Clinical trial NCT02630251
Conditions: Cancer Neoplasms
Keywords: Cancer Safety GSK2820151 Dose escalation Tolerability Pharmacodynamics Pharmacokinetics
Sponsor: GlaxoSmithKline
Start date: 2016-04-25; Completion date: 2018-12-13
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study drug, GSK2820151, is a Bromodomain (BRD) and Extra-Terminal (BET) inhibitor arising from a distinct structural class. GSK2820151 potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study is to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK2820151 in subjects with advanced or recurrent solid tumors. The objective is to determine the safety, tolerability and maximum tolerated dose (MTD) of GSK2820151 in subjects 18 years or older with advanced or recurrent solid tumors. Eligible subjects with advanced or recurrent solid tumors will be enrolled in the dosing cohorts until MTD is established. All subjects will receive study drug. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent. The duration of study will depend on recruitment rates and the timing of subjects' duration on study (withdrawal rates due to toxicity or progression). It is anticipated that approximately 30 to 50 subjects will be enrolled.

Detailed description:
GSK has decided to discontinue further development of GSK2820151 due to challenges in recruitment.

Arms: arm 1: An accelerated dose escalation phase will be utilized in order to minimize sub-optimal drug exposures, followed by a conventional 3+3 dose escalation phase to achieve MTD. Initially, one subject per dose cohort will be recruited (accelerated dose escalation phase) until the first instance of a \>=Grade 2 drug related toxicity or dose-limiting toxicity (DLT). Further cohorts will be recruited in blocks of three subjects (3+3 dose escalation phase). Projected dose levels are 3 mg, 6 mg, 12 mg, 20 mg, 40 mg, 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg. Additional subjects may be enrolled at previously cleared dose levels in order to obtain further data for PK and/or PD analysis. Once MTD is determined, additional subjects (18 subjects total at MTD) may be enrolled to collect additional safety data.
Interventions: intervention 1: GSK2820151
Intervention descriptions: intervention 1: GSK2820151 is provided as capsules containing 1 mg, 5 mg, 10 mg, 50 mg, or 100 mg of GSK2820151 as free base equivalent to be administered orally. The dosing regimen is as follows: Week 1 - once daily on days 1, 3, 4, and 5; Week 2 - once daily on days 1, 2, 3, 4, 5; and Weeks 3 and beyond - once daily continuously.

Protocol documents:
Prot_000.pdf: 
2014N215112_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201893
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I Open-Label, Dose Escalation Study to Investigate the 
Safety, Pharmacokinetics, Pharmacodynamics, and Clinical 
Activity of GSK2820151 in Subjects with Advanced or 
Recurrent Solid Tumors
Compound Number:
GSK2820151
Development Phase:
I
Effective Date:
08-JUN-2017
Protocol Amendment Number:  04
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2014N215112_04
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201893
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N215112_00
2014-DEC-15
Original
2014N215112_01
2015-JUN-19
Amendment No. 1
Amendment 1 includes, change in the Primary Medical Monitor, the clarification of Dose 
Escalation Schedules (Section 4.2) to make it clearer. Minor corrections in the summary 
of gastrointestinal risk. In light of emerging data from preclinical studies of embryo-fetal 
development, reproductive risk section, inclusion criterion #9 and guidance on 
contraception use were updated. List of prohibited and permitted medicines has been 
revised. Added more clarity on study termination criteria and greater flexibility on W3D4 
PK samples window period. Statement on pregnancy follow-up inserted. Reference list 
updated.
2014N215112_02
2015-OCT-06
Amendment No. 2
Amendment 2 is mainly in response to Food and Drug Administration (FDA) request and 
includes: changes in the Medical Monitors; modified the inclusion criteria and other 
relevant parts of the protocol to allow only patients with histologically or cytologically 
confirmed solid malignancy that is either metastatic or unresectable; revised hematologic 
Dose-limiting toxicity (DLT) definition for platelets which now also include Grade 3 
thrombocytopenia with clinically significant bleeding in addition to Grade 4 
thrombocytopenia (platelets <25,000/mm3); added in the Dose Stopping Safety Criteria to 
permanently discontinue the patients from GSK2820151 who experience symptomatic 
(symptoms consistent with acute coronary syndrome) troponin elevation. Also, included 
an interim analysis for futility and safety review when 20 patients would have been 
recruited at the RP2D. Added clarification around collection of blood sample for 
pharmacokinetics (Section 8.4.1)
2014N215112_03
2016-MAY-23
Amendment No. 3
Amendment 3 includes
Inclusion criterion # 3 has been amended to allow the subjects who had progressed >3 
prior line therapies. Exclusion criterion # 2 has been deleted to lift the restriction of 3 
prior lines of cytotoxic therapy.
MUGA Scan that had been stated as a second optional method for the measurement of 
ejection fraction has been removed from inclusion criterion #7.
Clarification was made on the collection time for screening holter monitoring in Section 
8.3.7. It was not intended to have holter required at Day-1 but rather performed within the 
14 day screening window as outlined in the T/E table. Also, time points for holter 
monitoring were matched with triplicate ECGs time points. Time & Events Table was 


2014N215112_04
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GlaxoSmithKline
Document Number
Date
Version
updated to reflect the same.
Minor correction made on AEs and SAEs reporting period in Section 9.2.
Added more clarity on pain assessment which will be performed using Wong-Baker 
Faces Pain Rating scale. Appendix 11:  Wong-Baker Faces Pain Rating scale added.
A clarification on the collection and processing of safety cytokines, PK and protein 
biomarker samples process was made in Time & Events Table.
Section 7.1.2.2, typo corrected “Non-drug anti-cancer therapies (e.g., radiation therapy, 
surgery, and/or tumor embolization) will not be permitted from the screening visit 
through the post-study follow-up visit.”
2014N215112_04
2017-JUN-08
Amendment No. 4
Amendment 4 applies to all sites. Updates were made throughout the protocol to correct 
minor inconsistencies, spelling errors and provide further clarification. Salient changes 
include: 

GSK Medical Monitor change

4.6.1 Risk Assessment to include current available data

5.1 Inclusion Criteria: update to contraception use in Inclusion 9 and 10

Changes made in Exclusion Criteria Section 5.2
o
clarification made on prior therapy (exclusion criterion-2) and
anticoagulation use (exclusion criterion-3)
o
added to exclusion criterion-4 restricted use of NSAIDs and aspirin
o
updated exclusion criterion-13 to include history of bleeding and added 
known bleeding disorders

update to Section 7.1 Prohibited Medication and Non-Drug Therapies:
o
guidance on the use of exclusionary medications 
o
prohibited & cautionary medication tables updated

Contraception requirements updated in Section 7.3 Lifestyle Restrictions

Corrections made in Time & Events Table 8.1


2014N215112_04
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GlaxoSmithKline
Document Number
Date
Version
o
addition of triplicate ECG on W1D2
o
clarification around Pulmonary Function Tests
o
Correction made in Table 8 Time and Events: Laboratory Assessments
o
addition of Factor VII assay testing

Added more clarity to troponin sample collection (Section 8.3.10 Troponin 
Measurement) and urine PK sample collection (Section 8.4.2 Urine Sample 
Collection for Pharmacokinetics)

Appendix 7: dose adjustment/stopping safety criteria updated for QTcF, 
troponin, LVEF, hypo & hyperglycemia, diarrhea, mucositis, pneumonitis and 
thrombocytopenia toxicities.

Appendix 12: NYHA Functional Classification System for Heart Failure 
Added


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After Hours 
Contact 
Information
Site Address
Primary 
Medical 
Monitor
MBBS, 
MBA, 
MSc
GlaxoSmithKline
Stockley Park West, 1-3 
Ironbridge Road, 
Uxbridge, Middlesex, 
UB11 1BT, United 
Kingdom
Secondary 
Medical 
Monitor 
MD, 
MPH
ICON Clinical Research 
LLC
2100 Pennbrook 
Parkway 
North Wales, PA 
United States, 19454 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.  
Regulatory Agency Identifying Number(s):  124949
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201893
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201893......................................................12
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.2.
Dose Escalation and Duration of Study.......................................................18
4.2.1.
Planned Dose Levels...................................................................19
4.2.2.
Accelerated Dose Escalation .......................................................19
4.2.3.
3 + 3 Dose Escalation..................................................................20
4.2.4.
Dose-Limiting Toxicity..................................................................21
4.2.5.
Non-Limiting Toxicities.................................................................22
4.2.6.
Alteration of Schedule..................................................................23
4.2.7.
Intra-Subject Dose Escalation......................................................23
4.3.
Type and Number of Subjects.....................................................................24
4.4.
Design Justification.....................................................................................24
4.5.
Dose Justification........................................................................................25
4.5.1.
Human Pharmacokinetic Extrapolation ........................................25
4.5.2.
Starting Dose...............................................................................25
4.6.
Benefit: Risk Assessment ...........................................................................26
4.6.1.
Risk Assessment .........................................................................27
4.6.2.
Benefit Assessment.....................................................................33
4.6.3.
Overall Benefit:Risk Conclusion...................................................33
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............33
5.1.
Inclusion Criteria.........................................................................................33
5.2.
Exclusion Criteria........................................................................................35
5.3.
Screening/Baseline/Run-in Failures............................................................38
5.4.
Withdrawal/Stopping Criteria.......................................................................38
5.4.1.
Liver Chemistry Stopping Criteria ................................................39
5.4.1.1.
Study Treatment Restart or Rechallenge....................41
5.4.2.
QTc Stopping Criteria ..................................................................42
5.4.3.
LVEF Stopping Criteria ................................................................42
5.4.4.
Valvular Toxicity Stopping Criteria ...............................................43
5.4.5.
Other Stopping Criteria ................................................................43
5.5.
Subject and Study Completion....................................................................44
6.
STUDY TREATMENT ............................................................................................45
6.1.
GSK2820151..............................................................................................45
6.2.
Treatment Assignment................................................................................45
6.3.
Packaging and Labeling..............................................................................45
6.4.
Preparation/Handling/Storage/Accountability..............................................45
6.5.
Compliance with Study Treatment Administration.......................................46
6.6.
Treatment of Study Treatment Overdose....................................................46
6.7.
Treatment after the End of the Study ..........................................................47


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7.
MEDICATION,  DIETARY AND LIFESTYLE RESTRICTIONS ...............................47
7.1.
Concomitant Medications and Non-Drug Therapies....................................47
7.1.1.
Permitted Medications and Non-Drug Therapies..........................47
7.1.2.
Prohibited Medications and Non-Drug Therapies.........................48
7.1.2.1.
Prohibited Medications ...............................................48
7.1.2.2.
Prohibited Non-Drug Therapies ..................................49
7.1.3.
Cautionary Medications ...............................................................50
7.2.
Dietary Restrictions.....................................................................................51
7.3.
Lifestyle Restrictions (Contraception)..........................................................51
7.3.1.
Female Subjects..........................................................................51
7.3.2.
Male Subjects..............................................................................52
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................53
8.1.
Time and Events Tables .............................................................................54
8.2.
Screening and Critical Baseline Assessments ............................................62
8.2.1.
Critical Baseline Assessments.....................................................62
8.2.2.
Visit Windows ..............................................................................62
8.3.
Safety .........................................................................................................63
8.3.1.
Physical Exams ...........................................................................63
8.3.2.
ECOG Performance Status..........................................................63
8.3.3.
Vital Signs....................................................................................63
8.3.4.
Pain .............................................................................................64
8.3.5.
Echocardiogram...........................................................................64
8.3.6.
Safety Electrocardiograms (ECG)................................................64
8.3.6.1.
Routine ECG Monitoring.............................................64
8.3.6.2.
Evaluation of QTc.......................................................64
8.3.7.
Telemetry.....................................................................................64
8.3.8.
Holter Monitoring .........................................................................65
8.3.9.
Clinical Safety Laboratory Assessments ......................................66
8.3.10.
Troponin Measurement................................................................68
8.3.11.
Pregnancy ...................................................................................68
8.4.
Pharmacokinetics .......................................................................................68
8.4.1.
Blood Sample Collection for Pharmacokinetics............................69
8.4.2.
Urine Sample Collection for Pharmacokinetics ............................69
8.4.3.
Pharmacokinetic Sample Analysis ...............................................69
8.5.
Pharmacokinetic/Pharmacodynamic Analysis.............................................70
8.6.
Efficacy.......................................................................................................70
8.7.
Translational Research...............................................................................71
8.7.1.
Biologic Effects of GSK2820151..................................................71
8.7.2.
RNA Expression Research ..........................................................71
8.7.3.
Effects of GSK2820151 on Systemic Markers of 
Inflammation................................................................................72
8.8.
Pharmacogenetic Analysis..........................................................................72
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: DATA 
COLLECTION, REPORTING, AND FOLLOW-UP..................................................73
9.1.
Definition of AE/SAE...................................................................................73
9.1.1.
Cardiovascular and Death Events................................................73
9.1.2.
Other Sentinel Events..................................................................73
9.1.3.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................74
9.2.
Time period and Frequency for collecting AE and SAE information ............74


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9.2.1.
Method of Detecting AEs and SAEs.............................................74
9.2.2.
Follow-up of AEs and SAEs.........................................................75
9.2.3.
Regulatory Reporting Requirements for SAEs .............................75
10. DATA MANAGEMENT ...........................................................................................75
11. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................76
11.1.
Hypotheses.................................................................................................76
11.2.
Continual Reassessment Method ...............................................................76
11.2.1.
Description of Continual Reassessment Method..........................76
11.2.1.1.
Implementation of N-CRM ..........................................77
11.2.1.2.
Bayesian Prior............................................................77
11.3.
Sample Size Considerations.......................................................................77
11.3.1.
Sample Size Assumptions ...........................................................77
11.3.2.
Sample Size Re-estimation or Adjustment...................................77
11.4.
Data Analysis Considerations .....................................................................77
11.4.1.
Analysis Populations....................................................................77
11.4.2.
Interim Analysis ...........................................................................78
11.5.
Key Elements of Analysis Plan ...................................................................78
11.5.1.
Primary Analyses.........................................................................78
11.5.2.
Secondary Analyses ....................................................................78
11.5.2.1.
Pharmacokinetic Analyses..........................................78
11.5.2.1.1.
Pharmacokinetic Parameters..................78
11.5.2.1.2.
Statistical analysis of 
pharmacokinetic parameters...................79
11.5.2.2.
Efficacy Analysis ........................................................79
11.5.2.3.
Safety Analyses..........................................................80
11.5.2.4.
Extent of Exposure .....................................................80
11.5.2.5.
Adverse Events ..........................................................80
11.5.2.6.
Clinical Laboratory Evaluations ..................................80
11.5.3.
Other Analyses ............................................................................80
12. STUDY GOVERNANCE CONSIDERATIONS........................................................81
12.1.
Posting of Information on Publicly Available Clinical Trial Registers............81
12.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................81
12.3.
Quality Control (Study Monitoring) ..............................................................82
12.4.
Quality Assurance.......................................................................................82
12.5.
Study and Site Closure ...............................................................................82
12.6.
Records Retention......................................................................................83
12.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................84
13. REFERENCES.......................................................................................................85
14. APPENDICES........................................................................................................88
14.1.
Appendix 1: Abbreviations and Trademarks................................................88
14.2.
Appendix 2: ECOG Performance Status .....................................................92
14.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................93
14.4.
Appendix 4: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................97


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14.5.
Appendix 5: Genetic Research .................................................................100
14.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................103
14.6.1.
Definition of Adverse Events......................................................103
14.6.2.
Definition of Serious Adverse Events.........................................104
14.6.3.
Definition of Cardiovascular Events ...........................................106
14.6.4.
Recording of AEs and SAEs ......................................................106
14.6.5.
Evaluating AEs and SAEs..........................................................107
14.6.6.
Reporting of SAEs to GSK.........................................................108
14.7.
Appendix 7: Guidelines for Management of Toxicity .................................109
14.7.1.
Dose Adjustments for Toxicity....................................................109
14.8.
Appendix 8: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria – adapted from RECIST 1.1 
[Eisenhauer, 2009]....................................................................................116
14.8.1.
Assessment Guidelines .............................................................116
14.8.2.
Guidelines for Evaluation of Disease .........................................117
14.8.2.1.
Measurable and Non-measurable Definitions ...........117
14.8.2.1.1.
Measurable lesion ................................117
14.8.2.1.2.
Non-measurable lesion.........................117
14.8.3.
Baseline Documentation of Target and Non-Target 
Lesions ......................................................................................117
14.8.4.
Response Criteria......................................................................118
14.8.4.1.
Evaluation of target lesions.......................................118
14.8.4.2.
Evaluation of non-target lesions................................119
14.8.4.3.
New lesions..............................................................120
14.8.4.4.
Evaluation of overall response..................................120
14.8.4.5.
Evaluation of best overall response..........................121
14.8.4.6.
Confirmation Criteria.................................................121
14.9.
Appendix 9: Cockcroft and Gault Method for Calculated Creatinine 
Clearance .................................................................................................122
14.10. Appendix 10: Collection of Pregnancy Information....................................123
14.11. Appendix 11: Pain Assessment (Wong-Baker Faces Pain Rating 
scale)........................................................................................................124
14.12. Appendix 12: NYHA Functional Classification System for Heart 
Failure ......................................................................................................125
14.13. Appendix 13: Protocol Amendment Changes............................................126


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1.
PROTOCOL SYNOPSIS FOR STUDY 201893
Rationale
The Bromodomain (BRD) and Extra-Terminal (BET) family is comprised of four 
different proteins that bind via their bromodomains to acetylated histone tails in order to 
regulate transcription, cell growth, and survival. In preclinical models, small molecules 
that inhibit the binding of BET proteins to histones have been associated with potential 
therapeutic benefit for multiple human malignancies. The study drug, GSK2820151, is a 
BET inhibitor arising from a distinct structural class to that previously progressed to 
clinical studies. GSK2820151 potently inhibits tumor growth in vitro and in vivo in 
animal models. This first time in human (FTIH), open-label, dose escalation study will 
assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary 
clinical activity of GSK2820151 in subjects with advanced or recurrent solid tumors.
Objectives/Endpoints
Objectives
Endpoints
Primary

To determine the safety, tolerability and 
maximum tolerated dose (MTD) of 
GSK2820151 in subjects 18 years or older 
with advanced or recurrent solid tumors.

Adverse events (AEs), serious adverse 
events (SAEs), dose reductions or delays, 
withdrawals due to toxicities and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, electrocardiogram 
(ECG), cardiotoxicity, gastrointestinal, etc.)
Secondary

To determine a recommended Phase 2 
dose (RP2D) of GSK2820151 in subjects 18 
years or older.

Safety profile (AEs, SAEs, dose-limiting 
toxicities [DLTs]), clinical response, and PD 
data

To characterize the pharmacokinetics (PK) 
of GSK2820151 in subjects 18 years or 
older.

PK parameter values for GSK2820151 
following single and repeat-dose oral 
administration in subjects 18 years or older.

To evaluate the effect of treatment with 
GSK2820151 on tumor growth and subject 
survival.

Objective response rate (ORR) by various 
imaging modalities and progression free 
survival (PFS).

To evaluate cardiac safety, including the 
potential for corrected QT interval (QTc) 
prolongation, of GSK2820151 and to 
assess PK/QTc relationship.

Changes in cardiac safety including QTc 
following single and repeat-dose oral 
administration of GSK2820151.
Exploratory

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between 
GSK2820151 and safety and efficacy 
parameters.

Dose-related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
peripheral blood samples.

To evaluate systemic and ex vivo on-target 

Changes from baseline and dose/response 


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Objectives
Endpoints
BET inhibitory effects
relationship in ex vivo lipopolysaccharide 
(LPS)-induced cytokines, including 
Interleukin 6 (IL-6), in whole blood, and 
systemic cytokines, including IL-6.

To identify potential indicators of sensitivity 
or response to GSK2820151.

Transcriptomic studies of blood; correlation 
of baseline genetic and genomic profiles 
with response.
Overall Design
This study is a single-arm, open-label, dose-escalation study to determine the MTD (and 
a RP2D) based on the safety, pharmacokinetic, and pharmacodynamic profiles observed 
after oral administration of GSK2820151. Eligible subjects with advanced or recurrent 
solid tumors will be enrolled in the dosing cohorts until an MTD is established.
Treatment Arms and Duration
This is a single-arm study in which all subjects will receive the investigational agent. 
Subjects may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent. The duration of study will depend on recruitment rates 
and the timing of subjects’ duration on study (withdrawal rates due to toxicity or 
progression), with an approximate duration of 3 years.
Type and Number of Subjects
Approximately 30 to 50 subjects with will be enrolled in the study. The study population 
will be adults, with advanced or recurrent, histologically or cytologically confirmed, solid 
malignancy that is either metastatic or unresectable, who either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (radiographic documentation of progression is 
adequate for study participation).
The total number of subjects required will depend upon the number of escalation steps 
required to reach a MTD.
Analysis
After each dosing cohort, a Continual Reassessment Method (N-CRM) analysis will be 
used to recommend the next dose level based on observed dose-limiting toxicities 
(DLTs). Dose escalation decisions will be based on the totality of clinical safety 
assessment based on a combination of reported safety events, N-CRM recommendation, 
as well as pharmacokinetic and pharmacodynamic data.


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All data will be pooled and descriptive analyses summarized and listed by cohort at study 
conclusion. No formal statistical hypotheses will be tested. Analyses will be descriptive 
and exploratory.
Measurements

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: There 
will be extensive PK sampling during this study. Single safety PK blood draws may 
be collected for subjects with severe adverse events or adverse events of concern. 
Blood samples will be collected for analysis of protein biomarkers (cytokines and 
acute phase proteins) and messenger ribonucleic acid (mRNA). LPS induction of 
cytokines in whole blood will be assessed. 

EFFICACY MEASUREMENTS: ORR and PFS.

SAFETY MEASUREMENTS: Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events will be 
performed. Stringent cardiac safety monitoring will be required, consisting of:
o
≥ 48 hours of telemetry following the first dose (necessitating overnight stays in a 
research facility)
o
24 hours of ambulatory cardiac (Holter) monitoring in Week 1, Week 2, Week 3, 
and Week 9
o
Triplicate 12-lead ECGs prior to dosing on selected days and prior to drawing PK 
samples on serial PK sampling days. 
Extensive laboratory testing includes standard hematology, clinical chemistry, 
pancreatic, coagulation, and liver chemistry panels. Troponin, C-peptide, 1,5-
anhydroglucitol, glycosylated hemoglobin (hemoglobin A1c), and thyroid monitoring 
will also be performed. 


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2.
INTRODUCTION
GSK2820151 is a novel, orally available inhibitor of the Bromodomain (BRD) and Extra-
Terminal (BET) family of bromodomain-containing transcriptional regulators that is 
being developed for treatment of multiple solid malignancies.
2.1.
Study Rationale
The aim of this study is to establish a maximum tolerated dose for the BET inhibitor 
GSK2820151 in subjects with refractory, advanced solid malignancies where prognosis is 
particularly poor with limited effective treatment options. Preclinical studies have shown 
that small molecule-based inhibition of BET protein binding to chromatin with 
GSK2820151 inhibits proliferation of multiple solid tumor-derived cancer cell lines and 
results in significant anti-tumor activity in animal models of advanced disease [Chaidos, 
2014; Wyce, 2013]. 
Consistent with the published literature, GSK2820151 inhibits proliferation and induces a 
cytotoxic response in cell lines across a wide range of solid tumor types (Figure 1). 
GSK2820151 inhibits growth in a broad spectrum of human solid cancer and 
hematological (heme) cell lines.  These include Nuclear protein in testes (NUT) midline 
carcinoma (NMC), non-small cell lung cancer (NSCLC), neuroblastoma, cervical cancer, 
prostate cancer, small cell lung cancer (SCLC), colorectal cancer (CRC), acute myeloid 
leukemia (AML), multiple myeloma (MM), and lymphoma. By way of example in the 
largest panel of cell lines tested (n=149), eighty seven percent are highly sensitive to 
GSK2820151, exhibiting growth half maximal inhibitory concentration (IC50) (gIC50) 
values below 1.0 M (Figure 1)
Figure 1
Effect of GSK2820151 on the growth of human tumor-derived cell 
lines


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Bromodomains (BRDs) are found in a variety of proteins that recognize and bind to 
acetylated histone tails [Dhalluin, 1999]. This binding affects chromatin structure and 
facilitates the localization of transcriptional complexes to specific genes, thereby 
regulating gene transcription and messenger ribonucleic acid (mRNA) elongation [Dey, 
2003; Jang, 2005]. The BRD extra-terminal (BET) family of BRD proteins includes the 
BRD2, BRD3, BRD4, and BRDT proteins.
BET proteins have been shown to be involved in the regulation of transcription, cell 
growth, and survival. In addition, BRD4 has been shown to be directly involved in 
regulation of the cell cycle, as it remains associated with chromosomes through mitosis, 
specifically at the transcription start site (TSS) of genes expressed at the M/G1 phase of 
the cycle [Dey, 2009]. BRD4 is also a critical mediator of transcriptional elongation, 
functioning to recruit the positive transcription elongation factor complex (P-TEFb) 
[Itzen, 2014; Patel, 2013]. BRD4 inhibition, through blocking P-TEFb recruitment to 
chromosomes, results in decreased expression of growth-promoting genes [Hargreaves, 
2009]. 
The investigational agent GSK2820151 is a potent inhibitor of the BET family of 
proteins. The crystal structure of GSK2820151 in complex with the bromodomain 1 of 
BRD4 reveals the compound to bind as a histone mimetic. This binding mode has been 
shown previously for other compounds to inhibit the assembly of the transcriptional 
complex and the subsequent gene expression response [Nicodeme, 2010].
The role of BET proteins in malignancy is best demonstrated in Nuclear Protein in Testes 
(NUT) midline carcinoma (NMC), a rare, aggressive, and invariably lethal tumor with a 
median overall survival of 6.7 months [Bauer, 2012]. NMC is triggered by a translocation 
between the NUT gene and one of the BRD genes (typically BRD3 or BRD4) [French, 
2008]; the resulting fusion oncoprotein is retained in the cell nucleus via interactions with 
chromatin [Yan, 2011]. Treatment of patient-derived NMC lines with small molecule 
BET inhibitors leads to rapid growth inhibition and differentiation of cells to a non 
malignant phenotype. This has led to the further clinical investigation of compounds for 
this patient population.
While NMC is the prototypic BET-driven malignancy, other tumor types have been 
found to require functional BET for growth and progression [Fiskus, 2014; Trabucco, 
2014; Asangani, 2014]. Studies in leukemia and multiple myeloma (MM) cell lines have 
shown that small molecule inhibition of BET protein binding to chromatin can directly 
block expression of the gene myc and its downstream transcriptional functions, resulting 
in significant anti-tumor effects [Delmore, 2011; Mertz, 2011]. GSK2820151 has been 
studied extensively in cell culture and has been demonstrated to inhibit the growth of 
multiple solid tumor cell lines apart from NMC, including those derived from cancer of 
the bladder, breast, cervix, colon/rectum, prostate, and lung (see Figure 1 as well as 
investigator’s brochure [IB], Section 5.2.1.1 [GlaxoSmithKline Document Number 
2014N208278_00]). GSK2820151 has also demonstrated efficacy after oral 
administration in mouse xenograft models of SCLC and NMC (see IB, Section 5.2.1.2 
[GlaxoSmithKline Document Number 2014N208278_00]). Based on these observations, 
administration of GSK2820151 to humans is expected to have potential therapeutic 
applications in a broad array of solid malignancies.
Importantly, while the biochemical and phenotypic properties of GSK2820151 are 
comparable to those reported for BET inhibitors under clinical evaluation from the 


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benzodiazepine class, this agent is the first of its structural class to enter clinical trials. As 
such differential human pharmacokinetics, pharmacodynamics, or overall safety profile 
for GSK2820151 may provide beneficial improvements in therapeutic index for patients. 
It is on this basis that clinical trials with GSK2820151 are being proposed.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine the safety, tolerability and 
maximum tolerated dose (MTD) in subjects 
18 years or older with advanced or 
recurrent solid tumors.

Adverse events (AEs), serious adverse 
events (SAEs), dose reductions or delays, 
withdrawals due to toxicities and changes in 
safety assessments (e.g., laboratory 
parameters, vital signs, electrocardiogram 
(ECG), cardiotoxicity, gastrointestinal, etc.)
Secondary

To determine a recommended Phase 2 
dose (RP2D) of GSK2820151 in subjects 18 
years or older.

Safety profile (AEs, SAEs, dose-limiting 
toxicities [DLTs]), clinical response, and PD 
data 

To characterize the pharmacokinetics (PK) 
of GSK2820151 in subjects 18 years or 
older.

PK parameter values for GSK2820151 
following single and repeat-dose oral 
administration in subjects 18 years or older.

To evaluate the effect of treatment with 
GSK2820151 on tumor growth and subject 
survival.

Objective response rate (ORR) by various 
imaging modalities and progression free 
survival (PFS).

To evaluate cardiac safety, including the 
potential for corrected QT interval (QTc) 
prolongation, of GSK2820151 and to 
assess PK/QTc relationship.

Changes in cardiac safety including QTc 
following single and repeat-dose oral 
administration of GSK2820151.
Exploratory

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between 
GSK2820151 and safety and efficacy 
parameters.

Dose-related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
peripheral blood samples.

To evaluate systemic and ex vivo on-target 
BET inhibitory effects

Changes from baseline and dose/response 
relationship in ex vivo lipopolysaccharide 
(LPS)-induced cytokines, including 
interleukin 6 (IL-6), in whole blood, and 
systemic cytokines, including IL-6.

To identify potential indicators of sensitivity 
or response to GSK2820151.

Transcriptomic studies of blood; correlation 
of baseline genetic and genomic profiles 
with response.


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4.
STUDY DESIGN
4.1.
Overall Design
This study is a single-agent, open-label, dose-escalation study to determine the MTD (and 
RP2D), based on the safety, pharmacokinetic, and pharmacodynamic profiles observed 
after oral administration of GSK2820151. Eligible subjects with advanced or recurrent 
solid tumors will be enrolled in the dosing cohorts until MTD is established. All subjects 
will receive study drug. Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent (for specific stopping 
criteria, see Section 5.4). The duration of study will depend on recruitment rates and the 
timing of subjects’ duration on study (withdrawal rates due to toxicity or progression).
4.2.
Dose Escalation and Duration of Study
This study will utilize an accelerated dose escalation phase in order to minimize sub-
optimal drug exposures, followed by a conventional 3+3 dose escalation phase to 
achieve MTD. Initially, one subject per dose cohort will be recruited (accelerated dose 
escalation phase) until the first instance of a ≥ Grade 2 drug related non-hematological 
toxicity or dose-limiting toxicity (DLT, see Section 4.2.4).  Further cohorts will be 
recruited in blocks of three subjects (3+3 dose escalation phase). Additional subjects 
may be enrolled at previously cleared dose levels in order to obtain further data for PK 
and/or PD analysis.  Once MTD is determined, additional subjects (18 subjects total at 
MTD) may be enrolled to collect additional safety data (Figure 2). The total duration of 
study for each subject will be dependent upon the safety, tolerability and efficacy of 
GSK2820151.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on PK data,  the safety profile of the current and prior cohorts, as 
well as the predicted dose-limiting toxicity (DLT) rates on all potential doses from the 
Neuenschwander Continual Reassessment Method (N-CRM) analysis [Neuenschwander, 
2008]. N-CRM design is a type of Bayesian adaptive dose-escalation scheme (see Section 
11.2). The method is fully adaptive and makes use of all the DLT information available at 
the time of each dose assignment. The DLT information of all subjects enrolled in the 
trial are used to update the estimated dose-toxicity relationship and provide supportive 
information in addition to the 3+3 design in the next escalation/de-escalation decision.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects 
(Table 2). If necessary alternate schedules can be explored to determine additional 
biologically active doses even after a RP2D is defined.


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Figure 2
Dose Escalation Scheme
4.2.1.
Planned Dose Levels
Projected dose levels are 3 mg, 6 mg, 12 mg, 20 mg, 40 mg, 60 mg, 100 mg, 150 mg, 
200 mg, and 300 mg.  Additional doses and schedules may be explored based on 
emerging safety, PK, and PD data. 
4.2.2.
Accelerated Dose Escalation
One subject per dose level in the accelerated dose escalation phase will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 and will continue until 
one subject experiences Grade 2 drug related toxicity (based on National Cancer 
Institute- Common Terminology Criteria for Adverse Events, Version 4 (NCI-CTCAE 
v4.03 [NCI-CTCAE, 2010]) or dose-limiting toxicity (DLT, see Section 4.2.4). The 
accelerated dose titration scheme is described in Table 1. A single dose (Day 1) will be 
given to subjects in each cohort with the collection of blood samples for PK analysis at 
timed intervals. Once the final PK sample for Day 1 is obtained, subjects may begin 
repeat dosing on Day 3. The dose for Dose Level 2 and subsequent cohorts will be based 
on the pharmacokinetics (PK) and safety analysis of the previous cohort. Inter-subject 
variability in exposure and toxicity will also be considered when deciding on actual doses 
administered during dose-escalation. Dose escalation will occur according to the 
procedures outlined in Table 1. 


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A sufficient number of subjects will be enrolled in each cohort to ensure that data from at 
least one subject that has completed a full treatment cycle (4 weeks) of dosing is 
available prior to defining a new dose and starting the next cohort. The dose-escalation 
decision and rationale for the subsequent cohort(s) will be documented in writing with 
copies maintained at each study site and in the master study files at GlaxoSmithKline 
(GSK).
At the first occurrence of a DLT (refer to Section 4.2.4) or any Grade 2 toxicity based on 
NCI-CTCAE v4.03 (with the exception of Grade 2 alopecia, nausea, vomiting, diarrhea, 
hemoglobin, lymphopenia, taste changes or alkaline phosphatase in the presence of bony 
metastases) during the first 4 weeks, the Accelerated Dose Titration phase will be 
terminated and the ongoing cohort will be expanded up to 6 subjects to commence the 3 
+ 3 Dose-Escalation phase of the study.
Table 1
Accelerated Dose Titration Procedures
Dose Level
Toxicity
Dose Escalation
Accelerated Dose Titration Phase
Dose Level -1 
Lower doses may be explored if DLTs or significant 
toxicities are observed at Dose Level 1.
Dose Level 1 
Starting Dose: 3 mg daily
Subsequent Dose 
Levels 
No subjects with either a 
Grade 2 toxicity or a DLT in 
first 4 weeks of treatment
Escalate to next dose level with an increase of ≤ 
100%a
End of 
Accelerated Dose 
Titration Phase
One or more subjects with a 
≥Grade 2 toxicity or a DLT in 
first 4 weeks of treatment
Begin 3+3 dose-escalation phase
a.
Dose levels in Section 4.2.1 are suggestions; the final determination of the next dose level will be made at the 
dose escalation meeting in concert with the Investigators, GSK Medical monitor, and representatives from Safety, 
Statistics, and Clinical Pharmacology.  The final dose escalation decision will depend on all factors, as described 
in Section 11.2.1.
4.2.3.
3 + 3 Dose Escalation
If the accelerated dose titration ends due to grade 2 toxicity then two additional subjects 
will be enrolled to same dose level where as, if termination of accelerated dose titration is 
due to DLT, then up to 5 additional subjects will be enrolled at the same dose level to 
continue the treatment following the 3 + 3 Dose Escalation guidelines. Subjects will be 
entered in a staggered approach with at least 3 days between each subject to minimize the 
risk of inadvertently exceeding the MTD in multiple subjects. Dose escalation decisions 
will be made as outlined in Table 2 Escalation to the next dose level will not increase 
greater than 2 fold from the previous dose level. Intra-subject dose escalation may be 
considered as described in Section 4.2.7. Subjects should not be enrolled at a higher dose 
level until at least 3 subjects in the previous dose cohort complete 4 weeks of treatment.
Dose-limiting toxicity (DLT) is based on any observed toxicity in the first 4 weeks.  If 1 
of 3 subjects experiences a DLT at a particular dose level, 3 additional subjects will be 
enrolled at that dose level.  If 2 or more subjects experience a DLT at a particular dose 


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level, a lower (or intermediate) dose level may be explored to better define the maximum 
tolerated dose (MTD).
If 2 or more DLTs in 6 subjects are observed at any dose level, the MTD will have been 
exceeded (Table 2).
Table 2
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to next dose level with an increase of ≤ 100%a

If two or more subjects have the same Grade 2 drug-related 
adverse event, consider a <2-fold increasea taking into 
consideration the safety profile and dose-exposure relationship
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%a
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded. Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to a total of 12 subjects
1 or more out of 6 subjects at the 
highest dose level below the MTD
The dose is considered the recommended Phase 2 dose (RP2D).  At 
least 6 subjects must be evaluated at the RP2D dose.
a.
Dose levels in Section 4.2.1 are suggestions; the final determination of the next dose level will be made at the 
dose escalation meeting in concert with the Investigators, GSK Medical monitor, and representatives from Safety, 
Statistics, and Clinical Pharmacology.  The final dose escalation decision will depend on all factors, as described 
in Section 11.2.1.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects. If 
necessary alternate schedules can be explored to determine additional biologically active 
doses even after a RP2D is defined.
4.2.4.
Dose-Limiting Toxicity
An event is considered to be a dose-limiting toxicity (DLT) if the event is attributed 
(definitely, probably or possibly) to the study treatment during the first 4 weeks of 
treatment and meets the criteria described in Table 3, as graded when applicable by the 
NCI-CTCAE v4.03.
Subjects who are unable to receive at least 75% of the scheduled doses during the 4-
week DLT evaluation period will be replaced in the cohort unless the reason for the delay 
or discontinuation was due to a DLT.


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Table 3
Dose –Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 for 5 
days)

Febrile neutropenia (as defined by NCI-CTCAE v4.03 [concurrent 
Grade 4 neutropenia and fever >38.3C]) 

Grade 4 anemia of any duration

Grade 3 thrombocytopenia with clinically significant bleeding or grade 4 
thrombocytopenia (platelets <25,000/mm3)
Non-hematologic

Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) + 
bilirubin 2xULN (>35% direct) or ALT between 3-5 X ULN with 
bilirubin < 2xULN but with hepatitis symptoms or rash (See Section 
5.4.1 for Liver Stopping Criteria)

Grade 3 nausea, vomiting or diarrhea that does not improve within 24h 
despite appropriate supportive treatment(s)

Grade 4 nausea, vomiting, or diarrhea

Grade 3 hypertensionaa (uncontrolled despite addition of up to 
2 antihypertensive medications)

Grade 4 hypertension

Grade 3 or greater clinically significant non-hematologic toxicity 
(including QTc corrected by Fridericia's formula [QTcF]) per NCI-
CTCAE, v4.03 except toxicities listed in Section 4.2.5

Grade 2 troponin b elevation (central laboratory >ULN), measured on 
two separate occasions within 48 hours in order to confirm elevation 
and with other clinical signs, symptoms, laboratory tests consistent with 
cardiac toxicityb.
Other

Any toxicity resulting in a dose delay of >14 days of the intended next 
dose

Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and GSK Medical Monitor is considered to 
be a DLT
Toxicity Grading based on NCI-CTCAE v4.03
a.
Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not considered to be a 
DLT.
b.
In the event a troponin (central laboratory assessment) is not performed or a laboratory error occurs, 
considerations for a DLT criterion will involve review of two separate local troponin (I or T) assays done 
within 48 hours at a local investigator site. Troponin I or T elevations greater than the upper limit of 
normal, and > 10% coefficient of variance (CV%) for that assay will be considered as a grade 2 
elevation.
4.2.5.
Non-Limiting Toxicities
The following toxicities have been deemed to be non-serious for the purposes of this 
study. These toxicities will not be taken into account for dose escalation decisions unless, 
in the opinion of the investigator and the GSK Medical Monitor, they represent a dose-
limiting toxicity. For all other toxicities and their management, see Section 14.7.


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
Grade 3 or less:
o
Fatigue
o
Rash
o
Mucositis
o
Asthenia
o
Alopecia

Electrolyte imbalance or other laboratory abnormalities controlled within 24h
4.2.6.
Alteration of Schedule
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK and safety data.
Schedules that incorporate a recovery period may be explored (e.g., 2 weeks on, 1 week 
off). This approach will be considered if the safety and PK data suggest that a therapeutic 
exposure cannot be achieved using the initial schedule without excessive toxicity. The 
starting dose for the alternate schedule will be the highest completed dose level (at or 
below MTD) with the initial schedule. Escalation can then proceed as described using 
3 + 3 dose escalation.
Schedules that use a shorter recovery period, e.g., twice daily (BID) dosing, may also be 
explored. This approach will be considered if the safety, PK, and emerging PD data 
suggest that a sufficient therapeutic exposure cannot be achieved using the initial 
schedule. If a shorter recovery period is used, the initial dose level will be 50% of the 
highest completed dose level (at or below MTD) with the initial schedule. Escalation can 
then proceed as described using the 3 + 3 dose escalation. Alternative schedules with 
intense supportive care may also be explored.
The dosing schedule may also be adjusted to expand a prior dose cohort to further 
evaluate safety, pharmacokinetic and/or pharmacodynamic findings at a given dose level, 
or to add cohorts to evaluate additional dose levels. The study procedures for these 
additional subject(s) or cohort(s) will be the same as that described for other study 
subjects.
4.2.7.
Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced any Grade 2 or higher drug related toxicity prior to dose 
escalation in the accelerated dose escalation phase or a DLT in the 3+3 dose escalation 
phase and contingent upon the following: 
Additional subject(s) have been enrolled at a higher dose in the dose escalation phase and 
at least one subject has completed 4 weeks of dosing on that regimen without a DLT; and 
after review of all safety data and approval by a GSK Medical Monitor, a subject on a 
lower dose level may be increased up to the highest dose level tested. In this case the 
subject may begin dosing at the higher dose level as it will have already been 
demonstrated to be tolerable. 


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Subjects approved for intra-subject dose escalation will require additional limited PK 
sampling at the higher dose, as determined by GSK Clinical Pharmacology. Additional 
safety assessments such as insulin/glucose or cardiac monitoring may be specified at the 
time of dose escalation or schedule modification based on the safety profile in previous 
subjects at the higher dose level. Intra-subject dose escalations or schedule modification 
will be discussed with investigators and approved by the GSK Medical Monitor and 
safety monitoring required will be specified in writing.
4.3.
Type and Number of Subjects
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) of GSK2820151 for further study. It is estimated 30 to 
50 evaluable subjects will be enrolled.
Approximately 30 to 50 subjects with refractory, histologically or cytologically 
confirmed, advanced (metastatic or unresectable) solid malignancies will be enrolled in 
the study. The study population will be adults, with advanced or recurrent, histologically 
or cytologically confirmed, solid malignancy that is either metastatic or unresectable, 
who either:

refuse or are not candidates for standard curative or palliative therapy

have a disease for which no non-investigational therapy exists

have progressed on prior therapy (radiographic documentation of progression is 
adequate for study participation).
If a subject discontinues the study before completing Week 4 due to reasons other than 
toxicity, additional subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator to ensure an adequate population for DLT and MTD 
evaluations.
4.4.
Design Justification
Given the high unmet medical need of relapsed/refractory, advanced solid tumors, a 
conventional Phase I study (201893) is proposed. The study comprises an accelerated 
dose titration to determine a MTD. While preliminary efficacy data will be collected as 
part of the course of the study, it will not be a primary endpoint. Overall, the aim of the 
study is to identify a RP2D for future evaluation of GSK2820151.
While dose escalation and subject enrollment will utilize a conventional 3+3 approach, 
determination of the particular dose to be tested in each cohort will utilize all available 
information, including input from the N-CRM model. The updated model from the N-
CRM analysis after each subject is evaluated will give more information about the 
expected DLT rate at each dose level and assist in the dose-escalation decision making 
process.


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4.5.
Dose Justification
4.5.1.
Human Pharmacokinetic Extrapolation
Human pharmacokinetics was predicted based on three species (mouse, rat and dog) 
using different allometric extrapolation. Whole blood human clearance predicted from 
mean of allometry was 6.5 ml/min/kg (~30% hepatic blood flow). Volume of distribution 
at steady state was predicted to be 2.8 L/kg with a moderate half life of ~5hr. 
Bioavailability is predicted to be ~69%.
4.5.2.
Starting Dose
The 28 day toxicology studies were conducted using the freebase of GSK2820151 
whereas the mesylate salt of GSK2820151 will be used on this clinical study. 
Comparison of systemic exposure between the freebase and mesylate versions of 
GSK2820151 at the same dose level (corrected for form) showed that systemic exposure 
was comparable in the rat, but the mesylate salt resulted in 2-4.6 fold higher exposure in 
the dog. Taking into account the difference in systemic exposure for the dog (and using 
the more conservative approach of 4.6 fold difference), the dose level required to achieve 
equivalent systemic exposure has been adjusted (i.e. highest non-severely toxic dose 
(HNSTD) freebase of 5 mg/kg is equivalent to HNSTD mesylate of 1.09 mg/kg.).
Three approaches have been considered to establish the starting dose for GSK2820151.

One tenth of the rat severely toxic dose in 10% of the animals (STD10) 
For GSK2820151, the STD10 was defined as 3 mg/kg in the rat following 
International Conference on Harmonization (ICH) S9 guidelines. 1/10 rat STD10 is 
1.8 mg/m2; this dose is not severely toxic to dogs and translates to a starting dose in 
man of 3 mg, assuming a 70 kg adult and adult surface area of 1.7 m2. 

One sixth of the dog HNSTD
For GSK2820151, the dog HNSTD is defined as 1.09 mg/kg. 1/6 dog HNSTD is 3.63 
mg/m2 which translates to a starting dose in man of  6 mg, assuming a 70 kg adult and 
adult surface area of 1.7 m2. 

The dose predicted to deliver a minimum anticipated biological effect t level
minimum anticipated biological effect level, (MABEL) dose.
The potential therapeutic effect of GSK2820151 was evaluated at single oral daily doses 
of 10 mg/kg (30 mg/m2) and 30 mg/kg (90 mg/m2) in OPM-2 transgenic non-obese 
diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model of 
multiple myeloma; 25 mg/kg (75 mg/m2) daily and 50 mg/kg (150 mg/m2) every other 
day in NCI-H526 SCLC xenograft model and 30 mg/kg (90 mg/m2) daily in NMC 
xenograft model. GSK2820151 was efficacious at 30 mg/kg in both studies and showed 
partial efficacy at 10 mg/kg dose in OPM-2 xenograft model. 25 mg/kg dose showed 
~24% reduction in tumor growth while 50 mg/kg showed ~54% reduction in tumor 
volume. The mouse MABEL dose of 10 mg/kg (30 mg/m2) would translate to a dose in 


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human of 125 mg using human equivalent dose calculation.  Taking a conservative 
approach, the starting dose will be 3 mg. 
The predicted human exposure at 3 mg is area under the curve from zero to 24 hours 
(AUC0-24) = 78.8 ng/h/mL and is approximately 6-fold lower than the exposure at the dog 
NOAEL / HNSTD and approximately 9- and 47-fold lower than the rat no observed 
adverse effect level (NOAEL) and STD10 exposures, respectively.
4.6.
Benefit: Risk Assessment
Summaries of findings from the non-clinical studies conducted with GSK2820151 can be 
found in the Investigator’s Brochure [GlaxoSmithKline Document Number 
2014N208278_00]. The following section outlines the risk assessment and mitigation 
strategy for this protocol: 


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiovascular Effects
QT Prolongation
QT prolongation was observed in dogs after 
single dosing  (10 mg/kg; up to 34 milliseconds 
[msec] and up to 48hr post dosing) and after 
repeat dosing  (≥ 30 mg/kg/day from Day 3; up 
to 21 msec). 
A direct effect on human ether-à-go-go-related 
gene [hERG] binding is unlikely.; Mechanism 
and risk for Torsades de Pointes is unclear.
Increased number of non-fatal arrhythmias were 
observed in 1 of 4 dogs which had highest drug 
exposure after a single dose of 100mg/kg (10x 
the dog 28 day maximum tolerated dose, or 
MTD).
Blood Pressure (BP)
Increases in blood pressure (mean, systolic & 
diastolic; systolic affected more than diastolic)
were observed  in dogs after single dosing ≥ 10 
mg/kg(mean up to 38 millimeters mercury
[mmHg] and up to 42 hours post dosing).
Heart Rate
Informed consent form (ICF) includes the risk of 
(fatal) arrhythmias and the risk of myocardial 
infarction
Drugs with a risk of Torsades de Pointes are 
prohibited, (refer to Section 7.1.2).
Protocol includes cardiovascular eligibility 
criteria, laboratory assessments (potassium and 
magnesium, N-terminal pro–B-Type natriuretic 
peptide [NT-proBNP], creatine kinase [CK], 
creatine kinase-MB isoenzyme [CK-MB], and 
troponins [local laboratory monitoring for troponin 
I or T based on availability and troponin T at 
central laboratory]), cardiac monitoring (ECGs, 
Holter monitoring and cardiac ejection fraction) 
during the study, and dose 
stopping/modifications criteria for the 
management of cardiac events (refer to 
Section 14.7.1).
All subjects will receive their first dose of study
medication (Week 1 Day 1) in the hospital with 
telemetry monitoring for the first 48 hours of 
dosing. Throughout the protocol, the role of 
intensive cardiac monitoring will be re-evaluated 
in an ongoing fashion with the aim of re-
evaluating cardiac risk mitigation strategy while 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Increased heart rate was observed after  single 
dosing (100 mg/kg; up to 24 beats per minute 
[BPM] between 9 and 19 hours post dosing) and
in one dog after repeat dosing  (100 mg/kg; up 
to 64 BPM post dosing). 
Cardiac Biomarkers
Reversible increases in serum cardiac troponin I 
(cTnI) levels were observed in male rats (up to 
3.3X) at 10 mg/kg/day for 28 days. Increased NT 
pro-ANP (up to 2.1X) in female rats given ≥1 
mg/kg/day for 28 days; no recovery after up to 5 
weeks off dose period. No histologic lesions
were observed in the heart on 28 day studies.
maintaining subject safety.
Gastrointestinal (GI) Effects
Gastrointestinal effects were the dose limiting 
toxicity (DLT) observed following repeat dosing
in rats (3 mg/kg/day) and dogs 
(10 mg/kg/day)
Clinical presentation included altered feces, 
reduced food consumption and body weight 
reductions.  These changes correlated with 
microscopic findings throughout the GI tract of 
rats given 6 mg/kg/day and dogs at 
20 mg/kg/day.  Microscopic findings in rats and 
dogs included erosion/ulceration, mucosal 
epithelium degeneration/regeneration and 
ICF includes the risk of gastrointestinal effects.
Protocol includes medical history, physical 
examination (including weight) and clinical 
laboratory assessments to assess toxicity in the 
GI tract. Subjects with a history of 
gastrointestinal bleeding in the past 6 months 
(Section 5.2) or active bleeding will be excluded.
Protocol also includes specific dose 
adjustment/stopping safety criteria for diarrhea 
and mucositis (refer to Section 14.7.1).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
inflammatory cell infiltration. Microscopic 
findings in dogs only included minimal to mild 
hemorrhages, villous atrophy and mild cecal 
lamina propria fibrosis . Signs of recovery were 
observed immediately after cessation of dosing; 
no abnormal microscopic findings were evident 
following a 3 to 5 week off dose period.
Lymphoid/Hematologic Effects
Lymphoid / hematologic toxicity was observed in 
rats given 3 mg/kg/day and in dogs given
≥5 mg/kg/day .
The effects manifested as hypocellularity in bone 
marrow, thymus and lymph nodes of rats and 
dogs and reduced cellularity of the  spleen in 
rats. This was accompanied peripherally by  
evidence of increased red cell turnover and/or 
mild haemolysis, reductions in red blood cells, 
platelets, basophils, eosinophils, lymphocytes,
and increases in neutrophils (in response to GI 
toxicity).  Effects on reticulocyte counts were 
variable. 
Regenerative response in blood cell parameters and 
microscopic observation of extramedullary 
haematopoiesis and increased cellularity in the lymph 
nodes and spleen was evident after up to five weeks 
off dose. Increased activated partial
thromboplastin time (APTT) was observed in 
male rats given 1 mg/kg/day and in dogs given
ICF includes the risk of lymphoid / hematologic
toxicity.
Protocol includes laboratory assessments 
(complete blood count [CBC] and coagulation 
factors [international normalized ratio (INR), 
prothrombin time (PT), partial thromboplastin 
time (PTT)], exclusion criteria if there is evidence 
of clinically significant bleeding episodes, 
monitoring for bruising/infection and dose 
stopping/modifications criteria (refer to Section
14.7.1).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
20 mg/kg/day . A mild decrease in APTT was 
observed in female rats given 3 mg/kg/day. 
Increases in fibrinogen was observed in dogs 
given 20 mg/kg/day. All of these effects were 
reversible.
Reproductive Effects
Animal reproductive studies have not been 
conducted with GSK2820151.
No ovarian changes were observed in toxicology 
studies of up to 4 weeks duration; however, an 
assessment of estrous cycling was not 
conducted. BRD2, BRD3, BRD4 and BRDT 
have crucial roles in reproduction and 
development [Paillisson, 2007; Trousdale, 2004] 
and would be expected to adversely affect 
embryofetal development. A compound with a 
similar pharmacology profile has shown 
detrimental effects on rat female fertility and 
embryo-fetal development (EFD) at clinically 
relevant exposures. This information indicates 
that GSK2820151 will likely have similar  effects 
on female fertility and EFD.
Testicular degeneration was observed in  rats
given 10 mg/kg/day and dogs given 
5 mg/kg/day. Disorganized spermatogenesis 
was also observed in dogs. Secondary changes  
ICF includes the risk of damage to reproductive 
organs such as testes or ovaries including 
potential risk to embryofetal development.
Protocol (refer to Section 7.3) includes specific 
contraceptive guidelines and precautions for 
males and females and pregnancy testing for 
female subjects and collecting testosterone (free 
and complete) for male subjects.
Due to the effects of GSK2820151 on the male 
reproductive system were observed in pre-
clinical settings and potential for GSK2820151 to 
be present in semen, men should adhere to the 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
in epididymides were also evident (hypospermia, 
degenerate germ cells and/or epithelial 
vacuolation in both species, and atrophy in dogs 
only).  
There was no evidence of reversibility of these 
findings within a three-week off dose period, but due 
to the length of the spermatogenic cycle 
(approximately two months), recovery may occur 
following a longer off dose period.
Reduced prostate weight was observed in rats 
and dogs.  Additionally, in rats, decreased 
secretory content in prostate (dosing at 3 
mg/kg/day) and in seminal vessels (dosing at 
10 mg/kg/day) were observed.  These effects 
were reversible.
contraceptive guidance detailed in the protocol
(refer to Section 7.3.2).
Hepatobiliary Effects 
Reversible minimal vacuolization of the
gallbladder and  biliary epithelium were observed
in dogs given 10 mg/kg/day. Decreased 
inflammatory cell infiltrate was observed in rats 
given ≥ 3 mg/kg/day and was still evident in 
some animals after an off dose period of up to 5 
weeks. This is considered indicative of the anti-
inflammatory pharmacology of BET 
bromodomain and extra-terminal inhibitors.. 
ICF includes the risk of hepatobiliary effects.
Protocol includes hepatic eligibility criteria, 
laboratory assessments during the study, and 
dose stopping/modifications criteria for the 
management of hepatic events (refer to Section
14.3 & Section 14.4).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Lung Effects
Minimal to mild prominent (foamy) alveolar 
macrophages were observed in rats 
administered ≥ 1 mg/kg/day. These effects were 
reversible. The clinical consequences of this 
finding are unknown.
ICF includes the risk of lung effects.
Protocol includes pulmonary function 
assessments at screening and as clinically 
appropriate afterwards (subjects with severe 
Chronic Obstructive Pulmonary Disease [COPD], 
history of pneumonitis, alveolar haemorrhage, 
chest radiation) chest x-ray at baseline and dose 
stopping/modifications criteria for pneumonitis
(refer to Section 14.7.1).
Effects on Teeth
Minimal to mild changes related to dentin 
formation in continuously growing incisors were 
observed  in rats given ≥ 3 mg/kg/day. A 
marginally increased incidence and/or severity
occurred after off dose period. No changes were 
observed in molar teeth of dogs.
Due to the differences between rodents and 
human, it is unlikely that these effects of teeth 
will affect human adults.


