Conditions: Carcinoma, Small Cell
Keywords: First time in humans Small cell lung carcinoma Oncology GSK2879552 LSD1 inhibitor
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
GSK2879552 is a potent, selective, mechanism-based inactivator of Lysine Specific Demethylase 1 (LSD1)/ CoRepressor for Element-1-Silencing Transcription factor (CoREST) activity. This is a phase I, open-label, multi-center, non-randomized, 2-part first time in human (FTIH) study for GSK2879552. Part 1 is a dose escalation phase to determine the recommended phase 2 dose (RP2D) for GSK2879552 based on the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles observed after oral administration of GSK2879552. Any dose level(s) may be expanded up to 12 subjects in order to collect additional data on PK and PD.The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM). Built-in safety constraints are in place to prevent exposing subjects to undue risk of toxicity. Once RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects will be enrolled to further evaluate the clinical activity and tolerability of GSK2879552 in subjects with relapsed/refractory SCLC.

Detailed description:

Arms:
arm 1: The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM).The dose escalation will complete when RP2D is determined. The RP2D will be the MTD or a lower dose that provides adequate PK exposure and biologic activity with superior tolerability. arm 2: Once the RP2D has been determined, an expansion cohort of up to 30 subjects will be enrolled in order to better characterize the clinical activity and safety profile of the RP2D

Interventions: intervention 1: GSK2879552
Intervention descriptions: intervention 1: Subjects will receive GSK2879552orally with approximately 200 milliliter (mL) of water.

Protocol document:
Prot_000.pdf: 
2013N173386_05
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1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamicas and clinical 
activity of GSK2879552 given orally in subjects with 
relapsed/refractory small cell lung carcinoma
Compound Number:
GSK2879552
Development Phase:
I 
Effective Date:
22-NOV-2016
Protocol Amendment Number:  04
Author (s):
Cancer Research Epigenetics Management, UP, PA, USA
Global Clinical Safety & Pharmacovigilance, UP, PA, USA
Global Clinical Safety & Pharmacovigilance, UP, PA, USA
Global Clinical Operational Sciences, RTP, NC, USA
Cancer Research Epigenetics Management, UP, PA, USA
Cancer Research Epigenetics Management, UP, PA, USA
Drug Metabolism and Pharmacokinetics, UM, PA, USA
Discovery Biometrics, UP, PA, USA
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N173386_01
2013-OCT-09
Original 
2013N173386_02
2013-NOV-20
Amendment No.: 01 
The starting dose, DLT criteria and safety management criteria are revised according to 
the regulatory input. One of the eligibility criteria is also modified to allow enrolment of 
patients without tumor tissues at baseline. Other changes are to clarify one of the 
exploratory objectives and endpoints, correct the investigational product storage 
conditions, clarify the definition of subject completion and allow flexibility in the timing 
of assessments
2013N173386_03
2015-MAR-06
Amendment No. 2
The protocol is amended to add two new dose strengths that will reduce the pill burden 
for subjects.
2013N173386_04
2015-MAY-27
Amendment No. 3
Additional eligibility criteria and safety monitoring measures are put in place to address 
recent safety findings. Primary end point and futility criteria for Part 2 are modified based 
on the compound’s mechanism of action. Other changes include additional urine and 
plasma sample collection for metabolite profiling (at the highest dose cohort in Part 1 
PK/PD expansion), update in concomitant medications, clarification on the timing for 
pre- and post-dose optional biopsies, and addressing the inconsistencies in the definition 
of febrile neutropenia.
2013N173386_05
2016-NOV-22
Amendment No. 4
Appendix 5 country specific IP label requirements for Korea have been modified.  Fetal 
hemoglobin testing requirement has also been removed for Korea.


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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time Phone 
Number
After-hours 
Phone/Cell/
Pager Number
GSK Address
Primary 
Medical 
Monitor
MD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP 4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP 4210
Collegeville, PA 19426, USA
Sponsor Registered Address:
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
GlaxoSmithKline
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee).  Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial submission
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200858
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
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SYNOPSIS...............................................................................................14
1.
INTRODUCTION....................................................................................................25
1.1.
Background – LSD1....................................................................................25
1.2.
Unmet Medical Needs For Small Cell Lung Carcinoma...............................25
1.3.
GSK2879552..............................................................................................25
1.3.1.
GSK2879552 - Background .........................................................25
1.3.2.
Pre-Clinical Pharmacology & Safety of GSK2879552 ..................26
1.3.3.
Pharmacokinetics of GSK2879552 in Humans ............................32
1.4.
Benefit:Risk Assessment ............................................................................32
1.4.1.
Benefit Assessment.....................................................................34
1.4.2.
Overall Benefit:Risk Conclusion...................................................34
2.
OBJECTIVES, ENDPOINTS AND HYPOTHESES.................................................34
2.1.
Part 1 Dose Escalation ...............................................................................34
2.2.
Part 2 Expansion ........................................................................................35
3.
INVESTIGATIONAL PLAN.....................................................................................36
3.1.
Discussion of Study Design ........................................................................36
3.2.
Part 1: Dose-Escalation ..............................................................................38
3.3.
PK/PD Expansion cohorts...........................................................................41
3.4.
Alternative Dosing and PK/PD Sampling Schedules ...................................42
3.5.
Dose-Limiting Toxicity.................................................................................42
3.6.
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose 
(RP2D) .......................................................................................................43
3.7.
Part 2: Expansion Cohort............................................................................43
3.8.
Intra-subject Dose-Escalation .....................................................................43
3.9.
Rationale ....................................................................................................43
3.9.1.
Rationale for Population...............................................................43
3.9.2.
Rationale for Dose.......................................................................44
3.9.2.1.
Predicted Effective Dose ............................................44
3.9.2.2.
Starting Dose..............................................................44
3.10.
Study Treatment .........................................................................................46
3.10.1.
Treatment Assignment.................................................................46
3.10.2.
Meals and Dietary Restrictions ....................................................46
3.10.3.
Blinding........................................................................................46
3.11.
Safety Management Guidelines..................................................................46
3.11.1.
Liver Chemistry Stopping Criteria ................................................46
3.11.1.1.
Liver Chemistry Monitoring Criteria.............................47
3.11.1.2.
Liver Chemistry Follow-up Procedures .......................47
3.11.2.
QTc Stopping Criteria ..................................................................49
3.11.3.
Mental Status Stopping Criteria ...................................................50
3.12.
Guidelines for Events of Special Interest and Dose Modifications...............50
3.12.1.
Dose Adjustment for toxicity ........................................................51
3.12.2.
Management of Thrombocytopenia..............................................51
3.12.3.
Management of Neutropenia........................................................54


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3.12.4.
Management of Anemia...............................................................54
3.12.5.
Platelet Transfusion Guideline .....................................................54
3.12.6.
CBC monitoring and PK sampling Guideline for Dose 
interruptions/modifications ...........................................................54
4.
INVESTIGATIONAL PRODUCT(S) ........................................................................55
4.1.
Description of Investigational Product.........................................................55
4.2.
Handling/Storage of GSK2879552, GSK Investigational Product................56
4.3.
Product Accountability ................................................................................56
4.4.
Treatment Compliance................................................................................56
4.5.
Treatment of Investigational Product Overdose ..........................................57
5.
STUDY POPULATION...........................................................................................57
5.1.
Number of Subjects ....................................................................................57
5.2.
Subject Selection Criteria............................................................................57
5.2.1.
Inclusion Criteria..........................................................................57
5.2.2.
Exclusion Criteria.........................................................................60
6.
COMPLETION OR WITHDRAWAL OF SUBJECTS...............................................61
6.1.
Screen and Baseline Failures .....................................................................61
6.2.
Subject Completion Criteria ........................................................................62
6.3.
Permanent Discontinuation from Study Treatment......................................62
6.4.
Study Completion .......................................................................................63
6.5.
Treatment after the End of the Study ..........................................................63
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................63
7.1.
Time and Events Table(s)...........................................................................64
7.2.
Demographic/Medical History and Baseline Assessments..........................70
7.2.1.
Critical Baseline Assessments.....................................................70
7.3.
Safety Evaluations......................................................................................71
7.3.1.
Physical Examinations.................................................................71
7.3.2.
ECOG Performance Status..........................................................71
7.3.3.
Montreal Cognitive Assessment...................................................71
7.3.4.
Vital Signs....................................................................................71
7.3.5.
Electrocardiogram........................................................................72
7.3.6.
Echocardiogram and/or Multi-gated Acquisition Scans ................72
7.3.7.
Laboratory Assessments .............................................................72
7.3.8.
Pregnancy Testing and Reporting................................................73
7.4.
Pharmacokinetics .......................................................................................74
7.4.1.
Blood Sample Collection for Pharmacokinetics............................74
7.4.2.
Urine Sample Collection for Pharmacokinetics ............................74
7.4.3.
Details on PK urine sample collection, processing, storage 
and shipping procedures are provided in the 
SPM.Pharmacokinetic Sample Analysis ......................................74
7.5.
Pharmacodynamics ....................................................................................75
7.6.
Translational Research...............................................................................75
7.6.1.
Tumor Biomarker Analysis...........................................................76
7.6.2.
Circulating cell free DNA (cfDNA) Analysis ..................................76
7.6.3.
Circulating biomarker analysis .....................................................76
7.6.4.
RNA Expression Research of a Subset of RNA Species..............77
7.7.
Evaluation of Anti-Cancer Activity ...............................................................77
7.7.1.
Disease Assessment ...................................................................77


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7.7.2.
Brain MRI and/or CT Scan...........................................................78
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................78
8.1.
Definition of an AE......................................................................................78
8.2.
Definition of an SAE....................................................................................79
8.2.1.
Sentinel Events............................................................................80
8.3.
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs .......................................................................................81
8.3.1.
Cardiovascular (CV) Events.........................................................81
8.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs.....................................................................................81
8.5.
Time Period and Frequency of Detecting AEs and SAEs............................82
8.5.1.
Method of Detecting AEs and SAEs.............................................82
8.5.2.
Prompt Reporting of SAEs and Other Events to GSK ..................82
8.5.3.
Regulatory reporting requirements for SAEs................................83
9.
STUDY TREATMENT RESTART OR RECHALLENGE .........................................84
9.1.
Rechallenge Following Liver Event That Are Possibly Related To 
Study Treatment .........................................................................................84
9.2.
Restart Following Transient, Resolving Liver Events Not Related to 
Study Treatment .........................................................................................85
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................86
10.1.
Permitted Medication(s)..............................................................................87
10.2.
Prohibited and Cautionary Medication(s) ....................................................87
10.2.1.
Drugs that may alter the Pharmacokinetics of 
GSK2879552...............................................................................87
10.2.2.
Drugs that may have their PKs altered by GSK2879552..............87
10.2.3.
Non-Drug Therapies ....................................................................88
11. LIFESTYLE AND/OR DIETARY RESTRICTIONS..................................................88
11.1.
Contraception .............................................................................................88
11.1.1.
Female Subjects..........................................................................88
11.1.2.
Male Subjects..............................................................................89
11.2.
Caffeine, Alcohol, Food, and Tobacco Restrictions.....................................90
12. DATA MANAGEMENT ...........................................................................................90
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................90
13.1.
Hypothesis(es)............................................................................................90
13.1.1.
Part 1: Dose-Escalation Phase ....................................................90
13.1.2.
Part 2: Expansion Cohort.............................................................90
13.2.
Sample Size Determination ........................................................................92
13.2.1.
Part 1: Dose-Escalation Phase ....................................................92
13.2.2.
Part 2: Expansion Cohort.............................................................92
13.3.
Sample Size Sensitivity...............................................................................93
13.3.1.
Sample Size Re-estimation..........................................................93
13.4.
Data Analysis Considerations .....................................................................93
13.4.1.
Analysis Populations....................................................................93
13.5.
Interim Analysis ..........................................................................................94
13.5.1.
Part 1: Dose-Escalation ...............................................................94
13.5.2.
Part 2: Expansion Cohort.............................................................94


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13.6.
Key Elements of Analysis Plan ...................................................................94
13.6.1.
Anti-Cancer Activity Analyses ......................................................94
13.6.2.
Safety Analyses...........................................................................95
13.6.2.1.
Extent of Exposure .....................................................95
13.6.2.2.
Adverse Events ..........................................................95
13.6.2.3.
Clinical Laboratory Evaluations ..................................95
13.6.2.4.
Other Safety Measures...............................................95
13.6.3.
Pharmacokinetic Analyses...........................................................96
13.6.3.1.
Pharmacokinetic Parameters......................................96
13.6.3.2.
Statistical Analysis of PK Data....................................96
13.6.4.
Pharmacokinetic/Pharmacodynamic Analyses.............................97
13.6.4.1.
Translational Research Analyses ...............................97
13.6.4.2.
Novel Biomarker(s) Analyses .....................................97
14. STUDY CONDUCT CONSIDERATIONS ...............................................................98
14.1.
Posting of Information on Clinicaltrials.gov..................................................98
14.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................98
14.3.
Urgent Safety Measures .............................................................................98
14.4.
Quality Control (Study Monitoring) ..............................................................98
14.5.
Quality Assurance.......................................................................................99
14.6.
Study and Site Closure ...............................................................................99
14.7.
Records Retention......................................................................................99
14.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................100
15. REFERENCES.....................................................................................................101
APPENDICES.............................................................................................................104
Appendix 1:  NYHA Functional Classification System...........................................104
Appendix 2: CKD-EPI EQUATION .......................................................................105
Appendix 3: ECOG Performance Status1.............................................................106
Appendix 4: Liver Safety Guidelines.....................................................................107
Appendix 5: Country Specific Requirements.........................................................110
Appendix 6 Simulation Results of N-CRM in Dose Escalation Phase ...................111
Appendix 7: Montreal Cognitive Assessment........................................................112
Appendix 8: Protocol Amendment Changes .........................................................113
Appendix 5: Country Specific Requirements.........................................................113
Appendix 5: Country Specific Requirements.........................................................114


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LIST OF ABBREVIATIONS
AE(s)
Adverse Event(s)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject 
AUC(0-)
Area under the concentration-time curve over the dosing interval
-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood urea nitrogen
Cav
Average concentration
CBC
Complete blood count
CfDNA
Circulating cell free DNA
CKD-EPI 
equation
The Chronic Kidney Disease Epidemiology Collaboration equation 
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
Cτ
Pre-dose (trough) concentration at the end of the dosing interval
CO2
Carbon dioxide
CoREST
CoRepressor for Element-1-Silencing Transcription factor
CPMS
Clinical Pharmacokinetic Modeling and Simulation
CR
Complete response
CRM
Continual Reassessment Method
CT
Computed tomography 
CTCs
Circulating tumor cells
CV
Coefficient of variance
DCR
Disease Control Rate
DHEA
Dehydroepiandrosterone
DILI
Drug Induced Liver Injury
DLT
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
EC
Ethics committee
EC50
Half maximal effective concentration
ECG(s)
Electrocardiogram(s)
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EIAC
Enzyme-inducing anticonvulsant 
FACTS
Fixed and Adaptive Clinical Trial Simulator 
FSH
Follicle Stimulating Hormone


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FTIH
First time in humans
GCP
Good Clinical Practice
g/dL
Grams per deciliter
GFR
Glomerular filtration rate 
GGT
Gamma glutamyltransferase
GI
Gastrointestinal 
GLP
Good Laboratory Practices
GSK
GlaxoSmithKline
H3K4
Histone H3 lysine 4
HBV
Hepatitis B Virus 
HCV
Hepatitis C Virus
HDACs
Histone Deacetylases
Hgb
Hemoglobin 
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HLA
Human leukocyte antigen 
HPLC
High-performance liquid chromatography
HNSTD
Highest Non- Severely Toxic Dose
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDSL
International Data Standards Library
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International normalization ratio
IP
Investigational Product
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous 
Ka
Absorption rate
kg
Kilogram
L
Liter
LFTs
Liver function tests
LLN
Lower limit of normal
ln
Naperian (natural) logarithm
LSD1
Lysine specific demethylase 1
LSLV
Last subject’s last visit
LVEF 
Left Ventricular Ejection Fraction
uM 
Micromole
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter


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MOCA
Montreal Cognitive Assessment
MPV
Mean platelet volume
MRI
Magnetic resonance imaging 
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
MUGA
Multigated  (radionuclide) angiogram
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
N-CRM
The Neuenschwander -Continuous Reassessment Method 
ng
Nanogram 
nM
Nanomole
NOAEL
No observed adverse effect level
NSAIDs
Non-steroidal anti-inflammatory drug 
NYHA
New York Heart Association
ORR
Objective Response Rate
PARP
poly ADP ribose polymerase
PCI
Potential clinical importance
PCR
Polymerase chain reaction 
PD
Progressive disease or pharmacodynamic
PET
Probability of early termination
PFS
Progression-free survival
PI
Principal Investigator 
PK
Pharmacokinetic
PR
Partial response
PRoGRP
Pro Gastrin Releasing Peptide
PT
Prothrombin time 
PTS
Platform Technology and Science
PTT
Partial thromboplastin time 
QTc
Corrected QT interval duration
QTcB
QT interval corrected for heart rate by Bazett’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
Ro
Accumulation ratio 
RP2D
Recommended Phase 2 Dose
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
Serious adverse event(s)
SCLC
Small Cell Lung Carcinoma
SD
Standard deviation or stable disease
SPM
Study Procedures Manual
STD
Severely Toxic Dose
t
Time of last observed quantifiable concentration
t1/2
Terminal phase half-life
τ
Dosing interval


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λz
Apparent terminal phase elimination rate constant 
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
US/USA
United States/United States of America
V/F
Apparent Volume of distribution following oral dosing
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
FACTS


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PROTOCOL SYNOPSIS
TITLE
A phase I open-label, dose escalation study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of GSK2879552 
given orally in subjects with relapsed/refractory small cell lung carcinoma
PROTOCOL NUMBER
200858
CLINICAL PHASE
I
COMPOUND(S)
GSK2879552
STUDY RATIONALE
GSK2879552 is a potent, selective, mechanism-based inactivator of 
LSD1/CoREST activity. GSK2879552 induces the expression of putative 
LSD1 target genes and has potent, predominantly cytostatic, anti-
proliferative activity in small cell lung carcinoma (SCLC). This FTIH, open-
label, dose escalation study will assess the safety, pharmacokinetics (PK), 
pharmacodynamics (PD), and preliminary clinical activity of GSK2879552 in 
subjects with relapsed/refractory SCLC.
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES
PART 1: Escalation Cohort
Objectives
Endpoints
Primary
1.
To determine the safety, tolerability 
and Recommended Phase 2 
Dose(s) (RP2D) and regimen of 
GSK2879552 given orally in adult 
subjects with SCLC.  
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety 
parameters (e.g., laboratory values, vital 
signs, ECGs, physical examinations).
Secondary 
1.
To characterize the 
pharmacokinetics of GSK2879552 
after single- and repeat-dose oral 
administration.
1.
GSK2879552 PK parameters following 
single-(Day 1) and repeat-dose (Day 15) 
administration of GSK2879552, including 
AUC, Cmax, tmax, t½ (terminal phase 
and/or effective half-life), accumulation 
ratio, and time invariance.
2.
To evaluate clinical activity after 
treatment with GSK2879552.
3.
To evaluate the relationship 
between GSK2879552 exposure 
and safety/ efficacy/PD parameters
2.
Disease Control Rate (DCR) (CR + PR + 
SD) at week 16 based on Response 
Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmax, 
Cmin or AUC (0-tau)), and ProGRP, 
platelet levels in blood, and 
safety/efficacy parameters. 
Exploratory
1.
To assess feasibility of a select 
gene panel for use as a PD assay 
for GSK2879552
2.
To investigate the impact of 
GSK2879552 on the RNA 
expression profile in tumor and 
blood to identify mechanisms of 
1.
Change from baseline expression in 
select genes in whole blood and tumor
2.
Transcriptomic (RNA) profile of tumor 
and whole blood pre- and post-treatment 
with GSK2879552.


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rational combination and potential 
resistance.
3.
To investigate relationship between 
tumor baseline genomic profile and 
response or resistance to 
GSK2879552.
4.
To discover circulating response 
and resistance biomarkers
5.
To investigate the impact of 
GSK2879552 on fetal haemoglobin
3.
Tumor DNA, RNA and protein markers at 
baseline.
4.
Circulating biomarkers (e.g. cfDNA, 
protein and RNA).
5.
Pre- and post-treatment fetal 
haemoglobin levels
6.
To characterize the metabolite 
profile of GSK2879552 after oral 
single and/or repeat-dosing in 
some subjects
7.
To determine the amount of 
GSK2879552 excreted in urine 
after oral single and/or repeat-
dosing
6.
GSK2879552 metabolites in plasma 
and/or urine
7.
Concentration of GSK2879552 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over time 
Hypothesis
No formal statistical hypotheses are being tested in Part 1 dose escalation.  Analysis of 
the data obtained from Part 1 will only utilize descriptive methods.
Part 2: Expansion Cohort
Objectives
Endpoints
Primary
1.
To evaluate clinical activity of 
GSK2879552 given orally in adult 
subjects with SCLC.
1.
Disease Control Rate (DCR) (CR + PR 
+ SD) at week 16 based on Response 
Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  
Secondary
1.
To evaluate the safety and 
tolerability of RP2D of 
GSK2879552
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety 
assessments (e.g., laboratory 
parameters, vital signs, physical 
examinations).
2.
To characterize the population PK 
of GSK28795522. 
2.
Population PK parameters for 
GSK2879552 such as clearance (CL/F) 
and volume of distribution (V/F), and 
relevant covariates which may influence 
exposure (e.g., age, weight, or disease 
associated covariates).
3.
To evaluate the relationship 
between GSK2879552 exposure 
and safety/efficacy/PD parameters. 
4.
To evaluate duration of response 
and progression free survival 
(PFS)
5.
To evaluate objective response 
rate (ORR)
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmin, 
Cmax or AUC (0-tau)), and ProGRP, 
platelet levels in blood, and 
safety/efficacy parameters.
4.
Duration of response and PFS
5.
% of subjects achieving complete 


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response and partial response
Exploratory
1.
To assess feasibility of a select 
gene panel for use as a PD assay 
for GSK2879552
2.
To investigate the impact of 
GSK2879552 on the RNA 
expression profile in blood to 
identify mechanisms of rational 
combination and potential 
resistance.
1.
Change from baseline expression in 
select genes in whole blood
2.
Transcriptomic (RNA) profile of whole 
blood pre- and post-treatment with 
GSK2879552.
3.
To investigate relationship 
between tumor baseline genomic 
profile and response or resistance 
to GSK2879552.
4.
To discover circulating response 
and resistance biomarkers
5.
To investigate the impact of 
GSK2879552 on fetal haemoglobin
3.
Tumor DNA, RNA and protein markers 
at baseline.
4.
Circulating biomarkers (e.g. cfDNA, 
protein and RNA).
5.
Pre- and post-treatment fetal 
haemoglobin levels
Hypothesis
Clinical response will be defined as Disease Control Rate (DCR) (CR + PR + SD) at 
week 16 based on RECIST 1.1.
The null hypothesis is: H0: DCR≤15% at week 16
The alternative hypothesis is: HA: DCR≥30% at week 16
STUDY DESIGN
This is a phase I, open-label, multi-center, non-randomized, 2-part 
FTIH study.
Part 1 is a dose escalation phase to determine the recommended 
phase 2 dose (RP2D) for GSK2879552 based on the safety, 
tolerability, PK, and PD profiles observed after oral administration 
of GSK2879552. Any dose level(s) may be expanded up to 12 
subjects in order to collect additional data on PK and PD.
In Cohort 1, a single subject will receive a dose of GSK2879552 
0.25 mg once daily. The subject in Cohort 1 must complete a full 28 
days of dosing, and the safety and PK data will be reviewed prior to 
starting Cohort 2. Starting with Cohort 2 the dose escalation will 
continue using the Neuenschwander -continuous reassessment 
method (N-CRM).  Built-in safety constraints are in place to prevent 
exposing subjects to undue risk of toxicity.  
Once RP2D is identified, an expansion cohort (Part 2) of up to 30 
subjects will be enrolled to further evaluate the clinical activity and 
tolerability of GSK2879552 in subjects with relapsed/refractory 
SCLC. 


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NUMBER OF SUBJECTS
It is estimated that approximately 20 subjects will be enrolled into 
Part 1 dose-escalation and additional 27 subjects into PK/PD 
expansion cohorts.  Up to 30 subjects will be enrolled in Part 2 
(expansion cohort) of the study.  A total of approximately 77 
subjects will be enrolled in the study.  Additional subjects/cohorts 
may be enrolled to allow for evaluation of additional dose levels. 
INCLUSION/ EXCLUSION 
CRITERIA
Subjects eligible for enrolment in the study must meet all of the 
following criteria:
1. Provided signed written informed consent
2. Males and females ≥18 years of age (at the time consent is 
obtained).
3.
Histologically or cytologically confirmed diagnosis of small 
cell lung carcinoma. Subjects must have measurable disease 
per RECIST 1.1 (for Part 2 only).
4.
Recurrent or refractory disease after receiving at least one 
prior standard/approved platinum-containing chemotherapy 
regimen, or where standard therapy is refused. Part 2 only: 
Subjects must have recurrent disease after receiving a 
maximum of two prior chemotherapy regimen including one 
platinum containing regimen. Note: Adjuvant/Neoadjuvant 
chemotherapy is not counted.  
5.
Eastern Cooperative Oncology Group (ECOG, Appendix 3) 
performance status of 0 or 1.
6. Tumor tissue requirements:

Availability of archival tissue, or willingness to 
undergo fresh biopsy at baseline. Patients without 
baseline tissue may be enrolled with approval from 
the GSK medical monitor.

Enrollment in PK/PD cohort may be limited to 
subjects with disease amenable to pre- and post-dose 
biopsies, and willingness to undergo biopsy
7. All prior treatment-related toxicities must be National 
Cancer Institute- Common Toxicity Criteria for Adverse 
Events (NCI-CTCAE), version 4.0 ≤Grade 1 at the time of 
enrollment (except for alopecia)
8. Adequate baseline organ function defined by


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System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
10 g/dL
Platelets
125 X 109/L
Prothrombin time (PT)/International 
normalized ratio (INR) and Partial 
thromboplastin time (PTT) 
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.25 X ULN1
ALT and AST
2.5 ULN without liver 
metastasis
5 x ULN if documented liver 
metastasis
Renal
Creatinine
OR
Calculated creatinine clearance by 
Chronic Kidney Disease 
Epidemiology Collaboration (CKD-
EPI) equation (Appendix 2) or 
measured from 24hr urine
≤1.5 X ULN
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by Echocardiogram 
(ECHO) 
Metabolic
TSH, T4
Vitamin B12
BUN
Na, K2, Ca, Cl, CO2
Glucose (fasting)
WNL
≥ LLN
≤1.5 X ULN
WNL
≤1.25 X ULN
1.
Isolated bilirubin >1.25 X ULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35% or subject has a diagnosis of Gilbert’s 
syndrome
2.
Replacement of K is allowed if below LLN
1.
NOTE:  Laboratory results obtained during Screening 
should be used to determine eligibility criteria.  In situations 
where laboratory results are outside the permitted range, the 
investigator may opt to retest the subject and the subsequent 
within range screening result may be used to confirm 
eligibility.  Subjects requiring transfusions to meet 
hematologic eligibility criteria are not eligible.
9. Women of childbearing potential must have a negative 
serum pregnancy test within 7 days of first dose of study 
treatment and agree to use effective contraception, as 
defined in Section 11.1, during the study and for 7 days 
following the last dose of study treatment.


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10. Men with a female partner of childbearing potential must 
have either had a prior vasectomy or agree to use effective 
contraception as described in Section 11.1 from the 
administration of the first dose of study treatment until 3 
months after the last dose of study treatment to allow for 
clearance of any altered sperm.
11. Able to swallow and retain orally administered study 
treatment and does not have any clinically significant 
gastrointestinal (GI) abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the 
stomach and/or bowels.
12. French subjects: In France, a subject will be eligible for 
inclusion in this study only if either affiliated to or a 
beneficiary of a social security category.
Subjects meeting any of the following criteria must not be enrolled 
in the study:
1.
Concurrent malignancy other than SCLC. History of other 
malignancy is allowed as long as there is no evidence of active 
disease or need for treatment.
2.
Currently receiving anti-cancer therapy (chemotherapy, 
radiation therapy, immuno- therapy, biologic therapy, hormonal 
therapy, surgery, and/or tumour embolization)
Exceptions: Zoledronic acid and denosumab to treat bone 
metastasis are allowed. 
3.
Prior treatment with temozolomide, dacarbazine or procarbazine
4.
Prior treatment with poly ADP ribose polymerase (PARP) 
inhibitors (e.g., olaparib, ABT-888)
5.
Baseline Montreal Cognitive Assessment (MOCA) score of 22 
or lower
6.
Received major surgery, radiotherapy, or immunotherapy 
within 4 weeks of GSK2879552 administration. Chemotherapy 
regimens with delayed toxicity within the last four weeks (six 
weeks for prior nitrosourea or mitomycin C). Chemotherapy 
regimens given continuously or on a weekly basis with limited 
potential for delayed toxicity or palliative radiation to a limited 
area (including cranial radiation for brain metastases) within the 
last two weeks. 
7.
Administration of an investigational drug within 28 days or 5 
half-lives, whichever is shorter preceding the first dose of study 
treatment(s) in this study. 
French subjects: The French subject has participated in any 
study using an investigational study treatment(s) during the 
previous 28 days.
8.
Subjects with current/a history of bleeding disorder or 


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coagulopathy (e.g., Von Willebrand disease, haemophilia) or 
who are at particularly high risk for bleeding complications, 
e.g., prior history of intracranial hemorrhage, clinically 
significant bleeding episodes in the last 6 months. 
9.
Requiring anticoagulants at therapeutic doses (e.g., warfarin, 
direct thrombin inhibitors, etc) or platelet inhibitor (e.g., aspirin, 
clopidogrel). The following are permitted:

Low molecular weight heparin

Low dose prophylactic warfarin ≤ 1 mg once daily 

Low dose aspirin ≤ 100 mg once daily if required for 
cardiac prophylaxis.
10. Current use of a prohibited medication (Section 10.2) or 
expected to require any of these medications during treatment 
with the investigational drug 
11. Evidence of severe or uncontrolled systemic diseases (e.g., 
severe/chronic infection, unstable or uncompensated 
respiratory, hepatic, renal, or cardiac disease) Any serious 
and/or unstable pre-existing medical (aside from malignancy 
exception above), 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
12. Known active Human Immunodeficiency Virus (HIV), 
Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) 
infections. Subjects with laboratory evidence of HBV clearance 
may be enrolled
13. Leptomeningeal metastases or spinal cord compression due to 
disease. 
14. Subjects with previously untreated or uncontrolled brain 
metastases.  
Note: Subjects previously treated for brain metastases that 

are asymptomatic and off corticosteroids, OR 

on stable dose of corticosteroids for at least 1 month 
prior to study Day 1 are permitted. 
Subject treated with gamma knife can be enrolled 2 weeks 
post-procedure as long as there are no post-procedure 
complications and the subject is clinically stable. In 
addition, subjects treated or currently taking enzyme-
inducing anticonvulsant (EIAC) are allowed on study.
15. Cardiac abnormalities as evidenced by any of the following:

Clinically significant uncontrolled arrhythmias or 
uncontrolled hypertension.

History or evidence of current ≥Class II congestive heart 
failure as defined by New York Heart Association 
(NYHA).


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
History of acute coronary syndromes (including unstable 
angina and myocardial infarction), coronary angioplasty, or 
stenting within the past 3 months. 

Baseline QTc interval using Bazett’s formula ≥450 msec or 
≥480 msec in subjects with Bundle Branch Block. QTc 
value based on single or average of triplicate ECGs 
obtained over a brief recording period.
16. Have a known immediate or delayed hypersensitivity reaction 
or idiosyncrasy to drugs chemically related to GSK2879552 or 
LSD1 inhibitors that contraindicates their participation.
17. Lactating female.
18. Consumption of Seville oranges, grapefruit, grapefruit hybrids 
or grapefruit juice and/or pommelos, exotic citrus fruits, from 
1 day prior to the first dose of study treatment(s) until the last 
dose of study drug. 
STUDY TREATMENT 
DOSE/ROUTE/ REGIMEN
Product 
name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 
5 mg of GSK2879552 as parent. 
Dosage 
form:
Capsule
Unit dose 
strength(s)
0.25 mg, 0.5 mg, 2 mg and 5 mg
Route/
Regimen
Oral
The initial dosing regimen will be continuous oral daily 
dosing. 
Subjects should take their doses fasted with 
approximately 200 mL of water.
Physical 
description:
0.25 mg GSK2879552: Opaque Size 3 capsule 
composed of a white body and a white cap with no 
identifying markings containing a white to slightly 
coloured powder.
0.5 mg GSK2879552: Opaque Size 1 capsule composed
of a light green body and a light green cap with no 
identifying markings containing a white to slightly 
coloured powder.
2 mg GSK2879552: Opaque Size 1 capsule composed 
of a pink body printed with two black lines and a pink cap 
printed with two black lines, containing a white to slightly 
coloured powder.
5 mg GSK2879552: Opaque Size 1 capsule composed 
of a Swedish Orange body and a Swedish Orange cap 
with no identifying markings containing a white to slightly 
coloured powder.
SAFETY ASSESSMENTS
Measurements to evaluate safety will include weight, height, heart 
rate (HR), blood pressure (BP), temperature, clinical laboratory tests, 
12-lead ECG, ECOG performance status, and physical examination. 


