Clinical trial NCT03666988
Conditions: Neoplasms
Keywords: Dose-escalation First time in humans Solid tumors GSK3368715 Diffuse Large B-Cell Lymphoma
Sponsor: GlaxoSmithKline
Start date: 2018-10-22; Completion date: 2021-03-04
Enrollment: 31 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Arginine methylation mediated by protein arginine methyl-transferases (PRMTs) is an important post-translational modification of proteins involved in a diverse range of cellular processes. Misregulation and overexpression of PRMT1 (a type I PRMT) has been associated with a number of solid and hematopoietic cancers. GSK3368715 leads to inhibition of tumor cell growth across tumor types with cytotoxic response observed in lymphoma, acute myeloid leukemia (AML) and a subset of solid tumor cell lines. This study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), food effect and preliminary clinical activity of GSK33368715 in participants with relapsed/refractory DLBCL and selected solid tumors with frequent methyl-thioadenosine phosphorylase (MTAP)-deficiency. The study will consist of two parts. In Part 1 (Dose Escalation) escalating doses of GSK3368715 will be evaluated and recommended phase 2 dose (RP2D) will be established in participants with selected solid relapsed/refractory tumors. Once a RP2D is identified, a food effect sub-study will be initiated to determine the effect of a high-fat, high calorie meal on the bioavailability of GSK3368715. In Part 2 (Dose Expansion), this RP2D will be further investigated in two expansion cohorts; participants with DLBCL (Expansion Cohort 2A) and relapsed/refractory solid tumors including pancreatic, bladder, and non-small cell lung cancer (NSCLC)(Expansion Cohort 2B). The study includes a screening period, an intervention period and follow up.

Detailed description:

Arms: arm 1: Eligible participants with solid relapsed/refractory tumors will receive escalating doses of GSK3368715 at a starting dose of 50 mg, administered orally once daily. arm 2: Additional participants in Part 1, treated at or close to the expected the maximum tolerated dose (MTD)/RP2D, will be evaluated for metabolic and biomarker profiling. Participants may be enrolled into this cohort(s) even after MTD/RP2D has been identified and Part 2 has been initiated. arm 3: Eligible participants will receive single dose of GSK3368715 at starting dose of 50 mg tablet orally in fasted state followed by fed state in Period 1 and Fed followed by fasted state in Period 2. arm 4: Eligible participants with relapsed/refractory DLBCL will receive RP2D of GSK3368715 established during Part 1, administered orally once daily. arm 5: Eligible participants with relapsed/refractory solid tumors (pancreas cancer, NSCLC, and bladder cancer) will receive RP2D of GSK3368715 established during Part 1, administered orally once daily.
Interventions: intervention 1: GSK3368715 intervention 2: GSK3368715
Intervention descriptions: intervention 1: GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule. intervention 2: GSK3368715 will be available in Immediate release (IR) white film coated tablet with dosing strengths of 50 mg, 100 mg and 250 mg to be administered orally once daily .

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A phase I, open-label, dose-escalation study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of GSK3368715 in 
participants with solid tumors and DLBCL
Protocol Number: 207675/ 03
Short Title: FTIH study of GSK3368715 in participants with solid tumors and DLBCL
Development Phase: Phase I
Compound Number: GSK3368715
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: Provided in the Study Reference 
Manual.
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) number IND136141
EudraCT number 2018-001629-20
Approval Date: 05-DEC-2019
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.


PPD
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 03
05-Dec-2019
Amendment 02
22-Feb-2019
Amendment 01
12-Jul-2018
Original Protocol
02-May-2018
Amendment 03: 05-DEC-2019
This amendment applies to all sites participating in the conduct of the study.
Overall Rationale for the Amendment:
Protocol Amendment 3 includes the following:
Updated clinical safety guidelines, clinical pharmacology, and the risks/mitigation 
strategy following the temporary pause in enrolment due to venous 
thromboembolic events (VTE) that have been observed in the dose escalation 
phase of the study. Also, the risk of biopsy collection has been added to the 
benefit/risk assessment table.
Changes to exclusion criteria to exclude participants who have 3 or greater 
Khorana score, and exclude participants who have prior history of VTE.

Addition to allowed anti-coagulation therapy - the use of oral anticoagulation 
using Factor Xa inhibitors such as Apixaban and Rivaroxaban is allowed on trial. 
Anticoagulation with oral Vitamin K antagonists such as Warfarin is not allowed.
Addition of exploratory coagulation markers and minor changes to other 
exploratory biomarkers being collected in the dose escalation phase of the study 
(Part 1).
Changes and clarifications made in the Schedule of Activities Tables; clarification 
of time windows for PK and PD samples, changes to some of the PK and PD 
sampling time points in the dose escalation and PK/PD cohorts in Part 1 and 
telemetry only required for doses of > 200mg.
Changes to DLT and stopping/exclusion criteria for QRS and VTEs, and update 
to the telemetry assessment.
Addition of food effect cohort into Part 1.
Addition of tablet formulation.
Further clarifications added to the sample size determination section.


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Addition of albumin in the clinical labs table (Table 9, Appendix 2).
Addition of guidelines of management of toxicity for VTEs in Appendix 12
Addition of Appendix 13 (Khorana score)
Administrative changes made throughout the document.


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Section # and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis
Addition of PK/PD cohort 
and food effect into the
overall design, also PK in 
fed and fasted state added 
to the objectives/endpoints.
VTE DLT criteria 
mentioned in the 
“Intervention groups and 
duration” section.
To add text to make it clear that the
PK/PD and food effect cohorts are
included in Part 1 of the study.
A brief statement has been added to this 
section around the new DLT criteria for 
any venous thrombo-embolic events.
Section 1.2 schema
New schema added.
To add clarity around the dose escalation, 
food effect and PK/PD cohort(s) in Part 1, 
and the planned transition of capsules to 
tablets in the food effect cohort and in 
Part 2 of the study.
Schedule of Activities 
tables, Section 1.3
Updates to Table 1 to
Table 3.
Changes in some of the 
PK and PD sampling 
collection times, 
clarification on time 
windows for certain PK and 
PD samples, addition of 
exploratory coagulation 
markers, up to 48 hour 
urine collections added to 
the PK/PD cohort, tumor 
imaging must include chest 
CT at screening and at all 
timepoints as stated in the 
Schedule of Activities 
tables
To add clarity.
PK and PD sampling time points have 
been adjusted to ensure that the 
maximum blood volume is not exceeded 
for any participant enrolled onto the study.
Tumor imaging – Chest CT scan added to 
further assess the participant, due to the
incidence of embolic and thrombotic 
events observed to date in the dose 
escalation phase of the study.
Schedule of Activities
tables, Section 1.3
Table 4 added – food 
effect cohort added to Part 
1
To determine the effect of a high-fat, high-
calorie meal on the bioavailability of 
GSK3368715 at or near the RP2D
Section 2.2.1.4 Clinical 
safety of GSK3368715
Detail added on the VTE
events that have occurred 
on the study. This led to a 
temporary pause in 
enrolment in the dose 
escalation phase of the 
study.
To explain the rationale for the temporary 
pause in enrolment. This section now 
includes additional guidelines for 
management of any VTEs and to ensure 
participant safety going forward as 
enrolment will re-commence.


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Section # and Name
Description of Change
Brief Rationale
Section 2.2.1.5 Clinical 
Pharmacology of 
GSK3368715
Updated information on the 
pharmacokinetics of the 
compound.
To add the latest information on the 
pharmacokinetics of the compound.
Section 2.3.1 Risk 
assessment
Addition of the VTE risk 
and the mitigation strategy 
around this risk.
Addition of risk of biopsy 
collections.
To add details on the VTE risk, and the 
procedures that are being put in place in 
this current amendment to mitigate that 
risk.
To add details on the risk of biopsy 
collections and the mitigation strategies 
for this risk.
Section 2.3.2 Benefit 
assessment and 
Section 2.3.3 Overall 
Benefit/Risk Conclusion
Addition of a sentence 
detailing some evidence of 
stable disease observed to 
date in the study (in dose 
escalation).
To provide a brief statement of some 
evidence of stable disease observed to 
date in the study (in Part 1, dose 
escalation).
Section 3, Objectives
To add in another 
exploratory objective into 
Part 1- the addition of 
some coagulation 
biomarkers.
To collect more data in Part 1 of the study 
on coagulation biomarkers, to gain more 
information to help with the safety 
assessments of any further potential 
VTEs.
Section 4.1.Overall 
Design, Section 4.1.1 
Part 1 (dose escalation 
phase)
To add in text around the 
occurrences of the VTEs 
and the plans for re-
initiation of enrolment.
To update the study design of Part 1 of 
the study.
Section 4.1.1.1 Food 
effect cohort
To add in details of the 
food effect cohort.
To add clarity and update the study 
design of Part 1 to include a food effect 
sub-study.
Section 4.1.3 Dose 
limiting toxicity
To add in details of the 
VTEs and the plans in 
place if more VTEs were to 
occur on re-initiation of the 
study.
To add clarity.
Section 4.1.4 Dose 
Escalation committee
Minor additions around 
VTEs and the DLT criteria.
To add clarity.
Section 4.2 Scientific 
rationale for study 
design
Added in details of the food 
effect study.
To gain more information of the 
bioavailability of GSK3368715 when 
administered in the fed and fasted state.


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Section # and Name
Description of Change
Brief Rationale
Section 4.3.2
Addition of a new section, 
Dose Justification for Food 
Effect Sub cohort
Details of a new food effect cohort added 
to this protocol amendment.
Section 5.1, Inclusion 
criterion, number 2
To include patients 
enrolled in the food effect 
sub-study.
To add clarity.
Section 5.2, Exclusion 
criteria
Update to criterion 8 (e) to 
allow for a QRS interval of 
<110 ms at screening or 
baseline
Addition of a new exclusion 
criterion (16) - a participant 
is considered high-risk for 
VTE as defined by either 
Khorana Score of >=3 or 
prior medical history of 
VTE
QRS interval value was updated following 
review of clinical safety data, to broaden 
eligibility
This new exclusion criterion 17 is being 
added in this current amendment to 
mitigate the risk of further VTEs occurring 
in participants, once re-enrolment starts,
Section 5.3.1, Meals 
and dietary restrictions
Addition of text for the food 
effect sub-study
To add clarity for the food effect cohort.
Section 6.1, Study 
Intervention
Addition of tablets
A tablet formulation is in development and 
will be introduced into the study
Section 6.7 
Concomitant therapy
Section 6.7.1 Prohibited 
medications
Update to the allowed anti-
coagulation therapy, to 
include the use of oral 
anticoagulation using
Factor Xa inhibitors such 
as Apixaban and 
Rivaroxaban on the trial.
Prohibited medications -
Anticoagulation with oral 
Vitamin K antagonists such 
as Warfarin is not allowed
Due to the risk of venous 
thromboembolism among cancer patients, 
additional anti-coagulation therapies (oral 
anticoagulation using Factor Xa inhibitors 
such as Apixaban and Rivaroxaban) are 
being allowed on the trial.
Section 7.1.3, QRS 
interval stopping 
criterion
Updated text added (an 
increase in the QRS 
interval of > 20 ms from 
baseline).
Based on evaluation of cardiac clinical 
safety data from 207675 
Section 7.1.4 PR 
interval stopping criteria
Updated text added (an 
increase in the PR interval 
to >250 msec in 
Based on evaluation of cardiac clinical 
safety data from 207675 


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Section # and Name
Description of Change
Brief Rationale
participants without pre-
existing AV-block).
Section 8.2.5 Telemetry
Text updated (continuous 
telemetry initially for at 
least 24 hours from the 
start of dose for the first 10 
participants at each dose 
level >200 mg).
Based on evaluation of cardiac clinical 
safety data from 207675.
Telemetry is only required for doses 
>200mg.
Section 8.6, 
Pharmacokinetics
Additional text to explain 
the sampling for the dose 
escalation, PK/PD cohort 
and the food effect cohort.
To add clarity.
Section 8.7 
Pharmacodynamics
Some minor additions to 
the exploratory biomarkers 
being collected.
To allow for additional exploratory 
biomarkers to be collected.
Section 8.9 Biomarkers 
and translational 
research
Removal of Circulating 
Cell-free DNA/RNA 
Analysis.
Addition of coagulation 
markers (Section 8.9.5).
Circulating Cell-free DNA/RNA analysis
will be removed from this amendment.
Exploratory coagulation biomarkers will be 
collected to gain more information to help 
with the safety assessments of any further 
potential VTEs.
Section 9.2 Sample 
Size Determination
Addition of some further 
details.
To add clarity.
Section 9.2.1.1 
Operating 
characteristics of the 
safety stopping rule for 
VTE events in dose 
escalation
Addition of a new 
subsection to add detail on 
the operating 
characteristics of the safety 
stopping rule for VTE 
events in dose escalation.
To add clarity around the safety stopping 
rule for VTE events in the dose escalation 
phase of the study.
Section 
9.6.3.2Statistical 
analysis of 
pharmacokinetic data
Addition of a new 
subsection to add detail on 
the statistical analysis of 
the PK data obtained from 
the food effect cohort.
New food effect cohort added, so this text 
is providing details of the statistical 
analysis of the PK data that will be 
obtained in this cohort.
Section 10.2, Appendix 
2, Clinical laboratory 
tests, Table 9
Clinical laboratory tests –
addition of albumin in the 
clinical chemistry panel.
To add clarity. Albumin was omitted from 
this table in error, in the previous protocol 
amendment.
Section 10.12, 
Inclusion of text around 
To add guidance for the investigators 


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Section # and Name
Description of Change
Brief Rationale
Appendix 12, 
Guidelines for 
management of toxicity
VTEs in the Dose 
Adjustment/Stopping 
Safety Criteria table
around what to do if any future VTEs 
occur on the study.
Section 10.13, 
Appendix 13, Khorana 
score
New appendix added.
To add clarity for the determination of 
Khorana scores.  Addition of a table 
showing “Predictive model for 
chemotherapy-associated VTE”.
Section 10.3.5 
Reporting of SAE to 
GSK
New text added for 
capturing SAEs on paper 
CRF (as back-up option).
To add details for the possibility of 
capturing SAEs on a paper CRF (as a 
back-up option to the preferred electronic 
data capture in the eCRF).
Section 10.3.6 
Definition of AESI
Section deleted.
Deleted text as there are no AEs of 
special interest stated in this study.


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
PROTOCOL SUMMARY........................................................................................15
1.1.
Synopsis.....................................................................................................15
1.2.
Schema ......................................................................................................17
1.3.
Schedule of Activities (SoA)........................................................................18
2.
INTRODUCTION....................................................................................................28
2.1.
Study Rationale ..........................................................................................28
2.2.
Brief Background ........................................................................................30
2.2.1.
GSK3368715...............................................................................30
2.2.1.1.
Nonclinical Safety.......................................................30
2.2.1.2.
Nonclinical Pharmacokinetics.....................................32
2.2.1.3.
Nonclinical Activity and Pharmacodynamics...............32
2.2.1.4.
Clinical Safety of GSK336715 ....................................33
2.2.1.4.1.
Adverse Events and Dose Limiting 
Toxicities ................................................33
2.2.1.4.2.
Venous Thromboembolism.....................33
2.2.1.4.3.
Cardiac Safety........................................34
2.2.1.5.
Clinical Pharmacology of GSK3368715......................34
2.2.2.
Potential GSK3368715 Combination Regimens...........................35
2.2.2.1.
GSK3368715 Combination with PRMT5 
inhibition.....................................................................35
2.2.2.2.
GSK3368715 Combination with Checkpoint 
Modulators .................................................................35
2.3.
Benefit/Risk Assessment ............................................................................35
2.3.1.
Risk Assessment .........................................................................36
2.3.2.
Benefit Assessment.....................................................................38
2.3.3.
Overall Benefit/Risk Conclusion...................................................38
3.
OBJECTIVES AND ENDPOINTS...........................................................................40
4.
STUDY DESIGN ....................................................................................................41
4.1.
Overall Design ............................................................................................41
4.1.1.
Part 1: Dose-Escalation Phase ....................................................42
4.1.1.1.
Food effect Cohort......................................................44
4.1.2.
Part 2: Expansion Cohorts...........................................................46
4.1.3.
Dose-Limiting Toxicity..................................................................47
4.1.4.
Dose Escalation Committee.........................................................50
4.2.
Scientific Rationale for Study Design ..........................................................51
4.3.
Dose Justification........................................................................................53
4.3.1.
Starting Dose Justification ...........................................................53
4.3.2.
Dose Justification for Food Effect Sub cohort ..............................54
5.
STUDY POPULATION...........................................................................................54
5.1.
Inclusion Criteria.........................................................................................54
5.2.
Exclusion Criteria........................................................................................58
5.3.
Lifestyle Restrictions...................................................................................61
5.3.1.
Meals and Dietary Restrictions ....................................................61


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5.4.
Screen Failures...........................................................................................62
6.
STUDY INTERVENTION........................................................................................62
6.1.
Study Intervention(s) Administered .............................................................62
6.2.
Dose Modification .......................................................................................64
6.3.
Method of Intervention Assignment.............................................................64
6.4.
Blinding.......................................................................................................64
6.5.
Preparation/Handling/Storage/Accountability..............................................64
6.6.
Intervention Compliance .............................................................................65
6.7.
Concomitant Therapy..................................................................................65
6.7.1.
Prohibited Medications/Therapy...................................................66
6.7.2.
Cautionary Medications ...............................................................66
6.8.
Intervention After the End of the Study .......................................................66
6.9.
Dose Delay.................................................................................................66
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................67
7.1.
Discontinuation of Study intervention..........................................................67
7.1.1.
Liver Chemistry Stopping Criteria ................................................68
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................69
7.1.2.
QTc Stopping Criteria ..................................................................69
7.1.3.
QRS Interval Stopping Criterion...................................................70
7.1.4.
PR Interval Stopping Criteria........................................................70
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................71
7.3.
Lost to Follow-Up........................................................................................71
7.4.
Participant and Study Completion...............................................................71
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................72
8.1.
Efficacy.......................................................................................................73
8.1.1.
Evaluation of Anti-Cancer Activity – Participants with Solid 
Tumors ........................................................................................74
8.1.2.
Evaluation of Anti-Cancer Therapy – Participants with 
Non-Hodgkin’s Lymphoma...........................................................74
8.2.
Safety Assessments ...................................................................................74
8.2.1.
Physical Examinations.................................................................74
8.2.2.
Vital Signs....................................................................................74
8.2.3.
Electrocardiograms......................................................................75
8.2.4.
Holter Monitoring .........................................................................75
8.2.5.
Telemetry.....................................................................................75
8.2.6.
Clinical Safety Laboratory Assessments ......................................75
8.3.
Adverse Events and Serious Adverse Events.............................................76
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................76
8.3.2.
Method of Detecting AEs and SAEs.............................................77
8.3.3.
Follow-up of AEs and SAEs.........................................................77
8.4.
Regulatory Reporting Requirements for SAEs ............................................77
8.4.1.
Pregnancy ...................................................................................78
8.4.2.
Cardiovascular and Death Events................................................78
8.4.3.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................79
8.5.
Intervention of Overdose.............................................................................79


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8.6.
Pharmacokinetics .......................................................................................80
8.7.
Pharmacodynamics ....................................................................................81
8.7.1.
Whole Blood ................................................................................81
8.7.2.
Tumor Biopsy ..............................................................................81
8.7.3.
Tumor Biopsy Collection/Surgical Procedures .............................81
8.8.
Genetics .....................................................................................................81
8.9.
Biomarkers and Translational Research .....................................................82
8.9.1.
Samples ......................................................................................82
8.9.2.
Exploratory Tumor Biomarker Analysis ........................................82
8.9.3.
Circulating Protein Analysis .........................................................83
8.9.4.
MTAP testing...............................................................................83
8.9.5.
Coagulation markers....................................................................83
8.10.
Patient Reported Outcomes (PRO).............................................................83
8.10.1.
Qualitative Telephone Interviews .................................................83
9.
STATISTICAL CONSIDERATIONS........................................................................84
9.1.
Hypotheses.................................................................................................84
9.1.1.
Dose Escalation...........................................................................84
9.1.2.
Dose Expansion...........................................................................84
9.2.
Sample Size Determination ........................................................................84
9.2.1.
Dose Escalation...........................................................................85
9.2.1.1.
Operating characteristics of the safety stopping 
rule for VTE events in dose escalation........................85
9.2.2.
Dose Expansion...........................................................................86
9.2.3.
Sample Size Sensitivity................................................................89
9.2.4.
Sample Size Re-estimation or Adjustment...................................89
9.3.
Analysis Populations...................................................................................89
9.4.
Interim Analysis ..........................................................................................90
9.4.1.
Dose escalation and safety analyses...........................................90
9.4.2.
Dose Expansion Cohorts .............................................................90
9.4.2.1.
Efficacy Analyses .......................................................90
9.5.
Final Analysis .............................................................................................91
9.6.
Key Elements of Analysis Plan ...................................................................91
9.6.1.
Efficacy Analyses.........................................................................91
9.6.2.
Safety Analyses...........................................................................92
9.6.2.1.
Extent of exposure......................................................92
9.6.2.2.
Adverse Events ..........................................................93
9.6.2.3.
Clinical Laboratory Evaluations ..................................93
9.6.2.4.
Other Safety Measures...............................................93
9.6.3.
Pharmacokinetic Analyses...........................................................93
9.6.3.1.
Pharmacokinetic Parameters......................................93
9.6.3.2.
Statistical analysis of Pharmacokinetic data ...............94
9.6.3.2.1.
Food Effect Sub-Study............................94
9.6.4.
Pharmacokinetic/Pharmacodynamic Analyses.............................95
9.6.5.
Other Analyses ............................................................................95
9.6.5.1.
Translational Research Analyses ...............................95
9.6.5.2.
Pharmacogenetic Analyses ........................................95
10. APPENDICES........................................................................................................96
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................96
10.1.1.
Regulatory and Ethical Considerations ........................................96


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10.1.2.
Financial Disclosure.....................................................................96
10.1.3.
Informed Consent Process ..........................................................97
10.1.4.
Data Protection............................................................................97
10.1.5.
Publication Policy.........................................................................98
10.1.6.
Dissemination of Clinical Study Data ...........................................98
10.1.7.
Data Quality Assurance ...............................................................98
10.1.8.
Source Documents ......................................................................99
10.1.9.
Study and Site Closure ..............................................................100
10.2.
Appendix 2: Clinical Laboratory Tests.......................................................101
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................103
10.3.1.
Definition of AE..........................................................................103
10.3.2.
Definition of SAE........................................................................104
10.3.3.
Definition of Cardiovascular Events ...........................................105
10.3.4.
Recording AE and SAE..............................................................105
10.3.5.
Reporting of SAE to GSK...........................................................107
10.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................109
10.4.1.
Definitions..................................................................................109
10.4.2.
Contraception Guidance ............................................................109
10.4.3.
Collection of Pregnancy Information ..........................................111
10.5.
Appendix 5: Genetics................................................................................113
10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study intervention Rechallenge Guidelines..................114
10.7.
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................118
10.8.
Appendix 8 Country Specific Requirements..............................................119
10.9.
Appendix 9: Abbreviations and Trademarks..............................................120
10.10. Appendix 10. Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria ..........................................................124
10.10.1. Response Criteria for Solid Tumors (RECIST version 1.1 
[Eisenhauer, 2009].....................................................................124
10.10.1.1. Assessment Guidelines ............................................124
10.10.1.2. Guidelines for Evaluation of Disease ........................125
10.10.1.2.1. Measurable and Non-measurable 
Definitions.............................................125
10.10.1.3. Baseline Documentation of Target and Non-
target Lesions...........................................................126
10.10.1.4. Response Criteria.....................................................126
10.10.1.4.1. Evaluation of target lesions...................126
10.10.1.4.2. Evaluation of non-target lesions............127
10.10.1.4.3. New lesions ..........................................128
10.10.1.4.4. Evaluation of overall response..............128
10.10.1.4.5. Evaluation of best overall 
response...............................................129
10.10.1.4.6. Confirmation Criteria:............................129
10.10.2. Evaluation, Staging and Response Assessments for Non-
Hodgkin’s Lymphoma: The Lugano Classification 
(according to Cheson, 2014)......................................................130
10.11. Appendix 11. ECOG Performance Status .................................................134
10.12. Appendix 12: Guidelines for Management of Toxicity ...............................135
10.12.1. Management of Selected Toxicities ...........................................135


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10.13. Appendix 13: Khorana Score ....................................................................139
10.14. Appendix 14: Protocol Amendment History...............................................140
11. REFERENCES.....................................................................................................146


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: A phase I, open-label, dose-escalation study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of GSK3368715 in 
participants with solid tumors and DLBCL
Short Title: First time in human (FTIH) study of GSK3368715 in participants with solid 
tumors and Diffuse Large B-Cell Lymphoma (DLBCL)
Rationale: Arginine methylation mediated by protein arginine methyltransferases 
(PRMTs) is an important post-translational modification of proteins involved in a diverse 
range of cellular processes such as gene regulation, ribonucleic acid (RNA) processing, 
deoxyribonucleic acid (DNA) damage response, and signal transduction. Type I PRMTs 
are responsible for asymmetric dimethylation of arginine (ADMA) residues. Mis-
regulation and overexpression of PRMT1 (a type I PRMT) has been associated with a 
number of solid and hematopoietic cancers. In non-clinical models, inhibition of the Type 
I PRMT family by the small molecule GSK3368715 leads to inhibition of tumor cell 
growth across tumor types with cytotoxic response observed in lymphoma, acute myeloid 
leukemia (AML) and a subset of solid tumor cell lines. Pre-clinical data indicate that the 
anti-proliferative activity of GSK3368715 is enhanced in tumor models in which the 
enzyme Methylthioadenosine phosphorylase (MTAP) is lost due to a deletion of the 
chromosome 9p21 locus. These homozygous deletions of chromosome 9p21 are frequent 
and occur in approximately 15% of all human cancers affecting in addition to MTAP, the 
critical tumor suppressors p16-INK4A and p19-ARF.
This first-time-in-human (FTIH), open-label, dose-escalation study will assess the safety, 
pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of 
GSK3368715 in participants with relapsed/refractory Diffuse-large B-cell lymphoma 
(DLBCL) and selected solid tumors with frequent MTAP-deficiency.  
Emerging pre-clinical data support the clinical development of combination regimens of 
GSK3368715 with novel, active agents such as the small-molecule PRMT5 inhibitor, 
GSK3326595 and/or with approved oncology therapies.  


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Objectives and Endpoints:
Objectives
Endpoints
Part 1: Dose Escalation
Primary
•
Determine RP2D and schedule of 
GSK3368715 administered orally to 
participants with advanced stage solid 
tumors
•
Incidence of dose limiting 
toxicity (DLT)
•
Incidence and severity of 
adverse events
Secondary
•
Evaluate the preliminary clinical activity 
of GSK3368715
•
Best overall response
•
Characterize the PK of GSK3368715, 
including PK in the fed and fasted state 
from the food effect sub-study
•
PK parameters (Maximum 
observed concentration
[Cmax], time to reach Cmax 
[Tmax], Area under the 
concentration-time curve
[AUC], others)
•
PK parameters (Cmax, Tmax 
and AUC) in the fed and 
fasted state from the food 
effect sub-study
Part 2: Dose Expansion
Primary
•
Evaluate the preliminary clinical activity 
of GSK3368715
•
Objective response rate 
(ORR)
Secondary
•
Characterize the safety of GSK3368715 
administered at the RP2D and schedule 
to participants with DLBCL, pancreatic 
cancer, NSCLC, and bladder cancer
•
Incidence and severity of 
adverse events
•
Further evaluate the clinical activity of 
GSK3368715
•
Progression-free survival 
(PFS)
•
Characterize the PK of GSK3368715
•
PK parameters (Cmax, 
Tmax, AUC, others)
Overall Design: The study will consist of two parts.  In Part 1 (Dose Escalation)
escalating doses of GSK3368715 will be evaluated in participants with selected solid 
relapsed/refractory tumors. This will include at least one PK/PD cohort, and a food effect 
cohort. Based on safety and tolerability, and the PK/PD characteristics, a Recommended 
Phase 2 Dose(s) (RP2D) and schedule(s) of GSK3368715 will be established. In Part 2,
this RP2D(s) will be further investigated in two expansion cohorts. Enrolment in the 
expansion cohorts will be limited to participants with DLBCL (Expansion Cohort 2A) 
and relapsed/refractory solid tumors (Expansion Cohort 2B) where MTAP deletion 
occurs at a frequency of approximately ≥25% (pancreatic, bladder, and non-small cell 
lung cancer).


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Number of Participants: It is estimated that up to approximately 60 participants will be 
enrolled in Part 1. In Part 2, approximately 141 participants will be recruited into 
Expansion Cohort 2A (~36 participants) and Expansion Cohort 2B (~ 105 participants).
Additional tumor-specific cohort(s) and combinations may be added by protocol 
amendment, based upon emerging pre-clinical data, or clinical data.
Intervention Groups and Duration: In Part 1 of the study, the participants will initially 
receive GSK3368715 orally. This will include at least one PK/PD cohort and a food 
effect cohort. The Dose Limiting Toxicity (DLT) period is 21 days, and under protocol 
amendment 3, there is an addition of a VTE-specific DLT period of 8 (1) weeks or until 
study discontinuation whichever occurs sooner. An end of treatment CT image is 
required if the participant withdraws before the end of the DLT observation period.
Alternative dosing schedules and intervention cycles may be investigated. In Part 2, the 
participants are expected to receive the RP2D established in Part 1. In case of unexpected 
toxicities, alternative GSK3368715 doses may be explored in Part 2. 
The study includes a screening period, an intervention period and follow up. Participants 
will be screened for eligibility beginning approximately 4 weeks before the start of 
intervention. Participants with confirmed partial response (PR) or complete response 
(CR) will be followed for response duration and may be eligible for additional 
intervention with GSK3368715 at the time of relapse/progression if determined to be 
deriving clinical benefit in the opinion of the investigator and with approval from the 
study Medical Monitor.
1.2.
Schema
GSK3368715 Dose Escalation, PK/PD cohort(s) and a food effect cohort (Part 1) 
and Dose Expansion (Part 2)


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Abbreviations: DL: GSK3368715 dose level; DLBCL: Diffuse-large B-cell lymphoma; po: oral dosing; qd: 
daily dosing
1.3.
Schedule of Activities (SoA)

A signed, written informed consent form (ICF) must be obtained from the 
participant prior to any study-specific procedures or assessments being performed. 
Protocol waivers or exemptions are not allowed except for immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Schedule of Activities table, are required for study conduct.

The timing of each assessment is listed in the Schedule of Activities (Table 1 and 
Table 2). Whenever vital signs, 12-lead electrocardiograms (ECGs) and blood 
draws are scheduled for the same nominal time, the assessments should occur in 
the following order: 12-lead ECG, vital signs, and blood draws. The timing of the 
assessments should allow the blood draw to occur at the exact time. Detailed 
procedures for obtaining each assessment are provided in the Study Reference 
Manual (SRM).

The timing and number of planned study assessments, including safety, 
laboratory, imaging, tumor biopsy, pharmacokinetic (PK), and pharmacodynamic 
(PD)/biomarkers, 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.

Any changes in the timing or addition of time points for any planned study 
assessments must be approved and documented by the relevant study team 
member and then archived in the sponsor and site study files, but these changes 
may not constitute a protocol amendment. The Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) will be informed of any safety issues 
that require alteration of the safety monitoring scheme or amendment of the 
Informed Consent Form (ICF.)


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Table 1
Screening Procedures
Procedure1
Notes
Informed consent
Informed consent can be signed within 45 days prior to first dose (following the signing of the ICF, all screening 
assessments for eligibility will begin approximately 4 weeks before the start of intervention)
Demography
Medical History (past and current)
Inclusion/Exclusion Criteria
Disease Characteristics
Anticancer Therapy
Participant Registration
Participant registration will occur after all screening assessments have been performed and the participant has met all 
eligibility requirements
Echocardiogram/MUGA
ECHO/MUGA required within 28 days prior to first dose. If an ECHO or MUGA was done at baseline, then that same 
test should be used for further evaluations
Full Physical Examination
See Section 8.2.1 for details
ECOG Performance Status
For definitions, see Appendix 11.
Vital Signs
Height and weight
Holter monitoring
Screening Holter monitoring for 24 hours
12-lead ECG (Triplicate)
HIV, HBsAg, HCV Antibody Screening
If test performed within 3 months prior to first dose of study intervention, testing at screening is not required.
Hematology/Clinical Chemistry
Refer to Appendix 2 for a complete listing of protocol required lab assessments.
Troponin (I or T)
Pregnancy test
Required for females of child bearing potential. A serum pregnancy test should be done at screening. Must be done ≤7
days of first dose.
Tumor Imaging
Must be obtained up to 4 weeks (28 days) before the first dose. Must include CT Chest. Must include CT abdomen if 
history of documented intra-abdominal disease for disease staging.
Tumor biopsy
Part 1: A fresh biopsy, obtained during screening, is preferred however, an archival tumor specimen is acceptable if it is 
not feasible to obtain a fresh biopsy.
Part 1 PK/PD cohort(s) only:  A fresh biopsy (and consent for an on-therapy biopsy) is required for enrollment in this 
cohort.
Part 2: A fresh biopsy, obtained during screening, is preferred, however archival tumor specimen is acceptable if it is not 
feasible to obtain a fresh biopsy.  An archival tumor specimen must have been obtained within 6 months of starting study 
drug unless approved by the study Medical Monitor.


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1. All assessments performed at Screening must be performed within 14 days prior to first dose unless otherwise specified in Table 1. 