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4.6.2.
Benefit Assessment
Study 201893 is an open-label, dose escalation study and the first study of this agent to 
be conducted in subjects with relapsed and/or refractory advanced solid malignancies for 
which no standard therapies are available. GSK2820151 has promising preclinical 
activity in cell lines; however it is unknown whether GSK2820151 will have clinical 
efficacy in subjects with solid tumors. As such, any potential beneficial effect for an 
individual subject attributable to GSK2820151 is unknown. Data obtained in Study 
201893 may assist in progressing the knowledge base on advanced malignancies and 
their treatment, or help identify individuals more likely to benefit or have side effects 
from GSK2820151.
4.6.3.
Overall Benefit:Risk Conclusion
Current data from preclinical development indicate GSK2820151 inhibits the BET family 
of BRD proteins, and that this inhibition may have clinical utility in the treatment of 
various tumors. Taking into account the measures taken to minimize risk to subjects 
participating in the Phase I clinical trials, the potential risks identified in association with 
GSK2820151 are justified by the anticipated benefits that may be afforded to subjects 
with relapsed/refractory advanced solid malignancies with otherwise limited therapeutic 
options.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the GSK2820151 Investigator 
Brochure [GlaxoSmithKline Document Number 2014N208278_00]. Approximately 30-
50 subjects with relapsed or advanced solid malignancies will be enrolled. All subjects 
must have failed refused or otherwise be ineligible for standard therapy, or have a tumor 
for which there is no standard therapy, prior to consideration for study. The total number 
of subjects required will depend upon the number of escalation steps required to reach a 
MTD.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and enrolled
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Written informed consent provided
2. Males and females 18 years old and greater


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3. Diagnosis of advanced or recurrent, histologically or cytologically confirmed, solid 
malignancy that is either metastatic or unresectable. At time of enrollment, subjects 
either:

refuse or are not candidates for standard curative or palliative therapy

have a disease for which no non-investigational therapy exists

have progressed on prior therapy (radiographic documentation of progression is 
adequate for study participation).
4. Subjects with solid tumors, with the exception of castration-resistant prostate cancer 
(CRPC), must demonstrate measurable disease, per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1.
5. All prior treatment- related toxicities must be NCI-CTCAE v4.03 ≤ Grade 1 (except 
alopecia [permissible at any Grade] and peripheral neuropathy [which must be ≤ 
Grade 2]) at the time of treatment allocation. 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1 
(See Appendix 2 for definitions). 
7. Adequate Baseline organ function as defined in Table 4.
Table 4
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
9 g/dL (subjects that required transfusion or growth 
factor need to demonstrate stable hemoglobin for 7 
days of 9 g/dL)
Platelets
100 X 109/L
PT/INR and PTT
≤ 1.5 X upper limit of normal (ULN)
Hepatic
Albumin
2.5 g/dL
Total bilirubin
≤1.5 X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of Gilbert’s 
syndrome)
Alanine aminotransferase (ALT) 
2.5 ULN 
OR
<5 x ULN is acceptable for subjects with documented 
liver metastases/tumor infiltration
Renal
Creatinine
OR
Creatinine clearance [either directly measured or 
calculated by Cockcroft-Gault formulab]
≤1.5 X ULN
≥ 40 mL/min
Cardiac
Ejection fraction
≥ 50% by echocardiogram 
Troponin (T)
Potassium
Magnesium
ULN 
≥Lower limit of normal (LLN) and ≤ULN
≥LLNa


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a.
Magnesium supplementation is permitted, as required, to maintain a serum magnerium concentrations LNN
b.
Cockcroft and Gault Method for Calculated Creatinine Clearance is provided in Appendix 9.
8. Able to swallow and retain orally administered medication.
9. A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented 
tubal ligation, hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, hysterectomy, or documented bilateral 
tubal oophorectomy; or postmenopausal defined as 12 months of spontaneous 
amenorrhea [in questionable cases a blood sample with simultaneous follicle 
stimulating hormone (FSH) >40 U/ml and estradiol <40 pg/ml (<140 pmol/L) is 
confirmatory]. Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse 
between the cessation of therapy and the blood draw; this interval depends on the 
type and dosage of HRT. Following confirmation of their post-menopausal status, 
they can resume use of HRT during the study without use of a contraceptive 
method.

Child-bearing potential and agrees to use one of the contraception methods 
(described in Section 7.3) from the time of the screening pregnancy test until at 
least 7 months after the last dose of study medication.

Negative serum pregnancy test ≤ 7 days prior to first study drug dose, for women 
of childbearing potential.

Female subjects who are lactating must discontinue nursing prior to the first dose 
of study treatment and must refrain from nursing throughout the treatment period 
and for 5 half-lives of GSK2820151 or at least 28 days (whichever is longer) 
following the last dose of study treatment.
10. Male subjects with female partners of child bearing potential must agree to use one 
of the methods of contraception specified (see Section 7.3.2). This method must be 
used from the time of the first dose of study medication until 16 weeks after the last 
dose of study medication. In addition, male subjects whose partners are or become 
pregnant while on study medication must continue to use condoms for 16 weeks 
following the last dose of study medication.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Primary malignancy of the central nervous system or malignancies related to 
human immunodeficiency virus (HIV) or solid organ transplant.
2.
Recent prior therapy, defined as follows:


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a.
Any investigational or Food and Drug Administration (FDA)-approved 
anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior 
to the first dose of GSK2820151. Note that an investigational drug is 
defined as a drug without an approved oncologic indication
b.
Any radiotherapy, chemotherapy, targeted therapy or immunotherapy
within 14 days or major surgery within 28 days or anti-neoplastic 
antibody or nitrosoureas/mitomycin C within 42 days prior to the first 
dose of GSK2820151. 
c.
Anti-androgen (e.g., bicalutamide) therapies for prostate cancer,, must be 
stopped 4 weeks prior to the first dose of GSK2820151. Second-line 
hormone therapies such as enzalutamide, abiraterone, or orteronel should 
be stopped 2 weeks prior to enrolment. Subjects with prostate cancer 
should remain on luteinizing hormone releasing hormone (LHRH) 
agonists or antagonists. Subjects with prostate cancer may also remain on 
low-dose prednisone or prednisolone (up to 10 mg/day) and still be 
eligible for this study.
d.
In addition, any therapy-related toxicity must have resolved to Grade 1 or 
less, with the exception of alopecia (acceptable at any Grade) and 
peripheral neuropathy (which must be Grade 2 or less prior to enrollment). 
3.
Therapeutic anticoagulation (e.g., warfarin, heparin) must be discontinued 7 days 
prior to the first dose of GSK2820151 and coagulation parameters must be 
normalized prior to the first dose of GSK2820151. Low (prophylactic) dose low 
molecular weight heparin (LMWH) is permitted. In addition, INR must be 
monitored in accordance with local institutional practices.
4.
Current use of a prohibited medication or planned use of any forbidden 
medications during treatment with GSK2820151 (see Section 7.1.2 for the list of 
medications).
NOTE: Aspirin up to 100mg PO daily is allowed. Concurrent use of non-steroidal 
anti-inflammatory drugs (NSAIDs) will be excluded except for cases where 
NSAIDs provide benefit over other analgesics (see Section 7.1.2 for details).
5.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study 
procedures, in the opinion of the Investigator.
6.
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for these conditions that have had stable central 
nervous system (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. Subject treated with gamma knife 
therapy can be enrolled 2 weeks post-procedure as long as there are no post-


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procedure complications/stable. In addition, subjects treated or currently taking 
enzyme-inducing anticonvulsant (EIAC) are allowed on study.
7.
Cardiac abnormalities as evidenced by any of the following:

History of or current “untreated” clinically significant uncontrolled 
arrhythmias.

Clinically significant conduction abnormalities or arrhythmias

Presence of cardiac pacemaker

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

History of acute coronary syndromes (including unstable angina and 
myocardial infarction), coronary angioplasty, or stenting within the past 3 
months. Subjects with a history of stent placement requiring ongoing 
antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to 
enroll.
8.
Following electrocardiogram (ECG) finding:

Baseline corrected QT (Fridericia’s formula) interval (QTcF) ≥450 msec 
NOTE:  Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.
9. Any of the following liver findings:

ALT >2.5xULN

ALT > 5xULN with liver metastases/tumor infiltration

Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 

Current active liver or biliary disease (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones, liver metastases or otherwise stable 
chronic liver disease per investigator assessment).
NOTE: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric 
varices, persistent jaundice or cirrhosis
10. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody 
test result at screening or within 3 months prior to first dose of study treatment.  
History of known HIV infection.
NOTE: Subjects 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.
11. Any serious known immediate or delayed hypersensitivity reaction(s) to 
GSK2820151 or idiosyncrasy to drugs chemically related to the investigational 
drug.


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12. Hemoptysis > 1 teaspoon in 24 hours within the last 28 days. 
13. Subjects with a history of known bleeding disorder(s) or history of clinical 
significant hemorrhage ( e.g., gastrointestinal, neurologic)  within the last 6 
months. 
14. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption such as malabsorption syndrome or major resection of the stomach 
and/or bowels.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed with study medication. In order to ensure transparent 
reporting of screen failure subjects, meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, and respond to queries from Regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry, hematologic/non-
hematologic toxicity, QTc prolongation, raised Troponin level as defined in Section 
14.7.1 or left ventricular ejection fraction (LVEF)/valvular dysfunction as defined in 
Section 5.4.1 through Section 5.4.5. After disease progression, subjects may be allowed 
to continue treatment with study drug if the Investigator strongly believes, and the GSK 
Medical Monitor concurs, that the subject could continue to receive benefit (for example 
in cases of an isolated new lesion, with the majority of the disease still under control).
In addition study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will
be recorded as the primary reason for permanent discontinuation on the eCRF. 
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated. 


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All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in Time 
and Events Tables (see Section 8.1). 
All subjects who permanently discontinue study treatment for any reason will be 
followed for survival and new anti-cancer therapy (including radiotherapy) every 6 
months until death, termination of the study by the sponsor, or until the subject has been 
followed for 2 years. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression. If subjects are unable or 
unwilling to attend clinic visits during follow-up, contact to assess survival may be made 
via another form of communication (e.g., telephone, email, etc.).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject 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.  
See Figure 3 and Figure 4 for liver stopping criteria for subjects without and with liver 
metastases, respectively.


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Figure 3
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.


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Figure 4
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria 
ALT>2.5xULN but ≤5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
5.4.1.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or institutional review board (IRB) approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 4 for full guidance. 


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5.4.2.
QTc Stopping Criteria
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.

QTcF interval ≥ 500 msec OR interval increase from baseline 60 msec: 
GSK2820151 will be discontinued unless the benefits of therapy outweigh 
the risk of rechallenge in the opinion of the investigator, the GSK Medical 
Monitor, as well as the GSK medical governance. In this situation, 
rechallenge may be permitted (see Appendix 7 for rechallenge guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
5.4.3.
LVEF Stopping Criteria
Echocardiography must be performed at Screening, Week 5 Day 1, Week 9 Day 1, and 
every 8 week thereafter and at the post-treatment follow-up visit as outlined in the Time 
and Events Table (Section 8.1).  Subjects who have an asymptomatic, absolute decrease 
of >10% in left ventricular ejection fraction (LVEF) compared with baseline and the 
ejection fraction is below the institution’s lower limit of normal (LLN) should 
temporarily discontinue GSK2820151 and have a repeat evaluation of LVEF within 1 
week.  Echocardiogram (ECHO) should be repeated every 1 to 2 weeks for 4 weeks or 
until LVEF recovery to above institutional LLN and within 10% of baseline.

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline) at any time during the next 4 weeks, after consultation with and 
approval from the GSK Medical Monitor, the subject may be restarted on 
GSK2820151 at a reduced dose.  For such subjects, monitoring of LVEF will be 
performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 16 
weeks and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK2820151 
should be permanently discontinued.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue treatment with GSK2820151.  Ejection fraction should be monitored every 


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4 weeks for a total of 16 weeks or until resolution.  If recovery occurs (LVEF 
>institutional LLN and symptom resolution) within 4 weeks, treatment with 
GSK2820151 may be restarted at a reduced dose in consultation with the GSK Medical 
Monitor.
Copies of all ECHOs and cardiology consultations performed on subjects who experience 
a >10% decrease in LVEF from baseline and whose cardiac ejection fraction is 
<institution’s LLN will be required by GSK for review.  Instructions for submitting 
qualifying ECHOs are provided in the Laboratory Manual.
5.4.4.
Valvular Toxicity Stopping Criteria
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by 
echocardiogram (ECHO) (Grade 2 mitral/tricuspid/aortic valvular toxicity per NCI-
CTCAE v4.03) should temporarily discontinue GSK2820151 and have a repeat 
evaluation by ECHO within 1 week.  ECHO should be repeated every 1 to 2 weeks for 4 
weeks or until valve recovery to baseline.

If the valve recovers to baseline any time during the next 4 weeks after 
consultation with and approval from the GSK Medical Monitor, the subject may 
be restarted on GSK2820151 at a reduced dose(s).  For such subjects, 
monitoring of the valve via ECHO will then be performed 2 and 4 weeks after 
rechallenge, and every 4 weeks thereafter for 16 weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then 
the subject should permanently discontinue GSK2820151.  The valve should
continue to be monitored via ECHO every 4 weeks for 16 weeks or until 
resolution.
Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with 
symptoms controlled by medical intervention) valvular toxicity must discontinue 
GSK2820151.  Valvular toxicity should continue to be monitored every 4 weeks for 16 
weeks or until resolution.  If recovery occurs (return to baseline via imaging AND 
symptom resolution) within 4 weeks, the subject may restart GSK2820151 at a reduced 
dose after consultation with and approval from the GSK Medical Monitor.
ECHO must be performed at baseline and at the final study visit.  Copies of all ECHO(s) 
and cardiology consultations performed on subjects who experience valvular toxicity will 
be required by GSK for review.  Instructions for submitting qualifying ECHOs are 
provided in the Study Reference Manual (SRM).
5.4.5.
Other Stopping Criteria
All subjects will require a chest X-ray and pulmonary function testing at screening, as 
defined in the Time and Events table.  Subjects with clinical concern for pneumonitis will 
be evaluated per institutional practice with input from the GSK medical monitor.  For 
management of suspected pneumonitis, including criteria for dose reduction and 
discontinuation of therapy, see Appendix 7.


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To monitor for thrombocytopenia, CBCs will be drawn twice weekly for the first three 
weeks of study, weekly for the next two weeks, and then every other week, as described 
in the Time and Events table.  Subjects who develop Grade 2 or greater 
thrombocytopenia may be monitored more frequently, as clinically indicated.  Please see 
Appendix 7 for suggested management of thrombocytopenia.
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics). Deaths, SAEs, and Grade 3/4 adverse events will be carefully evaluated for 
the possibility of causality.
If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, and/or if deaths related to study drug are observed, enrollment may be 
terminated and/or a lower-dose cohort may be opened or expanded. The final 
determination will be made by the Sponsor and investigators.
The sponsor may also terminate the study if the safety, pharmacokinetics (PK) or 
pharmacodynamic (PD) data suggest that an appropriate therapeutic exposure cannot be 
achieved using the dosing schedules defined in the protocol.
5.5.
Subject and Study Completion
A completed subject is one who has discontinued study treatment for reasons listed in 
Section 5.4 and completed a post-treatment follow-up visit or has died while receiving 
study treatment.  
A subject will be considered to have completed the study 2 years after the last treatment 
or if the subject dies or is still receiving study treatment or in follow-up at the time the 
study is closed or terminated, whichever is sooner.  Document the cause of death in the 
eCRF. The End of Study eCRF should only be completed when a subject is no longer 
being followed.  The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
6.1.
GSK2820151
The term ‘study treatment’ is used throughout the protocol to describe the administration 
of GSK2820151.
Study Treatment
Product name:
GSK2820151
Formulation description:
GSK2820151 capsules contain 1 mg, 5 mg, 10 mg, 50 mg, or 
100 mg of GSK2820151 as free base equivalent
Dosage form:
Capsule
Unit dose 
strength(s)/Dosage 
level(s):
1 mg, 5 mg, 10 mg, 50 mg, and 100 mg
Route of Administration
Oral
Dosing instructions:
The dosing regimen is detailed in Table 7 and is designed to permit 
collection of detailed safety and PK data.

Week 1: Once daily on days 1, 3, 4, and 5

Week 2: Once daily on days 1, 2, 3, 4, 5

Weeks 3 and beyond: Once daily continuously
GSK2820151 is to be administered orally, once daily, at 
approximately the same time of day, with no food or antacids for 
1 h before and 2 h after each dose
Physical description:
1 mg: Pink, Size 1 capsule
5 mg: Green, Size 1 capsule
10 mg: Swedish Orange, Size 1 capsule
50 mg: White Opaque, Size 0 capsule
100 mg: Blue Opaque, Size 0 capsule
6.2.
Treatment Assignment
Subjects will be assigned to receive GSK2820151 in an open-label fashion. There will be 
no placebo arm.
6.3.
Packaging and Labeling
GSK2820151 will be provided to the sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.
6.4.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 


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area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (e.g., receipt, reconciliation, and final disposition records). 

Further guidance and information for final disposition of unused study treatment are 
provided in the Laboratory Manual. 
Precaution will be taken to avoid direct contact with the study treatment. 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 or GSK study contact.
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK2820151.
6.5.
Compliance with Study Treatment Administration
At each visit, an evaluation of subject compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant subjects into 
compliance. 
Compliance with GSK2820151 will be assessed through querying the subject during the 
site visits and documented in the source documents and case report form (CRF). 
A record of the number of GSK2820151 tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
6.6.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2820151 greater than the protocol-specified dose within a 
24 hour time period will be considered an overdose.
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose the investigator (or treating physician) should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2820151 can no longer be detected systemically (at least 28 days for 
GSK2820151)

Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)


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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
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 subject.
6.7.
Treatment after the End of the Study
Post study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) therapy at 
the discretion of the treating physician.  New therapy should be documented on the CRF. 
Every effort should be made to complete the required withdrawal and follow up 
evaluations prior to initiating further therapy or dosing of an investigational agent (see 
Section 8.1 for follow-up assessments and procedures).
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
7.
MEDICATION,  DIETARY AND LIFESTYLE
RESTRICTIONS
7.1.
Concomitant Medications and Non-Drug Therapies
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the Screening Visit until the end of the study (Final Study Visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF. The minimum requirement is that drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates of 
administration should be recorded. Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter.
7.1.1.
Permitted Medications and Non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with erythropoietin, antibiotics, antiemetics, 
antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance 
with their institutional guidelines. Colony-stimulating factors like filgrastim and 
pegfilgrastim may be used as clinically indicated. The only caveat is that subjects should 
not receive those medications listed as prohibited in Section 7.1.2.1. 


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Bisphosphonates will be allowed if subjects have been on a stable dose for at least three 
months prior to receiving the first dose of GSK2820151.
7.1.2.
Prohibited Medications and Non-Drug Therapies
7.1.2.1.
Prohibited Medications
The use of certain medications and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study medication (and for the 
duration of the study) will not be allowed. If a prohibited medication is required for 
single use (such as for a procedure) while study treatment(s) is held, the GSK Medical 
Monitor can approve such use.
Subjects should not receive other anti-cancer therapy [including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormonal therapy 
(other than leuprolide or other LHRH agonists/antagonists), surgery or tumor 
embolization] while on treatment in this study. Other anti-cancer therapy should not be 
administered unless one of the following occurs: documented disease progression; 
unacceptable or unmanageable toxicity; subject is withdrawn from the study at the 
investigator’s discretion or consent is withdrawn; or no further clinical benefit is 
anticipated which requires permanent discontinuation of study drug. Note, palliative 
radiation and/or surgical intervention may be permitted (for example to address pain 
management) and should be discussed with the GSK medical monitor prior to invention 
to determine appropriate dosing and schedule. 
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc.) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that the subject’s PT/PTT values meet entry criteria.
Subjects may continue to use aspirin, but doses are not allowed to be greater than 100mg 
per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be excluded, 
except for when NSAIDs will provide benefit over other analgesics and then to be used 
with caution, including concomitant use of proton pump inhibitors.
Co-administration of the medications listed in Table 5 are PROHIBITED for 5 half-lives 
(or at least 14 days, whichever is longer) prior to the first dose of study drug until 
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone which is prohibited beginning 6 months prior to Screening 
through discontinuation from the study. [However, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines]). 


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Table 5
Drugs with a Risk of Torsades de Pointes that are Prohibited1
Amiodarone
Dronedarone
Moxifloxacin
Anagrelide
Droperidol
Papaverine
Azithromycin
Erythromycin
Pentamidine
Chloroquine
Escitalopram
Pimozide
Chlorpromazine
Flecainide
Procainamide
Cilostazol
Fluconazol
Propofol
Ciprofloxacin
Halofantrine
Quinidine
Citalopram
Haloperidol
Roxithromycin
Clarithromycin
Ibogaine
Sevoflurane
Cocaine
Ibutilide
Sotalol
Disopyramide
Levofloxacin
Sulpiride
Dofetilide
Levomepromazine
Sultopride
Domperidone
Levosulpiride
Terlipressin
Donepezil
Methadone
Thioridazine
Data Source: crediblemeds.org revision date 09 January 2017.
Drugs not available/used in the US have been omitted.
1The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (up to a maximum dose of 0.25 mg 
daily) and ondansetron (up to a maximum dose of 8 mg three times daily [TID]) are the 
only allowed drugs in this class (i.e. dolasetron and granisetron are not permitted).
7.1.2.2.
Prohibited Non-Drug Therapies
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the post-study 
follow-up visit. 
NOTE: Subjects may receive focal palliative radiation treatment during this study.  Any 
proposed radiation therapy must be approved by the investigator and the GSK Medical 
Monitor prior to initiation.
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit.
Herbal products include, but are not limited to: St. John’s Wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto , 
ginseng.
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation including marijuana.


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7.1.3.
Cautionary Medications
Co-administration of GSK2820151 and the following medications requires EXTREME 
CAUTION beginning 14 days prior to the first dose of study drug until discontinuation 
from the study, due to an increased risk of Torsades de Pointes. These medications 
include (but are not limited to):
Table 6
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution1
Alfuzosin
Foscarnet
Perphenazine
Apomorphine
Gemifloxacin
Pipamperone
Aripiprazole
Hydrocodone ER
Promethazine
Artenimole+piperaquine
Iloperidone
Rilpivirine
Asenapine
Imipramine
Risperidone
Atomoxetine
Isradipine
Saquinavir
Bedaquiline
Leuprolide
Sertindole
Buprenorphine
Lithium
Solifenacin
Clomipramine
Melperone
Tacrolimus
Clozapine
Mifepristone
Telavancin
Cyamemazine
Mirabegron
Telithromycin
Degarelix
Mirtazapine
Tetrabenazine
Delamanid
Moexipril/ hydrochlorothiazide
Tiapride
Desipramine
Nicardipine
Tizanidine
Dexmedetomidine
Norfloxacin
Tolterodine
Efavirenz
Nortriptyline
Trimipramine
Ezogabine
Ofloxacin
Tropisetron
Famotidine
Oxytocin
Vardenafil
Felbamate
Paliperidone
Venlafaxine
Fingolimod
Pasireotide
Zotepine
Flupentixol
Perflutren lipid microspheres
Perphenazine
Data Source: crediblemeds.org revision date 09 January 2017.
1The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject
Drugs  not available/used in the US have been omitted
After starting cautionary medications such as in Table 6, it is recommended that ECGs 
are implemented daily until the steady state of the new medication is reached. If there are 
ECG abnormalities, implement additional cardiotoxicity monitoring as addressed 
Appendix 7.
There is a low potential for GSK2820151 to induce or inhibit cytochrome P450 (CYP) 
enzymes.  GSK2820151 has been demonstrated to inhibit Breast Cancer Resistance 
Protein (BCRP [IC50=3.6 µM]) and thus may alter the metabolism of medications that are 
substrates of BCRP. These medications include 3-hydroxy-3-methyl-glutaryl-coenzyme 


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A reductase (HMG-CoA) reductase inhibitors (statins) as well as ciprofloxacin and other 
fluoroquinolones (though not levofloxacin).
Furthermore, GSK2820151 inhibits P-glycoprotein (PgP) at concentrations 100 µM.  
PgP substrates include medications such as statins and digoxin, which may have a narrow 
therapeutic index.  While co-administration of these agents with GSK2820151 is not 
prohibited, they should be used with caution and additional monitoring for adverse 
effects should be utilized. 
GSK2820151 may also interact with organic anion transporter 3 (OAT3).  Substrates of 
OAT3 include agents such as Penicillin G and indomethacin. While co-administration of 
these agents with GSK2820151 is not prohibited, they should be used with caution and 
additional monitoring for adverse effects should be utilized.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
7.2.
Dietary Restrictions
GSK2820151 will be administered under fasting conditions, with no food or antacids for 
1 h before and 2 h after each dose.  Requirements for fasting before and after dosing may 
be modified based on available pharmacokinetics (PK), pharmacodynamics (PD) and 
safety data. Fasting will consist of avoiding the oral ingestion of calorie-containing 
products; however, ingestion of water is permitted.  Subjects will be instructed to record 
the time and date of study treatments and meals in relation to dosing in the supplied GSK 
dosing diary.
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or PD sample during each serial PK 
sampling day (e.g., Days 1 and 18).
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug.
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast 
overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after 
administration of the morning dose.
If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose.
7.3.
Lifestyle Restrictions (Contraception)
7.3.1.
Female Subjects
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping study medication and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of 1%.


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Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are NOT acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of 1%

Non-hormonal intrauterine device (IUD) or intrauterine system (IUS) that meets the 
1% failure rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.

Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring subjects understand how to properly use these methods of contraception.
All hormonal means of birth control such as oral, injectable, dermal, subdermal or topical
contraceptives are NOT acceptable forms of birth control given that their efficacy has not 
been evaluated when given in combination with the investigational drugs.
7.3.2.
Male Subjects
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug.

Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview, OR

Condom use PLUS partner use of a highly effective contraceptive (≤1% rate of 
failure per year) such as occlusive cap (diaphragm or cervical/vault cap) plus 
spermicidal agent (foam/gel/film/cream/suppository), or intrauterine device. OR

Condom use PLUS partner use of hormonal birth control such as contraceptive 
subdermal implant, combined estrogen and progestogen oral contraceptive, 
injectable progestogen, contraceptive vaginal ring, or percutaneous contraceptive 
patches.
The above list does not apply to male subjects with a female partner of child bearing 
potential who are and will continue to be abstinent from penile-vaginal intercourse on a 
long term and persistent basis, when this is their preferred and usual lifestyle. Periodic 


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abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are NOT acceptable methods of contraception
In addition, male participants must refrain from donating sperm for duration of study and 
until 16 weeks after the last dose of study drug.
8.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table Section 8.1


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8.1.
Time and Events Tables
Table 7
Time and Events
Assessments
Notes
S
C
R
Refer to Section 8.4.2 for visit windows.
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed consent
Unless otherwise noted, screening 
assessments to be completed 
within 14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of 
day. No food or antacids 1h before 
and 2h after.
X
X
X
X
X
X
X
X
X
Daily
Review subject
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test/ 
testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine or 
serum test thereafter. Males: 
complete and free testosterone at 
SCR; free testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X


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Assessments
Notes
S
C
R
Refer to Section 8.4.2 for visit windows.
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Vital Signs
SBP, DBP, heart rate, respiratory 
rate, temp, O2 saturation
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain (using 
Wong-Baker 
Faces Pain 
Rating scale)
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function tests 
(spirometry, 
Diffusing 
capacity of the 
lungs for carbon 
monoxide
[DLCO], and 
room air
O2 saturation at 
rest via pulse 
oximetry)
All patients will have PFTs at 
baseline; afterwards as clinically 
indicated (e.g., in patients with 
severe Chronic Obstructive 
Pulmonary Disease [COPD], 
history of pneumonitis, alveolar 
haemorrhage and chest radiation
etc)
X
Adverse events
continuous from signing of informed consent
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
12-lead ECGs 
Triplicate SCR ECGs within 35 
X
O
O
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X


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Assessments
Notes
S
C
R
Refer to Section 8.4.2 for visit windows.
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
(Triplicate)
days of first dose. For timing of 
triplicate ECGs on O days, see 
Table 9 and Table 10. Otherwise, 
triplicate ECGs at approximately 
same time of day, and prior to 
dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.
X
Holter monitoring
At least 24 h, on dosing days start 
at least 60 min predose.
X
X
X
X
X
X
Telemetry
Start at least 60 min predose and 
for at least 48 h.
X
X
Efficacy
Cross-sectional 
(Computed 
tomography [CT] 
or magnetic 
resonance 
imaging [MRI]), 
functional 
(Positron 
emission 
tomography 
[PET]), or 
nuclear (bone 
scan) imaging
Appropriate imaging modality 
should be selected by the 
investigator depending on disease 
histology and location. SCR 
assessment within 2 weeks of first 
dose. Target lesions to be 
identified at SCR and followed.  
See Section 14.8.1 for guidelines.
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 9 and Table 10
PK and 
biomarker 
samples
X
X
X
X
X
X
Samples for 
X
X
X
X
X


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Assessments
Notes
S
C
R
Refer to Section 8.4.2 for visit windows.
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
mRNA
LPS blood 
sample
X
PK Urine 
samples 
X
X
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last 
treatment or upon death, whichever is sooner. Document the cause of death. 
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOT=End-of-Treatment; O= For timing of triplicate ECGs on O days, see Table 9 and Table 10; q4W=every 4 weeks; q8W=every 8weeks; SBP=systolic blood 
pressure; SCR=Screening; W=week 


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Table 8
Time and Events: Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
W1D1, W1D2: local lab sample 
3X/24h; central lab sample 
1X/24h. All other timepoints 
including unscheduled collect 2 
samples: 1 for local, 1 for central 
lab
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X1
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if PT, INR or aPTT 
are ≥1.5XULN, or in case of 
bleeding event
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Fasting blood glucose and insulin 
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 –Anhydroglucitol
(1,5 AG)
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
Thyroid stimulating hormone 
(TSH), free T3, free T4. If TSH is 
abnormal at W1D1, continue
monitor TSH, free T3 and free T4 
going forward
X
X
X
X
X
X


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NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Urinalysis
X
X
X
X
X
X
Pregnancy test, females
Serum pregnancy test within 7
days of first dose; urine or serum 
test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at 
SCR; free testosterone thereafter
X
X
X
X
X
X
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
This is collected as part of the 
Predose PK sample and is sent to
Myriad via Covance.
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, 
perform third generation 
immunoassay on same sample to 
confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
1. If any parameter (i.e., platelets) shows a downward trend, additional analyses should be performed within 2-3 days to monitor.


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Table 9
Time and Events: Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
minutes prior to the 
15 min and 30 min 
PK draws and within 
15 minutes prior to 
the other PK draws.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling
X
0-2h
2-24h
mRNA whole blood 
sample
X
X
X
X
X
X
LPS whole blood 
sample
X
X
X
X
X
X
Plasma samples will be divided at the site into two, one sample will be shipped to GSK DMPK facility where bioanalysis of PK is performed and the second sample will be sent  via 
Covance to  Myriad for systemic cytokine assessment and acute phase protein assessment. The frequency of sampling may be changed (likely reduced) based on data from the first
few subjects assessed. .
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after administration of 
the morning dose.


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Table 10
Time and Events: Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days
(+2 to +7 days for alternate dosing schedule)
W9D1 +4 days
(if dose has been escalated, 
+4 to +7 days)
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±4h
24h 
±1h
48h 
±1h
pre 
dose
0.5-2h
4 - 8h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min prior to the 15 
min and 30 min PK 
draws and within 15 
minutes prior to the 
other PK draws
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
0-2h
2-24h
mRNA whole blood 
sample
X
X
LPS whole blood 
sample
Plasma samples will be divided at the site into two, one sample will be shipped to GSK DMPK facility where bioanalysis of PK is performed and the second sample will be sent  via 
Covance to  Myriad for systemic cytokine assessment and acute phase protein assessment. The frequency of sampling may be changed (likely reduced) based on data from the first 
few subjects assessed.
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after administration of 
the morning dose.


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8.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Details concerning 
concomitant medication will be recorded starting from screening through post-study 
follow-up. At a minimum, the drug name, route of administration, dose and frequency of 
dosing, along with start and stop dates should be recorded.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging studies, etc.) and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
8.2.1.
Critical Baseline Assessments
The following are required at baseline:

imaging (e.g., CT of the Chest/Abdomen/Pelvis or MRI of the Abdomen/Pelvis) at 
the discretion of the investigator, based on the subject’s disease. At each post 
baseline assessment, evaluations of the sites of disease identified by these scans are 
required.

cardiology evaluation including echocardiogram, 12-lead ECG and Holter 
monitoring  
8.2.2.
Visit Windows
Screening (baseline to pre-dose): All assessments should be completed within 14 days 
prior to screening. Note for females, pregnancy testing should be performed within 7 
days prior to first dose. Also, clinical labs performed during screening within 72 hours of 
first dose do not need to be repeated on Day 1.
Week 1: Based on subject and clinic schedule, Week 1 Day 3 assessments can be 1 
day. 
Week 2 to Week 9: Based on subject and clinic schedule, assessments can be 3 days. 


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Monthly visits after Week 9 until Week 52: After the first disease assessment has been 
completed then the month clinic visits can be scheduled 5 days.
Monthly visits after Week 52: clinic visits can be scheduled 7 days.
Discontinuation visit: should be 14 days from last dose of study drugs. If a subject is 
unable to return to the clinic due to hospitalization, site staffs are encouraged to telephone 
the subject for assessment of adverse events.
8.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 8.1). Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring.
Note that this section details the procedures used to evaluate for safety and toxicity for 
this study. For management and recording of any suspected Adverse Events, refer to 
Section 9, Appendix 6 and Appendix 7.
8.3.1.
Physical Exams
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological system, lungs, cardiovascular system, abdomen (liver 
and spleen), lymph nodes and extremities. Height and weight will also be measured and 
recorded.
A brief physical examination will include 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
8.3.2.
ECOG Performance Status
The performance status will be assessed using the ECOG scale (Appendix 2) as specified 
in the Time and Events Table (Section 8.1).
8.3.3.
Vital Signs

Vital sign measurements to be measured in semi-supine position after 5 minutes rest 
will include temperature, systolic and diastolic blood pressure, pulse rate, and 
respiratory rate. 

In case of an abnormal first reading, three readings of blood pressure and pulse 
rate should be taken, the first reading should be rejected and the second and 
third averaged to give the measurement to be recorded in the CRF. 

Vital signs will be measured more frequently if warranted by clinical condition of the 
subject.  On days where vital signs are measured multiple times, temperature does 
not need to be repeated unless clinically indicated. 


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Refer to the Study Reference Manual (SRM) for details regarding measurement of vital 
signs.
8.3.4.
Pain
Pain will be assessed using Wong-Baker Faces Pain Rating scale (Appendix 11).
8.3.5.
Echocardiogram
For all subjects, trans-thoracic echocardiograms (TTEs) will be performed at screening 
and at assessment times as outlined in Table 7. TTEs should be evaluated and compared 
to baseline by the same reader. 
ECHO data may be transferred and reviewed by an independent cardiologist. Instructions 
for submission of qualifying ECHO scans are provided in the Study Procedure Manual 
(SPM) .
8.3.6.
Safety Electrocardiograms (ECG)
Safety ECGs will be performed at the time points specified in Table 7 using a standard 
12-lead ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals. Details will be provided in the SPM.
8.3.6.1.
Routine ECG Monitoring
Triplicate 12-lead ECGs should be performed at Screening and at all other time points, 
including on Serial Pharmacokinetic sampling days.
Standard 12-lead ECGs (Safety ECGs) will be performed as part of the real-time 
assessment of subjects and may not be included in the primary QT analysis. Safety ECGs
should be reviewed by the investigator on an ongoing basis for safety purposes. The 
dosing for each new week in the first cycle should not begin until the safety ECG has 
been reviewed and no significant abnormalities have been detected
ECG data may be transferred and reviewed by an independent central reviewer. 
Instructions for submission of ECGs are provided in the SPM.
8.3.6.2.
Evaluation of QTc
All ECGs must include QTcF measurements. For the definition of QTcF and 
management strategies for QTcF 500 msec, see Section 5.4.2 and Appendix 7.
8.3.7.
Telemetry
In addition to Safety ECG assessments, monitoring for potential adverse arrhythmias will 
be conducted utilizing continuous inpatient telemetry monitoring as outlined in Table 7
for at least 48 hours from the start of the first dose. If clinically indicated, telemetry may 
be extended past 48 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.


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8.3.8.
Holter Monitoring
In addition to the Safety ECGs performed during the study, continuous 12-lead ECGs 
(obtained via a Holter monitor) will be acquired while subjects are at the site. Dual snap 
electrodes will be utilized to enable simultaneous collection of Holter and safety ECG 
data.
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 Time and Events and should be 
obtained prior to phlebotomy and vital sign time points.
Collection of critical ECG data shortly after meals or during sleep should be avoided 
since QT prolongation occurs at these times and a change in the QT-RR relationship 
occurs during sleep. Meals should be administered according to the guidelines provided 
in Section 7.2 and in the Laboratory Manual as meal and snack times will need to be 
adjusted accordingly on dosing and ECG sampling days. 
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory. Around each of the designated time points, 3 ECGs will be 
selected approximately 2 minutes apart. In order to increase consistency of ECG 
interpretation, a limited number of central ECG over-readers will be used throughout the 
study. All ECGs for a given subject will be over-read by the same reader from the central 
validated ECG laboratory. The central reader will be blinded to subject identifiers (e.g., 
subject number, age, and sex), treatment assignment, and study day when Holter data
were collected. The final intervals and morphology analyses entered into the database 
will be those generated by the central ECG laboratory. 
QT/QTcF values will be determined using time matched ECGs obtained from the Holter 
monitor on following time points: screening, Week 1 Day 1; Week 1 Day 5, Week 2 Day 
4 and Week 3 Day 4 and Week 9 Day 1. The mean from triplicate ECGs will be 
evaluated at each time point. For a given time point, the mean QTcF from 3 separate 
beats should be analyzed on each ECG. Analysis of Lead II will be conducted with V5 as 
back-up and one of the remaining precordial leads as an alternative when T waves are not 
well defined in Leads II or V5. QTcF for an individual beat will be calculated from the 
preceding RR interval since using the average heart rate (RR) intervals from the ECG 
could result in inaccurate QTcF calculations due to beat to beat variations in the RR 
intervals. 
QT values should not be reported when the rhythm is other than sinus rhythm (sinus 
rhythm with normal respiratory variation is acceptable), and in intraventricular 
conduction delays (IVCD, QRS >120 msec). The other ECG information (including the 
rhythm and presence of IVCD) should be reported. The choice of the 3 consecutive beats 
to be measured should avoid ectopic beats and the first beat after an ectopic beat. If 
IVCD occur, these should be reported.


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8.3.9.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 11, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule. 
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the Laboratory Manual. 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 subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF. 
Refer to the Laboratory Manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws. 
All protocol required safety laboratory assessments, as defined in Table 11, are 
performed at the institution’s local laboratory. All non-safety assessments (e.g., 
pharmacokinetic samples and translational samples) will be assessed by a central 
laboratory. Please refer to the Laboratory Manual for appropriate processing and handling 
of samples to avoid duplicate and/or additional blood draws.
Some laboratory assessments (e.g., testosterone) can vary throughout the day. It is 
recommended but not mandated that laboratory assessments are collected at 
approximately the same time on each clinic day. If abnormal testosterone levels are 
observed, repeat measurements should occur at the approximate baseline timing to ensure 
this is a trend and not a single outlying event.


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Table 11
Clinical Laboratory Tests
Serum Chemistry
Blood urea nitrogen
Sodium
Magnesium 
Potassium
aspartate aminotransferase
Total and direct bilirubin
Uric acid
Creatinine
Chloride
alanine aminotransferase
Albumin
Fasting Glucose
Total carbon dioxide
alkaline phosphatase
Total protein
Creatine phosphokinase
Ionized calcium
gamma-glutamyltransferase
Total calcium
Hematology
Platelet count
Automated White Blood Cell 
Red blood cell count
Differential:
White blood cell count (absolute)
Neutrophils (absolute)
Hemoglobin
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL])
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB isoenzyme (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
Cytokine samples
Subjects should be instructed to fast (no food and only water allowed) for 10 hours prior 
to any fasting laboratory assessments (e.g., fasting glucose, fasting lipid panel, etc.). 
All laboratory results that are considered by the investigator clinically significantly 
abnormal during participation in the study or within 28 days after the last dose of study 
treatment should be recorded on the eCRF as AEs. In addition, these clinically significant 
abnormal laboratory results should be followed until the abnormality resolves or is 
determined to be stable. If such values do not return to normal within a period judged 
reasonable by the investigator, the etiology should be identified and the sponsor notified.


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8.3.10.
Troponin Measurement
. At W1D1 and W1D2 three local lab troponin samples (8hrs apart) should be drawn per 
day but only 1 central lab sample should be drawn per day. At other time-points 
(including unscheduled visit) only two samples should be drawn; 1 for local lab analysis 
and 1 for central lab analysis. Troponin T will be assessed at a central laboratory as a 
means of consistent evaluation across all subjects Whereas  second sample,  assessed at a 
local laboratory, will be used for purpose of subject management. Whenever possible, 
troponin T will be assayed by the local laboratory. However, either troponin I or troponin 
T may be assessed at a local laboratory. The same local laboratory test (troponin I or 
troponin T) should be used consistently for an individual subject throughout the study. 
8.3.11.
Pregnancy

Reporting of any pregnancies in female subjects and/or female partners of male 
subjects will be collected after the start of dosing and until 7 months following the 
last dose of GSK2820151.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy. The subject 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 premature termination of the pregnancy 
will be reported. Details on  follow-up  procedures outlined in Appendix 7.
8.4.
Pharmacokinetics
PK analyses will be the responsibility of GSK Clinical Pharmacokinetics Modeling & 
Simulation (CPMS). Plasma GSK2820151 concentration-time data will be analyzed by 
non-compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacology parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to Cmax
(tmax), area under the plasma concentration-time curve (AUC(0-) and AUC(0-∞) Week1 
Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from the ratio of AUC(0-) in Week 3 Day 4 / AUC(0-) in 
Week 1 Day 1. The ratio of AUC(0-) on Week 3 Day 4/ Week 1 Day 1 AUC(0-∞) will 
be calculated to assess time invariance. GSK2820151 concentrations will be determined 
in urine samples to determine urinary recovery of unchanged drug and renal clearance.
Plasma concentration-time data will be listed by dose and summarized using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum and maximum) by 
planned relative assessment time. Mean and/ or median values will be plotted over time. 
Individual plasma and urinary (if available) PK 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 will be reported.


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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 evaluated, dose 
proportionality of AUC and Cmax for GSK2820151 will be assessed using the power 
model (details will be provided in the Reporting and Analysis Plan [RAP]).
Plasma concentration-time data will be further analyzed using appropriate model(s) to 
determine population PK parameters (absorption rate (Ka), apparent clearance (CL/F) 
and volume of distribution (V/F)) and summary exposure measures (Cmax, AUC and 
Average observed concentration [Cav] = AUC/) and identify important covariates (e.g., 
age, weight, or disease related covariates).
8.4.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for PK analysis of GSK2820151 will be collected at the time points 
indicated in the Time and Events Schedule (Table 9 and Table 10). 
Each PK sample should be collected as close as possible to the planned time relative to 
the dose (i.e., time zero) administered to the subject on PK days. The actual date and time 
of each blood sample collection will be recorded along with the date and time of the prior 
dose administration. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring. This will not 
require a protocol amendment. In addition, plasma samples may be analyzed qualitatively 
for other circulating compound-related material and the results will be reported under a 
separate Drug Metabolism and Pharmacokinetics (DMPK) protocol.
Details on PK blood sample collection, processing, storage, and shipping procedures are 
provided in the Laboratory Manual.
8.4.2.
Urine Sample Collection for Pharmacokinetics
Urine samples for quantitative analysis of GSK2820151 will be collected over 24 hours 
in two samples (sample collected 0-2 hr and a second sample collected 2-24 hr) 
immediately following dosing on Week 1 Day 1 and Week 3 Day 4
The actual date and time of each urine sample collection will be recorded. In addition, 
pooled urine pH, the total volume of the pooled urine and the weight of the pooled urine 
will be measured and recorded in the eCRF.
Details of urine sample collection, processing, storage, and shipping procedures are 
provided in the Laboratory Manual.
8.4.3.
Pharmacokinetic Sample Analysis
Plasma sample analysis will be performed under the management of Bioanalytical 
Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics (DMPK), Platform 
Technology and Science (PTS), GlaxoSmithKline. Concentrations of GSK2820151 will 
be determined in plasma samples using the currently approved bioanalytical 


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methodology. Raw data will be stored in the Good Laboratory Practices (GLP) Archives, 
GlaxoSmithKline. 
Once the plasma samples have been analyzed for GSK2820151, any remaining plasma 
may be analyzed for other compound-related metabolites and the results reported under a 
separate GSK PTS-DMPK protocol.
Urine sample analysis may be performed under the management of Bioanalytical Science 
and Toxicokinetics, DMPK, PTS, GlaxoSmithKline. Concentrations of GSK2820151 
may be determined in urine samples using an investigative analytical methodology. Urine 
raw data will be stored in the GLP Archives, GlaxoSmithKline. 
The urine samples may be analyzed for compound-related metabolites and the results will 
be reported under a separate DMPK protocol.
8.5.
Pharmacokinetic/Pharmacodynamic Analysis
Observed or predicted concentrations and/or exposures will be combined with safety, 
efficacy, and/or PD measures of interest to examine potential exposure response 
relationships.
The relationship between QTcF and concentration expressed as Cmax, Cav, and 
instantaneous time-matched concentration will be plotted graphically. A linear mixed 
effects analysis of the slope of the QTcF-concentration responses adjusting for baseline 
will be evaluated as a means of estimating QTcF effect in lieu of a thorough QT study.
Other quantitative safety parameters and biomarkers of interest including changes in 
troponin levels will be plotted graphically against summary exposure measures (e.g., 
Cmax, C, 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), exposure producing 50% of the maximum effect (EC50), and maximum 
effect (Emax).
Overall efficacy data and overall tumor burden may be described using ordered 
categorical model and continuous models with summary exposure parameters (e.g., 
Cmax, C, and Cav) as covariates derived from the population PK analysis. Further 
model details will be provided in the RAP.
8.6.
Efficacy
The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or a partial response (PR) at any time as per RECIST 1.1. 

Lesion assessment  will be conducted according to Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] as outlined below and in Appendix 
8. 


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
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 2 weeks prior to the first 
dose of GSK2820151, then every 8 weeks starting W1D1 thereafter, and at the final 
study visit.  See the Time and Events Table (Section 8.1) for the schedule of 
assessments of anti-cancer activity. 

For subjects with CRPC without measurable disease by RECIST criteria, serial 
prostate specific antigen (PSA) measurements will be drawn at the disease 
assessment time points defined in the Time and Events Table (Section 8.1).  
Response will be defined by the number of subjects who achieve a 50% decrement in 
their baseline PSA (PSA50).

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 more than 8 weeks prior to the 
subject’s withdrawal from study and progressive disease has not been documented, a 
disease assessment should be obtained at the time of withdrawal from study.

Subjects whose disease responds (either complete response [CR] or partial response 
[PR]) should have a confirmatory disease assessment performed 4 weeks after the 
date of assessment during which the response was 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.
8.7.
Translational Research
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Further details on the translational research analyses will be addressed in the RAP.
8.7.1.
Biologic Effects of GSK2820151
Exploratory analysis may be performed to examine potential relationships between drug 
exposure and markers of BET target inhibition (e.g., cytokines, acute phase proteins, 
relevant transcripts, and/or proteins) or between anticancer activity and potential markers 
of sensitivity (e.g., genetic alterations).
8.7.2.
RNA Expression Research
Related BET inhibitors have been shown to modulate the expression of a number of 
different genes in unstimulated whole blood between 1 h and 6 h. The mRNA levels of 
31 such genes form a ‘signature’ panel which will also be used as a biomarker of 
engagement of pharmacology and will be measured using mRNA isolated from whole 


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blood. The modulation of a number of these genes will also be measured as changes in 
systemic proteins as well as in the analysis of the ex vivo assay blood samples (e.g., 
Chemokine [C-C motif] ligand 2 [CCL2] and Interleukin 8 [IL-8]) thus relating mRNA 
and protein expression with drug concentration. Other translational research studies, such 
as transcriptomics profiling, will also be performed using whole blood mRNA from 
selected patients.
8.7.3.
Effects of GSK2820151 on Systemic Markers of Inflammation
GSK2820151 has been shown to inhibit LPS-induced IL-6 across different human cell 
populations and species. The action of the compound is through inhibition of the 
assembly of transcriptional complexes required to express the protein. Pre-clinical studies 
demonstrate that blood concentration of drug correlates to the degree of inhibition of LPS 
induced IL-6 in ex vivo whole blood samples. Therefore, this biomarker will be used as 
an indication of pharmacology and will be aligned with PK sampling. Since inhibition of 
BET family proteins is known to inhibit a range of pro-inflammatory mediators and acute 
phase proteins, a number of additional proteins (46) will also be measured from these ex 
vivo samples.
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, CCL2, macrophage inflammatory protein 1 alpha [MIP1-α], IL-8) will also be 
measured in plasma samples taken during PK sampling and at the time of any Grade 2 
fever or symptoms indicative of a potential cytokine storm. This will assess systemic 
inflammatory response in the subject using biomarkers such as pro-inflammatory 
cytokines and acute phase proteins and correlate the systemic response to drug with that 
in stimulated and unstimulated blood. These biomarkers are expected to change over days 
rather than hours, based on the plasma half lives and pre-clinical data, such that sampling 
will also be performed after repeat dosing.
8.8.
Pharmacogenetic Analysis
An important objective of the clinical study is pharmacogenetic (PGx) research. 
Participation in PGx is optional but all subjects who are eligible for the clinical study will 
be given the opportunity to participate. Subjects may decline participation without effect 
on their medical care or care during the clinical study. A separate consent signature is 
required for PGx research.
Subjects who provide consent will have a blood sample taken for analysis. The 
presence/absence of genetic variations in host deoxyribonucleic acid (DNA) from blood 
will be analyzed to determine their relationship with response (safety, tolerability, 
pharmacokinetics, and efficacy) to treatment with GSK2820151. 
Information regarding pharmacogenetic research is included in Appendix 5. In approving 
the clinical protocol, the independent ethics committee/institutional review board 
(IEC/IRB) (and, where required, the applicable regulatory agency) also approve the PGx 
assessments unless otherwise indicated. Where permitted by regulatory authorities, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 


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When PGx assessments are not approved, then the approval for the rest of the study will 
clearly indicate this and therefore, PGx assessments will not be conducted.
Information regarding genetic research is included in. Appendix 5
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DATA COLLECTION, REPORTING, AND FOLLOW-UP
9.1.
Definition of AE/SAE
The definitions of an AE or SAE can be found in Appendix 6. The severity of adverse 
events will be graded utilizing the NCI-CTCAE v4.03. Additional details regarding 
management of specific AEs or SAEs are described in Appendix 7.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
9.1.1.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.1.2.
Other Sentinel Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE.


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9.1.3.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition, are not to be reported as AEs or SAEs.
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
9.2.
Time period and Frequency for collecting AE and SAE 
information

At each visit/contact, AEs and SAEs will be collected from the first dose (start of 
Study Treatment) until 28 days after the last dose of study treatment or until the start 
of new anti-cancer therapy-whichever occurs first.

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

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 subject consents to participate in the study up to and 
including any follow-up contact. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 6
9.2.1.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 


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
“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
9.2.2.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 6.
9.2.3.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate, according to local requirements.
10.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system. 
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug. 
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy. Subject initials will not be 
collected or transmitted to GSK according to GSK policy.