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AEs and laboratory results will be graded according to the NCI-
CTCAE v4.0. Planned time points for all safety assessments are 
listed in the Time and Events Tables (Section 7.1)
PHARMACOKINETIC/ 
PHARMACODYNAMIC 
ASSESSMENT(S)
For all subjects in the dose escalation cohorts in Part 1, serial blood 
samples for analysis of GSK2879552 concentrations will be 
collected on Days 1, 8 and 15 at planned time points as listed in the 
Time and Event Table (Section 7.1). Pre-dose blood sample will be 
also collected on Days 4 and 22. Thereafter, pre-dose blood sample 
for analysis of GSK2879552 concentrations will be collected every 
week for 4 weeks, followed by every 4 weeks. Pre-dose and 24 hour 
urine sample will be collected on Day 1, and 24 hour urine sample 
will be collected starting from pre-dose on Day 15 until dosing on 
Day 16. Pre-dose blood samples for PD, biomarker and translational 
research will be collected at Screening and on Days 1, 2, 4, 8, 15, 22 
and at the end of treatment visit.
Pre-dose and post-dose tumor biopsies may be required from a 
subset of subjects in Part 1, PK/PD expansion cohorts. A minimum 
of five pairs of evaluable pre- and post-dose biopsies may be 
collected at selected doses based on emerging PK/PD data.
For subjects in the highest dose of Part 1 PK/PD expansion cohort, 
additional blood samples for GSK2879552 metabolite profiling will 
be collected on Days 1 and 15 at the same time points as listed in the 
Time and Event Table (Section 7.1). Additional urine sample will be 
also collected for GSK2879552 metabolite profiling from the 24 
hour urine sample.
For all subjects in Part 2 expansion cohorts, limited blood samples 
for analysis of GSK2879552 concentrations will be collected on 
Days 1 and 15 at planned time points as listed in the Time and Event 
Table (Section 7.1). Pre-dose blood sample will be also collected on 
Days 8, 22, and every 4 week thereafter. Pre-dose blood samples for 
PD, biomarker and translational research will be collected on Days 1, 
8, 15, 22 and at the end of treatment visit.
Alterations may be made to the PK/PD sampling schedule based on 
the results of emerging PK, PD, and safety data.
CLINICAL ACTIVITY 
ASSESSMENT
Disease assessment will be performed every 8 weeks in all subjects 
(Parts 1 and 2). Disease assessment may include imaging and 
physical examination. All post-baseline assessments require imaging 
of disease sites identified by baseline scans, and they include 
chest/abdomen/pelvis (if applicable) CT scans with contrast and 
brain MRI scan, if the disease is present at baseline.
Disease progression and response evaluations will be determined 
according to the definitions established in the RECIST 1.1.   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 


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same method of assessment and the same technique will be used 
when assessing response. The clinical activity will be evaluated by 
disease control rate at week 16 in Part 2. 
TRANSLATIONAL 
RESEARCH
Comparative examination of pre-treatment, on- treatment and post-
treatment markers (which may include DNA, RNA, protein, cell, 
blood or tissue examination) of subjects may be performed to 
uncover known or novel candidate biomarkers/profiles which could 
be used to predict response to treatment with GSK2879552, measure 
PD and/or response to treatment, or provide new insights into SCLC 
and medically related conditions.
STATISTICAL METHODS
The total number of subjects to be enrolled in Part 1 will depend on 
the number of subjects needed to characterize individual dose 
cohorts. Results of simulations for the dose-escalation phase are 
shown in Appendix 6.  Based on these simulations, the sample size 
for the dose-escalation portion is expected to be approximately 19-22 
subjects. It is anticipated that approximately 57 subjects will be 
enrolled in Part 1 including PK/PD expansion cohorts.  
An initial dose escalation will be used to establish the RP2D for 
GSK2879552.  Once the final dose is confirmed, at least 12 and up 
to 30 subjects will be enrolled at that dose, using decision rules 
defined in Figure 3. The sample size and stopping rules are based on 
the methodology of Lee et al. [Lee, 2008].  The assumptions 
underlying the design are detailed below. 
H0: DCR≤15%
The alternative hypothesis is:
HA:DCR≥30%
Starting with 12 subjects and allowing for a maximum sample size of 
30, this design will have a type I error rate () of 0.15 and 80% 
power.  The trial is not designed to stop early for efficacy, but is 
designed to stop early for futility if the predictive probability of 
success is 5% or less.  The type I error rate, power, and predictive 
probability of success to stop early for futility were derived from 
explicitly stating the minimum and maximum sample size, futility 
stopping rate, and selection of the optimizing criterion as the 
maximization of power under the alternative hypothesis. The design 
will have a type I error rate of less than 0.15 and a power greater 
than 80% for a sample size exceeding 30 subjects. The Bayesian 
prior used in determining the design was Beta (0.15, 0.85), a 
distribution with a mean response rate of 15%.  Under the null 
hypothesis, if the true disease control rate is 15%, the expected 
sample size of the design is 24 subjects and probability of early 
termination (PET) is 75%. Under the alternative hypothesis, if the 
true disease control rate is 30%, the expected sample size of the 
design is 29.0 subjects and PET is 10%.
All Subjects Population: This will consist of all subjects who 


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received at least one dose of study treatment. Safety and clinical 
activity data will be evaluated based on this population.
The Pharmacokinetic Population: This will consist of those 
subjects in All Subjects Population and for whom a PK sample is 
obtained and analyzed.
The Pharmacodynamic Population: This will consist of those 
subjects in All Subjects Population and who contribute 
PD/Biomarker samples.
Additional details of the statistical analysis plan will be provided in 
the reporting and analysis plan (RAP).


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1.
INTRODUCTION
1.1.
Background – LSD1
LSD1, lysine specific demethylase 1, is a histone H3 lysine 4 mono-methyl (H3K4me1) 
and di-methyl (H3K4me2) demethylase responsible for controlling the expression of 
genes that regulate differentiation.  LSD1 is frequently found as a component of 
transcriptional repressive complexes along with other proteins associated with repression 
such as CoREST (CoRepressor for Element-1-Silencing Transcription factor) and 
HDACs (Histone Deacetylases) 1 and 2 [You, 2001; Shi, 2003].  These data suggest that 
LSD1 localization and activity correlates with transcriptional repression and that 
inhibition of LSD1 will result in increased expression of LSD1 target genes.
LSD1 activity is essential for the maintenance of pluripotency in embryonic stem cells by 
regulating the balance between H3K4 and H3K27 methylation, thereby keeping 
differentiation associated genes silenced [Adamo, 2011].  LSD1 also plays a critical role 
in normal hematopoietic differentiation by mediating repression of a key gene expression 
program in hematopoietic progenitors [Saleque, 2007].  
1.2.
Unmet Medical Needs For Small Cell Lung Carcinoma
Small cell lung carcinoma (SCLC) accounts for 15-20% of all lung cancers in the US. 
Estimated new cases of lung cancer (SCLC and non-small cell lung cancer combined) in 
the US in 2013 are 228,190 and estimated death are 159,480, accounting for about 27% 
of all cancer deaths [American Cancer Society, 2013]. Although SCLC is highly 
responsive to initial chemotherapy, patients with extensive stage SCLC frequently relapse 
with resistant disease [Hurwitz, 2009].  The response rate to second line treatment is 
dependent on the time to relapse from first line chemotherapy.  For those who have 
refractory disease (time to relapse < 3 months), response rate to second line treatment is 
very low (<10%).  For those with more sensitive disease, response rate to single-agent 
second line therapy is approximately 25%.  However, the duration of response is short 
and the overall survival is 5.3 months [Sundstrøm, 2005].
LSD1 is highly expressed in primary small cell lung carcinoma (SCLC).  Ninety-eight 
percent of SCLC tumors represented in a tissue microarray demonstrated very high 
expression for LSD1 protein.  A corresponding tissue microarray containing normal 
tissue, including lung, was tested and had no positive staining for LSD1.
1.3.
GSK2879552
1.3.1.
GSK2879552 - Background
An overview of the pre-clinical studies of GSK2879552 is provided below.  Detailed 
information concerning the biology, pharmacology, pharmacokinetics (PK), and safety 
can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_01].


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GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 1.7 µM, kinact = 0.1 min-1).  While the initial reversible potency (Ki) of 
GSK2879552 is moderate, complete inhibition of the enzyme is achieved over time due 
to the irreversible, mechanism-based nature of the inhibition.  GSK2879552 induces the 
expression of putative LSD1 target genes and has potent, predominantly cytostatic, anti-
proliferative activity in small cell lung carcinoma (SCLC) with median EC50 = 25 nM, 
range = 2 - 240 nM.  In total, 9/28 SCLC lines were found to be sensitive to 
GSK2879552 treatment while the sensitivity of an additional 7 SCLC lines could not be 
determined.  
1.3.2.
Pre-Clinical Pharmacology & Safety of GSK2879552
Pharmacology
GSK2879552 causes an increase in histone 3 lysine 4 di-methylation (H3K4me2) at 
promoters of putative LSD1 target genes.  H3K4 methylation is associated with actively 
transcribed genes.  Consistent with increased promoter H3K4me2, GSK2879552 causes 
increased expression of a set of genes in sensitive and insensitive SCLC cell lines 
(average NCI-H526 EC50 = 31 nM) in vitro.  The specific genes that are upregulated are 
unique to each SCLC cell line. Studies are ongoing to assess whether common biological 
pathways are primarily affected as a result of LSD1 inhibition in SCLC. Additionally, 
GSK2879552 decreases gene and protein expression of progastrin releasing peptide 
(ProGRP), a neuroendocrine protein commonly secreted from SCLCs, in both sensitive 
and insensitive SCLC cell lines.
GSK2879552 activity in SCLC has been further characterized using in vivo subcutaneous 
xenograft models.  GSK2879552 induces the expression of LSD1 target genes in NCI-
H526 SCLC subcutaneous xenografts following a single oral dose. Similarly, 
GSK2879552 induces expression of potential LSD1 target genes in whole blood of 
immunocompetent mice following a single oral dose. In both SCLC tumors and whole 
blood, maximal gene activation occurs between 6 and 24 hours after dosing and subsides 
by 72 hours.  Fifty percent of the genes assessed reached > 2-fold expression relative to 
vehicle treated animals at 1.7 mg/kg (predicted exposure of 234 ng*hr/mL).  
GSK2879552 inhibits the growth of NCI-H526 SCLC tumors grown subcutaneously in 
nude mice (Table 1). Higher doses were tolerated with 4 days on/3 days off dosing with 
greater tumor growth inhibition.


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Table 1
Summary of tumor growth inhibition in NCI-H526 xenografts treated 
with GSK2879552
Dose
Exposure
NCI-H526
(mg/Kg)
(ng*hr/mL)1
Daily
EOD
2on 2off
4on 3off
45
6300
26%
76%2
15
2100
N.T.
5
700
N.T.
38%
29%
64%2
1.5
210
57%2
42%
0.5
70
48%2
0.15
21
36%
0.05
7
7%
Dose/schedule combinations shaded in black were not tested.  N.T. = not tolerated, EOD = every other day.
1.
Exposures are extrapolated from mouse PK study N10194-15
2.
p < 0.05
Pharmacokinetics  The nonclinical pharmacokinetics of GSK2879552 were similar 
across species. In vitro, GSK2879552 binding to plasma proteins varied between species 
and was around 64% in mice, 81% in rats, 42% in dogs and 55% in human at a 
concentration of 0.02 uM (~8 ng/mL). Oral bioavailability was moderate to high (59% in 
mice, >100% in rats and 85% in dogs). Steady state volume of distribution was moderate 
to high in all species. GSK2879552 had high clearance in mice and rats and moderate 
clearance in dogs with a low intrinsic clearance in microsomes and hepatocytes from all 
species, including humans. GSK2879552 half life was 1 to 3 hours in all species. 
Systemic exposure to GSK2879552 generally increased dose-proportionally in rats and 
dogs.
General Toxicology
The systemic toxicity of GSK2879552 administered orally once daily for up to 4 weeks 
has been evaluated in mice, rats and dogs.  Screening genotoxicity studies have also been 
conducted.  Summaries of principal findings following single and repeat dosing of 
GSK2879552 are presented in Table 2.  A comparison of systemic exposures achieved in 
these studies is presented in Table 3.  Details of principal toxicological findings are 
discussed below.
Morbidity and mortality:  In rats given GSK2879552 at doses of up to 100 mg/kg/day 
for 7 days or up to 0.3 mg/kg/day for 14 days, no morbidity and/or mortality was 
observed.  GSK2879552 administration was associated with hematologic effects at all 
doses (detailed below), macroscopic and microscopic evidence of multifocal hemorrhage 
in multiple organs at 1 mg/kg/day for 7 days and microscopic evidence of decreased 
bone marrow cellularity at 0.3 mg/kg/day for 14 days.  
GSK2879552-related morbidity and/or mortality were observed in rats and dogs given 
repeat doses of 0.4 mg/kg/day or 0.1 mg/kg/day, respectively.  In rats given a dose of 
0.4 mg/kg/day of GSK2879552 for up to 4 weeks, morbidity was observed in 5 of 38 rats 
between Days 7 and 17.  Rats were killed due to deteriorating clinical condition with 
clinical signs including red nasal discharge, pale extremities, subdued behavior, partial 


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eye closure, irregular breathing, piloerection and slow movements; these were considered 
to be associated with a severe reduction in platelet counts.  Similar findings occurred in 
dogs.  Following dosing of 1 mg/kg/day GSK2879552 for 7 daily doses or intermittent 
dosing for 2 cycles of 4 days on-dose and 3 days off-dose, morbidity was observed in 1 of 
2 dogs in the daily dosing group at Day 13 and in 1 of 2 dogs in the intermittent dosing 
group at Day 8.  In a 4 week, daily dosing study, morbidity was observed in 1 of 10 dogs 
at 0.1 mg/kg/day on Day 14 and in 8 of 10 dogs at 0.3 mg/kg/day between Days 13 and 
15.  Dogs were killed due to adverse clinical observations which included body weight 
loss (1 mg/kg/day), subdued behavior, decreased activity, reluctance to move, unsteady 
gait, swaying, slight high stepping and slight stiffening of hind limbs.  At necropsy, there 
were findings in various parts of the digestive tract (red discoloration) and the lymphoid 
system (red or dark discoloration), correlating microscopically with the lymphoid 
necrosis and hemorrhage.  These effects were secondary to pharmacology-driven severe 
thrombocytopenia (up to 95% decrease in the affected animals). 
Taken together, GSK2879552, even at doses as large as 100 mg/kg/day, lacks serious 
acute toxicity.  However, pharmacology-mediated severe hematologic toxicity, 
principally thrombocytopenia, leads to secondary morbidity 7 to 14 days following 
initiation of dosing at doses ≥0.4 mg/kg/day in rats and 0.1 mg/kg/day in dogs.
Hematologic Toxicity:  The primary effect of GSK2879552 was hematopoietic 
pancytopenia, principally thrombocytopenia, (in mice, rats and dogs), neutropenia 
(primarily in rats), and decreased reticulocytes (rats and dogs).  In the bone marrow of 
rats and dogs, there was a shift to immaturity of the megakaryocytic, granulocytic and 
erythroid lineages.  There was an increase in monocyte counts in rats and dogs.  In 
concordance with the critical role played by LSD1 in the maturation of several 
hematopoietic lineages [Sprussel, 2012], these hematopoietic effects of GSK2879552 
represent an on-target pharmacologic effect rather than an off-target, cytotoxic effect or 
inflammatory response.
In rats, hematopoietic effects of GSK2879552 were characterized primarily by a 
dose-dependant thrombocytopenia and neutropenia. Dose dependent thrombocytopenia 
was observed at doses of 0.1 mg/kg/day, reaching a maximum 98% reduction at 
0.4 mg/kg/day.  During treatment, there was increased mean platelet volume (MPV).  
Following 14 days treatment there was also a decrease in mean collagen-induced platelet 
aggregation.  Following 4 weeks treatment platelet counts recovered in the off-dose 
period with an initial rebound to approximately 1.5-fold control values 1 week after 
4 weeks of dosing at 0.4 mg/kg/day.  Neutropenia had a rapid onset (within 7 days) and 
was dose-dependent at doses 0.03 mg/kg/day, reaching a maximum 94% decrease at 
1 mg/kg/day.  Neutrophil counts began recovery either during the dosing period 
(0.03 mg/kg/day) or in the off-dose period at 0.1 mg/kg/day.  During the recovery phase 
of the 4 week study, neutrophil counts initially increased above control values (1.4 fold) 
and were comparable to controls by 14 days.  At doses of 0.2 mg/kg/day, GSK2879552 
also caused a decrease in red blood cell count, an increase in monocytes and an increase 
in reticulocytes that was of smaller magnitude than its effects on platelets and 
neutrophils.  The levels of RBCs, monocytes and reticulocytes returned to control values 
by the end of the 4 week recovery period.


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In rats, the hematopoietic effect of GSK2879552 (0.1 mg/kg/day) was associated with 
increased megakaryocyte cellularity (with a high proportion of immature cells) in the 
bone marrow and spleen (spleen weight was increased up to 2-fold at 0.4 mg/kg/day).  
Megakaryocytes were also present in the liver of rats given 0.2 mg/kg/day.  
Myelofibrosis and hyperostosis of trabecular bone was noted in rats given 0.4 mg/kg/day 
at the end of the 4 week dosing period that reversed following a 4 week off-dose period.  
Myeleofibrosis or hyperostosis was not observed in dogs.  Following administration of 
the thrombopoietin agonist romiplostim [Kuter, 2009] for 4 weeks, there was marked 
thrombocytosis in rats and primates and similar reversible bone marrow myelofibrosis 
and hyperostosis observed in rats but not in primates.
In dogs, the hematopoietic effect of GSK2879552 was characterized primarily by a 
time- and dose-dependent thrombocytopenia. In dogs given a single dose of 1 mg/kg, 
platelet counts began to decline three days after dosing, reached a nadir (60% decrease) 
on Day 7, began to recover on Day 9, rebounded to a peak of approximately 2-fold 
pretreatment values on Day 13 and returned to pretreatment values on Day 24.  A similar 
time course for platelet counts was observed in mice that received 5 daily doses of 
GSK2879552 at 15 or 45 mg/kg/day.  In repeat dose studies in dogs, thrombocytopenia 
occurred at doses 0.1 mg/kg/day, reaching a 94% decrease in platelet counts at 
1 mg/kg/day, and was associated with an increase in mean platelet volume of the 
remaining platelets at 0.3 mg/kg/day.  At 0.3 mg/kg/day in the 4 week study, the nadir 
in platelet counts was by Day 12 (85% decrease).  There was partial, dose-dependent 
recovery in platelet counts during the dosing period.  Following repeat dosing, platelet 
counts rebounded by up to 3-fold baseline values within 8 days and returned to control 
values by 4 weeks.  At doses of 0.1 mg/kg/day, GSK2879552 also affected other 
hematopoietic lineages, but to a lesser extent than platelets, including decreases in 
neutrophils (up to 31%) and in red blood cell count (up to 12%); the latter was associated 
with a regenerative increase in reticulocytes (up to 1.5-fold).  Monocytes were increased 
by up to 5-fold, remained elevated during the dosing period, did not decrease below 
pretreatment values after cessation of dosing and returned to pretreatment values by 
4 weeks after dosing.
The hematopoietic responses to GSK2879552 in dogs were different from that observed 
in rats in that 1) platelet counts showed no recovery during the dosing period in rats and 
2) neutrophil counts were only mildly affected in dogs.  The underlying mechanism for 
these differences is not currently understood.
Lymphoid Organs:  In both rats and dogs there were effects noted in lymph nodes and 
thymus that were reversible during the off-dose period.  In rat, this consisted of mild to 
moderate congestion in the mesenteric and mandibular lymph nodes and lower thymus 
weight.  In dogs, this consisted of red discolouration in the colon, caecum, ileo-
colocaecal area, and jejunum.  Microscopic findings in dogs were primarily necrosis of 
the Peyer’s patches in the jejunum (minimal) and the ileum (minimal to mild), minimal 
haemorrhage in the caecum and minimal to mild decreased lymphoid cellularity in the 
thymus.  In both species there were no effects on circulating lymphocyte counts.  
Although the mechanism underlying these effects on associated lymphoid tissue is 
currently unknown, the role that LSD1 plays in regulating cytokine expression [Janzer, 
2012] and B lymphocyte maturation [Su, 2009] may be involved.


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Genotoxicity:  In screening studies in vitro, GSK2879552 was not mutagenic in the 
bacterial mutation assay (Ames) and was not genotoxic in the human lymphocyte 
micronucleus assay.  These results suggest that GSK2879552 does not pose a genotoxic 
risk.
Reproduction:  There were no histologic effects of GSK2879552 on male or female 
reproductive organs in rats or dogs following 4 weeks dosing.  However, based on the 
expression of LSD1 in reproductive organs and investigations with LSD1 gene disruption 
[Godmann, 2007; Foster, 2010], GSK2879552 may adversely affect male and female 
fertility and embryofetal development.
Conclusion:  The dose-limiting toxicity in rat and dog oral toxicology studies conducted 
with GSK2879552 was a dose-dependent, reversible mild to severe thrombocytopenia 
that was observed after a single high dose (1 mg/kg in dogs) or after repeat doses as low 
as 0.1 mg/kg/day (rats and dogs).  Platelet counts began to decrease on the third day after 
the initiation of dosing and reached a nadir 7 days following a single dose and by 12 days 
after lower repeat doses.  In repeat dose studies in dogs, a partial, transient recovery of 
platelet counts occurred during the dosing phase, whereas no recovery in platelet counts 
occurred in rats during dosing.  During the off-dose period, platelet counts rebounded in a 
dose-dependent manner (the more suppression, the greater the rebound) peaking in 
approximately 10 days.  By 4 weeks after dosing, platelet counts returned to or near 
pretreatment values in rats and dogs.
GSK2879552 also caused a dose-dependent decrease in circulating neutrophils, 
reticulocytes and red blood cells (RBCs).  Neutropenia was more severe in rats than dogs.  
Neutrophil counts rebounded to above pretreatment levels only after cessation of dosing, 
peaking in 7 to 8 days in rats and in 14 days in dogs.  Recovery from suppression of 
reticulocyte counts, however, differed between rats and dogs.  In rats, suppression of 
reticulocyte counts fully recovered and maximally rebounded during the 4 week dosing 
period whereas, in dogs, recovery and rebound occurred after dosing, peaking in 20 days.  
The mild decrease in RBCs was primarily related to internal hemorrhaging secondary to 
thrombocytopenia, however the reduced reticulocytes may also have contributed to the 
decrease in RBCs.  By 4 weeks after dosing, neutrophil, reticulocyte and red blood cell 
counts returned to or near pretreatment values in rats and dogs.
GSK2879552 caused a dose-dependent increase in circulating monocytes in rats and 
dogs.  In both species, monocytes remained elevated during the dosing period, did not 
decrease below pretreatment values after cessation of dosing and returned to pretreatment 
values by four weeks after dosing.
The decreases in  circulating platelets, neutrophils and reticulocytes result from the 
pharmacologic activity of GSK2879552 on hematopoietic lineages in the bone marrow as 
evidenced by a shift to immaturity of progenitor cells in the megakaryocytic, granulocytic 
and erythroid lineages, while the increase in monocytes results from stimulation of 
monopoiesis.  Myelofibrosis and hyperostosis in rat (but not dog) was secondary to the 
marked regenerative response in the bone marrow in response to the peripheral blood 
cytopenias and likely represents a rodent specific response. Generally mild to moderate, 
reversible effects (reduced weight, cellularity or necrosis/hemorrhage) were observed in 


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lymphoid tissues of rats or dogs without an effect on circulating lymphocytes, of which 
the relationship to the pharmacology of GSK2879552 is uncertain.
As a result of severe thrombocytopenia, some rats (0.4 mg/kg/day) and dogs 
(0.1 mg/kg/day) on the 4 week toxicology studies were killed due to deteriorating 
clinical condition which included red nasal discharge, pale extremities, subdued behavior, 
partial eye closure, irregular breathing, piloerection and slow movements.
Based on the morbidity secondary to thrombocytopenia at 0.4 mg/kg/day, the no 
observed adverse effect level (NOAEL) in rats was 0.2 mg/kg/day.  Gender-averaged 
systemic exposure on Day 30 at the NOAEL was 367 ng.h/mL (mean AUC0-t) and 
81.3 ng/mL (mean Cmax).  In rats, the STD10 was considered to be 0.4 mg/kg/day.  Given 
the morbidity in dogs at 0.3 and 0.1 mg/kg/day, the NOAEL and highest non-severely 
toxic dose (HNSTD) is 0.03 mg/kg/day [mean AUC(0-t) 22.0 ng.h/mL, mean Cmax 6.1 
ng/mL, (gender averaged based on Day 27 values)].  
Table 2
Principal Toxicological Findings in Rats and Dogs Following Oral 
Administration of GSK2879552 as Single or Repeat Doses for up to 
4 Weeks
Finding
Rat
Dog
Effect 
Dose
(mg/kg)
No-Effect 
Dose
(mg/kg)
Effect 
Dose
(mg/kg)
No-Effect 
Dose
(mg/kg)
Morbidity/Mortality
Repeat Dose* 
0.4
0.3
0.1
0.03
Hematologic Toxicity
Platelets – decrease
0.1
0.03
0.1
0.03
Neutrophils – decrease
0.03
NA
0.3
0.1
Reticulocytes - decrease
0.3
0.2
0.3
0.1
Red Blood Cells - decrease
0.2
0.1
0.3
0.1
Monocytes – increase
0.2
0.1
0.1
0.03
Bone marrow - immature phenotype
0.1
0.03
0.03
ND
Myelofibrosis/hyperostosis
0.4
0.3
NO
NA
Lymphoid Organs
Lymph nodes – congestion
0.1
ND
NO
NA
Lymph nodules – necrosis/hemorrhage
NO
NA
0.03
ND
Thymus – decreased weight
0.2
0.1
NO
NA
Thymus – decreased cellularity
NO
NA
0.03
ND
Key:
* Animals killed due to deteriorating clinical condition with clinical signs including red nasal 
discharge, pale extremities, subdued behavior, partial eye closure, irregular breathing, piloerection 
and slow movements.  Macroscopic and microscopic evidence of hemorrhage.
NO = not observed;  NA = not applicable;  ND = not determined


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Table 3
Comparative Assessment of Systemic Exposure Following Oral 
Repeat Dose Administration of GSK2879552 to Rats and Dogs
Species
Dose
Cmax (ng/mL)
AUC (ng.h/mL)
(Duration)
(mg/kg/day)
Day 1
End of Study
Day 1
End of Study
Rat
(7-day)
1
348
335
1890
1770
10
3640
3880
17700
18400
100
34600
36600
221000
238000
Rat
(14-day)
0.03
3.66
4.90
20.2
36.9
0.1
14.2
23.3
98.9
139
0.3
69.6
76.6
375
413
Rat
(4 weeks)
0.1
26.1
35.2
120
171
0.2
55.4
81.3
260
367
0.4
117
151
606
714
Dog
(7 to 14-day)
0.3
103
88.7
166
157
1
299
243
674
549
Dog
14 day
0.03
7.13
10.7
9.50
22.5
0.1
32.3
37.4
112
176
Dog
(4 weeks)
0.03
6.27
6.68
16.0
22.0
0.1
25.8
31.7
62.2
81.0
0.3
107
NA
225
NA
Note:  Bold = NOAEL (no observed adverse effect level) 
Key:
NA = Not Available (animals terminated prior scheduled end of study)
1.3.3.
Pharmacokinetics of GSK2879552 in Humans
GSK2879552 pharmacokinetics have not yet been evaluated in humans. 
Pharmacokinetics of GSK2879552 in human were predicted using in vitro microsomes 
and hepatocytes data, as well as in vivo intravenous (IV) pharmacokinetic data from 
mice, rats, and dogs combined with simple allometric scaling and Dedrick 
transformation. The human blood clearance is predicted to be around 5.4 mL/min/kg for a 
70 kg human. The human blood volume of distribution is predicted to be most likely 
between 1.0 and 1.5 L/kg leading to a range of terminal half-life of 2.1 to 3.2 hours. 
Based on the good oral bioavailability in animals and the predicted low human clearance, 
the oral bioavailability is expected to be around 75% to 100% in humans.
1.4.
Benefit:Risk Assessment
Summaries of findings from non-clinical studies conducted with GSK2879552 can be 
found in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_01].  Toxicology studies performed in dogs, rats and mice suggest that the 
primary toxicities of GSK2879552 are hematologic.  The following Section outlines the 
risk assessment and mitigation strategy for this protocol.


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Lymphoid/hematologic 
and associated 
bleeding and infection 
risks 
The primary toxicity with GSK2879552 is a dose-
dependent mild-to-severe thrombocytopenia, 
observed in mice, rats and dogs.  A dose-
dependent mild-to-severe neutropenia was 
observed in rats, but not dogs, and was not 
associated with systemic infections.  Mild effects 
on the erythron were observed in rats and dogs 
which may reflect both a direct and indirect (i.e., 
secondary to bleeding/hemorrhage) effect on the 
erythroid lineage. In general, there was not 
hypocellularity observed in the bone marrow of 
these animals.
Informed Consent Form includes the risk of hematologic toxicity.
Protocol specifies: 
-
laboratory assessments (complete blood count [CBC] )
-
Exclusion criteria for subjects with recent history of significant bleeding or 
elevated bleeding risk
-
Monitoring for bleeding 
-
Monitoring for infection
-
Dose stopping/modification criteria
-
Anticoagulants (e.g., warfarin above 1 mg once daily, direct thrombin 
inhibitors, etc) at therapeutic doses or platelet inhibitors (e.g., aspirin above 
100 mg once daily, clopidogrel) are prohibited from fourteen days prior to the 
first dose of study drug through completion of the Final Study Visit.
-
Guideline for platelet transfusion    
Mental status change
Two (out of 16) subjects enrolled in 200858 study 
experienced encephalopathy.
Informed Consent Form is updated to include the risk of mental status change.
Protocol eligibility and monitoring criteria  are modified:
-
subjects who have received prior treatment with temozolomide, dacarbazine,
procarbazine or PARP inhibitors are excluded
-
Subjects should have baseline thyroid function, vitamin B12 level and 
metabolic panel within acceptable limits
-
Montreal Cognitive Assessment (MOCA) at baseline and weekly for the first 4 
weeks and monthly thereafter.
-
Subjects with baseline MOCA score of ≤ 22 are excluded
Protocol stopping criteria is modified:
-
Dosing will be held and neurology consult will be required if a decrease of 3 
points or more from baseline MOCA score or any score of < 22 occurs or in 
case of any other indication of early encephalopathy as determined by patient 
history or physical exam


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1.4.1.
Benefit Assessment
This is an open-label, dose escalation study and the first time in human study of this 
agent to be conducted in subjects with relapsed/refractory SCLC for which no standard 
therapies are anticipated to result in a durable remission. GSK2879552 has preclinical 
activity in SCLC cell lines, however it is unknown whether GSK2879552 will have 
clinical activity, thus any potential beneficial effect for an individual subject attributable 
to GSK2879552 is unknown. Data obtained in this study may assist in progressing the 
knowledge base on SCLC and its treatment, or help identify individuals more likely to 
benefit or have side-effects from GSK2879552. Study participants may benefit from the 
medical tests and screening performed during the study. 
1.4.2.
Overall Benefit:Risk Conclusion
Current data from GSK2879552 preclinical studies indicate a potential to induce the 
expression of putative LSD1 target genes and to inhibit tumor growth. Taking into 
account the measures taken to minimize risks to subjects participating in the Phase I 
clinical trial, the potential risks identified in association with GSK2879552 are justified 
by the anticipated benefits that may be afforded to subjects with relapsed/refractory 
SCLC.
2.
OBJECTIVES, ENDPOINTS AND HYPOTHESES
2.1.
Part 1 Dose Escalation
PART 1: Escalation Cohort
Objectives
Endpoints
Primary
1.
To determine the safety, tolerability 
and Recommended Phase 2 
Dose(s) (RP2D) and regimen of 
GSK2879552 given orally in adult 
subjects with small cell lung 
carcinoma (SCLC).  
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety parameters 
(e.g., laboratory values, vital signs, 
electrocardiograms [ECGs], physical 
examinations).
Secondary 
1.
To characterize the 
pharmacokinetics (PK) of 
GSK2879552 after single- and 
repeat-dose oral administration.
1.
GSK2879552 PK parameters following 
single-(Day 1) and repeat-dose (Day 15) 
administration of GSK2879552, including 
AUC, Cmax, time of occurrence of Cmax 
(tmax), t½ (terminal phase and/or effective 
half-life), accumulation ratio, and time 
invariance.
2.
To evaluate clinical activity after 
treatment with GSK2879552.
3.
To evaluate the relationship 
between GSK2879552 exposure 
and 
2.
Disease Control Rate (DCR) (CR + PR + 
SD) at week 16 based on Response 
Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmax, Cmin 
or AUC [0-tau]), and ProGRP, platelet 


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PART 1: Escalation Cohort
Objectives
Endpoints
safety/efficacy/Pharmacodynamic 
(PD) parameters
levels in blood, and safety/efficacy 
parameters. 
Exploratory
1.
To assess feasibility of a select 
gene panel for use as a PD assay 
for GSK2879552
2.
To investigate the impact of 
GSK2879552 on the RNA 
expression profile in tumor and 
blood to identify mechanisms of 
rational combination and potential 
resistance.
1.
Change from baseline expression in select 
genes in whole blood and tumor
2.
Transcriptomic (RNA) profile of tumor and 
whole blood pre- and post-treatment with 
GSK2879552.
3.
To investigate relationship between 
tumor baseline genomic profile and 
response or resistance to 
GSK2879552.
4.
To discover circulating response 
and resistance biomarkers
5.
To investigate the impact of 
GSK2879552 on fetal haemoglobin
3.
Tumor DNA, RNA and protein markers at 
baseline.
4.
Circulating biomarkers (e.g. circulating cell 
free DNA [cfDNA], protein and RNA).
5.
Pre- and post-treatment fetal haemoglobin 
levels
6.
To characterize the metabolite 
profile of GSK2879552 after oral 
single and/or repeat-dosing in 
some subjects
7.
To determine the amount of 
GSK2879552 excreted in urine 
after oral single and/or repeat-
dosing
6.
GSK2879552 metabolites in plasma and/or 
urine
7.
Concentration of GSK2879552 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time 
Hypothesis
No formal statistical hypotheses are being tested in Part 1 dose escalation.  Analysis of the 
data obtained from Part 1 will only utilize descriptive methods.
2.2.
Part 2 Expansion
Part 2: Expansion Cohort
Objectives
Endpoints
Primary
1.
To evaluate clinical activity of 
GSK2879552 given orally in adult 
subjects with SCLC.
1.
Disease Control Rate (DCR) (CR + PR + 
SD) at week 16 based on Response 
Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1.  
Secondary
1.
To evaluate the safety and 
tolerability of RP2D of GSK2879552
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety 
assessments (e.g., laboratory parameters, 
vital signs, physical examinations).