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Table 2
Schedule of Activities (SoA) for Dose Escalation (Part 1)
Procedure
DLT period (Days 1-21)3
D223
Continuation3
TDV1
Follow-
up
Notes
D12
D2
D3
D4
D8
D11
D15
D16
Safety
AE / SAE Review
SAEs from signing of ICF to 90 days after last dose
AESIs from first dose until 90 days after last dose
AEs from first dose until TDV visit
See footnote 1 for TDV visit window. (See Section 
8.3.1)
Concomitant 
Medication 
Continuous from first dose
All concurrent medications will be collected until at 
least 30 days after the last dose of study 
intervention.
Brief Physical 
Examination
X
X
X
X
Q1W
X
See Section 8.2.1 for details
ECOG PS
X
X
X
X
Q4W
X
See Appendix 11 for definitions.
Vital Signs
X
X
X
X
Q4W
X
Telemetry
X
X
Telemetry only required for doses > 200 mg and 
must start at least 60 min pre-dose and be 
continuous for 24h post-dose. See Section 8.2.5.
Holter monitoring
X
X
X
X
Holter monitoring must start at least 60 min pre-
dose and be continuous for 24h post-dose.
12-lead ECG 
(Triplicate)
X
X
X
X
X
X
Q1W
X
On serial PK days (Day 1, 8 and 15), triplicate 
ECGs will be obtained at or about the time of each 
PK sample collection, as described in the SRM. On 
other days, triplicate ECGs will be obtained pre-
dose.
Laboratory Assessments (Safety) – perform assessments pre-dose on each dosing day
Clinical Chemistry, 
Urinalysis and 
Coagulations
X
X
X
X
Q1W
X
Refer to Appendix 2 for complete list of required 
laboratory assessments. 
Hematology
X
X
X
X
X
X
Q1W
X
Hematology twice per week for the first two weeks 
(see Section 2.3.1). Refer to Appendix 2 for 
complete list of required laboratory assessments.
Pregnancy test
X
X
Q4W
X
Perform only in women of child bearing potential 
(WOCBP). Pregnancy tests during intervention
phase and at discontinuation may be either serum 


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Procedure
DLT period (Days 1-21)3
D223
Continuation3
TDV1
Follow-
up
Notes
D12
D2
D3
D4
D8
D11
D15
D16
or urine. Final pregnancy test must be performed 
within 150 days after last study intervention.
Study intervention
Administer study 
drug
X
================Daily Dosing=============
A dose will be administered on Day 1, no dose will 
be given on Day 2 or Day 3 of the first cycle, after 
which, daily dosing will occur through the 
remainder of cycle 1 and all subsequent cycles. 
GSK3368715 should be administered in a fasted 
state at approximately the same time of day (± 
4 h), with no food for 1 hour before and 2 hours 
after each dose. See Section 5.3.1 for dosing 
instructions on serial PK days.
Efficacy Assessment
Tumor Imaging. 
Must include CT 
Chest. Must
include CT 
abdomen if history 
of documented 
intraabdominal 
disease. 
Week 9 Day1
then every 8 
weeks until 
Week 33 Day 1 
and then 
Q16W
X
Disease assessments will be performed until 
disease progression. Participants who discontinue 
for reasons other than PD will also be followed until 
the start of subsequent anti-cancer intervention. 
CR or PR should be confirmed as per response 
criteria in Appendix 10.
Patient Reported Outcomes
Telephone 
interview
(Part 2 only)
Week 9
X
Qualitative telephone interview to be completed 
within 21 days following the week 9 disease 
assessment and then again following the TDV. 
Participants who have the TDV within 30 days of 
the week 8 interview are not required to repeat the 
interview 
Follow-up for 
Survival
Q12W
Participants will be followed every 12 weeks for 
survival and subsequent anti-cancer therapy. The 
survival follow-up visit will commence after
discontinuation of study treatment. Participants 
should be contacted every 12 weeks (±2 weeks) 


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Procedure
DLT period (Days 1-21)3
D223
Continuation3
TDV1
Follow-
up
Notes
D12
D2
D3
D4
D8
D11
D15
D16
until death, termination of the study or participant 
has been followed for 2 years.
Tumor Specimens
Tumor biopsy 
(Optional unless 
participant is in 
PK/PD cohort, see 
Table 3 below) 
(X) 
On intervention biopsies are optional (unless
medically indicated) for individual participant(s)
Pharmacokinetics (PK), Pharmacodynamics (PD) and Pharmacogenomics (Genomics Research)
PK plasma 
samples
(parent drug and 
metabolites 
profiling for 
participants are in 
PK/PD cohort, see 
Table 3 below).
X
X
X
X
X
X
X
X
Q4W
On Day 1, patients will be administered 
GSK3368715 as a single oral dose followed by a 
72 h intervention-free period to evaluate PK of the 
parent compound and its metabolites in plasma 
samples. Plasma metabolites will be analyzed at 
the timepoints indicated in Table 3 below. PK 
samples following Day 1 dose will be collected at 
Pre-dose, 15 ± 5 min, 30 ±5 min, 1h ± 5 min, 1.5h 
± 5 min, 2h ± 10 min, 3h ± 10 min, 4h ± 10 min, 6h 
± 30 min, 8h ± 30 min, 12h ±2h, 24h ±2h, 48h ±
2h, 72h ± 2 hrs post-dose. The 48 hr and 72 hr 
timepoints could be removed with emerging data. 
PK samples on Day 8 will be collected at Pre-dose, 
1.h ± 5 min and 4h ± 10 min. PK samples on 
Day 15 will be collected at Pre-dose, 30 ±5 min, 1h 
± 5 min, 2h ± 10 min, 3h ± 10 min, 4h ± 10 min, 6h 
± 30 min, 8h ± 30 min, 12h ±2h, 24h ±2h (prior to 
next dose) post-dose. On Day 22) and then every 4 
weeks during the continuation phase, only pre-
dose PK samples should be collected.  All pre-dose 
PK samples should be collected within 2h prior to
the dose being administered.
Plasma for 
circulating free 
X
X
X
X
Plasma for circulating free MMA, ADMA and/or
SDMA will be collected pre-dose on Day 1 and 4h 


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Procedure
DLT period (Days 1-21)3
D223
Continuation3
TDV1
Follow-
up
Notes
D12
D2
D3
D4
D8
D11
D15
D16
ADMA and SDMA 
(for Part 1, and 
PK/PD cohorts 
only)
post-dose ± 30 minutes) on Days 8,15 and 22. 
Refer to collection details within the SRM.
Plasma for 
exploratory 
biomarkers
X
X
X
X
X
X
X
Plasma for circulating biomarker analysis will be 
collected pre-dose on Day 1, 4h post dose ± 30 
minutes on Days 2, 8,15 and 22, at first disease 
assessment and at TDV. Refer to collection details 
within the SRM.  
Blood for TCR 
sequencing
X
X
X
X
Whole blood for TCR sequencing will be collected 
pre-dose on Days 1, 15, at first and second 
disease assessments and TDV. Refer to collection 
details within the SRM.
Whole Blood for 
PD biomarkers (for 
Part 1 and PK/PD 
cohort only)
X
X
X
Whole Blood for biomarker analysis will be 
collected pre-dose on Day 1, 4hrs post-dose ±30 
minutes on Day 15, and pre-dose and 4h post-dose 
±30 minutes on Day 22. Refer to collection details 
within the SRM.
Whole blood for 
biomarker analysis 
(PAX tube)
X
X
X
X
PAX whole blood samples will be collected pre-
dose on Day 1, 4hr post-dose ± 30 minutes on 
Days 8 and 15 and on the TDV visit. Refer to 
collection details within the SRM.
Plasma and Serum 
for Coagulation 
markers
X
X
X
X
Plasma and serum samples will be collected pre-
dose on Day 1 and 4hr ± 30 minutes post-dose on 
Days 8, 15 and 22.
Genetic sample
X
Informed consent must be given prior to sample 
collection. See Appendix 5.
Abbreviations: ADMA = asymmetric dimethylation of arginine; AE = Adverse event; AE = Adverse event of special interest; CR = Complete response; D = Day; 
ECG = Electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of intervention; h = hour; HBsAg = Hepatitis B surface antigen; HCV = 
Hepatitis C Virus; HIV = Human Immunodeficiency Virus; MUGA = Multigated (radionuclide) angiogram; PD = Pharmacodynamic; PK = Pharmacokinetic; PR = 
Partial response; SAE = Serious adverse event; SCR Screening; SDMA = symmetric dimethylation of arginine; SRM = Study Reference Manual; TCR = T-cell 
receptor; TDV = Treatment Discontinuation Visit; Q1W = Once every week; Q3W = Once every 3 weeks Q4W = Once every 4 weeks; Q8W = Once every 8 weeks.


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1.
The assessments required at the study intervention discontinuation visit must be completed within 30 days from the date that study intervention was 
discontinued and must occur prior to the start of subsequent anti-cancer therapy; the window for this visit is +10 days. 
2.
Day 1 assessments significantly different from screening assessments, especially those that are inconsistent with eligibility criteria, should be immediately 
discussed with the sponsor PRIOR to initiating study intervention. Day 1 labs may be skipped if screening labs were drawn Day -3, Day -2 or Day -1.
3.
Visit Windows: With the exception of Screening and Week 1 visits (Day 1, 2, 3 and 4) and unless otherwise specified, assessments performed from Day 8 on
will have a ± 3 day window. For Screening and Day 1 visits, all procedures must be completed before first dose.


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Table 3
Schedule of Activities (SoA) (PK/Biomarker/Metabolite Cohort[s])
PK/PD/Biomarker/Metabolite Cohort(s); Samples collected in this section are in addition to any samples collected in Table 2
Procedure
First Intervention Period (Days 1-21)
Continuation
TDV1
Follow-
up
Notes
D1
D2
D3
D4
D8
D11
D15
D16
D22
Plasma 
(metabolite 
profiling)
X
X
X
X
X
X
Metabolites of GSK3368715 will be 
analyzed by utilizing samples collected for 
PK plasma as described in Table 2.  
Plasma metabolites will be analyzed from 
PK plasma samples collected on Day 1 at 
Pre-dose, 15 ± 5 min, 30 ±5 min, 1h ± 5 
min, 1.5h ± 5 min, 2h ± 10 min, 3h ± 10 
min, 4h ± 10 min, 6h ± 30 min, 8h ± 30 
min, 12 ±2h, 24 ±2h, 48 ± 2h, 72 ± 2 hrs 
post-dose. The 48 and 72 hr timepoints 
could be removed with emerging data. On 
Day 15 PK samples for metabolites will be 
collected at Pre-dose, 30 ±5 min, 1h ± 5 
min, 2h ± 10 min, 3h ± 10 min, 4h ± 10 
min, 6 ± 30 min, 8h ± 30 min, 12 ±2h, 24
±2h, (prior to next dose) post-dose. All pre-
dose PK samples should be collected 
within 2h prior to the dose being 
administered
Urine (48-hour 
collection for PK 
and metabolite 
profiling)
0-24h
24-
48h
0-
24h
A separate container will be used to collect 
urine from the time of dosing until 24h 
post-dose and 24-48h on Days 1 and 24 h 
post dose on Day 15.
Tumor biopsy
X
On intervention biopsies are required 
between Day 15 and Day 20. Additional 
timepoints may be considered for biopsies 
after discussion between sponsor and 
investigator, if participants consent, for a 
maximum of 4 study related biopsies per 
participant.


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1.
The assessments required at the treatment discontinuation visit (TDV) must be completed within 30 days from the date that study intervention was 
discontinued and must occur prior to the start of subsequent anti-cancer therapy; the window for this visit is +10 days
Table 4
Schedule of Activities (SoA) (Food effect cohort)
Food effect cohort (Section 4.1.1.1); samples collected in this section are in addition to any samples, studies, and visits described in Table 2)3
D1
D2
D3
D4
D5 4
D6
D7
D8
D9 and beyond
Administer study 
drug1
X
X
-------------daily dosing------------------>
Plasma PK 
samples2
X
X
X
X
X
X
X
X
X3
1.
Study drug should be administered in fed or fasted state, based on assignment as described in Section 4.1.1.1
2.
PK samples on Days 1 and 4/5 should be collected at 0 (pre-dose), 0.25h ± 5 min, 0.5h ± 5 min, 1h ± 5 min, 1.5h ± 5 min, 2h ± 10 min, 3h ± 10 min, 4h ± 10min, 6h ± 30 
min, 8h ± 30 min, 12h ± 2h, 24± 2h, 48± 2h and 72± 2h hours post dose
3.
Refer to Table 2 for subsequent PK sample requirements
4.
In order to accommodate clinic schedules, the Day 5 dosing (including all PK assessments) may be performed one day earlier (on Day 4), i.e. Days 5 to 8 
would shift to Days 4 to Day 7, and then all subsequent PK assessments from then on would follow the same schedule as in Table 2
NOTE: Participants in the food effect sub-study are subject to all screening, safety, PK, and efficacy evaluations detailed in Table 1 and Table 2. Samples collected 
in this section are in addition to any samples collected in Table 2, with the exception of Day 1-8 PK collections, in which the time points in Table 4 supersede those in 
Table 2
Any participant who experiences vomiting at or between 0.25-3 h will be removed from statistical analysis of PK comparability between fasted/fed state


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2.
INTRODUCTION
2.1.
Study Rationale
Arginine methylation is an important post-translational modification of proteins involved 
in a diverse range of cellular processes such as gene regulation, ribonucleic acid (RNA)
processing, deoxyribonucleic acid (DNA) damage response, and signal transduction. This 
protein arginine methylation is catalysed by a family of protein arginine 
methyltransferases (or PRMTs) which can be differentiated into the three classes of Type 
I, Type II and Type III enzymes. As shown in Figure 1, all three PRMT classes produce 
the intermediate monomethylarginine (MMA). This intermediate is subsequently 
converted by Type I PRMTs to generate Asymmetrical Dimethylated Arginine (ADMA) 
and by Type II PRMTs to generate Symmetrical Dimethyl Arginine (SDMA).
Figure 1
Arginine methylation by PRMTs
Yang and Bedford, Nature Reviews Cancer, 2013
The Type I class of PRMTs comprises the individual enzymes PRMT1, -3, -4, -6, and -8. 
Due to sequence similarities, PRMT2 is regarded as a type I enzyme as well, but catalytic 
activity has not been demonstrated so far. Apart from PRMT8, which has been found in 
brain tissue and HEK 293 (T) cells only, type I PRMTs are ubiquitously expressed.
Among the Type I class of PRMTs, the individual enzyme PRMT1 is the predominant 
Type I PRMT generating ~85% of cellular ADMA levels [Pawlak, 2000; Dhar, 2013].
Mis-regulation and overexpression of PRMT1 (a type I PRMT) has been associated with 
a number of solid and hematopoietic cancers [Yoshimatsu, 2011; Yang, 2013]. The link 
between PRMT1 and cancer biology has largely been through regulation of methylation 
of arginine residues found on relevant substrates. In several tumor types, PRMT1 can 
drive expression of aberrant oncogenic programs through methylation of histone H4 
[Zhao, 2008; Shia, 2012; Takai, 2014], as well as through its activity on non-histone 
substrates [Wei, 2014]. In many of these experimental systems, disruption of the 


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PRMT1-dependent ADMA modification of its substrates decreases the proliferative 
capacity of cancer cells [Cheung, 2007; Yang, 2013].
In non-clinical models, inhibition of the Type I PRMT family by GSK3368715 leads to 
inhibition of tumor cell growth across tumor types with cytotoxic response observed in 
lymphoma, acute myeloid leukemia (AML) and a subset of solid tumor cell lines. 
Additionally, GSK3368715 induces tumor growth inhibition and regression in mouse 
models, as a single agent and in combination with PRMT5 inhibition or anti-PD-1
immunotherapy. These results indicate that GSK3368715 may lead to anti-tumor activity 
and provide a novel therapeutic mechanism for the intervention of hematological and 
solid tumors alone and in combination with other anti-tumor agents.  
MTAP Deficiency as a potential Biomarker for GSK3368715 Activity
The activity of GSK3368715 is frequently enhanced in cancer cell lines that are deficient 
in the enzyme Methylthioadenosine phosphorylase (MTAP). MTAP is a critical enzyme 
in the methionine salvage pathway that metabolizes 2-methylthioadenosine (MTA), 
leading to the regeneration of methionine and adenine. MTAP deficiency is caused by a 
homozygous gene deletion. The gene for MTAP is located on the human chromosome 
9p21 (chr9p21) locus. This locus also includes the gene for the Cyclin Dependent Kinase 
Inhibitor 2A (CDKN2A) which encodes the two critical tumor suppressors p16-INK4a 
and p19-ARF. The chr9p21 locus, is deleted in approximately 15% of all human tumors 
leading to a combined loss of the p16-INK4a and p19-ARF tumor suppressors and a 
deficiency in MTAP expression as shown in Figure 2.
Figure 2
Frequency of homozygous deletion of CDKN2A (p16-INK4a) and 
MTAP in Primary Tumor Tissues
      = Primary tumor tissue for expansion cohorts
MTAP deficiency can be detected across multiple human solid and hematologic 
malignancies including approximately up to 40% of glioblastoma, 25% of melanoma, 


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pancreatic adenocarcinoma, and Diffuse-large B-cell lymphoma (DLBCL) as well as 
15% of non-small cell lung cancers (NSCLC). 
Deficient MTAP enzymatic activity in ch9p21 mutant tumor cells leads to an increase in 
the intracellular levels of the MTAP metabolite, MTA. MTA has been shown to be a 
potent inhibitor of the enzymatic activity of the important Type II PRMT enzyme 
PRMT5. In consequence, accumulation of intracellular MTA in MTAP-deficient tumor 
cells results in lower cellular levels of PRMT-5 mediated SDMA generation.  
Based on these observations, Part 2 of the FTIH study will investigate the hypothesis that 
the therapeutic index of GSK3368715 is enhanced in MTAP-deficient tumors in which 
endogenous PRMT5 is partially inhibited, thereby sensitizing cells to Type 1 PRMT 
inhibition.  This FTIH is designed as an open-label, dose-escalation study to assess the 
safety, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK3368715 and to 
evaluate the preliminary clinical activity in participants with frequently MTAP-deficient 
relapsed/refractory DLBCL and selected solid tumors harbouring deletions of MTAP or 
wild type MTAP in Part 2.
2.2.
Brief Background
2.2.1.
GSK3368715
An overview of the nonclinical studies of GSK3368715 are provided below.  Detailed 
information concerning the biology, pharmacology, PK, and safety can be found in the 
Investigators’ Brochure (IB) [GlaxoSmithKline Document Number 2017N334333_02].
GSK3368715 is a potent, reversible, S-adenosyl methionine (SAM) uncompetitive, 
inhibitor of Type I PRMTs 1, 3, 4, 6, and 8 (Ki*app= 1.5/81.0#/19.0/2.4/2.0 nM; # Kiapp). A 
crystal structure of GSK3368715 with PRMT1 reveals that the compound is bound in the 
protein substrate binding pocket. GSK3368715 inhibits asymmetric arginine 
dimethylation leading to accumulation of MMA with a cellular EC50 = 13.6 0.3 nM. 
2.2.1.1.
Nonclinical Safety
The systemic toxicity of GSK3368715 has been evaluated in rats and dogs administered 
GSK3368715 orally (once daily) for up to 4 weeks. Recovery was assessed following a 
4-week or 2-week off-dose period in the rat and dog, respectively, in which time the 
majority of the findings had partially or completely recovered, with the exception of 
testicular and epididymidal changes which had progressed and is not uncommon for this 
limited recovery interval, and in the thymus and lymph nodes.  Screening genotoxicity 
studies have also been conducted; GSK3368715 was not genotoxic, and does not pose a 
phototoxic risk as it does not absorb in the UV/vis range. Summaries of principal findings 
following single and repeat dosing of GSK3368715 and a comparison of systemic 
exposures achieved in these studies are presented below additional details regarding the 
principal toxicological findings can be found in the IB [GlaxoSmithKline Document 
Number 2017N334333_02].
The dose-limiting toxicities observed in the rat and the dog following repeat 
administration of GSK3368715 were gastrointestinal effects associated with poor 


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tolerability including body weight loss/decreased body weight gain. Microscopic 
erosions/ulcerations were observed in the GI tract of the rats (stomach) and dogs (oral 
cavity and upper gastrointestinal tract). These findings were resolved at the end of the 
two week off-drug period for the dog, but reversibility was not assessed at doses that 
caused gastrointestinal effects in rats.
Mild, reversible changes in hematopoietic cellularity were noted in the bone marrow of 
the rat and the dog. The effect on red cell mass persisted through the off-dose period and 
reflected effects on erythropoiesis that occurred during dosing but expected to be fully 
recovered based on recovery and rebound of reticulocyte counts and the bone marrow 
regenerative response observed at the end of the off-dose phase. Complete blood counts
will be monitored regularly in this protocol (see Section 2.3.1).
Lymphoid changes were observed the thymus, mesenteric lymph node, spleen, and gut-
associated lymphoid tissues (GALT) in rats were likely due to test item effects on the T 
lymphocytes; thymus changes correlated, in part, to lower white blood cell and 
lymphocyte counts. In the dog, decreased lymphoid cellularity in the GALT of the small 
intestine (ileum), mesenteric lymph nodes and thymus associated with reversible 
decreases in lymphocyte counts was observed and remained unchanged after a 2-week 
off-dose period.  Based on the magnitude of the changes in circulating peripheral 
lymphocytes, these changes were considered non-adverse.
Reversible liver changes (hypertrophy in rat, and vacuolation in rat and dog) and 
increases in liver-associated enzymes were observed in the rat and dog. These changes 
were associated with microsomal enzyme induction in the rat. These changes are 
monitorable and clinically manageable (see Section 2.3.1). 
Testicular effects including degeneration in seminiferous tubules in the dog were detected 
at all doses in the rat and the dog. These changes are not considered dose-limiting for 
oncology products. Contraceptive requirements are detailed in Appendix 4.
Dose-dependent functional cardiovascular effects were seen in rats and dogs at exposures 
relevant to the maximal predicted clinical exposure including increased heart rate, blood 
pressure and increased PR and QRS intervals; these changes correlated with exposure to 
GSK3368715. The NaV1.5 channel is inhibited by GSK3368715 (IC50 = 168 µM (at 
2Hz)); therefore, the cardiovascular effects may be due to a direct effect on the NaV1.5 
channel which is primarily associated with cardiac tissue. Changes in QT and QTc were 
seen at doses above the maximum tolerated dose (MTD) following six doses of 
GSK3368715 (Total maximum observed concentration [Cmax] of 10-40ug/mL, ~20-80X 
predicted human efficacious exposure). No structural and/or morphological cardiac 
effects related to administration of GSK3368715 were observed in either species at any 
doses. Increased cardiovascular monitoring will be implemented in this protocol (See 
Schedule of Activities Table Section 1.3).
Based on the histopathology changes and increased liver-associated serum enzyme 
activity and bilirubin, a no observed adverse effect level (NOAEL) in the rat was not 
determined.   The severely toxic dose in 10% of the rats (STD 10) was 150 mg/kg/day 


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(mean AUC(0-t) 35.4 g.h/mL, mean Cmax 4.59 g/mL; gender averaged based on 
Day 28 values). 
Based on adverse pathology in the digestive tract and in the testes noted at all doses, a no 
observed adverse effect level (NOAEL) could not be determined in the dog.  Based on 
the moribundity of male dogs given 25 mg/kg/day, the highest non-severely toxic dose 
(HNSTD) was 15 mg/kg/day (mean AUC(0-t) 10.6 g.h/mL, range 7.86 to 17.5 g.h/mL 
mean Cmax 3.34 g/mL, range 2.42 to 4.74 g/mL [gender-averaged based on Day 28 
values]).
2.2.1.2.
Nonclinical Pharmacokinetics
The nonclinical pharmacokinetics of GSK3368715 was similar across species. Oral 
bioavailability was moderate to high (28% in mice, 100% in rats and 68% in dogs). 
Steady-state volume of distribution was high in all species (about 18, 27 and 39 times 
total body water in mouse, rat and dog, respectively). In vivo, GSK3368715 had high 
clearance in dogs and rats and moderate clearance in mouse with a low intrinsic clearance 
in microsomes and hepatocytes from humans but moderate intrinsic clearance in rat, dog 
and high in mouse hepatocytes. In vitro, GSK3368715 binding to plasma proteins varied 
between species and percent unbound was around 35.7% in mice, 35.9% in rats and 
71.8% in dog and 64.2% in human at a concentration of 1µM. In a qualitative assessment 
of the metabolic profile, GSK3368715 primarily showed multiple metabolites formed via 
N-demethylation and O-dealkylation/oxidation. In human liver microsomes, 
GSK3368715 did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and 
CYP3A4/5, however it did inhibit CYP2D6 (IC50 = 22.6 µM). GSK3368715 half-life 
was 5.5 hours in the mouse, 7 hours in the rat and 12 hours in the dog.
2.2.1.3.
Nonclinical Activity and Pharmacodynamics
GSK3368715 inhibits growth in cancer cell lines across tumor types when tested. The 
concentration of GSK3368715 required for 50% growth inhibition (gIC50) was less than 
or equal to 2μM in 43% of all cell lines tested, including 80% of AML, 71% of 
melanoma, 70% of lymphoma, and 60% of kidney cancer cell lines. Cytotoxicity was 
most frequently observed in cell lines from AML and lymphoma, where 50% and 56% of 
cell lines had negative growth index values, respectively.
When tested in mouse xenograft studies, GSK3368715 induces tumor growth inhibition 
in lymphoma, breast, pancreatic and renal cell carcinoma models, with tumor regression 
observed at daily doses ≥150 mg/kg. Mouse models using human lymphoma and renal 
cell carcinoma cell lines indicate that 100% tumor growth inhibition is achieved at >90% 
of the maximal PD response, as measured by MMA induction in tumors.
In lymphoma cell lines, GSK3368715 induces gene expression changes that impinge 
upon key mechanisms central to lymphomagenesis, including but not limited to, 
inhibition of MYC and B-cell lymphoma protein 6 (BCL6) transcriptional programs. 
Additionally, treatment of lymphoma and breast cancer cell lines with GSK3368715 
induces thousands of alterations in splicing, including intron retention and exon skipping, 
consistent with changes in arginine methylation of numerous substrates of Type I PRMTs 
linked to splicing and RNA metabolism. Additionally, GSK3368715 demonstrates 


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immunomodulatory activity through upregulation of interferon pathways and pro-
inflammatory gene expression signatures in tumor cells. Together, these data suggest that 
multiple cancer relevant mechanisms are perturbed by GSK3368715 intervention.
2.2.1.4.
Clinical Safety of GSK336715
The first and to date only active clinical study evaluating GSK3368715 is this first time 
in human study 207675. In this study, GSK3368715 has been administered as an oral 
capsule dosed once daily to patients with solid tumors. As of the clinical data cut-off 
date, 23 October 2019, three daily oral dose levels (50 mg, 100 mg and 200 mg) have 
been evaluated. 
2.2.1.4.1.
Adverse Events and Dose Limiting Toxicities
A summary of adverse events is included in the GSK3368715 Investigator’s Brochure
[GlaxoSmithKline Document Number 2017N334333_02].  As of the clinical data cut-off 
date, 23 October 2019, two (2) participants had DLTs in the 200 mg cohort Dose Level 3 
(DL3). The first participant, a 72-year old male, experienced a Grade 3 thrombocytopenia 
in the context of progressive intra-abdominal metastases and portal/splenic vein 
thrombosis and was hospitalised. The investigator considered the event to be unrelated to 
GSK3368715. The second participant, a 68-year old male, experienced a Grade 3 atrial 
fibrillation. The investigator considered the event to be related to GSK3368715, however, 
the participant had pre-existing atrial ectopy and increased atrial area. These events led to 
permanent discontinuation of study drug.
In addition, there were eight (8) adverse events (four serious and four non-serious) of 
venous thromboembolism reported. None of them were considered drug-related by the 
investigators.
2.2.1.4.2.
Venous Thromboembolism
The sponsor paused enrolment of the study on 12 September 2019 due to the unexpected
incidence of venous thromboembolism (VTE). As of 25 September 2019, eight (8) out of 
19 participants (42%) experienced VTE.   

1/3 (33%) participants receiving DL1 (50 mg). None reported as SAE.

1/4 (25%) participants receiving DL2 (100 mg). None reported as SAE.

6/12 (50%) participants receiving DL3 (200 mg). Of those, 4/12 (33%) were SAEs.
The four (4) VTE cases reported as SAEs described two males and two females with a 
mean age of 67 years old. The time to onset in these VTEs were inconsistent, ranging 
from one day to 8 weeks after starting study drug. One VTE SAE event was fatal (i.e. 
participant who developed acute VTE after only one day drug exposure with existing 
chronic VTE). Of note, this participant had a very recent history of VTE, and entered the 
trial on anticoagulation with low molecular weight heparin. The other three VTE SAE 
events were considered resolved with sequelae after treatment with anticoagulant drugs. 
Among cases reported as an SAE, only one participant resumed study drug while on 
anticoagulant therapy, with a negative re-challenge. However, he permanently 
discontinued study drug approximately eight weeks later, due to disease progression. In 


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one participant, venous compression by locoregional disease progression (i.e. new lesions 
in pancreas/splenic vein thrombosis) could not be ruled out as a confounding factor. Two 
of the SAE cases were confounded by prior or concurrent history of VTE.
In addition, four (4) VTE cases were reported as non-serious AEs (one at 50 mg [DL1], 
one at 100 mg [DL2] and 2 at 200 mg [DL3]). For these participants (two females and 
two males), the mean age at the time of the VTE was 57 years old. The time to onset 
ranges from 4 to 8 weeks. Among these four (4) non-serious cases, only one resumed 
study drug while on anticoagulant therapy, with a negative re-challenge. Similarly, to the 
situation of the SAE cases, two participants locoregional disease progression could not be 
ruled out (i.e. new lesions in liver/portal vein thrombosis) and two participants were 
confounded by prior history of VTE. 
One participant with an SAE of portal /plenic vein thrombosis also had an incidentally 
discovered mural aortic thrombus, this is to date the only case of arterial 
thromboembolism on this trial.  
Due to the observed incidence of emobolic and thrombotic events, the study was put on 
enrolment pause and protocol amendment 3 now includes additional guidelines for 
management and stopping criteria for VTE..
2.2.1.4.3.
Cardiac Safety 
At the time of Amendment 3, a total of 19 participants have been dosed at 50-200 mg QD 
in study 207675 with GSK3368715. Concentration-QRS analysis with over 400 time-
matched data points showed an equal number of negative and positive changed in QRS 
duration at all concentrations with a slope of almost zero. No systematic dose dependent
increase in QRS duration or significant ventricular arrhythmias have been observed to 
date.
Based on these data, telemetry will no longer be required for any participants dosed at 
200 mg or below under Protocol Amendment 3. See also the Investigator Brochure
Version 2 [GlaxoSmithKline Document Number 2017N334333_02]. 
2.2.1.5.
Clinical Pharmacology of GSK3368715
Pharmacokinetics (PK) of GSK3368715 is currently being evaluated after administration 
of single and repeat daily oral administration of GSK3368715 at doses of 50mg to 200mg 
in study 207675. Concentrations are detected in plasma 0.25 hours after oral 
administration with peak concentrations at around 1.0 hours on average, then 
GSK3368715 declines bi-exponentially with a mean terminal elimination half-life of 20-
24 hours. A dose dependent increase in plasma exposures (both Cmax and AUC) of 
GSK3368715 were observed as doses increased from 50mg QD to 200 mg QD. 
Following multiple-dose administration, mean AUC was up to 2-4 fold higher on Day 15 
as compared to Day 1 in all dose groups, except for participants
 and
who 
showed much higher accumulation on Day 15 of 6-7 folds relative to Day 1.
PPD
PPD


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2.2.2.
Potential GSK3368715 Combination Regimens
2.2.2.1.
GSK3368715 Combination with PRMT5 inhibition
Overexpression of another PRMT, PRMT5 has been shown in several cancers including 
glioma, lung cancer, melanoma, mantle cell lymphoma, multiple endocrine neoplasia, 
prostate, and gastric cancer. PRMT5 is the predominant type II PRMT that catalyzes the 
formation of symmetric dimethylated arginine (SDMA). 
Co-intervention of cancer cells with GSK3368715 and a PRMT5 tool inhibitor
(GSK3326591) results in a cytotoxic response in 57% of the cell lines treated compared 
with 18% and 11% for GSK3368715 and GSK3203591 as single agents, respectively.
Deletion of the MTAP gene results in the accumulation of its metabolite, 2-
methylthioadenosine (MTA), a selective inhibitor of PRMT5 enzymatic activity 
[Kryukov, 2016; Marjon, 2016; Mavrakis, 2016].  Thus, MTAP deficiency may 
contribute to sensitivity and cytotoxic responses to GSK3368715 alone suggesting the 
potential utility of MTAP status as a predictive biomarker of response.  Due to its 
genomic proximity to the tumor suppressor CDKN2A(p16), the MTAP gene is frequently 
deleted in cancers including 40-56% of glioblastoma, 27-31% of pancreatic 
adenocarcinoma, 27-32% of bladder cancer, 25% of melanoma, 23% of lymphoma, and 
9-28% of non-small cell lung carcinoma. GSK3368715 alone induces a cytotoxic 
response in a subset of pancreatic cancer cell lines deficient for MTAP. Together, these 
data indicate that GSK3368715 intervention in combination with PRMT5 inhibition, 
through MTAP loss or a small molecule inhibitor, has potent anti-tumor activity in cancer 
cell lines across multiple tumor types.
2.2.2.2.
GSK3368715 Combination with Checkpoint Modulators
Cancer cell lines treated with GSK3368715 demonstrated altered expression of pro-
inflammatory, immune response gene families including tumor necrosis factor alpha
(TNF-) and interferon-gamma (IFN-) suggesting an immunomodulatory effect.  
Therefore, the anti-tumor activity of GSK3368715 was evaluated in an immune-
competent mouse tumor model as a single agent and in combination with the checkpoint 
modulator antibody anti-PD1. GSK3368715 alone and in combination with anti-PD1 has
significant effects on tumor growth inhibition and provides enhanced survival benefit 
relative to control mice. Surviving animals from all single agent and combination dosing 
groups are resistant to re-challenge with tumor cells without additional dosing of either 
agent. Collectively, these data suggest GSK3368715 may provide durable anti-tumor 
effects in an immune-competent setting and synergize with immune system checkpoint 
modulators such as anti-PD1.
2.3.
Benefit/Risk Assessment
The risk assessment and risk mitigation plan for the study are summarized below.
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of GSK3368715 may be found in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2017N334333_02].