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11.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
11.1.
Hypotheses
The primary endpoints of this study are safety and tolerability; the MTD and RP2D will 
also be determined. No formal statistical hypotheses will be tested. The primary focus 
will be on determining the recommended dose for further exploration, the safety profile, 
and the PK of GSK2820151 in subjects with advanced cancer. Analyses will be 
descriptive and exploratory.
11.2.
Continual Reassessment Method
11.2.1.
Description of Continual Reassessment Method
After all subjects in each cohort have completed the DLT observation period, a dosing 
recommendation for the next cohort will be made following an N-CRM analysis.  All
available data, including safety and PK data from current and prior cohorts will be 
reviewed at the dose escalation meeting. Although the N-CRM will be used to 
recommend the next dosing level, clinical judgment by the Medical Monitor in 
consultation with the study team and Investigators, and taking into account PK and PD 
data, will determine dose escalation as deemed appropriate.  
The N-CRM design makes use of a Bayesian logistic regression model relating dose and 
toxicity and is expected to locate the MTD efficiently while minimizing the number of 
subjects exposed to pharmacologically inactive or unsafe dose levels. 
The MTD will be defined as that dose that has the highest posterior probability of having 
a DLT rate within the Target Toxicity range and for which the posterior probability that 
the DLT rate lies within the Excessive Toxicity or the Unacceptable Toxicity range is less 
than 25%.
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 
0% - 16%

A dose falls in the Target Toxicity range if the probability of a DLT at the dose 
is 16% - 33%

A dose falls in the Excessive Toxicity range if the probability of a DLT at the 
dose is 33% - 60%

A dose falls in the Unacceptable Toxicity range if the probability of a DLT at 
the dose is 60% - 100%
An updated posterior estimate of the dose-toxicity curve will also be provided at the time 
of the dose-escalation meeting.


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11.2.1.1.
Implementation of N-CRM
The N-CRM model implementation will be performed using the Fixed and Adaptive 
Clinical Trial Simulator (FACTS) (Version 2.3 or higher) software from Tessella.
11.2.1.2.
Bayesian Prior
The N-CRM methodology requires that a Bayesian prior distribution for the dose-toxicity 
curve be pre-specified.  The Bayesian prior used for this design was determined using the 
quantile method.  For each dose, the most likely (median) presumed probability of DLT 
was specified, along with a 95% credible interval – an interval within which the team is 
95% a priori certain the probability of a DLT lies.  The 95% credible intervals are 
intentionally wide due to limited information about the toxicity profile of GSK2820151 
in humans and to allow the accumulating data to have more influence on dose 
recommendations than the prior.  Further details regarding the specific N-CRM model 
will be provided in the Reporting and Analysis Plan (RAP) and will be determined before 
the first dose-escalation meeting after consideration of all information gathered before 
then.
11.3.
Sample Size Considerations
11.3.1.
Sample Size Assumptions
The total number of subjects to be enrolled into this study will depend on the number of 
subjects needed to characterize individual dose cohorts for the determination of the 
maximum tolerated dose of GSK2820151; the final sample size is not driven by statistical 
considerations. However, it is anticipated that approximately 30 to 50 subjects will be 
enrolled with a maximum of 80 subjects.
11.3.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
11.4.
Data Analysis Considerations
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
11.4.1.
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2820151. Safety and anti-cancer activity will be evaluated based on this analysis 
population.
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.
Additional analysis populations may be defined in the RAP.


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11.4.2.
Interim Analysis
Interim analyses will be performed to determine if a dose-escalation is appropriate.  The 
primary driver for the dose-escalation decisions will be safety and tolerability of each 
dose cohort.
If this trial enrolls more than 20 patients at the recommended phase 2 dose (RP2D), an 
interim analysis for futility and complete review of safety data will be performed on first 
20 patients treated. This analysis will be used to evaluate the risk-benefit of continued 
treatment of these patients and to assess the risks related to delayed GSK2820151-related 
toxicities.
An interim analysis of the pharmacodynamic data will be conducted once an appropriate 
amount of data has been collected and has been batched for analysis. Interim analyses of 
the pharmacodynamic data may be conducted throughout the duration of the study.
11.5.
Key Elements of Analysis Plan
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
All data will be summarized and listed.
11.5.1.
Primary Analyses
As the primary endpoints of this study are safety and tolerability, the primary analyses 
will be descriptive in nature. Safety endpoints are described in Section 5.4.
The All Treated Population will consist of all subjects receiving at least one dose of study 
drug and will be used for the analysis of safety and efficacy data. Complete details of the 
analyses will be provided in the RAP.
11.5.2.
Secondary Analyses
11.5.2.1.
Pharmacokinetic Analyses
11.5.2.1.1. Pharmacokinetic Parameters
PK analyses will be the responsibility of CPMS, GSK. Plasma GSK2820151 
concentration-time data from dose escalation will be analyzed by non-compartmental 
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From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined. The ratio of AUC(0-) on Week 3 Day 4 AUC(0-) / 
Week 1 Day 1 AUC(0-) will be calculated to assess time invariance. GSK2820151 
concentrations will be determined in urine samples to determine urinary recovery of 
unchanged drug and renal clearance.
11.5.2.1.2. Statistical analysis of pharmacokinetic parameters
Statistical analyses of the PK parameters data will be conducted by Clinical Statistics, 
GSK. Plasma concentration-time data will be listed by dose, age group, 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 and urinary (if available) pharmacokinetic parameter 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 will be reported. 
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 GSK2820151 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. 
11.5.2.2.
Efficacy Analysis
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, PR, or stable disease) prior to the initiation 
of therapy.  Progressive disease (PD) will also be defined per RECIST 1.1 criteria.  
Otherwise, if the subject does not have a documented date of events, PFS will be 
censored at the date of the last adequate assessment. Further details on rules for censoring 
will be provided in the RAP.  PFS will be summarized using Kaplan-Meier methods.


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The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or a partial response (PR) at any time as per RECIST 1.1 criteria. 
Subjects with unknown or missing response will be treated as non-responders, i.e. these 
subjects will be included in the denominator when calculating the percentage. Exact 
methods for calculated confidence intervals will be given in the RAP.
The number and types of responses, as outlined in RECIST 1.1, will be listed and 
summarized, as appropriate.
11.5.2.3.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP.
11.5.2.4.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy
11.5.2.5.
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 v4.03.
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, SAEs, and AEs leading to discontinuation of study treatment.  AEs, if listed 
in the NCI-CTCAE v4.03, will be summarized by the maximum grade.  Otherwise, the 
AEs will be summarized by maximum intensity.
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by dose 
cohort.
AEs of special interest will be outlined in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
11.5.2.6.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.03.  Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criterion will be 
summarized using proportions.  Further details will be provided in the RAP.
11.5.3.
Other Analyses
Exploratory analyses may be performed to examine potential relationships between 
anticancer activity and changes in markers of BET target inhibition or tumor biology 


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(e.g., cytokines, acute phase proteins, relevant transcripts, and/or proteins) or between 
anticancer activity and potential markers of sensitivity.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Data for vital signs, electrocardiograms (ECGs), and echocardiograms (ECHOs) 
will be summarized based on predetermined criteria identified to be of potential clinical 
concern. Further details on the translational research analyses will be addressed in the 
RAP.
12.
STUDY GOVERNANCE CONSIDERATIONS
12.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
12.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research. 

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission. 

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 


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being deferred and the study, with the exception of the optional assessments, can be 
initiated.
12.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements. 

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
12.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
12.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites. 

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 


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applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action. 

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
12.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location. 

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff. 

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken. 

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.


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12.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, 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 subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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13.
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Asangani IA, Dommeti VL, Wang X, Malik R, et al. Therapeutic targeting of BET 
bromodomain proteins in castration-resistant prostate cancer. Nature. 2014; 510(7504): 
278-82.
Bauer DE, Mitchell CM, Strait KM, Lathan CS, et al.  Clinicopathologic Features and 
Long-term Outcomes of NUT Midline Carcinoma.  Clin CanRes. 2012; 18:5773-9.
Chaidos A, Caputo V, Gouvedenou K, Liu B, Liu B, et.al. Potent antimyeloma activity of 
the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 2014; 123(5): 697-
705.
Cockcroft DW, Gault MH.  Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron 1976; 16: 31-41.
Delmore JE, Issa GC, Lemieux ME, Ral PB, et al. BET bromodomain inhibition as a 
therapeutic strategy to target c-Myc. Cell 2011; 146: 904-917.
Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 
binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 
2003;100(15): 8758-63.
Dey A, Nishiyama A, Karpova T, McNally J, Ozato K. Brd4 marks select genes on 
mitotic chromatin and directs postmitotic transcription. Mol Biol Cell. 2009; 20(23): 
4899-909.
Dhalluin C, Carlson JE, Zeng L, He C, et. al. Structure and ligand of a histone 
acetyltransferase bromodomain. Nature 1999; 399: 491–496.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation 
criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 
45: 228-247.
Fiskus W, Sharma S, Qi J, Shah B, et al. BET Protein Antagonist JQ1 Is Synergistically 
Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-
TKI in AML Cells Expressing FLT-ITD. Mol Cancer Ther. 2014; 13(10); 2315–27.
French C, Ramirez C, Kolmakova J, Hickman TT, et al. BRD-NUT oncoproteins: a 
family of closely related nuclear proteins that block epithelial differentiation and 
maintain the growth of carcinoma cells. Oncogene, 2008; 27: 2237-42.
GlaxoSmithKline Document Number 2014N208278_00; GSK2820151 Investigator's 
Brochure. Version 1. 13-JAN-2015
Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-
dependent transcriptional elongation. Cell. 2009; 138(1): 129-45.


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Itzen F, Greifenberg AK, Bösken CA, Geyer M. Brd4 activates P-TEFb for RNA 
polymerase II CTD phosphorylation. Nucleic Acids Res. 2014; 42(12): 7577-90.
James LP. 2009. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Disp. 2009; 37: 1779-
1784.
Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain 
protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA 
polymerase II-dependent transcription. Mol Cell. 2005; 19(4): 523-34.
Mertz J, Conery AR, Bryant BM, Sandy P, et al.  Targeting MYC dependence in cancer 
by inhibiting BET bromodomains.  Proc Nat Acad Sci. 2011; 108: 16669-74.
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4.03, 
DCTD, NCI, NIH, DHHS, June 14, 2010.
Neuenschwander B, Branson M, and Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2008 27: 2420–39.
Nicodeme E, Jeffrey K, Schaefer U, Beinke S, et al. Suppression of inflammation by a 
synthetic histone mimic. Nature 2010; 478: 1119-1123.
NYHA, 1994; The Criteria Committee of the New York Heart Association (NYHA).  
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th
Ed. Boston, Mass:  Little, Brown & Co.; 1994:253-256.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and Response Criteria of the Eastern Cooperative Oncology Group, 1982.
Paillisson A, Levasseur A, Gouret P, Callebaut I, Bontoux M, Pontarotti P et al. 
Bromodomain testis-specific protein is expressed in mouse oocyte and evolves faster than 
its ubiquitously expressed paralogs BRD2, -3, and -4. Genomics, 2007;89: 215-23.
Patel MC, Debrosse M, Smith M, Dey A, et.al. BRD4 coordinates recruitment of pause 
release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription 
elongation of interferon-stimulated genes. Mol Cell Biol. 2013; 33(12): 2497-507.
Trabucco SE, Gerstein RM, Evens AM, Bradner JE, et al. Inhibition of bromodomain 
proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 
2014 Jul 9. Pii: clincanres.3346.2013. [Epub ahead of print]
Trousdale RK and Wolgemuth DJ. Bromodomain containing 2 (Brd2) is expressed in 
distinct patterns during ovarian folliculogenesis independent of FSH or GDF9 action. 
Molecular Reproduction and Development, 2004;68:261-8.
Wyce A, Ganji G, Smitheman KN, Chung CW, et al. BET inhibition silences expression 
of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PloS One 
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Yan J, Diaz J, Jiao J, Wang R, You J. Perturbation of BRD4 function by BRD4-NUT 
abrogates cellular differentiation in NUT midline carcinoma. J Biol Chem. 2011; 
286:27663-27675.


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14.
APPENDICES
14.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
C
Degrees Celsius
1,5 AG
1,5 –Anhydroglucitol
A1c
Glycosylated hemoglobin
ACLS
Advanced Cardiac Life Support
AE(s)
Adverse event(s)
ALT
Alanine aminotransferase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-∞)
Area under the curve from zero to infinity
AUC(0-24)
Area under the curve from zero to 24 hours
AUC(0-)
Area under the plasma concentration-time curve
BAL
Bronchoalveolar lavage
BCRP
Breast Cancer Resistance Protein
BET
Bromodomain & extra-terminal
BID
Twice daily
BP
Blood pressure
BPM
Beats per minute
BRD
Bromodomain
Cav
Average observed concentration
CBC
Complete blood count
CCL2
Chemokine (C-C motif) ligand 2
CK
Creatine kinase
CK-MB
Creatine kinase MB isoenzyme
Cmax
Maximum observed plasma concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
COPD
Chronic obstructive pulmonary disease
CPMS
Clinical Pharmacokinetics Modeling & Simulation
CR
Complete response
CRC
Colorectal cancer
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
Cτ
Trough concentration
CV
Cardiovascular
CV%
Percentage coefficient of variance
DHEA
Dehydroepiandrosterone


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dl
Deciliter(s)
DLT
Dose-limiting toxicity
DLCO
Diffusing capacity of the lungs for carbon monoxide
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
EC50
Exposure producing 50% of Emax
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECHO
Echocardiogram
eCRF
Electronic case report form
EFD
Embryo-fetal development
EIAC
Enzyme-inducing anticonvulsant
Emax
Maximum effect
FACTS
Fixed and Adaptive Clinical Trial Simulator
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram(s)
GCP
Good clinical practice
GI
Gastrointestinal
gIC50
growth half maximal inhibitory concentration
GLP
Good laboratory practices
GSK
GlaxoSmithKline
HbsAg
Hepatitis B surface antigen
HCTZ
Hydrochlorothiazide
HDL
High-density lipoprotein
hERG
Human ether-à-go-go-related gene
HIV
Human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A reductase
HNSTD
Highest non-severely toxic dose
hr
Hour(s)
HRT
Hormone replacement therapy
IB
Investigator’s brochure
IC50
half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC/IRB
Independent ethics committee/institutional review board
IL-6
Interleukin 6
IL-8
Interleukin 8
INR
International normalized ratio
IRB
Institutional review board
IUD
Intrauterine device
IUS
intrauterine system
IV
Intravenous
IVCD
Intraventricular conductance delay


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kg
Kilogram(s)
l
Liter(s)
LDL
Low-density lipoprotein
LHRH
Luteinizing hormone releasing hormone
LLN
Lower limit of normal
LMWH
Low molecular weight heparin
LPS
Lipopolysaccharide
LVEF
Left ventricular ejection fraction
m2
Meters squared
MABEL
Minimum anticipated biological effect level
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
MI
Myocardial infarction
min
Minute(s)
MIP1-α
Macrophage inflammatory protein 1 alpha
mIU
Milli International Units
ml
Milliliter(s)
M
Micromolar
mm3
Cubic millimeters
MM
Multiple myeloma
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSDS
Material safety data sheet
msec
Millisecond(s)
MTD
Maximum tolerated dose
NCI-CTCAE
National Cancer Institute- Common Terminology Criteria 
for Adverse Events
N-CRM
Neuenschwander - Continuous Reassessment Method
ng
Nanogram(s)
NMC
NUT midline carcinoma
NOAEL
No observed adverse effect level
NOD/SCID
Non-obese diabetic/severe combined immunodeficiency
NSCLC
Non-small cell lung cancer
NT-proBNP
N-terminal pro–B-Type natriuretic peptide
NUT
Nuclear protein in testes
NYHA
New York Heart Association
OAT3
organic anion transporter 3
ORR
Objective response rate
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PET
Positron emission tomography
PFS
Progression-free survival
pg
Picogram(s)
PgP
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetic


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pmol
Picomole(s)
PR
Partial response
PSA
Prostate specific antigen
PSA50
50% decrement in baseline PSA
PT
Prothrombin time
p-TEFB
Positive transcription elongation factor complex
PTS
Platform Technology & Science
PTT
Partial thromboplastin time
QTc
Corrected QT interval
QTcF
Corrected QT (Fridericia’s formula)
RAP
Reporting and Analysis Plan
RECIST
Response criteria in solid tumors
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
Ro
The observed accumulation ratio
RP2D
Recommended Phase 2 dose
SAE(s)
Serious adverse event(s)
SAS
Statistical Analysis System
SCLC
Small cell lung cancer
SD
Standard deviation
SPM
Study Procedure Manual
SRT
Safety review team
STD10
Severely toxic dose in 10% of the animals
t½
Half-life
TID
Three times daily
tmax
Time to Cmax
TSH
Thyroid Stimulating Hormone
TSS
Transcription start site
TTE
Transthoracic echocardiogram
ULN
Upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
CredibleMeds
FACTS
SAS
WinNonlin


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14.2.
Appendix 2: ECOG Performance Status
The performance status assessment is based on the ECOG scale [Oken, 1982]
0 = Fully active, able to carry on all pre-disease performance without restriction.
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work).
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5 = Dead.


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14.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and to 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/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
Subject 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 subjects 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 treatment 

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 subject until liver chemistries  
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 4) 

If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and may 
continue subject in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, 
aspartate aminotransferase [AST], alkaline 
phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor subjects 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 2 days 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 subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.


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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 treatment for that subject 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 subjects 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.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’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 Laboratory Manual.  


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Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Subject 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
Subject 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 subject 
safety. 

Subject can continue study treatment  

Subject 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 subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
For subjects 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 
subjects twice monthly until liver chemistries 
normalize or return to within baseline
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
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,et al.  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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14.4.
Appendix 4: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available.
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment) [Hunt, 2010]
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.
Approval by GSK for rechallenge with study treatment can be considered where:


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
Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available.  

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 9.
2. Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded


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
Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 9.
References:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS,et al.  Drug-induced liver injury 
following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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14.5.
Appendix 5: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and response to medicine, including GSK2820151 or any concomitant 
medicines.
US Food and Drug Administration states that an in vitro companion diagnostic device 
(IVD) could be essential for the safe and effective use of a corresponding therapeutic 
product to:

Identify patients who are most likely to benefit from a particular therapeutic 
product;

Identify patients likely to be at increased risk for serious adverse reactions as a 
result of treatment with a particular therapeutic product;

Monitor response to treatment for the purpose of adjusting treatment (e.g. 
schedule, dose, discontinuation) to achieve improved safety or effectiveness
Global regulatory requirements for IVD companion diagnostic tests are evolving.  If a 
DNA-based IVD companion diagnostic device might be needed to identify patients who 
are appropriate for the GSK medicinal product(s) under investigation in this protocol, 
then GSK should collect and retain DNA samples from subjects who carry the genetic 
variant of interest as well as DNA samples from subjects who do not carry the genetic 
variants of interest to validate the performance of the companion diagnostic.  Any IVD 
companion diagnostic research objectives should be described in subject informed 
consent forms.
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in the RAP prior to initiation of 
the analysis. Planned analyses and results of genetic investigations will be reported either 
as part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response. 

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample. 
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner. GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


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


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14.6.
Appendix 6: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
14.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This 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. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


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Events NOT meeting definition of an AE include:

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 subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
14.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.


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d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
Refer to Appendix 2 for the required liver chemistry follow-up instructions


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14.6.3.
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
14.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.


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14.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe: An event that prevents normal everyday activities. - an AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
14.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and e-mail it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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14.7.
Appendix 7: 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.
14.7.1.
Dose Adjustments for Toxicity
Table 12
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
QTcF
If >30msec and < 60 msec 
change from baseline  AND 
manual QTcF <500 (average 
of three ECGs over at least 
15 minutes)

Continue current dose of GSK2820151

Supplement electrolytes, particularly 
potassium and magnesium, to recommended 
levels:
(1) Maintain serum potassium > 4mol/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 
(average of three ECGs over 
at least 15 minutes)

Discontinue GSK2820151 and notify the GSK 
Medical Monitor. 
(1) Supplement electrolytes to recommended 
levels:
a.
Maintain serum potassium > 4mol/L
b.
Maintain serum magnesium levels >0.85 
mmol/L
(2) Rule out other potential etiologies for 
prolonged QTcF such as cardiac ischemia
(3) Discontinue any concomitant medications 
with potential for QTcF prolongation.
(4) Consider telemetry monitoring if clinically 
indicated.

This subject may consider restarting study 
treatment at a previous dose level if the following 
criteria for QTcF rechallenge are met:

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless 
under the following conditions: 
(1)
QTcF event reduced to <450 msec,
(2)
potassium and magnesium levels are within 
institutional normal range,
(3)
a favorable risk/benefit profile (in the medical 
judgement of the Investigator and the GSK 
Medical Monitor),


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
(4)
approval within GSK medical governance:
a.
agreement with SERM MD and PPL,
b.
review with Chair or co-Chair of the 
GSK QT panel,
c.
SERM VP and Clinical VP approval
d.
Head Unit Physician approval
(5)
Institutional IRB (or equivalent) approval, and
(6)
The subject is re-consented regarding the 
possible increased risk of QTc prolongation. 

If approval for re-challenge is granted, the 
subject must be re-consented (with a 
separate informed consent specific to QTc 
prolongation)

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the 
subject should complete the following activities post-
dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be 
monitored weekly for two weeks, and then next 
assessment at 4 weeks post-dose. 
If QTcF results have not resolved to baseline by 4 
weeks post-dose, then continue every 4-5 weeks until 
resolution
Troponin
Troponin level >ULN

Contact the subject immediately for evaluation of
symptoms and to obtain ECG. Repeat troponin 
within 24-48 hours or as soon as possible. 

If the subject is asymptomatic and repeat 
value is within the normal range, the subject 
may continue GSK2820151 with close follow-
up for symptoms, ECG monitoring and further 
troponin measurements as clinically 
indicated.

If the repeat value remains > ULN AND the 
subject is asymptomatic, hold GSK2820151, 
refer to a cardiologist, and contact the GSK 
Medical Monitor. May consider restarting 
study treatment at a reduced dose or dose 
level pre-event based on discussion with GSK 
Medical Monitor.

If the subject is symptomatic (symptoms 
consistent with acute coronary syndrome) OR
the troponin level is at or above the threshold 
for mycocardial infarction (MI) according to 
local lab parameters, discontinue 
GSK2820151 permanently and refer the 
subject immediately to a cardiologist or 
emergency medical facility for appropriate 
medical care.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
LVEF
Ejection fraction below the 
institution’s lower limit of 
normal (LLN)
AND
An asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline
Withhold GSK2820151 and repeat evaluation of LVEF 
within 2 weeks
If LVEF recovers (defined as LLN and absolute 
decrease 10% compared to baseline) at any time 
during the next 4 weeks, after consultation and 
approval of the GSK medical monitor, the subject may 
be restarted on investigational drug(s) at a reduced 
dose. Monitoring to be performed at 2 and 4 weeks 
after restarting investigational drug(s) and then per 
protocol specifications.
If LVEF does not recover within 4 weeks, permanently 
discontinue investigational drug(s). Evaluation by a 
cardiologist will be conducted. Ejection fraction should 
continue to be monitored at 2 weeks, 4 weeks and 
every 4 weeks until 16 weeks or resolution, whichever 
is longer.
Grade 3 or 4
Permanently discontinue GSK2820151. Evaluation by 
a cardiologist will be conducted. Ejection fraction 
should be monitored at 2 weeks, 4 weeks and then 
every 4 weeks until 16 weeks or resolution, whichever 
is longer.
Liver  
Refer to procedures outlined in Appendix 3: Liver 
Safety Required Actions and Follow up Assessments 
Hypo- and 
Hyperglycemia
Note: for 
management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use NCI-
CTCAE version 
v4.03 Grade 1-5
Fasting blood glucose >150 
mg/dL to 250 mg/dL (Mild 
hyperglycemia)

Monitor fasting and preprandial glucose.

If persistent over 2 repeats over 3-4 weeks, 
consult Diabetologist and consider starting 
metformin
Any blood glucose >250 
mg/dL (Moderate to Severe 
hyperglycemia)

Withhold GSK2820151 and instruct subject to 
notify investigator immediately.

Monitor for ketoacidosis as clinically 
indicated.

If subject has evidence of ketoacidosis, 
initiate prompt therapy. Antihyperglycemic 
therapy with insulin is preferred. Consult 
Diabetologist/Endocrinologist . Careful 
monitoring should be performed to control for 
rebound hypoglycemia as effect of 
investigational product(s) resolve.

May consider restarting GSK2820151 at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Fasting blood glucose 
<70 mg/dL (Moderate to 
Severe hypoglycemia)
Withhold GSK2820151
Provide sugar containing liquids and monitor
blood sugar closely. Check for insulin and c-
peptide levels. After blood sugar normalizes, may 
restart study treatment one dose level lower if the 
hypoglycemia cannot be attributed to any other 
cause, and fasting blood sugar will be monitored 
on a daily basis until the blood glucose level is 
stabilized.
Diarrhea
Grade 1

Initiate supportive care including loperamide. 
Grade 2

Initiate supportive care including loperamide.

Consider temporary discontinuation of 
GSK2820151 and discuss with GSK Medical 
Monitor.
Grade 3

Above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics as 
appropriate.

Withhold GSK2820151 until diarrhea has 
resolved to ≤Grade 1, continue diarrheal 
prophylaxisIf diarrhea recovers to ≤Grade 1 , 
discuss with medical monitor; consider resuming 
treatment at the same or lower dose based on 
clinical judgement.
Grade 4

Above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics as 
appropriate.

Discontinue GSK2820151 permanently
Mucositis
Grade 1 or 2

Encourage oral hygiene. Offer topical supportive 
anesthetics. Encourage adequate hydration.
Grade 3 or 4

Above, plus systemic opiate administration as 
needed. 

Consider IV hydration and hospital admission 
as appropriate. 

For mucositis Grade 3, withhold
GSK2820151 until mucositis is Grade 1 and 
resume the same dose of GSK2820151. If 
mucositis Grade 3 recurs, withhold
GSK2820151 until mucositis is Grade 1, 
then reduce GSK2820151 one dose level. If 
mucositis Grade 3 recurs a third time at 
reduced dose, discontinue GSK2820151 
permanently.

Pneumonitis
Grade 1

Consider evaluation by pulmonologist.

Consider room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins apart). 
If any decline is observed in O2 saturation, 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
withhold study drug, repeat chest x-ray to 
determine if progression of pneumonitis has 
occurred and consult pulmonologist.

Obtain high-resolution computed tomography 
(CT) scan of the chest if possible.
Grade 2

, then reduce dose by at least 25%. 

Must be evaluated by pulmonologist.

Consider pulmonary function tests 
including: spirometry, Diffusing Capacity of 
the Lung for Carbon Monoxide (DLCO), and 
weekly room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins apart). 
Repeat evaluations every 8-12 weeks until 
return to baseline.

Obtain high-resolution chest CT if possible.

Consider a bronchoscopy with biopsy 
and/or bronchoalveolar lavage. (BAL).

Treat only if symptomatic. Consider 
corticosteroids if symptoms are troublesome 
and infective origin is ruled out. Taper as 
medically indicated.

Withhold GSK2820151 until recovery to Grade 
1, then reduce dose by at least 25%. 
Discontinue GSK2820151 if no recovery to 
Grade 1 within 4 weeks. 
Grade 3 or 4

Discontinue GSK2820151 and refer for 
evaluation by pulmonologist

Required pulmonary function tests 
including: spirometry, DLCO, and room air 
O2 saturation at rest via pulse oximetry 
reading (X 2, 5 mins apart). Repeat 
evaluations at least every 8 weeks until 
return to baseline. 

Obtain high-resolution chest CT if possible.

Bronchoscopy with biopsy and/or BAL is 
recommended.

Consider corticosteroids if infective origin is 
ruled out. Taper as medically indicated.

Rechallenge Guidelines

Grade 3: Withhold GSK2820151 until 
recovery to < Grade 1. Discontinue 
GSK2820151 if no recovery to < Grade 1 
within 4 weeks. May consider restarting 
GSK2820151 at a reduced dose after 
discussion with GSK Medical Monitor if 
there is clinical benefit.

Grade 4: Rechallenge with GSK2820151 is 
not permitted


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Fever
Grade 1 

Continue current dose of GSK2820151 and 
monitor for change in severity. 
Grade 2

Temporarily discontinue GSK2820151 and 
monitor for change in severity. 

Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea. Assess vital signs.

Collect cytokine blood samples as outlined 
in the Laboratory Manual. Collect blood 
culture and investigate viral infections as 
applicable

Consider restarting study treatment at a reduced 
dose or dose level pre-event based on 
discussion with GSK Medical monitor.
Grade 3 or 4

Temporarily discontinue study medication and 
monitor for change in severity.

Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea.

Collect cytokine blood samples as outlined 
in the Laboratory Manual. Collect blood 
culture and investigate viral infections as
applicable.

Consider restarting study treatment at a reduced 
dose or dose level pre-event based on 
discussion with GSK Medical Monitor
Thrombocytopenia
Grade 1 (platelets <LLN to 
≥75,000/mm3) or Grade 2
(platelets <75,000 to 
≥50,000/mm3)

Continue dosing at same dose level with weekly 
or more frequent monitoring as necessary
Grade 3 (platelets <50,000 
to ≥25,000/mm3)

Withhold GSK2820151 and check aPTT, PT, and INR.  
Monitor CBC and coagulation studies twice a week 
until normal, or increase monitoring frequency if 
clinically indicated. 
Withhold GSK2820151 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are all 
≤ ULN. Drug may then be restarted at a lower dose 
level, after discussion with the medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued permanently or restarted at 
further lower dose level, after discussion with the 
medical monitor. If safety lab abnormalities recur to 
the same level following a second rechallenge, drug 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
will be discontinued permanently.
Grade 4 ( platelets≤ 25,000)
or any moderate to severe 
bleeding accompanied by  
drug related 
thrombocytopenia
Withhold GSK2820151 and check aPTT, PT, and INR.  
Monitor CBC and coagulation studies twice a week 
until normal, or increase monitoring frequency if 
clinically indicated. 
Withhold GSK2820151 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are all 
≤ ULN. Drug may then be restarted at a lower dose 
level, after discussion with the medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued permanently.
If platelet count does not recover to ≥25,000/mm3
(Grade 3) within 7 days and ≥50,000/mm3 (Grade 2) 
within 14 days, GSK2820151 should be permanently 
discontinued.
Any subject requiring transfusion support,
GSK2820151 should be permanently discontinued.

All Other Toxicity*
1

Continue dosing with no change 
2

Continue dosing with no change 
OR

Withhold GSK2820151 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)
3

1st episode: Withhold dose for one week intervals 
until drug-related Grade 2, then restart with no 
change. 

2nd episode: Utilize an alternative, less frequent 
schedule or reduce by one dose level. 

If no recovery to ≤Grade 1* after a 21 day delay, 
patient should go off protocol therapy.
4

Discontinue GSK2820151

In rare situations, based on discussion and 
written agreement between GSK medical monitor 
and investigator, if the subject is receiving benefit 
then the episode may be managed as per Grade 
3 toxicity.
*Note: Exceptions to drug-related Grade 1 requirement may be made for certain AEs as defined in Section 4.2.5.


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14.8.
Appendix 8: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria – adapted from RECIST 
1.1 [Eisenhauer, 2009]
14.8.1.
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 CRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules) [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 optimised 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.
14.8.2.
Guidelines for Evaluation of Disease
14.8.2.1.
Measurable and Non-measurable Definitions
14.8.2.1.1. 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 5mm.  If 
the slice thickness is greater than 5mm, 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

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm).  At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009].
14.8.2.1.2. Non-measurable lesion
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least 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. 
14.8.3.
Baseline Documentation of Target and Non-Target Lesions

All baseline lesion assessments must be performed within [28] days of 
randomization. 


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
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. 
14.8.4.
Response Criteria
14.8.4.1.
Evaluation of target lesions
Definitions for assessment of response for target lesion(s) are as follows:

Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis.

Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline).

Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm.


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
Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the five 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.
14.8.4.2.
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.
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 


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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"). 
14.8.4.3.
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.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
14.8.4.4.
Evaluation of overall response
Table 13 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 13
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable
Table 14 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 subjects with non-measurable only disease at baseline.


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Table 14
Evaluation of Overall Response for Subjects 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:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.8.4.5.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

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 7 day 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, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
14.8.4.6.
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.
Reference
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised 
RECIST guidelines (version 1.1). Europena Journal of Cancer. 2009; 45: 228-247.


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14.9.
Appendix 9: Cockcroft and Gault Method for Calculated 
Creatinine Clearance
Calculated creatinine
clearance (mL/min)  =
(140 age [yrs] ) weight (kg)
72 serum creatinine (mg/100mL)
Female patients: multiply by 0.85
[Cockcroft, 1976]


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14.10.
Appendix 10: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, 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 subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6. 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 subject who becomes pregnant while participating: 
o
will discontinue study medication

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.


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14.11.
Appendix 11: Pain Assessment (Wong-Baker Faces Pain 
Rating scale)
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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14.12.
Appendix 12: NYHA Functional Classification System for 
Heart Failure
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994] 
provides a simple way of classifying the extent of heart failure. It places subjects in one 
of four categories based on the level of limitation experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is 
increased.


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14.13.
Appendix 13: Protocol Amendment Changes
Amendment 1 (19-JUN-2015) from the Original Protocol (15-Dec-2014)
Where the Amendment Applies
Amendment 1 applies to all study centres. 
General Protocol Changes
Amendment 1 includes, change in the Primary Medical Monitor, the clarification of Dose 
Escalation Schedules (Section 4.2) to make it clearer. Minor corrections in the summary 
of gastrointestinal risk. In light of emerging data from preclinical studies of embryo-fetal 
development, reproductive risk section, inclusion criterion #9 and guidance on 
contraception use were updated. List of prohibited and permitted medicines has been 
revised. Added more clarity on study termination criteria and greater flexibility on W3D4 
PK samples window period. Statement on pregnancy follow-up inserted. Reference list 
updated.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Changes
TITLE PAGE
Authors:
Rationale for change: Additional author contributed to the amendment added and 
authors not involved in the study deleted.
Revised Text:
Addition of Author:
Deletion of Authors:
Medical monitor/Sponsor Information Page
Medical Monitor/SAE Contact Information:
Rationale for change: Primary medical monitor has changed.
PPD
PPD


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Revised Text:
Role
Name
Day Time Phone 
Number and email 
address
After Hours 
Contact 
Information
Site Address
Primary 
Medical 
Monitor
MD/PhD
MB, 
FFPM
GlaxoSmithKline
1250 South Collegeville
Gunnels Wood Road, 
UP4210
Collegeville, PA 19426, 
USAStevenage 
Hertfordshire
SG1 2NY, UK
Section 4.2. Dose Escalation and Duration of Study
Rationale for change: The change was made to give more clarity in the dose 
escalation schedules.
Revised Text:
First Paragraph:
This study will utilize an accelerated dose escalation phase in order to minimize sub-
optimal drug exposures, followed by a conventional 3+3 dose escalation phase to achieve 
MTD. At least one and up to six subjects will be recruited per cohort. Initially, one 
subject per dose cohort will be recruited  (accelerated dose escalation phase) until the first 
instance of a ≥ Grade 2 drug related non-hematological toxicity.  Further cohorts will be 
recruited in blocks of three subjects (3+3 dose escalation phase). Additional subjects may 
be enrolled at previously cleared dose levels in order to obtain further data for PK and/or 
PD analysis.  A maximum of six subjects will be assigned to any single dose. Once MTD 
is determined, up to 12 additional subjects (18 subjects total at MTD) may be enrolled to 
collect additional safety data (Figure 2). The total duration of study for each subject will 
be dependent upon the safety, tolerability and efficacy of GSK2820151.
4.2.2. Accelerated Dose Escalation
Rationale for change: The change was made to give more clarity in the dose 
escalation schedules.
Revised Text:
Third Paragraph:
At the first occurrence of a DLT (refer to Section 4.2.4) or any Grade 2 toxicity (based on 
NCI-CTCAE v4.03) (with the exception of Grade 2 alopecia, nausea, vomiting, diarrhea, 
hemoglobin, lymphopenia, taste changes or alkaline phosphatase in the presence of bony 
PPD
PPD
PPD


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metastases) during the first 4 weeks, the Accelerated Dose Titration procedure phase will 
be terminated.  Once a DLT occurs, and the ongoing cohort will be expanded up to 6 
subjects and dose-escalation will continue following to commence the 3 + 3 Dose-
Escalation guidelines phase of the study.
Section 4.2.3. 3 + 3 Dose Escalation
Rationale for change: The change was made to give more clarity in the dose 
escalation schedules.
Revised Text:
If the accelerated dose titration ends due to > grade 2 toxicity then tTwo additional 
subjects will be enrolled to the same dose level at which accelerated dose titration ends, 
for a total of at least 3 subjects at that dose level. where as, if termination of accelerated 
dose titration is due to DLT, then up to 5 additional subjects will be enrolled at the same 
dose level to continue the treatment following the 3 + 3 Dose Escalation guidelines. If no 
DLTs are observed in any of the 3 subjects, then dosing will proceed to the next higher 
dose level (≤2 fold increase in dose); however, if termination of accelerated dose titration 
is triggered by a DLT, then 5 additional subjects will be enrolled at that dose level.
Subjects will be entered in a staggered approach with at least 3 days between each subject 
to minimize the risk of inadvertently exceeding the MTD in multiple subjects. Dose 
escalation decisions will be made as outlined in Table 2 Escalation to the next dose level 
will not increase greater than 2 fold from the previous dose level. Intra-subject dose 
escalation may be considered as described in Section 4.2.7. Subjects should not be 
enrolled at a higher dose level until at least 3 subjects in the previous dose cohort 
complete 4 weeks of treatment.
Section 4.6.1. Risk Assessment
Rationale for change: To add clarity in summary data/rational for Risk for 
Gastrointestinal and Reproductive as potential risk of clinical significance. Also to add 
mitigation strategy for Reproductive.
Revised Text:
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Gastrointestinal (GI)
(Dose-limiting toxicity in rats 
and dogs)
Gastrointestinal effects were 
the dose limiting toxicityin both, 
observed following repeat 
dosing in rats and dogs at 
doses 6 3 and 
2010 mg/kg/day respectively.
Clinical presentation included 
altered feces, reduced food 
consumption and reduction in 
body weight; microscopic 
ICF includes the risk of 
gastrointestinal effects.
Protocol includes medical 
history, physical examination 
(including weight) and clinical 
laboratory assessments to 
assess toxicity in the GI tract. 
Subjects with a history of 
gastrointestinal bleeding in the 
past 6 months (Section 5.2) or 
active bleeding will be 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
changes observed at doses
6 and 20 mg/kg/day in rats
and dogs respectively included 
erosion / ulceration / 
haemorrhage / mucosal
epithelium 
degeneration/regeneration, 
villous atrophy, inflammatory 
cell infiltration and mild cecal 
lamina propria fibrosis (dogs 
only). Clinical presentation 
included altered feces, reduced 
food consumption and body 
weight reductions.  These 
changes correlated with 
microscopic findings 
throughout the GI tract of rats 
given 6 mg/kg/day and dogs 
at 20 mg/kg/day.  Microscopic 
findings included
erosion/ulceration, mucosal 
epithelium 
degeneration/regeneration and 
inflammatory cell infiltration 
(rats and dogs) and minimal to 
mild hemorrhages, villous 
atrophy and mild cecal lamina 
propria fibrosis (dogs only).
Signs of recovery were 
observed immediately after 
cessation of dosing; no 
abnormal microscopic findings 
were evident following a after 
up 3 to 5 weeks off dose
period.
excluded.
Protocol also includes specific 
dose adjustment/stopping 
safety criteria for diarrhea and 
mucositis.
Reproductive
Animal reproductive studies 
have not been conducted with 
GSK2820151. No ovarian 
changes were observed in 
toxicology studies of up to 4 
weeks duration; however, an 
assessment of estrous cycling 
was not conducted. BRD2, 
BRD3, BRD4 and BRDT have 
ICF includes the risk of 
damage to reproductive organs 
such as testes or ovaries 
including potential risk to 
embryofetal development.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and 
females and pregnancy testing 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
crucial roles in reproduction 
and development [Paillisson, 
2007; Trousdale, 2004] and 
would be expected to 
adversely affect embryofetal 
development. A compound 
with a similar pharmacology 
profile, has shown detrimental 
effects on rat female fertility 
and embryo-fetal development 
at clinically relevant exposures. 
This information indicates that 
GSK2820151 will likely have 
similar adverse effects on 
female fertility and embryo-
fetal development. 
Testicular degeneration was 
observed in both rats (10 
mg/kg) and dogs as well as 
disorganised spermatogenesis 
in dog at ≥5 mg/kg. Secondary 
changes were evident in 
epididymides (hypospermia, 
degenerate cells, atrophy, 
vacuolation).  
No evidence of reversibility 
within 3 week off dose period. 
Reversible reduced prostate 
weight (rat and dog) & 
decreased secretory content in 
prostate (rat ≥ 3 mg/kg/day) 
and seminal vesicles (rat 10 
mg/kg/day) were observed.
for female subjects and 
collecting testosterone (free 
and complete) for male 
subjects.
ICF includes the potential risk 
of reproductive effects.
Due to the effects of 
GSK2820151 on the male 
reproductive system and 
potential for GSK2820151 to 
be present in semen, men 
should adhere to the 
contraceptive guidance 
detailed in the protocol.
Section 5.1. Inclusion Criteria
Rationale for change: The change was made as emerging pre-clinical data favors the 
long term use of the contraception in female subjects after the last dose of study 
medication. 


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Revised Text:
Inclusion criterion 9: A female subject is eligible to participate if she is of:
Bullet point 2: Child-bearing potential and agrees to use one of the contraception 
methods (described in Section 7.3) for an appropriate period of time (as determined by 
the product label or investigator) prior to the start of dosing to sufficiently minimize the 
risk of pregnancy at that point. Female subjects must agree to use contraception until at 
least 4 weeks 7 months after the last dose of study medication.
Rationale for change: The reason for this change was because GSK2820151 may be 
carried in the semen.
Revised Text:
Inclusion criterion 10: Male subjects with female partners of child bearing potential must 
agree to use one of the methods of contraception specified (see Section 7.4). This method 
must be used from the time of the first dose of study medication until at least 16 weeks 
after the last dose of study medication. In addition, male subjects whose partners are or 
become pregnant on study medication must continue to use condoms for 7 days after 
stopping study medication.
Section 5.4.5. Other Stopping Criteria
Rationale for change: The change was made to add a criteria for termination of the 
study by the sponsor.
Revised Text:
Fourth paragraph onwards:
If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, and/or if deaths related to study drug are observed, enrollment may be 
terminated and/or a lower-dose cohort may be opened or expanded. The final 
determination will be made by the Sponsor and investigators.
The sponsor may also terminate the study if the safety, pharmacokinetics (PK) or 
pharmacodynamic (PD) data suggest that an appropriate therapeutic exposure cannot be 
achieved using the dosing schedules defined in the protocol.
Section 7.1.2.1. Prohibited Medications
Rationale for change: The change was made to update the list of drug with a risk of 
Torsades de Pointes that are prohibited based on the 2015 guidelines.


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Revised Text:
Table 5
Drugs with a Risk of Torsades de Pointes that are Prohibited
Amiodarone
Dronedarone
Pimozide
Anagrelide
Droperidol
Procainamide
Azithromycin
Erythromycin
Propofol
Chloroquine
Escitalopram
Quinidine
Chlorpromazine
Flecainide
Sevoflurane Quinidine
Cilostazol
Fluconazol
Sotalol
Ciprofloxacin
Halofantrine
Thioridazine
Citalopram
Haloperidol
Clarithromycin
Ibutilide
Cocaine
Levofloxacin
Disopyramide
Methadone
Dofetilide
Moxifloxacin
Donepezil
Pentamidine
Data Source: crediblemeds.org revision date 26 September 2014 4 May 2015.
Drugs not available/used in the US have been omitted
Section 7.1.3. Cautionary Medications
Rationale for change: The change was made to update the list of drug with a risk of 
Torsades de Pointes which are permitted for co-administration with extreme caution 
based on the 2015 guidelines.
Revised Text:
Table 6
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution
Alfuzosin
Iloperidone
Ranolazine
Apomorphine
Isradipine
Rilpivirine
Aripiprazole
Lithium
Risperidone
Atazanavir
Mifepristone
Saquinavir
Atomoxetine
Mirabegron
Tacrolimus
Bedaquiline
Mirtazapine
Telavancin
Clomipramine
Moexipril/HCTZ
Telithromycin
Clozapine
Nicardipine
Tetrabenazine
Desipramine
Norfloxacin
Tizanidine
Dexmedetomidine
Nortriptyline
Tolterodine
Dihydroartemisinin+piperaquine
Ofloxacin
Toremifene
Dolasetron
Olanzapine
Trimipramine
Famotidine
Ondansetron
Vardenafil
Felbamate
Oxytocin
Venlafaxine


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Fingolimod
Paliperidone
Ziprasidone
Foscarnet
Pasireotide
Fosphenytoin
Perflutren lipid microspheres
Gemifloxacin
Promethazine
Granisetron
Quetiapine
Data Source: crediblemeds.org revision date 26 September 2014 04 May 2015 Note: This list is not exhaustive.  
Drugs  and/or drug names not available/used in the US have been omitted
Section 8.1. Time and Events Tables
Rationale for change: Window period for PK and biomarker samples at W3D4 
changed from +2 to +7 days to allow greater flexibility for 2-on-1-off dosing.
Revised Text: 
Table 10 Time and Events: Pharmacokinetics and Biomarker Sampling, 
Week 3 and Week 9
Addition of text in the table header: W3D4 + 2 days (+2 to +7 days for alternate dosing schedule)
Section 8.3.10. Pregnancy
Rationale for change: The change was made as emerging pre-clinical data favors the 
long term use of the contraception in female subjects after the last dose of study 
medication. Also follow-up details added for recording the safety of the subject.
Revised Text:

Details of all Reporting of any pregnancies in female subjects and/or female partners 
of male subjects will be collected after the start of dosing and until 14 days7 months
following the last dose of GSK2820151.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy. The subject 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 premature termination of the pregnancy 
will be reported. Details on and should follow-up the procedures outlined in 
Appendix 7.
Section 13. REFERENCES
Rationale for change: Data sources were added/updated


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Revised Text:
James LP. 2009. Pharmacokinetics of Acetaminophen-Protein Adducts... in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Disp, 2009; 37: 1779-
1784.
Addition of References:
Paillisson A, Levasseur A, Gouret P, Callebaut I, Bontoux M, Pontarotti P et al.  
Bromodomain testis-specific protein is expressed in mouse oocyte and evolves faster than 
its ubiquitously expressed paralogs BRD2, -3, and -4. Genomics, 2007;89: 215-23.
Trousdale RK and Wolgemuth DJ. Bromodomain containing 2 (Brd2) is expressed in 
distinct patterns during ovarian folliculogenesis independent of FSH or GDF9 action. 
Molecular Reproduction and Development, 2004;68:261-8.


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Amendment 2 (06-OCT-2015) from the Amendment 1 (19-JUN-2015)
Where the Amendment Applies
Amendment 2 applies to all study centres. 
General Protocol Changes
Amendment 2 is mainly in response to FDA request and includes: changes in the Medical 
Monitors; modified the inclusion criteria and other relevant parts of the protocol to allow 
only patients with histologically or cytologically confirmed solid malignancy that is 
either metastatic or unresectable; revised hematologic DLT definition for platelets which 
now also include Grade 3 thrombocytopenia with clinically significant bleeding in 
addition to Grade 4 thrombocytopenia (platelets <25,000/mm3); added in the Dose 
Stopping Safety Criteria to permanently discontinue the patients from GSK2820151 who 
experience symptomatic (symptoms consistent with acute coronary syndrome) troponin 
elevation. Also, included an interim analysis for futility and safety review when 20 
patients would have been recruited at the RP2D. Added clarification around collection of 
blood sample for pharmacokinetics (Section 8.4.1)
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Changes
Medical monitor/Sponsor Information Page
Medical Monitor/SAE Contact Information:
Rationale for change: Primary and secondary medical monitor have changed.
Updated contact information of both the medical monitors.


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Revised Text:
Role
Name
Day Time Phone 
Number and email 
address
After Hours 
Contact 
Information
Site Address
Primary 
Medical 
Monitor
 
 MB, 
FFPM
MD, 
D.Phil., 
FRCPath
GlaxoSmithKline
Gunnels Wood Road
Stevenage Hertfordshire
SG1 2NY, UK
GlaxoSmithKline
Stockley Park West, 1-3 
Ironbridge Road, 
Uxbridge, Middlesex, 
UB11 1BT, United 
Kingdom
Secondary 
Medical 
Monitor 
MD/PhD
MD, 
MPH
GlaxoSmithKline
1250 South Collegeville 
Road, 
UP4210
Collegeville, PA 19426, 
USA
ICON Clinical Research 
LLC
2100 Pennbrook 
Parkway 
North Wales, PA 
United States, 19454
Protocol Synopsis
Type and Number of Subjects
Rationale for change: The change was made in response to the FDA request for 
further clarifying the type of subjects to be involved in the study. 
Revised Text:
First paragraph and first two bullet points:
Approximately 30 to 50 subjects with will be enrolled in the study. The study population 
will be adults, with advanced or recurrent, histologically or cytologically confirmed, solid 
malignancy that is either metastatic or unresectable, who either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,
PPD
PPD
PPD
PPD
PPD
PPD


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Section 4.2.4 Dose-Limiting Toxicity
Rationale for change: The change was made in response to FDA request to 
incorporate Grade 3 thrombocytopenia with bleeding as DLT.
Revised Text:
Table 3
Dose –Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 neutropenia (absolute neutrophil count [ANC] 
<500/mm3 for 5 days)

Febrile neutropenia (as defined by NCI-CTCAE v4.03
[concurrent Grade 4 neutropenia and fever >38.3C]) 

Grade 4 anemia of any duration

Grade 3 thrombocytopenia with clinically significant bleeding or
Ggrade 4 thrombocytopenia (platelets <25,000/mm3)
Section 4.3. Type and Number of Subjects
Rationale for change: The change was made in response to the FDA request for 
further clarifying the type of subjects to be involved in the study. 
Revised Text:
Second Paragraph and first two bullet points:
Approximately 30 to 50 subjects with refractory, histologically or cytologically 
confirmed, advanced (metastatic or unresectable) solid malignancies will be enrolled in 
the study. The study population will be adults, with advanced or recurrent, histologically 
or cytologically confirmed, solid malignancy that is either metastatic or unresectable, 
who either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,
Section 5.1. Inclusion Criteria
Rationale for change: The change was made in response to the FDA request for 
further clarifying the inclusion criteria of subjects to be involved in the study. 
Revised Text:
Inclusion criterion 3: Diagnosis of advanced or recurrent, histologically or cytologically 
confirmed, solid malignancy that is either metastatic or unresectable. At time of 
enrollment, subjects either:
Bullet point 1: refuse standard curative or palliative therapy,


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Bullet point 2: are not candidates for standard curative or palliative therapy,
Section 5.4. Withdrawal/Stopping Criteria
Rationale for change: The change was made to incorporate the “raised Troponin 
level” for further clarifying the Withdrawal/Stopping Criteria.
Revised Text:
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry, hematologic/non-
hematologic toxicity, QTc prolongation, raised Troponin level as defined in Section 
14.7.1 or left ventricular ejection fraction (LVEF)/valvular dysfunction as defined in 
Section 5.4.1 through Section 5.4.5.
Section 8. Study Assessments and Procedures
Rationale for change: The change was made to correct the typographical error in 
Table 10 – window period (W9D1)
Revised Text:
Table 10
Time and Events: Pharmacokinetics and Biomarker Sampling, Week 3 
and Week 9
W3D4 + 2 days
(+2 to +7 days for alternate dosing schedule)
W9D1 ±4 +4 
days
(if dose has been 
escalated, +4 to 
+7 days)
EOT
pre 
dose
15 
min 
± 
5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±4h
24h 
±1h
48h 
±1h
pre 
dose
0.5-
2h
4 -
8h
Section 8.2.2. Visit Windows
Rationale for change: The change was made to correct the typographical error in 
window period (Week 2 to Week 4)
Revised Text:
Third Paragraph:
Week 2 to Week 4: Based on subject and clinic schedule, assessments can be +3
3 days.


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Section 8.4.1. Blood Sample Collection for Pharmacokinetics
Rationale for change: The change was made for clarification on blood sampling and 
analysis for PK 
Revised Text:
Second Paragraph:
Each PK sample should be collected as close as possible to the planned time relative to 
the dose (i.e., time zero) administered to the subject on PK days. The actual date and time 
of each blood sample collection will be recorded along with the date and time of the prior 
dose administration. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring. This will not 
require a protocol amendment. In addition, plasma samples may be analyzed qualitatively 
for other circulating compound-related material and the results will be reported under a 
separate Drug Metabolism and Pharmacokinetics (DMPK) protocol.
Section 11.4.2. Interim Analysis
Rationale for change: The change was made in response to the FDA request for 
inclusion of the Interim analysis for monitoring the safety of subjects.
Revised Text:
Second paragraph:
If this trial enrols more than 20 patients at the recommended phase 2 dose (RP2D), an 
interim analysis for futility and complete review of safety data will be performed on first 
20 patients treated. This analysis will be used to evaluate the risk-benefit of continued 
treatment of these patients and to assess the risks related to delayed GSK2820151-related 
toxicities.
Section 14.7. Appendix 7: Guidelines for Management of Toxicity
Rationale for change: The change was made in response to the FDA request to 
permanently withdraw the subjects who experience symptoms consistent with acute 
coronary syndrome in addition to raised troponin level.


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Revised Text:
Table 12
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Troponin
Troponin level >ULN

Evaluate immediately for symptoms and obtain 
ECG. Repeat troponin within 24-48 hours or as 
soon as possible. 

If the repeat value is within the normal range, 
the subject may continue GSK2820151 with 
close follow-up for symptoms, ECG 
monitoring and further troponin 
measurements as clinically indicated.