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Part 2: Expansion Cohort
Objectives
Endpoints
2.
To characterize the population PK of 
GSK28795522. 
2.
Population PK parameters for 
GSK2879552 such as clearance (CL/F) 
and volume of distribution (V/F), and 
relevant covariates which may influence 
exposure (e.g., age, weight, or disease 
associated covariates).
3.
To evaluate the relationship 
between GSK2879552 exposure 
and safety/efficacy/PD parameters. 
4.
To evaluate duration of response 
and progression free survival (PFS)
5.
To evaluate objective response rate 
(ORR)
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmin, Cmax 
or AUC [0-tau]), and ProGRP, platelet 
levels in blood, and safety/efficacy 
parameters.
4.
Duration of response and PFS
5.
% of subjects achieving complete 
response and partial response
Exploratory
1.
To assess feasibility of a select 
gene panel for use as a PD assay 
for GSK2879552
2.
To investigate the impact of 
GSK2879552 on the RNA 
expression profile in blood to identify 
mechanisms of rational combination 
and potential resistance.
1.
Change from baseline expression in 
select genes in whole blood
2.
Transcriptomic (RNA) profile of whole 
blood pre- and post-treatment with 
GSK2879552.
3.
To investigate relationship 
between tumor baseline genomic 
profile and response or resistance 
to GSK2879552.
4.
To discover circulating response 
and resistance biomarkers
5.
To investigate the impact of 
GSK2879552 on fetal 
haemoglobin
3.
Tumor DNA, RNA and protein markers at 
baseline.
4.
Circulating biomarkers (e.g. cfDNA, 
protein and RNA).
5.
Pre- and post-treatment fetal haemoglobin 
levels
Hypothesis
Clinical response will be defined as Disease Control Rate (DCR) (CR + PR + SD) at week 
16 based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.  
The null hypothesis is: H0: DCR ≤15% at week 16
The alternative hypothesis is: HA: DCR ≥30% at week 16
3.
INVESTIGATIONAL PLAN
3.1.
Discussion of Study Design
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table 
(Section 7.1), are essential.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 


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the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a phase I, open-label, multi-center, non-randomized, 2-part first time in human 
(FTIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), 
pharmacodynamics (PD) and clinical activity of GSK2879552 given orally (Figure 1). 
Figure 1
Study Schema
Part 1 is a dose escalation phase to determine the recommended phase 2 dose (RP2D) for 
GSK2879552 based on the safety, tolerability, PK, and PD profiles observed after oral 
administration of GSK2879552. Eligible subjects with relapsed/refractory SCLC will be 
enrolled in the dose escalation cohorts. Any dose level(s) may be expanded up to 12 
subjects in order to collect additional data on PK and PD.
Once RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects will be 
enrolled to further evaluate the clinical activity and tolerability of GSK2879552 in 
subjects with relapsed/refractory SCLC. 
The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose will be 0.25 mg once daily. Alterations to the dose and schedule may be 
incorporated based on emerging PK, PD, and tolerability/safety data.  
Subjects may continue treatment in the study until disease progression (investigator 
assessed), unacceptable toxicity, or withdrawal of consent. Subjects enrolled in Part 2 
who discontinue study treatment for reasons other than Response Evaluation Criteria in 
Solid Tumors (RECIST)-defined disease progression will continue to have protocol 
defined radiological assessments until disease progression per RECIST 1.1, start of new 


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anti-cancer therapy or withdrawal from study.  Every effort should be made to continue 
radiological assessments until radiological progression per RECIST is observed. The 
duration of study will depend on recruitment rates and timing of subjects’ duration on 
study.
3.2.
Part 1: Dose-Escalation
In Cohort 1, a single subject will receive a dose of GSK2879552 0.25 mg once daily. The 
subject in Cohort 1 must complete a full 28 days of dosing, and the safety and PK data 
will be reviewed prior to starting Cohort 2.  If the first subject becomes inevaluable for 
reasons other than toxicity, another subject will be recruited.  The dose-escalation 
decision and rationale will be documented in writing with copies maintained at each 
study site and in the master study files at GlaxoSmithKline (GSK). 
Starting with Cohort 2 the dose escalation will continue using the Neuenschwander -
continuous reassessment method (N-CRM) [Neuenschwander, 2008]. A sufficient 
number of subjects will be enrolled in each cohort to ensure that data from at least one 
subject that has completed the first 28 days of dosing is available prior to defining a new 
dose and starting the next cohort.  In addition, subjects who fail to take at least 75% of 
their scheduled doses in the first 28 days for reasons other than toxicity (e.g., dose 
limiting toxicities) will be replaced.
Maximum Dose Increment 
Built-in safety constraints are in place to prevent exposing subjects to undue risk of 
toxicity. The dose increment will be no more than 100% of the current dose in the 
absence of any safety signals. The dose increment will be no more than 50% of the 
current dose after one grade ≥ 2 non-hematologic drug related toxicity (except alopecia, 
fatigue, asthenia, nausea, vomiting and electrolyte abnormalities as described below), 
dose limiting toxicity (DLT), Grade 2 thrombocytopenia lasting over 7 days or Grade 3 
neutropenia lasting over 7 days is observed.  The maximum allowable dose increment 
will be determined based on the prior dose level data. 
Number of Subjects in a Cohort
The dose escalation will continue with 1 subject per cohort until any of the following 
events are observed, and then each subsequent cohort will consist of a minimum of 2 
subjects.  

Dose limiting toxicity

Grade 2 thrombocytopenia over 7 days 

Grade 3 neutropenia.

Any Grade 2 or higher non-hematologic adverse event (except alopecia) that is 
considered related to the study medication with the following exceptions:

Grade 3 fatigue, asthenia, nausea, and vomiting that respond to standard medical 
care within 72hrs, electrolyte abnormalities unrelated to underlying malignancy 
and corrected within 72 hrs 


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
Any grade adverse event that is considered in the judgment of the investigator 
and GSK Medical Monitor to be serious and related to the drug and requiring
additional subjects to better understand the toxicity.
When 2 or more subjects are enrolled in a cohort, dosing start will be staggered by at 
least 1 week interval between the subjects.
The subsequent cohorts may revert to 1 subject per cohort in either of the following 2 
scenarios: 

2 additional subjects are added at the dose where Grade 2 toxicity is seen in the 
initial subject and no Grade 2 or higher toxicity is seen in either of the 2 new 
subjects.

Subjects treated at next higher dose level do not have a Grade 2 or higher toxicity.
However, the dose escalation may continue with multiple subjects per cohort per the 
clinical judgment of the Medical Monitor and internal dose-escalation committee in 
consultation with the investigators. The decision on the number of subjects will be 
documented in writing together with the dose escalation decision and the rationale.
Completion of Dose Escalation
The dose escalation will complete when RP2D is determined. The RP2D will be the 
MTD or a lower dose that provides adequate PK exposure and biologic activity with 
superior tolerability.  The identification of MTD may not be necessary if a clear RP2D 
emerges without reaching the MTD.  The final determination of RP2D will be based on 
the N-CRM suggested dose level, or the biologically active dose (e.g., clinical response), 
the safety profile, and available PK and PD data generated from all subjects in Part 1.  If 
necessary, alternate schedules can be explored to determine additional biologically active 
doses even after a RP2D is defined.
Dose Escalation Committee 
An internal dose-escalation committee will be comprised of the following GSK 
representatives: Medical Monitor, Safety Physician or Scientist, Clinical Scientist, 
Biostatistician, PK and PD Scientists, and Study Operation Lead.  The dose-escalation 
committee will review available relevant data on demographics, all adverse events 
including non-DLT toxicities, laboratory assessments, 12-lead ECGs, and dose 
administration logs, as well as PK and PD data. On the basis of a review of these data and 
in joint discussions with the participating investigators, a determination will be made as 
to whether dose escalation should continue as recommended by the N-CRM. 
Description of the Continual Reassessment Method
After each cohort, a dosing recommendation for the next cohort will be made using the 
N-CRM.  All available data, including safety, PK and PD 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 and 


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internal dose-escalation committee in consultation with the investigators can halt or 
reduce dose escalation or de-escalate as deemed appropriate at any time during the trial. 
The N-CRM design is a type of Bayesian adaptive dose escalation scheme that assumes a 
two-parameter logistic model for the toxicity rate based on dose.  It is a modified version 
of the original Continual Reassessment Method (CRM) [O’Quigley, 1990]. A CRM-
based design uses a statistical model for dose and toxicity, and is expected to locate the 
MTD efficiently while minimizing the number of subjects exposed to pharmacologically 
inactive dose levels. 
The method is fully adaptive and makes use of all the DLT information available at the 
time of each dose assignment.  In contrast, the 3+3 method only uses information from 
one dosing cohort at a time.  
At the time of each dose escalation decision, the Fixed and Adaptive Clinical Trial 
Simulator (FACTS, Version 2.3 or higher, Tessella) will be used to obtain, for each 
potential dose, the posterior probabilities that the DLT rate for that dose lies in each of 
four toxicity intervals (underdosing, target dose range, excessive toxicity, and 
unacceptable toxicity).  The four DLT toxicity intervals are defined as follows:

[0%,16%) Underdosing 

[16%, 33%) Target dose range 

[33%, 60%) Excessive toxicity 

[60%, 100%) Unacceptable toxicity
The recommended dose will be the dose with the highest posterior probability of lying in 
the target dose range with the additional requirement that the sum of the posterior 
probabilities of the DLT rate lying in the excessive toxicity or unacceptable toxicity 
range is less than 25%.  Selection of the next dose is also subject to the built-in safety 
constraints of maximum allowed dose increment. An updated estimate of the toxicity 
curve will be provided at the time of the dose escalation meeting.
Note that de-escalation as well as escalation is possible using this method.
Bayesian Prior
The N-CRM methodology requires that a Bayesian prior for the toxicity curve be pre-
specified.  The Bayesian prior used for this design was determined using the quantile 
method.  For each dose, an estimate of the median probability of DLT was specified, 
along with a 95% credible interval.  The 95% credible intervals are intentionally wide 
due to limited information about the toxicity profile of GSK2879552 in humans. Table 4
shows the median prior probability of experiencing a DLT at the given dose along with a 
95% credible interval around the median:


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Table 4
Specified Prior Probability of DLT
Anticipated Dose
(mg)
Median Probability 
of Toxicity
2.5% Quantile for 
Probability of 
Toxicity
97.5% Quantile for 
Probability of 
Toxicity
0.25
0.02
0.01
0.73
0.5
0.05
0.02
0.75
1
0.07
0.04
0.8
1.5
0.1
0.06
0.82
2
0.12
0.08
0.84
2.5
0.15
0.1
0.86
3
0.2
0.12
0.88
4
0.3
0.14
0.9
5
0.42
0.15
0.92
6
0.5
0.16
0.95
8
0.6
0.17
1
10
0.8
0.18
1
12
0.9
0.2
1
A graphical presentation of the prior is displayed in the Figure 2. In the figure, the x-axis 
is natural log (dose/reference dose), where the reference dose is set to 3 mg.  Doses are 
the projected doses.  Actual doses used during the conduct of the trial may vary.
Figure 2
Prior Distribution For The Probability of DLT Given Dose
3.3.
PK/PD Expansion cohorts
Any dose level(s) in Part 1 may be expanded up to 12 subjects in order to collect 
adequate data on safety, PK or PD.  Pre-dose and post-dose tumor biopsies may be 
required from a subset of subjects in PK/PD expansion cohorts. A minimum of five pairs 


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of evaluable pre- and post-dose biopsies may be collected at selected doses based on 
emerging PK/PD data.  
Subjects may be enrolled at previously completed dose levels for the purpose of 
obtaining additional PK or PD data.  A reduced PK schedule may be used in subjects 
enrolled to obtain additional PD samples. These subjects may have the dose escalated to a 
higher completed dose level (not exceeding the maximum tolerated dose [MTD]) once 
the necessary PK/PD procedures have been completed. 
3.4.
Alternative Dosing and PK/PD Sampling Schedules
Alterations may be made to the dosing schedule and/or PK/PD sampling schedule based 
on the results of emerging PK, PD, and safety data, and documented in the SPM. These 
would not require a protocol amendment.
Schedules that incorporate a recovery period may be explored (e.g., 4 days on/3 days off). 
This approach may be considered if higher exposure is desired for an improved clinical 
activity (i.e., higher response rate) or therapeutic exposure cannot be achieved without 
excessive toxicity.  If MTD was not exceeded with the initial schedule, the starting dose 
for the alternate schedule will be the one dose level higher than the highest completed 
dose level. If MTD was exceeded with the initial schedule, the starting dose for the 
alternate schedule will be no higher than the highest tested daily dose. 
3.5.
Dose-Limiting Toxicity
An event will be considered a DLT if it occurs within the first 28 days of treatment, and 
meets one of the following criteria unless it can be clearly established that the event is 
unrelated to treatment:

Recurrent Grade 3 anemia after initial transfusion or Grade 3 anemia lasting > 7 days 
in subjects who are not transfused.

Grade 4 neutropenia 

Grade 3 neutropenia > 7 days duration

Febrile neutropenia as defined by CTCAE v.4.0

Grade 3 thrombocytopenia requiring dose reduction 

Grade 4 thrombocytopenia lasting > 3 days or of any duration if associated with 
clinically significant bleeding 

Drug related Grade 3 or 4 non-hematologic toxicity. Fatigue, asthenia, nausea, 
vomiting or new electrolyte disturbance that respond to standard medical care within 
72 hours are exceptions. In addition, electrolyte disturbances associated with 
underlying malignancy are also excluded.

Drug related Grade 2 toxicity (at any time during treatment) that in the judgment of 
the investigator and GSK Medical Monitor is dose-limiting.

Treatment delay of 14 days or greater due to unresolved drug-related toxicity. 


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3.6.
Maximum Tolerated Dose (MTD) and Recommended Phase 2 
Dose (RP2D)
The MTD is defined as the dose with the highest posterior probability of subjects 
experiencing a DLT in the first 28 days on treatment in the target interval [16%,33%], 
and for which the probability that the DLT rate lies within the excessive toxicity or the 
unacceptable toxicity windows is less than 25%.  The interval boundaries of 16% and 
33% are chosen to be consistent with the traditional 3+3 design toxicity boundary which 
is 1/6 and 1/3.
The RP2D will be MTD or a lower dose that provides adequate PK exposure and biologic 
activity with superior tolerability.  Up to 12 additional subjects will be enrolled at the 
dose to further define the safety and tolerability of the dose and schedule.  
3.7.
Part 2: Expansion Cohort
Once the RP2D has been determined, an expansion cohort of up to 30 subjects will be 
enrolled in order to better characterize the clinical activity and safety profile of the RP2D. 
3.8.
Intra-subject Dose-Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced a DLT, and contingent upon one of the following:

A higher dose level cohort has been cleared without a DLT 

If a dose level has been cleared and no subjects have been identified for enrolment 
at the next dose level, and after the subject has competed a minimum of 8 weeks 
of dosing on that regimen without a DLT, that subject may be escalated to the 
next higher dose level.  In this case, the subject must follow the dosing schedule 
outlined in the Time and Events Table (starting at Day 1) as he/she will be the 
first subject exposed to the higher dose level. 
Decision on intra-subject dose escalation will be made after review of all safety data and 
approval by a GSK Medical Monitor and discussion with the investigator.
3.9.
Rationale
3.9.1.
Rationale for Population
SCLC is initially responsive to chemotherapy; however, patients ultimately relapse and 
the response to second line therapy is poor with overall survival of less than 6 months.
Additionally, current chemotherapy regimens for SCLC often have substantial and for 
some patients, intolerable toxicity. Thus, there is a need for new treatments for this 
disease. Among the cell lines tested, the anti-proliferative activity of GSK2879552 is 
largely limited to SCLC and acute myeloid leukemia. This may suggest a unique 
requirement for LSD1 in these tumor types. Both are poorly differentiated tumors and 
GSK2879552 promotes phenotypic changes associated with differentiation in human 
AML cells. While the biological mechanisms involved in differentiation of SCLC are not 


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as well understood, we hypothesize that inhibition of LSD1 may invoke a similar 
mechanism in SCLC. GSK2879552 induces the expression of putative LSD1 target 
genes and has potent, predominantly cytostatic, anti-proliferative activity in small cell 
lung carcinoma (SCLC) cell lines with median EC50 = 25 nM. In total, 9/28 SCLC lines 
were found to be sensitive to GSK2879552 treatment while the sensitivity of an 
additional 7 SCLC lines could not be determined. GSK2879552 thus may have clinical 
activity in SCLC, either as a monotherapy or ultimately in combination with standard 
chemotherapy.
3.9.2.
Rationale for Dose
3.9.2.1.
Predicted Effective Dose
The potential therapeutic dose for GSK2879552 in human was derived using available 
preclinical PK, in vitro SCLC cell line data and in vivo PD and efficacy data from SCLC 
tumor xenograft studies. 
In vitro, GSK2879552 showed inhibition of proliferation of small cell lung carcinoma 
with a median EC50 = 25 nM (range = 2 - 240 nM). 
The effect of GSK2879552 was evaluated at daily doses of 0.05 mg/kg up to 15 mg/kg in
a mouse NCI-H526 xenograft model. Daily doses of 0.5 mg/kg and 1.5 mg/kg showed 
significant decreases in tumor growth of 48% and 57% respectively.
The anticipated effective daily doses in humans are around 1.2 mg to 3.5 mg, computed 
to provide free AUCs similar to the ones predicted for mice receiving  0.5 mg/kg and 1.5 
mg/kg, respectively. These predictions have taken into account the 25% difference in 
plasma protein binding between human and mouse and assume 100% oral bioavailability.
3.9.2.2.
Starting Dose
Three approaches have been considered to establish the starting dose for GSK2879552 in 
subjects with SCLC assuming a 70 kg adult with a surface area of 1.8 m2. 
1.
One tenth of the rat severely toxic dose (STD10) as per ICH S9 guidance
The STD10 in the rat was defined as 0.4 mg/kg (free AUC of 137 ng.h/mL and total 
AUC of 714 ng.h/mL) administered daily for 4 weeks. The main finding was 
thrombocytopenia leading to morbidity in 5 of 38 rats.  One-tenth (1/10) of the rat STD10 
is 0.24 mg/m2. This dose would be well tolerated in dogs as it is less than half of the low 
dose evaluated on the 4 week study (0.03 mg/kg or 0.6 mg/m2) which was the NOAEL 
and HNSTD.  The NOAEL on the 4 week rat study was 0.2 mg/kg (free AUC of 71 
ng.h/mL and total AUC of 367 ng.h/mL).  A starting dose based on 1/10 of the rat STD10 
would translate to a starting dose in man of 0.43 mg using the human equivalent dose 
calculation. 
2.
One sixth of the dog highest non severely toxic dose (HNSTD) as per ICH S9 
guidance
The HNSTD in the dog was defined as 0.03 mg/kg (free AUC of 12.8 ng.h/mL and total 
AUC of 22 ng.h/mL) administered daily for 4 weeks. The only finding at this dose was 


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the observation of immature hematopoietic cells in the bone marrow.  It was also the 
NOAEL.  A starting dose based on 1/6 of the dog HNSTD would be 0.1 mg/m2 and 
translates to a starting dose in man of 0.18 mg using the human equivalent dose 
calculation. 
3.
The minimum anticipated biologically effective dose (MABEL) 
The principle pharmacologic/toxicologic effect of GSK2879552 in normal animals was 
hematopoietic maturational arrest leading to peripheral cytopenias.  The most sensitive 
lineage was platelets.  In rats, the MABEL was 0.1 mg/kg/day (0.6 mg/m2; free AUC of 
32.8 ng.h/mL and total AUC of 171 ng.h/mL) for causing a mild (26%) reduction in 
platelet counts and immature hematopoietic cell phenotype in the bone marrow.  In dogs, 
the MABEL was 0.03 mg/kg/day (0.6 mg/m2; free AUC of 12.8 ng.h/mL and total AUC 
of 22 ng.h/mL) for causing an immature hematopoietic cell phenotype in the bone 
marrow, but this dose was not associated with a reduction in circulating platelets.  The rat 
and dog MABEL doses would translate to a dose in man of 1.1 mg using the human 
equivalent dose calculation.  The MABEL dose in humans based on the exposure in rats 
and dogs is predicted to be 1.6 mg and 0.6 mg, respectively.
The potential therapeutic effect of GSK2879552 was evaluated at daily doses of 0.05 
mg/kg up to 15 mg/kg in a mouse NCI-H526 xenograft model. A dose of 0.05 mg/kg 
provided a no meaningful effect on tumor growth (7% decrease), while a dose of 0.15 
mg/kg showed a non-significant decrease in tumor growth of 36% (predicted free AUC 
of 7.7 ng.h/mL and total AUC of 21 ng.h/mL). The MABEL dose in humans based on the 
exposure in mice at 0.15 mg/kg is predicted to be 0.4 mg. 
Conclusion:  
The proposed starting dose of 0.25 mg was selected with the goal of administering a 
pharmacologically active dose that is reasonably safe to use, in accordance with ICH S9. 
The selection of this dose also takes into consideration the nature of the dose limiting 
toxicity seen in GLP studies.  In both rodent and non-rodent species, the dose-limiting 
toxicities were hematologic, principally thrombocytopenia, which resulted from an 
expected pharmacologic effect of maturational arrest rather than a cytotoxic effect on the 
bone marrow.  Hematologic toxicity is monitorable, manageable with supportive care and 
dose interruptions as required and is reversible.  Eligibility criteria have been designed to 
mitigate risks associated with the potential for severe cytopenias and close monitoring of 
hematologic parameters, as well as dose modification and supportive care guidelines are 
outlined in the protocol.  The starting dose of 0.25 mg daily has a predicted total exposure 
of 11.4 ng.h/mL with a Cmax of 1.4 ng/mL (free AUC of 5.2 ng.h/mL and free Cmax of 
0.65 ng/mL)
Refer to the IB [GlaxoSmithKline Document Number 2013N168888_01] for additional
information on the preclinical biology and toxicology studies.


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3.10.
Study Treatment
3.10.1.
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study, except for subjects who are allowed intra-subject dose escalation 
and start the treatment from Day 1 with the new subject numbers allocated to them.
3.10.2.
Meals and Dietary Restrictions
Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, 
pommelos, or exotic citrus fruits is not permitted from 1 day prior to the first dose of 
study treatment(s) until the last dose of study drug.
Study treatment(s) will be administered under fasting conditions, either 1 hour before or 
2 hours after a meal.
On serial PK sampling days, subjects should fast overnight (i.e., at least 8 hours) and
should continue fasting until at least 2 hours after administration of the morning dose.
Fasting will consist of avoiding the oral ingestion of calorie-containing products; 
however, ingestion of water is permitted.  Any ongoing, usual concomitant medications 
may be administered while fasting.
3.10.3.
Blinding
This is an open-label study.
3.11.
Safety Management Guidelines
3.11.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of study treatment(s) and the 
follow-up period.  Study treatment(s) will be stopped if any of the following liver 
chemistry stopping criteria is/are met:
1.
Alanine aminotransferase (ALT) 3 X (times) upper limit of normal (ULN) and 
bilirubin 2 Xs ULN (or ALT 3 X ULN and international normalization ratio 
[INR] >1.5)
NOTE: Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury).
2.
ALT 5 X ULN.
3.
ALT 3 X ULN if associated with the appearance or worsening of rash or hepatitis 
symptoms (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or 
jaundice) or hypersensitivity ( such as fever, rash or eosinophilia).


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4.
ALT 3 X ULN persists for 4 weeks.
5.
ALT 3 X ULN and cannot be monitored weekly for 4 weeks.
In subjects with documented liver metastasis at baseline, following liver chemistry 
stopping criteria is applied:
6.
ALT 5X ULN and twice the baseline ALT ULN
7.
ALT 3 X ULN and 1.5 X baseline ALT ULN if associated with the appearance or 
worsening of rash or hepatitis symptoms (fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity ( such as fever, rash or 
eosinophilia).
8.
ALT 3 X ULN and 1.5 X baseline ALT ULN persists for 4 weeks.
9.
ALT 3 X ULN and 1.5 X baseline ALT ULN and cannot be monitored weekly for 4 
weeks.
Subjects with ALT 3 X ULN and <5 Xs ULN (for patients with liver metastases at 
baseline use ALT 3 X ULN and 1.5 X baseline ALT ULN and ALT <5X ULN and 
twice the baseline ALT ULN) and bilirubin <2 X ULN, who do not exhibit hepatitis 
symptoms or rash, can continue study treatment(s) as long as they can be monitored 
weekly for 4 weeks.  See below for details on weekly follow-up procedures for these 
subjects.
3.11.1.1.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3 X ULN but <5X ULN and bilirubin <2 X ULN, without 
symptoms indicative of hepatitis or rash, and who can be monitored safety for 4 weeks, 
the following actions should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality 
to discuss subject safety.

Continue administration of study drug(s).

Evaluate liver chemistries (ALT, AST, alkaline phosphatise, bilirubin) weekly 
until they resolve, stabilize or return to within baseline levels.

If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5 
(Section 3.11.1), then proceed as described in Section 3.11.1.2).

If, after 4 weeks of monitoring, ALT <3X ULN and bilirubin <2 X ULN, then 
monitor subjects twice monthly until liver chemistries normalize or return to 
within baseline values.
3.11.1.2.
Liver Chemistry Follow-up Procedures
Refer to the diagram in Appendix 4 for a visual presentation of the procedures listed 
below.


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The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 3.11.1

Immediately withdraw the subject from study treatment. 

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment(s) cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event electronic case report forms (eCRFs).  If the event also 
meets the criteria of a serious adverse event (SAE) (see Section 8.2), the SAE data 
collection tool will be completed separately with the relevant details.

Restart or rechallenge of study treatment requires GSK approval as described in 
Section 9
Safety Follow-Up Procedures for subjects with ALT 3 times ULN (for patients with 
liver metastases at baseline use ALT 3 X ULN and 1.5 X baseline ALT ULN):

Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase 
[AST], alkaline phosphatase [ALP], and bilirubin) resolve, stabilize or return to 
within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3 times ULN and bilirubin 2 
times ULN (or ALT 3 times ULN and INR >1.5):

This event is considered an SAE (see Section 8.2)  Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3 times ULN (for patients with liver metastases 
at baseline use ALT 3 X ULN and 1.5 X baseline ALT ULN), every attempt must be 
made to also obtain the following:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (IgM) antibody.

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).

Hepatitis C ribonucleic acid (RNA).

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).


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
Hepatitis E IgM antibody (if subject resides outside the United States (US) or 
Canada, or has traveled outside US or Canada in past 3 months).

Blood sample for PK analysis, obtained within 48 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment(s) prior to blood sample draw on the eCRF.  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 included in the SPM.

Serum creatine phosphokinase and lactate dehydrogenase.

Fractionate bilirubin, if total bilirubin 2 times ULN.

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia, on the AE eCRF.

Record use of concomitant medication(s), acetaminophen, herbal remedies, other 
over-the-counter medication(s), or putative hepatotoxins on the Concomitant 
Medications eCRF.

Record alcohol use on the Liver Events eCRF.
The following are required for subjects with ALT 3 times ULN and bilirubin 2 times 
ULN (>35% direct) or ALT 3 X ULN and INR >1.5 but are optional for other abnormal 
liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Liver imaging (ultrasound, magnetic resonance imaging [MRI] or computed 
tomography [CT] scan) to evaluate liver disease.

Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed.

Serum acetaminophen adduct high-performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen contribution to liver injury in subjects with 
definite or likely acetaminophen use in the preceding week [James, 2009]). 

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 
antibody. .  NOTE:  if hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where 
needed) – as outlined in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793.
3.11.2.
QTc Stopping Criteria
If a subject meets any of the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  


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
QT interval corrected for heart rate by Bazett’s formula (QTcB) >530 msec
1Based on 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(s) withheld.
QTc will be repeated at least weekly, until the QTc prolongation resolves to Grade 1 or 
baseline.  Once the QTc prolongation resolved, the subject may be re-started on the study 
treatment(s) if the investigator and GSK Medical Monitor agree that the subject will 
benefit from further treatment.
For subjects recruited in France, please refer to Appendix 5 for the French specific QTc 
stopping criteria.
3.11.3.
Mental Status Stopping Criteria
Study treatment will be held and neurology consult obtained if any of the 3 criteria below 
are met: 

A decrease of 3 points or more from baseline MOCA score 

Any MOCA score of <22

Any other indication of early encephalopathy as determined by patient history or 
physical exam
The treatment may resume if one of the following criteria is met:

A reversible cause other than study treatment is identified and both MOCA score 
and symptoms return to baseline.
Evaluated by a neurologist and found to have no clear signs/symptoms of 
encephalopathy or other cognitive dysfunction. This is applicable only in the absence of 
decrease in MOCA score.All treatment restarts must be approved by GSK medical 
monitor 
The treatment should be permanently discontinued for subjects with documented 
symptoms with no other cause, even if they return to baseline.
3.12.
Guidelines for Events of Special Interest and Dose 
Modifications
The severity of AEs will be graded utilizing the National Cancer Institute- Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0.  Guidelines for dose 
modifications and interruptions for management of common toxicities associated with the 
study treatment(s) are provided in this section. 


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3.12.1.
Dose Adjustment for toxicity
In the event of a DLT  or other clinically significant adverse event, treatment will be 
withheld and supportive therapy administered as clinically indicated. See Table 5 Dose 
Adjustment Guideline for drug related non-hematologic toxicities based on worst grade.
Table 5
Dose Adjustment Guideline for Drug Related Non-Hematologic 
Toxicity
Worst Grade
Dose Adjustment
G1
No change in dose
G2
Continue dosing with no change OR
Consider holding for up to 2 weeks for toxicity to resolve to baseline or ≤ Grade 1, then 
continue at the same dose OR dose reduce by at least 25% if the toxicity is considered a 
DLT.
G3 and 4
Holdfor up to 2 weeks for toxicity to resolve to baseline or ≤ Grade 1, then dose reduce by 
at least 25%.
If no recovery to ≤Grade 1* or baseline after 14 days, patient should be withdrawn.
1.
*Note: Exceptions to drug-related Grade 1 requirement may be made for rash, alopecia, quickly reversible (<72 
hours) laboratory abnormality (example: electrolyte changes).
If the toxicity or event resolves to baseline or Grade 1 within 14 days of stopping 
therapy, treatment with GSK2879552 may be restarted with at least 25% dose reduction. 
For a non-DLT, the treatment with GSK2879552 could restart at a full dose, if deemed 
appropriate.
If the toxicity does not resolve to Grade 1 or baseline within 14 days, the subject should 
be withdrawn from the treatment permanently (Section 6.3).  However, if the investigator 
and GSK Medical Monitor agree that further treatment will benefit the subject, treatment 
can restart with at least 25% dose reduction once the toxicity resolves to Grade 1 or 
baseline. 
If >2 consecutive dose reductions are required to resolve the toxicity to Grade 1 or 
baseline, the subject will be withdrawn from study.
Following a dose reduction subjects may be re-escalated to a higher dose level if the 
event is felt to be unlikely to recur and with the approval of the GSK Medical Monitor.
See Section 3.12.2- Section 3.12.4 for dose adjustment guidelines for thrombocytopenia, 
neutropenia and anemia. For hepatotoxicity, rechallenge guideline in Section 9.1 should 
be followed.   
3.12.2.
Management of Thrombocytopenia
In Part 1 Dose Escalation, complete blood count (CBC) will be monitored twice weekly 
for the first 3 weeks, weekly for the next 5 weeks, and then every 4 weeks. In Part 2 
Expansion, CBC will be monitored weekly for the first 3 weeks and thenevery 4 weeks. 
CBC monitoring frequency will follow planned monitoring frequency described above or 


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as detailed in Table 6, whichever is more frequent. Platelet monitoring and 
thrombocytopenia management guideline may change based on emerging data.


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Table 6
Thrombocytopenia management guideline
Grade
Platelet count
Monitoring
Dose Adjustment*
G1
<Lower limit of normal 
(LLN) - 75,000/mm3
Monitor as per protocol
Continue at the same dose.
G2
<75,000 - 50, 000/mm3
Weekly for 2 weeks. Then,

if stable, monitor per protocol.

if falling, continue with weekly 
monitoring until stable
Continue at the same dose.
G3
<50,000 - 25,000/mm3
Twice weekly for 2 weeks. Then,

if stable, monitor per protocol.

if falling, continue to monitor twice 
weekly until stable. 

If platelet count is < 50K but > 25K for more than 3 days and stable, 
continue at the same dose.

