the same as the month of last disease 
assessment and the last disease assessment is PD, minimum of (last 
date of disease assessment + 1, last day of the month) will be used for 
the day;
o
If both conditions above are met, the later date will be used for the day;
o
Otherwise, a ‘01’ will be used for the day;

Completely or partial missing end dates will remain missing, with no imputation 
applied;
Treatment end 
date

In general, completely missing end dates are not imputed

The imputed treatment end date will be used to calculate cumulative dose and 
duration of treatment as specified in Section 11.6.2 .
For non-continual treatment

If treatment end date is missing for a cycle, treatment start date for the cycle will 
be used.
11.8.
Appendix 8: Values of Potential Clinical Importance
To identify values of potential clinical importance, National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v [5.0]) will be used to assign 
grades for laboratory parameters including clinical chemistry, hematology, liver function 
tests.
The clinical importance for vital signs (temperature and blood pressure) are also 
identified using NCI-CTCAE v [5.0] with details below. Pulse rate below 60 beats/min is 
indicated as low and above 100 beats/min is indicated as high.
 
2019N419040_00


CONFIDENTIAL
205013
35
Grade 0
Grade 1
Grade 2
Grade 3
Temperature
<38
38-39
>39-40
>40
Systolic Blood Pressure
<120
120-139
140-159
>=160
Diastolic Blood Pressure
<80
80-89
90-99
>=100
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings.
 
2019N419040_00


CONFIDENTIAL
205013
36
11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
ITT
Intent-To-Treat
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TFL
Tables, Figures & Listings 
 
2019N419040_00


CONFIDENTIAL
205013
37
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS 
 
2019N419040_00


CONFIDENTIAL
205013
38
11.10.
Appendix 10: List of Data Displays
Please note that in all tables, listings, and figures, the term “subject(s)” is used to refer to 
“participants”.
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.6
N/A
Efficacy
2.1
                    N/A
Safety
3.1 to 3.6
N/A
Pharmacokinetic
4.1 to 4.2
4.1
Section
Listings
ICH Listings
1 to 25
Other Listings
26 to 34
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Section 11.10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
11.10.3.
Deliverables
Delivery 
Description
SAC 
Final Statistical Analysis Complete
 
2019N419040_00


CONFIDENTIAL
205013
39
11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title 
Programming Notes
Deliverable
Subject Disposition
1.1
All Treated 
Subjects
ES1
Summary of Subject Status and Reason for Study 
Withdrawal – Part 1
ICH E3, FDAAA, EudraCT
SAC
1.2
Enrolled
NS1
Summary of Number of Participant by Country and Site 
ID– Part 1
EudraCT/Clinical Operations
SAC
Demographic and Baseline Characteristics
1.3
All Treated 
Subjects
DM1
Summary of Demographic Characteristics– Part 1
ICH E3, FDAAA, EudraCT
SAC
1.4
All Treated 
Subjects
DM5
Summary of Race and Racial Combinations– Part 1
ICH E3, FDA, FDAAA, EudraCT
SAC
Exposure and Treatment Compliance
1.5
All Treated 
Subjects
POP_T1
Summary of Exposure to GSK3145095– Part 1
SAC
Protocol Deviation
  1.6
All Treated
DV1
Summary of Important Protocol Deviations – Part 1
ICH E3
SAC  
 
 
 