If the repeat value remains > ULN AND the 
subject is asymptomatic, withhold
GSK2820151, refer to a cardiologist, and 
contact the GSK Medical Monitor. May 
consider restarting study treatment at a 
reduced dose or dose level pre-event based 
on discussion with GSK Medical Monitor.

If the subject is symptomatic (symptoms 
consistent with acute coronary syndrome) 
OR the troponin level is at or above 
approaches the threshold for mycocardial 
infarction (MI) according to local lab
parameters, hold discontinue GSK2820151 
permanently and refer the subject 
immediately to a cardiologist or emergency 
medical facility for appropriate medical care.

May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor.


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Amendment 3 (23-MAY-2016) from the Amendment 2 (06-OCT-2015)
Where the Amendment Applies
Amendment 3 applies to all study centres. 
General Protocol Changes
Amendment 3 includes:

Inclusion criterion # 3 has been amended to allow the subjects who had 
progressed >3 prior line therapies. Exclusion criterion # 2 has been deleted to lift 
the restriction of 3 prior lines of cytotoxic therapy.

MUGA Scan that had been stated as a second optional method for the 
measurement of ejection fraction has been removed from inclusion criterion #7.

Clarification was made on the collection time for screening holter monitoring in 
Section 8.3.7. It was not intended to have holter required at Day-1 but rather 
performed within the 14 day screening window as outlined in the T/E table. Also, 
time points for holter monitoring were matched with triplicate ECGs time points. 
Time & Events Table was updated to reflect the same.

Minor correction made on AEs and SAEs reporting period in Section 9.2.

Added more clarity on pain assessment which will be performed using Wong-
Baker Faces Pain Rating scale. Appendix 11:  Wong-Baker Faces Pain Rating 
scale added.

A clarification on the collection and processing of safety cytokines, PK and 
protein biomarker samples process was made in Time & Events Table.

No Triplicate ECG on W1D2, Time & Events Table corrected.

Section 7.1.2.2, typo corrected “Non-drug anti-cancer therapies (e.g., radiation 
therapy, surgery, and/or tumor embolization) will not be permitted from the 
screening visit through the post-study follow-up visit.”
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Changes
Protocol Synopsis
Type and Number of Subjects
Rationale for change: Limiting the prior number of therapies to 3 was posing 
restrictions on patients screening so removed to allow more flexibility. There was 
discrepant information within the 201893 Protocol Amendment 2, regarding the time 


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points for the holter monitoring which should be in line with triplicate ECG time points; 
so corrections were made.
Revised Text:
First paragraph, fourth bullet point:
Approximately 30 to 50 subjects with will be enrolled in the study. The study population 
will be adults, with advanced or recurrent, histologically or cytologically confirmed, solid 
malignancy that is either metastatic or unresectable, who either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (up to three lines of prior cytotoxic agents are 
permitted) (radiographic documentation of progression is adequate for study 
participation).
The total number of subjects required will depend upon the number of escalation steps 
required to reach a MTD.
Analysis
Measurements

SAFETY MEASUREMENTS: Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events will be 
performed. Stringent cardiac safety monitoring will be required, consisting of:
o
≥ 48 hours of telemetry following the first dose (necessitating overnight stays in a 
research facility)
o
24 hours of ambulatory cardiac (Holter) monitoring in Week 1, Week 2, Week 34, 
and Week 9
Section 4.3. Type and Number of Subjects
Rationale for change: Limiting the prior number of therapies to 3 was posing 
restrictions on patients screening so removed to allow more flexibility.
Revised Text: 
Second paragraph, fourth bullet point:
Approximately 30 to 50 subjects with refractory, histologically or cytologically 
confirmed, advanced (metastatic or unresectable) solid malignancies will be enrolled in 
the study. The study population will be adults, with advanced or recurrent, histologically 


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or cytologically confirmed, solid malignancy that is either metastatic or unresectable, 
who either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy therapy (up to three lines of prior cytotoxic agents 
are permitted) (radiographic documentation of progression is adequate for study 
participation).
Section 5.1. Inclusion Criteria
Rationale for change: Limiting the prior number of therapies to 3 was posing 
restrictions on patients screening so removed to allow more flexibility.
Revised Text:
Inclusion criterion #3, fourth bullet point:
3. Diagnosis of advanced or recurrent, histologically or cytologically confirmed, solid 
malignancy that is either metastatic or unresectable. At time of enrollment, subjects 
either:

refuse standard curative or palliative therapy,

are not candidates for standard curative or palliative therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (up to three lines of prior cytotoxic agents are 
permitted) (radiographic documentation of progression is adequate for study 
participation).
Rationale for change: The optional use of the MUGA scan was not included in the 
inclusion criteria of the synopsis, and sites are advised to use Echocardiogram only
Revised Text:
Inclusion criterion #7, Table 4:
Cardiac
Ejection fraction
≥ 50% by echocardiogram or multigated acquisition 
scan (MUGA)
Section 5.2. Exclusion Criteria
Rationale for change: Limiting the prior number of therapies to 3 was posing 
restrictions on patients screening so removed to allow more flexibility.


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Revised Text:
Exclusion criterion #2 deleted::
2.
More than three prior lines of cytotoxic therapy.
Section 7.1.2.2. Prohibited Non-Drug Therapies
Rationale for change: Minor correction has been made.
Revised Text:
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the transition screening visit through the post-
study follow-up visit. 
8.1. Time and Events Tables
Rationale for change: There was discrepant information within the 201893 Protocol 
Amendment 2, regarding the time points for the holter monitoring which should be in line 
with triplicate ECG time points; so corrections were made. In previous versions 
(including Protocol Amendment 2), only pain assessment was mentioned in the protocol. 
The information that Wong Baker Validated Scale will be used for pain assessment has 
been added as an additional information. A clarification on the collection and processing 
of safety cytokines, PK and protein biomarker samples has been added.
Revised Text:
Table 7
Time and Events
Under “Assessments”Column:
Pain (using Wong-Baker Faces Pain Rating scale)
Under “Cardiac Monitoring” Row:
12-lead ECG on Week 1, D2 changed from O to X
Holter monitoring has been added on Week 2, D4 and Week 3, D4 (indicated as X) and 
deleted on Week 2, D5 and Week 4, D1 (indicated as X).
Table 8
Time and Events: Laboratory Assessments
Under Notes column for Safety Cytokines:
This is collected as part of the Predose PK sample and is sent to GSK DMPK Myriad via 
Covance.
Table 9 Time and Events: Pharmacokinetics and Biomarker Sampling, 
Week 1 and Week 2


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Footnotes:
Plasma samples will be divided at the site into two, one sample will be shipped to GSK 
DMPK facility where bioanalysis of PK is performed and the second sample will be sent
shipped via Covance to a vendor Myriad for systemic cytokine assessment (pre-dose and 
at 15 min, 30 min, 1 hr, 2 hr, and 4hr) and acute phase protein assessment at pre-dose and 
at 2,4, 8 and 24 hr post-dose. The frequency of sampling may be changed (likely reduced) 
based on data from the first few subjects assessed.
Table 10 Time and Events: Pharmacokinetics and Biomarker Sampling, 
Week 3 and Week 9
Footnotes:
Plasma samples will be divided at the site into two, one sample will be shipped to GSK 
DMPK facility where bioanalysis of PK is performed and the second sample will be sent 
shipped via Covance to a vendor Myriad for systemic cytokine assessment and acute 
phase protein assessment at pre-dose and at 2, 4, 8 and 24 hr post-dose. The frequency of 
sampling may be changed (likely reduced) based on data from the first few subjects 
assessed.
Section 8.3.3. Vital Signs
Rationale for change: The pain assessment method information has been added as an 
additional information.
Revised Text:
Last paragraph:
Pain will be assessed using Wong-Baker Faces Pain Rating scale (Appendix 11).
Section 8.3.7. Holter Monitoring
Rationale for change: There was discrepant information within the 201893 Protocol 
Amendment 2, regarding the time points for the holter monitoring which should be in line 
with triplicate ECG time points; so corrections were made.
Revised Text:
Fifth paragraph:
Baseline QT/QTcF values will be determined on Study Day -1 using time matched ECGs 
obtained from the Holter monitor at approximately the same on following time points as 
planned for: screening, Week 1 Day 1 to 2; Week 21 Day 3 to 4 5, Week 3 2 Day 5 to 6 4
and Week 4 3 Day 7 to 4 and Week 59 Day 1. The mean from triplicate ECGs will be 
evaluated at each time point. For a given time point, the mean QTcF from 3 separate 
beats should be analyzed on each ECG. Analysis of Lead II will be conducted with V5 as 
back-up and one of the remaining precordial leads as an alternative when T waves are not 


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well defined in Leads II or V5. QTcF for an individual beat will be calculated from the 
preceding RR interval since using the average heart rate (RR) intervals from the ECG 
could result in inaccurate QTcF calculations due to beat to beat variations in the RR 
intervals. 
Section 8.3.8. Clinical Safety Laboratory Assessments
Rationale for change: Minor correction has been made.
Revised Text:
The abbreviated term SRM has been replaced by Laboratory Manual throughout the 
section.
Section 8.4.1. Blood Sample Collection for Pharmacokinetics
Rationale for change: Minor correction has been made.
Revised Text:
Third paragraph:
Details on PK blood sample collection, processing, storage, and shipping procedures are 
provided in the SRM Laboratory Manual.
Section 8.4.2. Urine Sample Collection for Pharmacokinetics
Rationale for change: Minor correction has been made.
Revised Text:
Third paragraph:
Details of urine sample collection, processing, storage, and shipping procedures are 
provided in the SRM Laboratory Manual.
Section 9.2. Time period and Frequency for collecting AE and SAE 
information
Rationale for change: Minor correction has been made.
Revised Text:
First bullet point:

At each visit/contact, AEs and SAEs will be collected from the first dose (start of 
Study Treatment) until 28 days after the last dose of study treatment or until the start 
of new anti-cancer therapy-whichever occurs first. the follow-up contact (see Section 
9.2.2), at the timepoints specified in the Time and Events Table (Section 8.1).


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Section 14.1. Appendix 1: Abbreviations and Trademarks
Rationale for change: Deleted the abbreviation which is not used in the document.
Revised Text:
Deleted text:
MUGA
Multigated acquisition scan
Section 14.3. Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Rationale for change: Minor correction has been made.
Revised Text:
Table footnote #6:
6. PK sample may not be required for subjects known to be receiving placebo or non-
GSK comparator treatments.)  Record the date/time of the PK blood sample draw and 
the date/time of the last dose of study treatment prior to blood sample draw on the 
CRF. If the date or time of the last dose is unclear, provide the subject’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 Laboratory 
Manual.
Section 14.7.1. Dose Adjustments for Toxicity
Rationale for change: Minor correction has been made.
Revised Text:
Table 12
Dose Adjustment/Stopping Safety Criteria
The abbreviated term SRM has been replaced by Laboratory Manual throughout the 
Table.
Section 14.11. Appendix 11: Pain Assessment (Wong-Baker Faces Pain 
Rating scale)
Rationale for change: The pain assessment method information has been added as an 
additional information.
Revised Text:
A new section/appendix has been added:


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Amendment 4 (DD-MMM-YYYY) from the Amendment 3 (23-MAY-2016)
Where the Amendment Applies
Amendment 4 applies to all study centres. 
General Protocol Changes
Updates were made throughout the protocol to correct minor inconsistencies, spelling 
errors and provide further clarification. 
The most salient changes in Amendment 4 include: 

GSK Medical Monitor change

Section 4.6.1 Risk Assessment to include current available data

Section 5.1 Inclusion Criteria: update to contraception use in Inclusion 9 and 10

Changes made in Exclusion Criteria Section 5.2
o
clarification made on prior therapy (exclusion criterion-2) and 
anticoagulation use (exclusion criterion-3)
o
added to exclusion criterion-4 restricted use of NSAIDs and aspirin
o
updated exclusion criterion-13 to include history of bleeding and added 
known bleeding disorders

update to Section 7.1 Prohibited Medication and Non-Drug Therapies:

guidance on the use of exclusionary medications 

prohibited & cautionary medication tables updated

Contraception requirements updated in Section 7.3 Lifestyle Restrictions

Corrections made in Time & Events Table 8.1
o
addition of triplicate ECG on W1D2
o
clarification around Pulmonary Function Tests
Correction made in Table 8 Time and Events: Laboratory Assessments
o
addition of Factor VII assay testing

Added more clarity to troponin sample collection (Section 8.3.10 Troponin 
Measurement) and urine PK sample collection (Section 8.4.2 Urine Sample 
Collection for Pharmacokinetics)

Appendix 7: dose adjustment/stopping safety criteria updated for QTcF, troponin, 
LVEF, hypo & hyperglycemia, diarrhea, mucositis, pneumonitis and 
thrombocytopenia toxicities.

Appendix 12: NYHA Functional Classification System for Heart Failure Added
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text
List of Specific Changes
Medical monitor/Sponsor Information Page


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Medical Monitor/SAE Contact Information:
Rationale for change: Previous Medical Monitor left the company
Revised Text: 
Role
Name
Day Time Phone 
Number and email 
address
After Hours 
Contact 
Information
Site Address
Primary 
Medical 
Monitor
MD, 
D.Phil., 
FRCPath
MBBS,
MBA, 
MSc
GlaxoSmithKline
Stockley Park West, 1-3 
Ironbridge Road, 
Uxbridge, Middlesex, 
UB11 1BT, United 
Kingdom
Section 4.2. Dose Escalation and Duration of Study
Rationale for change: The change was made to give more clarity in the dose 
escalation criterion.
Revised Text: 
First paragraph
This study will utilize an accelerated dose escalation phase in order to minimize sub-
optimal drug exposures, followed by a conventional 3+3 dose escalation phase to 
achieve MTD. Initially, one subject per dose cohort will be recruited (accelerated dose 
escalation phase) until the first instance of a ≥Grade 2 drug related non-hematological 
toxicity or dose-limiting toxicity (DLT, see Section 4.2.4).  Further cohorts will be 
recruited in blocks of three subjects (3+3 dose escalation phase). Additional subjects 
may be enrolled at previously cleared dose levels in order to obtain further data for PK 
and/or PD analysis.  Once MTD is determined, additional subjects (18 subjects total at 
MTD) may be enrolled to collect additional safety data (Figure 2). The total duration of 
study for each subject will be dependent upon the safety, tolerability and efficacy of 
GSK2820151.
Second paragraph
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data, and the safety profile of 
the current and prior cohorts, as well as the predicted optimal dose dose-limiting toxicity 
PPD
PPD
PPD


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(DLT) rates on all potential doses from the Neuenschwander,2008Continual 
Reassessment Method (N-CRM) analysis [Neuenschwander, 2009],.N-CRM design is a 
type of Bayesian adaptive dose-escalation scheme (see Section 11.2). The method is fully 
adaptive and makes use of all the DLT information available at the time of each dose 
assignment. The DLT information of all subjects enrolled in the trial are used to update 
the estimated dose-toxicity relationship and provide supportive information in addition to 
the 3+3 design in the next escalation/de-escalation decision.
Section 4.2.2 Accelerated Dose Escalation
Rationale for change: The change was made to give more clarity in the dose 
escalation criterion.
Revised Text: 
First paragraph
One subject per dose level in the accelerated dose escalation phase will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 and will continueing
until one subject experiences Grade 2 drug related toxicity (based on National Cancer 
Institute- Common Terminology Criteria for Adverse Events, Version 4 (NCI-CTCAE 
v4.03 [NCI-CTCAE, 2010]) or dose-limiting toxicity (DLT, see Section 4.2.4). The 
accelerated dose titration scheme is described in Table 1. A single dose (Day 1) will be 
given to subjects in each cohort with the collection of blood samples for PK analysis at 
timed intervals. Once the final PK sample for Day 1 is obtained, subjects may begin 
repeat dosing on Day 3. The dose for Dose Level 2 and subsequent cohorts will be based 
on the pharmacokinetics (PK) and safety analysis of the previous cohort. Inter-subject 
variability in exposure and toxicity will also be considered when deciding on actual doses 
administered during dose-escalation. Dose escalation will occur according to the 
procedures outlined in Table 1. 
Section 4.3. Type and Number of Subjects
Rationale for change: The change was made for clarifying the type of subjects to be 
involved in the study.
Revised Text: 
Second paragraph
Bullet point 1: refuse or are not candidates for standard curative or palliative therapy,
Bullet point 2: are not candidates for standard curative or palliative therapy,
Bullet point 3: have a disease for which no non-investigational therapy exists, OR


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Section 4.6.1. Risk Assessment
Rationale for change: Updates in Risk assessment table with information from recent studies
Revised Text: 
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiovascular Effects
QT Prolongation
QT prolongation was Oobserved in dogs after single 
dosinge in dogs (100 mg/kg; up to 34 milliseconds 
[msec] and up to 48 hr post dosing) and after repeat 
dosing in dogs (≥30 mg/kg/day from Day 3; up to 21 
msec). 
Mechanism is unclear (no clear link to A direct effect 
on human ether-à-go-go-related gene [hERG] 
binding is unlikely.); QT prolongation observed at 
unbound in vivo drug concentrations approximately 
100-fold lower than in vitro hERG inhibition 
(IC50).Mechanism and risk for Torsades de Pointes 
is unclear.
Increased number of non-fatal arrhythmias were
observed in 1 of 3 4 dogs which had highest drug 
exposure after a single dose of 100mg/kg (10x the 
dog 28 day maximum tolerated dose, or MTD).
Blood Pressure (BP)
Increases in blood pressure (mean, systolic & 
Informed consent form (ICF) includes the risk of (fatal) 
arrhythmias and the risk of myocardial infarction
Drugs with a risk of Torsades de Pointes are 
prohibited, (refer to Section 7.1.2).
Protocol includes cardiovascular eligibility criteria, 
laboratory assessments (potassium and magnesium, 
N-terminal pro–B-Type natriuretic peptide [NT-
proBNP], creatine kinase [CK], creatine kinase-MB 
isoenzyme [CK-MB], and troponins [local laboratory 
monitoring for troponin I or T based on availability and 
troponin T at central laboratory]), cardiac monitoring 
(ECGs, Holter monitoring and cardiac ejection 
fraction) during the study, and dose 
stopping/modifications criteria for the management of 
cardiac events (refer to Section 14.7.1).
All subjects will receive their first dose of study 
medication (Week 1 Day 1) in the hospital with
telemetry monitoring for the first 48 hours of dosing. 
Throughout the protocol, the role of intensive cardiac 
monitoring will be re-evaluated in an ongoing fashion 
with the aim of re-evaluating cardiac risk mitigation 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
diastolic; systolic affected more than diastolic) were
observed following single dose in dogs after single 
dosing ≥10 mg/kg. M (mean up to 38 millimeters 
mercury [mmHg] and up to 42 hours post dosing).
Heart Rate
Increased heart rate was observed after a single 
dosing and repeat doses of (100 mg/kg; in dogs 
(single dog up to 24 beats per minute ([BPM])
between 9 and 19 hours post dosing) and in one 
dog after repeat dosing a single dose and single dog
(100 mg/kg; up to 9464 bpm BPM post dosing)after 
repeat dosing. ). 
Cardiac Biomarkers
Reversible increases in serum cardiac troponin I 
(cTnI) levels were observed in male rats (up to 3.3X) 
at 10 mg/kg/day for 28 days. Increased NT pro-ANP 
(up to 2.1X) in female rats given ≥1 mg/kg/day for 
28 days; no recovery after up to 5 weeks off dose 
period. No histologic lesions were observed in the 
heart on 28 day studies.
strategy while maintaining subject safety.
Gastrointestinal (GI) Effects
Dose-limiting toxicity in rats and dogs)
Gastrointestinal effects were the dose limiting 
toxicity (DLT), observed following repeat dosing in 
rats (3 mg/kg/day) and dogs at  3 and 
(10 mg/kg/day) respectively.
ICF includes the risk of gastrointestinal effects.
Protocol includes medical history, physical 
examination (including weight) and clinical laboratory 
assessments to assess toxicity in the GI tract. 
Subjects with a history of gastrointestinal bleeding in 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Clinical presentation included altered feces, reduced 
food consumption and body weight reductions.  
These changes correlated with microscopic findings 
throughout the GI tract of rats given 6 mg/kg/day 
and dogs at 20 mg/kg/day.  Microscopic findings in 
rats and dogs included erosion/ulceration, mucosal 
epithelium degeneration/regeneration and 
inflammatory cell infiltration. (rats and dogs) and
Microscopic findings in dogs only included minimal 
to mild hemorrhages, villous atrophy and mild cecal 
lamina propria fibrosis (dogs only). Signs of recovery 
were observed immediately after cessation of 
dosing; no abnormal microscopic findings were 
evident following a 3 to 5 week off dose period.
the past 6 months (Section 5.2) or active bleeding will 
be excluded.
Protocol also includes specific dose 
adjustment/stopping safety criteria for diarrhea and 
mucositis (refer to Section 14.7.1).
Lymphoid/Hematologic Effects
Lymphoid / hematologic toxicity was observed in 
rats given 3 mg/kg/day and in dogs at ≥3 and
given ≥5 mg/kg/day respectively.
The effects manifested as hypocellularity in bone 
marrow, thymus and lymph nodes of rats and dogs 
and reduced cellularity of the thymus, lymph nodes 
and spleen in rats. This was accompanied 
peripherally by microscopic evidence of increased 
red cell turnover and/or mild haemolysis,. Peripheral 
effects included reductions in red blood cells, 
platelets, basophils, eosinophils, lymphocytes, and 
increases in neutrophils (in response to GI toxicity).  
ICF includes the risk of lymphoid / hematologic
toxicity.
Protocol includes laboratory assessments (complete 
blood count [CBC] and coagulation factors 
[international normalized ratio (INR), prothrombin time 
(PT), partial thromboplastin time (PTT)], exclusion 
criteria if there is evidence of clinically significant 
bleeding episodes, monitoring for bruising/infection 
and dose stopping/modifications criteria (refer to 
Section 14.7.1).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Effects on reticulocyte counts were variable. 
Regenerative response in blood cell parameters and 
microscopic observation of extramedullary 
haematopoiesis and increased cellularity in the 
lymph nodes and spleen was evident after up to five 
weeks off dose. 
Reversible iIncreased activated partial 
thromboplastin time (APTT) time was observed in 
male rats given 1 mg/kg/day and in dogs (≥1 
mg/kg/day and given 20 mg/kg/day respectively). A 
mild decrease in APTT was observed in female rats 
at given 3 mg/kg/day. Reversible iIncreases in 
fibrinogen (1.51X) was observed in dogs dosed at
given 20 mg/kg/day. All of these effects were 
reversible.
Regenerative response in blood cell parameters and 
microscopic observation of extramedullary 
haemopoiesis was evident after up to 5 weeks off-
dose.
Reproductive Effects
Animal reproductive studies have not been 
conducted with GSK2820151.
No ovarian changes were observed in toxicology 
studies of up to 4 weeks duration; however, an 
assessment of estrous cycling was not conducted.
BRD2, BRD3, BRD4 and BRDT have crucial roles in 
reproduction and development [Paillisson, 2007; 
ICF includes the risk of damage to reproductive 
organs such as testes or ovaries including potential 
risk to embryofetal development.
Protocol (refer to Section 7.3) includes specific 
contraceptive guidelines and precautions for males 
and females and pregnancy testing for female 
subjects and collecting testosterone (free and 


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Trousdale, 2004] and would be expected to 
adversely affect embryofetal development. A 
compound with a similar pharmacology profile has 
shown detrimental effects on rat female fertility and 
embryo-fetal development (EFD) at clinically 
relevant exposures. This information indicates that 
GSK2820151 will likely have similar adverse effects 
on female fertility and EFD embryo-fetal 
development.
Testicular degeneration was observed in both rats 
given (>10 mg/kg/day) and dogs given 5 
mg/kg/day. as well as dDisorganized 
spermatogenesis was also observed in dogs. at ≥5 
mg/kg. Secondary changes were evident in 
epididymides were also evident (hypospermia, 
degenerate germ cells and/or epithelial vacuolation 
in both species, and atrophy in dogs only,atrophy, 
vacuolation).  
There was no evidence of reversibility of these 
findings within a three-week off dose period, but due 
to the length of the spermatogenic cycle 
(approximately two months), recovery may occur 
following a longer off dose period.
No evidence of reversibility within 3 week off dose 
period. 
Reduced prostate weight was observed in rats and 
complete) for male subjects.
Due to the effects of GSK2820151 on the male 
reproductive system were observed in pre-clinical 
settings and potential for GSK2820151 to be present 
in semen, men should adhere to the contraceptive 
guidance detailed in the protocol (refer to Section
7.3.2).


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dogs.  Additionally, in rats, decreased secretory 
content in prostate (dosing at 3 mg/kg/day) and in 
seminal vessels (dosing at 10 mg/kg/day) were 
observed.  These effects were reversible.
Reversible reduced prostate weight (rat and dog) & 
decreased secretory content in prostate (rat ≥ 3 
mg/kg/day) and seminal vesicles (rat 10 mg/kg/day) 
were observed.
Liver and Gallbladder Hepatobiliary
Effects Hepatobiliary
Dog:Reversible Mminimal gallbladder vacuolization 
of the gallbladder and minimal vacuolization of
biliary epithelium were observed in dogs dosed at
given >1020 mg/kg/day. Effects were reversible.
Rat: Reversible dDecreased inflammatory cell 
infiltrate was observed in rats animals dosed at
given ≥3 mg/kg/day and was still evident in some 
animals after an off dose period of up to 5 weeks.
This is considered indicative of the anti-inflammatory 
pharmacology of BET (bromodomain and extra-
terminal) inhibitors..
ICF includes the risk of 
hepatic/gallbladderhepatobiliary effects.
Protocol includes hepatic eligibility criteria, laboratory 
assessments during the study, and dose 
stopping/modifications criteria for the management of 
hepatic events (refer to Section 14.3 & Section 14.4).
Lung Effects
Minimal to mild prominent (foamy) alveolar 
macrophages were observed in rats administered ≥ 
1 mg/kg/day. These Eeffects were reversible. The 
clinical consequences of this finding are unknown.
ICF includes the risk of lung effects.
Protocol includes pulmonary function assessments at 
screening and as clinically appropriate afterwards
(subjects with severe Chronic Obstructive Pulmonary 
Disease [COPD], history of pneumonitis, alveolar 
haemorrhage, chest radiation) chest x-ray at baseline 


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and dose stopping/modifications criteria for 
pneumonitis (refer to Section 14.7.1).
Effects on Teeth
Minimal to mild changes related to dentin formation 
in continuously growing incisors were observed of in
rats dosed at given ≥3 mg/kg/day. A Mmarginally 
increased incidence and/or severity occurred after 
off dose period. No changes were observed in molar 
teeth of dogs.
Due to the differences between rodents and human, it 
is unlikely that these effects of teeth will affect human
adults.


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Section 5. SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
Rationale for change: The change was made to correct the selection criteria of study 
population.
Revised Text: 
First paragraph
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the GSK2820151 Investigator 
Brochure [GlaxoSmithKline Document Number 2014N208278_00]. Approximately 30-
50 subjects with relapsed or advanced solid malignancies will be enrolled. All subjects 
must have failed refused or otherwise be ineligible for standard therapy, failed up to three 
lines of cytotoxic therapy, or have a tumor for which there is no standard therapy, prior to 
consideration for study. The total number of subjects required will depend upon the 
number of escalation steps required to reach a MTD.
Section 5.1 Inclusion Criteria 
Rationale for change: The update was made to eligibility criteria for participation of 
female subject of child bearing potential in the study
Revised Text: 
Inclusion criterion #3: Diagnosis of advanced or recurrent, histologically or cytologically 
confirmed, solid malignancy that is either metastatic or unresectable. At time of 
enrollment, subjects either:
Bullet point 1: Rrefuse or are not candidates for standard curative or palliative therapy,
Bullet point 2: are not candidates for standard curative or palliative therapy,
Bullet point 3: have a disease for which no non-investigational therapy exists, OR
Inclusion criterion #9: A female subject is eligible to participate if she is of
Bullet point 2: Child-bearing potential and agrees to use one of the contraception 
methods (described in Section 7.3) for an appropriate period of time (as determined by 
the product label or investigator) prior to the start of dosing to sufficiently minimize the 
risk of pregnancy at that point. Female subjects must agree to use contraception from the 
time of the screening pregnancy test until at least 7 months after the last dose of study 
medication.
Bullet point 3: Negative serum pregnancy test ≤ 7 days prior to first study drug dose, for 
women of childbearing potential.


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Inclusion criterion #10
Male subjects with female partners of child bearing potential must agree to use one of 
the methods of contraception specified (see Section 7.4). This method must be used from 
the time of the first dose of study medication until 16 weeks after the last dose of study 
medication. In addition, male subjects whose partners are or become pregnant while on 
study medication must continue to use condoms for 7 days after stopping 16 weeks 
following the last dose of study medication.
Section 5.2 Exclusion Criteria 
Rationale for change: Changes were made to prevent the hemorrhagic events in the 
patients while on the study.
Revised Text: 
Exclusion criterion #2: Recent prior therapy, defined as follows,
Bullet point a: Any investigational or Food and Drug Administration (FDA)-
approved anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior 
to the first dose of GSK2820151. Any nitrosoureas or mitomycin C within 42 days 
prior to the first dose of GSK2820151. Prior therapy with monoclonal antibodies is 
permitted so long as 14 days have elapsed since therapy and all therapy-related 
toxicity has resolved to Grade 1 or less.  Note that an investigational drug is defined 
as a drug without an approved oncologic indication
Bullet point b:Any radiotherapy, chemotherapy, targeted therapy or immunotherapy
within 14 days or major surgery within 28 days or anti-neoplastic antibody or 
nitrosoureas/mitomycin C within 42 days prior to the first dose of GSK2820151. 
Bullet point c: Anti-androgen (e.g., bicalutamide) therapies for prostate cancer,such 
as bicalutamide, must be stopped 4 weeks prior to the first dose of 
GSK2820151enrollment. Second-line hormone therapies such as enzalutamide, 
abiraterone, or orteronel should be stopped 2 weeks prior to enrolment. Subjects with 
prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) 
agonists or antagonists. Subjects with prostate cancer may also remain on low-dose 
prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.
Exclusion criterion #3
Therapeutic anticoagulation (e.g., warfarin, heparin) must be discontinued 7 days prior to 
the first dose of GSK2820151 and coagulation parameters must be normalized prior to 
the first dose of GSK2820151. Low (prophylactic) dose (prophylactic) low molecular 
weight heparin (LMWH) is permitted. In addition, INR must be monitored in accordance 
with local institutional practices.


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Exclusion criterion #4
Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK2820151 (see Section 7.1.2 for the list of medications).
NOTE: Aspirin up to 100mg PO daily is allowed. Concurrent use of non-steroidal anti-
inflammatory drugs (NSAIDs) will be excluded except for cases where NSAIDs provide 
benefit over other analgesics (see Section 7.1.2 for details).
Exclusion criterion #8:
Any of the fFollowing electrocardiogram (ECG) findings:

Baseline Ccorrected QT (Fridericia’s formula) interval (QTcF) ≥450 msec 
Exclusion criterion #13:
Subjects with a history of known bleeding disorder(s) or Hhistory of clinical significant 
hemorrhage (majore.g., gastrointestinal, neurologic) bleeding within the last 6 months. 
Section 5.3 Screening/Baseline/Run-in Failures
Rationale for change: Corrections and clarification have been made to this section. 
Revised Text: 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolleddosed with study medication. In order to ensure 
transparent reporting of screen failure subjects, meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and respond to queries from 
Regulatory authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any Serious Adverse Events.
Section 5.4 Withdrawal/Stopping Criteria
Rationale for change: Corrections and clarification have been made to this section.
Revised Text: 
Seventh paragraph deleted
All subjects who permanently discontinue study treatment without disease progression 
will be followed for progression according to the protocol schedule until:

new anti-cancer therapy is initiated


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
progression

death, or

subject has been followed for 2 years after stopping treatment. 
Eigth paragraph
All subjects who permanently discontinue study treatment for any reason will be 
followed for survival and new anti-cancer therapy (including radiotherapy) every 6 
months until death, termination of the study by the sponsor, or until the subject has been 
followed for 2 years. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression. If subjects are unable or 
unwilling to attend clinic visits during follow-up, contact to assess survival may be made 
via another form of communication (e.g., telephone, email, etc.).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:
Section 5.5 Subject and Study Completion
Rationale for change: Corrections and clarification have been made to this section. 
Revised Text:
Second paragraph
A subject will be considered to have completed the study 2 years after the last treatment 
or if the subject dies or is still receiving study treatment or in follow-up at the time the 
study is closed or terminated, whichever is sooner.  Document the cause of death in the 
eCRF. A subject will be considered to have withdrawn from the study if the subject has 
not died and is lost to follow-up, has withdrawn consent, or at the investigator’s 
discretion is no longer being followed.The End of Study eCRF should only be completed 
when a subject is no longer being followed.  The end of the study is defined as the last 
subject’s last visit.
Section 7. MEDICATION, DIETARY AND LIFESTYLE RESTRICTIONS
Rationale for change: Corrections and clarification have been made to this section. 
Revised Text: 
Section name revised
MEDICATION, LIFESTYLE, AND DIETARY AND LIFESTYLE RESTRICTIONS


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Section 7.1.1 Permitted Medications and Non-Drug Therapies
Rationale for change: Minor correction has been made. 
Revised Text:
First paragraph
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with erythropoietin, antibiotics, antiemetics, 
antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance 
with their institutional guidelines. Colony-stimulating factors like filgrastim and 
pegfilgrastim may be used in cycles 2 and beyond as clinically indicated. The only caveat 
is that subjects should not receive those medications listed as prohibited in Section 
7.1.2.1. 
Section 7.1.2.1 Prohibited Medications 
Rationale for change: The change was made to update the list of drug with a risk of 
Torsades de Pointes that are prohibited based on the 2017 guidelines mentioned on 
crediblemeds.org.
Revised Text:
Previous Second paragraph deleted
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc.) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that the subject’s PT/PTT values meet entry criteria.
Two New paragraphs (third and fourth) added
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc.) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that the subject’s PT/PTT values meet entry criteria.
Subjects may continue to use aspirin, but doses are not allowed to be greater than 100 mg 
per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be excluded, 
except for when NSAIDs will provide benefit over other analgesics and then to be used 
with caution, including concomitant use of proton pump inhibitors.
Fifth paragraph
Co-administration of the following medications listed in Table 5 are PROHIBITED for 
5 half-lives (or at least 14 days, whichever is longer) prior to the first dose of study drug 
until discontinuation from the study drug due to unacceptable risk of Torsades de Pointes 


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(with the exception of amiodarone which is prohibited beginning 6 months prior to 
Screening through discontinuation from the study. [However, there may be situations 
when the subject is on study and Advanced Cardiac Life Support (ACLS) requires the use 
of amiodarone, which should be used as per local clinical guidelines]). These medications 
include (but are not limited to):
Table 5
Drugs with a Risk of Torsades de Pointes that are Prohibited1
Amiodarone
Dronedarone
MoxifloxacinPimozide
Anagrelide
Droperidol
PapaverineProcainamide
Azithromycin
Erythromycin
Pentamidine Propofol
Chloroquine
Escitalopram
PimozideQuinidine
Chlorpromazine
Flecainide
ProcainamideSevoflurane
Cilostazol
Fluconazol
PropofolSotalol
Ciprofloxacin
Halofantrine
QuinidineThioridazine
Citalopram
Haloperidol
Roxithromycin
Clarithromycin
IbogaineIbutilide
Sevoflurane
Cocaine
IbutilideLevofloxacin
Sotalol
Disopyramide
LevofloxacinMethadone
Sulpiride
Dofetilide
Levomepromazine Moxifloxacin
Sultopride
Domperidone
Levosulpiride
Terlipressin
Donepezil
MethadonePentamidine
Thioridazine
Data Source: crediblemeds.org revision date 4 May 2015 09 January 2017.
Drugs not available/used in the US have been omitted.
1The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject
Previous fifth paragraph deleted
At time of screening, if a subject is currently receiving any of the listed prohibited 
medications/substances, the medication or substance must be discontinued for a period of 
5 half lives (or at least 14 days, whichever is longer) prior to the administration of the 
first dose of study drug in order for the subject to meet study eligibility.
Sixth paragraph
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (up to a maximum dose of 0.25 mg 
daily) and ondansetron (up to a maximum dose of 8 mg three times daily [TID]) are the 
only allowed drugs in this class (i.e. dolasetron and granisetron are not permitted).
Section 7.1.3 Cautionary Medications
Rationale for change: The change was made to update the list of drug with a risk of 
Torsades de Pointes which are permitted for co-administration with extreme caution 
based on the 2017 guidelines mentioned on crediblemeds.org.


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Revised Text:
Table 6
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution1
AlfuzosinAlfuzosin
FoscarnetIloperidone
PerphenazineRanolazine
ApomorphineApomorphine
GemifloxacinIsradipine
PipamperoneRilpivirine
AripiprazoleAripiprazole
Hydrocodone ERLithium
PromethazineRisperidone
Artenimole+piperaquineAtazanavir
IloperidoneMifepristone
RilpivirineSaquinavir
AsenapineAtomoxetine
ImipramineMirabegron
RisperidoneTacrolimus
AtomoxetineBedaquiline
IsradipineMirtazapine
SaquinavirTelavancin
BedaquilineClomipramine
LeuprolideMoexipril/Hydrochlor
othiazide (HCTZ)
SertindoleTelithromycin
BuprenorphineClozapine
LithiumNicardipine
SolifenacinTetrabenazine
ClomipramineDesipramine
MelperoneNorfloxacin
TacrolimusTizanidine
ClozapineDexmedetomidine
MifepristoneNortriptyline
TelavancinTolterodine
CyamemazineDihydroartemisinin+
piperaquine
MirabegronOfloxacin
TelithromycinToremifene
DegarelixDolasetron
MirtazapineOlanzapine
TetrabenazineTrimipramine
DelamanidFamotidine
Moexipril/ hydrochlorothiazide
Ondansetron
TiaprideVardenafil
DesipramineFelbamate
NicardipineOxytocin
TizanidineVenlafaxine
DexmedetomidineFingolimod
NorfloxacinPaliperidone
TolterodineZiprasidone
EfavirenzFoscarnet
NortriptylinePasireotide
Trimipramine
Ezogabine
OfloxacinPerflutren lipid 
microspheres
Tropisetron
FamotidineGemifloxacin
OxytocinPromethazine
Vardenafil
FelbamateGranisetron
PaliperidoneQuetiapine
Venlafaxine
Fingolimod
Pasireotide
Zotepine
Flupentixol
Perflutren lipid microspheres
Perphenazine
Data Source: crediblemeds.org revision date 04 May 2015 09 January 2017.
1The above table is not exhaustive and prohibited drugs are defined by the online version at the time of 
screening of the subject
Note: This list is not exhaustive.  Drugs not available/used in the US have been omitted
Fifth paragraph
GSK2820151 may also interact with organic anion transporter 3 (OAT3).  Substrates of 
OAT3 include agents such as Penicillin G, and indomethacin, and ciprofloxacin. While 
co-administration of these agents with GSK2820151 is not prohibited, they should be 
used with caution and additional monitoring for adverse effects should be utilized.
Section 7.3 Lifestyle Restrictions (Contraception)
Rationale for change: Corrections and clarification were made to this section. 


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Revised Text:
New heading, ‘Section 7.3 Lifestyle Restrictions (Contraception)’ replaced old heading 
‘Section 7.3 Female Subjects’ which was then moved to third level heading as Section 
7.3.1 Female Subjects
Section 7.3.1 Female Subjects
Rationale for change: The change was made to add criteria for pregnancy in female 
subjects of childbearing potential and also to clarify the hormonal means of birth control. 
Revised Text:
First paragraph
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping study medication and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of 1%.
Second paragraph, Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not NOT acceptable methods of contraception. 
Third paragraph, Contraceptive Methods with a Failure Rate of 1%
Bullet point 1: Non-hormonal Iintrauterine device (IUD) or intrauterine system (IUS) that 
meets the <1% failure rate as stated in the product label
Fifth paragraph
All Hhormonal means of birth control such as oral, injectable, dermal, subdermal or 
topical contraceptives are NOT acceptable forms of birth control given that their efficacy 
has not been evaluated when given in combination with the investigational drugs.
Section 7.3.2 Male Subjects
Rationale for change: The change was made to clarify the contraceptive measures to 
be taken by the male population. 
Revised Text:
First paragraph


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Bullet point 1: Vasectomy with documentation of azoospermia. The documentation on 
male sterility can come from the site personnel’s: review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview, OR
Bullet point 2: Condom use plusPLUS partner use of a highly effective contraceptive 
(≤1% rate of failure per year) such as occlusive cap (diaphragm or cervical/vault cap) 
plus spermicidal agent (foam/gel/film/cream/suppository), or intrauterine device. OR
Bullet point 3: Condom use PLUS partner use of hormonal birth control such as 
contraceptive subdermal implant, combined estrogen and progestogen oral contraceptive, 
injectable progestogen, contraceptive vaginal ring, or percutaneous contraceptive patches.
The above list does not apply to male subjects with a female partner of child bearing 
potential who are and will continue to be abstinent from penile-vaginal intercourse 
on a long term and persistent basis, when this is their preferred and usual lifestyle. 
Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject.Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are notNOT acceptable methods of 
contraception
Bullet point 4: In addition, male participants must refrain from donating sperm for 
duration of study and until 16 weeks after the last dose of study drug


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Section 8.1 Time and Events Table
Rationale for change: Corrections and clarifications were made to this section. 
Revised Text:
Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed 
consent
Unless 
otherwise 
noted, 
screening 
assessments 
to be 
completed 
within 14 
days of first 
dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register 
subject
X
TREATMENT PHASE
Study Drug
Administer 
study drug
Administer 
about same 
time of day. 
No food or 
antacids 1h 
before and 
2h after.
X
X
X
X
X
X
X
X
X
Daily
Review subject 
diary
Diary not 
required 
when dosed 
X
X
X
X
X
X
X


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Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
in clinic.
Safety
Pregnancy 
test/ 
testosterone
Females: 
serum 
pregnancy 
test within 7 
days of first 
dose; urine 
or serum test 
thereafter. 
Males: 
complete 
and free 
testosterone 
at SCR; free 
testosterone 
thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, 
heart rate, 
respiratory 
rate, temp, 
O2 
saturation
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain (using 
Wong-Baker 
Faces Pain
Rating scale)
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
Height at 
X
X
X
X
X
X
X
X
X
X


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Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
height
SCR only
Chest x-ray
X
Pulmonary 
function tests 
(spirometry, 
DLCO, and 
room air
O2 saturation 
at rest via 
pulse oximetry)
All patients 
will have 
PFTs at 
baseline; 
afterwards 
as clinically 
indicated 
(e.g., in 
patients with 
severe 
Chronic 
Obstructive 
Pulmonary 
Disease 
[COPD], 
history of 
pneumonitis, 
alveolar 
haemorrhag
e and chest 
radiation etc)
X
Adverse events
continuous from signing of informed consent
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring


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Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Echocardiogra
m
Within 35 
days of first 
dose
X
X
X
X
X
12-lead ECGs 
(Triplicate)
Triplicate 
SCR ECGs 
within 35 
days of first 
dose. For 
timing of 
triplicate 
ECGs on O 
days, see 
Table 9 and 
Table 10. 
Otherwise, 
triplicate 
ECGs at 
approximatel
y same time 
of day, and 
prior to dose 
on dosing 
days. If 
QTcF 
increase 
>30msec, 
ECGs daily 
through W2.
X
O
O
X
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter 
monitoring
At least 24 h, 
on dosing 
days start at 
X
X
X
X
X
X


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Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
least 60 min 
predose.
Telemetry
Start at least 
60 min 
predose and 
for at least 
48 h.
X
X
Efficacy
Cross-sectional 
(Computed 
tomography 
[CT] or 
magnetic 
resonance 
imaging [MRI]), 
functional 
(Positron 
emission 
tomography 
[PET]), or 
nuclear (bone 
scan) imaging
Appropriate 
imaging 
modality 
should be 
selected by 
the 
investigator 
depending 
on disease 
histology and 
location. 
SCR 
assessment 
within 2 
weeks of first 
dose. Target 
lesions to be 
identified at 
SCR and 
followed.  
See Section 
14.8.1 for 
guidelines.
X
X
X
X


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Assessments
Notes
SC
R
Refer to Section 8.4.2 for visit windows.
EO
T
Week 1
Week 2
W3
W4
W
5
W
7
W
9
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 9 and Table 10
PK and 
biomarker 
samples
X
X
X
X
X
X
Samples for 
mRNA
X
X
X
X
X
LPS blood 
sample
X
PK Urine 
samples 
X
X
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE


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Table 8
Time and Events: Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
W1D1, W1D2: local lab sample 
3X/24h; central lab sample 
1X/24h. All other timepoints
including Uunscheduled collect 2 
samples: 1 for local, 1 for central 
lab
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X1
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if PT, INR or aPTT 
are ≥1.5XULN, or in case of 
bleeding event
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Fasting blood glucose and insulin 
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 –Anhydroglucitol
(1,5 AG)
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
Thyroid stimulating hormone 
(TSH), free T3, free T4. If TSH is 
abnormal at W1D1, continue
monitor TSH, free T3 and free T4 
going forward
X
X
X
X
X
X


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NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Urinalysis
X
X
X
X
X
X
Pregnancy test, females
Serum pregnancy test within 7 
days of first dose; urine or serum 
test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at 
SCR; free testosterone thereafter
X
X
X
X
X
X
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
This is collected as part of the 
Predose PK sample and is sent to
Myriad via Covance.
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, 
perform third generation 
immunoassay on same sample to 
confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
1. If any parameter (i.e., platelets) shows a downward trend, additional analyses should be performed within 2-3 days to monitor.


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Section 8.2.2 Visit Windows
Rationale for change: Corrections and clarification were made to this section. 
Revised Text:
Week 2 to Week 49: Based on subject and clinic schedule, assessments can be 3 days. 
Week 4 to Week 9: Clinic visits can be scheduled 3 day.
Discontinuation visit: should be 14 to 28 days from last dose of study drugs. If a subject 
is unable to return to the clinic due to hospitalization, site staffs are encouraged to 
telephone the subject for assessment of adverse events.
Section 8.3.4 Pain and Section 8.3.5 Echocardiogram
Rationale for change: Corrections were made to this section.
Revised Text:
Section 8.3.4 Pain will be assessed using Wong-Baker Faces Pain Rating scale 
(Appendix 11). Echocardiogram split into two sections: Section 8.3.4 Pain and Section 
8.3.5 Echocardiogram
Section 8.3.5 Echocardiogram
Rationale for change: Corrections were made to this section.
Revised Text:
First paragraph
For all subjects, trans-thoracic echocardiograms (TTEs) will be performed at screening 
and at assessment times as outlined in Table 7. TTEs should be evaluated and compared 
to baseline by the same reader. Copies of all TTE scans performed on subjects who 
experience an absolute decrease >10% in left ventricular ejection fraction (LVEF) 
compared to baseline concurrent with LVEF < LLN will be required by GSK for review.
Second paragraph
TTE ECHO data may be transferred and reviewed by an independent cardiologist. 
Instructions for submission of qualifying TTE ECHO scans are provided in the Study 
Procedure Manual (SPM) Laboratory Manual.
Section 8.3.6 Safety Electrocardiograms (ECG)
Rationale for change: Minor correction was made to this section.
Revised Text:


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Safety ECGs will be performed at the time points specified in Table 7 using a standard 
12-lead ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals. Details will be provided in the Laboratory ManualSPM.
Section 8.3.6.1 Routine ECG Monitoring
Rationale for change: Minor correction was made to this section.
Revised Text:
Last paragraph
ECG data may be transferred and reviewed by an independent central reviewer. 
Instructions for submission of ECGs are provided in the Laboratory Manual SPM. 
Section 8.3.9 Clinical Safety Laboratory Assessments
Rationale for change: Minor correction was made to this section.
Revised Text:
Last paragraph
All laboratory tests with valuesresults that are considered by the investigator clinically 
significantly abnormal during participation in the study or within 28 days after the last 
dose of study treatment should be recorded on the eCRF as AEs. In addition, these 
clinically significant abnormal laboratory results should be followed until the abnormality 
resolves or is determined to be stable. If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
Section 8.3.10 Troponin Measurement
Rationale for change: The change was made for clarification on Troponin sampling 
and analysis. Minor corrections were also made to this section. 
Revised Text:
Two samples for troponin will be collected at each time-point as outlined in Table 8. At 
W1D1 and W1D2 three local lab troponin samples (8hrs apart) should be drawn per day 
but only 1 central lab sample should be drawn per day. At other time-points (including 
unscheduled visit) only two samples should be drawn; 1 for local lab analysis and 1 for 
central lab analysis. Troponin T will be assessed at a central laboratory as a means of 
consistent evaluation across all subjects. Whereas A second sample, will be assessed at a 
local laboratory, will be used for purposes of subject management. Whenever possible, 
troponin T will be assayed by the local laboratory. However, either troponin I or troponin 
T may be assessed at a local laboratory. The same local laboratory test (troponin I or 
troponin T) should be used consistently for an individual subject throughout the study. 


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Section 8.4.2 Urine Sample Collection for Pharmacokinetics
Rationale for change: The change was made for clarification on urine sampling and 
analysis for PK. 
Revised Text:
Second paragraph
The actual date and time of each urine sample collection will be recorded. In addition, 
pooled urine pH, the total volume of the pooled urine and the weight of the pooled urine 
will be measured and recorded in the eCRF.
Section 8.6 Efficacy
Rationale for change: Corrections and clarification were made to this section.
Revised Text:
First paragraph, 
Bullet point 1: Lesion assessment method and timing, evaluation of disease, disease 
progression and response criteria will be conducted according to Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] as outlined below and in 
Appendix 8. 
Bullet point 3: The baseline disease assessment will be completed within 2 weeks prior to 
the first dose of GSK2820151, then every 8 weeks starting W1D1 thereafter, and at the 
final study visit.  See the Time and Events Table (Section 8.1) for the schedule of 
assessments of anti-cancer activity. 
Section 11.4.2 Interim Analysis
Rationale for change: Clarification was made to this section.
Revised Text:
Last paragraph added
An interim analysis of the pharmacodynamic data will be conducted once an appropriate 
amount of data has been collected and has been batched for analysis. Interim analyses of 
the pharmacodynamic data may be conducted throughout the duration of the study.
Section 14.4 Appendix 4: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Rationale for change: Correction was made to this section. 
Revised Text:


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Text deleted-fourth Paragraph
Background Information on Drug Restart/Rechallenge
Section 14.7.1 Dose Adjustments for Toxicity
Rationale for change: Update made in the light of new information. 
Revised Text:
Table 12
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
QTcF
If 60 msec change from 
baseline occurs
OR
QTcF 500 
(average of three ECGs over 
at least 15 minutes)
If QTcF results have not resolved to baseline by 4 
weeks post-dose, then continue every 4-5 weeks until 
resolution
Troponin
Troponin level >ULN

Evaluate immediately forContact the subject 
immediately for evaluation of symptoms and to
obtain ECG. Repeat troponin within 24-48 hours 
or as soon as possible. 

If the subject is asymptomatic and repeat 
value is within the normal range, the subject 
may continue GSK2820151 with close follow-
up for symptoms, ECG monitoring and further 
troponin measurements as clinically 
indicated.

If the repeat value remains > ULN AND the 
subject is asymptomatic, hold GSK2820151, 
refer to a cardiologist, and contact the GSK 
Medical Monitor. May consider restarting 
study treatment at a reduced dose or dose
level pre-event based on discussion with GSK 
Medical Monitor.

If the subject is symptomatic (symptoms 
consistent with acute coronary syndrome) OR
the troponin level is at or above the threshold 
for mycocardial infarction (MI) according to 
local lab parameters, discontinue
GSK2820151 permanently and refer the 
subject immediately to a cardiologist or 
emergency medical facility for appropriate 
medical care.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
LVEF
Ejection fraction below the 
institution’s lower limit of 
normal (LLN)
AND
An asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline
Withhold GSK2820151 and repeat evaluation of LVEF 
within 2 weeks
If LVEF recovers (defined as LLN and absolute 
decrease 10% compared to baseline) at any time 
during the next 4 weeks, after consultation and 
approval of the GSK medical monitor, the subject may 
be restarted on investigational drug(s) at a reduced 
dose. Monitoring to be performed at 2 and 4 weeks 
after restarting investigational drug(s) and then per 
protocol specifications.
If LVEF does not recover within 4 weeks, permanently 
discontinue investigational drug(s). Evaluation by a 
cardiologist will be conducted. Ejection fraction should 
continue to be monitored at 2 weeks, 4 weeks and 
every 4 weeks until 16 weeks or resolution, whichever 
is longer.
Grade 3 or 4
Permanently discontinue GSK2820151. Evaluation by 
a cardiologist will be conducted. Ejection fraction 
should be monitored at 2 weeks, 4 weeks and then 
every 4 weeks until 16 weeks or resolution, whichever 
is longer.
Hypo- and 
Hyperglycemia
Note: for 
management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use NCI-
CTCAE version 
v4.03 Grade 1-5
(Mild) Fasting blood glucose 
>150 mg/dL to 250 mg/dL 
(Mild hyperglycemia)

Monitor fasting and preprandial glucose.

If persistent over 2 repeats over 3-4 weeks, 
consult Diabetologist and consider starting 
metformin
(Moderate to Severe) 
Fasting blood glucose <70 
mg/dL OR any blood 
glucose >250 mg/dL
Any blood glucose >250 
mg/dL (Moderate to Severe 
hyperglycemia)

WithholdHold GSK2820151 and instruct subject 
to notify investigator immediately.

If a blood glucose >250 mg/dL is observed, 
the subject should be evaluated Monitor for 
ketoacidosis as clinically indicated.

If subject has evidence of ketoacidosis, 
initiate prompt therapy. Antihyperglycemic 
therapy with insulin is preferred. Consult 
Diabetologist/Endocrinologist . Careful 
monitoring should be performed to control for 
rebound hypoglycemia as effect of 
investigational product(s) resolve.
o
This may necessitate inpatient 
management.
o
The action of insulin or other 
antihyperglycemic agents should be 
restored as study medication is cleared. If 
an antihyperglycemic agent is 
administered, then the subject should be 
observed closely for rebound 
hypoglycemia as the study medication is 
cleared.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
o
Intravenous insulin treatment is 
recommended.