If platelet count is < 50K but > 25K for more than 3 days and falling, 
interrupt dosing and resume treatment once platelet count >50K
at the same dose if platelet count recovers to > 50K within 7 
days.** For subjects receiving daily dosing on a continuous 
schedule, reduce dose by at least 25% if grade 3 
thrombocytopenia recurs,.
with reduced dose by at least 25% if platelet count recovers to > 
50K after 7 days.**. 
G3
<50,000 - 25,000/mm3
and bleeding
As above for G3
Interrupt dosing and resume treatment with reduced dose by at least 25% 
when bleeding stops and platelet count is >50K.**
Administer supportive care including platelet transfusions as indicated.
G4
<25,000 – 10, 000/mm3
Twice weekly
Interrupt dosing and resume treatment with reduced dose by at least 25% 
when platelet count is >50K. ** 
G4
<25,000 – 10, 000/mm3
and bleeding or
<10,000/mm3;
Twice weekly 
Interrupt dosing, initiate platelet transfusions as per guidelines [Slichter, 
2007], resume treatment with dose reduced by at least 50% when platelet 
count is >50K. **
1.
* Subjects receiving low dose aspirin should interrupt aspirin when platelet count is < 75,000 mm3.
2.
** When the treatment resume, platelet should be monitored twice weekly for 2 weeks at a minimum.
A prolonged dose interruption over 14 days would meet the treatment discontinuation criteria per Section 6.3.


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3.12.3.
Management of Neutropenia
For the following, dose should be interrupted and the treatment should resume with dose 
reduced by at least 25%:

febrile neutropenia (as defined by CTCAE v.4 )

Grade 4 neutropenia 

Grade 3 neutropenia lasting >7 days
3.12.4.
Management of Anemia
Below is the anemia management guideline. 
Grade 
Dose Adjustment
Grade 1 and 2 Continue at the same dose 
Grade 3
Interrupt dosing if Grade 3 anemia > 7 days in duration and/or recurs after 
transfusion. Resume treatment with reduced dose by at least 25% when 
hemoglobin (Hgb) ≥ 10 g/dL
Grade 4
Interrupt dosing and provide supportive care (including transfusion).
Resume treatment with reduced dose by at least 25% when Hgb ≥ 10 g/dL or 
discontinue study treatment
3.12.5.
Platelet Transfusion Guideline
Prophylactic platelet transfusion in the absence of active bleeding is required when 
platelet count is < 10,000 /mm3. Therapeutic platelet transfusion is required for platelets  
< 25,000 /mm3 accompanied by World Health Organization (WHO) bleeding grade of 2 
or higher.
WHO Bleeding grades 

Grade 1, petechiae, ecchymosis, occult blood in body secretions, and mild vaginal 
spotting 

Grade 2, evidence of gross hemorrhage not requiring red cell transfusions over 
routine transfusion needs (e.g., epistaxis, hematuria, hematemesis)

Grade 3, hemorrhage requiring transfusion of 1 or more units of red cells/day 

Grade 4, life-threatening hemorrhage, defined as massive bleeding causing 
hemodynamic compromise or bleeding into a vital organ (e.g., intracranial, 
pericardial, or pulmonary hemorrhage)
3.12.6.
CBC monitoring and PK sampling Guideline for Dose 
interruptions/modifications
When the treatment is held due to a hematologic AE, CBC and PK sample should be 
collected on the first day of dose interruption and 3-4 days after. If the treatment is held 


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for more than a week, additional PK and CBC sample should be collected at 1 week after 
the dose interruption. 
When the dose resumes at the same or reduced dose, a pre-dose PK sample and CBC 
should be collected on the day and twice weekly for the first 3 weeks. Once weekly pre-
dose and CBC monitoring should continue on weeks 4, 6, and 8 of the resumed dosing. 
If the dose was reduced, two post-treatment PK samples should be collected at week 2, 
between 0.5-1 hr and between 4-6 hours from dosing in addition to the pre-dose PK 
sample. 
Less frequent CBC monitoring and PK sample collection may be allowed for individual 
subjects, if warranted.
4.
INVESTIGATIONAL PRODUCT(S)
The term ‘study treatment’ is used throughout the protocol to describe investigational 
product (IP) received by the subject as per the protocol design.  
4.1.
Description of Investigational Product
Product 
name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 5 mg of GSK2879552 as 
parent. 
Dosage form:
Capsule
Unit dose 
strength(s)
0.25 mg, 0.5 mg, 2 mg and 5 mg
Route/
Regimen
Oral
The initial dosing regimen will be continuous oral daily dosing. 
Subjects should take their doses fasted with approximately 200 mL of water.
Physical 
description:
0.25 mg GSK2879552:  Opaque Size 3 capsule composed of a white body and a 
white cap with no identifying markings containing a white to slightly coloured 
powder.
0.5 mg GSK2879552: Opaque Size 1 capsule composed of a light green body and 
a light green cap with no identifying markings containing a white to slightly 
coloured powder.
2 mg GSK2879552:  Opaque Size 1 capsule composed of a pink body printed with 
two black lines and a pink cap printed with two black lines, containing a white to 
slightly coloured powder.
5 mg GSK2879552:  Opaque Size 1 capsule composed of a Swedish Orange 
body and a Swedish Orange cap with no identifying markings containing a white to 
slightly coloured powder.
GSK2879552 will be provided to sites by GSK.  The contents of the label will be in 
accordance with all applicable regulatory requirements.


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4.2.
Handling/Storage of GSK2879552, GSK Investigational 
Product
Handling
Under normal conditions of handling and administration, investigational product (IP) is 
not expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager.
Refer to the SPM for detailed procedures for the disposal and/or return of unused study 
treatment(s).
Storage
GSK2879552 must be stored in a secure area under the appropriate physical conditions 
for the product.  Access to and administration of the GSK2879552 will be limited to the 
investigator and authorized site staff.  GSK2879552 must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.  
GSK2879552 is to be stored at a temperature range of 2-8C (36-46F), protected from 
moisture.  Maintenance of a temperature log (manual or automated) is required.
4.3.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product (IP) dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  Refer to the Study Procedures Manual (SPM) for further detailed instructions 
on product accountability.
4.4.
Treatment Compliance
On clinic days, GSK2879552 should be taken in the clinic after safety procedures 
including blood sampling for CBC and PK/PD samplings, if applicable, are completed.  
When subjects self-administer study treatment(s) at home, subjects will be instructed to 
record time and date of dosing in the supplied GSK dosing diary. 
Compliance with GSK2879552 will be assessed through querying the subject during the 
site visits and reviewing the dosing diary, and documented in the source documents and 
eCRF. A record of the number of GSK2879552 capsules dispensed to and taken by each 
subject must be maintained and reconciled with study treatment and compliance records.  


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Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the eCRF.
4.5.
Treatment of Investigational Product Overdose
In the event of an overdose (defined as administration of more than the protocol-specified 
dose) of GSK2879552, the investigator should:

contact the GSK Medical Monitor immediately

closely monitor the subject for AEs/SAEs and laboratory abnormalities at least 7 
days 

document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the GSK Medical Monitor based on the clinical evaluation of the 
subject.
5.
STUDY POPULATION
5.1.
Number of Subjects
The number of dose levels and the level at which the maximum tolerated dose (MTD) or 
RP2D is reached cannot be determined in advance.  An adequate number of subjects will 
be enrolled into the study to establish the recommended dose(s) for further study.  It is 
estimated that approximately 20 subjects will be enrolled into Part 1 dose-escalation and 
additional 27 subjects into PK/PD expansion cohorts.  Up to 30 subjects will be enrolled 
in Part 2 (expansion cohort) of the study.  A total of approximately 77 subjects will be 
enrolled in the study.  Additional subjects/cohorts may be enrolled to allow for evaluation 
of additional dose levels. 
In Part 1 (dose-escalation) of the study, if subjects prematurely discontinue, additional 
subjects may be enrolled as replacement subjects at the discretion of the Sponsor in 
consultation with the investigator.  Subjects will not be replaced in Part 2 (expansion 
cohort) of the study.
5.2.
Subject Selection Criteria
5.2.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events 
(AEs), and other pertinent information on the GSK study treatment that may impact 
subject eligibility is provided in the Investigator Brochure (IB).
Deviations from inclusion 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.


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Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Provided signed written informed consent
2.
Males and females ≥18 years of age (at the time consent is obtained).
3.
Histologically or cytologically confirmed diagnosis of small cell lung carcinoma. 
Subjects must have measurable disease per RECIST 1.1 (for Part 2 only).
4.
Recurrent or refractory disease after receiving at least one prior standard/approved 
platinum-containing chemotherapy regimen, or where standard therapy is refused. 
Part 2 only: Subjects must have recurrent disease after receiving a maximum of two 
prior chemotherapy regimens including at least one platinum containing regimen. 
Note: Adjuvant/Neoadjuvant chemotherapy is not counted.  
5.
Eastern Cooperative Oncology Group (ECOG, Appendix 3) performance status of 0 
or 1.
6.
Tumor tissue requirements:

Availability of archival tissue, or willingness to undergo fresh biopsy at 
baseline. Patients without baseline tissue may be enrolled with approval from 
the GSK medical monitor.  

Enrollment in PK/PD cohort may be limited to subjects with disease 
amenable to pre- and post-dose biopsies, and willingness to undergo 
biopsy.
7.
All prior treatment-related toxicities must be National Cancer Institute- Common 
Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 ≤Grade 1 at the 
time of enrollment (except for alopecia)
8.
Adequate baseline organ function defined by


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System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
10 g/dL
Platelets
125 X 109/L
Prothrombin time (PT)/International normalized ratio 
(INR) and Partial thromboplastin time (PTT) 
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.25 X ULN1
ALT and AST
2.5 ULN without liver metastasis
5 x ULN if documented liver metastasis
Renal
Creatinine
OR
Calculated creatinine clearance by Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation (Appendix 2) or measured from 24hr urine
≤1.5 X ULN
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by Echocardiogram (ECHO) 
Metabolic
TSH, T4
Vitamin B12
BUN
Na, K2, Ca, Cl, CO2
Glucose (fasting)
WNL
≥ LLN
≤1.5 X ULN
WNL
≤1.25 X ULN
1.
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
2.
Replacement of K is allowed if below LLN
NOTE:  Laboratory results obtained during Screening should be used to 
determine eligibility criteria.  In situations where laboratory results are outside the 
permitted range, the investigator may opt to retest the subject and the subsequent 
within range screening result may be used to confirm eligibility.  Subjects 
requiring transfusions to meet hematologic eligibility criteria are not eligible.
9.
Women of childbearing potential must have a negative serum pregnancy test within 
7 days of first dose of study treatment and agree to use effective contraception, as 
defined in Section 11.1, during the study and for 7 days following the last dose of 
study treatment.
10. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception as described in Section 11.1 from 
the administration of the first dose of study treatment until 3 months after the last 
dose of study treatment to allow for clearance of any altered sperm.
11. Able to swallow and retain orally administered study treatment and does not have 
any clinically significant gastrointestinal (GI) abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach and/or bowels.
12. French subjects: In France, a subject will be eligible for inclusion in this study only 
if either affiliated to or a beneficiary of a social security category.


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5.2.2.
Exclusion Criteria
Deviations from 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.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Concurrent malignancy other than SCLC. History of other malignancy is allowed as 
long as there is no evidence of active disease or need for treatment.
2.
Currently receiving anti-cancer therapy (chemotherapy, radiation therapy, immuno-
therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization)
Exceptions: Zoledronic acid and denosumab to treat bone metastasis are allowed. 
3.
Prior treatment with temozolomide, dacarbazine or procarbazine
4.
Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, 
ABT-888)
5.
Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower
6.
Received major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK2879552 administration. Chemotherapy regimens with delayed toxicity within 
the last four weeks (six weeks for prior nitrosourea or mitomycin C). Chemotherapy 
regimens given continuously or on a weekly basis with limited potential for delayed 
toxicity or palliative radiation to a limited area (including cranial radiation for brain 
metastases) within the last two weeks. 
7.
Administration of an investigational drug within 28 days or 5 half-lives, whichever is 
shorter preceding the first dose of study treatment(s) in this study. 
French subjects: The French subject has participated in any study using an 
investigational study treatment(s) during the previous 28 days.
8.
Subjects with current/a history of bleeding disorder or coagulopathy (e.g., Von 
Willebrand disease, haemophilia) or who are at particularly high risk for bleeding 
complications, e.g., prior history of intracranial hemorrhage, clinically significant 
bleeding episodes in the last 6 months. 
9.
Requiring anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin 
inhibitors, etc) or platelet inhibitor (e.g., aspirin, clopidogrel). The following are 
permitted:

Low molecular weight heparin

Low dose prophylactic warfarin ≤ 1 mg once daily 

Low dose aspirin ≤ 100 mg once daily if required for cardiac prophylaxis.
10. Current use of a prohibited medication (Section 10.2) or expected to require any of 
these medications during treatment with the investigational drug 
11. Evidence of severe or uncontrolled systemic diseases (e.g., severe/chronic infection, 
unstable or uncompensated respiratory, hepatic, renal, or cardiac disease) Any 
serious and/or unstable pre-existing medical (aside from malignancy exception 
above), psychiatric disorder, or other conditions that could interfere with subject’s 


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safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the investigator
12. Known active Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or 
Hepatitis C Virus (HCV) infections. Subjects with laboratory evidence of HBV 
clearance may be enrolled
13. Leptomeningeal metastases or spinal cord compression due to disease. 
14. Subjects with previously untreated or uncontrolled brain metastases.  
Note: Subjects previously treated for brain metastases that 

are asymptomatic and off corticosteroids, OR 

on stable dose of corticosteroids for at least 1 month prior to study Day 1 are 
permitted. 
Subject treated with gamma knife can be enrolled 2 weeks post-procedure as 
long as there are no post-procedure complications and the subject is clinically 
stable. In addition, subjects treated or currently taking enzyme-inducing 
anticonvulsant (EIAC) are allowed on study.
15. Cardiac abnormalities as evidenced by any of the following:

Clinically significant uncontrolled arrhythmias or uncontrolled  hypertension.

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. 

Baseline QTc interval using Bazett’s formula ≥450 msec or ≥480 msec in 
subjects with Bundle Branch Block. QTc value based on single or average of 
triplicate ECGs obtained over a brief recording period.
16. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates 
their participation.
17. Lactating female.
18. Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, 
pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study 
treatment(s) until the last dose of study drug. 
6.
COMPLETION OR WITHDRAWAL OF SUBJECTS
6.1.
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to GSK.


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6.2.
Subject Completion Criteria
In Part 1, a subject will be considered to have completed the study if they complete 
screening assessments, at least 28 days of study treatment(s) and the post-treatment 
follow-up visit.
In Part 2, a subject will be considered to have completed the study if they are followed 
until disease progression, death or start of new anticancer treatment.
6.3.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 3.11.1. 
The investigator may discuss with a GSK Medical Monitor continuing a subject who is 
receiving benefit but has met the criteria for disease progression according to RECIST, if 
the following criteria are met: Investigator-determined clinical benefit (e.g. symptomatic 
improvement), lack of significant toxicity (no drug related grade 3/4 AEs within the last 3 
weeks) and no therapeutic alternatives expected to provide durable responses. 
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 (withdrawal of consent by subject or proxy)

investigator’s discretion

Adverse event that is considered by the investigator or a GSK Medical Monitor 
to warrant permanent discontinuation of study drug.

A clinically significant adverse event leading to an interruption of treatment for 
greater than 14 days.  If the investigator and GSK Medical Monitor conclude 
that continued treatment will benefit a subject who has had a > 14 day treatment 
delay, then the subject may continue therapy with the approval of the GSK 
Medical Monitor.

Adverse events requiring >2 dose reductions.

intercurrent illness that prevents further administration of study treatment(s)

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 
(AE)’ will be recorded as the primary reason for permanently discontinuation on the 
electronic case report form (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 Table (see Section 7.1) 
6.4.
Study Completion
A study will be considered completed, having met the study objectives, when all subjects 
have received treatment for approximately 6 months or have withdrawn from the study, 
whichever occurs first. At such time, subjects who have not been permanently withdrawn 
from study treatment and continue to benefit will be offered the opportunity to continue 
treatment in a separate rollover protocol.
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s 
last visit.
6.5.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment.
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments being performed.
The timing of each assessment is listed in the Time and Events Table (Section 7.1) The 
timing and number of the planned study assessments may be altered during the course of 
the study based on newly available data (e.g. to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the following assessments: 
safety, PK, PD/biomarker.  The change in timing or addition of time points for any of the 
planned study assessments listed above must be approved and documented by GSK, but 
this will not constitute a protocol amendment.  The institutional review board (IRB) or 
ethics committee (EC) will be informed of any safety issues that require alteration of the 
safety monitoring scheme.  
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECGs, vital signs, 
blood draws.  
If the blood draw is done first, there should be at least 15 minute interval before the vital 
signs and 12-lead ECGs measurements are taken.
Detailed procedures for obtaining each assessment are provided in the SPM.
On clinic days, study drug should be taken in the clinic after all the safety procedures 
(including CBC) and blood sampling for PK/PD, if applicable, are completed.


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Visit Window
Baseline disease assessment and ECHO/MUGA should be completed within 35 days
prior to dosing start and pregnancy testing 7 days prior. All other screening assessments 
should be completed within 14 days prior to dosing start.
Visits in the first 3 weeks will be allowed 1 day window. The only exceptions are pre-
and post -treatment biopsies on Day 1 and 15 where 7 days and 3 days window will be 
allowed, respectively.
Visits beyond the first 3 weeks will have 3 days window.
Post-baseline disease assessments will be allowed 7 days window. Subjects who are 
withdrawn from Part 2 for reasons other than disease progression and continue Q8 week 
disease assessment will be also allowed 7 days window. 
The End of Treatment visit should be completed within 14 days from the last dose.
Time Window for PK sampling
0.25, 0.5, 1 and 1.5 hours post dose sampling: 5 minutes
2, 3, 4 hours post dose sampling: 10 minutes
6 and 8 hours post dose sampling: 30 minutes
12 and 24 hours post dose sampling: 1 hour. The 24 hour sampling should be done 
before the next dose administration.
7.1.
Time and Events Table(s)
This section consists of the Time and Events Table(s) and supplemental footnotes to 
describe assessment windows and sequencing of study-specific assessments and 
procedures. 


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Time and Events Table: Part 1 – Dose Escalation
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
Office Visit
X
X
X
X
X
X
X
X
X
X
X
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
Study Drug Dosing14
< -------------------------------------------------- Daily or per dosing schedule -------------------------------------------
Review subject dosing diary
X
X
X
X
every 4 wks
X
Study Drug Dispensing from Pharmacy
X
every 4 wks
Complete physical exam
X
X
Montreal Cognitive Assessment
X
X
X
X
X
Wk 4 and every 4 wks
Brief physical exam
X11
X
every 4 wks
Performace status 
X
X11
X
every 4 wks
X
Vital Signs
X
X11
X
X
X
X
every 4 wks
X
Height and weight10
X
X11
X
every 4 wks
X
ECHO / MUGA
X
12-lead ECGs
X
X
X
every 4 wks
X
CBC
X
X11
X
X
X
X
X
X
Every week x 4 (wk 4-7), then every 4 wks
X
Chemistry Panel including liver 
function tests
X
X
X
every 4 wks
X
Vitamin B12, TSH, T4
X
Coagulation Panel including PT, PTT, 
INR
X
every 8 wks
X
Fetal hemoglobin 
X
X
X
X


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SCR
First Treatment Phase (28 days)
Continuation Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
(Hgb F)18
Pregnancy test8
X
every 4 wks
X
PK Blood samples
X1
X1
X4
X2
X3
X3
X4
Every week x 4 (wk 4-7), then every 4 wks4
Urine for PK  
X12
X5
X5
Blood samples for PD6 (whole blood) 
X
X
X
X
X
Blood samples for PD6 (serum)
X
X
X
X
X
Blood samples for circulating 
biomarkers6
(plasma)
X
X
X
Blood samples for translational 
research6
(Peripheral blood mononuclear cell)
X
X
X
X
Disease assessment 
X
every 8 wks
X7
Brain scan
X
As clinically indicated
Tumor tissue collection or biopsy
X13
X16
X16
X17
Adverse Events
continuous
Con Meds
continuous
Highest Dose in PK/PD expansion cohort ONLY
Blood for metabolite evaluation 
X9
X9
X9
X9
Urine for metabolite 
X15
X15
X15
X15
1.
A blood sample will be collected for PK analysis on D1 at following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hrs post dose. Additional samples may 
be collected at 33 (optional) and 48 hrs post dose in subjects not receiving a dose on Day 2 to better characterize the terminal half-life of GSK2879552, if needed.
2.
A blood sample will be collected for PK analysis on D8 at following time points: pre-dose, 0.5, 3 hrs post dose
3.
A blood sample will be collected for PK analysis on D15 at following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hrs post dose
4.
PK blood sample should be taken pre-dose at the same time as CBC. If the dose has been modified since the last PK sample and an unscheduled CBC sample is taken, 
a PK sample should be obtained together with the first unscheduled CBC sample. PK sample will not be collected beyond week 48. 


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5.
On D15, 24hr urine will be collected starting from pre-dose on Day 15 and for 24 hours, i.e., until dosing on Day 16. The 24hr urine will be measured and 5 ml aliquot will 
be taken. 
6.
Blood samples for PD, circulating biomarkers and translational research should be collected pre-dose.
7.
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.
8.
For women of child bearing potential only. Serum pregnancy test is required for screening and f/u visits. Urine pregnancy test is adequate during study visits.
9.
Additional samples will be collected for metabolite evaluation in the highest dose cohort in PK/PD expansion cohorts, in at least 6 subjects. The plasma samples will be 
collected at following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hrs post dose 
10. Height will be measured at screening only
11. These procedures do not need to be repeated on Day 1, if the screening visit was within 3 days and they were performed at screening.
12. A urine sample will be collected for PK analysis at pre-dose on D1
13. Baseline tumor tissue collection is mandatory for all subjects.  Archival tissue will be acceptable. In the absence of available archival tissue, fresh tissue biopsy will be 
required.
14. On clinic days, study drug should be taken in the clinic after safety procedures including CBC and PK/PD samplings, if applicable, are completed.
15. On Day 1, pre-dose urine (~100 ml) will be collected for metabolite study. On Days 1 and15, 24hr urine will be collected and measured, and 400 mL urine from at least 6 
subjects at the highest dose cohort in PK/PD expansion will be collected for metabolite identification purposes.
16. In a subset of subjects in PK/PD cohorts, fresh pre-treatment and post-treatment biopsies are required.  Pre-treatment and post-treatment biopsies are optional for all 
subjects not enrolled in PK/PD expansion cohorts. Day 1 biopsy (-7 days window) should be collected pre-dose, Day 15 (3 days window) biopsy can be collected pre-
or post- dose. Optional post-treatment biopsy can be collected at a later time point, if desired.
17. Biopsy at the time of progression is optional for all subjects.
18. Korea only: Hgb F not required


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Time and Events Table: Part 2 – Expansion Cohort
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Office Visit
X
X
X
X
X
every 4 wks 
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
Study Drug Dosing9
< ------------------------------------------- Daily or per dosing schedule ------------------------------------
Review subject dosing diary
X
X
X
every 4 wks
X
Study Drug Dispensing from pharmacy
X
every 4 wks
Complete physical exam
X
X
Montreal Cognitive Assessment
X
X
X
X
X
Wk 4 and every 4 weeks
Brief physical exam
X7
X
every 4 wks
ECOG PS
X
X7
X
every 4 wks
X
Vital Signs
X
X7
X
X
X
every 4 wks
X
Height and weight6
X
X7
X
every 4 wks
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
every 4 wks
X
CBC
X
X7
X
X
X
every 4 wks
X
Chemistry Panel including LFT
X
X
X
every 4 wks
X
Coagulation Panel including PT, PTT, INR
X
every 8 wks
X
Vitamin B12, TSH, T4
X
PK Blood samples
X1
X8
X2
X8
every 4 wks8
Fetal hemoglobin (Hgb F)12
X
X
X
X


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SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Pregnancy test4
X
every 4 wks
X
Blood samples for PD3 (serum)
X
X
X
X
X
Blood samples for circulating biomarkers3
(plasma)
X
X
X
Blood samples for translational research3
(CTC)
X
X
Wk 8
X
Disease assessment 
X
every 8 wks
X5
Brain scan
X
As clinically indicated 
Tumor tissue collection10
X
X
X
X
Adverse Events
continuous
Con Meds
continuous
1.
A serial blood samples will be collected for PK analysis on D1 at pre-dose, 0.5, and 3 hrs post dose, 
2.
A blood sample will be collected for PK analysis on D15 at pre-dose, between 0.5 to 1 hour, and between 4 and 6 hours
3.
Blood samples for PD, circulating biomarkers and translational research should be collected pre-dose.
4.
For women of child bearing potential only. Serum pregnancy test is required for screening and f/u visits. Urine pregnancy test is adequate during study visits.
5.
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.
6.
Height will be measured at screening only
7.
These procedures do not need to be repeated on Day 1, if the screening visit was within 3 days and they were performed at screening.
8.
PK blood sample should be taken pre-dose at the same time as CBC.
9.
On clinic days, study drug should be taken in the clinic after safety procedures including CBC and PK/PD samplings, if applicable are completed. PK sample will not be 
collected beyond week 48.
10. Baseline tumor tissue collection is mandatory for all subjects.  Archival tissue will be acceptable. In the absence of available archival tissue, fresh tissue biopsy will be 
required. Fresh biopsies on Day 1, Day 15 and at disease progression are optional for all subjects in Part 2.  Day 1 biopsy (-3 days window) should be collected pre-dose, 
Day 15 (3 days window) biopsy can be collected pre- or post- dose. Optional post-treatment biopsy can be collected at a later time point, if desired.
11. Subjects enrolled in Part 2 who discontinue study treatment for reasons other than RECIST-defined disease progression will continue to have protocol defined radiological 
assessments until disease progression per RECIST 1.1, start of new anti-cancer therapy or withdrawal from study.
12. Korea only: Hgb F not required


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7.2.
Demographic/Medical History and Baseline Assessments
The following demographic parameters will be captured during Screening: year of birth, 
gender, race and ethnicity.
Medical/medication history will be assessed. 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.
Fasting will be required for screening clinical laboratory tests.
Baseline (Screening) assessments will include:

Complete physical examination, including height (in cm) and weight (in kg).

Vital signs (blood pressure, temperature, respiratory rate, pulse rate)

Eastern Cooperative Oncology Group (ECOG) performance status

Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters, 
vitamin B12, thyroid (TSH, T4)

Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female 
subjects of childbearing potential only 

12-lead ECG

Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 

Baseline disease assessment: computed tomography (CT) scan (with IV contrast) of 
chest, abdomen and pelvis (if applicable)

Brain magnetic resonance imaging (MRI) with contrast or a CT scan (with/without 
contrast) if MRI is contraindicated 

Fresh tumor biopsy (preferred) or archival tumor tissue collection

Montreal Cognitive Assessment 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) 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.
7.2.1.
Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed at baseline.


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7.3.
Safety Evaluations
Any signs of bleeding, bruising and infection will be monitored closely throughout the 
study, 
Planned time points for all safety assessments are provided in the Time and Events Table 
(Section 7.1).and will include physical exam, vital signs, clinical laboratory tests 
including chemistry and hematology, ECGs and ECOG performance status. AEs and 
toxicities will be assessed throughout the study and will be graded according to NCI-
CTCAE v. 4.0. 
Additional time points for safety assessment may be added during the course of the study 
based on emerging pharmacokinetic and safety data to ensure appropriate safety 
monitoring.
7.3.1.
Physical Examinations
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, 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).
7.3.2.
ECOG Performance Status
The performance status will be assessed using the Eastern Cooperative Oncology Group 
(ECOG) scale (Appendix 3) as specified in the Time and Events Table (Section 7.1).
7.3.3.
Montreal Cognitive Assessment
Montreal Cognitive Assessment (MOCA) was designed as a rapid screening instrument 
for mild cognitive dysfunction. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visuoconstructional skills, 
conceptual thinking, calculations, and orientation. Time to administer the MOCA is 
approximately 10 minutes.
The test and administration instructions are freely accessible for clinicians at
www.MOCAtest.org. English version 7.1 is shown in Appendix 7.
7.3.4.
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, temperature, 
respiration rate and heart rate.  Vital signs should be measured after resting for at least 5 
minutes in a semi-supine position.  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.  
Refer to the SPM for details regarding measurement of vital signs.


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7.3.5.
Electrocardiogram
Single 12-lead electrocardiogram (ECGs) will be obtained at designated time points 
during the study using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and corrected QT (QTc) intervals.  At each assessment a 12-lead 
ECG will be performed by qualified personnel at the site after the subject has at least a 5 
minute rest and is in a semi-recumbent or supine position.  
Refer to Section 3.11.2 for QTc withdrawal criteria.  Additional QTc readings may be 
necessary.
7.3.6.
Echocardiogram and/or Multi-gated Acquisition Scans
ECHOs or MUGA scans will be performed at baseline to assess cardiac ejection fraction 
and cardiac valve morphology for the purpose of study eligibility, as specified in the 
Time and Events Table (Section 7.1). Additional ECHO assessments may be performed if 
clinically warranted.  The evaluation of the echocardiographer should include an 
evaluation for left ventricular ejection fraction (LVEF).
7.3.7.
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 7, should be performed 
according to the Time and Events Table (Section 7.1). Details for the preparation and 
shipment of samples will be provided in the Study Procedures Manual (SPM).
Prior to administration of the first dose of study treatment, results of laboratory 
assessments should be reviewed.  Any laboratory test with a value outside the normal 
range may be repeated (prior to the first dose) at the discretion of the investigator.
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 28 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
Hematology, clinical chemistry, and additional parameters to be tested are listed in Table 
7


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Table 7
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
Mean corpuscular volume (MCV)
Neutrophils
White blood cell (WBC) Count 
(absolute) 
Mean corpuscular hemoglobin 
(MCH)
Lymphocytes
Reticulocyte Count
Mean corpuscular hemoglobin 
concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Mean platelet volume (MPV)
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase (AST)
Total and direct bilirubin1
Creatinine
Chloride
Alanine 
aminotransferase (ALT)
Uric Acid
Glucose
Total carbon dioxide (CO2)
Gamma glutamyl 
transferase (GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Phosphorus
Lactate Dehydrogenase
(LDH)
Thyroid Stimulating 
Hormone
T4
Vitamin B12
Other tests
Coagulation Panel including PT, PTT, INR
Fetal hemoglobin (Hgb F)2
Other screening tests
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
1.
Direct bilirubin should be assessed only if total bilirubin is elevated beyond the upper limit of normal 
(ULN)
2.
Korea only: fetal Hgb F not required
7.3.8.
Pregnancy Testing and Reporting
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -HCG pregnancy 
test performed within 7 days prior to the first dose of study treatment(s).  Subjects with 
positive pregnancy test result must be excluded from the study.  Subjects with negative 
pregnancy test result must agree to use an effective contraception method as described 
below during the study until 14 days following the last dose of study treatment(s).
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an adverse event (AE) or serious adverse event (SAE).  Spontaneous abortions must be 
reported as an SAE.


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Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment(s), must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for pharmacokinetic (PK) analysis of GSK2879552 will be collected at 
the time points indicated in the Time and Events Schedule (Section 7.1).  Additional 
blood samples will be collected for metabolic profiling in one of the PK/PD expansion 
cohort of Part 1 at the time points indicated in the Time and Events Schedule (Section 
7.1)
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 would 
not require a protocol amendment.
Details on PK blood sample collection, processing, storage and shipping procedures are 
provided in the SPM.
7.4.2.
Urine Sample Collection for Pharmacokinetics
Urine samples for pharmacokinetic (PK) analysis of GSK2879552 will be collected at the 
time points indicated in the Time and Events Schedule (Section 7.1).  Additional urine 
sample will be collected for metabolic profiling in one of the PK/PD expansion cohort of 
Part 1 (at MTD or RP2D only) at the time points indicated in the Time and Events 
Schedule (Section 7.1)
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 urine sample collection will be recorded.
7.4.3.
Details on PK urine sample collection, processing, storage and 
shipping procedures are provided in the SPM.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 GSK2879552 will 
be determined in plasma samples using the currently approved bioanalytical 
methodology.  Raw data will be stored in the Good Laboratory Practices (GLP) Archives, 


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GlaxoSmithKline.Once the plasma samples have been analysed for GSK2879552, any 
remaining plasma may be analysed 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, Drug Metabolism and Pharmacokinetics, Platform Technology and 
Science, GlaxoSmithKline.  Concentrations of GSK2879552 may be determined in urine 
samples using an investigative analytical methodology.  Urine raw data will be stored in 
the Good Laboratory Practices (GLP) Archives, GlaxoSmithKline. 
The urine samples may be analyzed for compound-related metabolites and the results will 
be reported under a separate DMPK protocol.
7.5.
Pharmacodynamics

Changes from baseline in circulating ProGRP levels will be assessed in blood

Change from baseline in a gene expression panel, including but not limited to GFI1B, 
KCNJ5, RND2, SERPINE2, ASB4, CACNB3, CD59A, SPARC, and STAB1 will be 
assessed in whole blood 

Changes in markers including, but not limited to, ProGRP and SCLC-specific LSD1 
target genes or proteins in paired baseline and post-treatment tumor tissue will be 
assessed
7.6.
Translational Research
Translational or biomarker research may be performed on archival tissue, fresh tumor 
biopsies and blood samples collected on study to better understand SCLC and mechanism 
of action of and response or resistance to GSK2879552.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. 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 provided in the RAP.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK2879552 or provide new insights into SCLC and medically related conditions.  
Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles 
may yield known and novel candidate biomarkers/profiles and new insights which relate 
to the action of GSK2879552.
All samples maybe retained for a maximum of 15 years after the last subject completes 
the study.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with SCLC or medically related conditions and/or the action of 
GSK2879552 may be identified by application of DNA/gene, RNA and protein analysis 
of blood and tumor tissue including, but not limited to, the following analyses:


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
DNA analyses may be performed for somatic mutations and copy number by next-
generation sequencing or alternative methodology. DNA methylation status may be 
assessed using methylation array technology.  These analyses may be performed 
using DNA from blood or tumor tissue.