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2.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK3368715
Cardiovascular 
Increased QRS and PR intervals in rat and dog. 
Exclusion of participants with cardiac 
abnormality
Increased cardiac monitoring as per Schedule 
of Activities (Section 1.3)
Cardiac stopping criteria (See Section 7.1.2) 
Gastrointestinal
Ulcerations/erosions in the upper gastrointestinal 
tract in rat and dog associated with reduced food 
consumption, body weight loss, emesis, 
abnormal feces, and/or salivation.
Exclusion of participants with significant 
malabsorptive gastrointestinal abnormalities
Guidelines for management of diarrhea, 
nausea, vomiting included in Appendix 12.
Hematologic/Lymphoid
Mild, reversible increased hematopoietic 
cellularity (with immature phenotype) in the bone 
marrow of rat and dog at tolerated doses; 
decreased cellularity at non-tolerated doses.  
Decreased lymphoid organ cellularity.  Mild 
decreases in circulating RBC, WBC and/or 
platelets.
Exclusion of participants with clinically 
significant bleeding
Laboratory assessments for complete blood 
counts 
Guidelines for management of 
thrombocytopenia and anemia included in 
Appendix 12
Dose stopping/modification criteria (Appendix
12)


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatic
Reversible hepatocyte hypertrophy and
vacuolation and increases in serum liver-
associated enzymes in rat and dog.

Exclusion of uncontrolled hepatic disease

Routine monitoring of liver chemistry

Stopping criteria/rechallenge guidelines 
(See Appendix 6).
Testicular/Reproductive Effects
Testicular effects including degeneration in 
seminiferous tubules in rat and dog.
Male contraceptive language included in 
Appendix 4
Thromboembolic Risk
A higher than expected incidence of venous 
thromboembolism was observed in the first 19
participants treated on clinical study 207675. 
Change in inclusion/exclusion criteria, to 
exclude participants at high risk of VTE. 
Extended monitoring time for VTE events to 
clear dose prior to dose escalation. 
Include cohort stopping rules for VTE
Resume enrollment under protocol 
amendment 03 at reduced dose of 100 mg po 
daily
Limit dose escalation to 50 mg increments.
Study procedures
Biopsy
A tissue biopsy is required in PK/PD cohorts to 
evaluate tumor expression of the biomarkers
pathway. Risks associated with a tumor biopsy 
depend upon the location and type of biopsy 
performed. Pain, infection, bleeding may occur 
after the procedure. Additional risks depending 
on the location of the biopsy may include 
pneumothorax, pneumonia, injury to surrounding 
nerves or organs, hospitalization, and, rarely, 
death.
Participants will be informed of the specific 
risks associated with the biopsy to be 
performed through the ICF. Participants at 
increased risk or not well suited to undergo a 
biopsy should not be enrolled in a cohort that 
requires a fresh biopsy. Participants will be 
treated according to local practice.


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2.3.2.
Benefit Assessment
Data obtained in this study may assist in growing the knowledge base on 
relapsed/refractory solid tumors and DLBCL and their treatment, or help identify 
individuals more likely to benefit or have side-effects from GSK3368715. Study 
participants may benefit from the medical tests and screening performed during the study.
Four of 19 subjects treated to date have experienced a period of radiologically 
documented stable disease of at least 8 weeks duration.
2.3.3.
Overall Benefit/Risk Conclusion
Epigenetic alteration resulting in the loss of gene expression by transcription silencing 
occur approximately 10- times more frequently than genetic alterations and have thus, 
long been thought of as a separate mechanism driving malignant transformation and 
carcinogenesis. However, data recently derived from the whole exome sequencing of 
thousands of human cancers have led to the unexpected discovery of a ‘crosstalk’ 
between the tumor genome and the epigenome caused by many inactivating mutations in 
genes that control the epigenome. These mutations have the potential to disrupt DNA 
methylation patterns, histone modifications and nucleosome positioning and hence, gene 
expression. Genetic alteration of the epigenome therefore contributes to cancer just as 
epigenetic process can cause point mutations and disable DNA repair functions. The 
‘crosstalk’ between the genome and the epigenome offers new possibilities for 
manipulations of epigenetic alterations for cancer prevention, detection, and therapy. 
The Type 1 protein arginine methyltransferases (PRMTs) are believed to be involved in 
this ‘crosstalk’. Aberrant regulation and overexpression of PRMT1, a member of the 
Type I class of PRMTs has been associated with the development and dissemination of 
solid tumors and hematologic malignancies. Moreover, deficiency of MTAP, a gene that 
is frequently deleted concomitantly with the tumor suppressor p16 gene (also known as 
cyclin-dependent kinase inhibitor 2A), appears to sensitize tumor cells to cytotoxicity 
induced through Type 1 PRMT1 inhibition. 
GSK3368715 is a first-in-class agent selectively targeting Type 1 PRMTs. In preclinical 
studies, GSK3368715 has demonstrated broad anti-tumor efficacy in vitro and in vivo.  
Loss of MTAP enhances sensitivity and cytotoxic response to GSK3368715 in select 
tumor types. These preclinical studies strongly support the clinical development of 
GSK3368715 in patients with solid tumors and hematologic malignancies initially as 
single agent and in the future potentially in combination with other intervention
modalities. Tumor indications with more frequent MTAP deficiencies may be more 
susceptible to GSK3368715 induced cytotoxicity.  
In this first time in humans (FTIH) study only participants with advanced stage solid 
tumors or relapsed/refractory DLBCL will be enrolled. All participants in this study will 
have exhausted all approved and effective therapies prior to receiving GSK3368715. The 
study protocol has been specifically designed to (i) carefully monitor all participants and 
thereby, minimize the clinical risk of intervention-related toxicities and to (ii) enrich the 
study population for tumor indications with higher sensitivity for GSK3368715 study 
intervention. 


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Considering the novel and very relevant mode-of-action, the anti-tumor activity observed 
in pre-clinical tumor models, the availability of a relevant biomarker for enrichment, and 
the clinical monitoring measures incorporated into this study protocol, the sponsor 
believes that the potential clinical benefit associated with GSK3368715 study 
intervention outweighs the risk of severe, intervention-emergent toxicities. This 
assessment is maintained after initial clinical evaluation in 19 participants in a Phase 1 
population with advanced cancer without alternative therapeutic options.  


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3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Part 1: Dose Escalation
Primary
•
Determine RP2D and schedule of 
GSK3368715 administered orally to 
participants with advanced stage solid 
tumors
•
Incidence of DLT
•
Incidence
and severity
of 
adverse events
Secondary
•
Evaluate the preliminary clinical activity 
of GSK3368715
•
Best overall response
•
Characterize the PK of GSK3368715, 
including the PK in the fed and fasted 
state in the food effect sub-study
•
PK parameters (Cmax, Tmax, 
AUC, others)
•
PK parameters (Cmax, Tmax 
and AUC) in the fed and 
fasted state in the food effect 
sub-study
Part 2: Dose Expansion
Primary
•
Evaluate the preliminary clinical activity 
of GSK3368715
•
Objective response rate 
(ORR)
Secondary
•
Characterize the safety of GSK3368715 
administered at the RP2D and schedule to 
participants with DLBCL, pancreatic 
cancer, NSCLC, and bladder cancer
•
Incidence and severity of 
adverse events
•
Further evaluate the clinical activity of 
GSK3368715
•
Progression-free survival 
(PFS)
•
Characterize the PK of GSK3368715
•
PK parameters (Cmax, Tmax, 
AUC, others)
Part 1 and Part 2
Exploratory
•
Evaluate time to response (TTR), duration of response (DOR) and overall survival 
(OS)
•
Evaluate changes in PD biomarkers relevant to define the molecular mode-of-
action of GSK3368715
•
Investigate biomarkers such as, but not restricted to, MTAP deficiency and 
CDKN2A gene deletion, as potentially predictive of sensitivity or resistance to 
GSK3368715
•
Characterize the relationship between PK, PD, and clinical activity of 
GSK3368715
•
Evaluate the relationship of pharmacogenetic profile in host DNA and response to 
GSK3368715 therapy
•
Determine the impact of GSK3368715 on function and health-related quality of 
life
•
Determine the amount of GSK3368715 excreted in urine from participants in the 


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PK/PD expansion cohorts
•
Characterize the metabolic profile of GSK3368715 (in the PK/PD expansion 
cohorts
•
Investigate biomarkers such as, but not restricted to, D-dimer, fibrinogen and 
Factor VIII to evaluate whether GSK3368715 affects the coagulation cascade
4.
STUDY DESIGN
4.1.
Overall Design
This is a first time in human (FTIH), open-label, repeat-dose, non-randomized, 
multicenter study to evaluate the safety, tolerability, PK, PD, preliminary clinical activity 
and establish a recommended dose of GSK3368715 in participants with 
refractory/relapsed solid tumors and DLBCL.
The study will consist of a dose-escalation phase, including at least one PK/PD cohort 
and a food effect cohort, (Part 1) and dose expansion phase (Part 2):

Part 1: GSK3368715 doses will be escalated using the Neuenschwander 
continual reassessment method (N-CRM). The populations enrolled will be 
participants with selected solid relapsed/refractory tumors. Based on safety and 
tolerability, and the PK/pharmacodynamic characteristics of the molecule, 
recommended Phase 2 (RP2D) dose(s) and schedule(s) will be established. 

Part 2: the safety and preliminary clinical activity of GSK3368715 administered 
at the RP2D and schedule will be further evaluated in two expansion cohorts 

Expansion Cohort 2A: Participants with relapsed/refractory Diffuse-large 
B-cell lymphoma (DLBCL)

Expansion Cohort 2B: Participants with selected relapsed/refractory 
solid tumors where MTAP deletion occurs at a frequency of 
approximately ≥25% (e.g., pancreatic, bladder, and non-small cell lung 
cancer). 
Note: In both expansion cohorts, both MTAP proficient and deficient participants will 
be enrolled. Separate analysis will be conducted for MTAP deficiency or MTAP 
proficiency/wild type within each specific disease histology. 
Based on the emerging safety- and molecular activity profile of GSK3368715 
combination regimens with novel, active agents such as the small-molecule PRMT5 
inhibitor, GSK3326595 and/or with approved oncology therapies may be considered. 
Rationale for these future combinations will be provided before the initiation of that 
combination and added by way of a protocol amendment.
The study includes a screening period, an intervention period and follow up. Participants 
will be screened for eligibility beginning approximately 4 weeks before the start of 


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intervention. Participants may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent. For participants who discontinue 
intervention prior to a determination of PD, the follow-up period includes disease 
assessments every 8 weeks until documented PD. Following PD or for participants that 
discontinue study intervention, participants will be contacted every 12 weeks to assess 
survival status for 2 years from the start of the study. Participants with confirmed partial 
response (PR) or complete response (CR) will be followed for response duration.
Assessment of disease status will be performed by the Investigator in accordance with 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and the latest version of 
Lugano Criteria for NHL.
4.1.1.
Part 1: Dose-Escalation Phase
Cohort Size:  The initial dose cohort(s) will include up to three participants per 
GSK3368715 dose level. Cohorts will be expanded at the first instance of a ≥ Grade 2 
drug-related non-hematological toxicity. From there on, a minimum of 3 and a maximum 
of 12 DLT evaluable participants may be assigned to any single dose at the discretion of 
the Dose Escalation Committee (DEC) as outlined in the Dose Escalation Plan.
Replacement: If a participant fails to receive at least 75% of the planned doses within 
the 21-day DLT observation period for reasons other than toxicity (e.g., concurrent 
illness or disease progression), the participant will be replaced by additional participant(s) 
assigned to the same dose level and will not be counted as DLT evaluable.
Dose Escalation: After each dose cohort, a dosing recommendation for the next cohort 
will be made using the Neuenschwander Continual Reassessment Method (N-CRM) 
[Neuenschwander, 2008]. 
The N-CRM design makes use of a Bayesian logistic regression model relating dose and 
toxicity and is expected to locate the target dose level efficiently while minimizing the 
number of participants exposed to pharmacologically inactive or unsafe dose levels. The 
N-CRM method is fully adaptive and makes use of all DLT information, therefore is 
expected to locate the target dose level efficiently.
The N-CRM estimates, for each potential dose, the posterior probabilities that the DLT 
rate lies in each of four toxicity ranges:

A dose falls in the Under-dosing range if the probability of a DLT at the dose is, 
16%.

A dose falls in the Target Toxicity range if the probability of a DLT at the dose is 
≥16% and <33%.

A dose falls in the Excessive Toxicity range if the probability of a DLT at the 
dose is ≥33%, and <60%.

A dose falls in the Unacceptable Toxicity range if the probability of a DLT at the 
dose is ≥60%
At the time of each dose-escalation decision, the dose with the highest posterior 
probability of lying in the Target Toxicity range will be the model-recommended dose for 


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the next cohort. Additionally, the following constraints for the recommended dose will be 
maintained:

The posterior probability of the DLT rate lying in the Excessive Toxicity or 
Unacceptable Toxicity range is less than 25%.

VTE safety rules
Upon re-initiation of enrolment under Protocol Amendment 3, details of a 
VTE meeting the DLT criteria are given in Section 4.1.3 and in Table 6.

Upon re-initiation of enrolment under Protocol Amendment 3 at 100mg , 
dose escalation steps will be considered in maximal steps of 50 mg,
depending on the pharmacodynamic effects and the safety profile observed in 
previous cohorts, taking into consideration the updated DLT criteria (see 
Table 6).

Note: GSK3368715 dose de-escalation is also possible using this method.
An updated posterior estimate of the dose-toxicity curve will also be provided at the time 
of the dose-escalation meeting. Further details about the N-CRM approach are provided 
in Section 9. Although the N-CRM will be used to recommend the next dosing level, the 
DEC (i) will review all available data, including safety, PK and PD data from current and 
prior cohorts, (ii) can halt or reduce the GSK3368715 dose based on clinical judgement at 
any time during the trial, and (iii) can recommend alternative schedule(s) if emerging 
data suggest that continuous daily dosing will result in excessive toxicity or limited 
efficacy (Section 4.1.4). Note: if an alternative schedule is evaluated, the starting dose at 
the time of a schedule change will be the dose for which the target toxicity level was not 
exceeded using once daily dosing schedule.
Dose Schedule:  GSK3368715 will be dosed initially orally (po) Based on emerging
safety-, PK-, and PD- data, the DEC may recommend to evaluate alternative dosing 
schedule(s). The starting dose for an alternative dosing schedule will not exceed the 
highest GSK3368715 dose declared safe by the DEC at the time of the proposed schedule 
change. 
During dose escalation, the first dose will be staggered by at least 24 hours between the 
participants enrolled within a cohort. This staggered dosing start is not required for 
participants enrolling at previously cleared doses.
PK/PD/Metabolite/Biomarker-Cohort: At GSK3368715 dose levels near to the 
expected RP2D, the DEC may recommend to expand a cohort(s) to up to 12 participants 
for additional PK- and PD-, metabolite- and/or biomarker-sample collection. 
Under protocol amendment 03, a 100mg PK/PD cohort will be opened on resuming 
enrolment, and a 50mg PK/PD cohort may be opened in parallel. An additional PK/PD 
cohort may be opened later at a different dose level. The total maximal number of 
participants enrolled on PK/PD cohorts will be approximately 30. 
The DEC may mandate to: 
(1) take pre- and post-dose tumor biopsies, 


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(2) collect additional urine-, plasma-, and/or whole blood samples, and/or 
(3) perform 18fluorodeoxyglucose (FDG) positron emission tomography (PET) (i.e. 
FDG-PET)/computer tomography (CT) (PET/CT) scan assessments. in the 
additional participants enrolled in these GSK3368715 cohort(s).  
The intention is to generate more comprehensive data at therapeutically relevant 
GSK3368715 dose level(s) in order to (i) establish a dose-response curve for 
GSK3368715 on the basis of PD-biomarkers, (ii) further characterize the metabolism of 
GSK3368715, and/or (iii) investigate the molecular mode-of-action of GSK3368715 on 
the basis of exploratory biomarkers. Participants may be enrolled into these 
PK/PD/Metabolite/Biomarker cohort(s) even after the MTD and/or RP2D has been 
identified and study Part 2 has been initiated.
Maximum-tolerated Dose: MTD is the highest GSK3368715 dose that emerges from 
the evaluation of safety-, PK-, and PD-data guided by the N-CRM statistical design 
during the DLT evaluation period. 
Recommended Phase 2 Dose: RP2D of GSK3368715 will be determined after review of 
all available safety-, PK-, PD-, and clinical efficacy data in accordance with the N-CRM 
design. The RP2D will be equivalent with the MTD or a lower GSK3368715 dose that
provides adequate PK exposure and biologic activity with superior tolerability. 
Note: If necessary, alternate dosing schedules can be explored to determine additional 
biologically active doses even after a RP2D is defined.
4.1.1.1.
Food effect Cohort
Once a RP2D is identified, a food effect sub-study may be initiated.  It will be an open-
label, randomized, single dose, two period, cross over study to investigate the effect of a 
high-fat, high-calorie meal on the bioavailability of GSK3368715 with a tablet 
formulation at or near the RP2D.  Initiation or completion of this sub-study is not 
required prior to initiating part 2. GSK3368715 dosing (fed then fasted, or fasted then 
fed) will be separated by at least 3days. A minimum of 12 participants in the United 
States may be enrolled in the sub-study. A participant requiring dose reduction or 
discontinuation from study before completion of at least 48 hours after dosing in 
fasted/fed state in the sub-cohort will be replaced by a new participant. All participants 
enrolled to the sub-study, on completion of their participation in this segment of the 
study, will continue on a daily dosing schedule until discontinuation criteria are met, as 
described in Section 7.1.
The food effect sub-study will be open to participants with histologically- or 
cytologically confirmed solid malignancies as described for Part 1 in Section 5.1.
The high-fat (approximately 50% of the total caloric content of the meal), high-calorie
meal (approximately 800 to 1000 calories) will be the representative example given by
the 2002 US Food and Drug Administration (FDA) guidance [FDA, 2002]. Additional
details of the required meal will be provided in the SRM.


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Participants enrolled in the sub-study will be assigned to one of two sequences, as 
described in Table 5; equal numbers will be assigned to each sequence. The schedule of 
visits for participants enrolled in the sub-study is detailed in Table 4 in Section 1.3. Upon
completion of the sub-study, all participants will continue to undergo scheduled 
assessments as described in Table 2. Additional details, including the process of sequence 
assignment, will be provided in the SRM.


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Table 5
Food Effect Sub-Study
Food effect cohort (single dose administrations)
Sample size
Sequence
Period 1 (W1D1)
Period 2 (W1D4/D5)
6
1
Fasted
Fed
6
2
Fed
Fasted
Fasted: Participants should take nothing by mouth apart from water and other 
medications for at least 8 hours prior to dosing and should continue fasting until at least 4 
hours after administration of the morning dose. Participants should be administered the 
drug product with 240 mL (8 fluid ounces) of water. Water will be allowed as desired 
except for one hour before and after drug administration. Participants will receive 
standardized meals approximately 4 and 10 hours post dose.
Fed: Following an overnight fast (at least 8 hours), participants should start the
recommended high fat, high calorie breakfast 30 minutes prior to administration of the
drug product. Study participants should eat this meal in 30 minutes or less; however, the 
drug product should be administered 30 minutes after start of the meal. The drug product
should be administered with 240 mL (8 fluid ounces) of water. No food should be
allowed for at least 2 hours post-dose. Water will be allowed as desired except for one
hour before and after drug administration.
4.1.2.
Part 2: Expansion Cohorts
Part 2 (Dose Expansion) will start after the RP2D is determined in Part 1.
The intention of Part 2 is to (i) collect additional information on the safety and PK/PD 
characteristics of GSK3368715 and (ii) to evaluate the clinical activity of GSK3368715
in selected disease populations.  
Part 2 will consist of two expansion cohorts:

Expansion Cohort 2A: Up to 36 participants with DLBCL will be enrolled.  
Based on the assumed prevalence of MTAP deletions, it is expected that ~ 23 % 
of participants (or ~ 8 out of 36 participants) will present with DLBL deficient of 
MTAP. 
For DLBCL cohort (Part 2A), this cohort will be evaluated separately from the 
solid tumor cohorts (Part 2B). A Bayesian adaptive design based on hierarchical 
model will be used to allow interim monitoring of the response rate and allow 
information borrowing between the MTAP defined subgroups within the cohort. 
The interim futility analysis will be performed every 2-3 months with minimum 
of 5 additional evaluable participants from the entire cohort. The first interim 
futility analysis will be performed when at least 5 participants become evaluable 
from each of the MTAP defined subgroups. Data from both subgroups will be 
included in the analysis to form the Bayesian hierarchical model. Any subgroup 
with posterior probability of ORR > 10% sufficiently low (<20%) will be 
declared as ineffective and terminated for enrollment according to the design.


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
Expansion Cohort 2B: Up to 105 participants with pancreas cancer, NSCLC, 
and bladder cancer, will be enrolled. The number of participants with a specific 
tumor histology in this cohort will is not fixed but will ultimately not exceed 35 
participants of any specific tumor histology.
The three tumor histologies were selected on the basis of the higher frequency of 
MTAP deletions which is assumed to be ~ 30% in pancreatic cancer, ~27-32% in 
bladder cancer, and ~9-28% in NSCLC. 
A Bayesian adaptive design based on hierarchical model will be used to allow 
interim monitoring of the response rate in this expansion cohort on ongoing basis. 
The design will also allow information borrowing across the three different 
histologies as well as between the MTAP defined subgroups within each 
histology. Participants enrolled in Part 1 who were treated at the RP2D of 
GSK3368715 and have the same disease histology as required for Expansion 
Cohort 2B will be included in the analyses as appropriate.
The first interim futility analysis will be performed when at least 5 participants 
become evaluable from MTAP proficient subgroup within any cohort. Data from 
all participants across all tumor types in part 2B will be included in the analysis to 
form the Bayesian hierarchical model. Details about the futility rules are specified 
in Section 9.4.2.1.
MTAP-Testing for Expansion Cohort 2A and -2B: Homozygous deletion of the tumor 
suppressor protein p16 (CDKN2A) on chromosome 9p21 is prevalent in cancer (in ~ 15-
40% of all cancers) and commonly (in more than 90% of instances [Huang, 2009; 
Kirovski, 2011; Su, 2014]) involves co-deletion of the adjacent gene for MTAP. 
Because of the high frequency and prognostic relevance, molecular testing for p16 
(CDKN2A)-deletion is commonly conducted and p16 is a marker present on most 
molecular panels. Local molecular testing for p16 (CDKN2A) deletion will be utilized to 
prospectively stratify the Part 2 population; and will be followed by retrospective central 
confirmatory MTAP-deletion testing. 
It is expected that participants whose tumor harbors an MTAP-deletion or wild-type 
MTAP are equally represented in the 2 expansion cohorts. In expansion cohorts, the 
intention is to stratify enrollment such that approximately 50% of participants within each 
of the three solid tumor types and the DLBCL cohort have an MTAP deletion. 
In order to achieve the expected number of participants whose tumor harbors a MTAP-
deletion, prospective MTAP testing may be implemented if the local p16 (CDKN2A) 
testing does not deliver the required number of enriched participants in concordance with 
the retrospective MTAP testing. 
4.1.3.
Dose-Limiting Toxicity
All toxicities will be graded using National Cancer Institute – Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE), version 5. 


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An AE is considered to be a dose-limiting toxicity (DLT) if the event is considered by the 
investigator to be clinically relevant and attributed (definitely, probably or possibly) to 
the study intervention during the first 21 days of intervention and meets at least one of the 
criteria listed in Table 6.
In addition, there are clear VTE DLT criteria:

Upon re-initiation of enrolment under Protocol Amendment 3, any cohort in Part 
1 with two (2) grade 2 venous thromboembolism (VTE) that requires systemic 
anticoagulation or ≥grade 3 VTE in up to 6 participants will be considered not 
cleared and enrolment at this dose level and higher dose levels will be 
permanently stopped.

Upon re-initiation of enrolment under Protocol Amendment 3, any cohort in Part 
1 with ≥3 grade 2 venous thromboembolism (VTE) that requires systemic 
anticoagulation or Grade ≥3 VTEs out of up to 10 participants will be considered 
not cleared and enrolment at this dose level and higher dose levels will be 
permanently stopped.

Upon re-initiation of enrolment under Protocol Amendment 3 at 100mg, dose 
escalation steps will be considered in maximal steps of 50 mg depending on the 
pharmacodynamic effects and the safety profile observed in previous cohorts, 
taking into consideration the updated DLT criteria (see Table 6).

Grade 2 venous thromboembolism (VTE) that requires systemic anticoagulation 
or grade 3 VTE, regardless of investigator assessed causality, will be considered 
a DLT during the first 8 (1) weeks or until study discontinuation (e.g., disease 
progression), whichever occurs sooner.

An end of treatment CT image is required if the participant withdraws before the 
end of the VTE DLT observation period (Table 6). 
If an AE is considered related to the underlying disease it is not defined as a DLT.


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Table 6
Dose-Limiting Toxicity Criteria
DLT criteria for Non-hematologic Toxicity
AST or ALT 
•
Grade 3
•
Grade 4
•
ALT ≥ 5xULN
•
ALT ≥3xULN persists for ≥ 4 weeks
•
ALT ≥3xULN and bilirubin ≥2xULN (>35% direct 
bilirubin)
•
ALT ≥3xULN and INR >1.5, if INR measured
•
ALT ≥3xULN associated with symptoms (new or 
worsening) believed to be related to liver injury or 
hypersensitivity
Nausea
•
Grade 3 persisting >3 days despite BSCa
Vomiting
•
Grade 3 or 4 persisting > 3 days despite BSC
a
Diarrhea
•
Grade 3 or 4 persisting > 3 days despite BSC
a
Fatigue
•
Grade 3 persisting > 5 days
Hypertension
•
Grade 3 that cannot be controlled with medical 
therapy
•
Grade 4
ECG-change
•
> 20 msec extension of the QRS-interval compared 
to baseline
Laboratory abnormality
•
Grade 3 persisting > 3 days despite BSC
a
•
Grade 4
Any other
•
Grade 2 leading to frequent dose interruptions 
despite BSCa and limiting GSK3368715 dosing to 
<80% of expected dose
•
Grade 
2
requiring 
delay 
of 
GSK3368715 
administration for > 14 days
•
Grade ≥3 


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DLT criteria for Hematologic Toxicity
Neutropenia
•
Grade 3 persisting > 3 days despite BSC
a
•
Febrile neutropenia
•
Grade 4
Thrombocytopenia
•
Grade 3 persisting > 3 days despite BSC
a
•
Grade 3 associated with clinically significant 
hemorrhage
•
Grade 4
Any otherb
•
Grade 2 and 3 leading to frequent dose 
interruptions despite BSCa and limiting 
GSK3368715 dosing to < 80% of expected dose
•
Grade 3 persisting > 3 days despite BSC
a
•
Grade 4
Venous 
Thromboembolism
•
Grade 2 venous thromboembolism (VTE) that 
requires systemic anticoagulation or VTE Grade ≥3 
during the first 8 (1) weeks or until study 
discontinuation (e.g., disease progression), 
whichever occurs sooner.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BSC=best supportive care; DLT=dose-
limiting toxicity; ECG=electrocardiogram; ULN=upper limit of normal 
a.
Best supportive care if available, according to institutional standards
b.
With the exception of lymphocytopenia
For participants who experience a toxicity that meets the criteria of DLT, administration 
of GSK3368715 will be held pending management and resolution of the toxicity.
Participants who withdraw from the study before completing 21 days of intervention for 
reasons other than DLT may be replaced at the discretion of the sponsor. 
Guidance for the management of toxicity, including dose modification algorithms, is 
provided in Appendix 12.
4.1.4.
Dose Escalation Committee
The Dose Escalation Committee (DEC) will be established by GSK to monitor 
intervention-emergent data on an ongoing basis throughout study conduct for the purpose 
of ensuring the continued safety of participants enrolled in this study. The DEC will be 
chaired by the GSK medical monitor and membership will include a GSK scientist, GSK 
pharmacovigilance physician, GSK statistician, GSK pharmacologist, along with 
additional GSK staff as appropriate and all participating investigators. 
In Part 1, the DEC will review relevant safety, PK, and PD data generated immediately 
after all participants treated in the same dose cohort have passed the DLT period, as 
defined in the Dose Escalation Plan. Although the escalation of the GSK3368715 dose 
will be guided by the N-CRM, the DEC can override this recommendation. 


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In Part 2, the members from the DEC will continue to routinely assess cumulative safety 
data as a safety evaluation team. This team may decide to stop further enrolment if 
intervention-emergent toxicity is determined to result in an unfavourable change in 
participant risk/benefit.
In addition, throughout the conduct of the study the DEC may decide to:
1. Modify the dose escalation of GSK3368715 proposed by the N-CRM based on 
clinical judgement. Note: GSK3368715 dose steps will not exceed 50 mg dose 
increments under protocol amendment 03.  
2. Investigate alternative dosing regimens 
3. Modify the timing, frequency, and/or type of safety assessments performed during 
study conduct 
4. Request intervention of additional participants at previously completed dose 
levels for the purpose of obtaining additional safety, PK, PD, metabolite, or 
biomarker data (i.e. PK/PD/Metabolite/Biomarker-Cohort).
5. Recommend intra-participant dose escalation allowing participants to be moved 
from a lower to a higher GSK3368715 dose, not exceeding the MTD if the DEC
has declared the next dose cohort as safe
6. Decide on intervention beyond initial evidence of disease progression in 
participants who receive clinical benefit (i.e., stable Eastern Cooperative 
Oncology Group or ECOG performance status and no clinical symptoms 
indicative of rapid disease progression)
7. Increase the size of an expansion cohort or recommend to add additional 
expansion cohorts to further characterize the safety and efficacy profile of 
GSK3368715
8. Halt enrolment into any cohorts as deemed appropriate based on emerging clinical 
data at any time during the trial.
During Part 1 of the study, the DEC will meet at least after each dose cohort is fully 
recruited and all participants have completed the DLT evaluation period. The 
schedule of dose escalation meetings will depend on the frequency of DLT and when 
an RP2D is determined. During Part 2 of the study, the DEC will meet approximately 
after every 10 participants in each expansion cohort have been on study for ≥ 2 
cycles. 
Documentation of DEC meeting outcomes will be maintained by GSK. Decisions 
with potential impact on the safety of study participants (i.e. unfavourable change in 
risk/benefit assessment) will be promptly communicated to regulatory authorities and 
study sites as appropriate.
4.2.
Scientific Rationale for Study Design
Given the high unmet medical need of relapsed/refractory advanced solid tumors and
non-Hodgkin’s lymphoma, this two-part Phase I study (207675) is proposed. This study 
evaluates the safety, tolerability, pharmacology, and preliminary clinical activity of 
GSK3368715. The study comprises a dose-escalation part to identify the MTD/


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recommended expansion dose followed by two expansion cohorts to determine 
preliminary efficacy.
In Part 1, blood, serum and urine collections will be performed to characterize the 
pharmacokinetic and pharmacodynamic parameters of GSK3368715.
Cohort(s) of additional participants in Part 1, treated at or close to the expected 
MTD/RP2D, will be evaluated more extensively for metabolic and biomarker profiling. 
This cohort will provide samples for biomarker, pharmacodynamic, and metabolite 
assessment. Analysis of human samples will provide first-hand information on 
metabolism and disposition of GSK3368715 in humans. In addition to assessing known 
pharmacodynamic biomarkers, exploratory efforts will be conducted to evaluate the 
mechanism of action of GSK3368715, and discover novel pharmacodynamic and 
predictive biomarkers from blood, plasma, and tumor.
A subset of participants in Part 1, treated at or near the RP2D, will be evaluated more
extensively to evaluate the effect of food on the pharmacokinetics of GSK3368715
(Section 4.1.1.1). This cohort will provide data that can be used to modify dosing 
instructions for participants in this and future studies (e.g., GSK3368715 may be taken 
without respect to food, or GSK3368715 must be taken on an empty stomach).
Once a RP2D dose of GSK3368715 has been identified that is safe, tolerable and 
demonstrates pharmacodynamic activity, enrolment into Part 2 may begin. 
The intent of Part 2 is to evaluate MTAP as a potential selection biomarker in participants 
exposed to GSK3368715 at the RP2D.  MTAP deficiency in tumor tissue will be 
evaluated as a potential biomarker to select participants for GSK3368715 study 
intervention and emerging data will be used to adaptively recruit participants based on 
MTAP status. to achieve approximately 50% of participants within each tumor type 
having an MTAP deletion. 