May consider restarting GSK2820151 at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.
Fasting blood glucose 
<70 mg/dL (Moderate to 
Severe hypoglycemia)
Withhold GSK2820151
Provide sugar containing liquids and monitor
blood sugar closely. Check for insulin and c-
peptide levels. After blood sugar normalizes, may 
restart study treatment one dose level lower if the 
hypoglycemia cannot be attributed to any other 
cause, and fasting blood sugar will be monitored 
on a daily basis until the blood glucose level is 
stabilized.
Diarrhea
Grade 3

Above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics as 
appropriate.

HWithhold GSK2820151 and discuss with GSK 
Medical Monitor until diarrhea has resolved to 
≤Grade 1, continue diarrheal prophylaxis

If diarrhea recovers to less than ≤ Grade 1 2, 
discuss with medical monitor; consider resuming 
treatment at the same or lower dose based on 
clinical judgement.
Mucositis
Grade 3 or 4

Above, plus systemic opiate administration as 
needed. 

Consider IV hydration and hospital admission 
as appropriate. 

For mucositis >Grade 3, withhold 
GSK2820151 until mucositis is <Grade 1 and 
resume the same dose of GSK2820151. If 
mucositis >Grade 3 recurs, withhold 
GSK2820151 until mucositis is <Grade 1, 
then reduce GSK2820151 one dose level. If 
mucositis >Grade 3 recurs a third time at 
reduced dose, discontinue GSK2820151 
permanently.

May restart GSK2820151 at a reduced dose or 
dose level pre-event based on discussion with 
GSK Medical monitor.
Pneumonitis
Grade 1

Continue GSK2820151 at current dose.

Consider evaluation by pulmonologist.

Consider room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins apart). 
If any decline is observed in O2 saturation, 
withhold study drug, repeat chest x-ray to 
determine if progression of pneumonitis has 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
occurred and consult pulmonologist.Repeat 
evaluations every 8-12 weeks until return to 
baseline.

Obtain high-resolution computed tomography 
(CT) scan of the chest if possible.
Grade 2

Hold GSK2820151 until recovery to < Grade 1, 
then reduce dose by at least 25%. 

Consider Must be evaluatedion by 
pulmonologist.

Consider pulmonary function tests 
including: spirometry, Diffusing Capacity of 
the Lung for Carbon Monoxide (DLCO), and 
weekly room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins apart). 
Repeat evaluations every 8-12 weeks until 
return to baseline.

Obtain high-resolution chest CT if possible.

Consider a bronchoscopy with biopsy 
and/or bronchoalveolar lavage. (BAL).

Treat only if symptomatic. Consider 
corticosteroids if symptoms are 
troublesome and infective origin is ruled 
out. Taper as medically indicated.

Withhold GSK2820151 until recovery to < Grade 
1, then reduce dose by at least 25%.  
Discontinue GSK2820151 if no recovery to 
Grade 1 within 4 weeks. May consider 
escalation to pre-event dose after discussion with 
GSK Medical Monitor
Grade 3 or 4

Hold Discontinue GSK2820151 and refer for 
evaluation by pulmonologist

Required pulmonary function tests 
including: spirometry, DLCO, and room air 
O2 saturation at rest via pulse oximetry 
reading (X 2, 5 mins apart). Repeat 
evaluations at least every 8 weeks until 
return to baseline. 

Obtain high-resolution chest CT if possible.

Bronchoscopy with biopsy and/or BAL is 
recommended.

Consider corticosteroids if infective origin is 
ruled out. Taper as medically indicated.

Rechallenge Guidelines

Grade 3: Hold Withhold GSK2820151 until
recovery to < Grade 1. Discontinue 
GSK2820151 if no recovery to < Grade 1 
within 4 weeks. May consider restarting 
GSK2820151 at a reduced dose after 
discussion with GSK Medical Monitor if 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
there is clinical benefit.

Grade 4: Rechallenge with GSK2820151 is 
not permitted
Thrombocytopenia
Grade 1 (platelets <LLN to 
≥75,000/mm3) or Grade 2 
(platelets <75,000 to 
≥50,000/mm3) Count 
50,000)

Continue dosing at same dose level with weekly 
or more frequent monitoring as necessary
Grade 3 (platelets <50,000 
to ≥25,000/mm3) Count 
25,000 – 50,000)

After discussion with medical monitor and using 
sound clinical judgement, continue at same dose 
or adjust dose (e.g. consider reduced daily 
dosing or dosing on alternate days). Monitor 
CBC at least twice a week, more frequently if 
necessary 
Withhold GSK2820151 and check aPTT, PT, and INR.  
Monitor CBC and coagulation studies twice a week 
until normal, or increase monitoring frequency if 
clinically indicated. 
Withhold GSK2820151 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are all 
≤ ULN. Drug may then be restarted at a lower dose 
level, after discussion with the medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued permanently or restarted at 
further lower dose level, after discussion with the 
medical monitor. If safety lab abnormalities recur to 
the same level following a second rechallenge, drug 
will be discontinued permanently.
Grade 4 (Count
platelets≤25,000) or any 
moderate to severe bleeding 
accompanied by drug 
related thrombocytopenia
Interrupt study medication and monitor CBC every 2-3 
days Withhold GSK2820151 and check aPTT, PT, and 
INR.  Monitor CBC and coagulation studies twice a 
week until normal, or increase monitoring frequency if 
clinically indicated. 
Withhold GSK2820151 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are all 
≤ ULN. Drug may then be restarted at a lower dose 
level, after discussion with the medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued permanently.
If platelet count does not recover to ≥25,000/mm3
(Grade 3) within 7 days and ≥50,000/mm3 (Grade 2) 
within 14 days, GSK2820151 should be permanently 
discontinued.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Any subject requiring transfusion support, 
GSK2820151 should be permanently discontinued.

If platelet counts recover to Grade 2, 
discuss with medical monitor resuming 
treatment at the same or adjusted dose 
based on sound clinical judgement.

Platelet transfusion is allowed based on 
institutional guidelines. In case of platelet 
transfusion, hold drug for at least 7 days 
from day of transfusion, and if platelet 
counts recover to Grade 2 consider 
initiating treatment at a lower dose using 
sound clinical judgement and after 
consulting with the GSK medical monitor. 

Discontinue treatment if drug has to be held 
for >14 days or greater than 2 dose 
reductions are required.
All Other Toxicity*
1

Continue dosing with no change 
2

Continue dosing with no change 
OR

HoldWithhold GSK2820151 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)
3

1st episode: HoldWithhold dose for one week 
intervals until drug-related Grade 2, then 
restart with no change. 

2nd episode: Utilize an alternative, less frequent 
schedule or reduce by one dose level. 

If no recovery to ≤Grade 1* after a 21 day delay, 
patient should go off protocol therapy.
*Note: Exceptions to drug-related Grade 1 requirement may be made for certain AEs as defined in Section 4.2.5.
Section 14.10 Appendix 10: Collection of Pregnancy Information
Rationale for change: Correction was made to this section. 
Revised Text:
Bullet point 2: Information will be recorded on the appropriate form and submitted to 
GSK within 2 weeks 24 hours of learning of a subject's pregnancy.
Section 14.12 Appendix 12: NYHA Functional Classification System for 
Heart Failure


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


2014N215112_00
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GlaxoSmithKline group of companies
201893
1
TITLE PAGE
Division: Worldwide Development
Information Type: Clinical Protocol
Title:
A Phase I Open-Label, Dose Escalation Study to Investigate the 
Safety, Pharmacokinetics, Pharmacodynamics, and Clinical 
Activity of GSK2820151 in Subjects with Advanced or 
Recurrent Solid Tumors
Compound Number:
GSK2820151
Development Phase
I
Effective Date:              15-DEC-2014
Authors:
 
Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved.
Unauthorised copying or use of this information is prohibited.
PPD


PPD


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After Hours Contact 
Information
Site Address
Primary 
Medical 
Monitor
MD/PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
UP4210
Collegeville, PA 19426, 
USA
Secondary 
Medical 
Monitor 
MD/PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
UP4210
Collegeville, PA 19426, 
USA
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): 124949
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study.
Investigator Name:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201893........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
3.
OBJECTIVES AND ENDPOINTS...........................................................................14
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.2.
Dose Escalation and Duration of Study.......................................................15
4.2.1.
Planned Dose Levels...................................................................17
4.2.2.
Accelerated Dose Escalation .......................................................17
4.2.3.
3 + 3 Dose Escalation..................................................................18
4.2.4.
Dose-Limiting Toxicity..................................................................19
4.2.5.
Non-Limiting Toxicities.................................................................20
4.2.6.
Alteration of Schedule..................................................................20
4.2.7.
Intra-Subject Dose Escalation......................................................21
4.3.
Type and Number of Subjects.....................................................................21
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................23
4.5.1.
Human Pharmacokinetic Extrapolation ........................................23
4.5.2.
Starting Dose...............................................................................23
4.6.
Benefit:Risk Assessment ............................................................................24
4.6.1.
Risk Assessment .........................................................................25
4.6.2.
Benefit Assessment.....................................................................30
4.6.3.
Overall Benefit:Risk Conclusion...................................................30
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................33
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Liver Chemistry Stopping Criteria ................................................37
5.4.1.1.
Study Treatment Restart or Rechallenge....................39
5.4.2.
QTc Stopping Criteria ..................................................................39
5.4.3.
LVEF Stopping Criteria ................................................................40
5.4.4.
Valvular Toxicity Stopping Criteria ...............................................41
5.4.5.
Other Stopping Criteria ................................................................41
5.5.
Subject and Study Completion....................................................................42
6.
STUDY TREATMENT ............................................................................................43
6.1.
GSK2820151..............................................................................................43
6.2.
Treatment Assignment................................................................................43
6.3.
Packaging and Labeling..............................................................................43
6.4.
Preparation/Handling/Storage/Accountability..............................................43
6.5.
Compliance with Study Treatment Administration.......................................44
6.6.
Treatment of Study Treatment Overdose....................................................44
6.7.
Treatment after the End of the Study ..........................................................45


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7.
MEDICATION, LIFESTYLE, AND DIETARY RESTRICTIONS ...............................45
7.1.
Concomitant Medications and Non-Drug Therapies....................................45
7.1.1.
Permitted Medications and Non-Drug Therapies..........................45
7.1.2.
Prohibited Medications and Non-Drug Therapies.........................46
7.1.2.1.
Prohibited Medications ...............................................46
7.1.2.2.
Prohibited Non-Drug Therapies ..................................47
7.1.3.
Cautionary Medications ...............................................................47
7.2.
Dietary Restrictions.....................................................................................49
7.3.
Female Subjects.........................................................................................49
7.4.
Male Subjects.............................................................................................50
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................50
8.1.
Time and Events Tables .............................................................................51
8.2.
Screening and Critical Baseline Assessments ............................................59
8.2.1.
Critical Baseline Assessments.....................................................59
8.2.2.
Visit Windows ..............................................................................59
8.3.
Safety .........................................................................................................60
8.3.1.
Physical Exams ...........................................................................60
8.3.2.
Performance Status.....................................................................60
8.3.3.
Vital Signs....................................................................................60
8.3.4.
Echocardiogram...........................................................................61
8.3.5.
Safety Electrocardiograms (ECG)................................................61
8.3.5.1.
Routine ECG Monitoring.............................................61
8.3.5.2.
Evaluation of QTc.......................................................61
8.3.6.
Telemetry.....................................................................................61
8.3.7.
Holter Monitoring .........................................................................62
8.3.8.
Clinical Safety Laboratory Assessments ......................................63
8.3.9.
Troponin Measurement................................................................64
8.3.10.
Pregnancy ...................................................................................64
8.4.
Pharmacokinetics .......................................................................................65
8.4.1.
Blood Sample Collection for Pharmacokinetics............................65
8.4.2.
Urine Sample Collection for Pharmacokinetics ............................66
8.4.3.
Pharmacokinetic Sample Analysis ...............................................66
8.5.
Pharmacokinetic/Pharmacodynamic Analysis.............................................66
8.6.
Efficacy.......................................................................................................67
8.7.
Translational Research...............................................................................68
8.7.1.
Biologic Effects of GSK2820151..................................................68
8.7.2.
RNA Expression Research ..........................................................68
8.7.3.
Effects of GSK2820151 on Systemic Markers of 
Inflammation................................................................................68
8.8.
Pharmacogenetic Analysis..........................................................................69
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: DATA 
COLLECTION, REPORTING, AND FOLLOW-UP..................................................69
9.1.
Definition of AE/SAE...................................................................................69
9.1.1.
Cardiovascular and Death Events................................................69
9.1.2.
Other Sentinel Events..................................................................70
9.1.3.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................70
9.2.
Time period and Frequency for collecting AE and SAE information ............70
9.2.1.
Method of Detecting AEs and SAEs.............................................71
9.2.2.
Follow-up of AEs and SAEs.........................................................71


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9.2.3.
Regulatory Reporting Requirements for SAEs .............................71
10. DATA MANAGEMENT ...........................................................................................72
11. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................72
11.1.
Hypotheses.................................................................................................72
11.2.
Continual Reassessment Method ...............................................................72
11.2.1.
Description of Continual Reassessment Method..........................72
11.2.1.1.
Implementation of N-CRM ..........................................73
11.2.1.2.
Bayesian Prior............................................................73
11.3.
Sample Size Considerations.......................................................................73
11.3.1.
Sample Size Assumptions ...........................................................73
11.3.2.
Sample Size Re-estimation or Adjustment...................................74
11.4.
Data Analysis Considerations .....................................................................74
11.4.1.
Analysis Populations....................................................................74
11.4.2.
Interim Analysis ...........................................................................74
11.5.
Key Elements of Analysis Plan ...................................................................74
11.5.1.
Primary Analyses.........................................................................74
11.5.2.
Secondary Analyses ....................................................................75
11.5.2.1.
Pharmacokinetic Analyses..........................................75
11.5.2.1.1.
Pharmacokinetic Parameters..................75
11.5.2.1.2.
Statistical analysis of 
pharmacokinetic parameters...................75
11.5.2.2.
Efficacy Analysis ........................................................76
11.5.2.3.
Safety Analyses..........................................................76
11.5.2.4.
Extent of Exposure .....................................................76
11.5.2.5.
Adverse Events ..........................................................76
11.5.2.6.
Clinical Laboratory Evaluations ..................................77
11.5.3.
Other Analyses ............................................................................77
12. STUDY GOVERNANCE CONSIDERATIONS........................................................77
12.1.
Posting of Information on Publicly Available Clinical Trial Registers............77
12.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................77
12.3.
Quality Control (Study Monitoring) ..............................................................78
12.4.
Quality Assurance.......................................................................................78
12.5.
Study and Site Closure ...............................................................................79
12.6.
Records Retention......................................................................................79
12.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................80
13. REFERENCES.......................................................................................................81
14. APPENDICES........................................................................................................83
14.1.
Appendix 1: Abbreviations and Trademarks................................................83
14.2.
Appendix 2: ECOG Performance Status .....................................................87
14.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................88
14.4.
Appendix 4: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................92
14.5.
Appendix 5: Genetic Research ...................................................................95


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14.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................98
14.6.1.
Definition of Adverse Events........................................................98
14.6.2.
Definition of Serious Adverse Events...........................................99
14.6.3.
Definition of Cardiovascular Events ...........................................101
14.6.4.
Recording of AEs and SAEs ......................................................101
14.6.5.
Evaluating AEs and SAEs..........................................................102
14.6.6.
Reporting of SAEs to GSK.........................................................103
14.7.
Appendix 7: Guidelines for Management of Toxicity .................................104
14.7.1.
Dose Adjustments for Toxicity....................................................104
14.8.
Appendix 8: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria – adapted from RECIST 1.1 
[Eisenhauer, 2009]....................................................................................112
14.8.1.
Assessment Guidelines .............................................................112
14.8.2.
Guidelines for Evaluation of Disease .........................................113
14.8.2.1.
Measurable and Non-measurable Definitions ...........113
14.8.2.1.1.
Measurable lesion ................................113
14.8.2.1.2.
Non-measurable lesion.........................113
14.8.3.
Baseline Documentation of Target and Non-Target 
Lesions ......................................................................................114
14.8.4.
Response Criteria......................................................................114
14.8.4.1.
Evaluation of target lesions.......................................114
14.8.4.2.
Evaluation of non-target lesions................................115
14.8.4.3.
New lesions..............................................................116
14.8.4.4.
Evaluation of overall response..................................116
14.8.4.5.
Evaluation of best overall response..........................117
14.8.4.6.
Confirmation Criteria.................................................117
14.9.
Appendix 9:  Cockcroft and Gault Method for Calculated Creatinine 
Clearance .................................................................................................118
14.10. Appendix 10: Collection of Pregnancy Information....................................119


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1.
PROTOCOL SYNOPSIS FOR STUDY 201893
Rationale
The Bromodomain (BRD) and Extra-Terminal (BET) family is comprised of four 
different proteins that bind via their bromodomains to acetylated histone tails in order to 
regulate transcription, cell growth, and survival. In preclinical models, small molecules 
that inhibit the binding of BET proteins to histones have been associated with potential 
therapeutic benefit for multiple human malignancies. The study drug, GSK2820151, is a 
BET inhibitor arising from a distinct structural class to that previously progressed to 
clinical studies. GSK2820151 potently inhibits tumor growth in vitro and in vivo in 
animal models. This first time in human (FTIH), open-label, dose escalation study will 
assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary 
clinical activity of GSK2820151 in subjects with advanced or recurrent solid tumors.
Objectives/Endpoints
Objectives
Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) of 
GSK2820151 in subjects 18 years or 
older with advanced or recurrent solid 
tumors.

Adverse events (AEs), serious adverse 
events (SAEs), dose reductions or 
delays, withdrawals due to toxicities 
and changes in safety assessments 
(e.g., laboratory parameters, vital 
signs, electrocardiogram (ECG), 
cardiotoxicity, gastrointestinal, etc.)
Secondary

To determine a recommended Phase 2 
dose (RP2D) of GSK2820151 in subjects 
18 years or older.

Safety profile (AEs, SAEs, dose-limiting 
toxicities [DLTs]), clinical response, and 
PD data

To characterize the pharmacokinetics 
(PK) of GSK2820151 in subjects 18 years 
or older.

PK parameter values for GSK2820151 
following single and repeat-dose oral 
administration in subjects 18 years or 
older.

To evaluate the effect of treatment with 
GSK2820151 on tumor growth and 
subject survival.

Objective response rate (ORR) by various 
imaging modalities and progression free 
survival (PFS).

To evaluate cardiac safety, including the 
potential for corrected QT interval (QTc)
prolongation, of GSK2820151 and to 
assess PK/QTc relationship.

Changes in cardiac safety including QTc 
following single and repeat-dose oral 
administration of GSK2820151.
Exploratory

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between 
GSK2820151 and safety and efficacy 
parameters.

Dose-related change in molecular 
markers (e.g., gene transcription and/or 
expression of proteins regulated by BRD 
proteins) in peripheral blood samples.


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Objectives
Endpoints

To evaluate systemic and ex vivo on-
target BET inhibitory effects

Changes from baseline and 
dose/response relationship in ex vivo
lipopolysaccharide (LPS)-induced 
cytokines, including Interleukin 6 (IL-6), in 
whole blood, and systemic cytokines, 
including IL-6.

To identify potential indicators of 
sensitivity or response to GSK2820151.

Transcriptomic studies of blood; 
correlation of baseline genetic and 
genomic profiles with response.
Overall Design
This study is a single-arm, open-label, dose-escalation study to determine the MTD (and 
a RP2D) based on the safety, pharmacokinetic, and pharmacodynamic profiles observed 
after oral administration of GSK2820151. Eligible subjects with advanced or recurrent 
solid tumors will be enrolled in the dosing cohorts until an MTD is established.  For a 
schematic representation of the study, please refer to Figure 2.
Treatment Arms and Duration
This is a single-arm study in which all subjects will receive the investigational agent.
Subjects may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent. The duration of study will depend on recruitment rates 
and the timing of subjects’ duration on study (withdrawal rates due to toxicity or 
progression), with an approximate duration of 3 years.
Type and Number of Subjects
Approximately 30 to 50 subjects with will be enrolled in the study. The study population 
will be adults, with advanced or recurrent solid malignancy, who either:

refuse standard therapy,

are not candidates for standard therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (up to three lines of prior cytotoxic agents are 
permitted).
The total number of subjects required will depend upon the number of escalation steps 
required to reach a MTD.
Analysis
After each dosing cohort, a Neuenschwander Continual Reassessment Method (N-CRM) 
[Neuenschwander, 2008] analysis will be used to recommend the next dose level based 
on observed dose-limiting toxicities (DLTs). Dose escalation decisions will be based on 


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the totality of clinical safety assessment based on a combination of reported safety events, 
N-CRM recommendation, as well as pharmacokinetic and pharmacodynamic data.
All data will be pooled and descriptive analyses summarized and listed by cohort at study 
conclusion. No formal statistical hypotheses will be tested. Analyses will be descriptive 
and exploratory.
Measurements

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: There 
will be extensive PK sampling during this study. Single safety PK blood draws may 
be collected for subjects with severe adverse events or adverse events of concern. 
Blood samples will be collected for analysis of protein biomarkers (cytokines and 
acute phase proteins) and messenger ribonucleic acid (mRNA). LPS induction of 
cytokines in whole blood will be assessed. 

EFFICACY MEASUREMENTS: ORR and PFS.

SAFETY MEASUREMENTS: Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events will be 
performed. Stringent cardiac safety monitoring will be required, consisting of:
o
≥ 48 hours of telemetry following the first dose (necessitating overnight stays in a 
research facility)
o
24 hours of ambulatory cardiac (Holter) monitoring in Week 1, Week 2, Week 4, 
and Week 9
o
Triplicate 12-lead ECGs prior to dosing on selected days and prior to drawing PK 
samples on serial PK sampling days. 
Extensive laboratory testing includes standard hematology, clinical chemistry, 
pancreatic, coagulation, and liver chemistry panels. Troponin, C-peptide, 1,5-
anhydroglucitol, glycosylated hemoglobin (hemoglobin A1c), and thyroid monitoring 
will also be performed. 


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2.
INTRODUCTION
GSK2820151 is a novel, orally available inhibitor of the Bromodomain (BRD) and Extra-
Terminal (BET) family of bromodomain-containing transcriptional regulators that is 
being developed for treatment of multiple solid malignancies.
2.1.
Study Rationale
The aim of this study is to establish a maximum tolerated dose for the BET inhibitor 
GSK2820151 in subjects with refractory, advanced solid malignancies where prognosis is 
particularly poor with limited effective treatment options. Preclinical studies have shown 
that small molecule-based inhibition of BET protein binding to chromatin with 
GSK2820151 inhibits proliferation of multiple solid tumor-derived cancer cell lines and 
results in significant anti-tumor activity in animal models of advanced disease [Chaidos, 
2014; Wyce, 2013]. 
Consistent with the published literature, GSK2820151 inhibits proliferation and induces a 
cytotoxic response in cell lines across a wide range of solid tumor types (Figure 1). 
GSK2820151 inhibits growth in a broad spectrum of human solid cancer and 
hematological (heme) cell lines.  These include NUT (Nuclear protein in testes) midline 
carcinoma (NMC), non-small cell lung cancer (NSCLC), neuroblastoma, cervical cancer, 
prostate cancer, small cell lung cancer (SCLC), colorectal cancer (CRC), acute myeloid 
leukemia (AML), multiple myeloma (MM), and lymphoma. By way of example in the 
largest panel of cell lines tested (n=149), eighty seven percent are highly sensitive to 
GSK2820151, exhibiting growth IC50 (gIC50) values below 1.0 M (Figure 1)
Figure 1
Effect of GSK2820151 on the growth of human tumor-derived cell 
lines


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Bromodomains (BRDs) are found in a variety of proteins that recognize and bind to 
acetylated histone tails [Dhalluin, 1999]. This binding affects chromatin structure and 
facilitates the localization of transcriptional complexes to specific genes, thereby 
regulating gene transcription and messenger ribonucleic acid (mRNA) elongation [Dey, 
2003; Jang, 2005]. The BRD extra-terminal (BET) family of BRD proteins includes the 
BRD2, BRD3, BRD4, and BRDT proteins.
BET proteins have been shown to be involved in the regulation of transcription, cell 
growth, and survival. In addition, BRD4 has been shown to be directly involved in 
regulation of the cell cycle, as it remains associated with chromosomes through mitosis, 
specifically at the transcription start site (TSS) of genes expressed at the M/G1 phase of 
the cycle [Dey, 2009]. BRD4 is also a critical mediator of transcriptional elongation, 
functioning to recruit the positive transcription elongation factor complex (P-TEFb)
[Itzen, 2014; Patel, 2013]. BRD4 inhibition, through blocking P-TEFb recruitment to 
chromosomes, results in decreased expression of growth-promoting genes [Hargreaves, 
2009].
The investigational agent GSK2820151 is a potent inhibitor of the BET family of 
proteins. The crystal structure of GSK2820151 in complex with the bromodomain 1 of 
BRD4 reveals the compound to bind as a histone mimetic. This binding mode has been 
shown previously for other compounds to inhibit the assembly of the transcriptional 
complex and the subsequent gene expression response [Nicodeme, 2010].
The role of BET proteins in malignancy is best demonstrated in Nuclear Protein in Testes 
(NUT) midline carcinoma (NMC), a rare, aggressive, and invariably lethal tumor with a 
median overall survival of 6.7 months [Bauer, 2012]. NMC is triggered by a translocation 
between the NUT gene and one of the BRD genes (typically BRD3 or BRD4) [French, 
2008]; the resulting fusion oncoprotein is retained in the cell nucleus via interactions with 
chromatin [Yan, 2011]. Treatment of patient-derived NMC lines with small molecule 
BET inhibitors leads to rapid growth inhibition and differentiation of cells to a non 
malignant phenotype. This has led to the further clinical investigation of compounds for 
this patient population.
While NMC is the prototypic BET-driven malignancy, other tumor types have been 
found to require functional BET for growth and progression [Fiskus, 2014; Trabucco, 
2014; Asangani, 2014]. Studies in leukemia and multiple myeloma (MM) cell lines have 
shown that small molecule inhibition of BET protein binding to chromatin can directly 
block expression of the gene myc and its downstream transcriptional functions, resulting 
in significant anti-tumor effects [Delmore, 2011; Mertz, 2011]. GSK2820151 has been 
studied extensively in cell culture and has been demonstrated to inhibit the growth of 
multiple solid tumor cell lines apart from NMC, including those derived from cancer of 
the bladder, breast, cervix, colon/rectum, prostate, and lung (see Figure 1 as well as 
investigator’s brochure [IB], Section 5.2.1.1 [GlaxoSmithKline Document Number 
2014N208278_00]). GSK2820151 has also demonstrated efficacy after oral 
administration in mouse xenograft models of SCLC and NMC (see IB, Section 5.2.1.2
[GlaxoSmithKline Document Number 2014N208278_00]). Based on these observations, 
administration of GSK2820151 to humans is expected to have potential therapeutic 
applications in a broad array of solid malignancies.
Importantly, while the biochemical and phenotypic properties of GSK2820151 are 
comparable to those reported for BET inhibitors under clinical evaluation from the 


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benzodiazepine class, this agent is the first of its structural class to enter clinical trials. As 
such differential human pharmacokinetics, pharmacodynamics, or overall safety profile 
for GSK2820151 may provide beneficial improvements in therapeutic index for patients. 
It is on this basis that clinical trials with GSK2820151 are being proposed.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) in 
subjects 18 years or older with 
advanced or recurrent solid tumors.

Adverse events (AEs), serious adverse 
events (SAEs), dose reductions or 
delays, withdrawals due to toxicities 
and changes in safety assessments 
(e.g., laboratory parameters, vital 
signs, electrocardiogram (ECG), 
cardiotoxicity, gastrointestinal, etc.)
Secondary

To determine a recommended Phase 2 
dose (RP2D) of GSK2820151 in subjects 
18 years or older.

Safety profile (AEs, SAEs, dose-limiting 
toxicities [DLTs]), clinical response, and 
PD data 

To characterize the pharmacokinetics 
(PK) of GSK2820151 in subjects 18 years
or older.

PK parameter values for GSK2820151 
following single and repeat-dose oral 
administration in subjects 18 years or 
older.

To evaluate the effect of treatment with 
GSK2820151 on tumor growth and 
subject survival.

Objective response rate (ORR) by various 
imaging modalities and progression free 
survival (PFS).

To evaluate cardiac safety, including the 
potential for corrected QT interval (QTc)
prolongation, of GSK2820151 and to 
assess PK/QTc relationship.

Changes in cardiac safety including QTc 
following single and repeat-dose oral 
administration of GSK2820151.
Exploratory

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between 
GSK2820151 and safety and efficacy 
parameters.

Dose-related change in molecular 
markers (e.g., gene transcription and/or 
expression of proteins regulated by BRD 
proteins) in peripheral blood samples.

To evaluate systemic and ex vivo on-
target BET inhibitory effects

Changes from baseline and 
dose/response relationship in ex vivo
lipopolysaccharide (LPS)-induced 
cytokines, including interleukin 6 (IL-6), in 
whole blood, and systemic cytokines, 
including IL-6.

To identify potential indicators of 
sensitivity or response to GSK2820151.

Transcriptomic studies of blood; 
correlation of baseline genetic and 
genomic profiles with response.


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4.
STUDY DESIGN
4.1.
Overall Design
This study is a single-agent, open-label, dose-escalation study to determine the MTD (and 
RP2D), based on the safety, pharmacokinetic, and pharmacodynamic profiles observed 
after oral administration of GSK2820151. Eligible subjects with advanced or recurrent 
solid tumors will be enrolled in the dosing cohorts until MTD is established. All subjects 
will receive study drug. Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent (for specific stopping 
criteria, see Section 5.4). The duration of study will depend on recruitment rates and the 
timing of subjects’ duration on study (withdrawal rates due to toxicity or progression).
4.2.
Dose Escalation and Duration of Study
This study will utilize an accelerated dose escalation phase in order to minimize sub-
optimal drug exposures, followed by a conventional 3+3 dose escalation phase to achieve 
MTD. At least one and up to six subjects will be recruited per cohort. Initially, one 
subject per dose cohort will be recruited until the first instance of a ≥ Grade 2 drug 
related non-hematological toxicity.  Further cohorts will be recruited in blocks of three 
subjects. Additional subjects may be enrolled at previously cleared dose levels in order to 
obtain further data for PK and/or PD analysis.  A maximum of six subjects will be 
assigned to any single dose. Once MTD is determined, up to 12 additional subjects (18 
subjects total at MTD) may be enrolled to collect additional safety data (Figure 2). The 
total duration of study for each subject will be dependent upon the safety, tolerability and 
efficacy of GSK2820151.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predicted optimal dose from the Neuenschwander Continual 
Reassessment Method (N-CRM) analysis, a type of Bayesian adaptive dose-escalation 
scheme (see Section 11.2). The method is fully adaptive and makes use of all the DLT 
information available at the time of each dose assignment. The DLT information of all 
subjects enrolled in the trial are used to update the estimated dose-toxicity relationship 
and provide supportive information in addition to the 3+3 design in the next 
escalation/de-escalation decision.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects
(Table 2). If necessary alternate schedules can be explored to determine additional 
biologically active doses even after a RP2D is defined.


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Figure 2
Dose Escalation Scheme


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4.2.1.
Planned Dose Levels
Projected dose levels are 3 mg, 6 mg, 12 mg, 20 mg, 40 mg, 60 mg, 100 mg, 150 mg, 
200 mg, and 300 mg.  Additional doses and schedules may be explored based on 
emerging safety, PK, and PD data. 
4.2.2.
Accelerated Dose Escalation
One subject per dose level in the accelerated dose escalation phase will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 and continuing until one 
subject experiences Grade 2 drug related toxicity (based on National Cancer Institute-
Common Terminology Criteria for Adverse Events, Version 4 (NCI-CTCAE v4 [NCI-
CTCAE, 2010]) or dose-limiting toxicity (DLT, see Section 4.2.4). The accelerated dose 
titration scheme is described in Table 1. A single dose (Day 1) will be given to subjects in 
each cohort with the collection of blood samples for PK analysis at timed intervals. Once 
the final PK sample for Day 1 is obtained, subjects may begin repeat dosing on Day 3. 
The dose for Dose Level 2 and subsequent cohorts will be based on the pharmacokinetics 
(PK) and safety analysis of the previous cohort. Inter-subject variability in exposure and 
toxicity will also be considered when deciding on actual doses administered during dose-
escalation. Dose escalation will occur according to the procedures outlined in Table 1. 
A sufficient number of subjects will be enrolled in each cohort to ensure that data from at 
least one subject that has completed a full treatment cycle (4 weeks) of dosing is 
available prior to defining a new dose and starting the next cohort. The dose-escalation 
decision and rationale for the subsequent cohort(s) will be documented in writing with 
copies maintained at each study site and in the master study files at GlaxoSmithKline 
(GSK).
At the first occurrence of a DLT (refer to Section 4.2.4) or any Grade 2 toxicity (based on 
NCI-CTCAE v4) (with the exception of Grade 2 alopecia, nausea, vomiting, diarrhea, 
hemoglobin, lymphopenia, taste changes or alkaline phosphatase in the presence of bony 
metastases) during the first 4 weeks, the Accelerated Dose Titration procedure will be 
terminated.  Once a DLT occurs, the ongoing cohort will be expanded up to 6 subjects 
and dose-escalation will continue following the 3 + 3 Dose-Escalation guidelines.


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Table 1
Accelerated Dose Titration Procedures
Dose Level
Toxicity
Dose Escalation
Accelerated Dose Titration Phase
Dose Level -1 
Lower doses may be explored if DLTs or significant 
toxicities are observed at Dose Level 1.
Dose Level 1 
Starting Dose: 3 mg daily
Subsequent Dose 
Levels 
No subjects with either a 
Grade 2 toxicity or a DLT in 
first 4 weeks of treatment
Escalate to next dose level with an increase of ≤ 
100%a
End of 
Accelerated Dose 
Titration Phase
One or more subjects with a 
≥Grade 2 toxicity or a DLT in 
first 4 weeks of treatment
Begin 3+3 dose-escalation phase
a: Dose levels in Section 4.2.1 are suggestions; the final determination of the next dose level will be made at the dose 
escalation meeting in concert with the Investigators, GSK Medical monitor, and representatives from Safety, Statistics, 
and Clinical Pharmacology.  The final dose escalation decision will depend on all factors, as described in Section 
11.2.1.
4.2.3.
3 + 3 Dose Escalation
Two additional subjects will be enrolled to the dose level at which accelerated dose 
titration ends, for a total of at least 3 subjects at that dose level. If no DLTs are observed 
in any of the 3 subjects, then dosing will proceed to the next higher dose level (≤2 fold 
increase in dose); however, if termination of accelerated dose titration is triggered by a 
DLT, then 5 additional subjects will be enrolled at that dose level. Subjects will be 
entered in a staggered approach with at least 3 days between each subject to minimize the 
risk of inadvertently exceeding the MTD in multiple subjects. Dose escalation decisions 
will be made as outlined in Table 2 Escalation to the next dose level will not increase 
greater than 2 fold from the previous dose level. Intra-subject dose escalation may be 
considered as described in Section 4.2.7. Subjects should not be enrolled at a higher dose 
level until at least 3 subjects in the previous dose cohort complete 4 weeks of treatment.
Dose-limiting toxicity (DLT) is based on any observed toxicity in the first 4 weeks.  If 1 
of 3 subjects experiences a DLT at a particular dose level, 3 additional subjects will be 
enrolled at that dose level.  If 2 or more subjects experience a DLT at a particular dose 
level, a lower (or intermediate) dose level may be explored to better define the maximum 
tolerated dose (MTD).
If 2 or more DLTs in 6 subjects are observed at any dose level, the MTD will have been 
exceeded (Table 2).


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Table 2
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to next dose level with an increase of ≤ 100%a

If two or more subjects have the same Grade 2 drug-related 
adverse event, consider a <2-fold increasea taking into 
consideration the safety profile and dose-exposure relationship
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%a
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded. Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to a total of 12 subjects
1 or more out of 6 subjects at the 
highest dose level below the MTD
The dose is considered the recommended Phase 2 dose (RP2D).  At 
least 6 subjects must be evaluated at the RP2D dose.
a: Dose levels in Section 4.2.1 are suggestions; the final determination of the next dose level will be made at the dose 
escalation meeting in concert with the Investigators, GSK Medical monitor, and representatives from Safety, Statistics, 
and Clinical Pharmacology.  The final dose escalation decision will depend on all factors, as described in Section 
11.2.1.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects. If 
necessary alternate schedules can be explored to determine additional biologically active 
doses even after a RP2D is defined.
4.2.4.
Dose-Limiting Toxicity
An event is considered to be a dose-limiting toxicity (DLT) if the event is attributed 
(definitely, probably or possibly) to the study treatment during the first 4 weeks of 
treatment and meets the criteria described in 
Table 3, as graded when applicable by the NCI-CTCAE v4.
Subjects who are unable to receive at least 75% of the scheduled doses during the 4-
week DLT evaluation period will be replaced in the cohort unless the reason for the delay 
or discontinuation was due to a DLT.
Table 3
Dose –Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 neutropenia (absolute neutrophil count [ANC]
<500/mm3 for 5 days)

Febrile neutropenia (as defined by NCI-CTCAE v4 [concurrent 
Grade 4 neutropenia and fever >38.3C])

Grade 4 anemia of any duration

Grade 4 thrombocytopenia (platelets <25,000/mm3)
Non-hematologic

ALT >3x upper limit of normal (ULN) + bilirubin 2xULN (>35% 
direct) or ALT between 3-5 X ULN with bilirubin < 2xULN but 
with hepatitis symptoms or rash (See Section 5.4.1 for Liver 


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Toxicity
DLT Definition
Stopping Criteria)

Grade 3 nausea, vomiting or diarrhea that does not improve 
within 24h despite appropriate supportive treatment(s)

Grade 4 nausea, vomiting, or diarrhea

Grade 3 hypertensiona (uncontrolled despite addition of up to 
2 antihypertensive medications)

Grade 4 hypertension

Grade 3 or greater clinically significant non-hematologic toxicity 
(including QTcF) per NCI-CTCAE, v4 except toxicities listed in 
Section 4.2.5

Grade 2 troponin elevation (central laboratory >ULN), 
measured on two separate occasions within 48 hours in order 
to confirm elevation and with other clinical signs, symptoms, 
laboratory tests consistent with cardiac toxicityb.
Other

Any toxicity resulting in a dose delay of >14 days of the 
intended next dose

Grade 2 or higher toxicity that occurs beyond 28 days which in 
the judgment of the investigator and GSK Medical Monitor is 
considered to be a DLT
Toxicity Grading based on NCI-CTCAE v4
a.
Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not 
considered to be a DLT.
b.
In the event a troponin (central laboratory assessment) is not performed or a laboratory error 
occurs, considerations for a DLT criterion will involve review of two separate local troponin (I 
or T) assays done within 48 hours at a local investigator site. Troponin I or T elevations 
greater than the upper limit of normal, and > 10% coefficient of variance (CV) for that assay 
will be considered as a grade 2 elevation.
4.2.5.
Non-Limiting Toxicities
The following toxicities have been deemed to be non-serious for the purposes of this 
study. These toxicities will not be taken into account for dose escalation decisions unless, 
in the opinion of the investigator and the GSK Medical Monitor, they represent a dose-
limiting toxicity. For all other toxicities and their management, see Section 14.7.

Grade 3 or less:
o
Fatigue
o
Rash
o
Mucositis
o
Asthenia
o
Alopecia

Electrolyte imbalance or other laboratory abnormalities controlled within 24h
4.2.6.
Alteration of Schedule
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK and safety data.


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Schedules that incorporate a recovery period may be explored (e.g., 2 weeks on, 1 week 
off). This approach will be considered if the safety and PK data suggest that a therapeutic 
exposure cannot be achieved using the initial schedule without excessive toxicity. The 
starting dose for the alternate schedule will be the highest completed dose level (at or 
below MTD) with the initial schedule. Escalation can then proceed as described using 
3 + 3 dose escalation.
Schedules that use a shorter recovery period, e.g., twice daily (BID) dosing, may also be 
explored. This approach will be considered if the safety, PK, and emerging PD data 
suggest that a sufficient therapeutic exposure cannot be achieved using the initial 
schedule. If a shorter recovery period is used, the initial dose level will be 50% of the 
highest completed dose level (at or below MTD) with the initial schedule. Escalation can 
then proceed as described using the 3 + 3 dose escalation. Alternative schedules with 
intense supportive care may also be explored.
The dosing schedule may also be adjusted to expand a prior dose cohort to further 
evaluate safety, pharmacokinetic and/or pharmacodynamic findings at a given dose level, 
or to add cohorts to evaluate additional dose levels. The study procedures for these 
additional subject(s) or cohort(s) will be the same as that described for other study 
subjects.
4.2.7.
Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced any Grade 2 or higher drug related toxicity prior to dose 
escalation in the accelerated dose escalation phase or a DLT in the 3+3 dose escalation 
phase and contingent upon the following: 
Additional subject(s) have been enrolled at a higher dose in the dose escalation phase and 
at least one subject has completed 4 weeks of dosing on that regimen without a DLT; and 
after review of all safety data and approval by a GSK Medical Monitor, a subject on a 
lower dose level may be increased up to the highest dose level tested. In this case the 
subject may begin dosing at the higher dose level as it will have already been 
demonstrated to be tolerable. 
Subjects approved for intra-subject dose escalation will require additional limited PK 
sampling at the higher dose, as determined by GSK Clinical Pharmacology. Additional 
safety assessments such as insulin/glucose or cardiac monitoring may be specified at the 
time of dose escalation or schedule modification based on the safety profile in previous 
subjects at the higher dose level. Intra-subject dose escalations or schedule modification 
will be discussed with investigators and approved by the GSK Medical Monitor and 
safety monitoring required will be specified in writing.
4.3.
Type and Number of Subjects
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) of GSK2820151 for further study. It is estimated 30 to 
50 evaluable subjects will be enrolled.


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Approximately 30 to 50 subjects with will be enrolled in the study. The study population 
will be adults, with advanced or recurrent solid malignancy, who either:

refuse standard therapy,

are not candidates for standard therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (up to three lines of prior cytotoxic agents are 
permitted).
If a subject discontinues the study before completing Week 4 due to reasons other than 
toxicity, additional subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator to ensure an adequate population for DLT and MTD 
evaluations.
4.4.
Design Justification
Given the high unmet medical need of relapsed/refractory, advanced solid tumors, a 
conventional Phase I study (201893) is proposed. The study comprises an accelerated 
dose titration to determine a MTD. While preliminary efficacy data will be collected as 
part of the course of the study, it will not be a primary endpoint. Overall, the aim of the 
study is to identify a RP2D for future evaluation of GSK2820151.
While dose escalation and subject enrollment will utilize a conventional 3+3 approach, 
determination of the particular dose to be tested in each cohort will utilize all available 
information, including input from the N-CRM model. The updated model from the N-
CRM analysis after each subject is evaluated will give more information about the 
expected DLT rate at each dose level and assist in the dose-escalation decision making 
process.


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4.5.
Dose Justification
4.5.1.
Human Pharmacokinetic Extrapolation
Human pharmacokinetics was predicted based on three species (mouse, rat and dog) 
using different allometric extrapolation. Whole blood human clearance predicted from 
mean of allometry was 6.5 ml/min/kg (~30% hepatic blood flow). Volume of distribution 
at steady state was predicted to be 2.8 L/kg with a moderate half life of ~5hr. 
Bioavailability is predicted to be ~69%.
4.5.2.
Starting Dose
The 28 day toxicology studies were conducted using the freebase of GSK2820151 
whereas the mesylate salt of GSK2820151 will be used on this clinical study. 
Comparison of systemic exposure between the freebase and mesylate versions of 
GSK2820151 at the same dose level (corrected for form) showed that systemic exposure 
was comparable in the rat, but the mesylate salt resulted in 2-4.6 fold higher exposure in 
the dog. Taking into account the difference in systemic exposure for the dog (and using 
the more conservative approach of 4.6 fold difference), the dose level required to achieve 
equivalent systemic exposure has been adjusted (i.e. highest non-severely toxic dose 
(HNSTD) freebase of 5 mg/kg is equivalent to HNSTD mesylate of 1.09 mg/kg.).
Three approaches have been considered to establish the starting dose for GSK2820151.

One tenth of the rat severely toxic dose in 10% of the animals (STD10)
For GSK2820151, the STD10 was defined as 3 mg/kg in the rat following 
International Conference on Harmonization (ICH) S9 guidelines. 1/10 rat STD10 is 
1.8 mg/m2; this dose is not severely toxic to dogs and translates to a starting dose in 
man of 3 mg, assuming a 70 kg adult and adult surface area of 1.7 m2. 

One sixth of the dog HNSTD
For GSK2820151, the dog HNSTD is defined as 1.09 mg/kg. 1/6 dog HNSTD is 3.63 
mg/m2 which translates to a starting dose in man of  6 mg, assuming a 70 kg adult and 
adult surface area of 1.7 m2. 

The dose predicted to deliver a minimum anticipated biologicaleffect t level
minimum anticipated biological effect level, (MABEL) dose.
The potential therapeutic effect of GSK2820151 was evaluated at single oral daily doses 
of 10 mg/kg (30 mg/m2) and 30 mg/kg (90 mg/m2) in OPM-2 transgenic non-obese 
diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenograft model of 
multiple myeloma; 25 mg/kg (75 mg/m2) daily and 50 mg/kg (150 mg/m2) every other 
day in NCI-H526 SCLC xenograft model and 30 mg/kg (90 mg/m2) daily in NMC 
xenograft model. GSK2820151 was efficacious at 30 mg/kg in both studies and showed 
partial efficacy at 10 mg/kg dose in OPM-2 xenograft model. 25 mg/kg dose showed 
~24% reduction in tumor growth while 50 mg/kg showed ~54% reduction in tumor 
volume. The mouse MABEL dose of 10 mg/kg (30 mg/m2) would translate to a dose in 


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human of 125 mg using human equivalent dose calculation.  Taking a conservative 
approach, the starting dose will be 3 mg. 
The predicted human exposure at 3 mg is area under the curve from zero to 24 hours 
(AUC0-24) = 78.8 ng/h/mL and is approximately 6-fold lower than the exposure at the dog 
NOAEL / HNSTD and approximately 9- and 47-fold lower than the rat no observed 
adverse effect level (NOAEL) and STD10 exposures, respectively.
4.6.
Benefit:Risk Assessment
Summaries of findings from the non-clinical studies conducted with GSK2820151 can be 
found in the Investigator’s Brochure [GlaxoSmithKline Document Number 
2014N208278_00]. The following section outlines the risk assessment and mitigation 
strategy for this protocol: 


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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Cardiovascular
QT Prolongation
Observed after single dose in dogs (100 mg/kg; 
up to 34 msec and up to 48hr post dosing) and 
after repeat dosing in dogs (≥ 30 mg/kg/day from 
Day 3; up to 21 msec). 
Mechanism is unclear (no clear link to human 
ether-à-go-go-related gene [hERG] binding); QT 
prolongation observed at unbound in vivo drug 
concentrations approximately 100-fold lower than 
in vitro hERG inhibition (IC50).
Increased number of arrhythmias observed in 1 
of 3 dogs which had highest drug exposure after 
a single dose of 100mg/kg (10x the dog 28 day 
MTD).
Blood Pressure (BP)
Increases in blood pressure (mean, systolic & 
diastolic; systolic affected more than diastolic) 
observed following single dose in dogs. Mean up 
to 38 mmHg and up to 42 hours post dosing.
Heart Rate
Increased heart rate after a single and repeat 
Informed consent form (ICF) includes the risk of 
(fatal) arrhythmias and the risk of myocardial 
infarction
Drugs with a risk of Torsades de Pointes are 
prohibited, (refer to Section 7.1.2).
Protocol includes cardiovascular eligibility 
criteria, laboratory assessments (potassium and 
magnesium, N-terminal pro–B-Type natriuretic 
peptide [NT-proBNP], creatine kinase [CK], 
creatine kinase-MB [CK-MB], and troponins 
[local laboratory monitoring for troponin I or T 
based on availability and troponin T at central 
laboratory]), cardiac monitoring (ECGs, Holter 
monitoring and cardiac ejection fraction) during 
the study, and dose stopping/modifications 
criteria for the management of cardiac events.
All subjects will receive their first dose of study 
medication (Week 1 Day 1) in the hospital with 
telemetry monitoring for the first 48 hours of 
dosing. Throughout the protocol, the role of 
intensive cardiac monitoring will be re-evaluated 
in an ongoing fashion with the aim of re-
evaluating cardiac risk mitigation strategy while 
maintaining subject safety.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
doses of 100 mg/kg in dogs (single dog up to 24 
beats per minute (BPM) between 9 and 19 hours 
post dosing after a single dose and single dog up 
to 94 bpmafter repeat dosing. ). 
Cardiac Biomarkers
Reversible increases in serum cardiac troponin I 
(cTnI) levels were observed in male rats (up to 
3.3X) at 10 mg/kg/day for 28 days. Increased NT 
pro-ANP (up to 2.1X) in female rats given ≥1 
mg/kg/day for 28 days; no recovery after up to 5 
weeks off dose period. No histologic lesions in 
the heart on 28 day studies.
Gastrointestinal (GI)
(Dose-limiting toxicity in rats and dogs)
Gastrointestinal effects were the dose limiting 
toxicity in both rats and dogs at doses 6 and 
20 mg/kg/day respectively.
Clinical presentation included altered feces, 
reduced food consumption and reduction in body 
weight; microscopic changes observed at doses
6 and 20 mg/kg/day in rats and dogs 
respectively included erosion / ulceration / 
haemorrhage / mucosal epithelium 
degeneration/regeneration, villous atrophy, 
inflammatory cell infiltration and mild cecal 
lamina propria fibrosis (dogs only).
Signs of recovery immediately after cessation of 
ICF includes the risk of gastrointestinal effects.
Protocol includes medical history, physical 
examination (including weight) and clinical 
laboratory assessments to assess toxicity in the 
GI tract. Subjects with a history of 
gastrointestinal bleeding in the past 6 months 
(Section 5.2) or active bleeding will be excluded.
Protocol also includes specific dose 
adjustment/stopping safety criteria for diarrhea 
and mucositis.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
dosing; no microscopic findings after up to 5 
weeks off dose.
Lymphoid/Hematologic
Lymphoid / hematologic toxicity was observed in 
rats and dogs at ≥3 and ≥5 mg/kg/day 
respectively.
The effects manifested as hypocellularity in bone 
marrow of rats and dogs and reduced cellularity 
of the thymus, lymph nodes and spleen in rats 
accompanied by microscopic evidence of 
increased red cell turnover. Peripheral effects 
included reductions in red blood cells, platelets 
and increases in neutrophils (in response to GI 
toxicity).  Effects on reticulocyte counts were 
variable. 
Reversible increased activated thromboplastin 
(APTT) time in rats and dogs (≥1 mg/kg/day and 
20 mg/kg/day respectively). A mild decrease in 
APTT in female rats at 3 mg/kg/day. Reversible 
increases in fibrinogen (1.51X) in dogs dosed at 
20 mg/kg/day.
Regenerative response in blood cell parameters 
and microscopic observation of extramedullary 
haemopoiesis was evident after up to 5 weeks 
off-dose.
ICF includes the risk of lymphoid / hematologic
toxicity.
Protocol includes laboratory assessments 
(complete blood count [CBC] and coagulation 
factors [international normalized ratio (INR), 
prothrombin time (PT), partial thromboplastin 
time (PTT)], exclusion criteria if there is evidence 
of clinically significant bleeding episodes, 
monitoring for bruising/infection and dose 
stopping/modifications criteria.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Reproductive
Testicular degeneration was observed in both 
rats (10 mg/kg) and dogs as well as disorganised 
spermatogenesis in dog at ≥5 mg/kg. Secondary 
changes were evident in epididymides 
(hypospermia, degenerate cells, atrophy, 
vacuolation). 
No evidence of reversibility within 3 week off 
dose period. 
Reversible reduced prostate weight (rat and dog) 
& decreased secretory content in prostate (rat ≥ 
3 mg/kg/day) and seminal vesicles (rat 10 
mg/kg/day) were observed.
ICF includes the risk of damage to reproductive 
organs such as testes or ovaries.
Protocol includes specific contraceptive 
guidelines and precautions for males and 
females and pregnancy testing for female 
subjects and collecting testosterone (free and 
complete) for male subjects.
ICF includes the potential risk of reproductive 
effects.
Liver and Gallbladder Effects Hepatobiliary
Dog: Minimal gallbladder vacuolization and 
minimal vacuolization of biliary epithelium in 
dogs dosed at 20 mg/kg/day. Effects were 
reversible.
Rat: Reversible decreased inflammatory cell 
infiltrate in animals dosed at ≥ 3 mg/kg/day. 
ICF includes the risk of hepatic/gallbladder 
effects.
Protocol includes hepatic eligibility criteria, 
laboratory assessments during the study, and
dose stopping/modifications criteria for the 
management of hepatic events.
Lung Effects
Minimal to mild prominent (foamy) alveolar 
macrophages were observed in rats 
administered ≥ 1 mg/kg/day. Effects were 
reversible. The clinical consequences of this 
finding are unknown.
ICF includes the risk of lung effects.
Protocol includes pulmonary function 
assessments as appropriate (subjects with 
severe Chronic Obstructive Pulmonary Disease 
[COPD], history of pneumonitis, alveolar 
haemorrhage, chest radiation) chest x-ray at 
baseline and dose stopping/modifications criteria 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
for pneumonitis.
Teeth
Minimal to mild changes related to dentin 
formation in continuously growing incisors of rats 
dosed at ≥ 3 mg/kg/day. Marginally increased 
incidence and/or severity after off dose period. 
No changes observed in molar teeth.
Due to the differences between rodents and 
human, it is unlikely that these effects of teeth 
will affect human adults.