Circulating cell free-DNA analysis of blood/plasma

Circulating biomarker RNA and protein analysis of blood/plasma

Analysis of protein or RNA expression by immunohistochemistry (IHC) or 
alternative method may also be performed for genes of interest including, but not 
limited to, L-MYC, N-MYC or C-MYC

RNA transcriptome analysis of blood and tumor tissue samples

Measurement of the levels of a subset of RNA species on blood and tumor tissue 
samples
7.6.1.
Tumor Biomarker Analysis
In order to further characterize biomarkers related to the activity of GSK2879552, 
expression of DNA/genes, RNA and proteins will be assessed in archival tissue and 
tumor biopsies collected on study. 
7.6.2.
Circulating cell free DNA (cfDNA) Analysis
Tumor-specific circulating nucleic acid (cfDNA) levels detected in plasma or serum have 
been found to correlate with increasing tumor burden and decline following therapy.  
Furthermore, cfDNA in cancer subjects can harbor many genetic alterations (mutations, 
microsatellite alterations, aberrant methylation), which are generally consistent with the 
tumor. Thus, tumor-specific circulating cfDNA has the potential to be a useful biomarker 
of therapeutic response as well as offering a less invasive blood based technique for 
identifying and selecting subjects for certain treatments.  Given the promise of cfDNA 
blood based test for subject selection, cfDNA will be collected to determine whether 
mutations or other genomic changes in cfDNA correlate with that in the tumor tissue 
from which it is derived. This test will also be explored to correlate decreasing cfDNA 
levels with decreasing tumor burden.
7.6.3.
Circulating biomarker analysis
Levels of circulating biomarkers may be assessed to determine relationships between 
biomarker expression and response to GSK2879552, as well as to better understand the 
expression of circulating biomarkers in SCLC.
Biomarkers circulating in the plasma have been found to correlate with tumor pathway 
activation. Blood-based markers have the important advantage that specimens are readily 
available, simple to prepare and store, and can be taken prior to and during treatment. 
This allows for the assessment of predictive markers based on the baseline evaluation as 
well as markers of activity and resistance based on changes that occur during treatment. 


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Therefore, a broad panel of biomarkers in cell-free DNA and circulating tumor cells 
(CTCs) along with burden may be evaluated in plasma and correlated with clinical 
outcome to treatment with GSK2879552.
7.6.4.
RNA Expression Research of a Subset of RNA Species
Blood and tumor tissue samples will be collected for RNA expression analyses of a 
subset of RNA species.
RNA expression studies may be conducted using quantitative reverse transcription 
polymerase chain reaction (RT-PCR), and/or alternative equivalent technologies, which 
can facilitate the simultaneous measurement of the relative abundances of hundreds of 
RNA species resulting in a RNA expression profile for each blood and tumor tissue 
sample. The RNAs assayed may be those involved with the pathogenesis of SCLC, the 
absorption, distribution, metabolism, or excretion of GSK2879552, or in the subject’s 
response to GSK2879552. In addition, continuing research may identify other proteins or 
regulatory RNAs that may be involved in response to GSK2879552 or the pathogenesis 
of SCLC. The RNAs that code for these proteins and/or regulatory RNAs may also be 
studied. This will enable the evaluation of changes in RNA expression profiles that may 
correlate with biological response relating to SCLC and medically related conditions or 
the action of GSK2879552.
7.7.
Evaluation of Anti-Cancer Activity
7.7.1.
Disease Assessment
Disease assessment may include imaging (e.g., CT, MRI, bone scan, plain radiography) 
and physical examination (as indicated for palpable/superficial lesions). All post-baseline 
assessments require imaging of disease sites identified by baseline scans:

Chest/Abdomen/Pelvis (if applicable) CT scan with contrast

Brain MRI scan, if disease present at baseline. A CT scan with and without 
contrast may be performed if a MRI is contraindicated.
Disease assessment will be completed within 5 weeks prior to the first dose of 
GSK2879552, then every 8 weeks thereafter, and at the final study visit. See the Time 
and Events Table (Section 7.1) for the schedule of assessments of anti-cancer activity.  
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays.  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.
Disease progression and response evaluations will be determined according to the 
definitions established in the RECIST 1.1. 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 


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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.
GSK requires sites to provide electronic copies (upload digital images or images on CD) 
of scans for all subjects enrolled in Part 2 for central storage which may be transferred to 
a central independent imaging center. This includes baseline scans and all scans 
performed during the course of the study. GSK may request an independent review of 
scans. See SPM for additional details.  
7.7.2.
Brain MRI and/or CT Scan
A magnetic resonance imaging (MRI) with contrast will be performed at Screening (see 
Time and Events Table Section 7.1) to rule out any new untreated brain metastases and to 
verify stability of brain metastases if present.  A CT scan with and without contrast may 
be performed if a MRI is contraindicated.
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE) 
as outlined in Section 8.1 and Section 8.2, respectively.
8.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An adverse event (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.  For marketed medicinal 
products, this also includes failure to produce expected benefits, abuse, or misuse. 
Examples of events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade 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/serious adverse event [SAE]). 
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 


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resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

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.

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. 
8.2.
Definition of an SAE
A serious adverse event (SAE) is 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-subject setting. Complications that occur during hospitalization are 
adverse events (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.
d.
Results in disability/incapacity, or
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. 


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f.
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.
Protocol-Specific SAEs:

All events of possible study treatment-induced liver injury with 
hyperbilirubinemia defined as alanine aminotransferase (ALT) 3 times upper 
limit of normal (ULN) and bilirubin ≥2 times ULN (>35% direct) (or 
ALT ≥3 times ULN and international normalization ratio (INR) >1.5, if INR is 
measured) or termed ‘Hy’s Law’ events (INR measurement is not required and 
the threshold value stated will not apply to patients receiving anticoagulants).
NOTE:  Bilirubin fractionation is performed if testing is available.  If testing is 
not available, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury.  If testing is 
unavailable and a subject meets the criterion of total bilirubin ≥2 times ULN, 
then the event is still reported as a serious adverse event (SAE).  If INR is 
obtained, include values on the SAE form.  INR elevations >1.5 suggest severe 
liver injury.

Any new primary cancers
8.2.1.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing 
all SAEs for possible Sentinel Events which is mandated at GSK.  The GSK medical 
monitor may request additional clinical information on an urgent basis if a possible 
Sentinel Event is identified on SAE review.  The current GSK-defined Sentinel Events 
are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis


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8.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., electrocardiogram [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 adverse event (AE) or serious adverse event (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. 
However, 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.
8.3.1.
Cardiovascular (CV) Events
Investigators will be required to fill out event specific data collection tools 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

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
8.4.
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
a serious adverse event (SAE).  Death due to disease under study is to be recorded on the 
Death electronic case report form (eCRF).  However, if the underlying disease (i.e., 


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progression) is greater than that which would normally be expected for the subject, or if 
the investigator considers that there was a causal relationship between treatment with 
study treatment(s) or protocol design or procedures and the disease progression, then this 
must be reported as a SAE.
8.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an adverse event (AE) or serious adverse event (SAE). 
AEs will be collected from the time the first dose of study treatment is administered until 
28 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must 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 reported to GSK within 
24 hours, as indicated in Section 8.2.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 28 days, the investigator may report any AE that they 
believe possibly related to study treatment.   
8.5.1.
Method of Detecting AEs and SAEs
Care must 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?” 
8.5.2.
Prompt Reporting of SAEs and Other Events to GSK
Serious adverse events (SAEs), pregnancies, and liver function abnormalities and any 
other events meeting pre-defined criteria will be reported promptly by the investigator to 
GSK as described in the following table once the investigator determines the event meets 
the protocol definition for that event.


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
“CV events” and/or 
“death”
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Liver chemistry abnormalities:
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)c
24 hoursa
SAE data collection 
tool;
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicableb
24 hours
Updated SAE data 
collection tool. 
Updated Liver Event 
eCRFb
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks
24 hoursa
Liver Event eCRFb
24 hours
Updated Liver Event 
eCRFb
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN
24 hoursa
Liver Event eCRF 
does not need to be 
completed unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeksb
a.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
b.
Liver event documents should be completed as soon as possible
c.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on adverse events (AEs) 
and serious adverse events (SAEs) are provided in the Study Procedures Manual (SPM).
8.5.3.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.


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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, IRB/EC 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/EC, if appropriate according to local requirements.
9.
STUDY TREATMENT RESTART OR RECHALLENGE
If subject meets liver event stopping criteria do not restart/rechallenge subject with study 
treatment unless:
1) GSK Medical Governance approval is granted (as described below),
2) Ethics and/or IRB approval is obtained, if required, and
3) 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.
9.1.
Rechallenge Following Liver Event That Are Possibly 
Related To Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with 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 with initial liver injury (e.g. fever, rash, eosinophilia) [Andrade, 
2009]  

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;  
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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 rechallange with study treatment can be considered where:

Principal Investigator (PI) 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 laboratory monitoring may 
resume as per protocol.

If subject exhibits protocol-defined liver chemistry elevations, study treatment 
should be permanently discontinued as protocol specified. 

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 8.3-and Section 8.5. 
9.2.
Restart Following Transient, Resolving Liver Events Not 
Related to Study Treatment
Restart refers to resuming study treatment following liver events meeting stopping 
criteria 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 human leukocyte antigen (HLA) markers of liver 
injury.


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Approval by GSK for study treatment restart can be considered where:

Principal Investigator (PI) 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.

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 protocol defined stopping criteria for liver chemistry elevations are met, study 
treatment must be stopped.

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 8.3 and Section 8.5. 
10.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit).  Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the electronic case 
report form (eCRF).  Additionally, a complete list of all prior anti-cancer therapies will 
be recorded in the eCRF.


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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.
10.1.
Permitted Medication(s)
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate.
Low molecular weight heparin, low dose prophylactic warfarin ≤1 mg once daily, or low 
dose aspirin ≤ 100 mg once daily (if required for cardiac prophylaxis) is permitted.
Zoledronic acid and denosumab to treat bone metastasis are permitted.
The use of G-CSF is not recommended while the patient is taking the study medication. 
However, it can be administered during dose interruptions to speed recovery from 
neutropenia at the investigator’s discretion.
10.2.
Prohibited and Cautionary Medication(s)
Subjects should not receive other anti-cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, and hormone therapy other than for replacement) while 
on treatment in this study.  Subjects should not receive any other investigational anti-
cancer drugs within 28 days or five half-lives, whichever is shorter with a minimum of 14 
days, preceding the first dose of GSK2879552.
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc) or 
platelet inhibitor (e.g., clopidogrel) are prohibited from 14 days prior to the first dose of 
study drug through completion of the Final Study Visit. 
10.2.1.
Drugs that may alter the Pharmacokinetics of GSK2879552
All co-meds should be used with caution since little is known about the mechanism of 
clearance of GSK2879552. In vitro data in human microsomes and hepatocytes suggest 
that GSK2879552 has a negligible turnover.
10.2.2.
Drugs that may have their PKs altered by GSK2879552
The potential for pharmacokinetic interactions with drugs likely to be co-administered 
with GSK2879552 in vivo has not been assessed. In vitro data suggests that GSK2879552 
has very low potential to inhibit CYP enzymes. GSK2879552 has also been shown to not 
activate human PXR which is known to induce several drug metabolizing enzymes. 
GSK2879552 is not an inhibitor of human efflux transporters P-glycoprotein (P-gp) and 
breast cancer resistance protein (BCRP) and uptake transporters organic anion 
transporting polypeptide 1B1 (OATP1B1) and OATP1B3. 


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Co-administration of sensitive and narrow therapeutic index medications affected by 
strong inhibitors of OCT and MATE should be avoided when possible or monitored 
carefully. Examples of such drugs are dofetillide, pilsicainide and procainamide. 
10.2.3.
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 palliative radiation treatment during this study. 
Subjects will abstain from using herbal preparations/medications within 14 days prior to 
the first dose of GSK2879552 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, and ginseng
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation including marijuana. 
11.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
11.1.
Contraception
11.1.1.
Female Subjects
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant during the study 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. 


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Complete abstinence from sexual intercourse for 7days prior to first dose of study
treatment, through the dosing period, and for at least 7 days after the last dose of study 
treatment.
Contraceptive Methods with a Failure Rate of <1%

Oral contraceptives (either combined or progesterone only) if not contraindicated for 
this subject population or per local practice. 

Estrogenic vaginal ring if not contraindicated for this subject population or per local 
practice.

Percutaneous contraceptive patches if not contraindicated for this subject population 
or per local practice. 

Implants of levonorgestrel if not contraindicated for this subject population or per 
local practice.  

Injectable progesterone if not contraindicated for this subject population or per local 
practice. 

Intrauterine device or intrauterine system 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 vaginal 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.
11.1.2.
Male Subjects
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods:

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.
Complete abstinence from sexual intercourse from the first dose, through the dosing 
period, and for 3 months after the last dose of study treatment.


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
Condom (during non-vaginal intercourse with any partner - male or female) OR

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual 
intercourse with a female)
11.2.
Caffeine, Alcohol, Food, and Tobacco Restrictions
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., Part 1, Days 1 and 15).
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pommelos, exotic citrus fruits, from 1 day prior to the 
first dose of study treatment until the last dose of study drug.
12.
DATA MANAGEMENT
For this study, data will be collected using defined electronic case report forms (eCRFs), 
transmitted electronically to GSK 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.  AEs and concomitant medications terms will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA) and an internal 
validated medication dictionary, GSK Drug.  Electronic CRFs (eCRFs), including queries 
and audit trails, will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
13.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
13.1.
Hypothesis(es)
13.1.1.
Part 1: Dose-Escalation Phase
No formal statistical hypotheses are being tested.  Analysis of the data obtained from this 
study will be focused on comparison between dose cohorts and only descriptive methods 
will be used in analysis of the data obtained from this study.
13.1.2.
Part 2: Expansion Cohort
The sample size and stopping rules are based on the methodology of Lee et al. [Lee, 
2008].  The predictive probability design is similar to a Green-Dahlberg design in that it 
allows for early stopping for futility.  The differences are that the predictive probability 
design allows for evaluation of stopping rules after each subject, rather than at only two 


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stages, once a minimum number of subjects are evaluable.  In this particular study, we 
will stop only for futility.  
Clinical response will be defined as disease control rate (DCR) (CR + PR + SD)  based 
on  RECIST 1.1 at week 16. Biologic activity of cytostatic agents is characterized by the 
stabilization of the disease rather than the shrinkage of tumor lesions. As they slow or 
stop the growth of tumors and the developmentof metastases, DCR may be a more 
appropriate end point in the evaluation of cytostatic agents [Francart, 2006; Lara, 2008]
such as GSK2879552. 
The null hypothesis is:
H0: DCR ≤15%
The alternative hypothesis is:
HA:DCR ≥30%
After 12 subjects have been enrolled to examine safety and efficacy, the observed 
unconfirmed disease control rate at 16 weeks will guide further enrolment according to 
the rules summarized in Figure 3. In order to stop for futility as quickly as possible if
there is no sign of efficacy, confirmation of responses is not required.  A maximum of 30 
subjects will be enrolled in the Part 2 expansion cohort. All available data will be 
considered in making enrollment decisions.


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Figure 3
Stopping Rules for Cohort Expansion: GSK2879552
Number of Subjects Responding (i.e., controlled disease) at 16 
weeks
Number of 
Subjects
0
1
2
3
4
≥5
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1.
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no 
response in fourteen subjects, then the predictive probability for success will be 5.0% or less (the futility criterion) 
and consideration should be given to stop enrolment.
13.2.
Sample Size Determination
13.2.1.
Part 1: Dose-Escalation Phase
The total number of subjects to be enrolled in Part 1 will depend on the number of 
subjects needed to characterize individual dose cohorts. Results of simulations for the 
dose-escalation phase are shown in Appendix 6.  Based on these simulations, the sample 
size for the dose-escalation portion is expected to be approximately 19-22 subjects. 
However, it is anticipated that approximately 57 subjects will be enrolled including 
PK/PD expansion cohorts.  
13.2.2.
Part 2: Expansion Cohort
An initial dose escalation will be used to establish the RP2D for GSK2879552.  Once the 
final dose is confirmed, at least 12 and up to 30 subjects will be enrolled at that dose, 
using decision rules based on the disease control rate (DCR) as defined in Figure 3. The 


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sample size and stopping rules are based on the methodology of Lee et al. [Lee, 2008].  
The assumptions underlying the design are detailed below. 
H0: DCR ≤15%
The alternative hypothesis is:
HA:DCR ≥30%
Starting with 12 subjects and allowing for a maximum sample size of 30, this design will 
have a type I error rate () of 0.15 and 80% power.  The trial is not designed to stop early 
for efficacy, but is designed to stop early for futility if the predictive probability of 
success is 5% or less.  The type I error rate, power, and predictive probability of success 
to stop early for futility were derived from explicitly stating the minimum and maximum 
sample size, futility stopping rate, and selection of the optimizing criterion as the 
maximization of power under the alternative hypothesis.  The design will have a type I 
error rate of less than 0.15 and a power greater than 80% for a sample size exceeding 30 
subjects. The Bayesian prior used in determining the design was Beta (0.15, 0.85), a 
distribution with a mean response rate of 15%.  Under the null hypothesis, if the true 
DCR at 16 weeks is 15%, the expected sample size of the design is 24 subjects and 
probability of early termination (PET) is 75%. Under the alternative hypothesis, if the 
true DCR at 16 weeks is 30%, the expected sample size of the design is 29 subjects and 
PET is 10%.
13.3.
Sample Size Sensitivity
No sample size sensitivity was performed.
13.3.1.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
13.4.
Data Analysis Considerations
13.4.1.
Analysis Populations
All Subjects Population: This will consist of all subjects who received at least one dose 
of study treatment. Safety and clinical activity data will be evaluated based on this 
population.
The Pharmacokinetic Population: This will consist of those subjects in All Subjects 
Population and for whom a PK sample is obtained and analyzed.
The Pharmacodynamic Population: This will consist of those subjects in All Subjects 
Population and who contribute PD/Biomarker samples.


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13.5.
Interim Analysis
13.5.1.
Part 1: Dose-Escalation
No formal interim analysis will be performed for Part 1 of the study.  Safety, PK, 
PD/biomarker data will be examined during Part 1. Prior to determining GSK2879552
dose for the next cohort, exploratory analysis will be conducted to assess the relationship 
of GSK2879552 dose levels with safety, PK and PD parameters using all data from 
available cohorts. 
13.5.2.
Part 2: Expansion Cohort
After the initial 12 subjects have enrolled at the RP2D dose, response data will be 
reviewed on an ongoing basis and the number of responses observed will be compared 
with the stopping rules provided in Section 13.1.2.
13.6.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(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.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be information, 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. 
Demographic and baseline characteristics will be summarized.
13.6.1.
Anti-Cancer Activity Analyses
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria. If the data warrant, the response data will be summarized by dose level.
Clinical response will be defined as disease control rate (DCR) (CR + PR + SD) based on 
RECIST 1.1 at week 16.  The primary aim of Part 2 is to detect a clinically meaningful 
disease control rate of 30% relative to a 15% disease control rate suggesting no activity.


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13.6.2.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, 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. 
For Part 1, DLTs will be listed for each subject and summarized according to GSK 
International Data Standards Library (IDSL) standards. All other relevant safety data will 
be listed and summarized according to the GSK IDSL standards as well. Complete details 
of the safety analyses will be provided in the RAP.
13.6.2.1.
Extent of Exposure
Extent of exposure of GSK2879552 will depend on tolerability of the subjects to the 
doses administered and the course of their disease. The number of subjects exposed to 
GSK2879552 will be summarized for each dose level administered.
13.6.2.2.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class.  
Adverse events (AEs) will be graded by the investigator according to the NCI-CTCAE, 
(version 4.0).
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 (version 4.0), will be summarized by the maximum grade.  
Otherwise, the AEs will be summarized by maximum intensity. 
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following AE 
of special interest will be summarized separately: thrombocytopenia 
The incidence of deaths and the primary cause of death will be summarized and listed.
13.6.2.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (version 4.0).  Laboratory test results outside the 
reference ranges that do not have associated NCI-CTCAE criteria will be summarized 
using proportions.  Further details will be provided in the RAP.
13.6.2.4.
Other Safety Measures
Data for vital signs, ECGs, and ECHOs will be summarized based on predetermined 
criteria identified to be of potential clinical importance (PCI).  Further details will be 
provided in the RAP.


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13.6.3.
Pharmacokinetic Analyses
13.6.3.1.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK. 
Non-compartmental Pharmacokinetic Analyses
Pharmacokinetic analysis of GSK2879552 in Part 1 will be conducted by non-
compartmental methods. The following pharmacokinetic parameters will be determined if 
data permit:

maximum observed plasma concentration (Cmax)

time to Cmax (tmax)

area under the plasma concentration-time curve (AUC[0-t] and/or AUC[0-∞]) 
after single dose and AUC(0-t) and AUC(0-) after repeated administration

apparent terminal phase elimination rate constant (λz)

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 Day 
15/ AUC(0-) in Day 1. The ratio of AUC(0-) on Day 15/ Day 1 AUC(0-) will be 
calculated to assess time invariance. 
GSK2879552 concentrations may be determined in urine samples to determine urinary 
recovery of unchanged drug and renal clearance.
Metabolic Profiling
In a subset of subjects, plasma samples will be pooled and analyzed qualitatively for 
circulating metabolites; 0-24 hour urine samples will also be analyzed for GSK2879552 
and compound related metabolites. These results will be performed under a separate 
DMPK protocol and reported separately.
Population Pharmacokinetics
Plasma concentration-time data from Part 2 (Expansion Cohort) will be combined with 
data from Part 1 and analyzed using a population approach. A nonlinear mixed effects 
model will be used 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 Cav = AUC/) and identify relevant covariates (e.g., age, weight, or 
disease related covariates).
13.6.3.2.
Statistical Analysis of PK Data
Statistical analyses of the PK parameters data will be the responsibility of Discovery 
Biometrics, GSK.


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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, Coefficient of variance [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 GSK2879552 will be assessed using the power 
model (details will be provided in the RAP). 
13.6.4.
Pharmacokinetic/Pharmacodynamic Analyses
Observed or predicted concentrations will be combined with safety, efficacy, and/or 
pharmacodynamic measures of interest to examine potential exposure response 
relationships.
Quantitative safety parameters and biomarkers of interest will be plotted graphically 
against summary exposure measures (eg; Cmax, Ctrough, 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; e.g. slope, baseline (E0), or exposure producing 
50% of the maximum effect (EC50), and maximum effect (Emax).
Overall efficacy data and overall tumor burden may be described using categorical model 
and/or continuous models with summary exposure parameters (eg; Cmax, Ctrough, and 
Cav) as covariates derived from the population PK analysis.
13.6.4.1.
Translational Research Analyses
Exploratory analysis may be performed to examine potential relationships between 
anticancer activity and changes in markers of LSD 1 target inhibition or tumor biology or 
between anticancer activity and potential markers of sensitivity or resistance.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. 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 provided in the RAP.
13.6.4.2.
Novel Biomarker(s) Analyses
The results of these biomarker investigations may be reported separately from the main 
clinical study report.  All endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.


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14.
STUDY CONDUCT CONSIDERATIONS
14.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
14.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and applicable country-specific 
regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/EC review and approval of study protocol and any subsequent amendments

Subject informed consent

Investigator reporting requirements
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
14.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/EC is notified.
14.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP and GSK procedures, the site will be 
contacted 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 include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.


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The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure 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, ICH GCP, and all applicable regulatory requirements.
14.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site.  Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study.  In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
14.6.
Study and Site Closure
The end of the study will be defined as the date of the last visit of the last subject 
enrolled.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/EC promptly and provide the reason(s) for the suspension/termination.
14.7.
Records Retention
Following closure of the study, the investigator or 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 


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be easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
14.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, 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 results summary will be posted to the GSK Clinical Study Register no later than 
eight months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.


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15.
REFERENCES
Adamo A, Sesé B, Boue S, Castaño J, Paramonov I, Barrero MJ, Izpisúa Belmonte JC. 
(2011) LSD1 regulates the balance between self-renewal and differentiation in human 
embryonic stem cells. Nat Cell Biol 13(6): 652-60
American Cancer Society 
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/docum
ent/acspc-036845.pdf.2013
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Foster CT, Dovey CM, Lezina L, Lou JL, Gant, TW, Barlev N, Bradley A, Cowley SM. 
Lysine-specific demethylase 1 regulates the embryonic transcriptome and CoREST 
stability. Molecular and Cellular Biology. 2010;30:4851-63
Francart J et al. Progression-free survival rate as primary end point for phase II cancer 
clinical trials: application to mesothelioma- The EORTC Lung Cancer Group. J Clin 
Oncol. 2006; 24(19):3007-12.
GlaxoSmithKline Document Number 2013N168888_01. GSK2879552 Investigator's
Brochure.  Report Date: 01-MAR-2015.
Godmann M, Auger V, Ferraroni-Aguiar V, Di Sauro A, Sette C, Behr R, Kimmins S. 
Dynamic regulation of histone H3 methylation at lysine 4 in mammalian 
spermatogenesis, Biology of Reproduction. 2007;77:754-64
Hu, X., Li, X., Valverde, K., Fu, X., Noguchi, C., Qiu, Y., Huang, S.  LSD1-mediated 
epigenetic modification is required for TAL1 function and hematopoiesis. Proc. Natl. 
Acad. Sci. 2009; 106: 10141-10146.
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.
Hurwitz JL, McCoy F, Scullin P, Fennell DA. Oncologist. New advances in the second-
line treatment of small cell lung cancer. The Oncologist 2009 Oct;14(10):986-94..
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 
1779-1784. 
Janzer A, Lim S, Fronhoffs F, Niazy N, Buettner R, Kirfel J. Lysine-specific demethylase 
1 (LSD1) and histone deacetylase 1 (HDAC1) synergistically repress proinflammatory 
cytokines and classical complement pathway components. Biochemical and Biophysical 
Research Communications. 2012;421:665-70


2013N173386_05
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Kuter DJ, Mufti GJ, Bain BJ, Hasserjian RP, Davis W, Rutstein M.  Evaluation of bone 
marrow reticulin formation in chronic immune thrombocytopenia patients treated with 
romiplostim. Blood. 2009;114:3748-56
Lara PN et all. Disease control rate at 8 weeks predicts clinical benefit in advanced non-
small-cell lung cancer: results from Southwest Oncology Group randomized trials. J Clin 
Oncol. 2008; 26(3):463-7
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 2008; 5(2):93-106.
NCI Common Terminology Criteria for Adverse Events, Version 4, DCTD, NCI, NIH, 
DHHS, 28 May 2009.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials, Stat in Med. 2008 27:2420-2439
O’Quigley J, Pepe, M, Fisher, L: Continual Reassessment Method: A Practical Design for 
Phase I Clinical Trials in Cancer, Biometrics 1990 46: 33-48.
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. 
Saleque, S., Kim, J., Rooke, H.M., Orkin, S.H.  Epigenetic regulation of hematopoietic 
differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1.  
Mol Cell 2007; 27: 262-272.
Shi, Y., Sawada, J., Sui, G., Affar el, B., Whetstine, J.R., Lan, F., Ogawa, H., Luke, M.P., 
Nakatani, Y., and Shi, Y. (2003). Coordinated histone modifications mediated by a CtBP 
co-repressor complex. Nature 422, 735–738.
Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc 
Hematol Educ Program. 2007:172-8.
Sprussel A, Schulte JH, Weber S, Necke M, Handschke K, Thor, T, Pajtler KW, 
Schramm A, König K, Diehl L, Mestdagh P, Vandesompele J, Speleman F, Jastrow H, 
Heukamp LC, Schüle R, Dührsen U, Buettner R, Eggert A, Göthert JR. Lysine-specific 
demethylase 1 restricts hematopoietic progenitor proliferation and is essential for 
terminal differentiation. Leukemia. 2012;26:2039-51
Su ST, Ying HY, Chiu YK, Lin FU, Chen MY, Lin KI. Involvement of histone 
demethylase LSD1 in Blimp-1-mediated gene repression during plasma cell 
differentiation. Molecular and Cellular Biology. 2009;29:1421-31
Sundstrøm S, Bremnes RM, Kaasa S, Aasebø U, Aamdal S; Second-line chemotherapy in 
recurrent small cell lung cancer. Results from a crossover schedule after primary 
treatment with cisplatin and etoposide (EP-regimen) or cyclophosphamide, epirubicin, 
and vincristin (CEV-regimen). Lung Cancer. 2005 May;48(2):251-61. 


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You A, Tong, J.K., Grozinger, C.M., and Schreiber, S.L. (2001). CoREST is an integral 
component of the CoREST- human histone deacetylase complex. Proc. Natl. Acad. Sci. 
USA 98, 1454–1458.


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APPENDICES
Appendix 1:  NYHA Functional Classification System
The New York Heart Association (NYHA) Functional Classification: Class I, II, III 
or IV Heart Failure [NYHA, 1994] provides a simple way of classifying the extent of 
heart failure.  It places subjects in one of 4 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.
Reference:
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.


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Appendix 2: CKD-EPI EQUATION
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is a new 
equation, published in 2009 (Levey, 2009), to estimate glomerular filtration rate (GFR) 
from serum creatinine, age, sex, and race for adults age ≥ 18 years. 
The equation is given below for creatinine in mg/dL: 
Race
Sex
Serum Creatinine,
Scr (mg/dL)
Equation (age in years for ≥ 18)
Black
Female
≤ 0.7
GFR = 166 × (Scr/0.7)-0.329 × (0.993)Age
Black
Female
> 0.7
GFR = 166 × (Scr/0.7)-1.209 × (0.993)Age
Black
Male
≤ 0.9
GFR = 163 × (Scr/0.9)-0.411 × (0.993)Age
Black
Male
> 0.9
GFR = 163 × (Scr/0.9)-1.209 × (0.993)Age
White or other
Female
≤ 0.7
GFR = 144 × (Scr/0.7)-0.329 × (0.993)Age
White or other
Female
> 0.7
GFR = 144 × (Scr/0.7)-1.209 × (0.993)Age
White or other
Male
≤ 0.9
GFR = 141 × (Scr/0.9)-0.411 × (0.993)Age
White or other
Male
> 0.9
GFR = 141 × (Scr/0.9)-1.209 × (0.993)Age
CKD-EPI equation expressed as a single equation:
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 
[if black] where Scr is serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, α 
is -0.329 for females and -0.411 for males, min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of 
Scr /κ or 1.
The equation is given below for creatinine in µmol/L: 
Race
Sex
Serum
Creatinine,
Scr (µmol/L)
Equation (age in years for ≥ 18)
Black
Female
≤ 61.9
GFR = 166 × (Scr/61.9)-0.329 × (0.993)Age
Black
Female
> 61.9
GFR = 166 × (Scr/61.9)-1.209 × (0.993)Age
Black
Male
≤ 79.6
GFR = 163 × (Scr/79.6)-0.411 × (0.993)Age
Black
Male
> 79.6
GFR = 163 × (Scr/79.6)-1.209 × (0.993)Age
White or other
Female
≤ 61.9
GFR = 144 × (Scr/61.9)-0.329 × (0.993)Age
White or other
Female
> 61.9
GFR = 144 × (Scr/61.9)-1.209 × (0.993)Age
White or other
Male
≤ 79.6
GFR = 141 × (Scr/79.6)-0.411 × (0.993)Age
White or other
Male
> 79.6
GFR = 141 × (Scr/79.6)-1.209 × (0.993)Age
GFR = 141 × min (Scr /κ, 1)κ × max (Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] where Scr is serum creatinine in µmol/L, κ is 61.9 for females and 79.6 
for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr
/κ or 1, and max indicates the maximum of Scr /κ or 1.
Reference:
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.