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4.3.
Dose Justification
4.3.1.
Starting Dose Justification
The starting dose for GSK3368715 has been selected based on preclinical toxicology, 
pharmacokinetic data from various species and pharmacodynamics (PD) and efficacy 
data from mouse xenograft tumor models (See IB for the latest information)
[GlaxoSmithKline Document Number 2017N334333_02]. In addition, an integrated 
tumor exposure-PD response model was built to predict efficacious doses.
The Severely Toxic Dose in 10% rats (STD10) as per International Conference on 
Harmonization (ICH) S9 guidance was 150mg/kg/day for 28 days and the highest non-
severely toxic dose (HNSTD) in the dog was 15mg/kg/day for 28 days (GlaxoSmithKline 
Document Number 2017N334333_02).
Using one tenth of the rat STD10 as per ICH S9 guidance, where STD10 is defined as 
150 mg/kg/day administered daily for 4 weeks, translates to 146 mg using the human 
equivalent dose calculation (60 kg adult with a surface area of 1.62 m2).
Using one sixth of the dog HNSTD as per ICH S9 guidance, where HNSTD is defined as 
15 mg/kg/day administered daily for 4 weeks, translates to 81 mg using the human 
equivalent dose calculation (60 kg adult with a surface area of 1.62 m2).
Minimally anticipated biologic effect level (MABEL): Mouse pre-clinical studies in the 
Toledo xenograft model revealed that tumor growth inhibition was associated with a 
minimum 30% increase in MMA in tumor tissues at doses of 10 mg/Kg/Day. Based on 
this, the MABEL exposures were defined as total AUC (0-24) of 1300 ng∙hr/ml (free 
AUC [0-24] of 500 ng∙hr/mL). For prediction of human dose which will reach MABEL 
exposure levels, the human pharmacokinetic parameters were predicted using preclinical 
PK IV data (mouse, rat and dog) and scaling to the human time and concentration scale 
using complex Dedrick plots with correction for maximum lifespan potential 
(Boxenbaum, 1983). The predicted human PK parameters are estimated to be 9.6 
mL/min/Kg (Clearance), 25 L/Kg (Steady state volume of distribution), 48 hr (Half-Life) 
and 49% (Bioavailability). Accounting for higher free fraction in human (% unbound 
64.2) relative to mouse (% unbound 35.7), projects human equivalent free MABEL 
exposures to be reached at 62 mg.
Potential therapeutic doses: An integrated tumor exposure-biomarker response model was 
utilized to describe the relationship between GSK3368715 tumor exposure and MMA 
increase in Toledo xenograft studies. Based on the model and predicted human PK, a 
projected human dose of 250 mg QD/110 mg BID will achieve a 95% increase in MMA 
induction; 99% increase is projected at doses around 900 mg QD and supports escalation 
upwards of 250 mg QD.
After considering the potential range of starting doses based on toxicology,
pharmacology, and xenograft models, the proposed starting dose of 50 mg once daily was 
selected. Compared with total exposures observed in the most sensitive species, dogs at 
HNSTD, the starting dose provided 16- fold and 33-fold safety margins for the steady
state AUC and Cmax, respectively.


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4.3.2.
Dose Justification for Food Effect Sub cohort
Food effect sub-study will be initiated at RP2D with tablets.
Preliminary physiologically based pharmacokinetic (PBPK) modeling suggests that 
GSK3368715 absorption is not limited by solubility or permeability, and is expected to 
be not as much affected by food. Further, PBPK modeling to-date and in vitro data from 
TinyTIM# suggest similar performance between capsules and tablets, and no substantial 
food effect. 
#In-vitro model that mimics dynamic motility, volumes, secretion and digestion in the 
upper GI tract, designed by TNO/Triskelion [GlaxoSmithKline Document Number
2019N422334_01]
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. Specific information 
regarding warnings, precautions, contraindications, AEs, and other pertinent information 
on the GSK investigational product or other study intervention that may impact 
participant eligibility is provided in the IBs/IB supplements. Deviations from inclusion 
and exclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, or participant safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age:
1. Participant must be ≥18 to years of age inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2. Diagnosis of one of the following:
Part 1 (Dose Escalation and food effect cohort): 

Histologically-
or cytological-confirmed diagnosis of solid tumor 
malignancy that is metastatic or non-resectable 

Have received all standard treatment options or are no longer eligible for 
additional standard treatment options 

Evaluable disease that may be measured directly by the size of the tumor 
or can be evaluated by other methods.

Availability of a biopsy of the tumor tissue obtained at any time from the 
initial diagnosis to study entry. Although a fresh biopsy, which is 


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obtained during screening, is preferred, archival tumor specimen is 
acceptable if it is not feasible to obtain a fresh biopsy. 
For participants in the PK/PD cohort, a fresh biopsy and consent for one on 
treatment biopsy are required for enrollment. 
Part 2 (Dose Expansion):

Cohort 2A & 2B:
The availability of archival tumor tissue, or willingness to undergo a fresh 
biopsy to determine S-methyl-5'-thioadenosine phosphorylase (MTAP)
status (any archival tumor specimen must have been obtained within 6
months prior to starting study drug unless approved by the study Medical 
Monitor). Local MTAP or CDKN2A results are acceptable for enrollment 
but must be confirmed through central laboratory testing.

Cohort 2A:
Histologically- or cytological-confirmed diagnosis of Diffuse-large B-cell 
lymphoma (DLBCL)
Relapse or refractory disease after at least 1 but not more than 4 lines of 
prior therapy 
At least 1 measurable site of disease according to the Lugano 
Classification. The site of disease must be greater than 1.5 cm in the long 
axis regardless of short axis measurement or greater than 1.0 cm in the 
short axis regardless of long axis measurement, and clearly measurable in 
2 perpendicular dimensions.

Cohort 2B:
Pancreatic Cancer
o
Histologically or cytologically confirmed adenocarcinoma of the 
pancreas
o
Unresectable, locally advanced (Stage III), or metastatic (Stage IV) 
disease
o
Relapsed or refractory disease after at least 1 prior line of approved, 
systemic therapy
o
At least 1 measurable tumor lesion per RECIST 1.1 (Appendix 10)
Non-small cell lung Cancer (NSCLC)
o
Histologically or cytologically confirmed NSCLC
o
Stage IV disease
o
Tested for presence of EML4-ALK rearrangement
o
Received at least 2 prior lines of approved, systemic therapy, of which 
1 therapy has to be a platinum containing regimen.
or


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Failed a first-line platinum-containing regimen in combination with an 
anti-PD1 monocloncal antibody and refused a second-line regimen 
despite being informed about the different therapeutic options and 
their specific clinical benefit by the investigator; the content of this 
informed consent discussion including the therapeutic options 
reviewed by the investigator need to be documented and the 
participant needs to sign a specific consent form
o
At least 1 measurable tumor lesion per RECIST 1.1.
Transitional cell carcinoma of the Urothelium
o
Histologically or cytologically confirmed transitional cell carcinoma 
(TCC) of the urothelium (urinary bladder, urethra, ureter or renal 
pelvis) including mixed pathology with predominantly (i.e., > 50% of 
the histopathology sample) TCC with the exception of neuroendocrine or 
small cell carcinoma
o
Unresectable, locally advanced (T4b) or metastatic (lymph node or 
visceral) disease
o
Relapsed or refractory disease after at least 1 prior line of approved
systemic therapy
o
At least 1 measurable tumor lesion per RECIST 1.1.
3. Adequate organ function as defined by:
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobina
Solid malignancy: 9 g/dL
Non-Hodgkin’s Lymphoma: 8 g/dL
Plateletsa
100 X 109/L
PT/INR and PTT
1.5 X upper limit of normal (ULN), unless participant is receiving 
systemic anticoagulation
Hepatic
Albumin
2 g/dL
Total bilirubin
1.5 x ULN
NOTE: Isolated bilirubin >1.5 X ULN is acceptable if:
bilirubin is fractionated and direct bilirubin <35% OR
participant has a diagnosis of Gilbert’s syndrome
Alanine aminotransferase (ALT) 
Part 1 and 2: 2.5 ULN
Part 2 ONLY: <5 x ULN is acceptable for participants with 
documented liver metastases/tumor infiltration
Renal
Calculated creatinine clearance by 
Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation or 
measured from 24hr urine
≥ 50 mL/min


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Cardiac
Ejection fraction
Lower limit of normal (LLN) by echocardiogram (minimum of 
50%) / MUGA
ECG:QTcFb
<450 ms
a.
Participants that require transfusion or initiation of growth factor support in order to achieve 
necessary platelet and/or hemoglobin must maintain adequate values for at least 7 days without 
transfusion or while on growth factor in order to be eligible for participation
b.
Baseline QTc interval using Fridericia’s formula based on average of triplicate ECGs obtained over a brief 
recording period.
4. Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
5. Able to swallow and retain orally-administered medication.
Sex
6. Female Participants: A female participant is eligible to participate if she is not 
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%, as described in Appendix 4 during the intervention period 
and for at least 120 days, corresponding to the time needed to eliminate any 
study intervention(s) (e.g., 5 terminal half-lives) after the last dose of study 
intervention. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
A WOCBP must have a negative highly sensitive pregnancy test (urine as 
required by local regulations) within 7 days before the first dose of study 
intervention.
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 2.
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
Male Participants: Male participants are eligible to participate if they agree to the 
following during the intervention period and for at least 100 days, corresponding to time 
needed to eliminate study intervention(s) (e.g., 5 terminal half-lives) plus 90 days after 
the last dose of study intervention:
Refrain from donating sperm
Plus either:
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 


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OR
Must agree to use contraception/barrier as detailed below
o
Agree to use a male condom and should also be advised of the benefit 
for a female partner to use a highly effective method of contraception 
as a condom may break or leak when having sexual intercourse with a 
woman of childbearing potential who is not currently pregnant
o
Agree to use male condom when engaging in any activity that allows 
for passage of ejaculate to another person
Informed consent
7. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply
Prior or Concomitant Diseases:
1.
History of malignancy other than the disease under study.
EXCEPTION NOTE: Participants who have been disease-free for 5 years, or 
participants with a history of completely resected non-melanoma skin cancer or 
successfully treated in situ carcinoma are eligible. Participants with second 
malignancies that are indolent or definitively treated may be enrolled even if less 
than 5 years have elapsed since treatment. Consult GSK Medical Monitor if 
unsure whether second malignancies meet requirements specified above
2. Primary central nervous system (CNS) tumors, Glioblastoma multiforme (GBM), 
symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
EXCEPTION NOTE: Participants previously treated for these conditions that 
have had stable CNS disease (verified with consecutive imaging studies) for 
>1months, are asymptomatic and off corticosteroids, or are on stable dose of
corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of 
brain metastases must be confirmed with imaging. Participant treated with gamma 
knife therapy can be enrolled 2 weeks post-procedure as long as there are no post-
procedure complications/they are stable.
3. Any severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes, 
or active infection). 
4. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other 
conditions that could interfere with participant’s safety, obtaining informed consent 
or compliance to the study procedures, in the opinion of the Investigator.


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5. Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption
such as malabsorption syndrome or major resection of the stomach and/or bowels.
6. History of known human immunodeficiency virus (HIV) infection or positive HIV 
test result at screening.
7. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening to first dose of study intervention.
NOTE: Participants with positive Hepatitis C antibody due to prior resolved 
disease can be enrolled only if a confirmatory negative Hepatitis C RNA 
polymerase chain reaction (PCR) is obtained.
8. Any of the following cardiac abnormalities:
a) Uncontrolled high blood pressure.
b) Any history of coronary artery disease, including acute coronary syndromes, 
myocardial infarction, unstable angina, and history of coronary angioplasty, 
or stenting 
c) Presence of a cardiac pacemaker or implanted defibrillator.
d) AV-block (asymptomatic 2nd degree Type II or 3rd degree and any degree AV 
block if related to heart disease or if symptomatic), RBBB (right bundle 
branch block), LBBB (left bundle branch block), and any fasicular 
hemiblocks. 
e) A QRS interval at Screening or Baseline ≥110 msec.
f)
Patients with any symptomatic or sustained arrhythmias (past or present), 
including but not limited to:
o
Atrial fibrillation.
o
Atrial flutter
o
Ventricular tachycardia
o
Ventricular fibrillation
o
Supraventricular tachycardia
g) Current or past congestive heart failure.
h) Evidence of a left ventricular ejection fraction below the institutional lower 
limit of normal on Screening echocardiogram.
i)
Evidence of significant structural heart disease on echocardiography at 
Screening (including any valvular disease greater than “mild” in severity)
j)
Cardiac troponin > upper limit of the reference range at Screening.
Prior or Concomitant Anti-cancer Therapies
9. Treatment with any local or systemic anti-neoplastic therapy or investigational anti-
cancer agent within 14 days or 4 half-lives, whichever is longer, up to a maximum 
wash-out period of 28 days prior to initiation of study drug administration
EXCEPTION NOTE: Anti-androgen therapies for prostate cancer, such as 
bicalutamide, must be stopped 28 days prior to first dose of GSK3368715. 
Second-line hormone therapies such as enzalutamide or abiraterone should be 
stopped 14 days prior to enrolment. Participants with prostate cancer may remain 
on (i) luteinizing hormone-releasing hormone (LHRH) agonists or antagonists
and/or (ii) low-dose prednisone or prednisolone (up to 10 mg/day).


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Nitrosureas and mitomycin C must be stopped within 42 days prior to first dose of 
GSK3368715.
10. Allogeneic hematopoietic stem-cell transplantation
11. Toxicities from previous anti-cancer therapies have not resolved to baseline or NCI-
Common terminology criteria for adverse events (CTCAE) v5 ≤ Grade 1 (except 
fatigue and alopecia [permissible at any grade] and peripheral neuropathy [which 
must be ≤ Grade 2]) at the time of starting study intervention.


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Prior or Concomitant Therapies:
12. Major surgery (i.e. requiring general anesthesia) within 3 weeks before screening, or 
not fully recovered from major surgery, or major surgery planned during study 
participation
EXCEPTION NOTE: Planned surgical procedures to be conducted under local 
anesthesia are allowed.
13. Prior organ transplantation
14. Current use of a prohibited medication or planned use of any forbidden medications 
during intervention with GSK3368715
15. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
16. Participant is considered high-risk for VTE as defined by either Khorana Score of 3 
(see Appendix 13), or prior medical history of VTE. Note: Participants with Khorana 
score of 2 should be considered for prophylactic anticoagulation per current ASCO 
guidelines (Key, 2019) if deemed appropriate by the investigator. 
5.3.
Lifestyle Restrictions
5.3.1.
Meals and Dietary Restrictions
On serial PK days (Day 1, Day 8 and Day 15), participants should fast from 8 hours prior 
to dose until 2 hours after dose. On all other days, GSK3368715 should be administered 
on an empty stomach at approximately the same time of day (± 4 h), with no food for 1 
hour before and 2 hours after each dose. Requirements for fasting before and after dosing 
may be modified based on available PK, PD and safety data. The exact timing of the 
meals administered will be recorded on serial PK days.
On serial PK days, 8 and 15 and for two days prior to each serial PK day other than Day 
1 (Days 6 and 7 and 13 and 14), participants should attempt to take GSK3368715 within 
a 1 hour window (i.e., 23-25 hours) after the last dose.
Participants will abstain from alcohol, tobacco, caffeine- or xanthine-containing products 
(eg, coffee, tea, cola drinks, and chocolate) for 24 hours before the start of dosing until 
after collection of the final PK and/or PD sample on Day16. In addition, participants 
should also abstain from ingesting these products prior to clinic visits on days scheduled 
for periodic PK and PD sample collection throughout the study. 
Refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice for 
at least 24 hours before the start of study intervention until after the final dose. 
For participants in the food effect sub-study, the administration of GSK3368715 on the 
‘fed’/’fasted’ days will be performed as described in Section 4.1.1.1. For all other days, it
will be administered as described above.


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5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. Rescreened participants should be assigned the same participant 
number as for the initial screening if rescreening for same arm of study. Please refer to 
the Study Reference Manual for more details.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The term ‘study intervention’ is used throughout the protocol to 
describe any combination of products received by the participant as per the protocol 
design.
6.1.
Study Intervention(s) Administered
The participants in each cohort will receive GSK3368715 orally, administered as either a 
capsule or tablet formulation (please refer to Section 1.2 and Section 1.3 for more detail).
During the DLT observation period, participants will only receive capsules, and may 
receive the tablet formulation if the participant continues on treatment at the end of Part 
1.
. 


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Table 7
Study intervention
ARM Name
GSK3368715
Intervention Name
N/A
Type 
Drug
Dose Formulation
1.
API in Hydroxypropyl Methylcellulose (HPMC) Capsule
2.
Immediate release (IR) white film-coated tablet containing API and excipients
Unit Dose Strength(s)
1.
Capsule: 25 mg, 100 mg, 250 mg as free-base drug substance
2.
Tablet: 50 mg, 100 mg and 250 mg as the free-base drug substance
Dosage Level(s)
As required by protocol
Route of Administration
Oral
IMP and NIMP
IMP (GSK3368715)
Sourcing
Provided centrally by the Sponsor 
Packaging and Labelling
Study intervention will be labelled as required as per country requirement
Current/Former Name(s) or Alias(es)
N/A


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6.2.
Dose Modification
Safety management guidelines, including dose modification algorithms, are provided. 
Please note, in cases where the investigator is directed to permanently discontinue study 
intervention, these instructions are mandatory as described in Section 7.
An overview of the available dose modification guidelines is presented in Appendix 12.
All AEs are to be graded according to NCI-CTCAE, version 5. All dose modifications 
and the reason(s) for the dose modification must be documented in the eCRF.
Investigators should refer to the IB for GSK3368715 [GlaxoSmithKline Document 
Number 2017N334333_02] and for additional information regarding the background of 
the drug and the management of other AEs or potential safety-related issues.
In case a dose modification is necessary, the dose level of one or both study interventions 
may be changed as determined by the investigator and sponsor/medical monitor.
6.3.
Method of Intervention Assignment
All screened participants will be identified by a unique participant number that will 
remain consistent for the duration of the study. Upon completion of all of the required 
screening assessments, eligible participants will be registered into the study by the 
investigator or authorized site staff. See SRM for additional information on screening and 
enrollment procedures.
6.4.
Blinding
This is an open-label study.
6.5.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study intervention accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM.


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5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Precaution will be taken to 
avoid direct contact with the study intervention.
6. A Material Safety Data Sheet (MSDS) describing occupational hazards and 
recommended handling precautions will be provided to the investigator. In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact. 
6.6.
Intervention Compliance
At each visit, an evaluation of participant compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant participants 
into compliance.
Compliance with GSK3368715 and other study interventions provided will be assessed 
through querying the participant during the site visits and documented in the source 
documents and eCRF.
A record of the number of GSK3368715 capsules and other study interventions dispensed 
to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop dates, including dates for 
intervention interruptions and/or dose reductions will also be recorded in the eCRF.
6.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives while on study intervention and for 30 days after last dose must be 
recorded in the eCRF along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants should receive full supportive care during the study, including transfusion of 
blood and blood products, and intervention with antibiotics, antiemetics, antidiarrheals, 
and analgesics, as appropriate.
Participants will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study intervention until the end of the study 
(Final Study Visit). 
A complete list of all prior anti-cancer therapies will be recorded in the eCRF.
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. The SRM will be 


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updated to include this information. Any such changes will be communicated to the 
investigative sites in the form of a letter.
The prophylactic use of low molecular weight heparin and oral anticoagulation using 
Factor Xa inhibitors such as Apixaban and Rivaroxaban is allowed on trial. Current 
ASCO 2019 Guidelines (Key, 2019) and the bleeding risk associated with above agents 
should be considered. 
If a participant experiences a VTE and requires therapeutic anticoagulation, treatment 
should be initiated without delay following best medical practice, GSK3368715 should 
be held and the situation should be discussed with the GSK medical monitor (see
Appendix 12, Table 14).
6.7.1.
Prohibited Medications/Therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Radiotherapy (strictly palliative radiotherapy while on study treatment may be 
acceptable if discussed with and approved by the sponsor).

Investigational interventions other than with GSK3368715.

Anticoagulation with oral Vitamin K antagonists such as Warfarin.
6.7.2.
Cautionary Medications
Co-administration of GSK3368715 and substrates of CYP2D6 should be avoided in order 
to prevent inadvertent over-exposure to these agents. GSK3368715 inhibits CYP2D6 in 
vitro (IC50 = 22.6 uM), indicating a potential for interaction between GSK3368715 and 
CYP2D6 substrates. 
No in vitro CYP phenotyping data are available for GSK3368715. In the absence of these 
data, potent inhibitors or inducers of CYP3A4 isoenzymes should not be co-administered 
with GSK3368715. 
6.8.
Intervention After the End of the Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the participant’s medical condition.
Refer to SOA (Section 1.3) for follow-up assessments of participants who are to be 
followed for disease progression and/or survival after they permanently discontinue from 
study intervention.
6.9.
Dose Delay
If there is a dose delay between 1 and 3 days, the procedures at the original scheduled 
visit (including dosing) should be performed as soon as possible. If the delay is >3 days, 
the visit and dose(s) will be considered missed. The procedures at the next scheduled visit 


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should be performed. Participants with dosing delays equivalent to 14 consecutive missed 
doses should discontinue study intervention(s) unless the treating investigator and 
Sponsor agree there is strong evidence supporting continued intervention.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Participants will receive study intervention until one of the following events occur earlier: 
disease progression (as determined by Appendix 10), death or unacceptable toxicity, 
including meeting stopping criteria for liver chemistry or cardiac parameters defined in 
Section 7.1.1 and Section 7.1.2.
7.1.
Discontinuation of Study intervention
In addition to the above, study intervention may be permanently discontinued for any of 
the following reasons:

Deviation(s) from the protocol

Request of the participant or proxy (withdrawal of consent by participant or 
proxy)

Investigator’s discretion

Participant is lost to follow-up

Study is closed or terminated.

Criteria described in Section 6.9 (Dose Delay)

Female participant who becomes pregnant while on study intervention

Criteria for discontinuation of study intervention(s) as described in Section 6.2
(Dose Modification Guidelines) have been met

Criteria described in Section 7.1.2 and Section 7.1.3 (QTc or QRS Stopping 
Criteria and LVEF Stopping Criteria) have been met

Criteria described in Section 7.1.4 (Stopping Rules for Clinical Deterioration)
have been met
If study intervention is permanently discontinued, the participant will remain in the study 
to be evaluated for safety and efficacy. See the SOA for data to be collected at the time of 
discontinuation of study intervention. The assessments required at the TDV should be 
completed within 30 days of the last dose of study intervention(s). The primary reason 
study intervention was permanently discontinued must be documented in the participant’s 
medical records and electronic case report form (eCRF).


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All participants who permanently discontinue study intervention(s) without disease 
progression will be followed for progression according to the protocol schedule until

New anti-cancer therapy is initiated

Disease progression

Death, or

Participant has been followed for 2 years after stopping intervention.
All participants who have disease progression will be followed for survival and new anti-
cancer therapy (including radiotherapy). Survival follow-up will continue from the time 
of study drug discontinuation until the earliest of the following: 1.) death or 2.) a 
maximum time period of 2 years has passed after discontinuing study intervention or 3.) 
study is closed for further follow-up (expected when70% of participants in the last part of 
the study have progressed or died). If participants are unable or unwilling to attend clinic 
visits during follow-up, contact to assess survival may be made via another form of 
communication (e.g., phone, email, etc.).
If the participant voluntarily discontinues from intervention due to toxicity, ‘adverse 
event (AE)’ will be recorded as the primary reason for permanently discontinuation on 
the eCRF.
Once a participant has permanently discontinued from study intervention, the participant
will not be allowed to be retreated.
All participants who discontinue from study intervention will have safety assessments at 
the time of discontinuation and during post-study intervention follow-up as specified in 
Schedule of Activities Table (see Section 1.3).
7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study intervention for abnormal liver tests is required when a 
participant meets the conditions outlined in Figure 3.


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Figure 3
Liver Chemistry Stopping Criteria
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Appendix 6.
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
with study intervention unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for intervention restart/rechallenge is signed by the participant
Refer to Appendix 6 for full guidance.
7.1.2.
QTc Stopping Criteria
For trial eligibility and discontinuation, ideally the same QT correction formula will be 
used for all participants within a single trial. However, GSK does recognize that because 
multiple sites from different countries may participate in a single trial, this may not 
always be possible since QT correction formulae pre-programmed by different 
manufacturers within ECG machines tend to vary. In these situations, the same QT 
correction formula must be used throughout the trial for an individual participant.

QTcF > 500 msec


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OR

Change from baseline of QTc > 60 msec
The QTcF correction formula must be used for each individual participant to determine 
eligibility for and discontinuation from the study. This formula may not be changed or 
substituted once the participant has been enrolled.
The QTc should be based on single or averaged QTcF values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.
See the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.3.
QRS Interval Stopping Criterion
An increase in the QRS interval of > 20 ms from baseline.
7.1.4.
PR Interval Stopping Criteria
An increase in the PR interval to >250 msec in participants without pre-existing AV-
block.
Stopping Rules for Clinical Deterioration
In order to adequately assess the antitumor effect of epigenetic agents, participants 
experiencing apparent progression as defined by RECIST version 1.1 guidelines may 
continue to receive intervention until progression is confirmed at the next imaging 
assessment at least 4 weeks later as indicated by RECIST guidelines. These 
considerations should be balanced by clinical judgment as to whether the participant is 
clinically deteriorating and unlikely to receive benefit from continued study intervention.
Participants who had documented reduction in tumor size or a prolonged period of stable 
disease may be eligible for additional intervention with GSK3368715 at the time of 
relapse/progression if determined to be deriving clinical benefit in the opinion of the 
investigator and with sponsor approval.
In cases where deterioration was assessed in the investigator’s opinion to have occurred
after a clinical event and is attributable to disease progression, is unlikely to reverse with
continued study intervention or managed by supportive care (e.g., bisphosphonates and/or
bone directed radiotherapy, thoracentesis, or paracentesis for accumulating effusions),
study intervention should be discontinued. The decision to stop intervention 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 CNS metastases


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Any setting where the initiation of new antineoplastic therapy has been deemed beneficial 
to the participant even in the absence of any such documented clinical event.
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural, compliance or administrative reasons.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

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.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. Refer to the SoA (Section 1.3) 
for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit 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, 
three 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.
7.4.
Participant and Study Completion
A participant will be considered to have completed the study if they are evaluable with 
regard to the primary endpoint, and are no longer being followed for progression or 
survival. Specifically:


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A participant enrolled in Part 1 will be considered to have completed the
study if they are DLT-evaluable, i.e.:

they complete screening assessments, at least 21 days of study intervention and 
the
post-intervention follow-up visit, or

they discontinue study intervention before Day 21 due to drug related toxicity. 
Participants who discontinue study intervention before day 21 or who received 
less than 75% of the intended dose in the first 21 days for reasons other than study 
drug related toxicity are not considered to have completed the study. 
Participants enrolled in Part 2 will be considered to have completed the study if:

they have completed at least 1 interpretable disease assessment
Participants who do not meet the above criteria and are no longer being followed for 
progression or survival are considered to have discontinued the study. 
The End of Study eCRF should only be completed when a participant is no longer being 
followed. 
The study may be considered completed for purposes of a final analysis when 70% of 
participants enrolled in Part 2 have progressed or died. If available, participants 
continuing on intervention at the time of final analysis may be offered the option to 
continue in a rollover trial.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3 Table 1-Table 
3). A brief description of the assessments is provided below. Further details on important 
assessments and any study-specific equipment are provided in Study Reference Manual.

Protocol waivers or exemptions are not allowed

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and 
was performed within the time frame defined in the SoA.


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
If assessments are scheduled for the same nominal time, then the assessments 
should occur in the following order: 12-lead ECG, vital signs, and blood draws. 
The timing of the assessments should allow the blood draw to occur at the exact 
nominal time.

The timing and number of planned study assessments may be altered during the 
course of the study based on newly available data (e.g., to obtain data closer to
the time of peak plasma concentrations) to ensure appropriate monitoring for the 
following assessments: safety, PK, pharmacodynamics/biomarker, or other 
assessments.

The change in timing or addition of time points for any planned study assessments 
must be approved by the relevant GSK study team member and then archived in 
the study Sponsor and site study files, but this will not constitute a protocol 
amendment.

The institutional review board (IRB)/ independent ethics committee (IEC) will be 
informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the informed consent form.

No more than 500 mL of blood for the purposes of this study, will be collected 
over the first 12 weeks of the study. No more than 120 mL of blood will be 
collected at each dosing visit, thereafter. The total volume will depend on how 
long the participant remains on intervention. There may be additional blood 
collection performed for non-study reasons.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy

Disease assessment modalities may include imaging (e.g., computed 
tomography [CT] scan, magnetic resonance imaging [MRI], bone scan, plain 
radiography) and physical examination (as indicated for palpable/superficial 
lesions).  

The baseline disease assessment will be completed within 4 weeks prior to the 
first dose of GSK3368715, then after 8 weeks of dosing (week 9 day 1) and 
every 8 weeks thereafter until the end of week 32 then every 16 weeks, until 
disease progression.  See the SoA (Section 1.3 Table 2) for the schedule of 
assessments of anticancer activity.  

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.  If the last radiographic assessment was 8 weeks or more
prior to the participant’s withdrawal from study intervention and PD has not 
been documented, a disease assessment should be obtained at the time of 
withdrawal from the study intervention.  

Participants whose disease responds (either complete response [CR] or partial 
response [PR]) should have a confirmatory disease assessment performed at 
least 4 weeks after the date of assessment during which the response was 


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demonstrated. More frequent disease assessments may be performed at the 
discretion of the investigator.

To ensure comparability between the baseline and subsequent assessments, the 
same method of assessment and the same technique will be used when 
assessing response.  
8.1.1.
Evaluation of Anti-Cancer Activity – Participants with Solid 
Tumors
Lesion assessment method and timing, evaluation of disease, disease 
progression and response criteria will be conducted according to RECIST 
(version 1.1) [Eisenhauer, 2009] as outlined below and in Appendix 10 of this 
protocol.
8.1.2.
Evaluation of Anti-Cancer Therapy – Participants with Non-
Hodgkin’s Lymphoma
Response will be assessed by the investigator every 8 weeks, as outlined in the SoA
(Section 1.3 Table 2), using standardized Lugano, as described in Appendix 10.
8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A full physical examination will be done at screening and will include, at a 
minimum, assessments of the Cardiovascular, Respiratory, Gastrointestinal and 
Neurological systems. Height and weight will also be measured and recorded.

A brief physical examination will be done at all other timepoints and will 
include, at a minimum, assessments of the skin, lungs, cardiovascular system, 
and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes rest and 
will include temperature, systolic and diastolic blood pressure, and pulse 
In the case of an abnormal first reading, three readings of blood pressure and/or 
pulse rate must be taken, whereby the first reading should be rejected and the 
second and third averaged to give the measurement to be recorded in the eCRF.

Vital signs will be measured more frequently of warranted by the clinical 
condition of the participant.
On days where vital signs are measured multiple times, temperature does not need 
to be repeated unless clinically indicated.


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If a participant develops a fever, refer to Appendix 12 for management guidelines.
8.2.3.
Electrocardiograms
Triplicate 12-lead ECG will be obtained as outlined in the SoA (Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. Refer to Section 7.1.2 for QTc withdrawal criteria and additional QTc
readings that may be necessary. In cases with equivocal findings a site cardiologist may 
aid in determining eligibility.

At each time point at which triplicate ECG are required, three individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.
8.2.4.
Holter Monitoring
Digital Holter ECG data will be obtained from 12-lead continuous Holter monitoring
device supplied by the Sponsor. ECG acquisition via the Holter monitoring device will be
performed at planned time points indicated in the SoA (Section 1.3) and should be
obtained prior to phlebotomy and vital sign time points.
Analysis of intervals and morphology from the continuous digital ECG data will be
acquired and stored electronically for all on-intervention timepoints. The 24 hour 
screening Holter to determine eligibility will be manually over-read by an external central
validated ECG laboratory. In cases with equivocal findings a site cardiologist may aid in 
determining eligibility.
8.2.5.
Telemetry
To complement real-time ECG assessments, monitoring for potential adverse arrhythmias 
will be conducted utilizing continuous telemetry as outlined in the SOA initially for at 
least 24 hours for the first 10 participants at each dose level > 200mg. If clinically 
indicated, telemetry may be extended past 24 hours. Participating sites will have trained 
staff capable of monitoring and responding in real time to any potential cardiac adverse 
event detected by telemetry. In addition, emergency resuscitation equipment including 
appropriate pharmacological agents will also be immediately accessible.
8.2.6.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 


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intervention should be repeated until the values return to normal or baseline or 
are no longer considered significantly abnormal by the investigator or Medical 
Monitor.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
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.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate
and/or additional blood draws.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs
will be graded by the investigator according to the National Cancer Institute- Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE), (version 5).
DLTs will be listed for each participant and summarized by dose cohort according to 
International Data Standards Library (IDSL) standards.
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 intervention or the 
study, or that caused the participant to discontinue the study intervention(s) (see 
Appendix 3).
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of intervention until the follow-up visit
at the time points specified in the SoA (Section 1.3). However, any SAEs 
assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to 
participate in the study.]


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
All AEs will be collected from the start of intervention until the follow-up visit 
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a participant consents to participate in a 
study up to 90 days after the last dose of study intervention(s). if another anti-
cancer agent is started during this time, SAEs should be recorded until 30 days 
after the last dose, or initiation of other anti-cancer agent (whichever is later). 

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.
8.3.2.
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.
8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3.
8.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met.