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4.6.2.
Benefit Assessment
Study 201893 is an open-label, dose escalation study and the first study of this agent to 
be conducted in subjects with relapsed and/or refractory advanced solid malignancies for 
which no standard therapies are available. GSK2820151 has promising preclinical 
activity in cell lines; however it is unknown whether GSK2820151 will have clinical 
efficacy in subjects with solid tumors. As such, any potential beneficial effect for an 
individual subject attributable to GSK2820151 is unknown. Data obtained in Study 
201893 may assist in progressing the knowledge base on advanced malignancies and 
their treatment, or help identify individuals more likely to benefit or have side effects 
from GSK2820151.
4.6.3.
Overall Benefit:Risk Conclusion
Current data from preclinical development indicate GSK2820151 inhibits the BET family 
of BRD proteins, and that this inhibition may have clinical utility in the treatment of 
various tumors. Taking into account the measures taken to minimise risk to subjects 
participating in the Phase I clinical trials, the potential risks identified in association with 
GSK2820151 are justified by the anticipated benefits that may be afforded to subjects 
with relapsed/refractory advanced solid malignancies with otherwise limited therapeutic 
options.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the GSK2820151 Investigator 
Brochure [GlaxoSmithKline Document Number 2014N208278_00]. Approximately 30-
50 subjects with relapsed or advanced solid malignancies will be enrolled. All subjects 
must have failed refused or otherwise be ineligible for standard therapy, failed up to three 
lines of cytotoxic therapy, or have a tumor for which there is no standard therapy, prior to 
consideration for study. The total number of subjects required will depend upon the 
number of escalation steps required to reach a MTD.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and enrolled
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability, or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Written informed consent provided


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2. Males and females 18 years old and greater
3. Diagnosis of advanced or recurrent solid malignancy. At time of enrollment, subjects 
either:

refuse standard therapy,

are not candidates for standard therapy,

have a disease for which no non-investigational therapy exists, OR

have progressed on prior therapy (up to three lines of prior cytotoxic agents are 
permitted).
4. Subjects with solid tumors, with the exception of castration-resistant prostate cancer 
(CRPC), must demonstrate measurable disease, per Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1.
5. All prior treatment- related toxicities must be NCI-CTCAE v4 ≤ Grade 1 (except 
alopecia [permissible at any Grade] and peripheral neuropathy [which must be ≤ 
Grade 2]) at the time of treatment allocation. 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1
(See Appendix 2 for definitions). 
7. Adequate organ function as defined in Table 4.


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Table 4
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
9 g/dL (subjects that required transfusion or growth 
factor need to demonstrate stable hemoglobin for 7 
days of 9 g/dL)
Platelets
100 X 109/L
PT/INR and PTT
≤ 1.5 X upper limit of normal (ULN)
Hepatic
Albumin
2.5 g/dL
Total bilirubin
≤1.5 x X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of Gilbert’s 
syndrome)
Alanine aminotransferase (ALT)
2.5 ULN
OR
<5 x ULN is acceptable for subjects with documented 
liver metastases/tumor infiltration
Renal
Creatinine
OR
Creatinine clearance [either directly measured or 
calculated by Cockcroft-Gault formulab]
≤1.5 X ULN
≥ 40 mL/min
Cardiac
Ejection fraction
≥ 50% by echocardiogram or multigated acquisition
scan (MUGA)
Troponin (T)
Potassium
Magnesium
ULN 
≥Lower limit of normal (LLN) and ≤ULN
≥LLNa
a.
Magnesium supplementation is permitted, as required, to maintain a serum magnerium concentrations LNN
b.
Cockcroft and Gault Method for Calculated Creatinine Clearance is provided in Appendix 9.
8. Able to swallow and retain orally administered medication.
9. A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a documented 
tubal ligation, hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion, hysterectomy, or documented bilateral 
tubal oophorectomy; or postmenopausal defined as 12 months of spontaneous 
amenorrhea [in questionable cases a blood sample with simultaneous follicle 
stimulating hormone (FSH) >40 U/ml and estradiol <40 pg/ml (<140 pmol/L) is 
confirmatory]. Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the contraception 
methods if they wish to continue their HRT during the study. Otherwise, they 
must discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse 
between the cessation of therapy and the blood draw; this interval depends on the 
type and dosage of HRT. Following confirmation of their post-menopausal status, 


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they can resume use of HRT during the study without use of a contraceptive 
method.

Child-bearing potential and agrees to use one of the contraception methods 
(described in Section 7.3) for an appropriate period of time (as determined by the 
product label or investigator) prior to the start of dosing to sufficiently minimize 
the risk of pregnancy at that point. Female subjects must agree to use 
contraception until at least 4 weeks after the last dose of study medication.

Negative serum pregnancy test ≤ 7 days prior to first study drug dose.

Female subjects who are lactating must discontinue nursing prior to the first dose 
of study treatment and must refrain from nursing throughout the treatment period 
and for 5 half-lives of GSK2820151 or at least 28 days (whichever is longer) 
following the last dose of study treatment.
10. Male subjects with female partners of child bearing potential must agree to use one of 
the methods of contraception specified (see Section 7.4). This method must be used 
from the time of the first dose of study medication until at least 16 weeks after the last 
dose of study medication.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Primary malignancy of the central nervous system or malignancies related to 
human immunodeficiency virus (HIV) or solid organ transplant.
2.
More than three prior lines of cytotoxic therapy.
3.
Recent prior therapy, defined as follows:
a.
Any investigational or Food and Drug Administration (FDA)-approved 
anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior 
to the first dose of GSK2820151. Any nitrosoureas or mitomycin C within 
42 days prior to the first dose of GSK2820151. Prior therapy with 
monoclonal antibodies is permitted so long as 14 days have elapsed since 
therapy and all therapy-related toxicity has resolved to Grade 1 or less.  
Note that an investigational drug is defined as a drug without an approved 
oncologic indication
b.
Any radiotherapy within 14 days or major surgery within 28 days prior to 
the first dose of GSK2820151. 
c.
Anti-androgen therapies for prostate cancer, such as bicalutamide, must be 
stopped 4 weeks prior to enrollment. Second-line hormone therapies such 
as enzalutamide, abiraterone, or orteronel should be stopped 2 weeks prior 
to enrolment. Subjects with prostate cancer should remain on luteinizing 
hormone releasing hormone (LHRH) agonists or antagonists. Subjects 
with prostate cancer may also remain on low-dose prednisone or 
prednisolone (up to 10 mg/day) and still be eligible for this study.


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d.
In addition, any therapy-related toxicity must have resolved to Grade 1 or 
less, with the exception of alopecia (acceptable at any Grade) and 
peripheral neuropathy (which must be Grade 2 or less prior to enrollment). 
4.
Therapeutic anticoagulation (e.g., warfarin, heparin) must be discontinued and 
coagulation parameters must be normalized prior to the first dose of 
GSK2820151. Low dose (prophylactic) low molecular weight heparin (LMWH) is 
permitted. In addition, INR must be monitored in accordance with local 
institutional practices.
5.
Current use of a prohibited medication or planned use of any forbidden 
medications during treatment with GSK2820151 (see Section 7.1.2 for the list of 
medications).
6.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study 
procedures, in the opinion of the Investigator.
7.
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for these conditions that have had stable central 
nervous system (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. Subject treated with gamma knife 
therapy can be enrolled 2 weeks post-procedure as long as there are no post-
procedure complications/stable. In addition, subjects treated or currently taking 
enzyme-inducing anticonvulsant (EIAC) are allowed on study.
8.
Cardiac abnormalities as evidenced by any of the following:

History of or current “untreated” clinically significant uncontrolled 
arrhythmias.

Clinically significant conduction abnormalities or arrhythmias

Presence of cardiac pacemaker

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

History of acute coronary syndromes (including unstable angina and 
myocardial infarction), coronary angioplasty, or stenting within the past 3 
months. Subjects with a history of stent placement requiring ongoing 
antithrombotic therapy (e.g., clopidogrel, prasugrel) will not be permitted to 
enroll.
9.
Any of the following electrocardiogram (ECG) findings:

Baseline Corrected QT (Fridericia’s formula) interval (QTcF) ≥450 msec 


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NOTE:  Any clinically significant ECG assessments should be reviewed by the site 
cardiologist prior to study entry.
10. Any of the following liver findings:

ALT >2.5xULN

ALT > 5xULN with liver metastases/tumor infiltration   

Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%). 

Current active liver or biliary disease (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones, liver metastases or otherwise stable 
chronic liver disease per investigator assessment).
NOTE: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric 
varices, persistent jaundice or cirrhosis
11. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody 
test result at screening or within 3 months prior to first dose of study treatment.  
History of known HIV infection.
NOTE: Subjects 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.
12. Any serious known immediate or delayed hypersensitivity reaction(s) to 
GSK2820151 or idiosyncrasy to drugs chemically related to the investigational 
drug.
13. Hemoptysis > 1 teaspoon in 24 hours within the last 28 days. 
14. History of major gastrointestinal bleeding within the last 6 months. 
15. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption such as malabsorption syndrome or major resection of the stomach 
and/or bowels.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory authorities, a minimal set of screen 
failure information is required including Demography, Screen Failure details, Eligibility 
Criteria, and any Serious Adverse Events.
5.4.
Withdrawal/Stopping Criteria
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry, hematologic/non-
hematologic toxicity, QTc prolongation, or left ventricular ejection fraction 
(LVEF)/valvular dysfunction as defined in Section 5.4.1 through Section 5.4.5. After 


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disease progression, subjects may be allowed to continue treatment with study drug if the 
Investigator strongly believes, and the GSK Medical Monitor concurs, that the subject 
could continue to receive benefit (for example in cases of an isolated new lesion, with the 
majority of the disease still under control).
In addition study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanent discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated. 
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in Time 
and Events Tables (see Section 8.1). 
All subjects who permanently discontinue study treatment without disease progression 
will be followed for progression according to the protocol schedule until:

new anti-cancer therapy is initiated

progression

death, or

subject has been followed for 2 years after stopping treatment. 
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy (including radiotherapy) every 6 months until death, 
termination of the study by the sponsor, or until the subject has been followed for 2 years. 
If subjects are unable or unwilling to attend clinic visits during follow-up, contact to 
assess survival may be made via another form of communication (e.g., telephone, email, 
etc.).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:


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
The site must attempt to contact the subject and re-schedule the missed visit as soon 
as possible. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
subject 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.  
See Figure 3 and Figure 4 for liver stopping criteria for subjects without and with liver 
metastases, respectively.


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Figure 3
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.


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Figure 4
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria 
ALT>2.5xULN but ≤5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
5.4.1.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or institutional review board (IRB) approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 4 for full guidance.
5.4.2.
QTc Stopping Criteria
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.


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
QTcF interval ≥ 500 msec OR interval increase from baseline 60 msec: 
GSK2820151 will be discontinued unless the benefits of therapy outweigh 
the risk of rechallenge in the opinion of the investigator, the GSK Medical 
Monitor, as well as the GSK medical governance. In this situation, 
rechallenge may be permitted (see Appendix 7 for rechallenge guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
5.4.3.
LVEF Stopping Criteria
Echocardiography must be performed at Screening, Week 5 Day 1, Week 9 Day 1, and 
every 8 week thereafter and at the post-treatment follow-up visit as outlined in the Time 
and Events Table (Section 8.1).  Subjects who have an asymptomatic, absolute decrease 
of >10% in left ventricular ejection fraction (LVEF) compared with baseline and the 
ejection fraction is below the institution’s lower limit of normal (LLN) should 
temporarily discontinue GSK2820151 and have a repeat evaluation of LVEF within 1 
week.  Echocardiogram (ECHO) should be repeated every 1 to 2 weeks for 4 weeks or 
until LVEF recovery to above institutional LLN and within 10% of baseline.

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline) at any time during the next 4 weeks, after consultation with and 
approval from the GSK Medical Monitor, the subject may be restarted on 
GSK2820151 at a reduced dose.  For such subjects, monitoring of LVEF will be 
performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 16 
weeks and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK2820151 
should be permanently discontinued.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue treatment with GSK2820151.  Ejection fraction should be monitored every 
4 weeks for a total of 16 weeks or until resolution.  If recovery occurs (LVEF 
>institutional LLN and symptom resolution) within 4 weeks, treatment with 
GSK2820151 may be restarted at a reduced dose in consultation with the GSK Medical 
Monitor.


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Copies of all ECHOs and cardiology consultations performed on subjects who experience 
a >10% decrease in LVEF from baseline and whose cardiac ejection fraction is 
<institution’s LLN will be required by GSK for review.  Instructions for submitting 
qualifying ECHOs are provided in the Study Reference Manual (SRM).
5.4.4.
Valvular Toxicity Stopping Criteria
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by 
echocardiogram (ECHO) (Grade 2 mitral/tricuspid/aortic valvular toxicity per NCI-
CTCAE v4) should temporarily discontinue GSK2820151 and have a repeat evaluation 
by ECHO within 1 week.  ECHO should be repeated every 1 to 2 weeks for 4 weeks or 
until valve recovery to baseline.

If the valve recovers to baseline any time during the next 4 weeks after 
consultation with and approval from the GSK Medical Monitor, the subject may 
be restarted on GSK2820151 at a reduced dose(s).  For such subjects, 
monitoring of the valve via ECHO will then be performed 2 and 4 weeks after 
rechallenge, and every 4 weeks thereafter for 16 weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then 
the subject should permanently discontinue GSK2820151.  The valve should 
continue to be monitored via ECHO every 4 weeks for 16 weeks or until 
resolution.
Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with 
symptoms controlled by medical intervention) valvular toxicity must discontinue 
GSK2820151.  Valvular toxicity should continue to be monitored every 4 weeks for 16
weeks or until resolution.  If recovery occurs (return to baseline via imaging AND 
symptom resolution) within 4 weeks, the subject may restart GSK2820151 at a reduced 
dose after consultation with and approval from the GSK Medical Monitor.
ECHO must be performed at baseline and at the final study visit.  Copies of all ECHO(s) 
and cardiology consultations performed on subjects who experience valvular toxicity will 
be required by GSK for review.  Instructions for submitting qualifying ECHOs are 
provided in the Study Reference Manual (SRM).
5.4.5.
Other Stopping Criteria
All subjects will require a chest X-ray and pulmonary function testing at screening, as 
defined in the Time and Events table.  Subjects with clinical concern for pneumonitis will 
be evaluated per institutional practice with input from the GSK medical monitor.  For 
management of suspected pneumonitis, including criteria for dose reduction and 
discontinuation of therapy, see Appendix 7.
To monitor for thrombocytopenia, CBCs will be drawn twice weekly for the first three 
weeks of study, weekly for the next two weeks, and then every other week, as described 
in the Time and Events table.  Subjects who develop Grade 2 or greater 
thrombocytopenia may be monitored more frequently, as clinically indicated.  Please see 
Appendix 7 for suggested management of thrombocytopenia.


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Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics). Deaths, SAEs, and Grade 3/4 adverse events will be carefully evaluated for 
the possibility of causality.
If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, and/or if deaths related to study drug are observed, enrollment may be 
terminated and/or a lower-dose cohort may be opened or expanded. The final 
determination will be made by the Sponsor and investigators.
5.5.
Subject and Study Completion
A completed subject is one who has discontinued study treatment for reasons listed in 
Section 5.4 and completed a post-treatment follow-up visit or has died while receiving 
study treatment.  
A subject will be considered to have completed the study 2 years after the last treatment 
or if the subject dies or is still in follow-up at the time the study is closed or terminated, 
whichever is sooner.  Document the cause of death in the eCRF. A subject will be 
considered to have withdrawn from the study if the subject has not died and is lost to 
follow-up, has withdrawn consent, or at the investigator’s discretion is no longer being 
followed. The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
6.1.
GSK2820151
The term ‘study treatment’ is used throughout the protocol to describe the administration 
of GSK2820151.
Study Treatment
Product name:
GSK2820151
Formulation 
description:
GSK2820151 capsules contain 1 mg, 5 mg, 10 mg, 50 mg, 
or 100 mg of GSK2820151 as free base equivalent
Dosage form:
Capsule
Unit dose 
strength(s)/Dosage 
level(s):
1 mg, 5 mg, 10 mg, 50 mg, and 100 mg
Route of Administration
Oral
Dosing instructions:
The dosing regimen is detailed in Table 7 and is designed to 
permit collection of detailed safety and PK data.

Week 1: Once daily on days 1, 3, 4, and 5

Week 2: Once daily on days 1, 2, 3, 4, 5

Weeks 3 and beyond: Once daily continuously
GSK2820151 is to be administered orally, once daily, at
approximately the same time of day, with no food or 
antacids for 1 h before and 2 h after each dose
Physical description:
1 mg: Pink, Size 1 capsule
5 mg: Green, Size 1 capsule
10 mg: Swedish Orange, Size 1 capsule
50 mg: White Opaque, Size 0 capsule
100 mg: Blue Opaque, Size 0 capsule
6.2.
Treatment Assignment
Subjects will be assigned to receive GSK2820151 in an open-label fashion. There will be 
no placebo arm.
6.3.
Packaging and Labeling
GSK2820151 will be provided to the sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.
6.4.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 


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area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (e.g., receipt, reconciliation, and final disposition records).

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.
Precaution will be taken to avoid direct contact with the study treatment. 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 or GSK study contact.
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK2820151.
6.5.
Compliance with Study Treatment Administration
At each visit, an evaluation of subject compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant subjects into 
compliance. 
Compliance with GSK2820151 will be assessed through querying the subject during the 
site visits and documented in the source documents and CRF. 
A record of the number of GSK2820151 tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
6.6.
Treatment of Study Treatment Overdose
For this study, any dose of GSK2820151 greater than the protocol-specified dose within a 
24 hour time period will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose the investigator (or treating physician) should:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2820151 can no longer be detected systemically (at least 28 days for 
GSK2820151)

Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case
basis)


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
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
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 subject.
6.7.
Treatment after the End of the Study
Post study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) therapy at 
the discretion of the treating physician.  New therapy should be documented on the CRF. 
Every effort should be made to complete the required withdrawal and follow up 
evaluations prior to initiating further therapy or dosing of an investigational agent (see 
Section 8.1 for follow-up assessments and procedures).
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
7.
MEDICATION, LIFESTYLE, AND DIETARY 
RESTRICTIONS
7.1.
Concomitant Medications and Non-Drug Therapies
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the Screening Visit until the end of the study (Final Study Visit). Any 
concomitant medication(s), including herbal preparations, taken during the study will be 
recorded in the eCRF. The minimum requirement is that drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates of 
administration should be recorded. Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter.
7.1.1.
Permitted Medications and Non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with erythropoietin, antibiotics, antiemetics, 
antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance 
with their institutional guidelines. Colony-stimulating factors like filgrastim and 
pegfilgrastim may be used in cycles 2 and beyond as clinically indicated.The only caveat 
is that subjects should not receive those medications listed as prohibited in Section 
7.1.2.1. 


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Bisphosphonates will be allowed if subjects have been on a stable dose for at least three 
months prior to receiving the first dose of GSK2820151.
7.1.2.
Prohibited Medications and Non-Drug Therapies
7.1.2.1.
Prohibited Medications
The use of certain medications and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study medication (and for the 
duration of the study) will not be allowed. If a prohibited medication is required for 
single use (such as for a procedure) while study treatment(s) is held, the GSK Medical 
Monitor can approve such use.
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc.) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that the subject’s PT/PTT values meet entry criteria.
Subjects should not receive other anti-cancer therapy [including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormonal therapy 
(other than leuprolide or other LHRH agonists/antagonists), surgery or tumor 
embolization] while on treatment in this study. Other anti-cancer therapy should not be 
administered unless one of the following occurs: documented disease progression; 
unacceptable or unmanageable toxicity; subject is withdrawn from the study at the 
investigator’s discretion or consent is withdrawn; or no further clinical benefit is 
anticipated which requires permanent discontinuation of study drug. Note, palliative 
radiation and/or surgical intervention may be permitted (for example to address pain 
management) and should be discussed with the GSK medical monitor prior to invention 
to determine appropriate dosing and schedule. 
Co-administration of the following medications are PROHIBITED for 5 half-lives (or at 
least 14 days, whichever is longer) prior to the first dose of study drug until 
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone which is prohibited beginning 6 months prior to Screening 
through discontinuation from the study. [However, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines]). These medications 
include (but are not limited to):


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Table 5
Drugs with a Risk of Torsades de Pointes that are Prohibited
Amiodarone
Dronedarone
Moxifloxacin
Anagrelide
Droperidol
Pentamidine
Azithromycin
Erythromycin
Pimozide
Chloroquine
Escitalopram
Procainamide
Chlorpromazine
Flecainide
Quinidine
Citalopram
Halofantrine
Sevoflurane
Clarithromycin
Haloperidol
Sotalol
Cocaine
Ibutilide
Thioridazine
Disopyramide
Levofloxacin
Dofetilide
Methadone
Data Source: crediblemeds.org revision date 26 September 2014
At time of screening, if a subject is currently receiving any of the listed prohibited 
medications/substances, the medication or substance must be discontinued for a period of 
5 half lives (or at least 14 days, whichever is longer) prior to the administration of the 
first dose of study drug in order for the subject to meet study eligibility.
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (up to a maximum dose of 0.25 mg 
daily) and ondansetron (up to a maximum dose of 8 mg three times daily [TID]) are the 
only allowed drugs in this class.
7.1.2.2.
Prohibited Non-Drug Therapies
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the transition visit through the post-study 
follow-up visit. 
NOTE: Subjects may receive focal palliative radiation treatment during this study.  Any 
proposed radiation therapy must be approved by the investigator and the GSK Medical 
Monitor prior to initiation.
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit.
Herbal products include, but are not limited to: St. John’s Wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto , 
ginseng.
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation including marijuana.
7.1.3.
Cautionary Medications
Co-administration of GSK2820151 and the following medications requires EXTREME 
CAUTION beginning 14 days prior to the first dose of study drug until discontinuation 
from the study, due to an increased risk of Torsades de Pointes. These medications 
include (but are not limited to):


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Table 6
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution
Alfuzosin
Iloperidone
Quetiapine
Apomorphine
Isradipine
Ranolazine
Aripiprazole
Lithium
Rilpivirine
Atazanavir
Mifepristone
Risperidone
Bedaquiline
Mirabegron
Saquinavir
Clozapine
Mirtazapine
Tacrolimus
Dexmedetomidine
Moexipril/HCTZ
Telavancin
Dihydroartemisinin+piperaquine
Nicardipine
Telithromycin
Dolasetron
Norfloxacin
Tetrabenazine
Famotidine
Ofloxacin
Tizanidine
Felbamate
Olanzapine
Tolterodine
Fingolimod
Oxytocin
Vardenafil
Foscarnet
Paliperidone
Venlafaxine
Fosphenytoin
Pasireotide
Ziprasidone
Gemifloxacin
Perflutren lipid microspheres
Granisetron
Promethazine
Data Source: crediblemeds.org revision date 26 September 2014
Note: This list is not exhaustive.  Drugs and/or drug names not available/used in the US have been omitted
After starting cautionary medications such as in Table 6, it is recommended that ECGs 
are implemented daily until the steady state of the new medication is reached. If there are 
ECG abnormalities, implement additional cardiotoxicity monitoring as addressed 
Appendix 7.
There is a low potential for GSK2820151 to induce or inhibit cytochrome P450 (CYP) 
enzymes.  GSK2820151 has been demonstrated to inhibit Breast Cancer Resistance 
Protein (BCRP [IC50=3.6 µM]) and thus may alter the metabolism of medications that are 
substrates of BCRP. These medications include HMG-CoA reductase inhibitors (statins) 
as well as ciprofloxacin and other fluoroquinolones (though not levofloxacin).
Furthermore, GSK2820151 inhibits P-glycoprotein (PgP) at concentrations 100 µM.  
PgP substrates include medications such as statins and digoxin, which may have a narrow 
therapeutic index.  While co-administration of these agents with GSK2820151 is not 
prohibited, they should be used with caution and additional monitoring for adverse 
effects should be utilized.
GSK2820151 may also interact with organic anion transporter 3 (OAT3).  Substrates of 
OAT3 include agents such as Penicillin G, indomethacin, and ciprofloxacin. While co-
administration of these agents with GSK2820151 is not prohibited, they should be used 
with caution and additional monitoring for adverse effects should be utilized.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.


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7.2.
Dietary Restrictions
GSK2820151 will be administered under fasting conditions, with no food or antacids for 
1 h before and 2 h after each dose.  Requirements for fasting before and after dosing may 
be modified based on available pharmacokinetics (PK), pharmacodynamics (PD) and 
safety data. Fasting will consist of avoiding the oral ingestion of calorie-containing 
products; however, ingestion of water is permitted.  Subjects will be instructed to record
the time and date of study treatments and meals in relation to dosing in the supplied GSK 
dosing diary.
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or PD sample during each serial PK 
sampling day (e.g., Days 1 and 18).
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug.
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast 
overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after 
administration of the morning dose.
If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose.
7.3.
Female Subjects
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.


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
Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring subjects understand how to properly use these methods of contraception.
Hormonal means of birth control such as oral contraceptives are NOT acceptable forms 
of birth control given that their efficacy has not been evaluated when given in 
combination with the investigational drugs.
7.4.
Male Subjects
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug.

Condom plus partner use of a highly effective contraceptive such as occlusive cap 
(diaphragm or cervical/vault cap) plus spermicidal agent 
(foam/gel/film/cream/suppository), or intrauterine device. OR

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception
8.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The 
exact timing of each assessment is listed in the Time and Events Table Section 8.1


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8.1.
Time and Events Tables
Table 7
Time and Events
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed consent
Unless otherwise noted, screening 
assessments to be completed 
within 14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of 
day. No food or antacids 1h before 
and 2h after.
X
X
X
X
X
X
X
X
X
Daily
Review subject 
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test/
testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine or 
serum test thereafter. Males: 
complete and free testosterone at 
SCR; free testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X


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Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Vital Signs
SBP, DBP, heart rate, respiratory 
rate, temp
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
continuous from signing of informed consent
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
12-lead ECGs 
(Triplicate)
Triplicate SCR ECGs within 35 
days of first dose. For timing of 
triplicate ECGs on O days, see 
Table 9 and Table 10. Otherwise, 
triplicate ECGs at approximately 
same time of day, and prior to 
dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.
X
O
O
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start 
at least 60 min predose.
X
X
X
X
X
X
Telemetry
Start at least 60 min predose and 
for at least 48 h.
X
X


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Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Efficacy
Cross-sectional 
(Computed 
tomography [CT] 
or magnetic 
resonance 
imaging [MRI]), 
functional 
(Positron 
emission 
tomography 
[PET]), or 
nuclear (bone 
scan) imaging
Appropriate imaging modality 
should be selected by the 
investigator depending on disease 
histology and location. SCR 
assessment within 2 weeks of first 
dose. Target lesions to be 
identified at SCR and followed.  
See Section 14.8.1 for guidelines.
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 9 and Table 10
PK and 
biomarker 
samples
X
X
X
X
X
X
Samples for 
mRNA
X
X
X
X
X
LPS blood 
sample
X
PK Urine 
samples 
X
X
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE


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Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last 
treatment or upon death, whichever is sooner. Document the cause of death. 
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOT=End-of-Treatment; O= For timing of triplicate ECGs on O days, see Table 9 and Table 10; q4W=every 4 weeks; q8W=every 8weeks; SBP=systolic blood 
pressure; SCR=Screening; W=week


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Table 8
Time and Events: Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
W1D1, W1D2: local lab sample 
3X/24h; central lab sample 
1X/24h. Unscheduled collect 2 
samples: 1 for local, 1 for central 
lab
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X1
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Fasting blood glucose and insulin 
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 –Anhydroglucitol
(1,5 AG)
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
Hemoglobin A1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
Thyroid stimulating hormone 
(TSH), free T3, free T4. If TSH is 
abnormal W1D1, monitor TSH, 
free T3 and free T4 going forward
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Pregnancy test, females
Serum pregnancy test within 7 
days of first dose; urine or serum 
test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at 
X
X
X
X
X
X


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NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
EOT
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
SCR; free testosterone thereafter
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
This is collected as part of the 
Predose PK sample and is sent to 
GSK DMPK.
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, 
perform third generation 
immunoassay on same sample to 
confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
1. If any parameter (i.e., platelets) shows a downward trend, additional analyses should be performed within 2-3 days to monitor.


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Table 9
Time and Events: Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
minutes prior to the 
15 min and 30 min 
PK draws and within 
15 minutes prior to 
the other PK draws.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling
X
0-2h
2-24h
mRNA whole blood 
sample
X
X
X
X
X
X
LPS whole blood 
sample
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment (pre-dose and at 15 min, 30 
min, 1 hr, 2 hr, and 4hr) and acute phase protein assessment at pre-dose and at 2,4, 8 and 24 hr post-dose. The frequency of sampling may be changed (likely reduced) based on data 
from the first few subjects assessed. .
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after administration of 
the morning dose.


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Table 10
Time and Events: Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days
W9D1 ±4 days
(if dose has been escalated, 
+4 to +7 days)
EOT
pre 
dose
15 min 
± 5m
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±4h
24h 
±1h
48h 
±1h
pre 
dose
0.5-2h
4 - 8h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min prior to the 15 
min and 30 min PK 
draws and within 15 
minutes prior to the 
other PK draws
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
0-2h
2-24h
mRNA whole blood 
sample
X
X
LPS whole blood 
sample
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for acute phase protein assessment at pre-dose and at 2, 4, 8 
and 24 hr post-dose. The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
On serial PK sampling days, subjects enrolled in the serial PK cohort should fast overnight (i.e., at least 8 hours) and should continue fasting until at least 2 hours after administration of 
the morning dose.


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8.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race, and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5. Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Details concerning 
concomitant medication will be recorded starting from screening through post-study 
follow-up. At a minimum, the drug name, route of administration, dose and frequency of 
dosing, along with start and stop dates should be recorded.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood
count, imaging studies, etc.) and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
8.2.1.
Critical Baseline Assessments
The following are required at baseline:

imaging (e.g., CT of the Chest/Abdomen/Pelvis or MRI of the Abdomen/Pelvis) at 
the discretion of the investigator, based on the subject’s disease. At each post 
baseline assessment, evaluations of the sites of disease identified by these scans are 
required.

cardiology evaluation including echocardiogram, 12-lead ECG and Holter 
monitoring  
8.2.2.
Visit Windows
Screening (baseline to pre-dose): All assessments should be completed within 14 days 
prior to screening. Note for females, pregnancy testing should be performed within 7 
days prior to first dose. Also, clinical labs performed during screening within 72 hours of 
first dose do not need to be repeated on Day 1.
Week 1: Based on subject and clinic schedule, Week 1 Day 3 assessments can be 1 
day. 
Week 2 to Week 4: Based on subject and clinic schedule, assessments can be +3 days. 
Week 4 to Week 9: Clinic visits can be scheduled 3 day.


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Monthly visits after Week 9 until Week 52: After the first disease assessment has been 
completed then the month clinic visits can be scheduled 5 days.
Monthly visits after Week 52: clinic visits can be scheduled 7 days.
Discontinuation visit: should be 14 to 28 days from last dose of study drugs. If a subject 
is unable to return to the clinic due to hospitalization, site staffs are encouraged to 
telephone the subject for assessment of adverse events.
8.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 8.1). Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring.
Note that this section details the procedures used to evaluate for safety and toxicity for 
this study. For management and recording of any suspected Adverse Events, refer to 
Section 9, Appendix 6 and Appendix 7.
8.3.1.
Physical Exams
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological system, lungs, cardiovascular system, abdomen (liver 
and spleen), lymph nodes and extremities. Height and weight will also be measured and 
recorded.
A brief physical examination will include 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
8.3.2.
Performance Status
The performance status will be assessed using the ECOG scale (Appendix 2) as specified 
in the Time and Events Table (Section 8.1).
8.3.3.
Vital Signs

Vital sign measurements to be measured in semi-supine position after 5 minutes rest 
will include temperature, systolic and diastolic blood pressure, pulse rate, and 
respiratory rate. 

In case of an abnormal first reading, three readings of blood pressure and pulse 
rate should be taken, the first reading should be rejected and the second and 
third averaged to give the measurement to be recorded in the CRF. 

Vital signs will be measured more frequently if warranted by clinical condition of the 
subject.  On days where vital signs are measured multiple times, temperature does 
not need to be repeated unless clinically indicated. 


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Refer to the Study Reference Manual (SRM) for details regarding measurement of vital 
signs.
8.3.4.
Echocardiogram
For all subjects, trans-thoracic echocardiograms (TTEs) will be performed at screening 
and at assessment times as outlined in Table 7. TTEs should be evaluated and compared 
to baseline by the same reader. Copies of all TTE scans performed on subjects who 
experience an absolute decrease >10% in left ventricular ejection fraction (LVEF) 
compared to baseline concurrent with LVEF < LLN will be required by GSK for review. 
TTE data may be transferred and reviewed by an independent cardiologist. Instructions 
for submission of qualifying TTE scans are provided in the SRM.
8.3.5.
Safety Electrocardiograms (ECG)
Safety ECGs will be performed at the time points specified in Table 7 using a standard 
12-lead ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals. Details will be provided in the SRM.
8.3.5.1.
Routine ECG Monitoring
Triplicate 12-lead ECGs should be performed at Screening and at all other time points, 
including on Serial Pharmacokinetic sampling days.
Standard 12-lead ECGs (Safety ECGs) will be performed as part of the real-time 
assessment of subjects and may not be included in the primary QT analysis. Safety ECGs 
should be reviewed by the investigator on an ongoing basis for safety purposes. The 
dosing for each new week in the first cycle should not begin until the safety ECG has 
been reviewed and no significant abnormalities have been detected
ECG data may be transferred and reviewed by an independent central reviewer. 
Instructions for submission of ECGs are provided in the SRM. 
8.3.5.2.
Evaluation of QTc
All ECGs must include QTcF measurements. For the definition of QTcF and 
management strategies for QTcF 500 msec, see Section 5.4.2 and Appendix 7.
8.3.6.
Telemetry
In addition to Safety ECG assessments, monitoring for potential adverse arrhythmias will 
be conducted utilizing continuous inpatient telemetry monitoring as outlined in Table 7
for at least 48 hours from the start of the first dose. If clinically indicated, telemetry may 
be extended past 48 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.


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8.3.7.
Holter Monitoring
In addition to the Safety ECGs performed during the study, continuous 12-lead ECGs 
(obtained via a Holter monitor) will be acquired while subjects are at the site. Dual snap 
electrodes will be utilized to enable simultaneous collection of Holter and safety ECG 
data.
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 Time and Events and should be 
obtained prior to phlebotomy and vital sign time points.
Collection of critical ECG data shortly after meals or during sleep should be avoided 
since QT prolongation occurs at these times and a change in the QT-RR relationship 
occurs during sleep. Meals should be administered according to the guidelines provided 
in Section 7.2 and in the SRM as meal and snack times will need to be adjusted 
accordingly on dosing and ECG sampling days. 
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory. Around each of the designated time points, 3 ECGs will be 
selected approximately 2 minutes apart. In order to increase consistency of ECG 
interpretation, a limited number of central ECG over-readers will be used throughout the 
study. All ECGs for a given subject will be over-read by the same reader from the central 
validated ECG laboratory. The central reader will be blinded to subject identifiers (e.g., 
subject number, age, and sex), treatment assignment, and study day when Holter ECGs 
were collected. The final intervals and morphology analyses entered into the database 
will be those generated by the central ECG laboratory. 
Baseline QT/QTcF values will be determined on Study Day -1 using time matched ECGs 
obtained from the Holter monitor at approximately the same time points as planned for: 
Week 1 Day 1 to 2; Week 2 Day 3 to 4, Week 3 Day 5 to 6 and Week 4 Day 7 to Week 5 
Day 1. The mean from triplicate ECGs will be evaluated at each time point. For a given 
time point, the mean QTcF from 3 separate beats should be analyzed on each ECG. 
Analysis of Lead II will be conducted with V5 as back-up and one of the remaining 
precordial leads as an alternative when T waves are not well defined in Leads II or V5. 
QTcF for an individual beat will be calculated from the preceding RR interval since using 
the average heart rate (RR) intervals from the ECG could result in inaccurate QTcF 
calculations due to beat to beat variations in the RR intervals. 
QT values should not be reported when the rhythm is other than sinus rhythm (sinus 
rhythm with normal respiratory variation is acceptable), and in intraventricular 
conduction delays (IVCD, QRS >120 msec). The other ECG information (including the 
rhythm and presence of IVCD) should be reported. The choice of the 3 consecutive beats 
to be measured should avoid ectopic beats and the first beat after an ectopic beat. If 
IVCD occur, these should be reported. 


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8.3.8.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 11, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre 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 subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All protocol required safety laboratory assessments, as defined in Table 11, are 
performed at the institution’s local laboratory. All non-safety assessments (e.g.,
pharmacokinetic samples and translational samples) will be assessed by a central 
laboratory. Please refer to the SRM for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
Some laboratory assessments (e.g., testosterone) can vary throughout the day. It is 
recommended but not mandated that laboratory assessments are collected at 
approximately the same time on each clinic day. If abnormal testosterone levels are 
observed, repeat measurements should occur at the approximate baseline timing to ensure 
this is a trend and not a single outlying event.
Table 11
Clinical Laboratory Tests
Serum Chemistry
Blood urea nitrogen
Sodium
Magnesium 
Potassium
aspartate aminotransferase
Total and direct bilirubin
Uric acid
Creatinine
Chloride
alanine aminotransferase
Albumin
Fasting Glucose
Total carbon dioxide
alkaline phosphatase
Total protein
Creatine phosphokinase
Ionized calcium
gamma-glutamyltransferase
Total calcium
Hematology
Platelet count
Automated White Blood Cell 
Red blood cell count
Differential:
White blood cell count (absolute)
Neutrophils (absolute)
Hemoglobin
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
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 Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, low density lipoprotein [LDL], high density lipoprotein [HDL])
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
Cytokine samples
Subjects should be instructed to fast (no food and only water allowed) for 10 hours prior 
to any fasting laboratory assessments (e.g., fasting glucose, fasting lipid panel, etc.). 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 28 days after the last dose of study treatment 
should be recorded on the eCRF as AEs. In addition, these clinically significant abnormal 
laboratory results should be followed until the abnormality resolves or is determined to 
be stable. If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
8.3.9.
Troponin Measurement
Two samples for troponin will be collected at each time-point as outlined in Table 8. 
Troponin T will be assessed at a central laboratory as a means of consistent evaluation 
across all subjects. A second sample will be assessed at a local laboratory for purposes of 
subject management. Whenever possible, troponin T will be assayed by the local 
laboratory. However, either troponin I or troponin T may be assessed at a local 
laboratory. The same local laboratory test (troponin I or troponin T) should be used 
consistently for an individual subject throughout the study. 
8.3.10.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until 14 days following the last dose of 
GSK2820151.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
7.


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8.4.
Pharmacokinetics
PK analyses will be the responsibility of GSK Clinical Pharmacokinetics Modeling & 
Simulation (CPMS). Plasma GSK2820151 concentration-time data will be analyzed by 
non-compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacology parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state.
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from the ratio of AUC(0-) in Week 3 Day 4 / AUC(0-) in 
Week 1 Day 1. The ratio of AUC(0-) on Week 3 Day 4/ Week 1 Day 1 AUC(0-∞) will 
be calculated to assess time invariance. GSK2820151 concentrations will be determined 
in urine samples to determine urinary recovery of unchanged drug and renal clearance.
Plasma concentration-time data will be listed by dose and summarized using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum and maximum) by 
planned relative assessment time. Mean and/ or median values will be plotted over time.
Individual plasma and urinary (if available) PK 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 will be reported.
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 evaluated, dose 
proportionality of AUC and Cmax for GSK2820151 will be assessed using the power 
model (details will be provided in the Reporting and Analysis Plan [RAP]).
Plasma concentration-time data will be further analyzed using appropriate model(s) to 
determine population PK parameters (absorption rate (Ka), apparent clearance (CL/F)
and volume of distribution (V/F)) and summary exposure measures (Cmax, AUC and 
Average observed concentration (Cav) = AUC/) and identify important covariates (e.g., 
age, weight, or disease related covariates).
8.4.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for PK analysis of GSK2820151 will be collected at the time points 
indicated in the Time and Events Schedule (Table 9 and Table 10). 
Each PK sample should be collected as close as possible to the planned time relative to 
the dose (i.e., time zero) administered to the subject on PK days. The actual date and time 
of each blood sample collection will be recorded along with the date and time of the prior 
dose administration. The timing of PK samples may be altered and/or PK samples may be 
obtained at additional time points to ensure thorough PK monitoring. This will not 
require a protocol amendment.


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Details on PK blood sample collection, processing, storage, and shipping procedures are 
provided in the SRM.
8.4.2.
Urine Sample Collection for Pharmacokinetics
Urine samples for quantitative analysis of GSK2820151 will be collected over 24 hours 
in two samples (sample collected 0-2 hr and a second sample collected 2-24 hr) 
immediately following dosing on Week 1 Day 1 and Week 3 Day 4
The actual date and time of each urine sample collection will be recorded.
Details of urine sample collection, processing, storage, and shipping procedures are 
provided in the SRM.
8.4.3.
Pharmacokinetic Sample Analysis
Plasma sample analysis will be performed under the management of Bioanalytical 
Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics (DMPK), Platform 
Technology and Science (PTS), GlaxoSmithKline. Concentrations of GSK2820151 will 
be determined in plasma samples using the currently approved bioanalytical 
methodology. Raw data will be stored in the Good Laboratory Practices (GLP) Archives, 
GlaxoSmithKline.
Once the plasma samples have been analyzed for GSK2820151, any remaining plasma 
may be analyzed for other compound-related metabolites and the results reported under a 
separate GSK PTS-DMPK protocol.
Urine sample analysis may be performed under the management of Bioanalytical Science 
and Toxicokinetics, DMPK, PTS, GlaxoSmithKline. Concentrations of GSK2820151 
may be determined in urine samples using an investigative analytical methodology. Urine 
raw data will be stored in the GLP Archives, GlaxoSmithKline.
The urine samples may be analyzed for compound-related metabolites and the results will 
be reported under a separate DMPK protocol.
8.5.
Pharmacokinetic/Pharmacodynamic Analysis
Observed or predicted concentrations and/or exposures will be combined with safety, 
efficacy, and/or PD measures of interest to examine potential exposure response 
relationships.
The relationship between QTcF and concentration expressed as Cmax, Cav, and 
instantaneous time-matched concentration will be plotted graphically. A linear mixed 
effects analysis of the slope of the QTcF-concentration responses adjusting for baseline 
will be evaluated as a means of estimating QTcF effect in lieu of a thorough QT study.
Other quantitative safety parameters and biomarkers of interest including changes in 
troponin levels will be plotted graphically against summary exposure measures (e.g., 
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effect models will be fitted to the data to estimate PK/PD parameters of interest; slope, 
baseline (E0), exposure producing 50% of the maximum effect (EC50), and maximum 
effect (Emax).
Overall efficacy data and overall tumor burden may be described using ordered 
categorical model and continuous models with summary exposure parameters (e.g., 
Cmax, C, and Cav) as covariates derived from the population PK analysis. Further 
model details will be provided in the RAP.
8.6.
Efficacy
The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or a partial response (PR) at any time as per RECIST 1.1. 

Lesion assessment method and timing, evaluation of disease, disease progression and 
response criteria will be conducted according to Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] as outlined below and in Appendix 
8. 

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 2 weeks prior to the first 
dose of GSK2820151, then every 8 weeks thereafter, and at the final study visit.  See 
the Time and Events Table (Section 8.1) for the schedule of assessments of anti-
cancer activity. 

For subjects with CRPC without measurable disease by RECIST criteria, serial 
prostate specific antigen (PSA) measurements will be drawn at the disease 
assessment time points defined in the Time and Events Table (Section 8.1).  
Response will be defined by the number of subjects who achieve a 50% decrement in 
their baseline PSA (PSA50).

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 more than 8 weeks prior to the 
subject’s withdrawal from study and progressive disease has not been documented, a 
disease assessment should be obtained at the time of withdrawal from study.

Subjects whose disease responds (either complete response [CR] or partial response 
[PR]) should have a confirmatory disease assessment performed 4 weeks after the 
date of assessment during which the response was 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.


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8.7.
Translational Research
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Further details on the translational research analyses will be addressed in the RAP.
8.7.1.
Biologic Effects of GSK2820151
Exploratory analysis may be performed to examine potential relationships between drug 
exposure and markers of BET target inhibition (e.g., cytokines, acute phase proteins, 
relevant transcripts, and/or proteins) or between anticancer activity and potential markers 
of sensitivity (e.g., genetic alterations).
8.7.2.
RNA Expression Research
Related BET inhibitors have been shown to modulate the expression of a number of 
different genes in unstimulated whole blood between 1 h and 6 h. The mRNA levels of 
31 such genes form a ‘signature’ panel which will also be used as a biomarker of 
engagement of pharmacology and will be measured using mRNA isolated from whole 
blood. The modulation of a number of these genes will also be measured as changes in 
systemic proteins as well as in the analysis of the ex vivo assay blood samples (e.g.,
CCL2 and IL-8) thus relating mRNA and protein expression with drug concentration.
Other translational research studies, such as transcriptomics profiling, will also be 
performed using whole blood mRNA from selected patients.
8.7.3.
Effects of GSK2820151 on Systemic Markers of Inflammation
GSK2820151 has been shown to inhibit LPS-induced IL-6 across different human cell 
populations and species. The action of the compound is through inhibition of the 
assembly of transcriptional complexes required to express the protein. Pre-clinical studies 
demonstrate that blood concentration of drug correlates to the degree of inhibition of LPS 
induced IL-6 in ex vivo whole blood samples. Therefore, this biomarker will be used as 
an indication of pharmacology and will be aligned with PK sampling. Since inhibition of 
BET family proteins is known to inhibit a range of pro-inflammatory mediators and acute 
phase proteins, a number of additional proteins (46) will also be measured from these ex 
vivo samples.
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, CCL2, MIP1-α, IL-8) will also be measured in plasma samples taken during PK 
sampling and at the time of any Grade 2 fever or symptoms indicative of a potential 
cytokine storm. This will assess systemic inflammatory response in the subject using 
biomarkers such as pro-inflammatory cytokines and acute phase proteins and correlate 
the systemic response to drug with that in stimulated and unstimulated blood. These 
biomarkers are expected to change over days rather than hours, based on the plasma half 
lives and pre-clinical data, such that sampling will also be performed after repeat dosing.


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8.8.
Pharmacogenetic Analysis
An important objective of the clinical study is pharmacogenetic (PGx) research. 
Participation in PGx is optional but all subjects who are eligible for the clinical study will 
be given the opportunity to participate. Subjects may decline participation without effect 
on their medical care or care during the clinical study. A separate consent signature is 
required for PGx research.
Subjects who provide consent will have a blood sample taken for analysis. The 
presence/absence of genetic variations in host DNA from blood will be analyzed to 
determine their relationship with response (safety, tolerability, pharmacokinetics, and 
efficacy) to treatment with GSK2820151. 
Information regarding pharmacogenetic research is included in Appendix 4. In approving 
the clinical protocol, the independent ethics committee/institutional review board 
(IEC/IRB) (and, where required, the applicable regulatory agency) also approve the PGx 
assessments unless otherwise indicated. Where permitted by regulatory authorities, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated. 
When PGx assessments are not approved, then the approval for the rest of the study will 
clearly indicate this and therefore, PGx assessments will not be conducted.
Information regarding genetic research is included in Appendix 4.
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DATA COLLECTION, REPORTING, AND FOLLOW-UP
9.1.
Definition of AE/SAE
The definitions of an AE or SAE can be found in Appendix 6. The severity of adverse 
events will be graded utilizing the NCI-CTCAE v4. Additional details regarding 
management of specific AEs or SAEs are described in Appendix 7.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
9.1.1.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 6 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities  (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
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The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.1.2.
Other Sentinel Events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE.
9.1.3.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition, are not to be reported as AEs or SAEs.
NOTE:If either of the following conditions apply, then the event must be recorded and 
reported as an SAE (instead of a DRE): 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
9.2.
Time period and Frequency for collecting AE and SAE 
information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 9.2.2), at the timepoints specified in the Time and Events 
Table (Section 8.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

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 subject consents to participate in the study up to and 
including any follow-up contact. 


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
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5
9.2.1.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
9.2.2.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
9.2.3.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate, according to local requirements.
10.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy. Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
11.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
11.1.
Hypotheses
The primary endpoints of this study are safety and tolerability; the MTD and RP2D will 
also be determined. No formal statistical hypotheses will be tested. The primary focus 
will be on determining the recommended dose for further exploration, the safety profile, 
and the PK of GSK2820151 in subjects with advanced cancer. Analyses will be 
descriptive and exploratory.
11.2.
Continual Reassessment Method
11.2.1.
Description of Continual Reassessment Method
After all subjects in each cohort have completed the DLT observation period, a dosing 
recommendation for the next cohort will be made following an N-CRM analysis.  All
available data, including safety and PK data from current and prior cohorts will be 
reviewed at the dose escalation meeting. Although the N-CRM will be used to 
recommend the next dosing level, clinical judgment by the Medical Monitor in 
consultation with the study team and Investigators, and taking into account PK and PD 
data, will determine dose escalation as deemed appropriate. 
The N-CRM design makes use of a Bayesian logistic regression model relating dose and 
toxicity and is expected to locate the MTD efficiently while minimizing the number of 
subjects exposed to pharmacologically inactive or unsafe dose levels. 
The MTD will be defined as that dose that has the highest posterior probability of having 
a DLT rate within the Target Toxicity range and for which the posterior probability that 


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the DLT rate lies within the Excessive Toxicity or the Unacceptable Toxicity range is less 
than 25%.
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 
0% - 16%

A dose falls in the Target Toxicity range if the probability of a DLT at the dose 
is 16% - 33%

A dose falls in the Excessive Toxicity range if the probability of a DLT at the 
dose is 33% - 60%

A dose falls in the Unacceptable Toxicity range if the probability of a DLT at 
the dose is 60% - 100%
An updated posterior estimate of the dose-toxicity curve will also be provided at the time 
of the dose-escalation meeting.
11.2.1.1.
Implementation of N-CRM
The N-CRM model implementation will be performed using the Fixed and Adaptive 
Clinical Trial Simulator (FACTS) (Version 2.3 or higher) software from Tessella.
11.2.1.2.
Bayesian Prior
The N-CRM methodology requires that a Bayesian prior distribution for the dose-toxicity 
curve be pre-specified.  The Bayesian prior used for this design was determined using the 
quantile method.  For each dose, the most likely (median) presumed probability of DLT 
was specified, along with a 95% credible interval – an interval within which the team is 
95% a priori certain the probability of a DLT lies.  The 95% credible intervals are 
intentionally wide due to limited information about the toxicity profile of GSK2820151 
in humans and to allow the accumulating data to have more influence on dose 
recommendations than the prior.  Further details regarding the specific N-CRM model 
will be provided in the Reporting and Analysis Plan (RAP) and will be determined before 
the first dose-escalation meeting after consideration of all information gathered before 
then.
11.3.
Sample Size Considerations
11.3.1.
Sample Size Assumptions
The total number of subjects to be enrolled into this study will depend on the number of 
subjects needed to characterize individual dose cohorts for the determination of the 
maximum tolerated dose of GSK2820151; the final sample size is not driven by statistical 
considerations. However, it is anticipated that approximately 30 to 50 subjects will be 
enrolled with a maximum of 80 subjects.


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11.3.2.
Sample Size Re-estimation or Adjustment
No sample size re-estimation will be performed.
11.4.
Data Analysis Considerations
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
11.4.1.
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2820151. Safety and anti-cancer activity will be evaluated based on this analysis 
population.
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.
Additional analysis populations may be defined in the RAP.
11.4.2.
Interim Analysis
Interim analyses will be performed to determine if a dose-escalation is appropriate.  The 
primary driver for the dose-escalation decisions will be safety and tolerability of each 
dose cohort.
11.5.
Key Elements of Analysis Plan
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
All data will be summarized and listed.
11.5.1.
Primary Analyses
As the primary endpoints of this study are safety and tolerability, the primary analyses 
will be descriptive in nature. Safety endpoints are described in Section 5.4.


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The All Treated Population will consist of all subjects receiving at least one dose of study 
drug and will be used for the analysis of safety and efficacy data. Complete details of the 
analyses will be provided in the RAP.
11.5.2.
Secondary Analyses
11.5.2.1.
Pharmacokinetic Analyses
11.5.2.1.1. Pharmacokinetic Parameters
PK analyses will be the responsibility of CPMS, GSK. Plasma GSK2820151 
concentration-time data from dose escalation will be analyzed by non-compartmental 
methods with WinNonlin.
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined. The ratio of AUC(0-) on Week 3 Day 4 AUC(0-) / 
Week 1 Day 1 AUC(0-) will be calculated to assess time invariance. GSK2820151 
concentrations will be determined in urine samples to determine urinary recovery of 
unchanged drug and renal clearance.
11.5.2.1.2. Statistical analysis of pharmacokinetic parameters
Statistical analyses of the PK parameters data will be conducted by Clinical Statistics, 
GSK. Plasma concentration-time data will be listed by dose, age group, 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 and urinary (if available) pharmacokinetic parameter 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 will be reported. 
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 GSK2820151 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 


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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.
11.5.2.2.
Efficacy Analysis
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, PR, or stable disease [SD]) prior to the 
initiation of therapy.  Progressive disease (PD) will also be defined per RECIST 1.1 
criteria. Otherwise, if the subject does not have a documented date of events, PFS will be 
censored at the date of the last adequate assessment. Further details on rules for censoring 
will be provided in the RAP.  PFS will be summarized using Kaplan-Meier methods.
The overall response rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or a partial response (PR) at any time as per RECIST 1.1 criteria. 
Subjects with unknown or missing response will be treated as non-responders, i.e. these 
subjects will be included in the denominator when calculating the percentage. Exact 
methods for calculated confidence intervals will be given in the RAP.
The number and types of responses, as outlined in RECIST 1.1, will be listed and 
summarized, as appropriate.
11.5.2.3.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP.
11.5.2.4.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy
11.5.2.5.
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 v4.
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, SAEs, and AEs leading to discontinuation of study treatment.  AEs, if listed 
in the NCI-CTCAE v 4, will be summarized by the maximum grade.  Otherwise, the AEs 
will be summarized by maximum intensity.
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by dose 
cohort.