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Appendix 3: ECOG Performance Status1
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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Appendix 4: Liver Safety Guidelines


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1
Patient exhibits liver injury on 
drug, while disease condition 
stable or improving 
Medical Monitor & GCSP Physician(s) to discuss benefit:risk and: 
Any fever, rash or eosinophilia, hypersensitivity with initial liver injury1 in this patient? 
Bilirubin >2xULN or INR>1.5 with initial injury in this patient, suggesting failing liver? 
Currently exhibits ALT >3xULN, bilirubin >2xULN, or INR>1.5
Any prior severe/fatal outcomes reported on drug rechallenge2,3 with this drug? 
Any evidence of preclinical hepatic liability/injury with this drug?
LOC Medical Director to be informed of rechallenge consideration & final decision
PI requests GSK approve drug readministration
with study treatment
PI promptly informed of decision & dosing regimen
Ethics Comm. or IRB review, if needed
Benefits/risks  discussed with patient & consent recorded in chart
Liver chemistries obtained twice weekly until stable
Safety Review Team records rechallenge outcome 
Global Safety Board notified of rechallenge outcomes 
Agree on study treatment reinitiation after Hepatotox Panel 
consult and approval by both GCSP SERM Head VP and 
Clinical Project Physician Lead VP. GSB available for input 
PI promptly informed of 
decision
Do not agree on 
study treatment 
reinitiation
1Andrade RJ. Expert Opin Drug Saf 2009;8:709-714.
2Papay JI. Regul Tox Pharm 2009;54:84-90.
3Hunt CM. Hepatol 2010;52:2216-2222.
GSK process for drug rechallenge approvals


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2
Patient exhibits liver injury on 
drug, while disease condition 
stable or improving 
Medical Monitor & GCSP Physician(s) to discuss etiology of liver injury and: 
Have liver chemistries decreased to normal, or ≤1.5x baseline and ALT<3xULN?
Any fever, rash or eosinophilia in this patient, or HLA assoc with liver injury1? 
Any evidence of alcoholic hepatitis or drug-induced liver injury in this patient? 
Any prior severe/fatal outcomes reported on drug restart2,3 with this drug?
LOC Medical Director to be informed of rechallenge consideration & final decision
PI requests GSK approve drug readministration
with study treatment
PI promptly informed of decision & dosing regimen
Ethics Comm. or IRB review, if needed
Benefits/risks  discussed with patient & consent recorded in chart
Liver chemistries obtained weekly until stable
Safety Review Team records drug restart outcome 
Global Safety Board notified of drug restart outcomes 
Agree on study treatment reinitiation after Hepatotox Panel 
consult and approval by both GCSP SERM Head VP and 
Clinical Project Physician Lead VP. GSB available for input 
PI promptly informed of 
decision
Do not agree on 
study treatment 
reinitiation
1Andrade RJ. Expert Opin Drug Saf 2009;8:709-714.
2Papay JI. Regul Tox Pharm 2009;54:84-90.
3Hunt CM. Hepatol 2010;52:2216-2222.
GSK process for drug restart approvals


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Appendix 5: Country Specific Requirements
France:
French Specific QTc Stopping Criteria:
In line with local requirements, a French subject that meets the criteria QTc1 below will 
have study treatment withheld:
QTcB > 500 msec
1Based on average corrected QT (QTc) interval value of triplicate electrocardiograms 
(ECGs) to include manual over-read.  For example, if an ECG demonstrates a prolonged 
QT interval, obtain 2 more ECGs over a brief period, and then use the averaged QTc 
values of the 3 ECGs to determine whether the subjects should have study treatment 
withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
No other known country specific requirements are currently required.
Korea:
Investigational Product Label:  subject identification number and visit 
number will not be included in the IP label. However, it will be tracked at 
site pharmacy when the IP is dispensed to each subject. (Note: This is an 
open label study, thus treatment number is not applicable)
GSK2879552 
PPD


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Appendix 6 Simulation Results of N-CRM in Dose Escalation Phase
Simulations were conducted to determine the average sample size and percentage of 
times each dose was selected under three different scenarios. For each scenario, 1000 
clinical trials were simulated.  Details are provided in Table 8.Doses are the projected 
doses.
The specified prior probabilities discussed in Section 3.3 were used to determine an 
explicit equation for the prior distribution using the FACTS software.  The parameters 
(s.d.) of the explicit distribution are = -0.9917 (1.382), ln()=0.3615 (0.8838),  and ρ=-
0.6808 where and ln() are distributed as bivariate normal with correlation ρ.
Table 8
Simulation Results Under Various Scenarios
Dose
(mg)
Scenario 1: Steep Dose-
Toxicity Curve
Scenario 2: Moderate Dose-
Toxicity Curve
Scenario 3: Shallow Dose-
Toxicity Curve
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
0.25
0.03
1
0.03
1.1
0.01
0.1
0.5
0.05
1.9
0.05
1.3
0.02
0.3
1
0.07
3.4
0.07
2.8
0.04
0.9
1.5
0.12
9.5
0.1
6.1
0.06
1.2
2
0.16
13.4
0.15
9.3
0.08
1.7
2.5
0.23
17.8
0.17
13.1
0.1
6
3
0.25
46
0.2
41.5
0.12
37.3
4
0.35
6.9
0.24
14.5
0.14
14.9
5
0.6
0.1
0.25
6.1
0.17
11.7
6
0.8
0
0.28
3.8
0.19
15.3
8
0.9
0
0.38
0.2
0.21
6.1
10
0.92
0
0.5
0.2
0.27
2.8
12
0.95
0
0.6
0
0.4
1.7
The average sample size over the 1000 clinical trials simulated under Scenarios 1-3 was 
18.6, 19.3, and 21 respectively.


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Appendix 7: Montreal Cognitive Assessment
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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Appendix 8: Protocol Amendment Changes
AMENDMENT 4
Where the Amendment Applies
Protocol Amendment 4 applies to Korea only
Summary of Amendment
Appendix 5 country specific IP label requirements for Korea have been modified.  Fetal 
hemoglobin testing requirement has also been removed for Korea.
PREVIOUS TEXT
Appendix 5: Country Specific Requirements
France:
French Specific QTc Stopping Criteria:
In line with local requirements, a French subject that meets the criteria QTc1 below will 
have study treatment withheld:
QTcB > 500 msec
1Based on average corrected QT (QTc) interval value of triplicate electrocardiograms 
(ECGs) to include manual over-read.  For example, if an ECG demonstrates a prolonged 
QT interval, obtain 2 more ECGs over a brief period, and then use the averaged QTc 
values of the 3 ECGs to determine whether the subjects should have study treatment 
withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
No other known country specific requirements are currently required.


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REVISED TEXT
Appendix 5: Country Specific Requirements
France:
French Specific QTc Stopping Criteria:
In line with local requirements, a French subject that meets the criteria QTc1 below will 
have study treatment withheld:
QTcB > 500 msec
1Based on average corrected QT (QTc) interval value of triplicate electrocardiograms 
(ECGs) to include manual over-read.  For example, if an ECG demonstrates a prolonged 
QT interval, obtain 2 more ECGs over a brief period, and then use the averaged QTc 
values of the 3 ECGs to determine whether the subjects should have study treatment 
withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
No other known country specific requirements are currently required.
Korea:
Investigational Product Label:  subject identification number and visit 
number will not be included in the IP label. However, it will be tracked at 
site pharmacy when the IP is dispensed to each subject. (Note: This is an 
open label study, thus treatment number is not applicable)
GSK2879552 
PPD


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PREVIOUS TEXT
Time and Events Table: Part 1 – Dose Escalation
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
Fetal 
hemoglobin 
(Hgb F)
X
X
X
X
REVISED TEXT
Time and Events Table: Part 1 – Dose Escalation
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
Fetal 
hemoglobin 
(Hgb F)18
X
X
X
X
(Footnote added)
18. Korea only: Hgb F not required
PREVIOUS TEXT
Time and Events Table: Part 2 – Expansion Cohort
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Fetal hemoglobin 
(Hgb F)
X
X
X
X
REVISED TEXT
Time and Events Table: Part 2 – Expansion Cohort
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Fetal hemoglobin 
(Hgb F)12
X
X
X
X
12. Korea only: Hgb F not required


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PREVIOUS TEXT
Table 7
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
Mean corpuscular volume (MCV)
Neutrophils
White blood cell (WBC) Count 
(absolute) 
Mean corpuscular hemoglobin 
(MCH)
Lymphocytes
Reticulocyte Count
Mean corpuscular hemoglobin 
concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Mean platelet volume (MPV)
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase (AST)
Total and direct bilirubin1
Creatinine
Chloride
Alanine 
aminotransferase (ALT)
Uric Acid
Glucose
Total carbon dioxide (CO2)
Gamma glutamyl 
transferase (GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Phosphorus
Lactate Dehydrogenase 
(LDH)
Thyroid Stimulating 
Hormone
T4
Vitamin B12
Other tests
Coagulation Panel including PT, PTT, INR
Fetal hemoglobin (Hgb F)
Other screening tests
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
1.
Direct bilirubin should be assessed only if total bilirubin is elevated beyond the upper limit of normal 
(ULN)


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REVISED TEXT
Table 7
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red blood cell (RBC) Count
Mean corpuscular volume (MCV)
Neutrophils
White blood cell (WBC) Count 
(absolute) 
Mean corpuscular hemoglobin 
(MCH)
Lymphocytes
Reticulocyte Count
Mean corpuscular hemoglobin 
concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Mean platelet volume (MPV)
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase (AST)
Total and direct bilirubin1
Creatinine
Chloride
Alanine 
aminotransferase (ALT)
Uric Acid
Glucose
Total carbon dioxide (CO2)
Gamma glutamyl 
transferase (GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Phosphorus
Lactate Dehydrogenase 
(LDH)
Thyroid Stimulating 
Hormone
T4
Vitamin B12
Other tests
Coagulation Panel including PT, PTT, INR
Fetal hemoglobin (Hgb F)2
Other screening tests
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
1.
Direct bilirubin should be assessed only if total bilirubin is elevated beyond the upper limit of normal 
(ULN)
2.
Korea only: fetal Hgb F not required


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AMENDMENT 3
Where the Amendment Applies
Protocol Amendment 3 applies to all sites participating in the conduct of the study
Summary of Amendment 
Additional eligibility criteria and safety monitoring measures are put in place to address 
recent safety findings. Primary end point and futility criteria for Part 2 are modified based 
on the compound’s mechanism of action. Other changes include additional urine and 
plasma sample collection for metabolite profiling (at the highest dose cohort in Part 1 
PK/PD expansion), update in concomitant medications, clarification on the timing for 
pre- and post-dose optional biopsies, and addressing the inconsistencies in the definition 
of febrile neutropenia.
LIST OF SPECIFIC CHANGES
Section 1.3.1
GSK2879552 Background
PREVIOUS TEXT
An overview of the pre-clinical studies of GSK2879552 is provided below.  Detailed 
information concerning the biology, pharmacology, pharmacokinetics (PK), and safety 
can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_00].
GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 767 nM, kinact = 0.1 min-1).  While the initial reversible potency (Ki) of 
GSK2879552 is moderate, complete inhibition of the enzyme is achieved over time due 
to the irreversible, mechanism-based nature of the inhibition.  GSK2879552 induces the 
expression of putative LSD1 target genes and has potent, predominantly cytostatic, anti-
proliferative activity in small cell lung carcinoma (SCLC) with median EC50 = 25 nM, 
range = 2 - 240 nM.  In total, 9/28 SCLC lines were found to be sensitive to 
GSK2879552 treatment while the sensitivity of an additional 7 SCLC lines could not be 
determined.  
REVISED TEXT
An overview of the pre-clinical studies of GSK2879552 is provided below.  Detailed 
information concerning the biology, pharmacology, pharmacokinetics (PK), and safety 
can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_001].
GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 1.7 µM 767 nM, kinact = 0.1 min-1).  While the initial reversible potency (Ki) 
of GSK2879552 is moderate, complete inhibition of the enzyme is achieved over time 
due to the irreversible, mechanism-based nature of the inhibition.  GSK2879552 induces 
the expression of putative LSD1 target genes and has potent, predominantly cytostatic, 
anti-proliferative activity in small cell lung carcinoma (SCLC) with median EC50 = 25 
nM, range = 2 - 240 nM.  In total, 9/28 SCLC lines were found to be sensitive to 
GSK2879552 treatment while the sensitivity of an additional 7 SCLC lines could not be 
determined.  


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Section 1.4 Benefit : Risk Assessment
PREVIOUS TEXT
Summaries of findings from non-clinical studies conducted with GSK2879552 can be 
found in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_00].  Toxicology studies performed in dogs, rats and mice suggest that the 
primary toxicities of GSK2879552 are hematologic.  The following Section outlines the 
risk assessment and mitigation strategy for this protocol.
Potential 
Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Lymphoid/he
matologic and 
associated 
bleeding and 
infection risks 
The primary toxicity with 
GSK2879552 is a dose-dependent 
mild-to-severe thrombocytopenia, 
observed in mice, rats and dogs.  
A dose-dependent mild-to-severe 
neutropenia was observed in rats, 
but not dogs, and was not 
associated with systemic 
infections.  Mild effects on the 
erythron were observed in rats 
and dogs which may reflect both a 
direct and indirect (i.e., secondary 
to bleeding/hemorrhage) effect on 
the erythroid lineage. In general, 
there was not hypocellularity 
observed in the bone marrow of 
these animals.
Informed Consent Form includes the risk of 
hematologic toxicity.
Protocol specifies: 
-
laboratory assessments (complete blood 
count [CBC] )
-
Exclusion criteria for subjects with recent 
history of significant bleeding or elevated 
bleeding risk
-
Monitoring for bleeding 
-
Monitoring for infection
-
Dose stopping/modification criteria
-
Anticoagulants (e.g., warfarin above 1 mg 
once daily, direct thrombin inhibitors, etc) at 
therapeutic doses or platelet inhibitors (e.g., 
aspirin above 100 mg once daily, 
clopidogrel) are prohibited from fourteen 
days prior to the first dose of study drug 
through completion of the Final Study Visit.
-
Guideline for platelet transfusion    
REVISED TEXT
Summaries of findings from non-clinical studies conducted with GSK2879552 can be 
found in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2013N168888_001].  Toxicology studies performed in dogs, rats and mice suggest that 
the primary toxicities of GSK2879552 are hematologic.  The following Section outlines 
the risk assessment and mitigation strategy for this protocol.


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Lymphoid/hematologic 
and associated 
bleeding and infection 
risks 
The primary toxicity with GSK2879552 is a dose-
dependent mild-to-severe thrombocytopenia, 
observed in mice, rats and dogs.  A dose-
dependent mild-to-severe neutropenia was 
observed in rats, but not dogs, and was not 
associated with systemic infections.  Mild effects 
on the erythron were observed in rats and dogs 
which may reflect both a direct and indirect (i.e., 
secondary to bleeding/hemorrhage) effect on the 
erythroid lineage. In general, there was not 
hypocellularity observed in the bone marrow of 
these animals.
Informed Consent Form includes the risk of hematologic toxicity.
Protocol specifies: 
-
laboratory assessments (complete blood count [CBC] )
-
Exclusion criteria for subjects with recent history of significant bleeding or 
elevated bleeding risk
-
Monitoring for bleeding 
-
Monitoring for infection
-
Dose stopping/modification criteria
-
Anticoagulants (e.g., warfarin above 1 mg once daily, direct thrombin 
inhibitors, etc) at therapeutic doses or platelet inhibitors (e.g., aspirin above 
100 mg once daily, clopidogrel) are prohibited from fourteen days prior to the 
first dose of study drug through completion of the Final Study Visit.
-
Guideline for platelet transfusion    
Mental status change
Two (out of 16) subjects enrolled in 200858 study 
experienced encephalopathy.
Informed Consent Form is updated to include the risk of mental status 
change.
Protocol eligibility and monitoring criteria  are modified:
-
subjects who have received prior treatment with temozolomide, 
dacarbazine, procarbazine or PARP inhibitors are excluded
-
Subjects should have baseline thyroid function, vitamin B12 level and 
metabolic panel within acceptable limits
-
Montreal Cognitive Assessment (MOCA) at baseline and weekly for the 
first 4 weeks and monthly thereafter.
-
Subjects with baseline MOCA score of ≤ 22 are excluded
Protocol stopping criteria is modified:
-
Dosing will be held and neurology consult will be required if a decrease 
of 3 points or more from baseline MOCA score or any score of < 22 
occurs or in case of any other indication of early encephalopathy as 
determined by patient history or physical exam


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Section 2.1
Part 1 Dose Escalation
PREVIOUS TEXT
PART 1: Escalation Cohort
Objectives
Endpoints
Secondary 
2.
To evaluate clinical response after 
treatment with GSK2879552.
2.
Objective response rate (% of subjects 
achieving complete response [CR], partial 
response [PR]) per Response Evaluation 
Criteria in Solid Tumors (RECIST) version 
1.1
Exploratory
6.
To characterize the metabolite profile 
of GSK2879552 after oral repeat-
dosing in some subjects
7.
To determine the amount of 
GSK2879552 excreted in urine after 
oral repeat-dosing
6.
GSK2879552 metabolites in plasma 
and/or urine
7.
Concentration of GSK2879552 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over time 
REVISED TEXT
PART 1: Escalation Cohort
Objectives
Endpoints
Secondary 
2.
To evaluate clinical response activity 
after treatment with GSK2879552.
2.
Disease Control Rate (DCR) (CR + PR + 
SD) at week 16 based on Objective 
response rate (% of subjects achieving 
complete response [CR], partial response 
[PR]) per Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1
Exploratory
6.
To characterize the metabolite profile 
of GSK2879552 after oral single 
and/or repeat-dosing in some subjects
7.
To determine the amount of 
GSK2879552 excreted in urine after 
oral single and/or repeat-dosing
6.
GSK2879552 metabolites in plasma 
and/or urine
7.
Concentration of GSK2879552 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over time 
Section 2.2
Part 2 Expansion
PREVIOUS TEXT
Objectives
Endpoints
Primary
1.
To evaluate clinical activity of 
GSK2879552 given orally in adult 
subjects with SCLC.
1.
Objective response rate (% of subjects 
achieving CR, PR) per RECIST 1.1


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Objectives
Endpoints
Secondary
1.
To evaluate the safety and 
tolerability of RP2D of GSK2879552
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety 
assessments (e.g., laboratory parameters, 
vital signs, physical examinations).
2.
To characterize the population PK of 
GSK28795522. 
2.
Population PK parameters for 
GSK2879552 such as clearance (CL/F) 
and volume of distribution (V/F), and 
relevant covariates which may influence 
exposure (e.g., age, weight, or disease 
associated covariates).
3.
To evaluate the relationship 
between GSK2879552 exposure 
and safety/efficacy/PD parameters. 
4.
To evaluate duration of response 
and progression free survival (PFS)
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmin, Cmax 
or AUC [0-tau]), and ProGRP, platelet 
levels in blood, and safety/efficacy 
parameters.
4.
Duration of response and PFS
Hypothesis
Clinical response will be defined as Objective Response Rate (CR + PR) based on 
RECIST 1.1.
The null hypothesis is: H0: RR ≤10%
The alternative hypothesis is: HA: RR ≥25%
REVISED TEXT
Objectives
Endpoints
Primary
1.
To evaluate clinical activity of 
GSK2879552 given orally in adult 
subjects with SCLC.
1.
Disease Control Rate (DCR) (CR + PR + 
SD) at week 16 based on Objective 
response rate (% of subjects achieving 
CR, PR) per RECIST 1.1
Secondary
1.
To evaluate the safety and 
tolerability of RP2D of GSK2879552
1.
AEs, SAEs, dose limiting toxicities, dose 
reductions or delays, withdrawals due to 
toxicities and changes in safety 
assessments (e.g., laboratory parameters, 
vital signs, physical examinations).
2.
To characterize the population PK of 
GSK28795522. 
2.
Population PK parameters for 
GSK2879552 such as clearance (CL/F) 
and volume of distribution (V/F), and 
relevant covariates which may influence 
exposure (e.g., age, weight, or disease 
associated covariates).
3.
To evaluate the relationship 
between GSK2879552 exposure 
and safety/efficacy/PD parameters. 
4.
To evaluate duration of response 
and progression free survival (PFS)
3.
Relationship between GSK2879552 
exposure markers (e.g. dose, Cmin, Cmax 
or AUC [0-tau]), and ProGRP, platelet 
levels in blood, and safety/efficacy 
parameters.
4.
Duration of response and PFS


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Objectives
Endpoints
5.
To evaluate objective response 
rate (ORR)
5.
% of subjects achieving complete 
response and partial response
Hypothesis
Clinical response will be defined as Disease Control Objective Response Rate (DCR) (CR 
+ PR+SD) at week 16 based on RECIST 1.1.
The null hypothesis is: H0: DCRRR ≤1510% at week 16
The alternative hypothesis is: HA: DCRRR ≥3025% at week 16
Section 3.11
Safety Management Guideline
NEW SECTION ADDED
3.11.3 Mental Status Stopping Criteria
Study treatment will be held and neurology consult obtained if: 

A decrease of 3 pointsor more from baseline MOCA score occurs and/or

Any other indication of early encephalopathy as determined by patient 
history or physical exam
The treatment may resume if one of the following criteria is met:

A reversible cause is identified and MOCA score returns to normal or 
symptoms return to baseline.

Evaluated by a neurologist and found to have no clear signs/symptoms of 
encephalopathy or other cognitive dysfunction. This is applicable only in the 
absence of decrease in MOCA score.
The treatment should be permanently discontinued for subjects with documented 
symptoms with no other cause, even if they return to baseline.
Section 3.12.2
Management of Thrombocytopenia
PREVIOUS TEXT


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Table 9
Thrombocytopenia management guideline
Grade
Platelet count
Monitoring
Dose Adjustment*
G3
<50,000 - 25,000/mm3
Twice weekly for 2 weeks. Then,

if stable, monitor per protocol.

if falling, continue to monitor twice 
weekly until stable. 

If platelet count is < 50K but > 25K for more than 3 days and stable, 
continue at the same dose.

If platelet count is < 50K but > 25K for more than 3 days and falling, 
interrupt dosing and resume treatment once platelet count >50K
at the same dose if platelet count recovers to > 50K within 7 
days.** If grade 3 thrombocytopenia recurs, reduce dose by at 
least 25%.
with reduced dose by at least 25% if platelet count recovers to > 
50K after 7 days.**. 
REVISED TEXT
Grade
Platelet count
Monitoring
Dose Adjustment*
G3
<50,000 - 25,000/mm3
Twice weekly for 2 weeks. Then,

if stable, monitor per protocol.

if falling, continue to monitor twice 
weekly until stable. 

If platelet count is < 50K but > 25K for more than 3 days and stable, 
continue at the same dose.

If platelet count is < 50K but > 25K for more than 3 days and falling, 
interrupt dosing and resume treatment once platelet count >50K
at the same dose if platelet count recovers to > 50K within 7 
days.** For subjects receiving daily dosing on a continuous 
schedule, If grade 3 thrombocytopenia recurs, reduce dose by at 
least 25% if grade 3 thrombocytopenia recurs
with reduced dose by at least 25% if platelet count recovers to > 
50K after 7 days.**. 


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Section 3.12.3
Management of Neutropenia
PREVIOUS TEXT
For the following, dose should be interrupted and the treatment should resume with dose 
reduced by at least 25% when neutrophil count is > 1000/mm3 and the temperature 
<38.5C for over 24 hrs:

febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever >38.5C 
and lasting >24 hr)

Grade 4 neutropenia 
Grade 3 neutropenia lasting >7 days
REVISED TEXT
For the following, dose should be interrupted and the treatment should resume with dose 
reduced by at least 25% when neutrophil count is > 1000/mm3 and the temperature 
<38.5C for over 24 hrs:

febrile neutropenia (as defined by CTCAE v.4 defined as concurrent Grade 4 
neutropenia and fever >38.5C and lasting >24 hr)

Grade 4 neutropenia 

Grade 3 neutropenia lasting >7 days
Section 3.12 Guidelines for Events of Special Interest and Dose 
Modifications
NEW SECTION ADDED
3.12.6.1
CBC monitoring and PK sampling Guideline for Dose 
interruptions/modifications
When the treatment is held due to an AE, CBC and PK sample should be collected 
on the first day of dose interruption and 3-4 days after. If the treatment is held for 
more than a week, additional PK and CBC sample should be collected at 1 week 
after the dose interruption. 
When the dose resumes at the same or reduced dose, a pre-dose PK sample and 
CBC should be collected on the day and twice weekly for the first 3 weeks.  On 
Week 2, two post-treatment PK samples should be collected between 0.5-1 hr and 
between 4-6 hours from dosing, in addition to the pre-dose PK sample. Pre-dose and 
weekly CBC monitoring should continue on weeks 4, 6, and 8 of the resumed dosing.
Less frequent CBC monitoring and PK sample collection may be allowed for 
individual subjects, if warranted.


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Section 5.2.1
Inclusion Criteria, #8
PREVIOUS TEXT
8.
Adequate baseline organ function defined by
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
10 g/dL
Platelets
125 X 109/L
Prothrombin time (PT)/International normalized ratio 
(INR) and Partial thromboplastin time (PTT) 
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.25 X ULN1
ALT and AST
2.5 ULN without liver metastasis
5 x ULN if documented liver metastasis
Renal
Creatinine
OR
Calculated creatinine clearance by Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation (Appendix 2) or measured from 24hr urine
≤1.5 X ULN
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by Echocardiogram (ECHO) 
1.
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


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REVISED TEXT
8.
Adequate baseline organ function defined by
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
10 g/dL
Platelets
125 X 109/L
Prothrombin time (PT)/International normalized ratio 
(INR) and Partial thromboplastin time (PTT) 
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.25 X ULN1
ALT and AST
2.5 ULN without liver metastasis
5 x ULN if documented liver metastasis
Renal
Creatinine
OR
Calculated creatinine clearance by Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) 
equation (Appendix 2) or measured from 24hr urine
≤1.5 X ULN
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by Echocardiogram (ECHO) 
Metabolic
TSH, T4
Vitamin B12
BUN
Na, K2, Ca, Cl, CO2
Glucose (fasting)
WNL
≥ LLN
≤1.5 X ULN
WNL
≤1.25 X ULN
1.
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
2.
Replacement of K is allowed if below LLN
Section 5.2.2
Exclusion Criteria
NEW TEXT ADDED 
3.
Prior treatment with temozolomide, dacarbazine or procarbazine
4.
Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., 
olaparib, ABT-888)
5.
Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower


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Section 7
STUDY ASSESSMENTS AND PROCEDURES
PREVIOUS TEXT
Visit Window
Baseline disease assessment should be completed within 35 days prior to dosing start and 
pregnancy testing 7 days prior. All other screening assessments should be completed 
within 14 days prior to dosing start.
Visits in the first 3 weeks will be allowed 1 day window. The only exceptions are pre-
and post -treatment biopsies on Day 1 and 15 where 3 days and 3 days window will be 
allowed, respectively.
REVISED TEXT
Baseline disease assessment and ECHO/MUGA should be completed within 35 days 
prior to dosing start and pregnancy testing 7 days prior. All other screening assessments 
should be completed within 14 days prior to dosing start.
Visits in the first 3 weeks will be allowed 1 day window. The only exceptions are pre-
and post -treatment biopsies on Day 1 and 15 where 37 days and 3 days window will be 
allowed, respectively.
Section 7.1 Time and Events Table(s)
PREVIOUS TEXT


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Time and Events Table: Part 1 – Dose Escalation
SCR
First Treatment Phase (28 days)
Continuatio
n Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
ECHO
X
Blood for 
metabolite 
evaluation 
X9
X9
Urine for 
metabolite 
X15
X15
1.
A blood sample will be collected for PK analysis on D1 at following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hrs post dose. Additional samples may be 
collected at 33 and 48 hrs post dose in subjects not receiving a dose on Day 2 to better characterize the terminal half-life ofGSK2879552, if needed.
15. On D15, 24hr urine will be collected and measured, and 400 mL urine from at least 6 subjects at the highest dose cohort in PK/PD expansion will be collected for metabolite 
identification purposes.
16. In a subset of subjects in PK/PD cohorts, fresh pre-treatment and post-treatment biopsies are required.  Pre-treatment and post-treatment biopsies are optional for all 
subjects not enrolled in PK/PD expansion cohorts. Day 1 biopsy (-3 days window) should be collected pre-dose, Day 15 ( 3 days window) biopsy can be collected pre- or 
post- dose. 
Time and Events Table: Part 2 – Expansion Cohort
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Blood samples for PD3 (whole blood)
X
X
X
Blood samples for circulating biomarkers3
(plasma)
X
X
X
Blood samples for translational research3
(PBMCs)
X
X
X
10. Baseline tumor tissue collection is mandatory for all subjects.  Archival tissue will be acceptable. In the absence of available archival tissue, fresh tissue biopsy will be 
required. Fresh biopsies on Day 1, Day 15 and at disease progression are optional for all subjects in Part 2.  Day 1 biopsy (-3 days window) should be collected pre-dose, 
Day 15 (3 days window) biopsy can be collected pre- or post- dose. 


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REVISED TEXT
Time and Events Table: Part 1 – Dose Escalation
SCR
First Treatment Phase (28 days)
Continuatio
n Phase
EOT
D 1
D 2
D 4
D 8
D 11
D 15
D 16
D 18
D 22
Montreal 
Cognitive 
Assessment
X
X
X
X
X
Wk 4 and 
every 4 
wks
ECHO/MOCA
X
Vitamin B12, 
TSH, T4
X
Blood for 
metabolite 
evaluation 
X9
X9
X9
X9
Urine for 
metabolite 
X15
X15
X15
X15
1.
A blood sample will be collected for PK analysis on D1 at following time points: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hrs post dose. Additional samples may be 
collected at 33 (optional) and 48 hrs post dose in subjects not receiving a dose on Day 2 to better characterize the terminal half-life ofGSK2879552, if needed.
15. On Day 1, pre-dose urine (~100 ml) will be collected for metabolite study. On Days 1 and 15, 24hr urine will be collected and measured, and 400 mL urine from at least 
6 subjects at the highest dose cohort in PK/PD expansion will be collected for metabolite identification purposes.
16. In a subset of subjects in PK/PD cohorts, fresh pre-treatment and post-treatment biopsies are required.  Pre-treatment and post-treatment biopsies are optional for all 
subjects not enrolled in PK/PD expansion cohorts. Day 1 biopsy (-37 days window) should be collected pre-dose, Day 15 (3 days window) biopsy can be collected pre- or 
post- dose. Optional post-treatment biopsy can be collected at a later time point, if desired.
Time and Events Table: Part 2 – Expansion Cohort
SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Montreal Cognitive Assessment
X
X
X
X
Wk 4 and every 4 weeks
Vitamin B12, TSH, T4
X


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SCR
First Treatment Phase (28 days)
Continuation Phase
EOT11
D 1
D 8
D 15
D 22
Blood samples for PD3 (whole blood)
X
X
X
Blood samples for translational research3
(PBMCs CTC)
X
X
Wk 8
X
10. Baseline tumor tissue collection is mandatory for all subjects.  Archival tissue will be acceptable. In the absence of available archival tissue, fresh tissue biopsy will be 
required. Fresh biopsies on Day 1, Day 15 and at disease progression are optional for all subjects in Part 2.  Day 1 biopsy (-3 days window) should be collected pre-dose, 
Day 15 (3 days window) biopsy can be collected pre- or post- dose. Optional post-treatment biopsy can be collected at a later time point, if desired.
Section 7.2. Demographic/Medical History and Baseline Assessments
PREVIOUS TEXT
Baseline (Screening) assessments will include:

Complete physical examination, including height (in cm) and weight (in kg).

Vital signs (blood pressure, temperature, respiratory rate, pulse rate)

Eastern Cooperative Oncology Group (ECOG) performance status

Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters 

Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female subjects of childbearing potential only 

12-lead ECG

Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 

Baseline disease assessment: computed tomography (CT) scan (with IV contrast) of chest, abdomen and pelvis (if applicable)

Brain magnetic resonance imaging (MRI) with contrast or a CT scan (with/without contrast) if MRI is contraindicated 

Fresh tumor biopsy (preferred) or archival tumor tissue collection


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REVISED TEXT
Fasting will be required for screening clinical laboratory tests.
Baseline (Screening) assessments will include:

Complete physical examination, including height (in cm) and weight (in kg).

Vital signs (blood pressure, temperature, respiratory rate, pulse rate)

Eastern Cooperative Oncology Group (ECOG) performance status

Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters, 
vitamin B12, thyroid (TSH, T4)

Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female 
subjects of childbearing potential only 

12-lead ECG

Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 

Baseline disease assessment: computed tomography (CT) scan (with IV contrast) of 
chest, abdomen and pelvis (if applicable)

Brain magnetic resonance imaging (MRI) with contrast or a CT scan (with/without 
contrast) if MRI is contraindicated 

Fresh tumor biopsy (preferred) or archival tumor tissue collection

Montreal Cognitive Assessment 
Section 7.3 Safety Evaluations
NEW SECTION ADDED
7.3.3 Montreal Cognitive Assessment
Montreal Cognitive Assessment (MOCA) was designed as a rapid screening 
instrument for mild cognitive dysfunction. It assesses different cognitive domains: 
attention and concentration, executive functions, memory, language, 
visuoconstructional skills, conceptual thinking, calculations, and orientation. Time 
to administer the MOCA is approximately 10 minutes. 
The test and administration instructions are freely accessible for clinicians at 
www.MOCAtest.org.  English version 7.1 is shown in Appendix 7. 