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention


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under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e g, summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
8.4.1.
Pregnancy

Details of all pregnancies in female participants will be collected after the start 
of study intervention and until 150 days after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.
Cardiovascular and Death Events
For any cardiovascular events and all deaths, whether or not they are considered SAEs, 
specific Cardiovascular (CV) and Death sections of the CRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
A CV event is defined as:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization 
8.4.3.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease
progression or hospitalization due to disease progression) does not need to be reported as
a SAE.
Death due to disease under study is to be recorded on the death eCRF form. However, if 
the underlying disease (i.e., progression) is greater than that which would normally be 
expected for the participant, or if the investigator considers that there was a causal 
relationship between intervention with study intervention(s) or protocol
design/procedures and the disease progression, then this must be reported as a SAE.
NOTE: If either of the following conditions apply, then the event must be recorded and
reported as a SAE (instead of a disease-related event):

The event is, in the investigator’s opinion, of greater intensity, frequency, or
duration than expected for the individual participant, or

The investigator considers that there is a reasonable possibility that the event was 
related to intervention with study intervention(s).
8.5.
Intervention of Overdose
For this study, any dose of GSK3368715 greater than the daily dose of study intervention
within a 24-hour time period [4 hours] will be considered an overdose.
There is no specific antidote for overdose with GSK3368715. 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.
In the event of an overdose, the investigator (or treating physician) should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3368715 can no longer be detected systemically (at least 28 days).
3. Obtain a plasma sample for PK analysis as soon as possible from the date of the 
last dose of study intervention if requested by the Medical Monitor (determined 
on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the 
overdosing in the CRF.


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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
8.6.
Pharmacokinetics
All participants enrolled in Part 1 (dose escalation/food effect) will receive a single dose 
on Day 1 and then begin continuous dosing after collection of the 72 hour PK sample. 
The timing of the PK samples may be altered and/or additional PK samples may be 
obtained at additional points to ensure thorough monitoring. 
For details of PK sample collection, please refer to Section 1, Table 2.
Day 1: participants will be administered GSK3368715 as a single oral dose followed by a 
72 hour intervention-free period to evaluate PK. PK samples following Day 1 dose will 
be collected at Pre-dose, 15 ± 5 min, 30 ±5 min, 1h ± 5 min, 1.5h ± 5 min, 2h ± 10 min, 
3h ± 10 min, 4h ± 10 min, 6h ± 30 min, 8h ± 30 min, 12 ±2h, 24 ±2h, 48 ± 2h, 72 ± 2 hrs 
post-dose. 
Day 8: PK samples will be collected at Pre-dose, 1.0h± 5 min, and 4h ± 10 min post-
dose.
Day 15: PK samples will be collected at Pre-dose, 30 ±5 min, 1h ± 5 min, 2h ± 10 min, 
3h ± 10 min, 4h ± 10 min, 6h ± 30 min, 8h ± 30 min, 12 ±2h, and 24 ±2h (prior to the 
next dose) post-dose. 
PK samples on other visit days should be collected pre-dose only.  All pre-dose PK 
samples at each visit should be collected within 1 hour prior to dose administration.
For details of PK sample collection for the PK/PD cohort in Part 1, please refer to Section 
1.3, Table 3.
For details of PK sample collection during the food effect cohort in Part 1, please refer to 
Section 1.3, Table 4.
Meal times will be recorded on all PK collection days for Part 1 (dose escalation and 
PK/PD cohort) and on the dosing days (Days 1 and 5) in the food effect cohort.
Whole blood samples of approximately 2 mL will be collected for measurement of 
GSK3368715 and its metabolites as specified in the SoA. Blood may be collected at 
additional time points during the study if warranted and agreed upon between the 
investigator and the sponsor. Instructions for the collection and handling of biological 
samples will be provided by the sponsor. The actual date and time (24-hour clock time) 
of each sample will be recorded. Details of PK blood sample collection, processing, 
storage and shipping, procedures will be provided in study reference manual (SRM). 
Urine samples for quantitative analysis of GSK3368715 will be collected after single 
dose and at steady state. The actual date, time of volume of each urine sample collection 
will be recorded. The urine samples may also be analysed for compound-related 
metabolites and the results will be reported under a separate DMPK protocol.


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Quantitative analysis of GSK3368715 from tumor samples collected pre-dose and on-
intervention from a limited number of participants will be performed as indicated in the 
SoA (Section 1.3).
8.7.
Pharmacodynamics
8.7.1.
Whole Blood
Whole blood samples will be collected for measurement of ADMA-hnRNP-A1 in 
peripheral blood mononuclear cells (PBMCs) and circulating free ADMA, SDMA and/or 
MMA levels in plasma as indicated in the SoA.
8.7.2.
Tumor Biopsy
Tumor samples will be collected pre-dose and on-intervention from a limited number of
participants for measurement of ADMA-hnRNP-A1, gene expression and immune 
markers such as, but not limited to, CD8 as indicated in the SoA (Section 1.3).
8.7.3.
Tumor Biopsy Collection/Surgical Procedures
Biopsies collected during the study will only occur after participant consent and at dose 
levels deemed relevant in terms of safety and efficacy. Suitable participants will be 
identified by investigator and deemed acceptable by Medical Monitor. Fresh pre-
treatment and on intervention biopsies are required for participants in PK/PD cohorts and 
optional for all other participants. During the study, it is expected that fresh biopsies will 
be provided pre-dose (within 14 days of the first dose), and at steady state (anticipated to 
be between Day 15 and Day 20) following GSK3368715 intervention. Additional 
optional timepoints include end of study and remission, especially if there is a question of 
residual viable tumor. No more than 4 fresh biopsies will be collected per participant as 
part of this study. Any fresh on-intervention biopsy should be accompanied by a plasma 
sample for PK analysis collected as close as possible to the time of biopsy (preferably 
within 1 h)
Participants undergoing fresh biopsies must have a platelet count of ≥75,000/mm3 and a 
PT, international normalized ratio (INR) and aPTT that are within normal limits and 
taken within 48 hours prior to the post-dose biopsy or any other planned surgical 
procedure. Further details regarding sample type and processing will be provided in the 
SRM.
8.8.
Genetics
Information regarding genetic research is included in Appendix 5.
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.


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In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
Details on processes for collection and shipment and destruction of these samples can be 
found in SRM.
8.9.
Biomarkers and Translational Research
8.9.1.
Samples
After completion of the clinical trial and/or during the conduct of the study, 
investigations may be performed on samples collected during the trial to detect factors or 
profiles that correlate with response to intervention with GSK3368715. Performance of 
these investigations may be conditional on the results of the clinical trial and samples will 
be selected for analysis on the basis of the clinical outcome.
Samples may be tested for immunophenotyping to evaluate the association with efficacy 
in response to intervention with GSK3368715. Additionally, comparative examination of 
post-dosing profiles in conjunction with pre-dosing profiles may yield known and novel 
candidate biomarkers/profiles and new insights which relate to the action of 
GSK3368715.
All samples will be retained for the length of time described in participant ICFs after the 
last participant completes the trial.
Novel candidate biomarkers and subsequently discovered biomarkers of biological 
response associated with lymphoma and solid tumors and/or the action of GSK3368715 
may be identified by application of:

DNA, RNA and protein analysis of tumor tissue.

DNA, RNA and protein analysis of PBMCs.

Circulating protein analysis of plasma.

Immunophenotyping of PBMCs and/or tumor tissues.

Coagulation markers from plasma and serum samples
Blood samples will be collected according to the SoA (Section 1.3). One or more 
timepoints could be removed with emerging data. 
8.9.2.
Exploratory Tumor Biomarker Analysis
To further characterize the participant population, DNA, RNA and/or protein 
measurements may be utilized to identify predictors of sensitivity or resistance to 
GSK3368715 utilizing baseline tissue (archival tissue or a recent biopsy) and in tissue 
obtained at disease progression.


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8.9.3.
Circulating Protein Analysis
Blood-based markers have the important advantage that specimens are readily available, 
simple to prepare and store, and can be obtained prior to and during intervention. This
allows for the assessment of predictive markers based on the baseline evaluation as well 
as markers of activity and resistance based on changes that occur during and/or after 
intervention. Additionally, levels of protein in plasma samples may be analyzed to better 
understand modulation of secretory proteins from the tumor or the immune system in 
response to intervention with GSK3368715 and how this correlates with efficacy. For 
instance, plasma samples collected at the time points provided in the SoA may be 
analyzed for Interferon gamma (IFN-gamma) and Tumor Necrosis Factor (TNF-alpha) 
signatures by investigating a panel of pro-inflammatory cytokines, immuno-regulatory 
factors and chemokines.
8.9.4.
MTAP testing
A requirement for inclusion in the study is the availability of archival tumor tissue, or 
willingness to undergo a fresh biopsy to determine MTAP status.
In part 1, MTAP testing will be performed retrospectively.
In Part 2, prospective MTAP testing is required to confirm MTAP deficiency for 
enrolment unless local MTAP or CDKN2A results are available. In this latter situation, 
central MTAP testing will be used to confirm MTAP deficiency.
Additionally, SDMA IHC may be conducted to correlate MTAP expression level and 
SDMA level with response.
Screen failure tissue, used for central testing will be retained. This tissue may be used in 
the validation of potential diagnostic assays to detect MTAP.
8.9.5.
Coagulation markers
Markers of hemostasis will be assessed and monitored over time to better understand the 
potential mechanism leading to venous thromboembolic (VTE) events. Analytes of 
interest may include, but not limited to, D-dimer, fibrinogen, soluble P-selectin and 
several factors from the extrinsic and intrinsic coagulation pathways, such as factors II, 
V, VII, VIII, IX, X, XI and XI and von Willebrand Factor..
8.10.
Patient Reported Outcomes (PRO)
8.10.1.
Qualitative Telephone Interviews
To further evaluate disease and intervention related symptoms and associated impacts on 
function and health-related quality of life, participants in Part 2 only, will participate in a 
qualitative interview conducted via telephone. The interview will be conducted by a 
trained interviewer in the participant’s native language and will be audio recorded for 
transcription and analysis.


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The telephone interview is to be completed within 21 days following completion of the 
week 8 disease assessment and following the intervention discontinuation visit in Part 2
of the study. Participants who have the intervention discontinuation visit (TDV) within 
30 days of the week 8 interview are not required to repeat the interview.
9.
STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
9.1.1.
Dose Escalation
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested in Part 1. The primary focus will be on determining the RP2D for further 
exploration, based upon the safety, PK, food effect on PK and efficacy profiles of 
GSK3368715.
9.1.2.
Dose Expansion
The primary goal of Part 2 is to evaluate clinical activity in each disease specific cohort 
for GSK3368715 for MTAP- subgroup and MTAP+ subgroup separately.
All evaluations in Part 2 are designed to exclude a 10% response rate representing best 
available therapy in favour of a 30% response rate.
9.2.
Sample Size Determination
The sample size for each part of the trial was chosen to adequately characterize the 
safety, clinical activity, PK, and pharmacodynamic marker data based on the objectives 
of each part of the study.
Part 1 will enroll approximately 60 participants. Dose escalation and de-escalation 
decisions will be guided by an N-CRM model. In Part 1 where an N-CRM design is 
utilized it is assumed that approximately 50 participants will complete the DLT 
evaluation period. Approximately 10 participants will be enrolled at a dose or doses near 
the MTD/RP2D in each PK/PD/Biomarker cohort. At least twelve (12) participants will 
be enrolled in the food effect sub cohort as per the minimum sample size 
recommendation from FDA food effect guidance.  For both Cmax and AUClast, a total 
sample size of 12 patients achieves 80% power at a 10% significance level when the 
actual ratio of the means in the presence or absence of food is 1.0, if the coefficient of 
variation (COV) on the original, unlogged scale is 0.206, and the equivalence limits of 
the mean ratio are 0.80 and 1.25; if the COV on the original, unlogged scale is 0.334, the 
equivalence limits of the mean ratio will be 0.70 and 1.428 to achieve the same level of 
power.
In Part 2, a maximum of 36 participants will be enrolled in the DLBCL cohort and up to 
35 participants will be enrolled in each of the solid tumor cohorts. If all cohorts enroll the 
maximum number of participants, this will result in 141 participants in total.


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Additional tumor-specific cohort(s) and combinations may be added by protocol 
amendment, based upon emerging pre-clinical data, or clinical data from the dose-
escalation portion of the study.
9.2.1.
Dose Escalation
N-CRM design is a type of Bayesian adaptive dose-escalation approach. The design 
classifies the DLT rate into four categories and makes dose recommendations based on 
posterior distribution of the four categories:

Under-dosing: DLT rate<16%

Target toxicity: 16%<=DLT rate<33%

Excessive toxicity: 33%<=DLT rate<60%

Unacceptable toxicity: DLT rate>=60%
At the end of DLT observation period for each dose level, the posterior distribution of 
DLT rate will be summarized by the posterior probability of the DLT rate falling into the 
interval of under-dosing, target toxicity, excessive toxicity, and unacceptable toxicity 
respectively. The recommended dose is the one that maximizes the probability of target 
toxicity while controlling the probability of excessive or unacceptable toxicity no more 
than 25%.
9.2.1.1.
Operating characteristics of the safety stopping rule for VTE events in 
dose escalation
Simulations were used to evaluate the design performance of the safety stopping rules 
planned for the safety evaluation of VTE events during the dose escalation phase (Part 1)
of this study. In these simulations, we simulate 100,000 independent trials and evaluate 
the performance of the model on average. In each simulation, a cohort is enrolled until
either 2 or more VTE events have been observed among 6 or fewer participants or 3 or 
more VTE events have been observed among 7-10 participants. 
Table 8 details the scenarios evaluated as well as the average number of participants 
dosed in each cohort, and the percentage of simulated trials that completed that dose 
level. Figure 4 graphically represents the operating characteristics of the safety stopping 
rules for each cohort. Each line of the plot represents a different true VTE incidence rate
detailed in Table 8. The scenarios considered a range from a true VTE incidence rate of 
5% to a true VTE incidence rate of 30%. Note that these simulations only take VTE 
events into consideration, and this VTE safety stopping rule will be evaluated in addition 
to the traditional DLT rules within the dose escalation framework detailed in Section 
4.1.1.
In low VTE incidence scenarios, the cohorts are more likely to fully recruit without 
stopping early for safety evaluation of the VTE rate.  For example, if the true population 
VTE incidence rate is 5%, only 3.8% of the simulations stopped early for safety, 
however, if the true population VTE incidence rate is 30%, 69.5% of our simulations 
stopped early for safety.


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Table 8
Simulation scenarios and probability of stopping for VTE safety 
stopping rule across various true VTE incidence rates
True VTE incidence
% of trials that stopped early for safety
5%
3.8
10%
13.6
15%
26.9
20%
42.1
25%
56.8
30%
69.5
Figure 4
Operating characteristics for the VTE safety stopping criteria
9.2.2.
Dose Expansion
Part 2A DLBCL Cohort
ORR will be analyzed using a Bayesian hierarchical model that allows information 
borrowing between MTAP proficient and MTAP deficient subgroups within the DLBLC
cohort. An MTAP defined subgroup will be considered as effective at the end of study if 
the posterior probability of ORR>10% is more than 85%. In this design, up to 30 
participants will be enrolled into each MTAP defined subgroup and up to 36 will be 


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enrolled for the entire cohort. The simulation results assuming 50:50 ratio between 
MTAP proficient participants and MTAP deficient participants are displayed in Table 9. 
Assume πg = Pr(response | intervention, group g) denote the probability of response for 
group g participants, where group g represents MTAP proficient subgroup or MTAP 
deficient subgroup, and π = Pr(response | intervention) denote the probability of response 
for the entire cohort. Let 
be the logit of the group g response rate, 
be 
the logit of the cohort response rate, i.e.,
and
The hierarchical model assumes 
), 
The prior distributions for 
are defined as follows: 
,
,
).
where IG(α, β) is the inverse gamma distribution defined by:
These choices of 
and 
correspond to a mean weight parameterization with mean 6.9 
and weight 2. The prior for 
centers the response rate at 10% (the assumed 
underlying control rate).


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Table 9
Design Characteristics for Bayesian Hierarchical Design for Part 2A 
DLBCL Cohorts
Scenarios for ORR
Proportion of MTAP- group meeting 
success criteria
Proportion of MTAP+ group 
meeting success criteria
0.3 in MTAP-;
0.3 in MTAP+
81.3%
81.7%
0.1 in MTAP-;
0.1 in MTAP+
8.3%
8.2%
0.3 in MTAP-;
0.1 in MTAP+
80.4%
10.3%
*The results are based on 5000 simulations with interim futility analysis starting after at least five
participants in each subgroup and being done every 12 weeks.
Part 2B Solid Tumor Cohorts
The primary endpoint of ORR will be assessed for each of the two MTAP defined 
subgroups (MTAP proficient and MTAP deficient) within each of the three solid tumor
cohorts in Part 2B. The primary analysis of ORR for each tumor cohort and MTAP 
defined subgroup is based on a Bayesian hierarchical model. The Bayesian hierarchical 
model will allow information borrowing across the three different cohorts as well as 
between MTAP proficient and MTAP deficient subgroups. The models focuses more on 
the MTAP- subgroups than MTAP+ subgroups. It borrows more across MTAP-
subgroups compared to MTAP+ subgroups when treatment works across MTAP-
subgroups and MTAP+ subgroups. An MTAP defined subgroup within one cohort will
be considered as effective at the end of study if the posterior probability of ORR>10% is 
more than 94%. Up to 35 participants will be enrolled into one disease specific cohort.
The simulation results under the scenario of 50:50 ratio between MTAP proficient 
participants and MTAP deficient participants are displayed in Table 10. The design has 
been simulated under nine scenarios for the true distribution of ORR effects across tumor 
cohort and MTAP defined subgroups. The probability of declaring effective for each 
subgroup within each disease specific cohort is provided. Additionally, the proportion of 
trials that correctly detect all effective subgroups (ignoring the design decisions for any 
ineffective subgroups) is provided.
Table 10
Design Characteristics for Bayesian Hierarchical Design for Part 2B
Solid Tumor Cohorts
Pancreatic
NSCLC
Bladder
ORR in truth
MTAP-
MTAP+
MTAP-
MTAP+
MTAP-
MTAP+
All Null
10%
10%
10%
10%
10%
10%
All effective
30%
30%
30%
30%
30%
30%
2 Eff in all comers
30%
30%
30%
30%
10%
10%
1 Eff in all comers
30%
30%
10%
10%
10%
10%
All Eff in MTAP-
30%
10%
30%
10%
30%
10%
2 Eff in MTAP-
30%
10%
30%
10%
10%
10%
1 Eff in MTAP-
30%
10%
10%
10%
10%
10%
1 Eff in all comers, 2 Eff in MTAP-
30%
30%
30%
10%
30%
10%
1 Eff in all comers, 1 Eff in MTAP-
30%
30%
30%
10%
10%
10%


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Pancreatic
NSCLC
Bladder
Proportion of trials declaring efficacy
(Power or Type I error)
All Null
0.015
0.021
0.025
0.031
0.023
0.031
All effective
0.904
0.838
0.914
0.831
0.913
0.831
2 Eff in all comers
0.817
0.758
0.812
0.783
0.117
0.074
1 Eff in all comers
0.631
0.688
0.066
0.051
0.068
0.055
All Eff in MTAP-
0.903
0.032
0.890
0.026
0.890
0.033
2 Eff in MTAP-
0.737
0.028
0.738
0.042
0.209
0.022
1 Eff in MTAP-
0.571
0.047
0.093
0.016
0.090
0.021
1 Eff in all comers, 2 Eff in MTAP-
0.934
0.595
0.851
0.067
0.857
0.072
1 Eff in all comers, 1 Eff in MTAP-
0.842
0.639
0.730
0.090
0.184
0.040
Proportion of trials picking all the effective subgroups correctly
All Null
NA
All effective
0.535
2 Eff in all comers
0.472
1 Eff in all comers
0.459
All Eff in MTAP-
0.777
2 Eff in MTAP-
0.614
1 Eff in MTAP-
0.571
1 Eff in all comers, 2 Eff in MTAP-
0.435
1 Eff in all comers, 1 Eff in MTAP-
0.440
9.2.3.
Sample Size Sensitivity
No analysis of sample size sensitivity was performed.
9.2.4.
Sample Size Re-estimation or Adjustment
Sample size re-estimation is not planned for this study.
9.3.
Analysis Populations
The All-Treated Population is defined as all participants who receive at least one dose 
of GSK3368715.
All Evaluable Population is defined as the study population used for decision-making at 
the interim futility analysis. Participants who have had Week 24 disease assessments, 
have progressed or died, or permanently discontinued from the study intervention will be 
included in this population.
The PK Population will consist of all participants from the All-Treated Population for 
whom a PK sample is obtained and analyzed.
Additional analysis populations may be defined in the Reporting and Analysis Plan 
(RAP).


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9.4.
Interim Analysis
9.4.1.
Dose escalation and safety analyses
The primary driver for the dose-escalation decision(s) will be safety and tolerability of 
each dose cohort.
For Part 1 dose escalation and de-escalation decisions will be guided by an N-CRM 
model. Predicted DLT rates will be provided with the aim of escalating to doses with 
small probability of excessive or unacceptable toxicity.
Further details regarding such analyses will be provided in the Reporting and Analysis 
Plan (RAP).
9.4.2.
Dose Expansion Cohorts
9.4.2.1.
Efficacy Analyses
Part 2A DLBCL Cohort
For Part 2A DLBCL cohort, the first interim analysis will be performed when at least 10 
participants become evaluable in each of the MTAP defined subgroup. Data from both 
subgroups will be included in the analysis to form the Bayesian hierarchical model. For 
each MTAP defined subgroup, the therapeutic effect will be declared insufficient and 
enrolment will be terminated if the posterior probability of ORR > 10% is sufficiently 
low (<20%) based on the hierarchical model. The interim futility analysis will be 
performed every 2-3 months depending on enrolment rate with minimum of additional 
five evaluable participants for the cohort. If only one subgroup is stopped early due to 
futility, the other subgroup will continue enrolment with the constraint of maximum of 30 
participants for one subgroup and maximum of 36 participants for the entire cohort.
Part 2B Solid Tumor Cohorts
For Part 2B solid tumor cohorts, the first interim futility analysis will be performed when 
at least five participants become evaluable from MTAP proficient subgroup within any 
cohort. Data from all three cohorts will be included in the analysis to form the Bayesian 
hierarchical model.
For each MTAP+ subgroup within an individual expansion cohort, the therapeutic effect 
will be declared insufficient and enrolment will be terminated to MTAP+ participants if 
there are at least 5 MTAP+ participants within that cohort and the posterior probability of 
ORR > 10% is sufficiently low (<20%) based on the hierarchical model. That is,
P (πj,MTAP+> 10% | current data) < 20%, for the j-th cohort
For each individual expansion cohort, the therapeutic effect will be declared insufficient 
and enrolment will be terminated to all participants (regardless of MTAP status) if at least 
5 MTAP+ and 5 MTAP- participants within that cohort have ORR data and the posterior 


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probability that the ORR is greater than 10% is sufficiently low (<20%) based on the 
hierarchical model. That is,
P (πj,MTAP+> 10% | current data) < 20%, for the j-th cohort AND
P (πj,MTAP-> 10% | current data) < 20%, for the j-th cohort
The interim futility analysis will be performed every 2-3 months depending on enrolment
with minimum additional five evaluable participants across all cohorts.
All evaluable population will be used for the interim futility analyses. Within each 
design, the cohort/subgroup may be stopped early for futility but not for efficacy.
The final decision to close a cohort or the study based on futility will be made by the 
Sponsor, taking into consideration the results of the futility analyses and the entirety of 
the available data. 
9.5.
Final Analysis
The final analyses will be conducted when the study is completed. Data from the dose 
escalation and expansion cohort will be combined as appropriate.
9.6.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and clinical study report.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of intervention and duration of follow-up.
Demographic and baseline characteristics will be summarized.
Unless otherwise specified, Part 1 will be summarized by dose, Part 2 will be 
summarized by disease type and MTAP status if applicable. Participants enrolled in Part 
1 dose escalation and treated at expansion cohort dose will be included in the analysis for 
Part 2 provided that the participant has the same tumor type as the expansion cohort.
9.6.1.
Efficacy Analyses
Anti-tumor activities will be evaluated based on the response criteria specific to the 
disease type.
Primary Efficacy Endpoint - ORR
The overall response (ORR) rate is defined as

Solid tumor: the percentage of participants with a confirmed complete response 
(CR) or a partial response at any time as per RECIST 1.1 (Appendix 10).


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
DLBCL: the percentage of participants with a confirmed complete response (CR) 
or a partial response (PR) based on Lugano Criteria (See Appendix 10).
Participants with unknown or missing response will be treated as non-responders, i.e. 
these participants will be included in the denominator when calculating the percentage. 
The analysis of ORR will only be performed for participants with measurable disease. 
The estimate of ORR along with 95% exact confidence interval (CI) will be provided.
The interim futility analyses for the dose expansion cohorts will be based on the All 
Evaluable population and final efficacy analysis will be based on the All-Treated 
Population.
Progression-Free Survival (PFS) is defined as the time from the first dose of study 
intervention to disease progression or death due to any cause, whichever occurs earlier. 
Participants who have not progressed or died at the time of the PFS analysis, will be 
censored at the date of last adequate disease assessment. In addition, participants with an 
extended time without adequate assessment or who start a new anti-cancer therapy prior 
to a PFS event will be censored at the date of last adequate disease assessment (e.g. 
assessment where visit level response is CR, PR, or stable disease [SD]) prior to the 
extended time without adequate assessment or initiation of new anti-cancer therapy, 
respectively. Further details on rules for censoring will be provided in the RAP. PFS will 
be summarized in Part 2 using Kaplan-Meier quantile estimates along with 95% CIs, if 
data warrant.
Duration of Response (DOR) is defined as the time from the onset of response to
disease progression or death due to any cause, whichever occurs earlier in participants 
who have achieved a response of CR or PR. The same censoring rules as for PFS will be 
used. DOR will be summarized in Part 2 using Kaplan-Meier quantile estimates along 
with 95% CIs, if data warrant.
Time to Response (TTR) is defined as the time from first dose to first evidence of 
response for participants achieving a CR or PR. If data warrant, TTR will be summarized 
descriptively using median and quartiles.
Overall Survival (OS), is defined as the time from the first dose of study intervention to 
the death due to any cause. Participants who’re alive at the time of OS analysis will be 
censored at the last date of known contact. If data warrant, OS will be summarized in Part 
2 using Kaplan-Meier quantile estimates along with 95% CIs, if data warrant.
9.6.2.
Safety Analyses
The All-Treated Population will be used for the analysis of safety data.
9.6.2.1.
Extent of exposure
The intervention exposure will be summarized with intervention duration and dose 
intensity (daily dose for oral daily dosing) as well as the dose modifications including 
dose reductions, dose interruptions/delays and dose escalations. Details will be specified 
in the RAP.


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9.6.2.2.
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 v5.
Events will be summarized with frequency and percentage by preferred term. Separate 
summaries will be provided for all AEs regardless of grade, intervention-related AEs, 
intervention-related AEs by maximum grade, serious adverse events (SAEs), 
intervention-related SAEs, AEs leading to discontinuation of study intervention, AEs 
leading to dose reductions and AEs leading to dose interruptions/delays. Details will be 
provided in the RAP.
DLTs will be listed and summarized by dose cohort for Part 1.
The incidence of deaths and the primary cause of death will be summarized.
9.6.2.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v5. Laboratory test results that do not have an 
associated NCI-CTCAE criterion will be summarized based on normal ranges. 
Summaries by visit will include data from scheduled assessments only, and all data will 
be reported according to the nominal visit date for which it was recorded (i.e., no visit 
windows will be applied). Unscheduled data will be included in ‘worse case post-
baseline’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study intervention. Further details will be 
provided in the RAP.
9.6.2.4.
Other Safety Measures
Data for vital signs, ECGs, and ECHOs and/or MUGA scans will be summarized based 
on predetermined criteria identified to be of potential clinical concern. Further details will 
be provided in the RAP.
9.6.3.
Pharmacokinetic Analyses
9.6.3.1.
Pharmacokinetic Parameters
Pharmacokinetic (PK) analysis of GSK3368715 (and its metabolite[s]), concentration-
time data will be conducted by non-compartmental methods under the direction of 
CPMS, CPEM, GSK. Calculations will be based on the actual sampling times recorded 
during the study. The following PK parameters will be determined if data permit:

maximum observed plasma concentration (Cmax)

time to Cmax (tmax)

area under the curve over a dosing interval (AUC(0-t), AUC(0-∞) and AUC(0-τ)

trough concentration (Cτ)


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
Time invariance (TI) and accumulation ratio (AR) as calculated by the following 
equations:
9.6.3.2.
Statistical analysis of Pharmacokinetic data
GSK3368715 plasma concentration-time data will be listed for each participant and 
summarized using descriptive statistics (n, mean, SD, median, minimum and maximum) 
by planned relative assessment time. PK parameters will be summarized using mean, 
standard deviation, median, minimum, maximum, and the standard deviation and 
geometric mean of log-transformed parameters.
Cmax and AUC (AUC(0-∞), single dose; and AUC(0-), steady state) will be plotted as a 
function of the dose administered. If more than 2 dose cohorts are required to reach MTD 
(or the recommended dose based on available safety, PK and response data), dose 
proportionality of AUC and Cmax for GSK3368715 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.
A nonlinear mixed effects model may be used to determine population pharmacokinetic 
parameters and identify important covariates (e.g., age, weight, or disease related 
covariates) and for PK/PD analysis. Further details of population PK and PK/PD analysis 
will be described in the separate RAP; results of such an analysis may be included in a 
report separate from the clinical study report.
9.6.3.2.1.
Food Effect Sub-Study
Pharmacokinetic (PK) parameters AUC(0-∞), AUC(0-t) and Cmax will be log-
transformed and analyzed separately using a mixed-effects model with fixed-effect term 
for fed status (fed or fasted), and participant as a random effect. Point estimates and their 
associated 90% CIs will be constructed for the differences between fed and in fasted 
state. The point estimates and their associated 90% CIs will be then back transformed to 
provide point estimates and 90% CIs for the ratios of fed/fasted. Non-parametric methods 
such as the


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Hodges and Lehmann estimator will be used to estimate the median differences between
the fed treatments and the fasted state treatments for tmax and t½. An associated 90% CI
for the median differences will be constructed.
Based on the US FDA guidance on food-effect bioavailability studies, the absence of a
food-effect will be established if the 90% CI of the ratio for Cmax and AUC, based on
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on
the clinical significance of the effect of food will be based on the magnitude of the
change and our understanding of the exposure-clinical response relationship. For the 
evaluation of food effect, tmax at fed and fasted status will be presented by participant
and dose cohort in tabular and graphical form.
9.6.4.
Pharmacokinetic/Pharmacodynamic Analyses
Observed or predicted concentrations will be combined with safety, efficacy, and other 
pharmacodynamic measures of interest to examine potential exposure response 
relationships.
Other quantitative safety parameters and biomarkers of interest will be plotted 
graphically against summary exposure measures (e.g., Cmax, Cτ, and Cav). Where 
evidence of a signal is seen, linear and non-linear mixed effect models will be fitted to 
the data to estimate PK/PD parameters of interest; slope, baseline (E0), concentration for 
50% of maximum effect (EC50) and maximum effect (Emax).
9.6.5.
Other Analyses
9.6.5.1.
Translational Research Analyses
The results of translational research investigations will be reported separately from the 
main clinical study report (CSR). All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data.
Further details on the translational research analyses will be addressed in the translational 
research RAP.
9.6.5.2.
Pharmacogenetic Analyses
Further details on pharmacogenetic (PGx) analyses will be addressed in the PGx RAP.


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10.
APPENDICES
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.


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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.1.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.


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10.1.5.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
10.1.6.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the CSR. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have 
the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
10.1.7.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 


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handling of noncompliance issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
clinical study report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.
10.1.8.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in SRM.


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10.1.9.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 11 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention 
Table 11
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline 
phosphatase
Albumin
Lipase
Amylase
Coagulation
PTT, PT/INR
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests

Highly sensitive serum or urine Beta human chorionic gonadotropin (βhCG)
pregnancy test (as needed for women of childbearing potential)2

Serology (HIV antibody, HBsAg, and hepatitis C virus antibody)

Cardiac Troponin I or TroponinT (local standard, no point-of-care assay)
The results of each test must be entered into the CRF.


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Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase;  βhCG = beta-human chorionic 
gonadotropin; BUN = blood urea nitrogen; HBsAg = Hepatitis B surface antigen; MCH = mean corpuscle 
haemoglobin; MCV = mean corpuscle volume; RBC = red blood cells; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cells
NOTES :
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring event are given in Section 7.1 and Appendix 7 All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if 
INR measured, which may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or 
IRB/IEC.


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


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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.
10.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention 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” ocurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective intervention 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 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.


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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 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV Event page of the CRF for the 
following AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism

Revascularization
10.3.4.
Recording AE and SAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK /AE/SAE CRF page.


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There may be instances when copies of medical records for certain cases are requested by 
GSK. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important that 
the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.


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The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator may 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 24 hours of receipt of 
the information.
10.3.5.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool.
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool as outlined in the SRM in order to report the event within 24 hours. The 
site will enter the SAE data into the electronic system as soon as it becomes available.
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information to the medical monitor by telephone.
Contacts for SAE reporting can be found in the SRM.


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


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10.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
10.4.1.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
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 enrolment.
10.4.2.
Contraception Guidance
Male participants
Male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following while on study intervention
and for 100 days after the last dose

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long-term and persistent basis) and agree to
remain abstinent.

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described below when having 
penile-vaginal intercourse with a woman of childbearing potential.


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Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration while on study intervention and for 100 days after the last 
dose

In addition male participants must refrain from donating sperm for duration of 
study and for 100 days after 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 
the Table below.
Highly Effective Contraceptive Methods
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)c
Bilateral tubal occlusion
Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable
Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant


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Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)
Pregnancy Testing
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test
Additional pregnancy testing should be performed at monthly intervals during the 
intervention period and at 150 days after the last dose of study intervention and as 
required locally.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
10.4.3.
Collection of Pregnancy Information
Male participants with partners who become pregnant
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating in 
this study. This applies only to participants who receive study intervention.
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to GSK within 24 hours of learning of the partner’s pregnancy.
Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to GSK
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.
Female Participants who become pregnant
Investigator will collect pregnancy information on any female participant, who becomes 
pregnant while participating in this study.
Information will be recorded on the appropriate form and submitted to GSK within 24 
hours of learning of a participant's pregnancy.
Participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
GSK Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date.