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AEs of special interest will be outlined in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
11.5.2.6.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.  Laboratory test results outside the reference 
ranges that do not have an associated NCI-CTCAE criterion will be summarized using 
proportions.  Further details will be provided in the RAP.
11.5.3.
Other Analyses
Exploratory analyses may be performed to examine potential relationships between 
anticancer activity and changes in markers of BET target inhibition or tumor biology 
(e.g., cytokines, acute phase proteins, relevant transcripts, and/or proteins) or between 
anticancer activity and potential markers of sensitivity.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Data for vital signs, electrocardiograms (ECGs), and echocardiograms (ECHOs) 
will be summarized based on predetermined criteria identified to be of potential clinical 
concern. Further details on the translational research analyses will be addressed in the 
RAP.
12.
STUDY GOVERNANCE CONSIDERATIONS
12.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
12.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable)


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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

Signed informed consent must be obtained for each subject prior to participation in 
the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated.
12.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
12.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s), and inspector(s) direct access to all 


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relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
12.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
12.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.


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
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
12.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, 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 subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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13.
REFERENCES
Asangani IA, Dommeti VL, Wang X, Malik R, et al. Therapeutic targeting of BET 
bromodomain proteins in castration-resistant prostate cancer. Nature. 2014; 510(7504): 
278-82.
Bauer DE, Mitchell CM, Strait KM, Lathan CS, et al.  Clinicopathologic Features and 
Long-term Outcomes of NUT Midline Carcinoma.  Clin CanRes. 2012; 18:5773-9.
Chaidos A, Caputo V, Gouvedenou K, Liu B, Liu B, et.al. Potent antimyeloma activity of 
the novel bromodomain inhibitors I-BET151 and I-BET762. Blood 2014; 123(5): 697-
705.
Delmore JE, Issa GC, Lemieux ME, Ral PB, et al. BET bromodomain inhibition as a 
therapeutic strategy to target c-Myc. Cell 2011; 146: 904-917.
Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 
binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 
2003;100(15): 8758-63.
Dey A, Nishiyama A, Karpova T, McNally J, Ozato K. Brd4 marks select genes on 
mitotic chromatin and directs postmitotic transcription. Mol Biol Cell. 2009; 20(23): 
4899-909.
Dhalluin C, Carlson JE, Zeng L, He C, et. al. Structure and ligand of a histone 
acetyltransferase bromodomain. Nature 1999; 399: 491–496.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation 
criteria in solid tumors: Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 
45: 228-247.
Fiskus W, Sharma S, Qi J, Shah B, et al. BET Protein Antagonist JQ1 Is Synergistically 
Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-
TKI in AML Cells Expressing FLT-ITD. Mol Cancer Ther. 2014; 13(10); 2315–27.
French C, Ramirez C, Kolmakova J, Hickman TT, et al. BRD-NUT oncoproteins: a 
family of closely related nuclear proteins that block epithelial differentiation and 
maintain the growth of carcinoma cells. Oncogene, 2008; 27: 2237-42.
GlaxoSmithKline Document Number 2014N208278_00; GSK2820151 Investigator's 
Brochure. Version 1. 
Hargreaves DC, Horng T, Medzhitov R. Control of inducible gene expression by signal-
dependent transcriptional elongation. Cell. 2009; 138(1): 129-45.
Itzen F, Greifenberg AK, Bösken CA, Geyer M. Brd4 activates P-TEFb for RNA 
polymerase II CTD phosphorylation. Nucleic Acids Res. 2014; 42(12): 7577-90.


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James LP. 2009. Pharmacokinetics of Acetaminophen - Protein Adducts ... Liver Failure. 
Drug Metab Disp, 37: 1779-1784.
Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain 
protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA 
polymerase II-dependent transcription. Mol Cell. 2005; 19(4): 523-34.
Mertz J, Conery AR, Bryant BM, Sandy P, et al.  Targeting MYC dependence in cancer 
by inhibiting BET bromodomains.  Proc Nat Acad Sci. 2011; 108: 16669-74.
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4.03, 
DCTD, NCI, NIH, DHHS, June 14, 2010.
Neuenschwander B, Branson M, and Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2008 27: 2420–39.
Nicodeme E, Jeffrey K, Schaefer U, Beinke S, et al. Suppression of inflammation by a 
synthetic histone mimic. Nature 2010; 478: 1119-1123.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group, 1982.
Patel MC, Debrosse M, Smith M, Dey A, et.al. BRD4 coordinates recruitment of pause 
release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription 
elongation of interferon-stimulated genes. Mol Cell Biol. 2013; 33(12): 2497-507.
Trabucco SE, Gerstein RM, Evens AM, Bradner JE, et al. Inhibition of bromodomain 
proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 
2014 Jul 9. pii: clincanres.3346.2013. [Epub ahead of print]
Wyce A, Ganji G, Smitheman KN, Chung CW, et al. BET inhibition silences expression 
of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS 
One 2013;8:e72967.
Yan J, Diaz J, Jiao J, Wang R, You J. Perturbation of BRD4 function by BRD4-NUT 
abrogates cellular differentiation in NUT midline carcinoma. J Biol Chem. 2011; 
286:27663-27675.


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14.
APPENDICES
14.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
C
Degrees Celsius
1,5 AG
1,5 –Anhydroglucitol
A1c
Glycosylated hemoglobin
ACLS
Advanced Cardiac Life Support
AE(s)
Adverse eEvent(s)
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the curve
AUC(0-∞)
Area under the curve from zero to infinity
AUC(0-24)
Area under the curve from zero to 24 hours
AUC(0-)
Area under the plasma concentration-time curve
BAL
Bronchoalveolar lavage
BCRP
Breast Cancer Resistance Protein
BET
Bromodomain & extra-terminal
BID
Twice daily
BPM
Beats per minute
BRD
Bromodomain
CBC
Complete blood count
CCL2
Chemokine (C-C motif) ligand 2
CK
Creatine kinase
CK-MB
Creatine kinase, MB isoenzyme
Cmin
Minimum observed plasma concentration
Cmax
Maximum observed plasma concentration
COPD
Chronic obstructive pulmonary disease
CPMS
Clinical Pharmacokinetics Modeling & Simulation
CR
Complete response
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
Cτ
Trough concentration
CV
Cardiovascular
CV
Coefficient of variance
DHEA
Dehydroepiandrosterone
dl
Deciliter(s)
DLT
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
EC50
Exposure producing 50% of Emax
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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eCRF
Electronic case report form
EIAC
Enzyme-inducing anticonvulsant
Emax
Maximum effect
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram(s)
GCP
Good clinical practice
GI
Gastrointestinal
gIC50
Growth inhibitory concentration 50
GLP
Good laboratory practices
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HDL
High-density lipoprotein
hERG
Human ether-à-go-go-related gene
HIV
Human immunodeficiency virus
HNSCT
Highest non-severely toxic dose
hr
Hour(s)
HRT
Hormone replacement therapy
IC50
half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC/IRB
Independent ethics committee/institutional review board
IL-6
Interleukin 6
IL-8
Interleukin 8
INR
International normalized ratio
IRB
Institutional review board
IUD/IUS
Intrauterine device/intrauterine system
IV
Intravenous
IVCD
Intraventricular conductance delay
kg
Kilogram(s)
l
Liter(s)
LDL
Low-density lipoprotein
LHRH
Luteinizing hormone releasing hormone
LLN
Lower limit of normal
LMWH
Low molecular weight heparin
LPS
Lipopolysaccharide
LVEF
Left ventricular ejection fraction
m2
Meters squared
MABEL
Minimum anticipated biological effect level
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
MI
Myocardial infarction
min
Minute(s)
MIP1-α
Macrophage inflammatory protein 1 alpha


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mIU
Milli International Units
ml
Milliliter(s)
M
Micromolar
mm3
Cubic millimeters
MM
Multiple myeloma
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSDS
Material safety data sheet
msec
Millisecond(s)
MTD
Maximum tolerated dose
MUGA
Multigated acquisition scan
MYC
V-myc avian myelocytomatosis viral oncogene homolog
NCI-CTCAE
National Cancer Institute- Common Terminology Criteria 
for Adverse Events
N-CRM
Neuenschwander - Continuous Reassessment Method
ng
Nanogram(s)
NMC
NUT midline carcinoma
NOAEL
No observed adverse effect level
NOD/SCID
Non-obese diabetic/severe combined immunodeficiency
NT-proBNP
N-terminal pro–B-Type natriuretic peptide
NUT
Nuclear protein in testes
NYHA
New York Heart Association
ORR
Objective response rate
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PET
Positron emission tomography
PFS
Progression-free survival
pg
Picogram(s)
PgP
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetic
pmol
Picomole(s)
PR
Partial response
PSA
Prostate specific antigen
PSA50
50% decrement in baseline PSA
PT
Prothrombin time
p-TEFB
Positive transcription elongation factor complex
PTS
Platform Technology & Science
PTT
Partial thromboplastin time
QTc
Corrected QT interval
QTcF
Corrected QT (Fridericia’s formula)
RAP
Reporting and Analysis Plan
RECIST
Response criteria in solid tumors
REML
Restricted maximum likelihood
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 dose


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SAE(s)
Serious adverse event(s)
SD
Standard deviation
SD
Stable disease
SPM
Study Procedures Manual
SRM
Study Reference Manual
SRT
Safety review team
STD10
Severely toxic dose in 10% of the animals
t½
Half-life
tmax
Time to Cmax
TSH
Thyroid Stimulating Hormone
TSS
Transcription start site
TTE
Transthoracic echocardiogram
ULN
Upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
WinNonlin


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14.2.
Appendix 2: ECOG Performance Status
The performance status assessment is based on the ECOG scale [Oken, 1982]
0 = Fully active, able to carry on all pre-disease performance without restriction.
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light house work, office work).
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5 = Dead.


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14.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and to 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/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
Subject 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 subjects 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 treatment 

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 subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 4) 

If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and may 
continue subject 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 subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor subjects 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 2 days 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 subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy CRF forms.


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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 treatment for that subject 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 subjects 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 subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’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/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Subject 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
Subject 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 subject 
safety. 

Subject can continue study treatment  

Subject 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 subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
For subjects 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 
subjects 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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14.4.
Appendix 4: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available.
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
Background Information on Drug Restart/Rechallenge
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment) [Hunt, 2010]
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.


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Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available.  

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.   

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 9.
2. Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 


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HLA genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 9.
References:

Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.

Hunt CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.

Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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14.5.
Appendix 5: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and response to medicine, including GSK2820151 or any concomitant 
medicines.
US Food and Drug Administration states that an in vitro companion diagnostic device 
(IVD) could be essential for the safe and effective use of a corresponding therapeutic 
product to:

Identify patients who are most likely to benefit from a particular therapeutic 
product;

Identify patients likely to be at increased risk for serious adverse reactions as a 
result of treatment with a particular therapeutic product;

Monitor response to treatment for the purpose of adjusting treatment (e.g. 
schedule, dose, discontinuation) to achieve improved safety or effectiveness
Global regulatory requirements for IVD companion diagnostic tests are evolving.  If a 
DNA-based IVD companion diagnostic device might be needed to identify patients who 
are appropriate for the GSK medicinal product(s) under investigation in this protocol, 
then GSK should collect and retain DNA samples from subjects who carry the genetic 
variant of interest as well as DNA samples from subjects who do not carry the genetic 
variants of interest to validate the performance of the companion diagnostic.  Any IVD 
companion diagnostic research objectives should be described in subject informed 
consent forms.
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in the RAP prior to initiation of 
the analysis. Planned analyses and results of genetic investigations will be reported either 
as part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
Blood sample is collected at the baseline visit, after the subject has been randomized 
and provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study. This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner. GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form. Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study. Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 


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


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14.6.
Appendix 6: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
14.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This 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. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


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Events NOT meeting definition of an AE include:

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 subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
14.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
e.
Results in death
f.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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.
g.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs.
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.


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
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
h.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
i.
Is a congenital anomaly/birth defect
j.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
k.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.
Refer to Appendix 2 for the required liver chemistry follow-up instructions


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14.6.3.
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
14.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.


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14.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe: An event that prevents normal everyday activities. - an AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
14.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and e-mail it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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14.7.
Appendix 7: 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.
14.7.1.
Dose Adjustments for Toxicity
Table 12
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
QTcF
If >30msec and < 60 msec 
change from baseline  AND 
manual QTcF <500 (average 
of three ECGs over at least 15 
minutes)

Continue current dose of GSK2820151

Supplement electrolytes, particularly 
potassium and magnesium, to 
recommended levels:
(1) Maintain serum potassium > 4mol/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 
(average of three ECGs over 
at least 15 minutes)

Discontinue GSK2820151 and notify the GSK
Medical Monitor. 
(1) Supplement electrolytes to recommended 
levels:
a.
Maintain serum potassium > 4mol/L
b.
Maintain serum magnesium levels 
>0.85 mmol/L
(2) Rule out other potential etiologies for 
prolonged QTcF such as cardiac ischemia
(3) Discontinue any concomitant medications 
with potential for QTcF prolongation.
(4) Consider telemetry monitoring if clinically 
indicated.

This subject may consider restarting study 
treatment at a previous dose level if the following 
criteria for QTcF rechallenge are met:

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless 
under the following conditions: 
(1)
QTcF event reduced to <450 msec,
(2)
potassium and magnesium levels are within 
institutional normal range,
(3)
a favorable risk/benefit profile (in the 
medical judgement of the Investigator and 
the GSK Medical Monitor),


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
(4)
approval within GSK medical governance:
a.
agreement with SERM MD and PPL,
b.
review with Chair or co-Chair of the 
GSK QT panel,
c.
SERM VP and Clinical VP approval
d.
Head Unit Physician approval
(5)
Institutional IRB (or equivalent) approval, 
and
(6)
The subject is re-consented regarding the 
possible increased risk of QTc 
prolongation. 

If approval for re-challenge is granted, the 
subject must be re-consented (with a 
separate informed consent specific to QTc 
prolongation)

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the 
subject should complete the following activities post-
dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be 
monitored weekly for two weeks, and then next 
assessment at 4 weeks post-dose. 
(3) If QTcF results have not resolved to baseline by 
4 weeks post-dose, then continue every 4-5 weeks 
until resolution
Troponin
Troponin level >ULN

Evaluate immediately for symptoms and obtain 
ECG. Repeat troponin within 24-48 hours or as 
soon as possible. 

If the repeat value is within the normal 
range, the subject may continue 
GSK2820151 with close follow-up for 
symptoms, ECG monitoring and further 
troponin measurements as clinically 
indicated.

If the repeat value remains > ULN AND the 
subject is asymptomatic, hold 
GSK2820151, refer to a cardiologist, and 
contact the GSK Medical Monitor

If the subject is symptomatic OR the 
troponin level approaches the threshold for 
mycocardial infarction (MI) according to 
local lab parameters, hold GSK2820151 
and refer the subject immediately to a 
cardiologist or emergency medical facility 
for appropriate medical care.

May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
LVEF
Ejection fraction below the 
institution’s lower limit of 
normal (LLN)
AND
An asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline

Temporarily discontinue GSK2820151 and 
repeat evaluation of LVEF within 2 weeks

If LVEF recovers (defined as LLN and 
absolute decrease 10% compared to 
baseline) at any time during the next 4 
weeks, after consultation and approval of 
the GSK medical monitor, the subject may 
be restarted on GSK2820151 at a reduced 
dose. 
o
Monitoring should be performed at 
2 and 4 weeks after restarting 
GSK2820151 and then per 
protocol specifications.

If LVEF does not recover within 4 weeks, 
permanently discontinue GSK2820151. 
Evaluation by a cardiologist will be 
conducted. Ejection fraction should 
continue to be monitored at 2 weeks, 4 
weeks and every 4 weeks until 16 weeks or 
resolution.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Grade 3 or 4

Permanently discontinue GSK2820151.

Evaluation by a cardiologist required.

Ejection fraction should be monitored at 2 
weeks, 4 weeks and then every 4 weeks 
until 16 weeks or resolution.
Liver 
Refer to procedures outlined in Appendix 3: Liver 
Safety Required Actions and Follow up Assessments
Hypo- and 
Hyperglycemia
Note: for 
management 
purposes, refer to 
mild, moderate 
and severe
intensity criteria; 
however for CRF 
reporting use NCI-
CTCAE version 4 
Grade 1-5
(Mild) Fasting blood glucose 
>150 mg/dL 

Monitor fasting and preprandial glucose.
(Moderate to Severe) Fasting 
blood glucose <70 mg/dL OR 
any blood glucose >250 mg/dL

Hold GSK2820151 and instruct subject to notify 
investigator immediately.

If a blood glucose >250 mg/dL is observed, 
the subject should be evaluated for 
ketoacidosis as clinically indicated.
o
This may necessitate inpatient 
management.
o
The action of insulin or other 
antihyperglycemic agents should be 
restored as study medication is cleared. 
If an antihyperglycemic agent is 
administered, then the subject should be 
observed closely for rebound 
hypoglycemia as the study medication is 
cleared.
o
Intravenous insulin treatment is 
recommended.

May consider restarting GSK2820151 at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.
Diarrhea
Grade 1

Initiate supportive care including loperamide. 
Grade 2

Initiate supportive care including loperamide.

Consider temporary discontinuation of 
GSK2820151 and discuss with GSK Medical 
Monitor.
Grade 3

Above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics 
as appropriate.

Hold GSK2820151 and discuss with GSK 
Medical Monitor.

If diarrhea recovers to less than Grade 2, 
discuss with medical monitor; consider 
resuming treatment at the same or lower dose 
based on clinical judgement.
Grade 4

Above plus consider intravenous (IV) hydration, 
hospital admission and prophylactic antibiotics 
as appropriate.

Discontinue GSK2820151 permanently


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Mucositis
Grade 1 or 2

Encourage oral hygiene. Offer topical supportive 
anesthetics. Encourage adequate hydration.
Grade 3 or 4

Above, plus systemic opiate administration as 
needed. 

Consider IV hydration and hospital 
admission as appropriate. 

May restart GSK2820151 at a reduced dose or 
dose level pre-event based on discussion with 
GSK Medical monitor.


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Pneumonitis
Grade 1

Continue GSK2820151 at current dose.

Consider evaluation by pulmonologist.

Consider room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins 
apart). Repeat evaluations every 8-12 
weeks until return to baseline.

Obtain high-resolution computed 
tomography (CT) scan of the chest if 
possible.
Grade 2

Hold GSK2820151 until recovery to < Grade 1, 
then reduce dose by at least 25%. 

Consider evaluation by pulmonologist.

Consider pulmonary function tests 
including: spirometry, DLCO, and room 
air O2 saturation at rest via pulse 
oximetry reading ( X 2, 5 mins apart). 
Repeat evaluations every 8-12 weeks 
until return to baseline.

Obtain high-resolution chest CT if 
possible.

Consider a bronchoscopy with biopsy 
and/or bronchoalveolar lavage. (BAL).

Treat only if symptomatic. Consider 
corticosteroids if symptoms are 
troublesome and infective origin is ruled 
out. Taper as medically indicated.

Discontinue GSK2820151 if no recovery to 
<Grade 1 within 4 weeks. May consider 
escalation to pre-event dose after discussion 
with GSK Medical Monitor
Grade 3 or 4

Hold GSK2820151 and refer for evaluation by 
pulmonologist

Required pulmonary function tests 
including: spirometry, DLCO, and room 
air O2 saturation at rest via pulse 
oximetry reading (X 2, 5 mins apart). 
Repeat evaluations at least every 8 
weeks until return to baseline. 

Obtain high-resolution chest CT if 
possible.

Bronchoscopy with biopsy and/or BAL is 
recommended.

Consider corticosteroids if infective origin 
is ruled out. Taper as medically indicated.

Rechallenge Guidelines

Grade 3: Hold GSK2820151 until 
recovery to < Grade 1. Discontinue 
GSK2820151 if no recovery to < Grade 1 
within 4 weeks. May consider restarting 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
GSK2820151 at a reduced dose after 
discussion with GSK Medical Monitor if 
there is clinical benefit.

Grade 4: Rechallenge with GSK2820151
is not permitted
Fever
Grade 1 

Continue current dose of GSK2820151 and 
monitor for change in severity. 
Grade 2

Temporarily discontinue GSK2820151 and 
monitor for change in severity. 

Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea. Assess vital signs.

Collect cytokine blood samples as 
outlined in the SRM. Collect blood culture 
and investigate viral infections as 
applicable

Consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.
Grade 3 or 4

Temporarily discontinue study medication and 
monitor for change in severity.

Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea.

Collect cytokine blood samples as 
outlined in the SRM. Collect blood culture 
and investigate viral infections as 
applicable.

Consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor
Thrombocytopenia
Grade 1 or 2 (Count 50,000)

Continue dosing at same dose level with 
weekly or more frequent monitoring as 
necessary
Grade 3 (Count 25,000 –
50,000)

After discussion with medical monitor and 
using sound clinical judgement, continue at 
same dose or adjust dose (e.g. consider 
reduced daily dosing or dosing on alternate 
days). Monitor CBC at least twice a week, 
more frequently if necessary 
Grade 4 (Count ≤ 25,000)

Interrupt study medication and monitor CBC 
every 2-3 days.

If platelet counts recover to Grade 2, 
discuss with medical monitor resuming 
treatment at the same or adjusted dose 
based on sound clinical judgement.

Platelet transfusion is allowed based on 


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Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
institutional guidelines. In case of platelet 
transfusion, hold drug for at least 7 days 
from day of transfusion, and if platelet 
counts recover to Grade 2 consider 
initiating treatment at a lower dose using 
sound clinical judgement and after 
consulting with the GSK medical monitor. 

Discontinue treatment if drug has to be held for 
>14 days or greater than 2 dose reductions are 
required.
All Other Toxicity*
1

Continue dosing with no change 
2

Continue dosing with no change 
OR

Hold GSK2820151 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)
3

1st episode: Hold dose for one week intervals 
until drug-related Grade 2, then restart with 
no change. 

2nd episode: Utilize an alternative, less frequent 
schedule or reduce by one dose level. 

If no recovery to ≤Grade 1* after a 21 day 
delay, patient should go off protocol therapy.
4

Discontinue GSK2820151

In rare situations, based on discussion and 
written agreement between GSK medical 
monitor and investigator, if the subject is 
receiving benefit then the episode may be 
managed as per Grade 3 toxicity.
*Note: Exceptions to drug-related Grade 1 requirement may be made for certain AEs as defined in Section 4.2.5.


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14.8.
Appendix 8: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria – adapted from RECIST 
1.1 [Eisenhauer, 2009]
14.8.1.
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 CRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules) [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 optimised 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.
14.8.2.
Guidelines for Evaluation of Disease
14.8.2.1.
Measurable and Non-measurable Definitions
14.8.2.1.1. 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 5mm.  If 
the slice thickness is greater than 5mm, 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

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm).  At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009].
14.8.2.1.2. Non-measurable lesion
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least 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. 


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14.8.3.
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. 
14.8.4.
Response Criteria
14.8.4.1.
Evaluation of target lesions
Definitions for assessment of response for target lesion(s) are as follows:

Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis.

Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline).

Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.


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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 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
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.
14.8.4.2.
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.


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
Not Evaluable (NE):  Cannot be classified by one of the four preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

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"). 
14.8.4.3.
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.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
14.8.4.4.
Evaluation of overall response
Table 13 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 13
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable
Table 14 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 subjects with non-measurable only disease at baseline.


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Table 14
Evaluation of Overall Response for Subjects 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:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.8.4.5.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

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 7 day 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, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
14.8.4.6.
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.
Reference
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: Revised 
RECIST guidelines (version 1.1). Europena Journal of Cancer. 2009; 45: 228-247.


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14.9.
Appendix 9:  Cockcroft and Gault Method for Calculated 
Creatinine Clearance
Calculated creatinine
clearance (mL/min)  =
(140 age [yrs] ) weight (kg)
72 serum creatinine (mg/100mL)
Female patients: multiply by 0.85
Cockcroft DW, Gault MH.  Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron 1976; 16: 31-41.


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14.10.
Appendix 10: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6. 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 subject who becomes pregnant while participating:
o
will discontinue study medication

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
GlaxoSmithKline Group of Companies 
 
201893 
1 
 
Division: World Wide Development 
Retention Category: GRS019 
Information Type: Reporting and Analysis Plan 
Title: 
Reporting and Analysis Plan for A Phase I Open-Label, Dose 
Escalation Study to Investigate the Safety, Pharmacokinetics, 
Pharmacodynamics, and Clinical Activity of GSK2820151 in 
Subjects with Advanced or Recurrent Solid Tumors [Study 
201893] 
Compound Number: GSK2820151 
Effective Date: 
08-FEB-2019 
 
Subject: Oncology, Reporting and Analysis Plan 
 
Author’s Name, Title and Functional Area:  
 
Principal Statistician, Biostatistics 
ICON Clinical Research 
 
 
Approved by:  
 
 
Statistics Director 
Clinical Statistics (UK) 
RD Projects Clinical Platforms & Sciences 
GSK 
 
 
Date 
 
 
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 
 
PPD
PPD


CONFIDENTIAL 
201893 
 
2 
 
TABLE OF CONTENTS 
ABBREVIATIONS ............................................................................................................4 
1. 
INTRODUCTION ......................................................................................................7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ...................................................8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................8 
2.2. 
Study Objective(s) and Endpoint(s) ...............................................................8 
2.3. 
Statistical Hypotheses ...................................................................................9 
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic Hypotheses .....................9 
2.5. 
Study Design ............................................................................................... 10 
3. 
PLANNED ANALYSES ........................................................................................... 11 
3.1. 
Interim Analyses ......................................................................................... 11 
3.2. 
Final Analyses ............................................................................................. 11 
4. 
SAMPLE SIZE CONSIDERATIONS ....................................................................... 12 
4.1. 
Sample Size Assumptions ........................................................................... 12 
4.2. 
Sample Size Re-estimation or Adjustment .................................................. 12 
5. 
ANALYSIS POPULATIONS .................................................................................... 12 
5.1. 
All Enrolled Population ................................................................................ 12 
5.2. 
All Treated Population ................................................................................. 12 
5.3. 
PK Population ............................................................................................. 12 
5.4. 
Analysis Datasets ....................................................................................... 12 
6. 
TREATMENT COMPARISONS .............................................................................. 12 
6.1. 
Data Display Treatment and Other Subgroup Descriptors ........................... 12 
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ....................................... 12 
8. 
DATA HANDLING CONVENTIONS ........................................................................ 13 
8.1. 
Premature Withdrawal and Missing Data .................................................... 13 
8.2. 
Derived and Transformed Data ................................................................... 13 
8.2.1. 
Reference dates ........................................................................... 13 
8.2.2. 
Study Day for Safety Measures .................................................... 13 
8.2.3. 
Study Day for Efficacy .................................................................. 13 
8.2.4. 
Duration and Elapsed Time .......................................................... 14 
8.2.5. 
Imputation of Partial Dates ........................................................... 14 
8.2.6. 
Imputation of Missing Exposure End Dates .................................. 17 
8.2.7. 
Baseline Definition ....................................................................... 17 
8.2.8. 
Change from baseline .................................................................. 18 
8.2.9. 
Multiple Assessments .................................................................. 18 
8.2.10. 
Actual Treatment .......................................................................... 18 
8.2.11. 
Extended Loss to Follow-up or Extended Time without an  
               Adequate Assessment .................................................................. 18 
8.2.12. 
Date Associated with Response ................................................... 18 
8.3. 
Values of Potential Clinical Importance ....................................................... 19 
8.3.1. 
Laboratory Parameters ................................................................ 19 


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8.3.2. 
Vital Signs .................................................................................... 19 
9. 
STUDY POPULATION ANALYSES ........................................................................ 20 
9.1. 
Disposition of Subjects ................................................................................ 20 
9.2. 
Protocol Deviations ..................................................................................... 20 
9.3. 
Demographic and Baseline Characteristics ................................................. 20 
9.4. 
Treatment Compliance ................................................................................ 20 
9.5. 
Concomitant Medications ............................................................................ 20 
9.6. 
Subsequent Anticancer Therapies .............................................................. 21 
10. EFFICACY ANALYSES .......................................................................................... 21 
11. SAFETY ANALYSES .............................................................................................. 23 
11.1. 
Extent of Exposure ...................................................................................... 23 
11.2. 
Adverse Events ........................................................................................... 23 
11.3. 
Adverse Events of Special Interest .............................................................. 23 
11.4. 
Deaths and Serious Adverse Events (SAEs) ............................................... 23 
11.5. 
Adverse Events Leading to Discontinuation of Study Treatment and/or  
            Withdrawal from the Study and Other Significant Adverse Events .............. 24 
11.6. 
Clinical Laboratory Evaluations ................................................................... 24 
11.7. 
Other Safety Measures ............................................................................... 25 
12. HEALTH OUTCOMES ANALYSES ........................................................................ 25 
13. PHARMACOKINETIC ANALYSES ......................................................................... 25 
13.1. 
Drug Concentration Measures .................................................................... 25 
13.2. 
Deriving and Summarizing Pharmacokinetic Parameters ............................ 25 
14. PHARMACOGENETIC DATA ANALYSES ............................................................. 26 
15. REFERENCES ....................................................................................................... 27 
16. APPENDIX 1: LIST OF DATA DISPLAYS .............................................................. 28 
16.1. 
Data Display Numbering ............................................................................. 28 
16.2. 
Deliverable .................................................................................................. 28 
16.3. 
ICH Listings................................................................................................. 28 
16.4. 
Non-ICH Listings ......................................................................................... 30 
 
 


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Abbreviations 
1,5 AG 
1,5 –Anhydroglucitol 
ADaM 
Analysis Data Model 
AE(s) 
Adverse event(s) 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUC(0-∞) 
Area under the curve from zero to infinity 
AUC(0-) 
Area under the plasma concentration-time curve 
BET 
Bromodomain & Extra-Terminal 
BRD 
Bromodomain 
-hCG 
Beta-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
Cav 
Average observed concentration 
CDISC 
Clinical Data Interchange Standards Consortium 
CK 
Creatine kinase 
CKMB 
Creatine kinase MB isoenzyme 
CL/F 
Clearance 
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical Study Report 
Cτ 
Trough concentration 
CV 
Cardiovascular 
CV% 
Percentage coefficient of variance 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FTIH 
First time in human 
GSK 
GlaxoSmithKline 
HDL 
High-density lipoprotein 
HGB 
Hemoglobin  
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDSL 
Integrated Data Standards Library 
IEC/IRB 
Independent ethics committee/institutional review board 
IL-6 
Interleukin 6 
INR 
International normalized ratio 
LDL 
Low-density lipoprotein 
LLN 
Lower limit of normal 


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LPS 
Lipopolysaccharide 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram(s) 
msec 
Millisecond(s) 
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute- Common Terminology Criteria 
for Adverse Events 
N-CRM 
Neuenschwander - Continuous Reassessment Method 
NQ 
Non-quantifiable 
NT-proBNP 
N-terminal pro–B-Type natriuretic peptide 
ORR 
Objective response rate 
PD 
Progressive disease 
PFS 
Progression free survival 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred term 
PTT 
Partial thromboplastin time 
FACTS 
Fixed and Adaptive Clinical Trial Simulator 
QTc 
Corrected QT interval 
QTcF 
Corrected QT (Fridericia’s formula) 
RAP 
Reporting and Analysis Plan 
RBC 
Red Blood Cell 
RECIST 
Response criteria in solid tumors 
Ro 
The observed accumulation ratio 
RP2D 
Recommended Phase 2 dose 
SAE(s) 
Serious adverse event(s) 
SOC 
System organ class 
SD 
Stable disease  
t½ 
Apparent terminal phase half-life 
tmax 
Time to Cmax 
TSH 
Thyroid Stimulating Hormone 
TTE 
Time to event  
ULN 
Upper limit of normal 
Vz/F 
Volume of distribution 
WBC 
White blood cells 
 
 
 


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Trademark Information  
Trademarks of the GlaxoSmithKline group of 
companies 
 
Trademarks not owned by the GlaxoSmithKline group of 
companies 
NONE 
 
FACTS 
 
 
SAS 
 
 
 


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1. 
INTRODUCTION 
This reporting and analysis plan (RAP) details all planned analyses required for a Clinical Study Report of 
study 201893. This is a first time in human (FTIH), open-label, dose escalation study will assess the safety, 
pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of GSK2820151 in subjects with 
advanced or recurrent solid tumors. 
For further information on the study design, see Protocol Amendment dated 08-JUN-2017 (2014N215112_04). 
The RAP was written by staff of ICON Clinical Research. The execution of the RAP, with exception to 
Neuenschwander - Continual Reassessment Method (N-CRM) - based analyses using the Fixed and Adaptive 
Clinical Trial Simulator (FACTS), will be undertaken by staff of ICON Clinical Research. 
All decisions regarding final analysis, as defined in this RAP document, have been made prior to Database 
Freeze of the study data. Effective November 17 2017, GSK has made the difficult decision to discontinue the 
development of GSK2820151 in solid tumors. This decision was made after careful consideration of the 
following factors:  
 
● With the increasing amount of clinical data now available on Bromodomain & Extra-Terminal (BET) 
inhibitors, the opportunity for GSK2820151 to show a differentiated profile with significant additional 
clinical benefit has decreased.  
● With more than 15 BET inhibitors in clinical development, it was very challenging to enroll to the BET 
inhibitor study (201893), which enrolled only 4 subjects over a period of 1.5 years.  
 
At the time the study termination decision was made, one subject was still receiving treatment. The study 
terminated when the last subject completed last scan on  
November 18 2018 and showed disease progression. A total of 5 subjects have enrolled into the study. 
 
Due to the early termination decision and the small number of subjects, only listings of the data will be 
generated. 


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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Protocol Section 
Change from Protocol 
Rationale 
Section 11.4.2 
Interim Analysis 
No interim analysis in SAP 
Sponsor made the decision to terminate the study 
early and no interim analysis needed 
Section 11.2 
Continual 
Reassessment 
Method 
No N-CRM analysis in SAP 
Sponsor made the decision to terminate the study 
early and did not get into N-CRM analysis phase 
Section 11 
Statistical 
Considerations 
and Data 
Analyses 
No summary tables and figures 
No statistical analysis of 
pharmacokinetic parameters 
Sponsor made the decision to terminate the study 
early and no tables/figures needed, only listings 
provided 
Section 8.3.9 
Clinical Safety 
Laboratory 
Assessments 
No Creatinine Phosphokinase 
This test was not collected per CRF 
Section 11.5.3 
Other Analyses 
No biomarker, 
pharmacodynamics exploratory 
analyses performed  
Sponsor made decision that biomarkers samples were 
not collected after 11Jan2018 and the biomarker 
samples collected by 11Jan2018 were destroyed. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary 
 To determine the safety, tolerability and 
maximum tolerated dose (MTD) of GSK2820151 
in subjects 18 years or older with advanced or 
recurrent solid tumors.   
 Adverse events (AEs), serious adverse events 
(SAEs), dose reductions or delays, withdrawals 
due to toxicities and changes in safety 
assessments (e.g., laboratory parameters, vital 
signs, electrocardiogram (ECG), cardiotoxicity, 
gastrointestinal, etc.) 
Secondary 


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Objectives 
Endpoints 
 
To determine a recommended Phase 2 dose 
(RP2D) of GSK2820151 in subjects 18 years or 
older. 
 
Safety profile (AEs, SAEs, dose-limiting 
toxicities [DLTs]), clinical response, and 
pharmacodynamics data 
 
To characterize the PK of GSK2820151 in 
subjects 18 years or older. 
 
PK parameter values for GSK2820151 following 
single and repeat-dose oral administration in 
subjects 18 years or older. 
 
To evaluate the effect of treatment with 
GSK2820151 on tumor growth and subject 
survival. 
 
Objective response rate (ORR) by various 
imaging modalities and progression free survival 
(PFS). 
 
To evaluate cardiac safety, including the 
potential for corrected QT interval (QTc) 
prolongation, of GSK2820151 and to assess 
PK/QTc relationship. 
 
Changes in cardiac safety including QTc 
following single and repeat-dose oral 
administration of GSK2820151. 
Exploratory 
 
To evaluate the exposure response 
(pharmacokinetic/pharmacodynamics [PK/PD]) 
relationship between GSK2820151 and safety 
and efficacy parameters.  
 
Dose-related change in molecular markers (e.g., 
gene transcription and/or expression of proteins 
regulated by BRD proteins) in peripheral blood 
samples. 
 
To evaluate systemic and ex vivo on-target BET 
inhibitory effects 
 
Changes from baseline and dose/response 
relationship in ex vivo lipopolysaccharide (LPS)-
induced cytokines, including interleukin 6 (IL-
6), in whole blood, and systemic cytokines, 
including IL-6. 
 
To identify potential indicators of sensitivity or 
response to GSK2820151.  
 
Transcriptomic studies of blood; correlation of 
baseline genetic and genomic profiles with 
response.  
2.3. 
Statistical Hypotheses 
The primary endpoints of this study are safety and tolerability; the MTD and RP2D will also be determined. No 
formal statistical hypotheses will be tested. The primary focus will be on determining the recommended dose 
for further exploration, the safety profile, and the PK of GSK2820151 in subjects with advanced cancer. 
Analyses will be descriptive and exploratory.   
2.4. 
Pharmacokinetic (PK) and PK/Pharmacodynamic Hypotheses 
There is no formal statistical hypothesis for PK and pharmacodynamic analyses. 


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2.5. 
Study Design 
This study is a single-agent, open-label, dose-escalation study to determine the MTD (and RP2D), based on the 
safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK2820151. 
Eligible subjects with advanced or recurrent solid tumors will be enrolled in the dosing cohorts until MTD is 
established. All subjects will receive study drug. Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent (for specific stopping criteria, see Protocol Section 
5.4). The duration of study will depend on recruitment rates and the timing of subjects’ duration on study 
(withdrawal rates due to toxicity or progression).  
This study will utilize an accelerated dose escalation phase in order to minimize suboptimal drug exposures, 
followed by a conventional 3+3 dose escalation phase to achieve MTD. Initially, one subject per dose cohort 
will be recruited (accelerated dose escalation phase) until the first instance of a ≥ Grade 2 drug related non-
hematological 
toxicity or dose-limiting toxicity (DLT, see Protocol Section 4.2.4). Further cohorts will be recruited in blocks 
of three subjects (3+3 dose escalation phase). Additional subjects may be enrolled at previously cleared dose 
levels in order to obtain further data for PK and/or pharmacodynamic analysis. Once MTD is determined, 
additional subjects (18 subjects total at MTD) may be enrolled to collect additional safety data (Figure 1). The 
total duration of study for each subject will be dependent upon the safety, tolerability and efficacy of 
GSK2820151. 
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose will be escalated based 
on PK data, the safety profile of the current and prior cohorts, as well as the predicted DLT rates on all potential 
doses from the N-CRM analysis [Neuenschwander, 2008]. N-CRM design is a type of Bayesian adaptive dose-
escalation scheme (see Protocol Section 11.2). The method is fully adaptive and makes use of all the DLT 
information available at the time of each dose assignment. The DLT information of all subjects enrolled in the 
trial are used to update the estimated dose-toxicity relationship and provide supportive information in addition 
to the 3+3 design in the next escalation/de-escalation decision.  
 
The RP2D will be determined based on the MTD or biologically active dose (example:clinical response), the 
safety profile, and available pharmacodynamic data generated from all subjects. If necessary alternate schedules 
can be explored to determine additional biologically active doses even after a RP2D is defined. 
 


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Figure 1: Dose Escalation Scheme 
Projected dose levels are 3 mg, 6 mg, 12 mg, 20 mg, 40 mg, 60 mg, 100 mg, 150 mg, 200 mg, and 300 mg. 
Additional doses and schedules may be explored based on emerging safety, PK, and pharmacodynamic data. 
Actual dose escalation doses and decisions, based on observed data, will be executed based on guidance 
described in Protocol Section 4.2.2 and Protocol Section 4.2.3. 
The schedule for study assessments can be found in Protocol Section 8. 
3. 
PLANNED ANALYSES 
In line with ICH E9 [European Agency for the Evaluation of Medicinal Products, 1998], membership of the 
analysis populations will be determined using the definitions in Section 5 of this RAP. 
3.1. 
Interim Analyses 
Interim PK data was reviewed at dose escalation meeting at each dose by GSK. Non Compartment analyses for 
Dose Escalation Cohorts was performed using Phoenix Winnonlin version 6.4 or higher under the supervision 
of clinical Pharmacology Modeling and Simulation (CPMS), GSK. 
No N-CRM analysis was performed for the study due to the termination of the study. 
3.2. 
Final Analyses 
Final analyses will be performed after all subjects have permanently discontinued study treatment and the final 
study database is frozen. 
See Sections 5 to 16 for details regarding the planned analyses and description of displays to be produced. 


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4. 
SAMPLE SIZE CONSIDERATIONS 
4.1. 
Sample Size Assumptions 
The total number of subjects to be enrolled into this study will depend on the number of subjects needed to 
characterize individual dose cohorts for the determination of the maximum tolerated dose of GSK2820151; the 
final sample size is not driven by statistical considerations. However, it is anticipated that approximately 30 to 
50 subjects will be enrolled with a maximum of 80 subjects. 
4.2. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation will be performed.  
5. 
ANALYSIS POPULATIONS 
5.1. 
All Enrolled Population 
The All Enrolled Population is defined as all subjects who have consented to participate in the study and have 
not screen failed.   
5.2. 
All Treated Population 
The All Treated Population is defined as all subjects who receive at least one dose of GSK2820151. Safety 
and anti-cancer activity will be evaluated based on this analysis population.   
5.3. 
PK Population 
The PK Population will consist of all subjects from the All Treated Population for whom a PK sample is 
obtained and analysed.   
5.4. 
Analysis Datasets 
Analysis datasets will be created according to Clinical Data Interchange Standards Consortium (CDISC) 
version 3.1.3/ Analysis Data Model (ADaM) version 1.0 standards, and data will be listed according to GSK 
Integrated Data Standards Library (IDSL) reporting standards. Formatting for dates, times, and decimal places 
will follow GSK standards except where specified. 
6. 
TREATMENT COMPARISONS 
There are no treatment comparisons in the study. 
6.1. 
Data Display Treatment and Other Subgroup DescriptorsUnless otherwise stated, all 
data will be pooled and listed by investigated GSK2820151 dose cohorts.  
7. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
SAS 9.3 or higher version will be used to perform all data analyses and generate listings. Data in the database 
will be presented in by-subject data listings. 


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8. 
DATA HANDLING CONVENTIONS 
8.1. 
Premature Withdrawal and Missing Data 
Because study treatment is dependent on the study endpoints (e.g., progression, i.e. not a fixed treatment 
duration), the length of treatment for each subject will depend on the efficacy and toxicity of the treatment, so 
the duration of treatment will vary across subjects. Similarly the duration of follow up will also vary. All 
available PFS data will be analyzed using suitable statistical methods; subjects with shorter treatment and 
follow-up due to the natural history of their disease or medical necessities of the treatment of their disease will 
not be considered to have missing PFS data. For endpoints which determine the percentage of responders, 
subjects with unknown/not evaluable or missing best overall response will be assumed to be non-responders, 
and will be included in the  denominator when calculating the percentages.  
In the event that the study is terminated, all available data will be listed. 
Missing data occurs when any requested data is not provided, leading to blank fields on the collection 
instrument. These data will be indicated by the use of a “blank” in subject listing displays. Answers such as 
“Not applicable” and “Not evaluable” are not considered to be missing data and should be displayed as such. 
There will be no other imputation for missing data other than what’s described in Section 8.2 for partial dates 
and for missing exposure end dates. 
8.2. 
Derived and Transformed Data 
The following sections provide a general description of the derived and transformed variables used to describe 
and analyze the data. Separate analysis dataset specifications provide full details on all data derivations and 
transformations including descriptions of core standard algorithms and standard oncology algorithms. The 
analysis dataset specifications will clearly communicate the content and source of the datasets supporting the 
statistical analyses. 
8.2.1. 
Reference dates 
Unless otherwise stated, the safety reference (start) date will be the start of treatment of GSK2820151.  This 
will also be the efficacy reference date for this study.  The reference date for baseline characteristics (e.g. age) 
will be the date of screening. 
8.2.2. 
Study Day for Safety Measures 
If the date of interest occurs on or after the safety reference date then the safety study day will be calculated as 
(date of interest - safety reference date) + 1.  If the date of interest occurs before the safety reference date then 
the safety study day will be calculated as (date of interest-safety reference date). There is no safety study day 0. 
8.2.3. 
Study Day for Efficacy 
If the date of interest occurs on or after the efficacy reference date then efficacy study day will be calculated as 
(date of interest - efficacy reference date) + 1. If the date of interest occurs prior to the efficacy reference date 


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then efficacy study day will be calculated as (date of interest – efficacy reference date). There is no efficacy 
study day 0.  
8.2.4. 
Duration and Elapsed Time 
Durations (e.g., the duration of an AE, duration of exposure, etc.) are calculated as the stop date minus the start 
date plus one. 
For elapsed time (e.g., the time since initial diagnosis): 
 
If the reference date is on or after the event date, then the elapsed time is the reference date minus the event 
date + 1. 
 
If the reference date is before the event date then the elapsed time is the reference date minus the event 
date. 
When reporting time to event (TTE) durations 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. These algorithms 
for time to event return decimal numbers, and ignore the actual numbers of days in the months or years between 
start date and stop date. The "year" used in these algorithms is 365.25 days long, and the "month" is one twelfth 
of that year. 
8.2.5. 
Imputation of Partial Dates 
Imputed partial dates will not be used to derive study day, duration (e.g., duration of AEs), or elapsed time 
variables. In addition, imputed dates are not used for deriving the last contact date in progression free survival 
analysis dataset. 
Imputed dates will not be displayed in listings. However, where necessary, display macros may impute dates as 
temporary variables for the purpose of sorting data in listings only. Partial dates may be imputed as outlined 
below.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to populate the numeric 
date variables with the imputed date and add a flag variable to the dataset that indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Example of Date Variables:  
XYZD_ - character date variable 
XYZDT - numeric date variable 
XYZDTFL - flag variable 


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Details on imputing partial dates for specific datasets are outlined below. 
Adverse Events (AE): 
Imputations in the adverse events dataset are used for slotting events to the appropriate study time periods and 
for sorting in data listings. 
Dataset 
Date 
Missing 
Element 
Rule 
Adverse 
Events 
(AE) 
Start 
Date 
day, 
month, 
and year 
 No Imputation for completely missing dates 
 
 
day, 
month 
 If study treatment start date is missing (i.e. subject did not start study 
treatment), then set start date = January 1. 
 Else if study treatment start date is not missing:  
o If year of start date = year of study treatment start date then  
 
If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date = 
January 1.  
 
Else set start date = study treatment start date.  
o Else set start date = January 1. 
 
 
day 
 If study treatment start date is missing (i.e. subject did not start study 
treatment), then set start date = 1st of month.  
 Else if study treatment start date is not missing:  
o If month and year of start date = month and year of study 
treatment start date then  
 
If stop date contains a full date and stop date is earlier 
than study treatment start date then set start date= 1st 
of month.  
 
Else set start date = study treatment start date. 
o Else set start date = 1st of month. 
 
End 
Date 
 
 No imputation for partial end dates will be performed 
 
Anticancer Therapy and Radiotherapy, Surgery, Concomitant Medication and Blood and Blood 
Supportive Care Products: 
Start dates are generally not imputed. If start dates need to be imputed for sorting in data listings, the rules of 
imputation is defined as below: 


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Dataset 
Date 
Missing 
Element 
Rule 
Anticancer 
Therapy  
 
Radiotherapy 
Surgical 
Procedures 
 Concomitant 
Medication 
 
Blood and Blood 
Supportive Care 
Products 
 
 
Start 
Date 
day, 
month, and 
year 
 
No Imputation for completely missing dates 
 
day, month 
 
If partial date contains a year only set to January 1st. 
 
day 
 
If partial date contains a month and year set to the 1st of the 
month. 
 
Time to Event and Overall Response: 
Start dates for follow-up anticancer therapy, radiotherapy (where applicable), and surgical procedures (where 
applicable) will be temporarily 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 anticancer therapy). Dates will only be 
imputed when a month and year are available but the day is missing. The imputed date(s) will not be stored on 
the anticancer therapy, radiotherapy, or surgical procedure datasets. The following rules will be used to impute 
the date when partial start dates are present on anticancer therapy radiotherapy, and/or surgical procedures 
dataset[s]: 
Dataset 
Date 
Missing 
Element 
Rule 
Anticancer 
Therapy  
 
Where 
applicable:  
Radiotherapy  
 
Surgical 
Procedures 
Start 
Date 
day, month, and 
year 
 
No Imputation for completely missing dates 


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Dataset 
Date 
Missing 
Element 
Rule 
 
 
day, month 
 
No imputation for missing day and month (note the 
eCRF should only allow for missing day) 
 
 
day 
 
If partial date falls in the same month as the last dose of 
study treatment, then assign to earlier of (date of last 
dose of study treatment+1, last day of month).  
 
If partial date falls in the same month as the subject’s 
last assessment and the subject’s last assessment is PD, 
then assign to earlier of (date of PD+1, last day of 
month).  
 
If both rules above apply, then assign to latest of the 2 
dates  
 
Otherwise, impute missing day to the first of the 
month. 
 
End 
Date 
 
 
No imputation for partial end dates will be performed 
The date of new anticancer therapy is derived as the earliest date of new anticancer therapy (e.g., 
chemotherapy), radiotherapy (where applicable), or cancer related surgical procedure (where applicable) and 
will include imputed dates. 
8.2.6. 
Imputation of Missing Exposure End Dates 
In general, completely missing dates are not imputed. However, subjects in oncology trials may still be on study 
treatment when analyses are performed and so may have missing exposure end dates in their last dosing record. 
Missing exposure end dates will be imputed. For subjects with missing exposure end dates at the time of data 
cutoff, the exposure end date will be imputed to the earliest of: the date of the data cutoff, the date of 
withdrawal from the study, or the death date. The imputed exposure end date will be used to calculate 
cumulative dose and exposure duration. Imputed exposure end dates will be stored on the study treatment end 
date variable. 
8.2.7. 
Baseline Definition 
Baseline will be defined as the most recent, non-missing value prior to or on the first study treatment dose date 
for GSK2820151. For laboratory data, baseline will be defined as the most recent, non-missing value from a 
central laboratory prior to or on the first study treatment dose date. If there are no central labs collected for a 
subject and lab test prior to or on the first dose of study treatment, the most recent, non-missing value from a 
local laboratory prior to or on the first dose of study treatment will be defined as the baseline value. 


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If the latest pre-dose value is collected on the day of treatment, the time of treatment will be used to identify the 
baseline value.  If the pre-dose time point value is identified as baseline, and the data is recorded in triplicate the 
average will be used. 
For subjects who did not receive study treatment during the study, baseline will be defined as the latest, non-
missing collected value. 
8.2.8. 
Change from baseline 
Change from baseline will be presented for ECG and ECOG data as described in Section 11.  
Change from baseline is calculated as: 
 
For records occurring after baseline: (visit value) – baseline value. 
For the triplicate measurements, the average value will be used as visit value. 
Unless otherwise stated, if either the baseline or visit value is missing, the change from baseline and/or percent 
change from baseline is set to missing as well. 
8.2.9. 
Multiple Assessments 
Data from all assessments (scheduled and unscheduled), including multiple assessments, will be included in 
listings.  
8.2.10. 
Actual Treatment 
A subjects’ actual treatment will be derived from exposure data.  
8.2.11. 
Extended Loss to Follow-up or Extended Time without an Adequate Assessment 
If two or more scheduled disease assessments are missed and are then followed by an assessment of progressive 
disease (PD) or death, PFS will be censored at the last adequate assessment prior to PD or death. As the 
scheduled disease assessment is every 8 weeks, a window of 119 days (16 weeks + 7 day window) will be used 
to determine whether there was an extended time without adequate assessment. That is, if the time difference 
between PD/death and last adequate assessment is more than 119 days, then PFS will be censored at the last 
adequate assessment prior to PD/death. 
8.2.12. 
Date Associated with Response 
For each disease assessment after baseline, a date will be associated with the response based on collective group 
of disease assessments made within the protocol visit window. For complete response (CR) and partial response 
(PR), this will be assigned to the latest date within the disease assessments. For stable disease (SD), Non-
CR/Non-PD or Not Evaluable, this will be assigned to the earliest date within the disease assessments. For PD, 
assign to the earliest assessment date associated with the progression. 


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8.3. 
Values of Potential Clinical Importance 
8.3.1. 
Laboratory Parameters 
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. 
To identify laboratory values of potential clinical importance, National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE v4.03 [NCI-CTCAE, 2010]) will be used to assign grades to the 
relevant laboratory parameters.  
8.3.2. 
Vital Signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.03 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 
Decrease from baseline Heart Rate 
Decrease to <60 
bpm 
Increase from baseline Heart Rate 
Increase to >100 
bpm 
 
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.03 will be used to assign 
categories that align with the grades for ‘Hypertension’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Increase from baseline 
Systolic Blood Pressure 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
mmHg 
Increase from baseline 
Diastolic Blood Pressure 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
mmHg 
 
Systolic blood pressure below 120 mmHg and diastolic blood pressure below 80 mmHg are considered as 
normal range and will receive Grade 0 designations. 