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Section 7.3.7.
Laboratory Assessments
PREVIOUS TEXT
Table 10
List of Clinical Laboratory Tests
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase (AST)
Total and direct bilirubin1
Creatinine
Chloride
Alanine 
aminotransferase (ALT)
Uric Acid
Glucose
Total carbon dioxide (CO2)
Gamma glutamyl 
transferase (GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Phosphorus
Lactate Dehydrogenase 
(LDH)
REVISED TEXT
Table 11
List of Clinical Laboratory Tests
Clinical Chemistry
Blood urea nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase (AST)
Total and direct bilirubin1
Creatinine
Chloride
Alanine 
aminotransferase (ALT)
Uric Acid
Glucose
Total carbon dioxide (CO2)
Gamma glutamyl 
transferase (GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Phosphorus
Lactate Dehydrogenase 
(LDH)
Thyroid Stimulating 
Hormone
T4
Vitamin B12
Section 7.5 Pharmacodynamics
PREVIOUS TEXT

Changes from baseline in circulating ProGRP levels will be assessed in blood

Change from baseline in a gene expression panel, including but not limited to GFI1B, 
KCNJ5, RND2, SERPINE2, ASB4, CACNB3, CD59A, SPARC, and STAB1 will be 
assessed in whole blood 

The impact of GSK2879552 treatment on platelet levels will also be assessed by 
complete blood count (CBC) analysis

Changes in markers including, but not limited to, ProGRP and SCLC-specific LSD1 
target genes or proteins in paired baseline and post-treatment tumor tissue will be 
assessed


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REVISED TEXT

Changes from baseline in circulating ProGRP levels will be assessed in blood

Change from baseline in a gene expression panel, including but not limited to GFI1B, 
KCNJ5, RND2, SERPINE2, ASB4, CACNB3, CD59A, SPARC, and STAB1 will be 
assessed in whole blood 

The impact of GSK2879552 treatment on platelet levels will also be assessed by 
complete blood count (CBC) analysis

Changes in markers including, but not limited to, ProGRP and SCLC-specific LSD1 
target genes or proteins in paired baseline and post-treatment tumor tissue will be 
assessed
Section 7.6.3
Circulating biomarker analysis, 2nd paragraph
PREVIOUS TEXT
Biomarkers circulating in the plasma have been found to correlate with tumor pathway 
activation. Blood-based markers have the important advantage that specimens are readily 
available, simple to prepare and store, and can be taken prior to and during treatment. 
This allows for the assessment of predictive markers based on the baseline evaluation as 
well as markers of activity and resistance based on changes that occur during treatment. 
Therefore, a broad panel of biomarkers may be evaluated in plasma and correlated with 
clinical outcome to treatment with GSK2879552.
REVISED TEXT
Biomarkers circulating in the plasma have been found to correlate with tumor pathway 
activation. Blood-based markers have the important advantage that specimens are readily 
available, simple to prepare and store, and can be taken prior to and during treatment. 
This allows for the assessment of predictive markers based on the baseline evaluation as 
well as markers of activity and resistance based on changes that occur during treatment. 
Therefore, a broad panel of biomarkers in cell-free DNA and circulating tumor cells 
(CTCs) along with burden may be evaluated in plasma and correlated with clinical 
outcome to treatment with GSK2879552.
Section 10.2.1
Drugs that may alter the Pharmacokinetics of 
GSK2879552
PREVIOUS TEXT
The precise in vivo metabolic and transporter liability for GSK2879552 has yet to be 
assessed. In vitro data in human microsomes and hepatocytes suggests that GSK2879552 
has a negligible turnover. GSK2879552 may be a substrate for liver and/or kidney 
transporters.
Therefore, substances that potently inhibit gut, liver and/or kidney transporters (Table 8) 
should be avoided during the course of the study where possible as these drugs could lead 
to higher/lower exposure in subjects, potentially leading to alterations of the 
pharmacologic effects of GSK2879552. Substances that moderately inhibit gut, liver 


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and/or kidney transporters (Table 9) should be used with caution during the course of the 
study.
Table 12
Prohibited Drugs Potentially Affecting GSK2879552 PK Resulting in 
Increased or Decreased GSK2879552 Exposure
PROHIBITED – strong inhibitors of gut, liver or kidney transporters since levels of GSK2879552 may 
be decreased/increased
Drug
Therapeutic Area
quinidine
Antiarrhythmics
clarithromycin, erythromycin, rifamycin class agents 
(e.g.  rifampin, rifabutin, rifapentine)
Antibiotics
itraconazole
Antifungals
lopinavir, nelfinavir, ritonavir
Antiretrovirals, Protease Inhibitors
gemfibrozil 
Hyperlipidemia
cyclosporine, valspodar
Miscellaneous
Table 13
Use with Caution – Drugs Potentially Increase/Decrease 
GSK2879552 Exposure
WITH CAUTION – moderate inhibitors of gut, liver or kidney transporters since levels of GSK2879552 
may be decreased/increased
Drug
Therapeutic Area
probenecid
Anti gout/hyperuricemia
Diflunisal, probenecid
Non-steroidal anti-inflammatory drug (NSAIDs)
REVISED TEXT
All co-meds should be used with caution since little is known about the mechanism 
of clearance of GSK2879552. In vitro data in human microsomes and hepatocytes 
suggest that GSK2879552 has a negligible turnover. 
The precise in vivo metabolic and transporter liability for GSK2879552 has yet to be 
assessed. In vitro data in human microsomes and hepatocytes suggests that GSK2879552 
has a negligible turnover. GSK2879552 may be a substrate for liver and/or kidney 
transporters.
Therefore, substances that potently inhibit gut, liver and/or kidney transporters (Table 8) 
should be avoided during the course of the study where possible as these drugs could lead 
to higher/lower exposure in subjects, potentially leading to alterations of the 
pharmacologic effects of GSK2879552. Substances that moderately inhibit gut, liver 
and/or kidney transporters (Table 9) should be used with caution during the course of the 
study.


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Table 14
Prohibited Drugs Potentially Affecting GSK2879552 PK Resulting in 
Increased or Decreased GSK2879552 Exposure
PROHIBITED – strong inhibitors of gut, liver or kidney transporters since levels of GSK2879552 may 
be decreased/increased
Drug
Therapeutic Area
quinidine
Antiarrhythmics
clarithromycin, erythromycin, rifamycin class agents 
(e.g.  rifampin, rifabutin, rifapentine)
Antibiotics
itraconazole
Antifungals
lopinavir, nelfinavir, ritonavir
Antiretrovirals, Protease Inhibitors
gemfibrozil 
Hyperlipidemia
cyclosporine, valspodar
Miscellaneous
Table 15
Use with Caution – Drugs Potentially Increase/Decrease 
GSK2879552 Exposure
WITH CAUTION – moderate inhibitors of gut, liver or kidney transporters since levels of GSK2879552 
may be decreased/increased
Drug
Therapeutic Area
probenecid
Anti gout/hyperuricemia
Diflunisal, probenecid
Non-steroidal anti-inflammatory drug (NSAIDs)
Section 10.2.2
Drugs that may have their PKs altered by GSK2879552
PREVIOUS TEXT
The potential for pharmacokinetic interactions with drugs likely to be co-administered 
with GSK2879552 in vivo has not been assessed. In vitro data suggests that GSK2879552 
has very low potential to inhibit CYP enzymes. GSK2879552 has also been shown to not 
activate human PXR which is known to induce several drug metabolizing enzymes.  
These results suggest that co-administration of sensitive and narrow therapeutic index 
medications affected by strong inhibitors of transporters should be used with caution 
(Table 10). 


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Table 16
Use with Caution - Drugs Potentially Affected by GSK2879552
USE WITH CAUTION – Monitor for side effects since levels of these drugs may be increased. 
Consider dose reduction.
Transporter Substrate
Therapeutic Area
atorvastatin, fluvastatin, pitavastatin,pravastatin, 
rosuvastatin,simvastatin
HMG-CoA Reductase Inhibitors
glyburide, repaglinide
Antidiabetics
bosentan
Pulmonary hypertension
dofetillide, pilsicainide, procainamide
Antiarrythmic
digoxin
Congestive heart failure
REVISED TEXT
The potential for pharmacokinetic interactions with drugs likely to be co-administered 
with GSK2879552 in vivo has not been assessed. In vitro data suggests that GSK2879552 
has very low potential to inhibit CYP enzymes. GSK2879552 has also been shown to not 
activate human PXR which is known to induce several drug metabolizing enzymes.  
GSK2879552 is not an inhibitor of human efflux transporters P-glycoprotein (P-gp) 
and breast cancer resistance protein (BCRP) and uptake transporters organic anion 
transporting polypeptide 1B1 (OATP1B1) and OATP1B3. 
Co-administration of sensitive and narrow therapeutic index medications affected 
by strong inhibitors of OCT and MATE should be avoided when possible or 
monitored carefully. Examples of such drugs are dofetillide, pilsicainide and 
procainamide.
These results suggest that co-administration of sensitive and narrow therapeutic index 
medications affected by strong inhibitors of transporters should be used with caution 
(Table 10). 
Table 17
Use with Caution - Drugs Potentially Affected by GSK2879552
USE WITH CAUTION – Monitor for side effects since levels of these drugs may be increased. 
Consider dose reduction.
Transporter Substrate
Therapeutic Area
atorvastatin, fluvastatin, pitavastatin,pravastatin, 
rosuvastatin,simvastatin
HMG-CoA Reductase Inhibitors
glyburide, repaglinide
Antidiabetics
bosentan
Pulmonary hypertension
dofetillide, pilsicainide, procainamide
Antiarrythmic
digoxin
Congestive heart failure


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Section 13.1.2
Part 2: Expansion Cohort
PREVIOUS TEXT
Clinical response will be defined as Objective Response Rate (ORR) (CR + PR) based on 
RECIST 1.1.
The null hypothesis is:
H0: RR ≤10%
The alternative hypothesis is:
HA:RR ≥25%
After 10 subjects have been enrolled to examine safety and efficacy, the number of 
observed unconfirmed objective responses will guide further enrolment according to the 
rules summarized in Figure 3. In order to stop for futility as quickly as possible as long as 
there is no sign of efficacy, the responses don’t need to be confirmed. A maximum of 30 
subjects will be enrolled in Part 2 expansion cohort. All available data will be considered 
in making enrollment decisions.


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Figure 4
Stopping Rules for Cohort Expansion: GSK2879552
Number of Responses
Number of Subjects
0
1
2
3
4
≥5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1.
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no 
response in fourteen subjects, then the predictive probability for success will be 5.0% or less (the futility criterion) 
and the study will be stopped
REVISED TEXT
Clinical response will be defined as disease control rate (DCR) Objective Response 
Rate (ORR) (CR + PR+SD) based on RECIST 1.1 at week 16. Biologic activity of 
cytostatic agents is characterized by the stabilization of the disease rather than the 
shrinkage of tumor lesions. As they slow or stop the growth of tumors and the 
developmentof metastases, DCR may be a more appropriate end point in the 
evaluation of cytostatic agents [Van Glabbeke M, 2009] such as GSK2879552.
The null hypothesis is:
H0: DCRRR ≤1510%
The alternative hypothesis is:
HA:DCRRR ≥3025%


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After 1210 subjects have been enrolled to examine safety and efficacy, the number of
observed unconfirmed disease control rate at week 16 objective responses will guide 
further enrolment according to the rules summarized in Figure 3. In order to stop for 
futility as quickly as possible as long as if there is no sign of efficacy, the confirmation 
of responses is not required don’t need to be confirmed. A maximum of 30 subjects will 
be enrolled in the Part 2 expansion cohort. All available data will be considered in 
making enrollment decisions.
Figure 5
Stopping Rules for Cohort Expansion: GSK2879552
Number of Subjects Responding (i.e., controlled disease) Responses 
at 16 weeks
Number of 
Subjects
0
1
2
3
4
≥5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
1.
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no 
response in fourteen subjects, then the predictive probability for success will be 5.0% or less (the futility 
criterion) and consideration should be given to stop enrolment the study will be stopped
Section 13.2.2
Part 2: Expansion Cohort
PREVIOUS TEXT
An initial dose escalation will be used to establish the RP2D for GSK2879552.  Once the 
final dose is confirmed, at least 10 and up to 30 subjects will be enrolled at that dose, 
using decision rules defined in Figure 3. The sample size and stopping rules are based on 


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the methodology of Lee et al. [Lee, 2008].  The assumptions underlying the design are 
detailed below. 
H0: p≤10%
The alternative hypothesis is:
HA:p≥25%
Starting with 10 subjects and allowing for a maximum sample size of 30, this design will 
have a type I error rate () of 0.15 and 85% power.  The trial is not designed to stop early 
for efficacy, but is designed to stop early for futility if the predictive probability of 
success is 5.0% or less.  The type I error rate, power, and predictive probability of 
success to stop early for futility were derived from explicitly stating the minimum and 
maximum sample size, futility stopping rate, and selection of the optimizing criterion as 
the maximization of power under the alternative hypothesis.  The Bayesian prior used in 
determining the design was Beta (0.15, 0.85), a distribution with a mean response rate of 
15%.  Under the null hypothesis, if the true response rate is 10%, the expected sample 
size of the design is 20 subjects and probability of early termination (PET) is 76%. Under 
the alternative hypothesis, if the true response rate is 25%, the expected sample size of 
the design is 29.0 subjects and PET is 11.4%.
REVISED TEXT
An initial dose escalation will be used to establish the RP2D for GSK2879552.  Once the 
final dose is confirmed, at least 12 10 and up to 30 subjects will be enrolled at that dose, 
using decision rules based on the disease control rate (DCR) as defined in Figure 3. 
The sample size and stopping rules are based on the methodology of Lee et al. [Lee, 
2008].  The assumptions underlying the design are detailed below. 
H0: pDCR≤15 10%
The alternative hypothesis is:
HA:pDCR≥30 25%
Starting with 1210 subjects and allowing for a maximum sample size of 30, this design 
will have a type I error rate () of 0.15 and 80 85% power.  The trial is not designed to 
stop early for efficacy, but is designed to stop early for futility if the predictive 
probability of success is 5.0% or less.  The type I error rate, power, and predictive 
probability of success to stop early for futility were derived from explicitly stating the 
minimum and maximum sample size, futility stopping rate, and selection of the 
optimizing criterion as the maximization of power under the alternative hypothesis.  The 
design will have a type I error rate of less than 0.15 and a power greater than 80% 
for a sample size exceeding 30 subjects. The Bayesian prior used in determining the 
design was Beta (0.15, 0.85), a distribution with a mean response rate of 15%.  Under the 
null hypothesis, if the true response rate DCR at 16 weeks is 1510%, the expected 
sample size of the design is 2420 subjects and probability of early termination (PET) is 


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7576%. Under the alternative hypothesis, if the true DCR at 16 weeks response rate is 
3025%, the expected sample size of the design is 29.0 subjects and PET is 10 11.4%.
Section 13.5.2
Part 2: Expansion Cohort
PREVIOUS TEXT
After the initial 10 subjects have enrolled at the RP2D dose, response data will be 
reviewed on an ongoing basis and the number of responses observed will be compared 
with the stopping rules provided in Section 13.1.2.
REVISED TEXT
After the initial 1210 subjects have enrolled at the RP2D dose, response data will be 
reviewed on an ongoing basis and the number of responses observed will be compared 
with the stopping rules provided in Section 13.1.2.
Section 13.6.1
Anti-Cancer Activity Analyse
PREVIOUS TEXT
The primary aim of Part 2 is to detect a clinically meaningful response rate of 30% 
relative to a 10% response rate suggesting no activity. 
Response rate is defined as the percentage of subjects who achieved CR and PR among
subjects who received at least one dose of treatment. Response rate and the associated 2-
sided 95% exact confidence limits will be provided. 
REVISED TEXT
Clinical response will be defined as disease control rate (DCR) (CR + PR + SD) 
based on RECIST 1.1 at week 16.  The primary aim of Part 2 is to detect a clinically 
meaningful response disease control rate of 30% relative to a 1510% response disease 
control rate suggesting no activity. 
Response rate is defined as the percentage of subjects who achieved CR and PR among 
subjects who received at least one dose of treatment. Response rate and the associated 2-
sided 95% exact confidence limits will be provided. 


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AMENDMENT 2
Where the Amendment Applies
Protocol Amendment 2 applies to all sites participating in the conduct of the study
Summary of Amendment
The protocol is amended to add two new dose strengths that will reduce the pill burden 
for subjects. The sponsor/medical monitor contact information is also updated.
List of Specific Changes
Medical Monitor and Sponsor Contact Information:
PREVIOUS TEXT
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
 
MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP 4210
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
MD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP 4401
Collegeville, PA 19426, USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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REVISED TEXT
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
M.D.
 
 MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP 4410 4210
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
 MD, 
PhD 
 
MD
GlaxoSmithKline
1250 South Collegeville Rd
Mailstop UP4210 4401
Collegeville, PA 19426, USA
Section 4.1 Description of Investigational Product
PREVIOUS TEXT
Product 
name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.25 mg or 2 mg of GSK2879552 as parent. 
Dosage form:
Capsule
Unit dose 
strength(s)
0.25 mg and 2 mg
Route/
Regimen
Oral
The initial dosing regimen will be continuous oral daily dosing. 
Subjects should take their doses fasted with approximately 200 mL of water.
Physical 
description:
0.25 mg GSK2879552:  Opaque Size 3 capsule composed of a white body and a 
white cap with no identifying markings containing a white to slightly coloured 
powder.
2 mg GSK2879552:  Opaque Size 1 capsule composed of a pink body printed with 
two black lines and a pink cap printed with two black lines, containing a white to 
slightly coloured powder.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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REVISED TEXT
Product 
name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 52 mg of GSK2879552 
as parent. 
Dosage form:
Capsule
Unit dose 
strength(s)
0.25 mg, 0.5 mg, 2 mg and 52 mg
Route/
Regimen
Oral
The initial dosing regimen will be continuous oral daily dosing. 
Subjects should take their doses fasted with approximately 200 mL of water.
Physical 
description:
0.25 mg GSK2879552:  Opaque Size 3 capsule composed of a white body and a 
white cap with no identifying markings containing a white to slightly coloured 
powder.
0.5 mg GSK2879552:  Opaque Size 1 capsule composed of a light green body 
and a light green cap with no identifying markings containing a white to 
slightly coloured powder.
2 mg GSK2879552:  Opaque Size 1 capsule composed of a pink body printed with 
two black lines and a pink cap printed with two black lines, containing a white to 
slightly coloured powder.
5 mg GSK2879552:   Opaque Size 1 capsule composed of a Swedish Orange 
body and a Swedish Orange cap with no identifying markings containing a 
white to slightly coloured powder.


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AMENDMENT 1
Where the Amendment Applies
Protocol Amendment 1 applies to all sites participating in the conduct of the study
Summary of Amendment
The original protocol is amended to incorporate changes in the starting dose, DLT 
criteria, and safety management following the regulatory input. One of the eligibility 
criteria is also modified to allow enrolment of patients without tumor tissues at baseline. 
Other changes are to clarify one of the exploratory objectives and endpoints, correct the 
investigational product storage conditions, clarify the definition of subject completion 
and allow flexibility in the timing of assessments.
List of Specific Changes
Section 2.1 Part 1 Dose Escalation, #1 under Exploratory
PREVIOUS TEXT
Objectives
Endpoints
Exploratory
1.
To assess feasibility of a select LSD1 
target gene panel for use as a PD 
assay for GSK2879552
1.
Change from baseline expression 
in LSD1 target genes in whole 
blood and tumor
REVISED TEXT
Objectives
Endpoints
Exploratory
1.
To assess feasibility of a select LSD1 
target gene panel for use as a PD 
assay for GSK2879552
1.
Change from baseline expression 
in select LSD1 target genes in 
whole blood and tumor
Section 2.2 Part 2 Expansion, #1 under Exploratory
PREVIOUS TEXT
Objectives
Endpoints
Exploratory
1.
To assess feasibility of a select LSD1 
target gene panel for use as a PD 
assay for GSK2879552
1.
Change from baseline expression 
in LSD1 target genes in whole 
blood and tumor


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REVISED TEXT
Objectives
Endpoints
Exploratory
1.
To assess feasibility of a select LSD1 
target gene panel for use as a PD 
assay for GSK2879552
1.
Change from baseline expression 
in select LSD1 target genes in 
whole blood and tumor
Section 3.1 Discussion of Study Design, 6th paragraph
PREVIOUS TEXT
The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose will be 0.5 mg once daily. Alterations to the dose and schedule may be 
incorporated based on emerging PK, PD, and tolerability/safety data.  
REVISED TEXT
The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose will be 0.25 0.5 mg once daily. Alterations to the dose and schedule may be 
incorporated based on emerging PK, PD, and tolerability/safety data.  
Section 3.2 Part 1: Dose Escalation, 1st paragraph
PREVIOUS TEXT
In Cohort 1, a single subject will receive a dose of GSK2879552 0.5 mg once daily. 
REVISED TEXT
In Cohort 1, a single subject will receive a dose of GSK2879552 0.25 0.5 mg once daily. 
Section 3.2 . Part 1: Dose-Escalation, 3rd bullet point under Number of 
Subjects in a Cohort
PREVIOUS TEXT
The dose escalation will continue with 1 subject per cohort until any of the following 
events are observed, and then each subsequent cohort will consist of a minimum of 2 
subjects.  

Grade 3 neutropenia lasting over 7 days.
REVISED TEXT
The dose escalation will continue with 1 subject per cohort until any of the following 
events are observed, and then each subsequent cohort will consist of a minimum of 2 
subjects.  

Grade 3 neutropenia lasting over 7 days.


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Section 3.2 . Part 1: Dose-Escalation, under Bayesian Prior
PREVIOUS TEXT
Table 4
Specified Prior Probability of DLT
Anticipated Dose
(mg)
Median Probability 
of Toxicity
2.5% Quantile for 
Probability of 
Toxicity
97.5% Quantile for 
Probability of 
Toxicity
0.5
0.05
0.02
0.75
1
0.07
0.04
0.8
1.5
0.1
0.06
0.82
2
0.12
0.08
0.84
2.5
0.15
0.1
0.86
3
0.2
0.12
0.88
4
0.3
0.14
0.9
5
0.42
0.15
0.92
6
0.5
0.16
0.95
8
0.6
0.17
1
10
0.8
0.18
1
12
0.9
0.2
1
A graphical presentation of the prior is displayed in the Figure 2.  In the figure, the x-axis 
is natural log (dose/reference dose), where the reference dose is set to 4 mg.  Doses are 
the projected doses.  Actual doses used during the conduct of the trial may vary.
REVISED TEXT
Table 4
Specified Prior Probability of DLT
Anticipated Dose
(mg)
Median Probability 
of Toxicity
2.5% Quantile for 
Probability of 
Toxicity
97.5% Quantile for 
Probability of 
Toxicity
0.25
0.02
0.01
0.73
0.5
0.05
0.02
0.75
1
0.07
0.04
0.8
1.5
0.1
0.06
0.82
2
0.12
0.08
0.84
2.5
0.15
0.1
0.86
3
0.2
0.12
0.88
4
0.3
0.14
0.9
5
0.42
0.15
0.92
6
0.5
0.16
0.95
8
0.6
0.17
1
10
0.8
0.18
1
12
0.9
0.2
1


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A graphical presentation of the prior is displayed in the Figure 2.  In the figure, the x-axis 
is natural log (dose/reference dose), where the reference dose is set to 4 3 mg.  Doses are 
the projected doses.  Actual doses used during the conduct of the trial may vary.
Section 3.2 . Part 1: Dose-Escalation, under Bayesian Prior
PREVIOUS FIGURE
Figure 2
Prior Distribution For The Probability of DLT Given Dose
REVISED FIGURE
Figure 2
Prior Distribution For The Probability of DLT Given Dose


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Section 3.5 Dose-Limiting Toxicity, 2nd bullet point
PREVIOUS TEXT

Grade 4 neutropenia > 7 days duration

Febrile neutropenia (defined as concurrent Grade 4 neutropenia and fever >38.5C 
and lasting >24 hr)
REVISED TEXT

Grade 4 neutropenia > 7 days duration

Grade 3 neutropenia > 7 days duration

Febrile neutropenia as defined by CTCAE v.4 (defined as concurrent Grade 4 
neutropenia and fever >38.5C and lasting >24 hr)
Section 3.9.2.2 
Starting Dose, under Conclusion
PREVIOUS TEXT
The proposed starting dose of 0.5 mg was selected with the goal of administering a 
pharmacologically active dose that is reasonably safe to use, in accordance with ICH S9.    
This dose is slightly lower than the predicted human MABEL dose range based on 
exposures in dogs and rats (0.6 to 1.6 mg) and less than half of the predicted human 
MABEL dose based on human equivalent dose calculation from the rat and dog studies 
(1.1 mg).  
The starting dose of 0.5 mg daily has a predicted total exposure of 22.8 ng.h/mL with a 
Cmax of 2.8 ng/mL (free AUC of 10.4 ng.h/mL and free Cmax of 1.3 ng/mL)
REVISED TEXT
The proposed starting dose of 0.25 0.5 mg was selected with the goal of administering a 
pharmacologically active dose that is reasonably safe to use, in accordance with ICH S9.    
This dose is slightly lower than the predicted human MABEL dose range based on 
exposures in dogs and rats (0.6 to 1.6 mg) and less than a quarterhalf of the predicted 
human MABEL dose based on human equivalent dose calculation from the rat and dog 
studies (1.1 mg).  
The starting dose of 0.25 0.5  mg daily has a predicted total exposure of 11.422.8
ng.h/mL with a Cmax of 1.42.8 ng/mL (free AUC of 5.210.4 ng.h/mL and free Cmax of 
0.651.3 ng/mL)


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Section 3.12.3 Management of Neutropenia, 2nd bullet point
PREVIOUS TEXT

Grade 4 neutropenia lasting >7 days
REVISED TEXT

Grade 4 neutropenia lasting >7 days

Grade 3 neutropenia lasting >7 days
Section 4.2 Handling/Storage of GSK2879552, GSK Investigational Product, 
2nd paragraph under Storage
PREVIOUS TEXT
GSK2879552 is to be stored at a temperature range of 2-8C (36-46F), protected from 
light.  Maintenance of a temperature log (manual or automated) is required.
REVISED TEXT
GSK2879552 is to be stored at a temperature range of 2-8C (36-46F), protected from 
lightmoisture.  Maintenance of a temperature log (manual or automated) is required.
Section 5.2.1 Inclusion Criteria #6
PREVIOUS TEXT
6. Tumor tissue requirements:

Availability of archival tissue, or willingness to undergo fresh biopsy at 
baseline.  

Enrollment in PK/PD cohort may be limited to subjects with disease amenable 
to pre- and post-dose biopsies, and willingness to undergo biopsy.
REVISED TEXT
6. Tumor tissue requirements:

Availability of archival tissue, or willingness to undergo fresh biopsy at 
baseline. Patients without baseline tissue may be enrolled with approval from the 
GSK medical monitor.   

Enrollment in PK/PD cohort may be limited to subjects with disease amenable 
to pre- and post-dose biopsies, and willingness to undergo biopsy.


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Section 6.2 Subject Completion Criteria
PREVIOUS TEXT
A subject will be considered to have completed the study if they complete screening 
assessments, at least 28 days of study treatment(s) and the post-treatment follow-up visit.
REVISED TEXT
In Part 1, aA subject will be considered to have completed the study if they complete 
screening assessments, at least 28 days of study treatment(s) and the post-treatment 
follow-up visit.
In Part 2, a subject will be considered to have completed the study if they are 
followed until disease progression, death or start of new anticancer treatment.
Section 7 Study Assessments and Procedures 
NEW TEXT added after the 3rd paragraph
If the blood draw is done first, there should be at least 15 minute interval before the 
vital signs and 12-lead ECGs measurements are taken.
Section 7.1 Time and Events Table: Part 1 Dose Escalation, footnote 16
PREVIOUS TEXT
Day 15 (3 days window) biopsy should be collected at least 24 hours after the previous 
dose.
REVISED TEXT
Day 15 (3 days window) biopsy should can be collected pre- or post-dose. at least 24 
hours after the previous dose.
Section 7.1 Time and Events Table: Part 2 Expansion Cohort, footnote 10
PREVIOUS TEXT
Day 15 (3 days window) biopsy should be collected at least 24 hours after the previous 
dose.
REVISED TEXT
Day 15 (3 days window) biopsy should can be collected pre- or post-dose. at least 24 
hours after the previous dose.


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Appendix 6 Simulation Results of N-CRM in Dose Escalation Phase
PREVIOUS TEXT
The parameters (s.d.) of the explicit distribution are = -0.3738(1.6211), ln()= 0.4401 
(0.239), and ρ=-0.9773 where and ln() are distributed as bivariate normal with 
correlation ρ.
Table 11
Simulation Results Under Various Scenarios
Dose
(mg)
Scenario 1: Steep Dose-
Toxicity Curve
Scenario 2: Moderate 
Dose-Toxicity Curve
Scenario 3: Shallow 
Dose-Toxicity Curve
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
0.5
0.05
4.3
0.05
5
0.02
1
1
0.07
6
0.07
5.1
0.04
2.4
1.5
0.12
11.6
0.1
7.1
0.06
1.5
2
0.16
16.2
0.15
11.3
0.08
2.5
2.5
0.23
17.4
0.17
9.4
0.1
2.9
3
0.25
33.7
0.2
24.4
0.12
16.2
4
0.35
10.3
0.24
16
0.14
14.4
5
0.6
0.5
0.25
8.2
0.17
12.9
6
0.8
0
0.28
12
0.19
28.6
8
0.9
0
0.38
1.4
0.21
12.3
10
0.92
0
0.5
0
0.27
4.1
12
0.95
0
0.6
0.1
0.4
1.2
The average sample size over the 1000 clinical trials simulated under Scenarios 1-3 was 
19.2, 19.9, and 22.3 respectively.


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REVISED TEXT
The parameters (s.d.) of the explicit distribution are =   -0.9917 (1.382) -
0.3738(1.6211), ln()=   0.3615 (0.8838), 0.4401 (0.239) and ρ=  -0.6808 0.9773 where 
and ln() are distributed as bivariate normal with correlation ρ.
Table 11
Simulation Results Under Various Scenarios
Dose
(mg)
Scenario 1: Steep Dose-
Toxicity Curve
Scenario 2: Moderate 
Dose-Toxicity Curve
Scenario 3: Shallow 
Dose-Toxicity Curve
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
0.25
0.03
1
0.03
1.1
0.01
0.1
0.5
0.05
1.9 4.3
0.05
1.3 5
0.02
0.3 1
1
0.07
3.4 6
0.07
2.8 5.1
0.04
0.9 2.4
1.5
0.12
9.5 11.6
0.1
6.1 7.1
0.06
1.2 1.5
2
0.16
13.4 16.2
0.15
9.3 11.3
0.08
1.7 2.5
2.5
0.23
17.8 17.4
0.17
13.1 9.4
0.1
6 2.9
3
0.25
46 33.7
0.2
41.5 24.4
0.12
37.3 16.2
4
0.35
6.9 10.3
0.24
14.5 16
0.14
14.9 14.4
5
0.6
0.1 0.5
0.25
6.1 8.2
0.17
11.7 12.9
6
0.8
0
0.28
3.8 12
0.19
15.3 28.6
8
0.9
0
0.38
0.2 1.4
0.21
6.1 12.3
10
0.92
0
0.5
0.2 0
0.27
2.8 4.1
12
0.95
0
0.6
0 0.1
0.4
1.7 1.2
The average sample size over the 1000 clinical trials simulated under Scenarios 1-3 was 
18.6, 19.3, 19.2, 19.9, and 21 22.3 respectively.