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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 intervention by the investigator, will be reported to GSK as described 
in Appendix 3. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating will discontinue study 
intervention


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10.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA
Genetic variation may impact a participant’s response to therapy, susceptibility, severity 
and progression of disease. 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
DNA samples will be used for research related to GSK3368715 or advanced solid tumors 
or DLBCL and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to GSK3368715 or study interventions of this drug class, and 
advanced solid tumors or DLBCL Genetic research may consist of the analysis of one or 
more candidate genes or the analysis of genetic markers throughout the genome [or 
analysis of the entire genome] (as appropriate)
DNA samples will be analyzed if it is hypothesized that this may help further understand 
the clinical data.
DNA samples will be analyzed by using appropriate descriptive and/or statistical analysis 
methods. A detailed description of any planned analyses will be documented in a RAP 
prior to initiation of the analysis. The samples may be analyzed as part of a multi-study 
assessment of genetic factors involved in the response to GSK3368715 or study 
interventions of this class. The results of genetic analyses may be reported in the CSR or 
in a separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
The samples will be retained while research on GSK3368715 (or study interventions of 
this class) or advanced solid tumors or DLBCL continues but no longer than 15 years 
after the last participant last visit or other period as per local requirements.


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10.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments and Study intervention Rechallenge 
Guidelines
Phase I liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
Participant with entry criteria ALT≤ 2.5 x ULN
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Liver Chemistry Stopping Criteria – Liver Stopping Event
Including participants with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN
ALT-absolute
Both ALT 5xULN and 2x baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
Both ALT 3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity


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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study intervention

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge participant with 
study intervention unless allowed per 
protocol and GSK Medical Governance 
approval is granted (refer to Appendix 6) 

If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study intervention and may 
continue participant in the study for any 
protocol specified follow up assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
96 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Viral hepatitis serology4

Only in those with underlying chronic hepatitis B at 
study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody5.

Blood sample for pharmacokinetic (PK) analysis, 
obtained 24-72h 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 
liver injury in participants with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). NOTE: not required in China

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.


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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study intervention for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.  


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Phase I Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Participant with entry criteria ALT≤2.5x ULN
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks
Participant with documented liver 
metastases/tumor infiltration at baseline
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant safety. 

Participant can continue study intervention  

Participant must return weekly for repeat liver chemistries 
(ALT, AST, alkaline phosphatase, bilirubin) until they 
resolve, stabilise or return to within baseline 

If at any time participant meets the liver chemistry stopping 
criteria, proceed as described above
For participants with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin 
<2xULN, monitor participants twice monthly until liver 
chemistries normalize or return to within baseline.
For participants with documented liver metastases/tumor 
infiltration at baseline AND entry criteria ALT>2.5 x ULN 
but ≤5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and <1.5x 
baseline value, and bilirubin <2xULN, monitor participants 
twice monthly until liver chemistries normalize or return to 
within baseline
References
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.
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.


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10.7.
Appendix 7: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting
There are no medical devices used in this protocol.


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10.8.
Appendix 8 Country Specific Requirements
No country specific requirements are required.


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10.9.
Appendix 9: Abbreviations and Trademarks
ADMA
Asymmetric dimethylation of arginine
AE(s)
Adverse Event(s)
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferease
AML
Acute Myeloid Leukemia
AST
Aspartate Aminotransferase
AUC
Area under the concentration-time curve 
BSC
Best Supportive Care
CDKN2A
Cyclin Dependent Kinase Inhibitor 2A
CI
Confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CNS
Central nervous system
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete Response
CRF
Case report form
CSR
Clinical Study Report
Ctau
Trough concentration
CT
Computerized Axial Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variance
CYP
Cytochrome
DCSI
Development core safety information
DEC
Dose Escalation Committee
DLBCL
Diffuse large B-cell lymphoma
DOR
Duration of response
DRE
Disease-related events
DILI
Drug Induced Liver Injury
DLT
Dose-Limiting Toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG(s)
Electrocardiogram(s)
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of Treatment
FACTS
Fixed and Adaptive Clinical Trial Simulator 
FTIH
First Time In Humans
GALT
Galactose-1-phosphate uridylyltransferase
GCP
Good Clinical Practice
GI
Gastrointestinal


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GLP
Good Laboratory Practices
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus 
HCV
Hepatitis C Virus
Hgb
Hemoglobin 
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HIPPA
Health Insurance Portability and Accountability Act
HLA
Human Leukocyte Antigen 
HNSTD
Highest Non- Severely Toxic Dose
HPLC
High-Performance Liquid Chromatography
HRT
Hormone Replacement Therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IDSL
International Data Standards
IEC
Independent Ethics Committee
IFN
Interferon
IND
Investigational New Drug
INR
International Normalization Ratio
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous 
Ka
Absorption rate
kg
Kilogram
L
Liter
LFTs
Liver Function Tests
LHRH
Leutinizing hormone- releasing hormone
LLN
Lower Limit of Normal
ln
Naperian (natural) logarithm
LSLV
Last Participant’s Last Visit
LVEF 
Left Ventricular Ejection Fraction
uM 
Micromole
MABEL
Minimum Anticipated Biological Effect Level
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MMA
Monomethylarginine
MPV
Mean Platelet Volume
MRI
Magnetic Resonance Imaging 


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MSDS
Material Safety Data Sheet
msec
Milliseconds
MTA
2-methylthioadenosine
MTAP
Methylthioadenosine phosphorylase
MTD
Maximum Tolerated Dose
MUGA
Multigated (radionuclide) angiogram
NCAS
Non-clinical assessment of safety
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for 
Adverse Events
N-CRM
The Neuenschwander -Continuous Reassessment Method 
ng
Nanogram 
NHL
Non-Hodgkins Lymphoma
nM
Nanomole
NOAEL
No Observed Adverse Effect Level
NSCLC
Non-small Cell Lung Cancer
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PBMC
Peripheral Blood Mononuclear Cells
PCI
Potential Clinical Importance
PCR
Polymerase Chain Reaction 
PD
Progressive Disease or Pharmacodynamic
PFS
Progression Free Survival
PI
Principal Investigator 
PK
Pharmacokinetic
PR
Partial Response
PRMT
Protein Arginine Methyl Transferase
PRO
Patient Reported Outcomes
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 Dose
QTc
Corrected QT interval duration
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RBC
Red Blood Cells
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event(s)
SAM
S-adenosyl methionine
SD
Standard Deviation 
SDMA
Symmetric dimethylated arginine
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected unexpected serious adverse reactions
TCC
Transitional Cell Carcinoma


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TCR
T-cell Receptor
TDV
Treatment (Intervention) Discontinuation Visit
Tmax
Time to reach maximum concentration
TNF
Tumor Necrosis Factor
TTR
Time to Reponse
ULN
Upper Limit of Normal
US/USA
United States/United States of America
VTE
Venous thromboembolism
WBC
White Blood Cells
WHO
World Health Organization
WOCPB
Woman of Childbearing Potential
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
MedDRA
SAS
WinNonlin


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10.10.
Appendix 10. Guidelines for Assessment of Disease, 
Disease Progression and Response Criteria
10.10.1.
Response Criteria for Solid Tumors (RECIST version 1.1
[Eisenhauer, 2009]
10.10.1.1. Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion.  Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.

All measurements 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 [Eisenhauer, 2009].
CT and MRI: Contrast enhanced CT with 5mm 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 [Eisenhauer, 2009].
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Eisenhauer, 2009].
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.  


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Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e.X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).  
Note:  PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments.
10.10.1.2. Guidelines for Evaluation of Disease
10.10.1.2.1.
Measurable and Non-measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 
5 mm.  If the slice thickness is greater than 5 mm, the minimum size of a 
measurable lesion must be at least double the slice thickness (e.g., if the slice 
thickness is 10 mm, a measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest X-ray.
Additionally, lymph nodes can be considered pathologically enlarged and measurable 
if

15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm).  At baseline and follow-up, only the 
short axis will be measured.
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques 
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. Note: non-
measurable only disease is not allowed per protocol.  


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10.10.1.3. Baseline Documentation of Target and Non-target Lesions

All baseline lesion assessments must be performed within 28 days of
randomization.

Lymph nodes that have a short axis of <10mm are considered non-pathological 
and should not be recorded or followed.

Pathological lymph nodes with <15mm and but ≥10mm short axis are considered 
non-measurable.

Pathological lymph nodes with ≥15mm short axis are considered measurable and 
can be selected as target lesions, however lymph nodes should not be selected as 
target lesions when other suitable target lesions are available.

Measurable lesions up to a maximum of 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 on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).
Note: Cystic lesions thought to represent cystic metastases 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.

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable. 
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions.

All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be group by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.
10.10.1.4. Response Criteria
10.10.1.4.1.
Evaluation of target lesions
Definitions for assessment of response for target lesions are as follows:

Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis.

Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as a reference, the baseline sum of the diameters (e.g. 
percent change from baseline).

Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.


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
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since 
the intervention started (e.g. percent change from nadir, where nadir is defined as 
the smallest sum of diameters recorded since intervention start). In addition, the 
sum must have an absolute increase from nadir of 5mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the 
sum of the diameters (e.g. sum of diameters is the sum of the longest diameters 
for non-nodal lesions and the short axis for nodal lesions).  When lymph nodes 
decrease to non-pathological size (short axis <10mm) they should still have a 
measurement reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments.  However, the sum of 
the diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented.  If an assessment 
of PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 
mm should be recorded and should contribute to the sum of the diameters, unless 
it is likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue 
to be measured.  The response at the time when the lesion reappears will depend 
upon the status of the other lesions.  For example, if the disease had reached a CR 
status then PD would be documented at the time of reappearance.  However, if the 
response status was PR or SD, the diameter of the reappearing lesion should be 
added to the remaining diameters and response determined based on percent 
change from baseline and percent change from nadir.
10.10.1.4.2.
Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. <10 
mm short axis).

Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline ≥ 10 mm short axis.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 

Not Applicable (NA):  No non-target lesions at baseline.

Not Evaluable (NE):  Cannot be classified by one of the four preceding 
definitions.


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Note:

In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.

In the presence of non-measurable only disease, consideration should be given to 
whether or not the increase in overall disease burden is comparable in magnitude 
to the increase that would be required to declare PD for measurable disease.

Sites of non-target lesions, which are not assessed at a particular timepoint based 
on the assessment schedule, should be excluded from the response determination 
(e.g. non-target response does not have to be "Not Evaluable"). 
10.10.1.4.3.
New lesions
New malignancies denoting disease progression must be unequivocal.  Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions.
Any equivocal new lesions should continue to be followed.  Intervention can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
10.10.1.4.4.
Evaluation of overall response
Table 12 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for participants with measurable disease at baseline.
Table 12
Evaluation of Overall Response for Participants with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable
Table 13 presents the overall response at an individual time point for all possible 
combinations of tumor responses in non-target lesions with or without the appearance of 
new lesions for participants with non-measurable only disease at baseline.


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Table 13
Evaluation of Overall Response for Participants with Non-
Measurable Only Disease at Baseline
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non CR/Non PD
No
Non CR/Non PD
NE
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response,  PD=progressive disease, and NE=Not Evaluable
Note: Participants with a global deterioration of health status requiring discontinuation of 
intervention without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is determined 
by evaluations of disease burden. Every effort should be made to document the objective 
progression even after discontinuation of intervention.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
10.10.1.4.5.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the intervention
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after first dose at a minimum interval of 49 days (based 
on the expected 56  ± 7day window). 

If the minimum time for SD is not met, best response will depend on the 
subsequent assessments.  For example if an assessment of PD follows the 
assessment of SD and SD does not meet the minimum time requirement the best 
response will be PD.  Alternatively, participants lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered not 
evaluable.
10.10.1.4.6.
Confirmation Criteria:

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first 
met.


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10.10.2.
Evaluation, Staging and Response Assessments for Non-
Hodgkin’s Lymphoma: The Lugano Classification (according to 
Cheson, 2014)
Evaluation, staging, and response criteria are summarized in 3 tables below.
Criteria for Involvement of Site
Tissue Site
Clinical
FDG Avidity
Test
Positive Finding
Lymph nodes
Palpable
FDG-avid 
histologies
PET-CT
Increased FDG uptake
Non avid disease
CT
Unexplained node enlargement
Spleen
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, solitary mass, 
miliary lesions, nodules
Non avid disease
CT
> 13 cm in vertical length, mass, 
nodules 
Liver
Palpable
FDG-avid 
histologies
PET-CT
Diffuse uptake, mass
Non avid disease
CT
Nodules
CNS
Signs, 
symptoms
CT
Mass lesion(s)
MRI
Leptomeningeal infiltration, 
mass lesions
CSF assessment
Cytology, flow cytometry
Other (eg, skin, 
lung, GI tract, 
bone, bone 
marrow)
Site 
dependent
PET-CTa, 
biopsy
Lymphoma involvement
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, 
magnetic resonance imaging; PET, positron emission tomography. 
a: PET-CT is adequate for determination of bone marrow involvement and can be considered highly 
suggestive for involvement of other extralymphatic sites. Biopsy confirmation of those sites can be 
considered if necessary. 
Staging System for Primary Nodal Lymphomas
Stage
Involvement
Extranodal (E) Status
Limited
I
One node or a group of adjacent nodes
Single extranodal lesions without 
nodal involvement
II
Two or more nodal groups on the same side 
of the diaphragm
Stage I or II by nodal extent with 
limited contiguous extranodal 
involvement
II bulkya
II as above with “bulky” disease
Not applicable
Advanced
III
Nodes on both sides of the diaphragm; 
nodes above the diaphragm with spleen 
involvement
Not applicable
IV
Additional noncontiguous extralymphatic 
involvement
Not applicable
NOTE. Extent of disease is determined by positron emission tomography–computed tomography for avid 
lymphomas and computed tomography for nonavid histologies. Tonsils, Waldeyer's ring, and spleen are 
considered nodal tissue. 
a: Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology 
and a number of prognostic factors.


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Criteria for Response Assessment of Non-Hodgkin’s Lymphoma
Response
Site
PET-CT-Based Response
CT-Based Response
Complete
Lymph 
nodes 
and 
extralymphatic 
sites
Complete metabolic response
Complete 
radiologic 
response 
(all 
of 
the 
following)
Score 1, 2, or 3a with or without a 
residual mass on 5PS2
It is recognized that in Waldeyer's ring 
or 
extranodal 
sites 
with 
high 
physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-
stimulating factors), uptake may be 
greater 
than 
normal 
mediastinum 
and/or liver. In this circumstance, 
complete metabolic response may be 
inferred if uptake at sites of initial 
involvement 
is 
no 
greater 
than 
surrounding normal tissue even if the 
tissue has high physiologic uptake
Target nodes/nodal masses 
must regress to ≤ 1.5 cm in 
LDi
No extralymphatic sites of 
disease
Non 
measured 
lesion
Not applicable
Absent
Organ 
enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
determinate, IHC negative
Partial
Lymph 
nodes 
and 
extralymphatic 
sites
Partial metabolic response
Partial remission (all of the 
following)
Score 4 or 5b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
At interim, these findings suggest 
responding disease
At end of intervention, these findings 
indicate residual disease
≥ 50% decrease in SPD of 
up to 6 target measurable 
nodes and extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm 
× 5 mm as the default value
When no longer visible, 0 × 
0 mm
For a node > 5 mm × 5 mm, 
but smaller than normal, use 
actual 
measurement 
for 
calculation
Nonmeasured 
lesion
Not applicable
Absent/normal, 
regressed, 
but no increase
Organ 
enlargement
Not applicable
Spleen must have regressed 
by > 50% in length beyond 
normal
New lesions
None
None


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Response
Site
PET-CT-Based Response
CT-Based Response
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with 
baseline 
(diffuse 
uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or biopsy 
or an interval scan
Not applicable
No response 
or 
stable 
disease
Lymph nodes 
and 
extralymphatic 
sites
No metabolic response
Stable disease
Score 4 or 5 with no significant change 
in FDG uptake from baseline at interim 
or end of intervention
< 
50% 
decrease 
from 
baseline in SPD of up to 6 
dominant, measurable nodes 
and extranodal sites; no 
criteria 
for 
progressive 
disease are met
Non measured 
lesion
Not applicable
No increase consistent with 
progression
Organ 
enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
Progressive 
disease
Individual 
target 
nodes/nodal 
masses
Extranodal 
lesions
Progressive metabolic disease
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or
New FDG-avid foci consistent with 
lymphoma 
at 
interim 
or 
end-of-
intervention assessment
Progressive disease requires 
at least 1 of the following:
PPD progression:
An individual node/lesion 
must be abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD 
nadir and
An increase in LDi or SDi 
from nadir.
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In 
the 
setting 
of 
splenomegaly, the splenic 
length must increase by > 
50% of the extent of its prior 
increase 
beyond 
baseline 
(eg, a 15-cm spleen must 
increase to > 16 cm). If no 
prior splenomegaly, must 
increase by at least 2 cm 
from baseline
New 
or 
recurrent 
splenomegaly
Non measured 
lesions
None
New or clear progression of 
preexisting 
nonmeasured 
lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, 
infection, 
inflammation). 
If 
uncertain regarding etiology of new 
Regrowth 
of 
previously 
resolved lesions
A new node > 1.5 cm in any 
axis


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Response
Site
PET-CT-Based Response
CT-Based Response
lesions, biopsy or interval scan may be 
considered
A new extranodal site > 1.0 
cm in any axis; if < 1.0 cm 
in any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma
Assessable disease of any 
size 
unequivocally 
attributable to lymphoma
Bone marrow
New or recurrent FDG-avid foci
New 
or 
recurrent 
involvement
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; 
PET, positron emission tomography; PPD, cross product of the LDi and perpendicular diameter; SDi, 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple 
lesions. 
a: A score of 3 in many patients indicates a good prognosis with standard intervention, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid underintervention). Measured 
dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected 
to be clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body 
and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include 
those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted 
on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but
should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result 
of chemotherapy or myeloid growth factors). 
b: PET 5PS: 
 
 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, 
which are protected by third party copyright laws and therefore have been excluded.


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10.11.
Appendix 11. ECOG Performance Status
Grade
Descriptions
1. Oken, 1982.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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10.12.
Appendix 12: Guidelines for Management of Toxicity
The following dose modification criteria should provide guidance for, but not act as a 
replacement for sound clinical judgment. The investigator should use clinical judgment to 
determine which drug may be contributing to the toxicity necessitating dose adjustment, 
and make the appropriate change for that drug. Dose modifications should be made after 
discussion with the GSK medical monitor.
10.12.1.
Management of Selected Toxicities
Table 14
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary
Grade 3 

Hold GSK3368715 until resolved to Grade ≤ 1 within ≤ 
14 days

Monitor complete blood count (CBC) at least twice a 
week

Discuss with GSK Medical Monitor  

Re-start GSK3368715 at a reduced dose

Discontinue GSK3368715 if not resolved to Grade ≤ 1
within ≤ 14 days
Grade 4

Discontinue GSK3368715

Monitor CBC every 2-3 days. 
Anemia
Grades 1 & 2 
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary
Grade 3 

Hold GSK3368715 until resolved to Grade ≤ 1 within ≤ 
14 days.

Transfuse and treat as necessary.

Monitor CBC at least twice a week.

Discuss with GSK Medical Monitor.

Re-start GSK3368715 at a reduced dose.

Discontinue GSK3368715 if not resolved to Grade ≤ 1
within ≤ 14 days.
Grade 4 

Discontinue GSK3368715.

Transfuse and treat as necessary.

Monitor CBC every 2-3 days.
PR Interval
An increase in the 
PR Interval to 
>250 msec

This interval should be based on the average of the 
triplicate ECGs

Discontinue GSK3368715

Contact the medical monitor

Maintain proper electrolytes similar to recommendations for 
QTcF


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QRS Interval
An increase of 
>20% from 
baseline

This interval should be based on the average of the 
triplicate ECGs

Discontinue GSK3368715

Contact the medical monitor

Maintain proper electrolytes similar to recommendations for 
QTcF
QTcF
If >30msec and < 
60 msec change 
from baseline  
AND manual 
QTcF <500 msec 
(average of three 
ECGs over at 
least 15 minutes)

Continue current dose of GSK3368715

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
(1) Maintain serum potassium > 4 mol/L
(2) Maintain serum magnesium levels >0.85 mmol/L

Discontinue any concomitant medications with potential 
for QTcF prolongation.

Consider 24 hour or longer telemetry monitoring if 
clinically indicated.
If 60 msec 
change from 
baseline occurs
OR
QTcF 500 msec
(average of three 
ECGs over at 
least 15 minutes)
Discontinue GSK3368715 and notify the GSK Medical Monitor.
Liver 
Refer to procedures outlined in Section 7.1.1 Liver Safety 
Required Actions and Follow up Assessments
Diarrhea
Grade 1
Initiate supportive care including loperamide. 
Grade 2

Initiate supportive care including loperamide.
Consider hold of GSK3368715
Discuss with GSK Medical Monitor.
Grade 3

Treat as above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics as 
appropriate.

Hold GSK3368715

Discuss with GSK Medical Monitor.

Re-start GSK3368715 at a reduced dose

Discontinue GSK3368715 if not resolved to Grade ≤1 within 
≤14 days
Grade 4

Above plus consider intravenous (IV) hydration, hospital 
admission and prophylactic antibiotics as appropriate.

Discontinue GSK3368715


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Nausea/Vomiting
Grade 1

Initiate supportive care with antiemetics as necessary. 
Grade 2

Initiate supportive care with antiemetics as necessary

Consider hold of GSK3368715 until resolved to Grade ≤ 1
within ≤ 14 days

Discuss with GSK medical monitor
Grade 3

Supportive care as above, plus consider intravenous (IV) 
hydration, hospital admission and IV nutrition as 
appropriate.
Hold GSK3368715 until resolved to Grade ≤ 1 within ≤ 14 
days
Discuss with GSK Medical Monitor.
Re-start GSK3368715 at same dose if resolved within ≤ 2 
days
Re-start GSK3368715 at reduced dose if resolved > 2 days
Discontinue GSK3368715 if not resolved to Grade ≤ 1 within 
≤ 14 days
Grade 4

Supportive care as above, plus consider intravenous (IV) 
hydration, hospital admission and IV nutrition as appropriate

Discontinue GSK3368715 if lasting >2 days despite 
supportive care
All Other Toxicity*
Grade 1

Continue dosing with no change 
Grade 2
Continue dosing with no change 
OR
Hold GSK3368715 for up to 1 week for toxicity to be < 
Grade 2, then continue at the same dose (dose reduction 
is required if the grade 2 toxicity is considered a DLT)
Grade 3

Hold GSK3368715 until resolved to Grade ≤ 1 within ≤ 14 
days

Discuss with GSK Medical Monitor

Re-start GSK3368715 at a reduced dose 
Discontinue GSK3368715 if not resolved to Grade ≤ 1 within 
≤ 14 days
Exception: In case of clinically insignificant laboratory 
abnormalities resolving ≤ 2 days, re-start at same GSK3368715 
dose possible after consultation of GSK Medical Monitor
Grade 4

Discontinue GSK3368715

Restart of GSK3368715 may be considered upon 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
agreement between the GSK medical monitor and 
investigator in case of toxicities such as laboratory 
abnormalities (1) not associated with severe clinical 
symptoms requiring hospitalization, (2) lasting ≤ 2 
days, and (3) responding to supportive care 
Venous 
Thromboembolism
Grade 2-4

Medical care including Anticoagulation and follow-up 
according to standard of care

Discontinue GSK3368715

Restart of GSK3368715 may be considered upon 
agreement between the GSK medical monitor and 
investigator in case the investigator believes there is 
benefit to the participant, participant is reconsented and the 
participant is appropriately anticoagulated.

In situations where full anticoagulation is not medically 
appropriate, discontinue GSK3368715
Note: Exceptions to the drug-related Grade 1 requirement may be made for certain AEs 
as defined in Section 4.1.3.


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10.13.
Appendix 13: Khorana Score 
Table 15
Predictive model for chemotherapy-associated VTE in the 
ambulatory setting
Patient characteristic
Points
VTE: venous thromboembolism
Source: Key, 2019
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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10.14.
Appendix 14: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
This amendment applies to all sites participating in the conduct of the study.
Amendment 02 22-FEBRUARY-2019
This amendment applies to all sites participating in the conduct of the study.
Overall Rationale for the Amendment:
Protocol Amendment 2 includes the following:
Changes and clarifications made in the Schedule of Activities Tables (Table 1-
Table 3). The SoA Tables have been modified to reflect that the first 21 days is 
the DLT Period. Revisions have also been made in the timings and frequency of 
some assessments. Visit windows have been added.
Update to CTCAE version 5.
Minor change to Inclusion criteria by not allowing participants with potential liver 
metastases (ALT < 5 x ULN) from Part 1 (Dose Escalation) 
Minor change to Exclusion Criteria by allowing 1st degree AV block and 2nd
degree type 1 AV block.
Addition of higher dose strength capsules (250mg).
Administrative changes made throughout the document
Section # and 
Name
Description of Change
Brief Rationale
1.1 Synopsis
Intervention Groups and 
Duration – Change First Cycle to 
DLT period
Cycle is considered to be study drug 
dispensation which is 28 days. DLT 
period is first 21 days and is now 
defined as this per the Schedule of 
Activities Table.
1.3 Schedule of 
Activities: Table 1 
Screening 
Procedures
Added Troponin I or T
Include further details to Tumor 
Troponin levels > upper limit are 
exclusionary as per criteria 8j. This 
testing was not originally included in 
the Screening Procedures table. Also 
added testing to Appendix 2 (Table 8).
There is a requirement for tumor 
samples at screening for those in 


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Section # and 
Name
Description of Change
Brief Rationale
biopsy requirements
PK/PD cohort compared to other 
cohorts 
1.3 Schedule of 
Activities: Table 2 
and 3 Schedule of 
Activities
Significant changes made in the 
Schedule of Activities tables.

First 21 days changed 
from First Cycle to DLT 
period

Day 21 visit changed to 
Day 22

Updated collection 
details for SAEs, AESIs 
and AEs 

Moved Q3W 
assessments for ECOG 
and Vital Signs to Q4W

Added Urinalysis and 
Coagulations to Clinical 
Chemistry assessments

Modified timepoints for 
Tumor Imaging

Clarified Telephone 
Interview is only in Part 
2

Clarified language that 
the Tumor biopsy is 
optional unless patient is 
in PK/PD cohort and 
increased window for 
optional biopsy  

Clarified language for 
extended 48 and 72 
hour PK timepoints for 
Day 1

Add a Day 22 sample for 
Circulating free (cf)
ADMA and SDMA 

Replaced Day 2 Whole 
Blood sample for PD 

First 21 days is DLT period, 
this is not considered first cycle 
(Section 1.1 Synopsis) 

Visit to occur after DLT period 
is completed

To align with Section 8.3.1

To align with PK visit days 
every 4 weeks

As per Appendix 2 (Table 8), 
not initially included in 
Schedule of Activities Table

Reduce imaging requirements 
after first 8 months on 
treatment 

As described in Section 8.10, 
not initially added to Schedule 
of Activities Table 

To add clarity for biopsy 
requirements per cohort

To add clarity

Recent preclinical data 
suggests that greater reduction 
of cfADMA may be observed 
upon longer periods of 
treatment with GSK3368715

Recent preclinical data suggest 
that no significant changes in 
the levels of intracellular 
ADMA-hnRNP-A1 would be 
expected on Day 2. Analysis of 


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Section # and 
Name
Description of Change
Brief Rationale
biomarkers with a Day 
22 sample

Add visit windows
PBMCs from Day 22 will 
increase the likelihood of 
observing greater changes for 
this biomarker.

To add clarity
4.1.1 Part 1: Dose 
Escalation Phase
Dose Escalation:
Move language here for dose 
increments after a grade 2 drug-
related toxicity from statistics 
Section (9.2.1)
Dosing increments should be found 
within Study Design Section 4
4.1.3 Dose-
Limiting Toxicity, 
5.2 Exclusion 
Criteria 11, 6.2 
Dose Modification, 
8.3 Adverse 
Events and 
Serious Adverse 
Events, 9.6.2.2 
Adverse Events, 
9.6.2.3 Clinical 
Laboratory 
Evaluations
Update CTCAE to version 5
New version released
5.1 Inclusion 
Criteria
Criteria 2 Type of Participant and 
Disease Characteristics - Moved 
tumor biopsy details here and 
removed criteria 6
Criteria 3 Adequate organ 
function – allow ALT <5x ULN 
only in Part 2
To add clarity
5.2 Exclusion 
Criteria
Criteria 8d – Remove 1st degree
AV block exclusion, clarify 2nd
and 3rd degree
Criteria 12 – Moved to Section 
6.7.1
AV block grade 1 and AV block grade 2 
Type 1 (Wenckebach) are frequently 
observed in normal young healthy 
volunteers (Am J Cardiol. 1977 
Mar;39(3):390-5.) and should not 
preclude participation in the absence of 
heart disease and in the absence of 
symptoms. 
5.3.1 Meals and 
Clarified that Day 8 is serial PK
Day 8 was omitted initially as a serial 


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Section # and 
Name
Description of Change
Brief Rationale
Dietary 
Restrictions
day.
PK day with requirements for fasting
Table 5 Study 
Intervention
Added 250mg dose strength
New dose strength added for higher 
dosing cohorts
6.7.1 Prohibited 
Medications
Moved radiotherapy here, added 
allowance for palliative 
radiotherapy and added Therapy 
to section title
To add clarity
6.7.1 Prohibited 
Medications, 8.5 
Intervention of 
Overdose, 9.6.3.1 
Pharmacokinetic 
Parameters, 
9.6.3.2 Statistical 
analysis of 
Pharmacokinetic 
data, 10.5 
Appendix 5: 
Genetics
Removed GSK3326595 
reference
GSK3326595 is not included in this 
protocol
7.1 
Discontinuation of 
Study Intervention
Clarified survival follow-up
timeframe
To add clarity on participant level
7.1.5 Stopping 
Rules for Clinical 
Deterioration
Copied language here for 
participants receiving clinical 
benefit but with disease 
progression from Summary 
section
To add clarity
7.4 Participant 
and Study 
Completion
Clarify definitions for study 
completion for Part 1 and Part 2
To provide clarity
8.0 Study 
Assessments and 
Procedures
The reference to study 
procedures and their timing 
changed from Section 1.3 to 
Table 1-Table 3.
To provide clarity
8.1 Efficacy
Update tumor imaging timepoints 
to align with updated Schedule 
of Activities Table
Reduce scan frequency after 8 months. 


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Section # and 
Name
Description of Change
Brief Rationale
8.2.4 Holter 
Monitoring
Clarified screening Holter vs on 
treatment Holter
To provide clarity
8.7.3 Tumor 
Biopsy 
Collection/Surgical
Procedures
Clarified tumor biopsy 
requirements per cohorts to align 
with updates made to Schedule 
of Activities Table
To provide clarity
8.10.1 Qualitative 
Telephone 
Interviews
Clarified that interviews will only 
be conducted in Part 2 
Align with Schedule of Activities Table
9.4.2.1 Efficacy 
Analyses
Clarify futility timeframe
To provide clarity
Whole Document
Administrative corrections were 
made throughout the protocol to 
correct minor inconsistencies 
and typographical errors
Provide clarity and correction.
Amendment 01 12-JULY-2018
This amendment applies to all sites participating in the conduct of the study.
Overall Rationale for the Amendment:
All revisions made were as per requirements from FDA.
Section # 
and Name
Description of Change
Brief Rationale
Section 4.1.3 
Dose-Limiting 
Toxicity –
Table 4
Modified DLT definitions to include 
1) non-hematologic toxicities of 
Grade ≥3 regardless of duration 
except those as indicated in Table 
4 and Grade 2 which lead to 
frequent dose interruptions despite 
best standard of care and limit 
dosing of GSK3368715 to <80% of 
expected dose or a delay of dosing 
>14 days  
2) Grade 3 thrombocytopenia with 
significant haemorrhage or other 
hematologic toxicities leading to 
Address required changes per FDA.


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Section # 
and Name
Description of Change
Brief Rationale
frequent dose interruptions despite 
best standard of care and limit 
dosing of GSK3368715 to <80% of 
expected dose
Section 5.1 
Inclusion 
Criteria, 
Number 2
Inclusion criteria for transitional cell 
carcinoma of the Urothelium 
updated to require participants to 
have progressed at least one line of 
systemic therapy.
Address required changes per FDA.
Section 
10.12.1 
Management 
of Selected 
Toxicities –
Table 11
Incorporate 
1) a hold of study drug, 
GSK3368715, for most related 
Grade 3 adverse events with 
possible re-start at reduced dose 
level for thrombocytopenia, anemia, 
diarrhea, nausea/vomiting, and all 
other non-hematologic toxicities as 
indicated in Table 11
2) discontinuation of study drug for 
related Grade 4 adverse events of 
any duration (excluding most lab 
abnormalities). 
Edited incorrect compound number 
from GSK3326595 to 
GSK3368715.
Address required changes per FDA.