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To identify temperature values of potential clinical importance, NCI-CTCAE v4.03 will be used to assign 
categories that align with the grades for ‘Hypothermia’ and ‘Fever’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Increase from baseline temperature 
Increase to 38 
Degrees C 
Decrease from baseline temperature 
Decrease to 35 
Degrees C 
 
9. 
STUDY POPULATION ANALYSES 
Unless otherwise stated, all data listings in this section will be based on the All Treated Population. 
9.1. 
Disposition of Subjects 
A listing of reasons for study withdrawal will be generated.  A listing of study treatment discontinuation will be 
generated. The listing will include last dose date, and reasons for study treatment discontinuation.  
9.2. 
Protocol Deviations 
All protocol deviations will be listed. A separated listing of inclusion/exclusion deviations will also be 
provided. 
9.3. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g., age, sex, ethnicity, race, baseline height, and baseline weight, body mass 
index) will be listed.  
Race and racial combinations, and family history will be listed.  
Disease characteristics, as well as these medical conditions, will be presented in data listings. 
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary and listed.  A listing of prior anti-
cancer therapy will show the relationship between Anatomical Therapeutic Chemical (ATC) Level 1, 
Ingredient, and verbatim text.  
Prior anti-cancer radiotherapy will be listed. Prior cancer and non-cancer related surgeries will be listed.  
9.4. 
Treatment Compliance 
A listing of scheduled and actual treatments will be produced.  
9.5. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary and listed. Listing for blood 
products or blood supportive care products will be provided.  


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9.6. 
Subsequent Anticancer Therapies 
Follow-up anticancer therapy will be coded using GSK Drug coding dictionary. A data listing for follow up 
anticancer therapy will be provided. 
Any follow-up anticancer surgeries will be listed. 
10. 
EFFICACY ANALYSES 
The evaluation of anticancer activity will be evaluated based on the All Treated Population as defined in 
Section 5 unless otherwise specified. Since this is a Phase I study, anticancer activity will be evaluated based on 
clinical evidence and response criteria.  Due to the very limited number of subjects, ORR was not calculated. It 
can be counted from the investigator assessed response listings if need.  
Lesion Assessment and Response  
Lesion assessment method and timing, evaluation of disease, disease progression and response criteria will be 
conducted according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) [Eisenhauer EA. 
etc, 2009] as outlined in Appendix 8 of the protocol. Data listings for response will be provided. 
Progression-Free Survival (PFS) 
PFS is defined as the interval of time (in weeks) between the start date of treatment and the earlier of the date of 
disease progression and the date of death due to any cause. Disease progression will be based on the 
assessments by the Investigator. 
The date of documented disease progression will be defined as the date of disease progression based on eCRF 
entries. If an assessment occurs over multiple days, the earliest date of progression will be used. The date of 
death should be taken from the Record of Death page. Death on study due to any cause will be included. 
If there is no adequate baseline assessment, the subjects will be censored at their start date of treatment. 
Subjects without any adequate post-baseline tumor assessments will be censored at the start date of treatment. If 
the subject received subsequent anti-cancer therapy prior to the date of documented events, PFS will be 
censored at the last adequate assessment (e.g. assessment where visit level response is CR, PR, or SD) prior to 
the initiation of therapy. Progressive disease (PD) will also be defined per RECIST 1.1 criteria. Otherwise, if 
the subject does not have a documented date of events, PFS will be censored at the date of the last adequate 
assessment.  
Subjects who progressed or died after an extended period without adequate assessment will be censored at their 
date of last adequate assessment prior to progression or death even if subsequent information is available 
regarding progression or death. The date of response at that assessment will be used for censoring. As the 
assessment schedule may change through the course of the protocol, specific rules for identifying extended loss 
to follow-up or extended time without an adequate assessment are provided in Section 8.2.11. 
For subjects who receive subsequent anticancer therapy the following rules will apply: 
 If the start date of the anticancer therapy is partial (i.e. either missing the day but has the month and year 
available or missing both day and month), the imputation rules described in Section 8.2.5 will be 
applied. No imputation will be made for completely missing dates. 


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 If anticancer therapy is started without documented disease progression or is started prior to documented 
disease progression, then PFS will be censored at the date of the last adequate assessment that is no later 
than the date of initiation of anticancer therapy (i.e. if an assessment occurs on the same day as the start 
of new anticancer therapy the assessment will be used - as it will be assumed the assessment occurred 
prior to the administration of new anticancer therapy). The date of response at the last adequate 
assessment will be used as the censoring value. 
A summary of the assignments for progression and censoring dates for PFS are specified in the following table. 
Table 1. 
Assignments for Progression and Censoring Dates for PFS Analysis 
Situation 
Date of Event 
(Progression/Death) or 
Censoring  
Outcome 
Event (Progression/Death) 
Or Censored 
No (or inadequate) baseline tumor 
assessments and the subject has not 
died (if the subject has died follow the 
rules for death indicted at the bottom 
of the table) 
Start Date of Treatment 
 
Censored 
No  post-baseline assessments and the 
subject has not died (if the subject has 
died follow the rules for death indicted 
at the bottom of the table) 
Start Date of Treatment 
Censored 
Progression documented between 
scheduled visits 
Date of assessment of 
progression1 
Event 
No progression (or death) and no  
initiation of new anti-cancer therapy 
Date of last ‘adequate’ 
assessment of response2 
Censored 
Received subsequent anti-cancer 
therapy prior to the date of 
documented events 
Date of last ‘adequate’ 
assessment of respnose2,3 
(prior to starting initiation of 
therapy) 
Censored 
Received subsequent anti-cancer 
therapy prior to any adequate 
assessment 
Start Date of Treatment 
Censored 
Received subsequent anti-cancer 
therapy and no progression (or death) 
Date of last ‘adequate’ 
assessment of respnose2,3 
(prior to starting initiation of 
therapy) 
Censored 
Death or progression after more than 
one missed visit 
Date of last ‘adequate’ 
assessment of response2 (prior 
to missed assessments) 
Censored 
Death 
Date of Death  
Event 


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1. The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or (ii) Date of 
radiological assessment showing unequivocal progression in non-target lesions, or (iii) Date of last radiological assessment of 
measured lesions (if progression is based on increase in sum of measured lesions) 
2. An adequate assessment is defined as an assessment where the Investigator determined response is CR, PR, or SD.  
3. If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is 
progression and the date is the date of the assessment of progression). If anti-cancer therapy is started prior to any adequate 
assessments, censoring date should be the start date of treatment. 
 
11. 
SAFETY ANALYSES 
Unless otherwise specified, all the safety analyses will be based on the All Treated  
Population as defined in Section 5. 
11.1. 
Extent of Exposure 
Extent of exposure to GSK2820151 will be listed. The subject’s average daily dose, defined as the cumulative 
dose divided by the duration of exposure for each subject, will be listed. 
All dose reductions and dose interruptions will be listed separately. 
11.2. 
Adverse Events 
AEs will be coded to the preferred term (PT) level using the Medical Dictionary for Regulatory Affairs 
(MedDRA dictionary  version 21.1) and grouped by system organ class (SOC). AEs will be graded by the 
investigator according to the NCI-CTCAE v4.03.   
All AEs will be listed.  
11.3. 
Adverse Events of Special Interest 
For any cardiovascular events detailed in Protocol Appendix 6 and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden cardiac death) and 
non-cardiovascular death.  CV and death data will be listed separately. 
11.4. 
Deaths and Serious Adverse Events (SAEs) 
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.  A 
listing will be generated to provide subject-specific details on subjects who died.  
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. 
Primary and secondary cause of death will be presented in subject data listings. 


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11.5. 
Adverse Events Leading to Discontinuation of Study Treatment and/or 
Withdrawal from the Study and Other Significant Adverse Events 
Separate AEs supportive listings will be generated with subject level details for those subjects: 
 
AEs leading to discontinuation of study treatment  
 
AEs leading to withdrawal from the study 
 
AEs leading to dose interruptions 
 
AEs leadings to dose reductions 
11.6. 
Clinical Laboratory Evaluations 
The assessment of laboratory toxicities will examine the following laboratory tests:  
Clinical Chemistry: Total and direct bilirubin, Aspartate aminotransferase (AST), Alanine aminotransferase 
(ALT), Alkaline phosphatase, Total Protein, Albumin, Sodium, Potassium, Calcium, Blood Urea Nitrogen 
(BUN), Creatinine, Chloride, Fasting Glucose, Ionized Calcium, Gamma-glutamyltransferase, Total carbon 
dioxide , Uric Acid, and Magnesium. 
 
Hematology: Hemoglobin (HGB), Platelet count, Red Blood Cell (RBC) count, White Blood Cell (WBC) 
count, Neutrophils (Absolute), Lymphocytes (Absolute), Monocytes (Absolute), Eosinophils (Absolute), 
Basophils (Absolute), Neutrophils (%), Lymphocytes (%), Monocytes (%), Eosinophils (%) and Basophils (%).  
Thyroid Function Test: Thyroid-stimulating hormone (TSH) and free thyroxine (T4 and T3) test.  
Urinalysis: pH, Microscopic examination, Specific gravity, Ketones, Protein, Glucose, Blood. 
Coagulation Test: Prothrombin Time, Partial Thromboplastin Time (PTT), International Normalized Ratio 
(INR), and Fibrinogen. 
Pancreatic Markers: Amylase, Lipase.  
Lipid Panel: Triglycerides, Total Cholesterol, low density lipoprotein (LDL), and high density lipoprotein 
(HDL).  
Serum: Creatine Kinase (CK), Creatine Kinase-MB isoenzyme (CKMB), Troponin I, Troponin T, N-terminal 
pro–B-Type natriuretic peptide (NT-proBNP), Thyroid-stimulating hormone (TSH), C-Peptide, 1,5-
Anhydroglucitol (1,5 AG), Hemoglobin A1C, and Insulin. 
Laboratory grades will be reported, where applicable, using the Common Terminology Criteria for Adverse 
Events (CTCAE v4.03). Listings of laboratory data will be provided. 


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11.7. 
Other Safety Measures 
Vital Signs 
A listing will be provided. Categories defined in Section 8.3.2 will be presented in the listing as well. 
Performance Status 
ECOG performance status will be listed. Change from baseline will be presented in the listing as well.   
ECG 
Listings of abnormal ECG findings and a listing of ECG values will be provided.  
Left ventricular ejection fraction (LVEF) 
LVEF results will be listed with subject level details including absolute change from baseline. 
12. 
HEALTH OUTCOMES ANALYSES 
No health outcomes analyses were planned for the study. 
13. 
PHARMACOKINETIC ANALYSES 
PK analysis of GSK2820151 drug concentration-time data and derivation of PK parameters will be conducted 
by non-compartmental methods using Phoenix WinNonlin Version 6.4 or higher under the direction of Clinical 
Pharmacology Modelling and Simulation (CPMS), GSK. Unless otherwise stated, all listings in this section will 
be based on the Pharmacokinetic population. 
13.1. 
Drug Concentration Measures 
Drug concentration-time data will be listed for each subject.  
13.2. 
Deriving and Summarizing Pharmacokinetic Parameters 
For subjects in the active treatment group, the pharmacokinetic parameters will be determined directly from the 
concentration-time data and will be extracted from the pharmacokinetic concentration file by CPMS GSK. 
 
For the calculation of individual pharmacokinetic profiles, if one or more non-quantifiable (NQ) values occur in 
a profile before the first measurable concentration, they will be assigned a value of zero concentration. If a 
single NQ value occurs between measurable concentrations in a profile, the NQ should generally be omitted (set 
to missing) in the derivation of pharmacokinetic parameters. If two or more NQ values occur in succession 
between measurable concentrations, these NQs and any subsequent measurable concentrations will be omitted 
(set to missing) for the derivation of pharmacokinetic parameters. 
NQs which occur after the last measurable concentration will be omitted (set to missing) in the derivation of 
pharmacokinetic parameters.  


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The following PK parameters will be determined if data permit:   
 
maximum observed concentration (Cmax) 
 
time to Cmax (tmax) 
 
area under the plasma concentration-time curve (AUC(0-t), AUC(0-∞) (Week1 Day1 only), AUC(0-τ)) 
 
apparent terminal phase half-life (t½)  
 
Trough concentration (Cτ) 
 
The observed accumulation ratio (Ro) 
The ratio of AUC(0-τ) on Week 3 Day 4 / Week 1 Day 1 AUC(0-τ) will be calculated to assess time 
invariance.  
 
Clearance (CL/F) and Volume of distribution (Vz/F) 
All derived PK parameters will be listed. 
14. 
PHARMACOGENETIC DATA ANALYSES 
Further details on PGx analyses discussed in the protocol may be identified/addressed in a separate RAP, if 
applicable.   


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15. 
REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 45: 228-247. 
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4.03, DCTD, NCI, NIH, 
DHHS, June 14, 2010.  
 Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. 
Statistics Med. 2008; 27:2420-2439. 
 
 


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16. 
 APPENDIX 1: LIST OF DATA DISPLAYS 
16.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Listings 
ICH Listings 
1 to 46 
Non-ICH Listings 
47 to 53 
16.2. 
Deliverable  
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 
16.3. 
ICH Listings 
No. 
Population 
Title  
Programming 
Notes 
Deliverable  
Subject Disposition 
1.  
All Treated 
Listing of Subject Consent 
ICH E3 
SAC  
2.  
All Treated 
Listing of Scheduled and Actual Treatment 
ICH E3 
SAC  
3.  
All Treated 
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC  
4.  
All Treated 
Listing of GSK2820151 Treatment 
Discontinuations 
ICH E3 
SAC  
Protocol Deviations 
5.  
All Treated 
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations 
ICH E3 
SAC 
6.  
All Treated 
Listing of Protocol Deviations 
 
 
Demographic and Baseline Characteristics 
7.  
All Treated 
Listing of Demographic Characteristics 
ICH E3 
SAC 
8.  
All Treated 
Listing of Race 
ICH E3 
SAC  
9.  
All Treated 
Listing of Family History 
ICH E3 
SAC  
10.  
All Treated 
Listing of Medical Conditions 
ICH E3 
SAC  
11.  
All Treated 
Listing of Disease Characteristics at Initial 
Diagnosis 
ICH E3 
SAC  
12.  
All Treated 
Listing of Disease Characteristics at Screening 
ICH E3 
SAC  
Prior and Concomitant Medications 
13.  
All Treated 
Listing of Prior Anti-Cancer Therapy 
Study specific 
SAC  
14.  
All Treated 
Listing of Prior Anti-Cancer Radiotherapy 
Study specific 
SAC  


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No. 
Population 
Title  
Programming 
Notes 
Deliverable  
15.  
All Treated 
Listing of Prior Cancer and Non-Cancer Related 
Surgical Procedures 
Study specific 
SAC  
16.  
All Treated 
Listing of Concomitant Medications 
ICH E3 
SAC  
17.  
All Treated 
Listing of Blood Products and Blood Supportive 
Care Products 
Study specific 
SAC  
18.  
All Treated 
Listing of Follow-Up Anti-Cancer Therapy 
Study specific 
SAC  
19.  
All Treated 
Listing of Follow-Up Surgical Procedures 
Study specific 
SAC  
Exposure and Treatment Compliance 
20.  
All Treated 
Listing of Exposure to GSK2820151 
ICH E3 
SAC  
21.  
All Treated 
Listing of Dose Interruptions 
ICH E3 
SAC  
22.  
All Treated 
Listing of Dose Reductions 
ICH E3 
SAC  
Adverse Events 
23.  All Treated 
Listing of Adverse Events Profiles 
ICH E3 
SAC  
Serious and Other Significant Adverse Events 
24.  
All Treated 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC  
25.  
All Treated 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC  
26.  
All Treated 
Listing of Adverse Events Leading to 
Discontinuations of GSK2820151 Treatment 
Profiles 
ICH E3 
SAC  
27.  
All Treated 
Listing of Adverse Events Leading to Dose 
Interruptions 
ICH E3 
SAC  
28.  
All Treated 
Listing of Adverse Events Leading to Dose 
Reductions 
ICH E3 
SAC  
29.  
All Treated 
Listing of Adverse Events Recorded as Dose-
Limiting Toxicities 
Study specific 
SAC  
30.  
All Treated 
Listing of Adverse Events of Special Interest 
Study specific 
SAC  
31.  
All Treated 
Listing of Deaths 
ICH E3 
SAC  
32.  
All Treated 
Listing of Subject Numbers for Specific Causes 
of Deaths 
ICH E3 
SAC  
All Laboratory 
33.  
All Treated 
Listing of Clinical Chemistry Data 
ICH E3 
SAC  
34.  
All Treated 
Listing of Hematology Data 
ICH E3 
SAC  
35.  
All Treated 
Listing of Thyroid Function Test Data 
ICH E3 
SAC  
36.  
All Treated 
Listing of Urinalysis Data 
ICH E3 
SAC  
37.  
All Treated 
Listing of Coagulation Data 
ICH E3 
SAC  


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No. 
Population 
Title  
Programming 
Notes 
Deliverable  
38.  
All Treated 
Listing of Pancreatic Markers Data 
ICH E3 
SAC  
39.  
All Treated 
Listing of Lipid Panel Data 
ICH E3 
SAC  
40.  
All Treated 
Listing of Serum Data 
ICH E3 
SAC  
Vital Signs 
41.  
All Treated 
Listing of Vital Signs 
ICH E3 
SAC  
ECOG 
42.  
All Treated 
Listing of ECOG Performance Status Scale 
ICH E3 
SAC  
ECG and LVEF 
43.  
All Treated 
Listing of Abnormal ECG Findings 
ICH E3 
SAC  
44.  
All Treated 
Listing of ECG Values 
ICH E3 
SAC  
45.  
All Treated 
Listing of Change from Baseline ECG Values 
ICH E3 
SAC  
46.  
All Treated 
Listing of Left Ventricular Ejection Fraction 
(LVEF) ECHO Results 
ICH E3 
SAC  
16.4. 
Non-ICH Listings 
No. 
Population 
Title  
Programming 
Notes 
Deliverable  
Efficacy Endpoints 
47.  
All Treated 
Listing of Investigator-Assessed Response 
(RECIST 1.1) 
Study specific 
SAC  
48.  
All Treated 
Listing of Investigator–Assessed Target Lesions 
(RECIST 1.1) 
Study specific 
SAC  
49.  
All Treated 
Listing of Investigator–Assessed Non-Target 
Lesions (RECIST 1.1) 
Study specific 
SAC  
50.  
All Treated 
Listing of Investigator–Assessed New Lesions      Study specific 
SAC  
51.  
All Treated 
Listing of Progression Free Survival (RECIST 
1.1) 
Study specific 
 


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No. 
Population 
Title  
Programming 
Notes 
Deliverable  
Pharmacokinetic 
52.  PK Population Listing of GSK2820151 Pharmacokinetic 
Concentration-Time Data 
ICH E3 
SAC 
53.  PK Population Listing of Derived GSK2820151 
Pharmacokinetic Parameters 
ICH E3 
SAC 
 


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32 
 
Listing 1  
Listing of Subject Consent 
Country: xxxxxx 
Investigator: xxxxx xxxxxx 
 
Center/ 
Subject ID 
Original Informed Consent 
 
Reconsented 
 
Pharmacogenetic 
Research Consent 
Date 
Consent  
Version 
Protocol  
Version 
 Date 
Consent  
Version 
Protocol  
Version 
 
Date 
Reason 
Date of 
Withdrawal 
 
 
 
 
  
 
 
  
 
 
xxxx/ 
xxxxxx 
ddMMMyyyy 
xxx 
xxx 
 ddMMMyyyy 
xxx 
xxx 
 ddMMMyyyy 
 
 
xxxx/ 
xxxxxx 
ddMMMyyyy 
xxx 
xxx 
 ddMMMyyyy 
xxx 
xxx 
  
xxx 
 
xxxx/ 
xxxxxx 
ddMMMyyyy 
xxx 
xxx 
 ddMMMyyyy 
xxx 
xxx 
 ddMMMyyyy 
 
ddMMMyyyy 
 
 
 


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Population: All Treated 
 
 
33 
 
Listing 2  
Listing of Scheduled and Actual Treatment 
 
Country: xxxxxx 
Center:  XXXX 
Investigator: xxxxxx xxxxxx 
 
Subject ID 
Planned Treatment 
Actual Treatment 
 
xxxx 
3 mg 
3 mg 
 
6 mg 
6 mg 
 
 


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Population: All Treated 
 
 
34 
 
Listing 3 
Listing of Reasons for Study Withdrawal 
 
Treatment = GSK2820151 xxx mg 
Center/ 
Subject ID 
Date of 
Withdrawal  
Study 
Day 
 
Primary Reason 
 
Subreason 
 
 
 
 
 
xxxx/ 
xxxxxx 
ddMMMyyyy  
x 
Study closed/terminated 
 
xxxx/ 
xxxxxx  
ddMMMyyyy  
x 
Lost to Follow-up 
 
xxxx/ 
xxxxxx 
ddMMMyyyy 
xx 
Investigator discretion 
 
… 
 
 
 
 
 
 
 
 
 
 
  


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35 
 
Listing 4 
Listing of GSK2820151 Treatment Discontinuations 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
Cumulative 
Dose (mg) 
Date of 
Last Dose 
Study 
Day 
Primary Reason for  
Treatment Discontinuation 
 
 
 
 
 
xxxxx/ 
xxxxxx 
xxx 
ddMMMyyyy 
xx 
xxxxxxxxxxxxxxxxx 
xxxxx/ 
xxxxxx 
xxx 
ddMMMyyyy 
xx 
xxxxxxxxxxxxxxxxx 
xxxxx/ 
xxxxxx 
xxx 
ddMMMyyyy 
xx 
xxxxxxxxxxxxxxxxx 
xxxxx/ 
xxxxxx 
xxx 
ddMMMyyyy 
xx 
Xxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
  
 
 


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Listing 5 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Type 
Criterion 
 
 
 
xxxxx/ 
xxxxxx 
Inclusion 
Written informed consent provided 
 
 
 
xxxxx/ 
xxxxxx 
Exclusion 
Prior malignancy of the central nervous system or malignancies related to human 
immunodeficiency virus (HIV) or solid organ transplant 
 
 
 
xxxxx/ 
xxxxxx 
xxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 


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Listing 6 
Listing of Protocol Deviations 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
Date of 
Deviation/ 
Study day 
Category 
Description 
 
 
 
 
xxxxxx/ 
xxxxxx 
 
ddMMMyyyy/ 
xx 
Prohibited medication or device 
xxxxxxxxxxxxx 
 
 
ddMMMyyyy/ 
xx 
Assessments and/or procedures/ 
Study treatment supply procedure 
xxxxxxxxxxx 
 
 
 
 
xxxxxx/ 
xxxxxxx 
ddMMMyyyy/ 
xx 
Eligibility criteria not met  
xxxxxxx 
 
 
 
 
xxxxx/ 
xxxxxx 
ddMMMyyyy/ 
xx 
Not withdrawn after developing 
withdrawal criteria/ 
Not discontinued from study treatment 
xxxxxxx 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
38 
 
Listing 7 
Listing of Demographic Characteristics 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Year of 
Birth[1] 
Age  
(Years) 
 
Sex 
Child-bearing 
Potential 
 
Ethnicity 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m^2) 
 
 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx  
xxxx 
xx 
F 
Pre-menarcheal 
Hispanic or Latino 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx  
xxxx 
xx 
F 
xxxxxxxxxxxxxx 
Not Hispanic or Latino 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
xxxx 
xx 
M 
 
Not Hispanic or Latino 
xxx.x 
xx.x 
xx.x 
 
[1] For calculating age, birthdate is imputed as June 30 in the year of birth. 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
39 
 
Listing 8 
Listing of Race 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
 
Race 
 
 
xxxxx/ 
xxxxxx  
African American/African Heritage 
Asian – East Asian Heritage 
 
 
xxxxx/ 
xxxxxx  
White – White/Caucasian/European Heritage 
 
 
xxxxx/ 
xxxxxx 
African American/African Heritage 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
40 
 
Listing 9 
Listing of Family History 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
A family history of premature coronary artery disease in women <65 yrs or  
men <55 years in first degree relatives only? 
 
 
xxxxx/ 
xxxxxx 
Yes 
xxxxx/ 
xxxxxx 
No 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
41 
 
Listing 10 
Listing of Medical Conditions 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
Category 
Medical Condition 
Status 
NCI CTCAE  
Grade 
Classification 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
Cardiovascular 
Risk Factors 
ANGINA PECTORIS  
Current 
 
xxxxx 
 
 
DIABETES  
Past 
 
xxxxx 
 
 
HYPERTENSION  
Current 
x 
 
 
 
 
Current 
 
xxxxx 
 
 
 
Current 
 
xxxxxxxxxxx 
 
 
 
Not assessed 
 
 
 
Other medical  
condition 
xxxxx 
Current 
 
xxxx 
 
 
xxxxxxx 
Past 
 
xxxx 
 
 
xxxxxxxxx 
Current 
x 
xxxx 
 
 
 
 
 
 
NCI-CTCAE version 4.03 
 
Programming note: As coding is not done for medical conditions in SDTM MH, please display MHTERM as verbatim term as in other AE listings.  


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
42 
 
Listing 11 
Listing of Disease Characteristics at Initial Diagnosis 
 
Treatment = xxxxxx 
 
 
Center/ 
Subject ID 
Primary 
Tumor 
Type 
 
Date of  
Diagnosis/ Time 
Since Diagnosis 
(Months) 
Histology of Tumor 
Histological 
Grade 
Primary 
Tumor HPV 
Status 
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Bladder 
ddMMMyyyy/10.2  
xxxx 
Well 
differentiated 
Negative 
xxxx/ 
xxxxxx 
Xxxx 
ddMMMyyyy/xxx.x 
xxxx 
xxx 
xxxxxxxx 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
43 
 
Listing 12 
Listing of Disease Characteristics at Screening 
 
Treatment = xxxxxx 
 
 
 
Center/ 
Subject ID 
 
Measurable 
Disease 
Non Target 
Lesions 
 
Stage 
Progress on 
Therapy? 
Date of Last 
Recurrence/Time from 
Last Recurrence 
(Months) 
Metastatic/ 
Unresectable 
Disease 
Number of 
Previous 
Radiotherapy 
Regimens 
 
 
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Yes 
Yes 
III 
YES 
ddMMMyyyy/xx.x 
Yes 
2 
xxxx/ 
xxxxxx 
.. 
.. 
IIIA 
NO 
ddMMMyyyy/x.x 
XXX 
1 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
44 
 
Listing 13 
Listing of Prior Anti-Cancer Therapy 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
ATC Level 1/ 
Preferred Term/ 
Verbatim Text 
Regimen 
Sequence/ 
Type [1] 
 
 
Intent 
Start Date/ 
Study Day/ 
Stop Date/ 
Study Day 
Duration of 
Therapy  
(Days) 
 
Small Molecule Targeted 
Therapy Type 
 
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Endocrine & metabolic/ 
Cytoxan/ 
CYTOXAN 
1/ 
C 
 
 
Neo-Adjuvant 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xxx  
AKT Inhibitor 
 
xxxxxxxxxx/ 
xxxxxxxxxx/ 
XXXXXXXX 
x/ 
H 
 
 
Induction 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xxx  
 
 
[1]Therapy Type: C=Chemotherapy, H=Hormonal Therapy, I=Immunotherapy, B=Biologic Therapy. 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
45 
 
  
Listing 14 
Listing of Prior Anti-Cancer Radiotherapy 
 
Treatment = xxxxxx 
 
 
Center/ 
Subject ID 
 
Body Site 
 
Cumulative 
Dose (unit)/ 
Intent 
Start Date/ 
Study Day/ 
Stop Date/ 
Study Day 
Duration of 
Therapy (Days) 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
RIGHT UPPER 
LOBE LUNG 
xxx (xxxx)/ 
Local/Regional 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xxx 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
CHEST 
xxx (xxxx)/ 
Palliative 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xxx 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
COLON 
xxx (xxxx)/ 
Local/Regional 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xx  
 
 
 
 
 
xxxxxx/ 
xxxxxx 
COLON 
xxx (xxxx)/ 
Local/Regional 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
xxx 
xx  
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
46 
 
Listing 15 
Listing of Prior Cancer and Non-Cancer Related Surgical Procedures 
 
Treatment = xxxxxx 
 
 
Center 
 
Subject 
Classification 
Date of 
Procedure 
Study 
Day 
 
Verbatim Term 
 
 
 
 
 
 
xxxxx 
xxxx 
Cancer related 
 
 
ddMMMyyyy 
-xx 
 
 
 
Cancer related 
ddMMMyyyy 
 xx 
 
 
 
 
 
 
 
 
xxxx 
Cancer related 
ddMMMyyyy 
 xx 
 
 
 
 
 
 
 
xxxxx 
xxxx 
Cancer related 
ddMMMyyyy 
 
-xx 
 
 
 
Other 
general 
ddMMMyyyy 
xxx 
Hysterectomy 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
47 
 
  
Listing 16 
Listing of Concomitant Medications 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
ATC Level 1/ 
Ingredient/ 
Verbatim Text 
Dose/  
Units/  
Freq/  
Route 
Date Started/ 
Study Day 
Date Stopped/ 
Study Day 
Medication 
Category 
Reason 
For Medication 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
Fluticasone propionate/ 
FLIXOTIDE/ 
Asthma 
xx/  
MG/ 
2XD/ 
IH 
ddMMMyyyy/ 
xx 
ddMMMyyyy/ 
xx 
General Concomitant 
Medication 
xxxxx 
xxxxx/ 
xxxxxx 
XXXXXXXXXX/ 
xxxxxxx 
xxx/  
xxx/ 
xxxx/ 
xx 
ddMMMyyyy/ 
xx 
ddMMMyyyy/ 
xx 
Concomitant Medication 
of Interest 
/Suspected in causing SAE 
xxxxx 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
48 
 
Listing 17 
Listing of Blood Products and Blood Supportive Care Products 
 
Treatment = xxxxx 
Center/ 
Subject 
ID 
For SF, was 
it admin-
istered? 
Product 
Product Type 
Date 
Quantity or 
Dose 
 
 
Unit 
Frequency 
 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
P 
Blood products 
Red Blood Cells 
ddMMMyyyy 
xxx 
 
 
 
 
 
Platelets 
ddMMMyyyy 
xxx 
 
 
 
 
 
Whole Blood 
ddMMMyyyy 
xxx 
 
 
 
 
 
Plasma - FFP 
ddMMMyyyy 
xxx 
 
 
 
 
 
Cryoprecipitate 
ddMMMyyyy 
xxx 
 
 
 
 
 
White Blood Cells 
ddMMMyyyy 
xxx 
 
 
… 
 
 
Other Blood Product, specify 
ddMMMyyyy 
xxx 
 
 
 
 
 
 
 
xxx 
 
 
 
 
Blood supportive 
care products 
darbepoetin alfa (Aranesp) 
ddMMMyyyy 
xxx 
 
 
 
 
 
eltrombopag (i.e. Promacta) 
ddMMMyyyy 
xxx 
 
 
 
 
 
pegfilgrastim (NeulastaR) 
ddMMMyyyy 
xxx 
 
 
 
 
 
romiplostim (i.e. NPlate) 
ddMMMyyyy 
xxx 
 
 
SF: stimulating Factor; P = Prophylactically; A = As treatment.  


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
49 
 
Listing 18 
Listing of Follow-Up Anti-Cancer Therapy 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
Best Response 
Time to 
Progression 
(Days) 
ATC Level 1/ 
Preferred Term/ 
Verbatim Text 
Start Date/ 
Study Day/ 
Stop Date/ 
Study Day 
Duration 
of 
Therapy 
Type 
of 
Therapy 
Reason for 
Stopping Therapy 
 
 
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Progressive 
disease 
xxx 
Endocrine & metabolic/ 
Cytoxan/ 
CYTOXAN 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
-xxx 
xxx d 
Chemotherapy 
xxxxx 
 
 
 
xxxxxxxx/ 
xxxxxxxxxx/ 
XXXXXXXXXX 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
-xxx 
xxx d 
Hormonal 
xxxxx 
 
 
 
xxxxxxxx/ 
xxxxxxxxxx/ 
XXXXXXXXXX 
ddMMMyyyy/ 
xxx/ 
ddMMMyyyy/ 
-xxx 
xxx d 
Radiation 
xxxxxxxxxxx 
 
Note: Follow-up surgeries are listed separately. 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
50 
 
Listing 19 
Listing of Follow-Up Surgical Procedures 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Classification 
Date of 
Procedure 
Study 
Day 
 
Verbatim Term 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
Cancer related 
 
 
ddMMMyyyy 
xx 
 
 
Cancer related 
ddMMMyyyy 
xx 
 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
Cancer related 
ddMMMyyyy 
 
xx 
 
 
Other surgical procedures 
ddMMMyyyy 
xxx 
Hysterectomy 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
51 
 
 Listing 20 
Listing of Exposure to GSK2820151 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Average Daily 
Dose 
Start Date/ 
Study Day 
 
 
Stop Date/  
Study Day 
 
 
Dose  
(mg) 
 
Cumulative  
Dose 
(mg) 
  
 
 
 
 
 
xxxx/ 
xxxxxx 
xxxx 
ddMMMyyyy 
xx 
xx/ 
xx 
xx 
xx 
 
 
 
 
 
 
Average daily dose is defined as the cumulative dose divided by the duration of exposure for each subject in days. 
The cumulative dose is the sum of the doses administered for a subject. 
 
 
Note: Average Daily Dose and Cumulative Dose are derived per subject.  Please only display once for each subject. 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
52 
 
Listing 21 
Listing of Dose Interruptions 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
 
Dosing Date/ 
Study Day/ 
Dose (mg) 
 
 
Primary Reason for Interruption/ 
Specify 
  
 
 
xxxxx/ 
xxxxxx 
 
42/ 
0.80 
xxxx/xxxxxxxxx 
 
 
 
 
PPD


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
53 
 
Listing 22 
Listing of Dose Reductions 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
 
 
Dosing Date/ 
Study Day/ 
Dose (mg) 
 
 
Primary Reason for Reduction/ 
Specify 
  
 
 
xxxxx/ 
xxxxxx 
ddMMMyyyy/ 
xx/ 
xx 
xxxx/xxxxxxxxx 
 
 
 
 
   


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
54 
 
Listing 23 
Listing of Adverse Events Profiles 
 
Treatment = xxxxxx 
 
Center/ 
Subject 
ID 
Age(Years)/ 
Sex/ 
Race 
Preferred Term/ 
Verbatim Text 
Outcome/ 
Onset Date/ 
Resolve Date/ 
Frequency/ 
Duration  
Maximum Grade/ 
Serious/ 
Withdrawal from 
Study 
Time since  
1st Dose/  
Last Dose  
Action(s) taken 
with Treatment/ 
Relation to GSK2820151 Treatment 
 
Dose 
Limiting 
Toxicity? 
  
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
 
 
65/ 
Female/ 
White 
Nausea/ 
NAUSEA 
Resolved/ 
ddMMMyyyy/ 
ddMMMyyyy/ 
Single Episode/ 
xx d 
Grade 4/ 
Yes/ 
Yes 
xx d/ 
xx d 
xxxxxxxxxxxxxx/ 
XXXX 
 
Yes 
 
 
 
 
 
 
 
 
 
  


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
55 
 
Same format for:  
 
Listing 24 
Listing of Fatal Serious Adverse Events 
 
Listing 25 
Listing of Non-Fatal Serious Adverse Events 
 
Listing 26 
Listing of Adverse Events Leading to Discontinuations of GSK2820151 Treatment Profiles 
 
 
Listing 27 
Listing of Adverse Events Leading to Dose Interruptions 
 
Listing 28 
Listing of Adverse Events Leading to Dose Reductions 
 
Listing 29 
Listing of Adverse Events Recorded as Dose-Limiting Toxicities 
 
Listing 30 
Listing of Adverse Events of Special Interest 
 
Programming Note: For Listing 30, Add the following footnote. 
“Adverse Events of Special Interest are defined as any cardiovascular or death events.” 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
56 
 
Listing 31 
Listing of Deaths 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
Primary Cause of Death/ 
Secondary Cause of Death 
Date of Death/ 
Study Day 
Time From  
Last Dose 
Last Dose 
(unit) 
 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
62/ 
M/ 
White 
xxxxxxxx/ 
xxxxxxxxxxxxx 
ddMMMyyyy/ 
xx 
xx d 
x/ 
xx 
 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
45/ 
F/ 
Black 
xxxxxxxx/ 
xxxxxxxxxxxxx 
ddMMMyyyy/ 
xx 
xx d 
x/ 
xx 
 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
61/ 
M/ 
South Asian 
xxxxxxxx/ 
xxxxxxxxxxxxx 
ddMMMyyyy/ 
xx 
xx d 
x/ 
xx 
 
 
 
 
 
 
xxxxxx/ 
xxxxxx 
52/ 
F/ 
White 
xxxxxxxx/ 
xxxxxxxxxxxxx 
ddMMMyyyy/ 
xx 
xx d 
x/ 
xx 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
57 
 
Listing 32 
Listing of Subject Numbers for Specific Causes of Deaths 
 
 
Primary Cause of Death 
 
Secondary Cause of Death 
 
Treatment 
Number of 
Subjects 
 
Subject Number 
 
 
 
 
 
 Cancer 
xxxxxxxxxxxxxxxxxxxx 
xxxxx 
2 
xxxxxx, xxxxxx 
 
 
xxxxx 
1 
xxxxxx 
 
 
 
 
 
 Myocardial infarction 
Haematologic Event 
xxxxx 
1 
xxxxxx 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
58 
 
Listing 33 
Listing of Clinical Chemistry Data 
 
Treatment =xxxxxx 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
Lab Test (units) 
Planned 
Time 
Collection 
Date  
Study 
Day 
Converted Data 
NR Flag 
[1] 
Grade 
[2] 
Result 
Low-High 
xxxxxx/ 
63/ 
Alk Phos (xxx) 
Screening 
ddMMMyyyy 
-x 
xx.xx 
xx.x– xx.x 
 
x 
xxxxxx 
Male/ 
 
Week 1 Day 1 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
 
x 
 
White 
 
Week x Day x 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
 
x 
 
 
 
… 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
H 
x 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (xxx) 
Screening 
ddMMMyyyy 
-x 
xx.xx 
xx.x- xx.x 
 
x 
 
 
 
Week 1 Day 1 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
H 
x 
 
 
 
Week x Day x 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
H 
x 
 
 
 
… 
ddMMMyyyy 
xx 
xx.xx 
xx.x- xx.x 
H 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Hemoglobin (xxx) 
Screening 
ddMMMyyyy 
-x 
xx.x 
x.x- xx.x 
 
x 
 
 
 
Week 1 Day 1 
ddMMMyyyy 
xx 
xx.x 
x.x- xx.x 
 
x 
 
 
 
Week x Day x 
ddMMMyyyy 
xx 
xx.x 
x.x- xx.x 
 
x 
 
 
 
… 
ddMMMyyyy 
xx 
xx.x 
x.x- xx.x 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Platelets (xxxx) 
Screening 
ddMMMyyyy 
-x 
xxx.x 
xxx.x-xxx.x 
 
x 
 
 
  
… 
ddMMMyyyy 
xx 
xxx.x 
xxx.x-xxx.x 
 
x 
 
[1] NR for Normal Range flag; H=Above range, L=Below range, N=Normal range. 
[2] NCI-CTCAE version 4.03 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
59 
 
Same format for: 
Listing 34 
Listing of Hematology Data 
 
Listing 35 
Listing of Thyroid Function Test Data 
 
Listing 36 
Listing of Urinalysis Data 
 
Listing 37 
Listing of Coagulation Data 
 
Listing 38 
Listing of Pancreatic Markers Data 
 
Listing 39 
Listing of Lipid Panel Data 
 
Listing 40 
Listing of Serum Data 
 
 
Programming note: for listing 35, please include lab tests as available in SDTM: Thyrotropin (xxx), Thyroxine, Free (pxxx), and 
Triiodothyronine, Free (xxx). 
 
Programming note for listing 36, please include qualitative urinalysis data (AVALC is populated) per RAP section 11.7. High, Low, NR Flag 
will be left blank.  
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
60 
 
  
   
Listing 41 
Listing of Vital Signs 
 
Treatment = xxxxx 
Note: L = Low, H = High. 
Systolic BP (mmHg): Grade 0 (<120), Grade 1 (>=120-<140), Grade 2 (>=140-<160) and Grade 3 (>=160), only applies to post-baseline records 
with increase from baseline. 
Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (>=80-<90), Grade 2 (>=90-<100), and Grade 3 (>=100), only applies to post-baseline records with 
increase from baseline. 
Heart Rate (beats/min): L (<60), H (>100), only applies to post-baseline records. 
Temperature (C): L (<=35), H (>=38), only applies to post-baseline records. 
 
 
Programming note: repeated readings are only applicable for BP measurements and Heart Rate for some assessments, e.g. Week 1 Day 2. 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
Planned  
Time 
Study 
Day 
Actual  
Date/Time   
Reading 
 
Systolic 
Blood 
Pressure 
(mmHg)/ 
Grade 
Diastolic 
Blood 
Pressure 
(mmHg)/ 
Grade 
Heart 
Rate  
(bests
/min) 
Respiratory 
Rate 
(breaths/mi
n) 
Temperature 
(C) 
Weight 
(kg) 
 
 
Screening 
 
 
 
 
 
 
 
 
xxx/ 
xxxxxx 
23/  
Male/  
White 
 Week 1 
Day 2 
-xx 
ddMMMyyyy  1 
/hh:mm 
xx/ 
Grade 0 
xx/ 
Grade 0 
xx H 
xx 
xx 
xx 
 
 
 
 
ddMMMyyyy  2 
/hh:mm 
xxx/ 
Grade 1 
xxx/ 
Grade 1 
xx  
 
 
 
 
 
ddMMMyyyy  3 
/hh:mm 
ddMMMyyyy 
Average 
/hh:mm 
 
 
xxx/ 
Grade 2 
 
xxx/ 
Grade 3 
xxx/ 
Grade 2 
 
xxx/ 
Grade 3 
Xx 
 
 
 
 
 
 
 
 
Week x Day 
x 
1 
ddMMMyyyy 
/hh:mm 
xxx/ 
Grade 3 
xxx/ 
Grade 3 
xx H 
xx  
xx H 
xx 
 
 
 
 
ddMMMyyyy 
/hh:mm 
xxx/ 
Grade 0 
xxx/ 
Grade 0 
xx H  
xx  
xx H 
xx 
 
 
 
 
ddMMMyyyy 
/hh:mm  
xxx/ 
Grade 2 
xxx/ 
Grade 2 
xx L 
xx  
xx L 
xx 
 
 
… 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
61 
 
Listing 42 
Listing of ECOG Performance Status Scale 
 
Treatment = xxxxx 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
Planned  
Time 
Study 
Day 
Actual  
Date 
ECOG Performance Status * 
Change from Baseline 
 
 
 
 
 
 
 
xxx/ 
xxxxxx 
23/  
Male/  
White 
Screening 
-xx 
ddMMMyyyy 
1 
 
 
 
Week x Day x 
xx 
ddMMMyyyy 
 
0 
x 
 
 
Week x Day x  
 
 
 
 
 
 
 
 
 
 
 
 
*0 = Fully active, able to carry on all pre-disease performance without restriction; 
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house 
work, office work; 
2 = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 
3 = Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 
4 = Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 
5 = Dead. 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
62 
 
Listing 43 
Listing of Abnormal ECG Findings 
 
Treatment = xxxxxx 
Vendor = ERT 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race      
 
Planned Time/ 
Date/Time/ 
Study Day 
 
 
 
Triplicate 
 
Result 
Clinically 
Significant 
? 
 
 
 
 
 
 
xxx/ 
xxxxxx 
65/     
White/   
Female 
Week x Day X Pre-dose/  
ddMMMyyyy 
hh:mm/ 
x 
 
 
 
 
1 
 
 
 
2 
 
3 
Abnormal 
 
 
Abnormal 
 
 
Abnormal 
 
No 
 
 
No 
 
 
No 
xxx/ 
xxxxxx 
58 
White/ 
Male 
Week x Day x 15m/ 
ddMMMyyyy 
hh:mm/ 
x 
X 
Abnormal 
 
 
Yes 
 
 
 
 
 
 
 
Programming note: ECG labs are collected by both local and central labs. Please display separately. 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
63 
 
Listing 44 
Listing of ECG Values 
 
Treatment = xxxxxx 
Vendor = ERT 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race            
 
Planned  
Time/ 
Date/Time/ 
Study Day 
 
 
Triplicate 
 
Heart  
Rate 
(beats/min.) 
PR 
Interval 
(msec) 
QRS 
Duration 
(msec) 
QT 
Interval 
(msec) 
QTc 
(Fridericia) 
(msec) 
 
 
 
 
  
 
 
 
 
xxx/ 
xxxxxx 
23/             
Male/ 
White 
Screening 
1 
 xx 
xxx 
xxx 
xxx 
xxx 
2 
 xx 
xxx 
xxx 
xxx 
xxx 
3 
 xx 
xxx 
xxx 
xxx 
xxx 
 
 
 
Average 
 xx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
  
 
 
 
 
 
 
Week X Day X 
Pre-dose 
xx 
 xx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
  
 
 
 
 
 
Programming note: ECG labs are collected by both local and central labs. Please display separately. 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
64 
 
Listing 45 
Listing of Change from Baseline ECG Values 
 
Treatment = xxxxxx 
Vendor = ERT 
 
 
 
 
 
Change from Baseline 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race                 
 
Planned  
Time/ 
Date/Time/ 
Study Day 
 
Heart  
Rate 
(beats/min.) 
PR 
Interval 
(msec) 
QRS 
Duration 
(msec) 
QT 
Interval 
(msec) 
QTc 
(Fridericia) 
(msec) 
 
 
 
  
 
 
 
 
xxx/ 
xxxxxx 
23/                 
Male/  
White 
Screening 
 xx 
xxx 
xxx 
xxx 
xxx 
Week X Day X Pre-dose 
 xx 
xxx 
xxx 
xxx 
xxx 
 
 
 
  
 
 
 
 
Note: Average values of each visit were used to calculate baseline and post-baseline values.  
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
65 
 
Listing 46 
Listing of Left Ventricular Ejection Fraction (LVEF) ECHO Results 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
 
Planned  
Time 
 
Study 
Day 
 
 
Scan Date 
 Vendor 
LVEF 
(%) 
Absolute Change 
From Baseline 
Scan Results 
 
 
 
 
 
 
 
 
 
xxx/ 
xxxxxx 
23/  
Male/  
White 
Screening 
-x 
ddMMMyyyy 
 VIRTUALSCOPICS xxx 
Normal 
 
 
 
 
ddMMMyyyy 
 WAYNE STATE 
UNIVERSITY 
PHYSICIAN GROUP 
xxx 
xxx 
Abnormal, Not 
Clinically 
Significant 
 
 
Week X Day X 
 
ddMMMyyyy 
 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
66 
 
Listing 47 
Listing of Investigator-Assessed Response (RECIST 1.1) 
 
Treatment = xxxxxx 
 
 
Center/ 
Subject ID 
Measurable 
Disease at 
baseline 
 
Planned 
Time 
 
 
Date 
 
Resp. 
Day 
Target 
Lesion 
Response 
Non-Target 
Lesion 
Response 
 
 
New Lesion 
 
 
Response [1] 
If PD, Method of 
Assessment/ 
Date [2] 
 
 
 
 
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Yes 
Screening 
ddMMMyyyy 
 xx 
 
 
 
 
 
 
xxxxxxxx 
ddMMMyyyy 
 xx 
SD 
SD 
No 
SD 
 
 
 
.. 
ddMMMyyyy 
xx 
PR 
SD 
No 
PR 
 
 
 
 
ddMMMyyyy 
xx 
PR 
SD 
No 
PR 
 
 
 
.. 
ddMMMyyyy 
xx 
PR 
SD 
No 
PD 
Radiological 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Response: CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, 
    NE = Not Evaluable, NA=Not Applicable. 
[2] Date provided of non-radiological assessment. 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
67 
 
Listing 48 
Listing of Investigator–Assessed Target Lesions (RECIST 1.1) 
 
Treatment = xxxxxx 
 
Center/ 
Subject 
ID 
Planned 
Time 
Sum LD 
(mm)/ 
Sum Non 
Lymph Node 
LD (mm)/ 
Sum Nadir 
(mm) 
Percent 
Change in 
Sum LD From 
Baseline 
Percent 
Change 
Nadir/ 
Absolute Change 
Nadir(mm) 
Target 
Lesion 
Response 
Lesion 
Number 
Organ/ 
Location 
Method/  
Slice Thickness/ 
Date/ 
Lesion Assessment Day 
LD(mm)[1]/ 
Target 
Lesion 
Status/ 
Specify 
the reason 
  
 
 
 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
Screening 
 
xx 
 
 
 
1 
Lung/ 
RIGHT UPPER 
QUADRANT 
CT scan/ 
xx/ 
ddMMMyyyy/ 
xx 
xx  
 
 
 
 
 
 
2 
Lymph nodes/ 
RIGHT AXILLA 
CT scan/ 
xx/ 
ddMMMyyyy/ 
xx 
xx 
 
 
xxxxxxxx 
 
 xx/ 
 xx 
  xx% 
  xx%/ 
  xx  
SD 
1 
 
 
 
 
2 
Lung/ 
RIGHT UPPER 
QUADRANT 
 
 
Liver/ 
Abdomen 
CT scan/ 
/ 
ddMMMyyyy/ 
xx 
 
CT scam 
Xx/ 
ddMMyyy/ 
xx 
xx/ 
Lesion 
split or 
divided 
 
 
Xx/ 
Not done/ 
Scan not 
performed 
 
 
 
 
 
 
 
 
 
 
[1] LD = Lesion diameter 
 
Programming note: Sum of Non Lymph Node LD, Sum of Nadir, and Lesion Status are only collected at post-baseline assessments. For slice 
thickness, it is only collected at baseline, please retain for post-baseline visits.  


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
68 
 
Listing 49 
Listing of Investigator–Assessed Non-Target Lesions (RECIST 1.1) 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
Planned Time 
Non-target 
Lesion 
Response 
Lesion 
Number 
Organ/ 
Location 
Method/  
Date/ 
Lesion Assessment Day 
Non-target 
Lesion Status/ 
Specify the reason 
  
 
 
 
 
 
 
xxxx/ 
xxxxxx 
Screening 
CR 
1 
Bone/ 
LUMBAR SPINE 
MRI/ 
ddMMMyyyy/ 
xx 
 Present 
 
 
 
2 
Bone/ 
THORACIC SPINE 
MRI/ 
ddMMMyyyy/ 
xx 
 Present 
 
 
 
3 
Lymph nodes/ 
RIGHT AXILLA 
Direct Measure by Physical Exam/ 
ddMMMyyyy/ 
xx 
 Present 
 
Week x Day x 
 
1 
Xxx 
Xxx 
Not assessable - xxxx 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
69 
 
Listing 50 
 
Listing of Investigator –Assessed New Lesions 
 
Treatment = xxxxxx 
 
Center/ 
Subject 
ID 
 Planned 
Time 
 
Lesion 
Number 
 
Organ/ 
Location 
Method/  
Date/ 
Lesion Assessment Day 
 
 
Lesion Status 
 
Week 12, 
Day 85 
 
1 
Lung/ 
RIGHT UPPER 
QUADRANT 
CT scan/ 
 
172 
Unequivocal 
 
 
2 
Lymph nodes/ 
RIGHT AXILLA 
Direct Measure by Physical Exam/ 
174 
Unequivocal 
 
Week 12, 
Day 85 
1 
Lung/ 
RIGHT UPPER 
QUADRANT 
CT scan/ 
181 
Equivocal 
 
Week 24, 
Day  
1 
Lung/ 
RIGHT UPPER 
QUADRANT 
CT scan/ 
 
231 
Unequivocal 
 
 
 
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: All Treated 
 
 
70 
 
Listing 51 
Listing of Progression Free Survival (RECIST 1.1) 
 
Treatment = xxxxxx 
Center/ 
Subject ID 
Age(Years)/ 
Sex/ 
Race 
Treatment Start 
Date/ 
Event or Censoring 
Date 
Endpoint Description for PFS 
PFS (weeks) 
New Anti-cancer 
Therapy Start Date 
 
 
 
 
 
 
xxxxx/ 
xxxxxx 
Female/ 
xx 
 
ddMMMyyyy/ 
ddMMMyyyy 
Event: Died 
xx 
xx.x  
 
ddMMMyyyy 
xxxxx/ 
xxxxxx 
Male/ 
xx 
ddMMMyyyy/ 
ddMMMyyyy 
Censor: xxxxxxxxxxxxx 
 
xx.x 
 
  
 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: PK Population 
 
 
 
71 
 
Listing 52 
Listing of GSK2820151 Pharmacokinetic Concentration-Time Data 
 
Treatment = xxxxxx 
 
Center/ 
Subject ID 
 
 
Planned  
Schedule 
 
 
Planned Time 
 
 
 
Date/Actual Time 
Time 
Deviation 
(Hours) 
Actual Relative 
Time (Hours) 
Concentration 
(ng/mL) 
 
 
 
 
 
 
 
xxx/ 
xxxxxx 
Week 1 Day 1 
Pre-dose 
ddMMMyyyy/hh:mm 
 x.xxx 
x.xx 
NQ  
 
 
15Min post Dose 
ddMMMyyyy/hh:mm 
  
 
xxxx.XXX 
 
 
30 Min post Dose 
ddMMMyyyy/hh:mm 
  
 
x.xxx 
 
 
1Hour post Dose 
ddMMMyyyy/hh:mm 
  
 
xxxx.xxx 
 
 
2Hour post Dose 
ddMMMyyyy/hh:mm 
  
 
xxxx.xxx 
 
 
4 Hour post Dose 
ddMMMyyyy/hh:mm 
  
 
xxxx.xxx 
 
 
 
 
 
  
 
 
 
. . . 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
NQ = Non-quantifiable. 


CONFIDENTIAL 
201893 
Protocol: GSK201893 
Page X of Y 
Population: PK Population 
 
 
 
72 
 
Listing 53 
Listing of Derived GSK2820151 Pharmacokinetic Parameters 
 
Treatment = xxxxx 
 
Center/ 
Cmax 
tmax 
AUC(0-t) 
AUC(0-tau) 
AUC(0-inf) 
t1/2 
C tau 
Ro [1] 
CL/F 
Vz/F 
Subject ID 
(ng/mL) 
(h) 
(h*ng/mL) (unit) 
(h*ng/mL) 
(h) 
(unit) 
 
(mL/h) 
(mL) 
 
 
 
 
 
 
 
 
 
 
 
xxx/ 
xxxxxx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
[1] Ratio of AUC(0-tau): AUC(0-tau) on Week 3 Day 4/AUC(0-tau) on Week 1 Day 1