2019N419040_00


CONFIDENTIAL
205013
40
11.10.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title 
Programming Notes
Deliverable
Clinical Response
2.1
All Treated
RE1a
Summary of Investigator-Assessed Best Response without
Confirmation for Subjects with Measurable Disease only at 
Baseline (RECIST 1.1 Criteria)
1. Include just the first two segments of 
the template. i.e. Best Response and 
Response rate.
2. P-value for response rate would not be 
reported.
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
41
11.10.6.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell Title 
Programming Notes
Deliverable
Adverse Events (AEs)
3.1
All Treated 
OAE7
Summary of All Adverse Events by Maximum Grade by 
Preferred Term
Use AE1 or AE1CP if Grade/Intensity not used; 
otherwise use AE5A/B (with a Total column across all 
grades/severities, which provides same detail as 
AE1.)
SAC
3.2
All Treated
AE15
Summary of Common (>=20%) Non-serious Adverse 
Events by Preferred Term (Number of Participant and 
Occurrences)
FDAAA, EudraCT
SAC
Laboratory: Chemistry
3.3
All Treated
OLB11C
Summary of Clinical Chemistry Changes from Baseline 
with Respect to The Normal Range
.
SAC
Laboratory: Hematology
3.4
All Treated
OLB11C
Summary of Haematology Changes from Baseline with
Respect to The Normal Range
SAC
ECG
3.5
All Treated
OECG1C
Summary of Maximum QTc Values Post-Baseline 
Relative to Baseline by Category– Part 1
IDSL
SAC
Vital Signs
3.6
All Treated
VS1
Summary of Change from Baseline in Vital Signs – Part1 ICH E3
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
42
11.10.7.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL / Example 
Shell
Title 
Programming Notes
Deliverable
PK Concentration
4.1
PK
PK01
Summary of GSK3145095 Plasma Pharmacokinetic 
Concentration-Time Data
IDSL
SAC
PK Parameters
4.2
PK
PK06
Summary of Derived GSK3145095 Plasma Pharmacokinetic 
Parameters (non-transformed and log-transformed)
IDSL
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
43
11.10.8.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL / Example 
Shell
Title 
Programming Notes
Deliverable 
[Priority]
PK
4.1
PK
PK16a/b
Individual GSK3145095 Plasma Concentration-Time Plots 
(Linear and Semi-log)
IDSL
Required for serial sampling but not 
sparse sampling. Required for late-
phase if PK data being analyzed by 
S&P and serial sampling was done.
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
44
11.10.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / Example 
Shell
Title 
Programming Notes
Deliverable
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
All Treated
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
All Treated
SD2
Listing of Reasons for Study Treatment Discontinuation
Remove “Number of cycles” column. 
Add investigational product as one of 
the column
SAC
Protocol Deviations
4.
All Treated
DV2
Listing of Important Protocol Deviations
SAC
5.
Screened
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
SAC
Populations Analysed
6.
All Treated
SP3
Listing of Participants Excluded from Any Population
e.g., participants screened but not 
randomized, participants randomized 
but not treated, participants with 
deviations leading to exclusion from per 
protocol population (can be separate 
listing per population).
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
45
Demographic and Baseline Characteristics
7.
All Treated
DM2
Listing of Demographic Characteristics
SAC
8.
All Treated
DM9
Listing of Race
SAC
Medical History and Concomitant Medications
9.
All Treated
MH2
Listing of Past/Current Medical Conditions
Oncology specific template to be used
SAC
10.
All Treated
OCM1A
Listing of Concomitant Medications
Include both prior and concomitant
medications
SAC
Exposure and Treatment Compliance
11.
All Treated
EX3
Listing of Exposure Data
Include a flag variable to indicate 
imputed date.
SAC
12.
All Treated
COMP2
Listing of Overall Compliance
SAC
Adverse Events
13.
All Treated
OAE04
Listing of All Adverse Events
ICH E3
SAC
14.
All Treated
OAE03
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
Serious and Other Significant Adverse Events
15.
All Treated
OAE04
Listing of Fatal Serious Adverse Events
SAC
16.
All Treated
OAE04
Listing of Non-Fatal Serious Adverse Events
SAC
17.
All Treated
AE8 / AECP8 / 
AE9 / AE9CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
Dose-Limiting Toxicities
18.
All Treated
DL3
Listing of Dose-Limiting Toxicities (DLT) During the 
Determinative Period
Required for dose escalation studies 
looking at dose-limiting toxicities.
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
46
All Laboratory
19.
All Treated
LB5A
Listing of All Laboratory Data
ICH E3
May be split into separate listings by 
chemistry, hematology, etc. Display 
ALL labs for a subject who experienced 
a value of potential clinical importance.
Recommended for oncology: LB5A; For 
healthy volunteer studies, LB5/6 is 
recommended.
SAC
ECG
20.
All Treated
EG3
Listing of All ECG Values for Participants with Any Value 
of Potential Clinical Importance
IDSL
Required for ClinPharm studies 
only. Display ALL ECGs for a 
subject who experienced a value 
of potential clinical importance.
SAC
Vital Signs                                       
21.
All Treated
VS4
Listing of Vital Signs
SAC
Deaths
22.
All Treated
DTH3
Listing of Deaths
ICH E3
SAC
Hepatobiliary (Liver)
23.
All Treated
MH2
Listing of Medical Conditions for Participants with Liver 
Stopping Events
IDSL
SAC
Performance Status
24.
All Treated
PS5A
Listing of Performance Status
Example PS5A is used to list ECOG 
Performance Status.
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
47
11.10.10. Non-ICH Listing
Non-ICH: Listings
No.
Population
IDSL / 
Example 
Shell
Title 
Programming Notes
Deliverable 
[Priority]
Disease Characteristics
25.
All Treated
DC3
Listing of Disease Characteristics at Initial Diagnosis
SAC
26.
All Treated
DC4
Listing of Disease Characteristics at Screening
SAC
27.
All Treated
MD2
Listing of Metastatic Disease at Screening
Include if this information is 
collected in the eCRF. Will not be 
appropriate for heme studies.
SAC
Anti-Cancer Therapy
28.
All Treated
AC6
Listing of Prior Anti-Cancer Therapy
SAC
29.
All Treated
AC7
Listing of Prior Anti-Cancer Radiotherapy
SAC
Surgical Procedures
30.
All Treated
OSP3
Listing of Prior Treatment Cancer Related Surgical 
Procedures
SAC
Substance Use
31.
All Treated
SU2
Listing of Substance Use
SAC
Responses
32.
All Treated
LA5
Listing of Investigator Assessed Lesion Assessments 
(RECIST v1.1 Criteria) -Part 1
SAC [1]
PK
33.
PK
PK07 
Listing of GSK3145095 Plasma Pharmacokinetic 
Concentration-Time Data  
IDSL
SAC
34.
PK
PK13 
Listing of Derived GSK3145095 Plasma Pharmacokinetic 
Parameters
IDSL
SAC
 
 
 
2019N419040_00


CONFIDENTIAL
205013
48
11.11.
Appendix 11: Example Mock Shells for Data Displays                                                                                               
Example:    POP_T1                                                                                                                                                                                               Page 1 of n                                        
Protocol:     205013
Population: All Treated Subjects   
Table X
Summary of Exposure to GSK3145095
Note: [1] Duration of exposure = end date of GSK3145095- start date of GSK3145095 + 1.
      [2] Average daily dose = Cumulative dose divided by duration of exposure. 
50 mg BID 
Duration of Exposure(weeks) [1]
n
X
Mean
X.XXX
SD
X.XXXX
Median
X.XXX
Min.
X.XX
Max.
X.XX
Average Daily Dose(mg) [2]
n
X
Mean
X.XXX
SD
X.XXXX
Median
X.XXX
Min.
X.XX
Max.
X.XX
 
 
 
2019N419040_00