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11.
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MTAP gene as a poor prognosticator in gastrointestinal stromal tumors. Clin Cancer Res 
2009:6963–72.
Key NS, Khorana AA, Kuderer NM, et al. Venous Thromboembolism Prophylaxis and 
Treatment in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin 
Oncol. 2019;[Epub ahead of print]
Kirovski G, Stevens AP, Czech B, Dettmer K, Weiss TS, Wild P et al. Down-regulation 
of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular 
carcinoma via accumulation of 5’-deoxy-5’- methylthioadenosine (MTA). Am J Pathol. 
2011;178:1145–52.
Kryukov, G.V., Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE et al. MTAP 
deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in 
cancer cells. Science. 2016;351(6278):1214-8.
Marjon, K. Cameron MJ, Quang P, Clasquin MF, Mandley E, Kunii K  et al, MTAP 
Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 
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al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to 
dependence on PRMT5. Science. 2016;351(6278):1208-13.
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phase I cancer trials. Statistics Med. 2008;27:2420-39.
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.
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is required for early postimplantation mouse development, but cells deficient in the 
enzyme are viable. Mol Cell Biol. 2000;20(13):4859-69.
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(2012).
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independent prognosis marker and the concordant loss of MTAP and p16 expression 
predicts short survival in non-small cell lung cancer patients. EJSO 40:1143-1150 (2014).
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Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the 
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Yoshimatsu M., Toyokawa G., Hayami S., Unoki M., Tsunoda T., Field HI, et al. 
Dysregulation of PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in 
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SAP_001.pdf: 
0 
 
 
 
Statistical Analysis Plan  
Study ID:  207675 
Official Title of Study:  Reporting and Analysis Plan for a phase I, open-label, dose-escalation 
study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of 
GSK3368715 in participants with solid tumors and DLBCL 
Date of Document: 05-MAR-2021 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
207675 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a phase I, open-label, dose-
escalation study to investigate the safety, pharmacokinetics, 
pharmacodynamics and clinical activity of GSK3368715 in 
participants with solid tumors and DLBCL 
Compound 
Number  
: GSK3368715 
Effective Date  
: Refer to Document date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the abbreviated Clinical Study Report for Protocol 207675. 
• 
This assumed CSR is abbreviated given the study was halted early. 
• 
This RAP is intended to describe planned safety, tolerability, PK, and efficacy 
analyses required for the study.  
 
RAP Author(s): 
Author 
Date 
Approval Method 
23FEB2021 
Email 
Senior Biostatistician 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
207675 
 
2 
 
RAP Team Reviewers: 
Reviewer 
Date 
Approval 
Method 
02MAR2021 
Email 
, Clinical Statistics, 
GlaxoSmithKline 
02MAR2021 
Email 
, Clinical 
Statistics, GlaxoSmithKline 
02MAR2021 
Email 
 Clinical 
Development Oncology, GlaxoSmithKline 
 
Email 
, Clinical Pharmacology Modelling and 
Simulation, GlaxoSmithKline 
02MAR2021 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 Biostatistics, GlaxoSmithKline  
05MAR2021 
Email 
 
 Biostatistics, 
GlaxoSmithKline  
04MAR2021 
Email 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 11 
2.4.1. 
Part 1 Dose Escalation ................................................................ 11 
2.4.2. 
Part 2 Dose Expansion ................................................................ 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.1.1. 
Dose Escalation Reviews ............................................................ 12 
3.1.2. 
Recommended Phase 2 Dose (RP2D) Analysis .......................... 13 
3.1.3. 
Interim futility analyses (IFA) Analyses ........................................ 14 
3.2. 
Final Analyses ............................................................................................ 14 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 15 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Reporting Conventions ............................................................................... 16 
5.3. 
Baseline Definitions .................................................................................... 17 
5.4. 
Multiple Assessments ................................................................................. 17 
5.5. 
Multicentre Studies ..................................................................................... 18 
5.6. 
Examination of Covariates, Other Strata and Subgroups ............................ 18 
5.6.1. 
Covariates and Other Strata ........................................................ 18 
5.6.1. 
Examination of Subgroups ........................................................... 18 
5.7. 
Multiple Comparisons and Multiplicity ......................................................... 18 
5.8. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 18 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
6.2. 
Subject’s Disposition ................................................................................... 19 
6.3. 
Protocol Deviations ..................................................................................... 19 
6.4. 
Demographic Characteristics ...................................................................... 19 
6.5. 
Concomitant Medications ............................................................................ 20 
6.6. 
Exposure Analysis ...................................................................................... 20 
6.7. 
Disease Characteristics .............................................................................. 20 
6.8. 
Prior Anti-Cancer Therapy .......................................................................... 20 
7. 
EFFICACY ANALYSES .......................................................................................... 21 
7.1. 
Primary Efficacy Analyses .......................................................................... 21 
7.1.1. 
Endpoint / Variables ..................................................................... 21 
7.2. 
Secondary Efficacy Analyses ...................................................................... 21 


 
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7.2.1. 
Summary Measure ...................................................................... 21 
7.2.2. 
Population of Interest ................................................................... 21 
7.2.3. 
Statistical Analyses / Methods ..................................................... 21 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 22 
8. 
SAFETY ANALYSES ............................................................................................. 23 
8.1. 
Extent of Exposure ..................................................................................... 23 
8.2. 
Adverse Events Analyses ........................................................................... 23 
8.3. 
Deaths and Serious Adverse Events ........................................................... 24 
8.4. 
Adverse Events Leading to Dose Modification of Study Treatment ............. 24 
8.5. 
Clinical Laboratory Analyses ....................................................................... 25 
8.5.1. 
Performance Status ..................................................................... 26 
8.5.2. 
ECG ............................................................................................. 26 
8.5.3. 
Vital Signs .................................................................................... 27 
8.5.4. 
Pregnancies ................................................................................. 27 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 28 
9.1. 
Endpoint / Variables .................................................................................... 28 
9.1.1. 
Drug Concentration Measures ..................................................... 28 
9.1.2. 
Derived Pharmacokinetic Parameters .......................................... 28 
9.1.3. 
Statistical Analysis of Pharmacokinetic Parameters ..................... 30 
9.1.4. 
Population of Interest ................................................................... 31 
10. BIOMARKER ANALYSES ...................................................................................... 31 
11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 31 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 31 
13. REFERENCES ....................................................................................................... 32 
14. APPENDICES ........................................................................................................ 33 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 33 
14.1.1. 
Exclusions from Per Protocol Population ..................................... 33 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 34 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 34 
14.3. 
Appendix 3: Assessment Windows ............................................................. 35 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 36 
14.4.1. 
Study Phases .............................................................................. 36 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 37 
14.5.1. 
Reporting Process ....................................................................... 37 
14.5.2. 
Reporting Standards .................................................................... 37 
14.5.3. 
Reporting Standards for Pharmacokinetic .................................... 38 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 39 
14.6.1. 
General ........................................................................................ 39 
14.6.2. 
Study Population .......................................................................... 39 
14.6.3. 
Safety .......................................................................................... 40 
14.6.4. 
Efficacy ........................................................................................ 40 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 41 
14.7.1. 
Premature Withdrawals ................................................................ 41 
14.7.2. 
Handling of Missing Data ............................................................. 41 


 
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14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 45 
14.8.1. 
ECG ............................................................................................. 45 
14.8.2. 
Vital Signs .................................................................................... 46 
14.9. 
Appendix 9: Abbreviations & Trademarks ................................................... 47 
14.9.1. 
Abbreviations ............................................................................... 47 
14.9.2. 
Trademarks ................................................................................. 48 
14.10. Appendix 10: List of Data Displays.............................................................. 49 
14.10.1. Data Display Numbering .............................................................. 49 
14.10.2. Deliverables ................................................................................. 49 
14.10.3. Study Population Tables .............................................................. 50 
14.10.4. Efficacy Tables ............................................................................ 51 
14.10.5. Safety Tables ............................................................................... 52 
14.10.6. Pharmacokinetic Tables ............................................................... 55 
14.10.7. Pharmacokinetic Figures ............................................................. 58 
14.10.8. ICH Listings ................................................................................. 59 
14.10.9. Non-ICH Listings .......................................................................... 62 
 


 
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1. 
INTRODUCTION 
This RAP is intended to describe planned safety, tolerability, pharmacokinetics (PK), and 
efficacy analyses to be performed in support of the Clinical Study Report for GSK 
Protocol 207675 Amendment 3, dated 05DEC2019.  
Protocol Revision Chronology: 
Version 01 
02-MAY-2018 
Original 
Version 02 
(Amendment 1) 
12-JUL-2018 
Changed included: 
- 
Modified DLT definitions. 
- 
Changes to inclusion criteria. 
- 
Incorporation of a hold of study drug for most 
related Grade 3 adverse events with possible re-
start at reduced dose level for thrombocytopenia, 
anemia, diarrhea, nausea/vomiting, and all other 
non-hematologic toxicities. 
- 
Incorporation of discontinuation of study drug for 
related Grade 4 adverse events of any duration 
(excluding most lab abnormalities). 
Version 03 
(Amendment 2) 
22-FEB-2019 
Changes included:  
- 
Changes and clarifications made in the Schedule of 
Activities Tables. 
- 
Update to CTCAE version 5. 
- 
Minor change to inclusion and exclusion criteria 
Addition of higher dose strength capsules  
Version 04 
(Amendment 3) 
05-DEC-2019 
Changes included: 
- 
Updated clinical safety guidelines, clinical 
pharmacology, and the risks/mitigation strategy 
following the temporary pause in enrolment due to 
venous thromboembolic events (VTE) that have 
been observed in the dose escalation phase of the 
study. Also, the risk of biopsy collection has been 
added to the benefit/risk assessment table. 
- 
Changes to exclusion criteria. 
- 
Addition to allowed anti-coagulation therapy. 
- 
Addition of exploratory coagulation markers and 
minor changes to other exploratory biomarkers 
being collected in the dose escalation phase of the 
study (Part 1). 
- 
Changes and clarifications made in the Schedule of 
Activities Tables 
- 
Changes to DLT and stopping/exclusion criteria for 
QRS and VTEs, and update to the telemetry 
assessment. 
- 
Addition of food effect cohort into Part 1. 
- 
Addition of tablet formulation. 


 
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- 
Further clarifications added to the sample size 
determination section. 
- 
Addition of albumin in the clinical labs table (Table 
9, Appendix 2). 
- 
Addition of guidelines of management of toxicity for 
VTEs in Appendix 12 
- 
Addition of Appendix 13 (Khorana score) 
- 
Administrative changes made throughout the 
document. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. Below is the list of analyses that will not be performed: 
• There will be no food effect sub-study analysis. Therefore, one of the secondary 
objectives from Part 1 analysis will not be performed. 
• There will be no Part 2 Dose Expansion cohort.  Thus, all analyses which support 
characterization of primary and secondary objectives for the Part 2 cohort (objective 
response rate analysis, progression-free survival incidence, severity of adverse events, 
and evaluation of PK parameters) will not be performed. 
• Recommended Phase 2 Dose (RP2D) Analysis will not be performed. 
• Interim futility analysis (IFA) will not be performed. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Part 1: Dose Escalation 
Primary Objective 
Primary Endpoints 
• 
Determine RP2D and schedule of 
GSK3368715 administered orally to 
participants with advanced stage solid 
tumors 
• 
Incidence of DLT 
• 
Incidence and severity of adverse events 
Secondary Objectives 
Secondary Endpoints 
• 
Evaluate the preliminary clinical 
activity of GSK3368715 
• 
Best overall response 
• 
Characterize the PK of GSK3368715 
• 
PK parameters (Cmax, Tmax, AUC, and others) 
 
Part 2: Dose Expansion 
Primary Objective 
Primary Endpoint 
• 
Evaluate the preliminary clinical 
activity of GSK3368715 
• 
Objective response rate (ORR) 


 
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Secondary Objectives 
Secondary Endpoints 
• 
Characterize the safety of 
GSK3368715 administered at the 
RP2D and schedule to participants 
with DLBCL, pancreatic cancer, 
NSCLC, and bladder cancer 
• 
Incidence and severity of adverse events 
• 
Further evaluate the clinical activity of 
GSK3368715 
• 
Progression-free survival (PFS) 
• 
Characterize the PK of GSK3368715 
• 
PK parameters (Cmax, Tmax, AUC, and others) 
Part 1 and Part 2 
Exploratory Objectives/Endpoints 
• 
Evaluate time to response (TTR), duration of response (DOR) and overall survival (OS) 
• 
Evaluate changes in PD biomarkers relevant to define the molecular mode-of action of GSK3368715 
• 
Investigate biomarkers such as, but not restricted to, MTAP deficiency and CDKN2A gene deletion, as 
potentially predictive of sensitivity or resistance to GSK3368715 
• 
Characterize the relationship between PK, PD, and clinical activity of GSK3368715 
• 
Evaluate the relationship of pharmacogenetic profile in host DNA and response to GSK3368715 
therapy 
• 
Determine the impact of GSK3368715 on function and health-related quality of life 
• 
Determine the amount of GSK3368715 excreted in urine from subjects in the PK/PD expansion cohorts 
• 
Characterize the metabolic profile of GSK3368715 (in the PK/PD expansion cohorts 
 


 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• 
The study includes two phases: Part 1 Dose Escalation and Part 2 
Dose Expansion. 
• 
Dose escalation use Neuenschwander continual reassessment method 
(N-CRM). 
• 
Cohorts will be expanded at the first instance of a ≥ Grade 2 drug-
related non-hematological toxicity. 
• 
Every dose level will enroll a minimum of 3 and a maximum of 12 
subjects. 
• 
Part 1 was planned to enroll up to 40 patients with relapsed/refractory 
solid tumors. Approx. 30 subjects for DLT evaluation and 10 subjects 
for PK/PD/Biomarker cohort(s) at a dose of or near MTD/RP2D. 
• 
Dose Escalation Committee (DEC): 
(i) will review all available data, including safety, PK and PD data from 
current and prior cohorts, 
(ii) can halt or reduce the GSK3368715 dose based on clinical 
judgement at any time during the trial, and 
(iii) can recommend alternative schedule(s) if emerging data suggest 
that continuous daily dosing will result in excessive toxicity or limited 
efficacy. 
Refer to Section 4.1.4 in protocol for the detailed descriptions of the 
DEC. 
• 
Maximum-tolerated Dose (MTD): The highest GSK3368715 dose that 
emerges from the evaluation of safety-, PK-, and PD-data guided by 
the N-CRM statistical design during the DLT evaluation period that 
does not produce unacceptable toxicity. 
• 
Recommended Phase 2 Dose (RP2D): Equivalent with the MTD or a 
lower GSK3368715 dose that provides adequate PK exposure and 
biologic activity with superior tolerability. 


 
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Overview of Study Design and Key Features 
• 
Part 2 was planned to enroll up to 141 patients. Specifically, Cohort 2A 
was planned to enroll up to 36 DLBCL participants. Cohort 2B was 
planned to enroll up to 35 participants for each indication of pancreatic 
cancer, NSCLC, and bladder cancer. 
• 
In both expansion cohorts, MTAP proficient and deficient participants 
were to be enrolled. 
• 
Participants may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent. 
Dosing 
• 
The starting dose of GSK3368715 is 50 mg, qd, po. 
• 
At the time of each dose-escalation decision, the dose that has the 
highest posterior probability of DLT lying in the target toxicity range 
(≥16% and <33%) with the constraint of posterior probability falling to 
unacceptable/excessive toxicity being less than 25% will be the model-
recommended dose for the next cohort. 
• 
The dose will not increase by more than half-logarithmical (3.2-fold) 
increments. 
• 
Dose de-escalation is also possible. 
• 
Based on the emerging data, alternative dosing schedule(s), or 
combination regimens with novel, active agents and/or with approved 
oncology therapies may be considered. 
• 
Any cohort in Part 1 with two (2) grade 2 venous thromboembolism 
(VTE) that requires systemic anticoagulation or ≥ grade 3 VTE in up to 
6 participants will be considered not cleared and enrolment at this dose 
level and higher dose levels will be permanently stopped. 
• 
Any cohort in Part 1 with ≥3 grade 2 venous thromboembolism (VTE) 
that requires systemic anticoagulation or Grade ≥3 VTEs out of up to 
10 participants will be considered not cleared and enrolment at this 
dose level and higher dose levels will be permanently stopped. 
• 
At 100mg, dose escalation steps will be considered in maximal steps of 
50 mg depending on the pharmacodynamic effects and the safety 
profile observed in previous cohorts, taking into consideration the 
updated DLT criteria. 
• 
Grade 2 venous thromboembolism (VTE) that requires systemic 
anticoagulation or ≥ grade 3 VTE, regardless of investigator assessed 
causality, will be considered a DLT during the first 8 (± 1) weeks or until 
study discontinuation (e.g., disease progression), whichever occurs 
sooner. 
• 
An end of treatment CT image is required if the participant withdraws 
before the end of the VTE DLT observation period. 
Time & 
Events 
• 
Refer to Table 2: Schedule of Assessments (SoA) in protocol  
Treatment 
Assignmen
t 
• 
The study is open-label and GSK3368715 is the only treatment 
assignment. 
Interim 
Analysis 
• 
The interim analysis was planned to be conducted separately for 
Cohorts 2A and 2B. 
• 
Timing of the first interim futility analysis: 
Cohort 2A: When at least 5 participants become evaluable from each of 
the MTAP defined subgroups. 


 
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Overview of Study Design and Key Features 
Cohort 2B: When at least 5 participants become evaluable from MTAP 
proficient subgroup within any histology cohort. 
• 
The interim futility analysis was planned to be performed every 2-3 
months with minimum of 5 additional evaluable participants from the 
entire Cohort 2A or Cohort 2B. 
• 
Within Cohort 2A, one Bayesian hierarchical model was to be used to 
borrow information between the MTAP defined subgroups. 
Within Cohort 2B, one Bayesian hierarchical model was to be used to 
borrow information between the MTAP defined subgroups and between 
the three indications.  
• 
Participants enrolled in Part 1 who were treated at the RP2D of 
GSK3368715 and have the same disease histology as required for 
Expansion Cohort 2B were to be included in the analyses as 
appropriate. 
• 
The above interim analyses will no longer be carried out due to the 
early termination of the study. 
Final 
Analysis 
• 
The study will be considered completed for purposes of a final analysis 
when 70% of participants enrolled in Part 2 have progressed or died. 
Due to the early termination during the Dose Escalation (Part 1) phase 
of this study, final analysis will occur prior to the above definition.  
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
2.4.1. 
Part 1 Dose Escalation 
No specific statistical hypotheses are being tested in Part 1. The primary objective is to 
determine RP2D. 
2.4.2. 
Part 2 Dose Expansion 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
  
 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
In Part 1, dose escalation meetings will be held to discuss dose escalation decisions after 
all patients in each dose cohort complete the DLT evaluation period of the first 21 days of 
intervention. Once all subjects in the DLT evaluation cohort (approx. 30 in total) have 
completed the first post baseline disease assessment, progressed or permanently 
discontinued from study treatment, a RP2D analysis will be conducted. 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
3.1.1. 
Dose Escalation Reviews 
The primary driver for the dose escalation decisions in Part 1 will be the incidence rate of 
DLT and other adverse events (AEs) of each dose cohort. The study uses 
Neuenschwander Continual Reassessment Method (N-CRM) [Neuenschwander, 2008] to 
guide dose escalation. An updated posterior estimate of the dose-toxicity curve will also 
be provided at the time of the dose-escalation meeting and the Dose Escalation 
Committee (DEC) will review all available data and decide if safe to escalate the dose.  
The N-CRM design makes use of a Bayesian logistic regression model relating dose and 
toxicity and makes use of DLT information from all doses. The N-CRM estimates, for 
each potential dose, the posterior probabilities that the DLT rate lies in each of four 
toxicity ranges: 
• 
A dose falls in the Under-dosing range if the probability of a DLT at the dose is 
<16%. 
• 
A dose falls in the Target Toxicity range if the probability of a DLT at the dose is 
≥16% and < 33%. 
• 
A dose falls in the Excessive Toxicity range if the probability of a DLT at the dose is 
≥33%, and <60%. 
• 
A dose falls in the Unacceptable Toxicity range if the probability of a DLT at the 
dose is ≥60%. 
At the time of each dose-escalation decision, the dose with the highest posterior 
probability of lying in the Target Toxicity range will be the model-recommended dose for 
the next cohort. Additionally, the following constraints for the recommended dose will be 
maintained: 
- 
The posterior probability of the DLT rate lying in the Excessive Toxicity or 
Unacceptable Toxicity range is less than 25%. 
- 
VTE safety rules 
o Upon re-initiation of enrolment under Protocol Amendment 3, details of a 
VTE meeting the DLT criteria are given in Section 4.1.3 and in Table 6. 


 
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- 
Upon re-initiation of enrolment under Protocol Amendment 3 at 100mg , dose 
escalation steps will be considered in maximal steps of 50 mg, depending on the 
pharmacodynamic effects and the safety profile observed in previous cohorts, 
taking into consideration the updated DLT criteria. 
- 
Note: GSK3368715 dose de-escalation is also possible using this method. 
An updated posterior estimate of the dose-toxicity curve will also be provided at the 
time of the dose-escalation meeting. Further details about the N-CRM approach are 
provided in Section 9 of Protocol Amendment 3. Although the N-CRM will be used 
to recommend the next dosing level, the DEC (i) will review all available data, 
including safety, PK and PD data from current and prior cohorts, (ii) can halt or 
reduce the GSK3368715 dose based on clinical judgement at any time during the 
trial, and (iii) can recommend alternative schedule(s) if emerging data suggest that 
continuous daily dosing will result in excessive toxicity or limited efficacy. Note: if 
an alternative schedule is evaluated, the starting dose at the time of a schedule change 
will be the dose for which the target toxicity level was not exceeded using once daily 
dosing schedule. 
3.1.1.1. 
Displays to Be Created for Dose Escalation Review 
For dose escalation decisions, ongoing data review will be primarily based on Tibco 
Spotfire Clinical Graphics (web-based data visualization tool). The following three 
listings will be created by Statistics and Programming group. The analysis will be based 
on the All-Treated Population. 
• Listing of All Adverse Events 
• Listing of Any Grade 2 and Above Lab Tests or Any Abnormal Lab Tests if Not 
Gradable 
• Listing of Exposure to GSK3368715 
For the first dose escalation meeting, only spreadsheets containing relevant study data 
will be supplied. For subsequent dose escalation meetings, SDTM datasets will be 
available and the two listings above may be provided. The Data Surveillance Tool may 
be used to create data visualizations to facilitate review.  
Details of the planned displays are presented in Appendix 10: List of Data Displays. 
3.1.2. 
Recommended Phase 2 Dose (RP2D) Analysis 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
RP2D of GSK3368715 was planned to be determined after review of all available safety-, 
PK-, PD-, and clinical efficacy data in accordance with the N-CRM design. The RP2D 
was planned to be equivalent with the MTD or a lower GSK3368715 dose that provides 
adequate PK exposure and biologic activity with superior tolerability. 


 
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3.1.2.1. 
Displays to Be Created for RP2D Analysis 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
3.1.3. 
Interim futility analyses (IFA) Analyses 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
3.2. 
Final Analyses 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
The final Part 1 analyses will be performed after all required database cleaning activities 
have been completed and Database Release (DBR) and Database Freeze (DBF) have 
been declared by Data Management.  
 
 


 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Study Population 
Evaluable 
• 
All participants who have had Week 24 disease 
assessments, have progressed or died, or permanently 
discontinued from the study intervention. 
 
All-Treated 
• 
All participants who received at least one dose of 
GSK3368715.  
• 
Study Population 
• 
Final Efficacy 
• 
Safety 
Pharmacokinetic 
(PK) 
• 
Participants in the All-Treated population from whom at 
least one PK sample was obtained, analysed, and was 
measurable.  
• 
PK 
Refer to Appendix 10: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarized and all protocol deviations, including both important and non-important, will 
be listed. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Specifications developed by PAREXEL.  
o Data will be reviewed prior to freezing the database to ensure all deviations are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate listing of all important 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 particular study population for this study. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
This is a single-arm, dose escalation and expansion study of GSK3368715. Data will be 
listed and summarized per the GSK reporting standards whenever applicable. In Part 1 
data will be listed and summarized by dose levels.  
Treatment Group Descriptions 
Data Displays for Reporting 
Description 
Order in TLF 
GSK3368715 50mg 
1 
GSK3368715 100mg 
2 
GSK3368715 200mg 
3 
5.2. 
Reporting Conventions 
• 
Unless otherwise specified, the denominator in percentage calculation at each 
scheduled visit will be based on the number of subjects with a non-missing value at 
each particular visit. 
• 
All data are reported according to the dose/regimen initially received by the subject.  
• 
Data will be listed by treatment group, site ID, and subject.   
• 
Planned times relative to investigational product dosing will be used in all summary 
tables and figures. 
• 
Actual, rather than planned, sampling times will be used in the derivation of PK 
parameters and in the individual concentration-time plots.  Planned times will be 
used in the descriptive summaries and in mean and median plots. Listings of PK 
concentration-time data will be done by actual sampling times relative to dosing 
time. 
• 
Unless stated otherwise, descriptive summaries will include n, mean, standard 
deviation (SD), median, minimum and maximum for continuous variables and n and 
percent for categorical variables.  Display minimum and maximum in the same 
precision as data was collected, mean and median using 1 additional decimal place, 
and SD using 2 additional decimal places.   
• 
This is a multicenter study.  Data from all study sites will be integrated and no 
controlling for site-effect will be considered in the statistical analyses. 
• 
Analyses are to be performed using the SAS System, Version 9.4 or higher.  
Programs will be imported into HARP and the final output will be produced by 
running drivers in HARP.  Some graphics may be produced using the TSCG (Tibco 
Spotfire Clinical Graphics) - comprising of S-Plus (R) 7.0.6 or higher.   
• 
Deviations from the analyses in the RAP will be identified in the final CSR. 
 


 
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5.3. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment within 14 days prior to first dose with a non-missing value, 
including those from unscheduled visits. For laboratory data, baseline will be the latest 
non-missing pre-dose value from central lab. If there are multiple assessments on the 
same day, the mean will be used as the baseline value. If a subject has an Unscheduled 
visit for Day 1, collected on the same date as a scheduled visit for Day 1, the planned Day 
1 takes precedence over the Day 1 unscheduled visit. 
For ECG analyses, subject level baseline is defined as the mean of triplicate baseline 
assessments. 
For subjects who did not receive any study intervention during the study, baseline will be 
defined as the latest, non-missing collected value. 
Unless otherwise stated, if baseline data is missing, no derivation will be performed and 
baseline will be set to missing. 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
(within 14 days prior 
to first dose) 
Day 1 (Pre-Dose) 
Efficacy 
Target and non-target 
lesions 
X 
 
Screening visit 
Safety 
Laboratory 
X 
X 
Latest up to Day 1 
Vital Signs  
X 
X 
Latest up to Day 1 
ECG* 
X 
X 
Latest up to Day 1 
*Average of triplicate assessments to be used. 
5.4. 
Multiple Assessments 
All data will be reported according to the nominal visit date for which it was reported 
(that is, no integration will be applied to combine multiple visits on the same day or 
different days during dataset creation). Unscheduled data will only be included in the 
display sections that report worst-case post-baseline (except for PK parameters). For 
summaries that collapse data across multiple planned time intervals, select the mean data 
at each collapsed interval. 
If multiple assessments on different days are reported for the same scheduled assessment, 
then the worst-case assessment for that scheduled assessment will be analysed. 
If multiple assessments are reported on the same date for the same scheduled planned 
time, then the mean of multiple measurements reported for the same date will be 
analysed.  


 
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If a subject has an Unscheduled visit for Day 1, collected on the same date as a scheduled 
visit for Day 1, the planned Day 1 takes precedence over the Day 1 unscheduled visit. 
For ECG data where 3 assessments are collected at each scheduled planned time, the 
average of the 3 measures will be used for analysis at each scheduled planned time. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings. 
5.5. 
Multicentre Studies 
Data from all participating centres will be pooled prior to analysis. 
It is anticipated that 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. 
5.6. 
Examination of Covariates, Other Strata and Subgroups 
5.6.1. 
Covariates and Other Strata 
All analyses are descriptive or unadjusted. No analyses are planned to adjust for any 
covariate and prognostic factor. 
5.6.1. 
Examination of Subgroups 
For Part 2, the efficacy analyses were planned to be conducted by disease cohort and by 
MTAP status. However, due to the early termination of the study, this will no longer be 
performed.  
5.7. 
Multiple Comparisons and Multiplicity 
No formal statistical comparison will be performed; therefore, no adjustments for 
multiple comparisons or multiplicity are planned. 
5.8. 
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 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Treated population, unless 
otherwise specified. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, populations analysed, demographic and baseline characteristics, prior and 
concomitant medications, exposure, and disease characteristics at initial diagnosis and at 
screening, will be based on GSK Core and Oncology Data Standards. Details of the 
planned displays are presented in  Appendix 10: List of Data Displays. 
6.2. 
Subject’s Disposition 
A summary of subject status and reason for study withdrawal and a summary of treatment 
status and reasons for discontinuation of study treatment will be presented. Reason for 
study withdrawal and reason for study treatment discontinuation will be listed separately.  
A summary and listing of screening status and screen failures will be provided using the 
screened population. 
Number of subjects by country and site will be summarized, along with a summary of 
study populations.  
6.3. 
Protocol Deviations 
Only important protocol deviations will be summarised and all protocol deviations will 
be listed. Protocol deviations will be classified as ‘important’ and ‘non-important’ based 
on Protocol Deviation Specifications. 
 A separate listing of inclusion/exclusion deviations will also be provided. 
6.4. 
Demographic Characteristics 
The demographic characteristics (e.g. race, race detail, age, ethnicity, sex, height, and 
baseline body weight) will be summarized and listed. Age, height, and weight will be 
summarized using the mean, standard deviation, minimum, median and maximum. Age 
will be also categorized as ≤18, 19-64, ≥65, per the GSK IDSL standard. The count and 
percentage will be computed for race, sex, and ethnicity. 
In a separate summary, age will be categorized as 18-64, 65-84 and ≥85 using EudraCT 
standard. Subject-level race detail will be listed. 
.  


 
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6.5. 
Concomitant Medications 
All concomitant medications will be summarized. Concomitant medications will be 
coded using GSK Drug coding dictionary and summarized. The summary of concomitant 
medications will show the number and percentage of participants taking concomitant 
medication by Ingredient. Multi-ingredient products will be summarized by their separate 
ingredients rather than as a combination of ingredients. Anatomical Therapeutic 
Chemical (ATC) classification Level 1 (Body System) information will be included in the 
dataset created but will not appear in the summary.  
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes Amoxycillin on two separate 
occasions, the participant is counted only once under the ingredient ‘Amoxycillin’. In the 
summary of concomitant medications, the ingredients will be summarized by the base 
only. 
6.6. 
Exposure Analysis 
Summaries of study treatment exposure will be created. This analysis is described in 
Section 8.1 ‘Extent of Exposure’. 
6.7. 
Disease Characteristics 
Disease characteristics at initial diagnosis including primary tumor type, histology, 
histological grade, and time since diagnosis to first dose will be summarized and listed. 
Also, disease characteristics at screening including staging, measurable disease, 
metastatic disease, and time since progression to first dose, will be summarized and 
listed. Metastatic disease characteristics at screening, including time since diagnosis of 
metastatic disease, and metastatic disease site, will be listed. Disease burden at baseline 
will also be summarised.  
6.8. 
Prior Anti-Cancer Therapy 
Participant-level data describing all prior anti-cancer therapies and cancer-specific 
surgeries, including the type and duration of therapies, will be provided as listings. 
 


 
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7. 
EFFICACY ANALYSES 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
Thus, only BOR for Part 1 will be summarized by treatment group: CR, PR, overall 
response (CR+PR), SD, PD and NE. All other planned analyses which are described 
below will not be performed. However, overall survival times will be listed and 
summarised.  
7.1. 
Primary Efficacy Analyses 
7.1.1. 
Endpoint / Variables 
Given there are no primary efficacy endpoints for Part 1 of the study and Part 2 analyses 
are not being performed, no primary efficacy analyses will be performed. 
7.2. 
Secondary Efficacy Analyses 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 
The number and percentage of participants with the BOR in the following response 
categories will be summarized by treatment group: CR, PR, overall response (CR+PR), 
SD, PD and NE. The corresponding exact 95% CI for ORR will also be provided. 
Participants with unknown or missing responses will be treated as non-responders, i.e., 
these participants will be included in the denominator when calculating percentages of 
response.  
7.2.1. 
Summary Measure 
A participant-level data listing of BOR will be provided, including the name of the 
corresponding visit, date of the response assessment, study day, and observed response.  
7.2.2. 
Population of Interest  
The secondary efficacy analyses will be based on All-Treated population, unless 
otherwise specified. 
7.2.3. 
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. 


 
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Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 
7.3. 
Exploratory Efficacy Analyses 
The Dose Escalation Committee (DEC) evaluated the DL100mg cohort and deemed it 
safe, but upon review of the cumulative safety, efficacy, PK and PD data, GSK decided 
that no further enrolment will take place on the study. As a result, all analyses 
corresponding to Part 2, as well as the Exploratory Objectives for both Part 1 and Part 2, 
will not be performed. However, all other Part 1 analyses will be performed. 


 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the All-Treated population, unless otherwise 
specified. 
8.1. 
Extent of Exposure 
Subject level details for extent of exposure to study treatment will be listed. The listing 
will be sorted by part, disease cohort, site, and subject ID. It will include start and stop 
dates, scheduled dose, actual dose, and number of days on the study treatment. 
The details of the planned displays are provided in Appendix 10: List of Data Displays. 
8.2. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs) and Serious 
(SAEs) will be based on GSK Core Data Standards.  
Dose limiting toxicity (DLT) will also be summarized and listed according to GSK 
Oncology Data Standards.  
AEs will be graded by the investigator according to the National Cancer Institute- 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0. AEs will be coded to 
the Preferred Term (PT) level using the Medical Dictionary for Regulatory Affairs 
(MedDRA).  
An overview summary of AEs, including counts and percentages of subjects with any 
AEs leading to dose reductions of GSK3368715 and AEs leading to dose interruptions of 
GSK3368715 will be produced. Separate listings of fatal serious adverse events (SAEs), 
non-fatal SAEs, reasons for considering as a SAE, AEs leading to permanent 
discontinuation of GSK3368715, AEs leading to dose interruptions of GSK3368715, AEs 
leading to dose reductions of GSK3368715, will be produced. 
Non-serious AEs that occurred in strictly 5% or more subjects (no rounding for the 
percentage will be used in terms of 5% threshold, e.g. events with 4.9% incidence rate 
should not be included in this table) will be summarized by PT.  
A summary of number and percentage of subjects with any AEs 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 subject: 
• 
Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade. 
• 
Any event row: Each subject with at least one AE will be counted only once at the 
maximum grade no matter how many events they have. 
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed by descending order of total incidence by SOC and PT. In the SOC row, the 


 
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number of subjects with multiple events under the same system organ class will be 
counted once.  
A study treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst-case scenario approach will be taken to 
handle missing relatedness data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. A summary table of study treatment-
related AEs by maximum grade will be displayed in descending order of total incidence 
by PT only.  
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced. 
The details of the planned displays are provided in Appendix 10: List of Data Displays. 
8.3. 
Deaths and Serious Adverse Events 
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date from this subject including death is supposed to appear in the database, which should 
be part of the data cleaning process. All deaths will be summarized based on the number 
and percentage of subjects. This summary will classify subjects by primary cause of 
death. A supportive listing will be generated to provide subject-specific details on 
subjects who died. 
A summary of the number and percentage of subjects and the number of occurrences of 
serious, drug-related serious adverse events will be created. 
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. The frequency and percentage of SAEs will be summarized in 
descending order of total incidence by PT only. 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.  
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for 
• 
Fatal SAEs  
• 
Non-fatal SAEs 
Reasons for AE considered as a SAE will be listed. 
8.4. 
Adverse Events Leading to Dose Modification of Study 
Treatment 
The following categories of AEs will be summarized separately in descending order of 
total incidence by PT only and separate supportive listings will be generated with subject 
level details for those subjects: 


 
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• 
SAEs Leading to Permanent Discontinuation of GSK3368715  
• 
AEs Leading to Dose Interruptions of GSK3368715 
• 
AEs Leading to Dose Reductions of GSK3368715 
8.5. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests and 
haematology laboratory tests will be based on GSK Core Data Standards. The details of 
the planned displays are in Appendix 10: List of Data Displays. 
Summaries by visit will include data from scheduled assessments only, and all data will 
be reported according to the nominal visit date for which it was recorded (i.e., no visit 
windows will be applied).  
Clinical Laboratory Tests are listed in Table 1. 
Table 1 
List of Clinical Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Count 
Hemoglobin 
Hematocrit 
RBC Indices: MCV, MCH, %Reticulocytes 
WBC count with Differential: Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils 
Clinical 
Chemistry 
BUN 
Creatinine 
Glucose 
Lipase 
Potassium 
Sodium 
Calcium 
Amylase 
AST (SGOT) 
ALT (SGPT) 
Alkaline phosphatase 
Total and direct bilirubin 
Total protein 
Albumin 
Coagulation 
PTT, PT/INR 
Routine 
Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, and ketones by dipstick 
• Microscopic examination (if blood or protein is abnormal) 


 
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Other 
Screening 
Tests 
• Highly sensitive serum or urine Beta human chorionic 
gonadotropin (βhCG) pregnancy test (as needed for women of 
childbearing potential) 
• Serology (HIV antibody, HBsAg, and hepatitis C virus antibody) 
• Cardiac Troponin I or TroponinT (local standard, no point-of-care 
assay) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; βhCG = 
beta-human chorionic gonadotropin; BUN = blood urea nitrogen; HBsAg = Hepatitis B surface 
antigen; MCH = mean corpuscle hemoglobin; MCV = mean corpuscle volume; RBC = red blood 
cells; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic 
transaminase; WBC = white blood cells 
 
Laboratory grades will be reported using the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. 
Summary of lab values change from baseline by scheduled visits using mean, median, 
standard deviation, minimum, and maximum will be provided. This will be done 
separately by chemistry and haematology tests.  
Missing baseline grade will be assumed as grade 0. For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labeled by direction, 
e.g. sodium will be summarized as hyponatremia and hypernatremia. 
A supporting listing of laboratory data for subjects with any value outside normal range 
will be provided. This will be done separately by chemistry and haematology tests. A 
separate listing of laboratory data with character values will also be provided. 
Detailed derivation of baseline assessment is specified in Section 5.3. 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
8.5.1. 
Performance Status 
ECOG performance status will be summarized at baseline and post-baseline scheduled 
visits. Summaries will use frequency and percentage of subjects at each planned 
assessment time. A summary of change from baseline by scheduled visits will be 
performed. 
8.5.2. 
ECG 
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits Also a summary of change from baseline in ECG values by visit will be 
produced. 


 
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8.5.3. 
Vital Signs 
Vital signs change from baseline will be summarized by scheduled visit using mean, 
median, standard deviation, minimum and maximum.  
In addition, vital sign values will be categorized as follows: 
• 
Systolic BP (mmHg):  
Grade 0 (<120), Grade 1 (120-139), Grade 2 (140-159) and Grade 3 (≥160) 
• 
Diastolic BP (mmHg):  
Grade 0 (<80), Grade 1 (80-89), Grade 2 (90-99), and Grade 3 (≥100) 
• 
Heart rate (beats/min): 
<60, 60-100, and >100 
• 
Temperature (°C):  
≤35, 36-37, ≥38 
A listing of vital signs with values of potential clinical importance will be provided. 
8.5.4. 
Pregnancies 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If subjects and subjects’ partner become 
pregnant while on the study, the information will be included in the narratives and no 
separate table or listing will be produced. 


 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Endpoint / Variables 
9.1.1. 
Drug Concentration Measures 
Two major metabolites of GSK3368715, GSK3963583 and GSK3983164, have been 
observed in humans.  
Concentration of GSK3368715 and metabolites (GSK3963583 and GSK3983164) in the 
plasma will be listed for each subject in ng/mL. 
Individual plots of concentration over time will be provided for each analyte using actual 
elapsed time for GSK3368715 and metabolites (GSK3963583 and GSK3983164) in 
ng/mL. 
Summaries of plasma concentration will be produced separately for GSK3368715 and 
metabolites (GSK3963583 and GSK3983164) in ng/mL. Plasma concentration-time data 
will be summarized using descriptive statistics (n, mean, SD, median, minimum and 
maximum) by planned relative assessment time. 
Mean and/or median values will be plotted over nominal time. GSK3368715 and 
metabolites (GSK3963583 and GSK3983164) concentration-time profiles will be 
overlaid on the same plot once concentrations have been converted to nM concentrations. 
The molecular weight of GSK3368715 and metabolites (GSK3963583 and 
GSK3983164) are 366.54 g/mol, 338.49 g/mol and 338.49 g/mol respectively. The 
concentration in nM will be computed for: 
- GSK3368715 as GSK3368715 concentration in ng/mL / molecular weight of 366.54 * 
1000 
- GSK3963583 as GSK3963583 concentration in ng/mL / molecular weight of 338.49 * 
1000 
- GSK3983164 as GSK3983164 concentration in ng/mL / molecular weight of 338.49 * 
1000. 
9.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters including Cmax, Tmax, AUC, AUC0-t, AUC0-tau, AUCinf, 
t½, λz will be calculated by standard non-compartmental analysis according to current 
working practices and using the currently supported version of WinNonlin. All 
calculations of non-compartmental parameters will be based on actual sampling times 
and concentrations in ng/mL. Pharmacokinetic parameters listed in Table 2 will be 
determined from the concentration-time data for GSK3368715 and metabolites 
(GSK3963583 and GSK3983164), as data permits.  
 


 
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Table 2 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
Cmax 
Maximum observed concentration; determined directly from the 
concentration-time curve. 
Tmax 
Time from first administration to occurrence of Cmax; determined directly from 
the concentration-time curve. 
Cτ 
Also referred to as “Ctrough”; observed concentration at the end of a dosing 
interval, immediately before the next administration; determined directly from 
the concentration-time curve. 
AUC(0-t)  
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) 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 extrapolated to infinity will be 
calculated as:  
AUC = AUC(0-t) + C(t) / lambda_z  
This will be calculated for Week 1/Day 1 only 
AUC(0-τ) 
Area under the concentration-time curve from time zero to the predose of the 
next dose. 
λz 
Apparent terminal phase elimination rate constant 
t½ 
Apparent terminal half-life will be calculated as: 
t½ = ln2 / λz 
TI 
Time invariance 
 
AR 
Accumulation ratio 
 
RCMAXM1 Metabolite to drug Cmax ratio 
RCMAXM1 = (Cmax of GSK3963583* MW of GSK3368715)/(Cmax of 
GSK3368715* MW of GSK396358) 


 
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Parameter 
Parameter Description 
RCMAXM2 Metabolite to drug Cmax ratio 
RCMAXM2 = (Cmax of GSK3983164* MW of GSK3368715)/ (Cmax of 
GSK3368715 * MW of GSK3983164) 
RAUCM1 
Metabolite to drug AUC(0-t) ratio 
RAUCM1 = (AUC(0-t) of GSK3963583* MW of GSK3368715)/(AUC(0-
t) of GSK3368715* MW of GSK396358) 
RAUCM2 
Metabolite to drug AUC(0-t) ratio 
RAUCM2 = (AUC(0-t) of GSK3983164* MW of GSK3368715)/ (AUC(0-
t) of GSK3368715 * MW of GSK3983164) 
 
The parameters which involve derivation of ratios including TI, AR, RCMAXM1,  
RCMAXM2, RAUCM1 and RAUCM1 will computed by Statistics and Programming. 
 
 
9.1.3. 
Statistical Analysis of Pharmacokinetic Parameters 
Plasma concentration-time data will be listed by dose, cohort and study day and 
summarized using descriptive statistics (n, mean, SD, median, minimum and maximum) 
by planned relative assessment time. Mean and/ or median values will be plotted over 
time. Individual plasma pharmacokinetic parameters values as well as a descriptive 
summary (mean, standard deviation, median, minimum, maximum, geometric mean, and 
the standard deviation, CV% and 95% confidence interval of log-transformed parameters 
(if applicable)) by dose, cohort and study day will be reported. 
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles).  
9.1.3.1. 
Dose Proportionality  
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-) or AUC(0-24), steady state), 
will be plotted as a function of the dose administered. Dose proportionality of AUC and 
Cmax for GSK3368715 following single dose administration and AUC(0-) or AUC(0-
24) 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 


 
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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.   
Part 1 Dose Proportionality Analysis 
Endpoint(s) 
• Cmax and AUC (AUC(0-∞), single dose, and AUC(0-) or AUC(0-24), steady state 
Model Specification 
• Proc Mixed code for dose proportionality analysis: 
PROC MIXED data=pkpar; 
BY paramcd; 
CLASS subjid; 
MODEL logpk = logdose / ddfm=kr; 
RANDOM subjid; 
RUN; 
Model Checking & Diagnostics 
• Refer to Appendix 10: Model Checking and Diagnostics for Statistical Analyses. 
9.1.4. 
Population of Interest  
The primary PK analyses will be based on the PK Population, unless otherwise specified. 
 
10. 
BIOMARKER ANALYSES 
Biomarker data is being collected, but there will be no biomarker analyses conducted. 
11. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
No POPPK analyses will be conducted.  
12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
No pharmacokinetic/pharmacodynamic analyses will be conducted.  


 
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13. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
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. 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statistics Med. 2008;27:2420-39. 
 


 
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14. 
APPENDICES 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
14.1.1. 
Exclusions from Per Protocol Population 
No Per Protocol population is defined and used for this study. 
 
 


 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
Refer to Protocol Section 1.3. 
 


 
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14.3. 
Appendix 3: Assessment Windows 
No assessment window will be applied. 
 


 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phases 
14.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
• 
Medication End Date < Study Treatment Start Date 
Concomitant 
• 
Study Treatment Start Date  ≤ Medication End Date ≤ Study Treatment Stop Date 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of partially missing dates for 
concomitant medication. 
 


 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software TSCG will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: gsk3368715\mid207675 
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 upon request. 
14.5.2. 
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  
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 subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables, except in cases where worst-case post-
baseline is calculated.  
• 
Unscheduled visits will not be included in figures, unless otherwise specified. 
• 
All unscheduled visits will be included in listings. 


 
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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 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic 
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 SOP_00000314000: Non-compartmental Analysis 
of Clinical Pharmacokinetic Data. 
Note: Concentration values will be imputed as per GUI_51487. 
ADPC data file  
To create ADPC the SDTM PC domain dataset will be merged with the 
Subject-Level Analysis Dataset (to get demographic information) and 
with SDTM EX domain (to get reference timepoint date). 
Reference timepoint date will be populated for both study drug and active 
metabolite based on study treatment information from SDTM EX 
domain. 
To populate analysis values in ADPC (AVAL(C)) adjustments to the 
PCSTRESN will be done based on imputation rules from "Non-
Compartmental Analysis of Pharmacokinetic Data, CPMS Global" 
document. 
Total Moiety parameter will be added, along with concentrations of study 
drug and active metabolite, and derived as the sum of study drug and 
active metabolite concentrations converted to nM units. 
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 summarised graphical 
displays only. Assign zero to NQ values. 
Pharmacokinetic Parameter Derivation 
PK Parameters to 
be Derived by PK 
Programmer 
The following PK parameters will be derived by the Programmer: Cmax, 
Tmax, and Cτ. 
Pharmacokinetic Parameter Data 
Is NQ impacted 
PK Parameters 
Rule Being 
Followed 
Yes. Refer to Standards for Handling NQ Impacted PK Parameters.  
 


 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
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 multiple assessments on different days are reported for the same scheduled assessment, then the 
worst-case assessment for that scheduled assessment will be analysed. 
• 
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 
• 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / 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 CR) is assigned to the latest 
date of disease assessment; for other response categories (SD, NE, PD), the date of response is 
assigned to the earliest date of disease assessments.    
Date of New Anti-Cancer Therapy 
• 
Derived as the earliest date of new anti-cancer systemic therapy, radiotherapy or cancer-related 
surgical procedure. 
• Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules 
specified in Section 14.7.2.1. 
14.6.2. 
Study Population 
Extent of Exposure 
• 
Missing treatment stop date will be imputed following rules specified in Section 14.7.2.1. 
• 
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 enrolled but did not report a treatment start date will be categorized 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. 


 
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Time since Initial Diagnosis 
• 
Calculated as the number of days from the Date of Initial Diagnosis: 
o If First Dose Date is missing           → Elapse Time = Missing  
o If Date of Initial Diagnosis is completely/partially missing       → Elapse Time = Missing  
o Otherwise       → Elapse Time = First Dose Date – Date of Initial Diagnosis + 1            
• 
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. 
 
14.6.3. 
Safety 
 
14.6.4. 
Efficacy  
Refer to Section 7 for endpoint derivation and information. 
 
 
 
Adverse Events 
Duration of AE 
• 
Calculated as the number of days from AE Start Date to AE Stop Date: 
o AE Start Date = Missing              → Elapse Time = Missing  
o AE Stop Date = Missing              → Elapse Time = Missing 
o Otherwise                                    → Elapsed Time = AE Stop Date – AE Start Date + 1 
o 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. 


 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
A participant enrolled in Part 1 will be considered to have completed the study if they 
are DLT-evaluable, i.e.: 
o they complete screening assessments, at least 21 days of study intervention 
and the post-intervention follow-up visit, or 
o they discontinue study intervention before Day 21 due to drug related toxicity. 
Participants who discontinue study intervention before day 21 or who received 
less than 75% of the intended dose in the first 21 days for reasons other than 
study drug related toxicity are not considered to have completed 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.  
14.7.2. 
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 subject 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. 
14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject 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. 
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: 
▪ 
If study treatment start date is missing (i.e. participant did not start study 
treatment), then set AE start date = 1st of month. 
▪ 
Else if study treatment start date is not missing: 
If month and year of AE start date = month and year of study treatment 
start date then 


 
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Element 
Reporting Detail 
 If AE stop date contains a full date and is earlier than study 
treatment start date, then set AE start date= 1st of month. 
 Else set AE start date = study treatment start date. 
Else set AE start date = 1st of month. 
o Missing Start Day and Month: 
▪ 
If study treatment start date is missing (i.e. participant did not start study 
treatment), then set AE start date = January 1. 
▪ 
Else if study treatment start date is not missing: 
If year of AE start date = year of study treatment start date then 
 If AE stop date contains a full date and is earlier than study 
treatment start date, then set AE start date = January 1. 
 Else set AE start date = study treatment start date. 
Else set AE start date = January 1. 
• 
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 
• 
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., subject 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., subject 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 
• 
Completing 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  


 
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Element 
Reporting Detail 
o If day is missing 
‒ Earliest of (last day of the month, date of last contact) will be used 
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, and surgical procedures 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; 
Prior Anti-Cancer 
Therapy/ 
Radiotherapy/ 
Surgical 
Procedures 
Start and end dates are generally not imputed. If start or end dates need to be imputed 
for an analysis (e.g., to calculate duration of prior therapy or elapsed time as 
covariates for efficacy analyses), following rules will be applied. Imputed dates are not 
used for summary of anti-cancer therapy or radiotherapy.  
• 
If start/end date is completely missing or both day and month are missing, no 
imputation will be applied 
• 
If day is missing for start date, first of the month will be used 
• 
If day is missing for stop date,  
o If first dosing date is the first of the month, minimum of (last day of the month, 
first dosing date) will be used 
o Else minimum of (last day of the month, first dosing date - 1) will be used 
Date of initial 
diagnosis/ Last 
recurrence/ 
Last progression 
Imputed to derive elapsed time (e.g., time since initial diagnosis, time from last 
progression); not used for summary of disease characteristics at initial diagnosis 
• 
If both month and day are missing, first of January will be used 
• 
If only day is missing, first of the month will be used 
Treatment end 
date 
• 
If there is more than one study treatment, imputation of missing treatment end 
date will be applied to all applicable treatments following rules below and 
treatment end date is the latest treatment end date across all study treatments. 
• In general, completely missing end dates are not imputed, with the following 
exceptions for imputation of missing treatment end date at interim analyses. 
• For imputation of missing exposure end date at an interim analysis when subjects 
are still on treatment, the following conventions will be applied: 


 
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Element 
Reporting Detail 
o If the missing end date is in the last exposure record, the earliest of: the date 
of the data cut-off, the date of permanently discontinued from the study 
treatment, the date of withdrawal from the study, or the death date will be 
used  
o If the missing end date is not in the last exposure record, treatment start date 
for the record will be used 
• The imputed treatment end date will be used to calculate cumulative dose and 
duration of treatment as specified in Section 14.6.2.  


 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) will be used to 
assign grades for laboratory parameters including clinical chemistry, hematology, liver 
function tests, QTc (Fridericia’s) values, and vital signs (heart rate, blood pressure, 
temperature).  
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. 
14.8.1. 
ECG 
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance:  
To identify QTc (Fridericia’s) values of potential clinical importance, NCI-CTCAE v5.0 
will be used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’). The CRF collects QTcF. Note that there is a slight inconsistency between 
CTCAE v5.0 and ICH E14 (Absolute QTc interval prolongation). It was decided to align 
with CTCAE for the oncology standard categories. 
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute QTcF interval 
450 to <481 (Grade 1) 
481 to <501 (Grade 2) 
501 (Grade 3) 
Msec 
Increase from baseline 
QTcF 
Increase of 31 to 60 
Increase of >60 
Msec 
 
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance:  
ECG Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute PR interval 
<110 (Low) 
>220 (High) 
Msec 
Absolute QRS interval 
<75 (L) 
>110 (H) 
Msec 
 
 


 
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14.8.2. 
Vital Signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v5.0 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’. 
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance: 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Heart Rate 
<60 (Low) 
>100 (High) 
bpm 
 
To identify blood pressure values of potential clinical importance, NCI-CTCAE v5.0 will 
be used to assign categories that align with the grades for ‘Hypertension’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Systolic 
Blood Pressure 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
mmHg 
Absolute Diastolic 
Blood Pressure 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
mmHg 
 
To identify temperature values of potential clinical importance, NCI-CTCAE v5.0 will be 
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Absolute Temperature 
35 (Low) 
38 (High) 
Degrees 
C 
 
 


 
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14.9. 
Appendix 9: Abbreviations & Trademarks 
14.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
A&R 
Analysis and Reporting  
BOR 
Best Overall Response 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
DBF 
Database Freeze 
DBR 
Database Release 
DEC 
Dose Escalation Committee 
DOB 
Date of Birth 
DOR 
Duration of response 
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 
IFA 
Interim futility analysis 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MTD 
Maximum-tolerated Dose 
N-CRM 
Neuenschwander continual reassessment method 
NSCLC 
Nonsmall-cell lung carcinoma 
ORR 
Objective response rate 
OS 
Overall survival 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 


 
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Abbreviation 
Description 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RP2D 
Recommended Phase 2 Dose 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SDTM 
Study Data Tabulation Model 
SoA 
Schedule of Assessments 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
TTR 
Time to response 
14.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
SAS 
 
 
 
 


 
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14.10. 
Appendix 10: List of Data Displays 
14.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.16 
N/A 
Efficacy 
2.1 
N/A 
Safety 
3.1 to 3.24 
N/A 
Pharmacokinetic 
4.1 to 4.2 
4.11 to 4.15 
Section 
Listings 
ICH Listings 
1 to 30 
Other Listings 
31 to 39 
 
14.10.2. 
Deliverables 
Delivery 
Description 
DE 
Dose Escalation 
SAC 
Final Statistical Analysis Complete 
 


 
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14.10.3. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
All Treated 
ES8 
Summary of Subject Status and Reason for Study Withdrawal 
ICH E3, FDAAA, EudraCT 
SAC 
1.2. 
All Treated 
SD4 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
SAC 
1.3. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
SAC 
1.4. 
Screened 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
SAC 
1.5. 
All Treated 
ES11 
Summary of Outcome of Adverse Events which Led to Study 
Withdrawal at Each Study Period/Phase 
EudraCT 
SAC 
Protocol Deviation 
1.6. 
All Treated 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Population Analysed 
1.7. 
Screened 
SP1A 
Summary of Study Populations  
IDSL 
SAC 
Demographic and Baseline Characteristics 
1.8. 
All Treated 
DM1 
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC 
1.9. 
Screened 
DM11 
Summary of Age Ranges 
EudraCT 
SAC 
Prior and Concomitant Medications 
1.10. 
All Treated 
MH1 
Summary of Past Medical Conditions 
ICH E3 
SAC 
1.11. 
All Treated 
MH1 
Summary of Current Medical Conditions 
ICH E3 
SAC 
1.12. 
All Treated 
CM8 
Summary of Concomitant Medications by Ingredient 
ICH E3 
SAC 
Exposure 
1.13. 
All Treated 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
SAC 


 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Disease Characteristics 
1.14. 
All Treated 
DC1 
Summary of Disease Characteristics at Initial Diagnosis 
ICH E3 
SAC 
1.15. 
All Treated 
DC2 
Summary of Disease Characteristics at Screening 
ICH E3  
SAC 
1.16. 
All Treated 
LA1 
Summary of Disease Burden at Baseline 
ICH E3 
SAC 
14.10.4. 
Efficacy Tables 
 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Responses 
2.1.  
All Treated 
RE1a 
Summary of Best Response without Confirmation (RECIST 1.1 
Criteria) 
 
SAC 


 
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14.10.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.1.  
All Treated 
AE5B 
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.2.  
All Treated 
AE5B 
Summary of All GSK3368715-Related Adverse Events by 
System Organ Class and Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.3.  
All Treated 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences) 
FDAAA, EudraCT 
 
SAC 
3.4.  
All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions 
 
SAC 
3.5.  
All Treated 
AE3 
Summary of Adverse Events Leading to Dose Interruptions 
 
SAC 
Serious Adverse Events 
3.6.  
All Treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
SAC 
3.7.  
All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment by Overall Frequency 
IDSL 
SAC 
3.8.  
All Treated 
AE3 
Summary of Drug-Related Serious Adverse Events 
 
SAC 
Deaths 
3.9.  
All Treated 
DTH1a 
Summary of Deaths 
IDSL 
Report time to death from last dose (in 
days) as in the mock 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory: Chemistry  
3.10. 
All Treated 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3 
SAC 
3.11. 
All Treated 
LB18 
Summary of Chemistry Grade Changes from Baseline 
ICH E3 
SAC 
3.12. 
All Treated 
LB3 
Summary of Chemistry Changes from Baseline with Respect to 
the Normal Range 
ICH E3 
SAC 
Laboratory: Haematology 
3.13. 
All Treated 
LB1 
Summary of Haematology Changes from Baseline 
ICH E3 
SAC 
3.14. 
All Treated 
LB18 
Summary of Haematology Grade Changes from Baseline 
ICH E3 
SAC 
3.15. 
All Treated 
LB3 
Summary of Haematology Changes from Baseline with Respect 
to the Normal Range 
ICH E3 
SAC 
ECG 
3.16. 
All Treated 
EG1 
Summary of ECG Findings  
IDSL 
SAC 
3.17. 
All Treated 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
SAC 
Vital Signs 
3.18. 
All Treated 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC 
Dose Modifications 
3.19. 
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK3368715 
ICH E3 
SAC 
3.20. 
All Treated 
ODMOD2 
Summary of Dose Interruptions of GSK3368715 
ICH E3 
SAC 
3.21. 
All Treated 
ODMOD8 
Summary of Dose Escalations of GSK3368715 
If applicable. 
SAC 
Dose Limiting Toxicity (DLT) 
3.22. 
All Treated 
DL1 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
ICH E3 
SAC 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Performance Status 
3.23. 
All Treated 
PS1A 
Summary of ECOG Performance Status 
ICH E3 
SAC 
3.24. 
All Treated 
PS3A 
Summary of Change in ECOG Performance Status from 
Baseline 
 
SAC 
 


 
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14.10.6. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
PK 
4.1 
PK 
PK01 
Summary of GSK3368715 Pharmacokinetic Concentration-
Time Data by Dose Level, Cohort and Study Day 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL 
 Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 
4.2 
PK 
PK01 
Summary of GSK3963583 Pharmacokinetic Concentration-
Time Data by Dose Level, Cohort and Study Day 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL  
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 
4.3 
PK 
PK01 
Summary of GSK3983164 Pharmacokinetic Concentration-
Time Data by Dose Level, Cohort and Study Day 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL  
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
4.4 
PK 
PK06 
Summary of Derived GSK3368715 Pharmacokinetic 
Parameters by Dose Level, Cohort and Study Day 
PK parameters: Cmax, Tmax, 
Ctrough, AUC0-t, AUC0-tau, 
AUCinf, t½, λz, TI and AR 
determined from the concentration-
time data in ng/ml; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable. 
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 
4.5 
PK 
PK06 
Summary of Derived GSK3963583 Pharmacokinetic 
Parameters by Dose Level, Cohort and Study Day 
PK parameters: Cmax, Tmax, 
Ctrough, AUC0-t, AUC0-tau, 
AUCinf, t½, λz, TI, AR,  RCMAXM1 
and RAUCM1 determined from the 
concentration-time data in ng/ml; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable. 
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 


 
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Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
4.6 
PK 
PK06 
Summary of Derived GSK3983164 Pharmacokinetic 
Parameters by Dose Level, Cohort and Study Day 
PK parameters: Cmax, Tmax, 
Ctrough, AUC0-t, AUC0-tau, 
AUCinf, t½, λz, TI, AR, RCMAXM2 
and RAUCM2 determined from the 
concentration-time data in ng/ml; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable. 
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 
4.10 
PK 
 
Summary Results of Single Dose Proportionality Assessment 
Using Power Model for GSK3368715 
 
SAC 


 
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14.10.7. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable  
PK 
4.11 
PK 
PK16 
Individual GSK3368715 Concentration-Time Plots (Linear and 
Semi-Log)by Dose Level, Cohort and Study Day 
ng/mL 
SAC 
4.12 
PK 
PK16 
Individual GSK3963583 Concentration-Time Plots (Linear and 
Semi-Log) by Dose Level, Cohort and Study Day 
ng/mL 
SAC 
4.13 
PK 
PK16 
Individual GSK3983164 Concentration-Time Plots (Linear and 
Semi-Log) by Dose Level, Cohort and Study Day 
ng/mL 
SAC 
4.14 
PK 
PK17 
Mean Concentration-Time Plots (Linear and Semi-Log) by 
Dose Level, Cohort and Study Day 
GSK3368715 and metabolites 
(GSK3963583 and GSK3983164) 
concentration time profiles will be 
overlaid on the same plot once 
concentrations have been 
converted to nM concentrations. 
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 
4.15 
PK 
PK18 
Median Concentration-Time Plots (Linear and Semi-Log) by 
Dose Level, Cohort and Study Day 
GSK3368715 and metabolites 
(GSK3963583 and GSK3983164) 
concentration time profiles will be 
overlaid on the same plot once 
concentrations have been 
converted to nM concentrations. 
Note: Separate 100mg dose by 
Dose Escalation, PK/PD and 
Combined (Dose Escalation and 
PK/PD) Cohorts. 
SAC 


 
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14.10.8. 
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 
ICH E3 
SAC 
3.  
All Treated 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC 
Protocol Deviations 
4.  
All Treated 
DV2 
Listing of Protocol Deviations  
ICH E3 
Report all PDs 
SAC 
5.  
All Treated 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC 
Demographic and Baseline Characteristics 
6.  
All Treated 
DM2 
Listing of Demographic Characteristics 
ICH E3 
SAC 
7.  
All Treated 
DM9 
Listing of Race 
ICH E3 
SAC 
Prior and Concomitant Medications 
8.  
All Treated 
CP_CM3  
Listing of Concomitant Medications 
IDSL 
Note: IDSL shell in development. 
Required for ClinPharm studies 
instead of a corresponding table. 
Not required for studies where a 
table is produced. 
SAC 
Exposure 
9.  
All Treated 
OEX3A 
Listing of Treatment Exposure to GSK3368715 
ICH E3 
DE, SAC 
Dose Modifications 
10.  
All Treated 
ODMOD10A 
Listing of Dose Reductions 
ICH E3 
SAC 


 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
11.  
All Treated 
ODMOD11A 
Listing of Dose Interruptions 
ICH E3 
SAC 
Response 
12.  
All Treated 
RE5 
Listing of Responses without Confirmation (RECIST 1.1 
Criteria) 
 
SAC 
13.  
All Treated, 
 
RE12 
Listing of Subject Best Response 
 
SAC 
Adverse Events 
14.  
All Treated 
AE8 
Listing of All Adverse Events 
ICH E3 
DE, SAC 
15.  
All Treated 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC 
Serious and Other Significant Adverse Events 
16.  
All Treated 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC 
17.  
All Treated 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC 
18.  
All Treated 
AE14 
Listing of Reasons for Considering as a Serious Adverse 
Event 
ICH E3 
SAC 
19.  
All Treated 
AE8 
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment 
ICH E3 
SAC 
20.  
All Treated 
AE8 
Listing of Adverse Events Leading to Dose Interruptions of 
Study Treatment 
ICH E3 
SAC 
21.  
All Treated 
AE8 
Listing of Adverse Events Leading to Dose reductions of 
Study Treatment 
ICH E3 
SAC 
Dose-Limiting Toxicities 
22.  
All Treated 
DL3 
Listing of Dose-Limiting Toxicities (DLT) During the 
Determinative Period 
 
SAC 


 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Deaths 
23.  
All Treated 
DTH3 
Listing of Deaths 
ICH E3 
SAC 
All Laboratory 
24.  
All Treated 
LB5A 
Listing of All Chemistry Laboratory Data for Participants with 
Any Value of Outside Normal Range 
ICH E3 
SAC 
25.  
All Treated 
LB5A 
Listing of All Hematology Laboratory Data for Participants with 
Any Value of Outside Normal Range 
ICH E3 
SAC 
26.  
All Treated 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC 
ECG 
27.  
All Treated 
EG3 
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
SAC 
28.  
All Treated 
OECG5A 
Listing of QTcF Values of Potential Clinical Importance 
 
SAC 
Vital Signs 
29.  
All Treated 
OVT7A 
Listing of Vital Signs with Values of Potential Clinical 
Importance 
 
SAC 
Performance Status 
30.  
All Treated 
PS5A 
Listing of Performance Status 
 
SAC 
 


 
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14.10.9. 
Non-ICH Listings 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Disease Characteristics 
31.  
All Treated 
DC3 
Listing of Disease Characteristics at Initial Diagnosis 
 
SAC 
32.  
All Treated 
DC4 
Listing of Disease Characteristics at Screening 
 
SAC 
33.  
All Treated 
MD2 
Listing of Metastatic Disease at Screening 
 
SAC 
Anti-Cancer Therapy 
34.  
All Treated 
AC6 
Listing of Prior Anti-Cancer Therapy 
List all prior anti-cancer therapy (but 
not radiotherapy or surgery) 
SAC 
35.  
All Treated 
AC7 
Listing of Prior Anti-Cancer Radiotherapy 
 
SAC 
Surgical Procedures 
36.  
All Treated 
OSP3 
Listing of Prior Cancer Related Surgical Procedures 
 
SAC 
Responses 
37.  
All Treated 
LA5 
Listing of Lesion Assessments (RECIST 1.1 Criteria) 
 
SAC 
PK 
38.  
PK 
PK07 
Listing of Pharmacokinetic Concentration-Time Data by Group 
IDSL 
SAC 
39.  
PK 
PK13  
Listing of Derived Pharmacokinetic Parameters by Group 
IDSL 
SAC