SAP_001.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
MID200858 
1 
 
 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan: A phase I open-label, dose 
escalation study to investigate the safety, pharmacokinetics, 
pharmacodynamics and clinical activity of GSK2879552 
given orally in subjects with relapsed/refractory small cell 
lung carcinoma. 
Compound Number 
: GSK2879552 
Effective Date 
: 23-JAN-2018 
 
Description: 
The purpose of this RAP is to describe the planned analyses and output to be included in 
the Clinical Study Report for Protocol 2013N173386_05 
This RAP is intended to describe the safety, tolerability, pharmacokinetic and 
pharmacodynamic analyses required for the study. 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
 
Author 
Date 
Approval Method 
PPD 
Principal Statistician, PAREXEL Intl. 
23-JAN-2018 
Email 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
MID200858 
2 
 
 
 
RAP Team Approvals: 
 
Approver 
Date 
Approval Method 
PPD 
Director, Clinical Development (Oncology 
Epigenetics Clinical) 
23-JAN-2018 
Email 
PPD 
Clinical Development Lead (Cancer Epigenetics) 
23-JAN-2018 
Email 
PPD 
Clinical Development Manager (Oncology 
CPSSO) 
23-JAN-2018 
Email 
PPD 
Senior Clinical Development Manager (PCPS) 
23-JAN-2018 
Email 
PPD 
Director (Clinical Pharmacology, Modelling and 
Simulation) 
23-JAN-2018 
Email 
PPD 
Principal Programmer Analyst (Oncology, 
Clinical Programming) 
23-JAN-2018 
Email 
PPD 
Statistics Leader, (Oncology, Clinical Statistics) 
23-JAN-2018 
Email 
PPD 
Data Quality Lead 
23-JAN-2018 
Email 
PPD 
Medical Writer (ICG, Inc.) 
23-JAN-2018 
Email 
 
Clinical Statistics and Clinical Programming Line Approvals: 
 
Approver 
Date 
Approval Method 
PPD 
Senior Director (Oncology, Clinical Statistics) 
23-JAN-2018 
Email 
PPD 
Programming Manager (Oncology, Clinical 
Programming) 
23-JAN-2018 
Email 


3 
CONFIDENTIAL 
MID200858 
 
 
 
 
TABLE OF CONTENTS 
 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION ................................................... 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s) ............................................................... 7 
2.3. 
Study Design ................................................................................................ 9 
2.4. 
Statistical Hypotheses ................................................................................. 11 
3. 
PLANNED ANALYSES ........................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.1.1. 
Part 1: Dose Escalation Phase..................................................... 12 
3.2. 
Final Analyses ............................................................................................ 12 
4. 
ANALYSIS POPULATIONS .................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 13 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 14 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 14 
5.2. 
Baseline Definitions .................................................................................... 14 
5.3. 
Multicentre Studies ..................................................................................... 14 
5.4. 
Other  Considerations  for  Data  Analyses  and  Data  Handling  
Conventions ................................................................................................ 15 
6. 
STUDY POPULATION ANALYSES ........................................................................ 16 
6.1. 
Overview of Planned Study Population Analyses ........................................ 16 
6.2. 
Disposition of Subjects ................................................................................ 16 
6.3. 
Protocol Deviations ..................................................................................... 16 
6.4. 
Demographic and Baseline Characteristics ................................................. 16 
6.5. 
Concomitant Medications ............................................................................ 16 
7. 
SAFETY ANALYSES.............................................................................................. 18 
7.1. 
Extent of Exposure...................................................................................... 18 
7.2. 
Adverse Events Analyses ........................................................................... 18 
7.3. 
Adverse Events of Special Interest ............................................................. 19 
7.4. 
Clinical Laboratory Analyses ....................................................................... 20 
7.4.1. 
Liver Function Analyses ............................................................... 22 
7.5. 
Other Safety Analyses ................................................................................ 22 
8. 
EFFICACY ANALYSES .......................................................................................... 24 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 25 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 25 
9.1.1. 
Endpoint / Variables ..................................................................... 25 
9.1.1.1. 
Drug Concentration Measures .................................... 25 
9.1.1.2. 
Derived Pharmacokinetic Parameters ......................... 25 
9.1.2. 
Population of Interest ................................................................... 25 
9.1.3. 
Statistical Analyses / Methods ..................................................... 26 


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9.1.3.1. 
Dose proportionality .................................................... 26 
9.1.3.2. 
Accumulation .............................................................. 27 
9.1.3.3. 
Time Invariance .......................................................... 27 
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 28 
10.1. Pharmacodynamic Analyses ....................................................................... 28 
10.2. Biomarker Analyses .................................................................................... 28 
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 29 
11.1. Statistical Analyses / Methods .................................................................... 29 
12. REFERENCES ....................................................................................................... 30 
13. APPENDICES ........................................................................................................ 31 
13.1. Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 31 
13.1.1. 
Exclusions from Per Protocol Population ..................................... 31 
13.2. Appendix 2: Schedule of Activities .............................................................. 32 
13.2.1. 
Protocol Defined Schedule of Events ........................................... 32 
13.3. Appendix 3: Assessment Windows ............................................................. 33 
13.4. Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 34 
13.4.1. 
Study Time Periods ...................................................................... 34 
13.4.1.1. Study Phases for Concomitant Medication ................. 34 
13.5. Appendix 5: Data Display Standards & Handling Conventions .................... 35 
13.5.1. 
Reporting Process ....................................................................... 35 
13.5.2. 
Reporting Standards .................................................................... 35 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 36 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 37 
13.6.1. 
General ........................................................................................ 37 
13.6.2. 
Study Population .......................................................................... 37 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 38 
13.7.1. 
Premature Withdrawals ................................................................ 38 
13.7.2. 
Handling of Missing Data ............................................................. 38 
13.7.2.1. Handling of Missing and Partial Dates ........................ 38 
13.8. Imputation of Missing Exposure End Dates ................................................. 43 
13.9. Appendix 8: Values of Potential Clinical Importance ................................... 44 
13.10. Appendix 9: Abbreviations & Trade Marks .................................................. 45 
13.10.1. Abbreviations ............................................................................... 45 
13.10.2. Trademarks ................................................................................. 47 
13.11. Appendix 10: List of Data Displays .............................................................. 48 
13.11.1. Data Display Numbering .............................................................. 48 
13.11.2. Mock Example Shell Referencing ................................................ 48 
13.11.3. Deliverables ................................................................................. 48 
13.11.4. Study Population Tables .............................................................. 49 
13.11.5. Efficacy Tables ............................................................................ 50 
13.11.6. Safety Tables ............................................................................... 50 
13.11.7. Pharmacokinetic Tables ............................................................... 54 
13.11.8. Pharmacodynamic Tables ........................................................... 55 
13.11.9. PK/PD Tables .............................................................................. 56 
13.11.10. PK/PD Figures ............................................................................. 57 
13.11.11. ICH Listings ................................................................................. 58 


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13.11.12. Non-ICH Listings .......................................................................... 61 


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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 
 
GlaxoSmithKline 
Document Number 
Date 
Version 
2013N173386_01 
09-OCT-2013 
Original 
2013N173386_02 
20-NOV-2013 
Amendment No. 01 
The starting dose, DLT criteria and safety management criteria are revised according to 
the regulatory input. One of the eligibility criteria is also modified to allow enrolment of 
patients without tumor tissues at baseline. Other changes are to clarify one of the 
exploratory objectives and endpoints, correct the investigational product storage 
conditions, clarify the definition of subject completion and allow flexibility in the timing 
of assessments. 
2013N173386_03 
06-MAR-2015 
Amendment No. 02 
The protocol is amended to add two new dose strengths that will reduce the pill burden 
for subjects. 
2013N173386_04 
27-MAY-2015 
Amendment No. 03 
Additional eligibility criteria and safety monitoring measures are put in place to address 
recent safety findings. Primary end point and futility criteria for Part 2 are modified based 
on the compound’s mechanism of action. Other changes include additional urine and 
plasma sample collection for metabolite profiling (at the highest dose cohort in Part 1 
PK/PD expansion), update in concomitant medications, clarification on the timing for 
pre- and post-dose optional biopsies, and addressing the inconsistencies in the definition 
of febrile neutropenia. 
2013N173386_05 
22-NOV-2016 
Amendment No. 4 
Appendix 5 country specific IP label requirements for Korea have been modified. Fetal 
hemoglobin testing requirement has also been removed for Korea. 
 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
 
Due to the business decision of terminating study MID200858, this RAP is developed for 
an abbreviated CPSR. Since Part 2 cohort expansion was not initiated prior to study 
closure, no statistical analysis will be performed for Part 2. 
 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 


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Table 1 
Changes to Protocol Defined Analysis Plan 
 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
Interim Analysis and CSR for 
Part 2 
• 
No Statistical Analysis for 
Part 2 
• 
Part 2 was not implemented 
• 
Full CSR 
• 
Abbreviated CSR 
• 
Study terminated 
 
2.2. 
Study Objective(s) and Endpoint(s) 
 
Part 1 Objectives 
Part 1 Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To determine the safety, tolerability 
and Recommended Phase 2 Dose(s) 
(RP2D) and regimen of GSK2879552 
given orally in adult subjects with 
SCLC. 
• 
AEs, SAEs, dose limiting toxicities, dose reductions or 
delays, withdrawals due to toxicities and changes in 
safety parameters (e.g., laboratory values, vital signs, 
ECGs, physical examinations). 
• 
Secondary Objectives 
• 
Secondary Endpoints 
• 
To characterize the pharmacokinetics 
of GSK2879552 after single- and 
repeat-dose oral administration. 
• 
GSK2879552 PK parameters following single-(Day 1) and 
repeat-dose (Day 15) administration of GSK2879552, 
including AUC, Cmax, tmax, t½ (terminal phase and/or 
effective half-life), accumulation ratio, and time 
invariance. 
• 
To evaluate clinical response after 
treatment with GSK2879552. 
• 
Disease Control Rate (DCR) (CR + PR + SD) at week 16 
based on Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1. 
• 
To evaluate the relationship between 
GSK2879552 exposure and safety/ 
efficacy/PD parameters 
• 
Relationship between GSK2879552 exposure markers 
(e.g. dose, Cmax, Cmin or AUC (0-tau)), and ProGRP, 
platelet levels in blood, and safety/efficacy parameters. 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess feasibility of a select gene 
panel for use as a PD assay for 
GSK2879552 
• 
Change from baseline expression in select genes in 
whole blood and tumor 
• 
To investigate the impact of 
GSK2879552 on the RNA expression 
profile in tumor and blood to identify 
mechanisms of rational combination 
and potential resistance. 
• 
Transcriptomic (RNA) profile of tumor and whole blood 
pre- and post-treatment with GSK2879552 
• 
To investigate relationship between 
tumor baseline genomic profile and 
response or resistance to 
GSK2879552 
• 
Tumor DNA, RNA and protein markers at baseline. 
• 
To discover circulating response and 
resistance biomarkers 
• 
Circulating biomarkers (e.g. cfDNA, protein and RNA) 
• 
To investigate the impact of 
GSK2879552 on fetal haemoglobin 
• 
Pre- and post-treatment fetal haemoglobin levels 
• 
To characterize the metabolite profile 
of GSK2879552 after oral single 
and/or repeat-dosing in some subjects 
• 
GSK2879552 metabolites in plasma and/or urine 
• 
To determine the amount of 
GSK2879552 excreted in urine after 
• 
Concentration of GSK2879552 in urine measured with an 
investigational bioanalytical method and extrapolated to 


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Part 1 Objectives 
Part 1 Endpoints 
oral single and/or repeat-dosing 
total amount excreted in urine over time 
 
 
Part 2 Objectives 
Part 2 Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To evaluate clinical activity of 
GSK2879552 given orally in adult 
subjects with SCLC. 
• 
Disease Control Rate (DCR) (CR + PR + SD) at week 16 
based on Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1. 
• 
Secondary Objectives 
• 
Secondary Endpoints 
• 
To evaluate the safety and tolerability 
of RP2D of GSK2879552 
• 
AEs, SAEs, dose limiting toxicities, dose reductions or 
delays, withdrawals due to toxicities and changes in 
safety assessments (e.g., laboratory parameters, vital 
signs, physical examinations). 
• 
To characterize the population PK of 
GSK28795522. 
• 
Population PK parameters for GSK2879552 such as 
clearance (CL/F) and volume of distribution (V/F), and 
relevant covariates which may influence exposure (e.g., 
age, weight, or disease associated covariates). 
• 
To evaluate the relationship between 
GSK2879552 exposure and 
safety/efficacy/PD parameters. 
• 
Relationship between GSK2879552 exposure markers 
(e.g. dose, Cmin, Cmax or AUC (0-tau)), and ProGRP, 
platelet levels in blood, and safety/efficacy parameters. 
• 
To evaluate duration of response and 
progression free survival (PFS) 
• 
Duration of response and PFS 
• 
To evaluate objective response rate 
(ORR) 
• 
% of subjects achieving response and partial response 
Exploratory Objectives 
Exploratory Endpoints 
• 
To assess feasibility of a select gene 
panel for use as a PD assay for 
GSK2879552 
• 
Change from baseline expression in select genes in 
whole blood 
• 
To investigate the impact of 
GSK2879552 on the RNA expression 
profile in blood to identify 
mechanisms of rational combination 
and potential resistance. 
• 
Transcriptomic (RNA) profile of whole blood pre- and 
post-treatment with GSK2879552. 
• 
To investigate relationship between 
tumor baseline genomic profile and 
response or resistance to 
GSK2879552 
• 
Tumor DNA, RNA and protein markers at baseline. 
• 
To discover circulating response and 
resistance biomarkers 
• 
Circulating biomarkers (e.g. cfDNA, protein and RNA). 
• 
To investigate the impact of 
GSK2879552 on fetal haemoglobin 
• 
Pre- and post-treatment fetal haemoglobin levels 


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2.3. 
Study Design 
 
Overview of Study Design and Key Features 
Design 
Features 
Part 1 
Dose Escalation Phase 
• 
In Cohort 1, a single subject will receive a dose of GSK2879552 0.25 mg once daily. 
The subject in Cohort 1 must complete a full 28 days of dosing, and the safety and PK 
data will be reviewed prior to starting Cohort 2. If the first subject becomes inevaluable 
for reasons other than toxicity, another subject will be recruited. The dose-escalation 
decision and rationale will be documented in writing with copies maintained at each 
study site and in the master study files at GlaxoSmithKline (GSK). 
• 
Starting with Cohort 2 the dose escalation will continue using the Neuenschwander - 
continuous reassessment method (N-CRM) [Neuenschwander, 2008]. A sufficient 
number of subjects will be enrolled in each cohort to ensure that data from at least 
one subject that has completed the first 28 days of dosing is available prior to defining 
a new dose and starting the next cohort. In addition, subjects who fail to take at least 
75% of their scheduled doses in the first 28 days for reasons other than toxicity (e.g., 
dose limiting toxicities) will be replaced. 
• 
Upon review of the safety, tolerability, clinical activity, PK, PD data, the RP2D or 
doses will be selected. 
PK/PD Expansion Cohort 
• 
Any dose level(s) in Part 1 may be expanded up to 12 subjects in order to collect 
adequate data on safety, PK or PD. Pre-dose and post-dose tumor biopsies may be 
required from a subset of subjects in PK/PD expansion cohorts. A minimum of five 
pairs of evaluable pre- and post-dose biopsies may be collected at selected doses 
based on emerging PK/PD data. 


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Overview of Study Design and Key Features 
• 
Subjects may be enrolled at previously completed dose levels for the purpose of 
obtaining additional PK or PD data. A reduced PK schedule may be used in subjects 
enrolled to obtain additional PD samples. These subjects may have the dose 
escalated to a higher completed dose level (not exceeding the maximum tolerated 
dose [MTD]) once the necessary PK/PD procedures have been completed. 
Part 2 
Expansion Cohort 
• 
Once the RP2D has been determined, a minimum of 10 and a maximum of 30 
subjects will be enrolled at the RP2D, assuming futility criteria, as defined below, are 
not met. 
• 
Definition of Clinical Benefit – Stopping Guidelines 
• 
Clinical benefit will be defined as objective response rate (ORR) (CR + PR) based 
on RECIST 1.1. The null hypothesis is: 
o H0: RR ≤10% 
• 
The alternative hypothesis is: 
o HA:RR ≥25% 
• 
After 10 subjects have been enrolled to examine safety and efficacy, the number of 
observed unconfirmed objective responses will guide further enrolment. In order to 
stop for futility as quickly as possible as long as there is no sign of efficacy, the 
responses don’t need to be confirmed. A maximum of 30 subjects will be enrolled in 
Part 2 expansion cohort. All available data will be considered in making enrollment 
decisions. The futility boundaries (inclusive) for subjects having clinical benefit are 
0/10, 1/17, 2/22, 3/27, and 4/30 subjects. 
Dosing 
• 
In Part 1, in Cohort 1, a single subject will receive a dose of GSK2879552 0.25 mg 
once daily. The subject in Cohort 1 must complete a full 28 days of dosing, and the 
safety and PK data will be reviewed prior to starting Cohort 2. 
• 
Starting with Cohort 2 the dose escalation will continue using the Neuenschwander - 
continuous reassessment method (N-CRM). 
• 
Upon review of the safety, tolerability, clinical activity, PK, PD data, the RP2D 
or doses will be selected. 
• 
Subjects may be enrolled at previously completed dose levels for the purpose 
of obtaining additional PK or PD data. 
• 
In Part 2, once the RP2D has been determined, subjects will be enrolled at the 
RP2D and will be evaluated for safety and efficacy while monitoring the futility 
stopping rules. 
Time & 
Events 
• 
Refer to Protocol Amendment 4 Section 7.1 Time and Event Table(s) 
Treatment 
Assignment 
• 
This is a non-randomized open-label study. 
• 
RAMOS was used for treatment assignment. 
Interim 
Analysis 
• For dose escalation in Part 1, there is no interim analysis. 
• For Part 2, interim analysis of futility for each cohort will be conducted continually once 
a minimum number of subjects for futility analysis complete the response evaluation. 
These interim analyses will not be formal analyses, but will be used to support the 


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Overview of Study Design and Key Features 
decision of early termination of study MID200858. 
NOTES: 
 Due to the business decision of study termination, Part 2 was not implemented. As a result, the 
remainder of this document contains no content related to Part 2 and will only provide information 
related to Part 1.
 
2.4. 
Statistical Hypotheses 
 
No formal statistical hypotheses are being tested for the dose escalation in Part 1. 
Analysis of the data obtained from dose escalation of Part 1 will only utilize descriptive 
methods. 


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3. 
PLANNED ANALYSES 
As this is an open-label study, the treatment allocation (dose) is collected in the eCRF 
and this will be the treatment information used for interim and final analyses. 
 
3.1. 
Interim Analyses 
 
The study will not utilize an Independent Data Monitoring Committee (IDMC). 
 
3.1.1. 
Part 1: Dose Escalation Phase 
 
Review of preliminary safety and available pharmacokinetic data will be performed after 
completion of each dosing cohort in Part 1. Preliminary safety and study population data 
may include a demographic summary, AE summary, AE summary by maximum toxicity 
category, SAE listing, listing of AEs that are reported to be DLT’s, and listing of AEs 
leading to dose modification. Spreadsheets containing relevant study data will also be 
supplied by the study data manager. 
 
The GSK study team, in collaboration with study investigators, will review PK and safety 
data to support: 
 
• 
whether the current dose had acceptable toxicity, 
• 
the next dose level(s), and 
• 
whether the pharmacodynamic cohort should be opened to enrollment at the 
current dose 
 
3.2. 
Final Analyses 
 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
 
1. All subjects have either permanently discontinued study treatment or have been 
enrolled in the study at least 12 months (starting from Day 1) 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
4. 
ANALYSIS POPULATIONS 
 
Population 
Definition / Criteria 
Analyses Evaluated 
All Randomized Subjects 
All participants assigned a randomization number. 
Subject accountability, 
Subject Disposition 
All Treated Subjects 
All subjects who receive at least one dose of study 
treatment. 
Dose escalation cohort 
reviews, Efficacy, Safety 
PK 
All subjects in the All Treated Subjects Population 
for whom a PK sample is obtained and analyzed. 
Pharmacokinetic 
Pharmacodynamic 
All subjects in the All Treated Subjects Population 
and who contributed PD/Biomarker samples. 
Change from baseline 
levels of 
pharmacodynamic 


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Population 
Definition / Criteria 
Analyses Evaluated 
markers and tumor DNA, 
RNA, and protein, cell 
proliferation markers. 
NOTES: 
 Refer to Appendix 10: List of Data Displays which details the population used for each data display.
 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be listed. 
 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. 
 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the listing of protocol deviations. 


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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
 
Treatment Group Descriptions 
RandAll NG 
Data Displays for Reporting 
Code 
Description 
Description 
Order 
A 
GSK2879552 
0.25 mg Daily 
1 
0.5 mg Daily 
2 
1.0 mg Daily 
3 
1.5 mg Daily 
4 
2.0 mg Daily 
5 
3.0 mg Daily 
6 
3.0 mg 4 days on/3 days off 
7 
3.0 mg 4 days on/10 days off 
8 
4.0 mg 4 days on/10 days off 
9 
 
5.2. 
Baseline Definitions 
Baseline is defined as the most recent, non-missing value prior to or on the first study 
treatment dose date. For laboratory data, baseline values will be defined as the most 
recent, non-missing value from a central laboratory prior to or on the first dose of study 
treatment. 
 
For subjects who did not receive study treatment during the study, baseline will be 
defined as the latest, non-missing collected value. 
 
For ECG analyses, subject level baseline is defined as the mean of triplicate baseline 
assessments. 
 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
will be set to missing. 
 
The baseline definition will be footnoted on all change from baseline displays. 
 
 
5.3. 
Multicentre Studies 
 
Data from all participating centres will be pooled prior to analysis. The number of 
subjects by County and Centre will be summarized. 


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5.4. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
 
Section 
Component 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.5 
Appendix 5: Data Display Standards & Handling Conventions 
13.6 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.9 
Appendix 8: Values of Potential Clinical Importance 


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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
 
The study population analyses will be based on the All Treated Subjects population, 
unless otherwise specified. 
 
Study population analyses will be based on GSK Core Data Standards. Details of the 
planned displays are presented in Appendix 10: List of Data Displays. 
 
6.2. 
Disposition of Subjects 
 
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who withdrew from the study, 
including primary reasons for study withdrawal. Reasons for study withdrawal will be 
presented in the order they are displayed in the eCRF. A listing of reasons for treatment 
discontinuation will also be provided. 
 
6.3. 
Protocol Deviations 
 
Important protocol deviations will be listed and will include inclusion and exclusion 
deviations as well as other deviations. 
 
6.4. 
Demographic and Baseline Characteristics 
 
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and 
baseline body weight will be summarized and listed. Age, height and weight will be 
summarized using the mean, standard deviation, minimum, median, and maximum. In 
addition, age will also be categorized and summarized by <18, 18-64, 65-74, and >74. 
The count and percentage will be computed for sex and ethnicity. A separate summary of 
age ranges will be produced for study disclosure requirements. 
 
Race and racial combinations will be summarized. 
Current and past medical conditions will be summarized. 
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary. A listing of 
prior anti-cancer therapy will show ATC Level 1, Ingredient, and verbatim text. Prior 
anti-cancer therapy and prior cancer related surgeries will be listed. 
 
6.5. 
Concomitant Medications 
 
Concomitant medications will be coded using GSK Drug coding dictionary and 
summarized. The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients. Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body 
System) information will be included in the dataset created but will not appear on the 
summary. 


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In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions, 
the subject is counted only once under the ingredient “Amoxycillin”. 
 
In the summary of concomitant medications, the ingredients will be summarized by the 
base only, using CMBASECD and CMBASE. 
 
Blood products or blood supportive care products with onset date within the on-therapy 
window will be included in the summary tables. The frequency and percentage of 
subjects using blood products and blood supportive care products after the start of study 
medication will be provided. 


18 
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7. 
SAFETY ANALYSES 
The safety analyses will be based on the All Treated Subjects population, unless 
otherwise specified.  All summaries will be presented by dose level and overall. 
 
Study population analyses will be based on GSK Core Data Standards. Details of the 
planned displays are presented in Appendix 10: List of Data Displays. 
 
7.1. 
Extent of Exposure 
 
Extent of exposure to GSK2879552 will be summarized and listed by dose level. 
 
The duration of exposure to study treatment in weeks (from first day to last day of 
treatment) will be summarised. Descriptive statistics including mean, median, standard 
deviation, minimum, and maximum will be calculated for time on study treatment. 
 
The subject’s average daily dose, defined as the cumulative dose divided by the duration 
of exposure for each subject, will be summarized. 
 
Dose reductions will be summarized by number of reductions and reasons for reductions. 
Dose escalations will be summarized by number of escalations and reasons for escalation. 
Dose interruptions will be summarised by number of interruptions, reasons for the 
interruptions, and interruption duration (days). The mean, standard deviation, median, 
minimum value, and maximum value will be computed for the duration of interruptions 
as well as the number and percentage of the interruptions ≤7, 8-14, 15-21 and >21 days. 
 
All the dose reductions, dose escalations and dose interruptions will be listed separately. 
 
7.2. 
Adverse Events Analyses 
 
Adverse events analyses including the analysis of adverse events (AEs), serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. The details 
of the planned displays are provided in Appendix 10: List of Data Displays. 
 
AEs will be graded according to the CTCAE, Version 4.0. Adverse events will be coded 
to the PT level using the MedDRA dictionary. The relationship of AE system organ, 
preferred term, and verbatim text will be listed. The subject numbers for individual AEs 
will be listed. 
 
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by System Organ Class (SOC) and Preferred 
term (PT) in descending order of total incidence. The summary will use the following 
algorithms for counting the subject: 
 ▪
Preferred term row: Subjects experiencing the same AE preferred term several 
▪ 
times with different grades will only be counted once with the maximum grade. 
Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 


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In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in descending order of total frequency. The common (>=5%) non-serious 
adverse events by system organ class and preferred term (number of participants and 
occurrences) will also be summarized. 
 
The relationship between MedDRA SOC, PT, and Verbatim Text will be listed. 
 
Summary tables will be provided for study treatment-related AEs. A study treatment- 
related AE is defined as an AE for which the investigator classifies the relationship to 
study treatment as “Yes”. A worst-case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. Two summary tables for treatment-related AEs will be 
provided: 
 
• Summary of treatment-related AE by maximum toxicity grade. For each toxicity 
grade, treatment-related AEs will be displayed in descending order of total 
incidence by PT only. 
 
• Summary of treatment-related AE by frequency. Treatment-related AEs will be 
displayed in descending order of total incidence by PT only. 
 
A listing of All AEs will be provided. 
 
Serious adverse events by system organ class and preferred term (number of participants 
and occurrences) will be summarized. All serious adverse events (SAEs) will be 
tabulated based on the number and percentage of subjects who experienced the event. 
The summary tables will be displayed in descending order of total incidence. 
 
Separate listings will be generated for all fatal SAEs and non-fatal SAEs. A listing will 
also be created for dose-limiting toxicities. 
 
7.3. 
Adverse Events of Special Interest 
 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each of the AESI. 
 
The events of special interest include: 
 ▪
▪ 
Encepalopathy 
▪ 
Thrombocytopenia 
▪ 
Hemorrhages 
▪ 
Diarrhea 
▪ 
Nausea & Vomiting 
▪ 
Constipation 
▪ 
Infections 
Neutropenia 


20 
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MID200858 
 
 
 ▪
▪ 
Fatigue 
Anemia 
Separate summaries of the number and percentage of subjects with each of these AESI 
will be provided by maximum grade.  The number and percentage of subjects with each 
of the preferred terms defining a given AESI will also be provided. The worst case 
approach will be applied at subject level for the event outcome and maximum grade, i.e. a 
subject will only be counted once as the worst case from all the events experienced by the 
subject. 
 
7.4. 
Clinical Laboratory Analyses 
 
Laboratory evaluations will be based on GSK Core Data Standards. The details of the 
planned displays are in Appendix 10: List of Data Displays. 
 
The assessment of laboratory toxicities will examine the following laboratory tests as 
specified in Table 2 below. 
 
Table 2 
Laboratory Tests 
 
Hematology 
Platelet count 
White blood cell (WBC) Count (absolute) 
Hemoglobin 
Automated WBC Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell (RBC) Indices (at screening and if Hemoglobin decrease ≥2 g/dL compared to baseline): 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin( MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Reticulocytes 
RBC 


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Clinical Chemistry 
Blood urea 
nitrogen 
Potassium 
Aspartate aminotransferase (AST) 
Total and Direct bilirubin1 
Creatinine 
Chloride 
Alanine aminotransferase (ALT) 
Glucose, random 
Total CO2 
Albumin 
Sodium 
Calcium2 
Alkaline phosphatase (ALP) 
Magnesium 
Phosphorus 
Lactate dehydrogenase (LDH) 
Fasting Lipid panel including fractionated serum cholesterol, triglycerides, total cholesterol, HDL and LDL 
Estimated glomerular filtration (Modification of Diet in Renal Disease) or 24 hr urine creatinine clearance3 
Beta-hCG pregnancy test for appropriate females (serum or urine) 
Coagulation 
Prothrombin time/International normalized ratio (PT/INR) 
Partial prothrombin time (PTT) 
Urinalysis 
Specific gravity 
pH – dipstick 
Glucose – dipstick 
Protein – dipstick 
Blood – dipstick 
Ketones – dipstick 
Microscopic examination required (if blood or protein by dipstick ≥1+) 
Urine total protein to creatinine ratio (UPC ratio) – (if protein by dipstick ≥2+) 
1. 
Bilirubin fractionation is required if total bilirubin >2x ULN 
2. 
For screening ionized calcium is acceptable 
3. 
The Modification of Diet in Renal Disease Equation will be used to determine an estimated glomerular filtration 
rate. 
 
Laboratory grades will be reported using the Common Terminology Criteria for Adverse 
Events (CTCAE v4.0). 
 
For hematology, RBC is not gradable by CTCAE v4.0. 
 
For clinical chemistry, BUN, LDH and estimated creatinine clearance are not gradable by 
CTCAE v4.0. For sodium, potassium, calcium, glucose, and magnesium there will be two 
bi-directional parameters (hyper and hypo) created and the tests will be graded by 
CTCAE v4.0 in both directions. 
 
For coagulation tests, INR and partial thromboplastin time are gradable by CTCAE v4.0 
but prothrombin time is not. 
 
For all laboratory results, displays for hematology, clinical chemistry, and liver function 
tests will be separately produced. 
 
Summaries of worst case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with a maximum post-baseline grade increasing from their 
baseline grade. Any increase in grade from baseline will be summarized along with any 
increase to a maximum grade of 3 and any increase to a maximum grade of 4. Missing 
baseline grade will be assumed as grade 0. For laboratory tests that are graded for both 


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low and high values, summaries will be done separately and labeled by direction, e.g., 
sodium will be summarized as hyponatremia and hypernatremia. 
 
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized for the 
worst case post-baseline. If a subject has a decrease to low and an increase to high during 
the post-baseline time period, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories. 
 
A supporting listing of all chemistry and haematology laboratory data will be provided. 
Detailed derivation of baseline assessment is specified in Section 5.2. 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
 
7.4.1. 
Liver Function Analyses 
 
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. 
 
Possible Hy’s law cases are defined as any elevated (ALT>3×ULN and total bilirubin 
≥2×ULN (with direct bilirubin 35% of total bilirubin, if direct bilirubin is measured)) 
OR (ALT ≥3 times ULN and INR >1.5, if INR is measured). Note that INR 
measurement is not required and the threshold value stated will not apply to patients 
receiving anticoagulants. 
 
7.5. 
Other Safety Analyses 
 
The analyses of non-laboratory safety assessment results will be based on GSK Core 
Data Standards, unless otherwise specified. The details of the planned displays are 
presented in Appendix 10: List of Data Displays. 
 
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit. 
 
ECG 
 
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst case post-baseline. The summaries for the QTc 
will use the collected value based on Bazett’s formula (QTcB). 
 
The QTcB values will be rounded to the integer and the values will be categorized into 
the following ranges: Grade 0 (<450), Grade 1 (450-480), Grade 2 (481-500), and Grade 
3 (≥501). Summaries of grades will display the number and percentage of subjects by 


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grade at each scheduled assessment time and in the worst case post-baseline. Similarly, 
grade changes relative to baseline grade will also be generated. 
 
Listings of abnormal ECG findings and a listing of ECG values will be provided. 
 
Vital Signs 
 
Vital Signs will be listed. 
 
Left Ventricular Ejection Fraction 
 
A listing of the left ventricular ejection fraction results will be generated. 
 
ECOG Performance Status 
 
A summary of change from baseline in ECOG performance status by scheduled visits 
will be performed. Summaries will use frequency and percentage of subjects at each 
planned assessment time. 
 
A supporting listing will also be provided. 
 
Montreal Cognitive Assessment (MOCA) 
 
A listing of the Montreal Cognitive Assessment will be generated. 


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8. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the All Treated Subjects population unless 
otherwise specified. All analyses will be presented by dose of study treatment. Details of 
the planned displays are provided in Appendix 10: List of Data Displays. 
 
Efficacy assessments are based on RECIST 1.1 criteria to assess clinical activity and 
disease status for all subjects and also on the modified RECIST criteria. The 
investigator-assessed best response with confirmation will be summarized by dose of 
study treatment. 
 
Subjects with Not Evaluable (NE) or missing response will be treated as non-responders; 
i.e. they will be included in the denominator when calculating the percentage. 
 
The investigator assessment of target lesion and non-target lesion will be listed, 
separately. A listing of investigator-assessed confirmed tumor response and baseline 
target lesions previously irradiated will be provided. Also, a listing of subject 
accountability and best response (with and without confirmation) will be generated. 


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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
 
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK. 
 
The results of the pharmacokinetic analysis may be provided in a report separate from the 
main CSR. 
 
9.1.1. 
Endpoint / Variables 
 
9.1.1.1. 
Drug Concentration Measures 
 
The GSK2879552 concentration-time data will be summarized by planned time point and 
dose cohort. Standard summary statistics will be calculated (i.e. mean, standard deviation, 
median, minimum and maximum). 
 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic) 
 
9.1.1.2. 
Derived Pharmacokinetic Parameters 
 
Pharmacokinetic analysis of GSK2879552 in Part 1 will be conducted by 
noncompartmental methods using WinNonlin (Version 6.3 or higher). The following 
pharmacokinetic parameters will be determined if data permit: 
 
• maximum observed plasma concentration (Cmax) 
• time to Cmax (tmax) 
• area under the plasma concentration-time curve (AUC[0-t] and/or AUC[0-∞]) after 
single dose and AUC(0-t) and AUC(0-τ) after repeated administration 
• apparent terminal phase elimination rate constant (λz) 
• apparent terminal phase half-life (t½) 
 
Trough concentration (Cτ) samples collected on the specified days. To estimate the extent 
of accumulation after repeat dosing, the observed accumulation ratio (Ro) may be 
determined from the ratio of AUC(0-τ) in Day 15/ AUC(0-τ) in Day 1. The ratio of 
AUC(0-τ) on Day 15/ Day 1 AUC(0-∞) will be calculated to assess time invariance. 
 
GSK2879552 concentrations may be determined in urine samples to determine urinary 
recovery of unchanged drug and renal clearance. 
 
9.1.2. 
Population of Interest 
 
All pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified. 


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9.1.3. 
Statistical Analyses / Methods 
 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
 
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics and listed. 
 
GSK2879552 concentration-time data will be listed for each subject and summarized by 
planned time point and dose cohort. 
 
Pharmacokinetic parameters will be listed and summarized descriptively (mean, standard 
deviation, median, minimum, maximum, geometric mean, and the standard deviation, 
CV% and 95% confidence interval (CI) of log-transformed parameters) by dose cohort. 
 
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
 
9.1.3.1. 
Dose proportionality 
 
If data permits, dose proportionality will be assessed using power model for: 
 
• AUC(0-∞) and Cmax on Day 1 
• AUC(0-τ) and Cmax on Day 15 
Dose proportionality of GSK2879552 AUC(0-∞) and Cmax following single dose 
administration and AUC(0-) and Cmax following repeat dose administration will be 
evaluated 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. 
 
Only dose cohorts with repeat daily dosing will be analysed (i.e. 0.25 mg – 3.0 mg daily 
dose cohorts). 


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9.1.3.2. 
Accumulation 
 
If data permits, accumulation using ANOVA will be performed for AUC(0-τ) on Day 15 
vs AUC(0-τ) on Day 1 by dose cohort.  Only dose cohorts with repeat daily dosing will 
be analysed (i.e. 0.25 mg – 3.0 mg daily dose cohorts). 
 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) based on AUC data will be determined as follows: 
 
Ro = AUC(0-)D15/ AUC(0-)D1 
 
Assuming both linear and time-invariant pharmacokinetics, the Ro at steady-state should 
be unity. 
 
An ANOVA with a random effect term for subject and fixed effect terms for day will be 
performed by dose on the loge-transformed PK parameters AUC(0-τ). Day will be 
treated as a class variable in the model. The accumulation ratio of GSK2879552 will be 
estimated by calculating the ratio of the geometric least squares (GLS) means of the PK 
parameter between Day 15 and Day 1 for all dose levels and the corresponding 90% CI 
for each ratio. 
 
The accumulation ratio will be summarized by dose. 
 
9.1.3.3. 
Time Invariance 
 
To evaluate whether the pharmacokinetics remains unaltered after repeat dosing a similar 
analysis to that described above will be carried out after loge-transformation of AUC(0- 
∞) for D1 and AUC(0-τ) for D15, the difference of which provides the steady-state ratio 
(Rs). 
 
A mixed effect model will be fitted with day as a fixed effect and subject as a random 
effect for each treatment (dose) separately. AUC(0-τ) on D15 will be compared to 
AUC(0-∞) on D1 in order to assess time invariance for each dose. The Kenward & Roger 
(KR) degrees of freedom approach will be used. The ratio and 90% confidence interval 
will be calculated by back-transforming the difference between the least square means for 
the two days and associated 90% confidence interval, for each dose. Assuming both 
linear and time-invariant pharmacokinetics, the Rs at steady-state should be one. 
 
The time invariance ratio will be summarized by dose. 
 
Only dose cohorts with repeat daily dosing will be analysed (i.e. 0.25 mg – 3.0 mg daily 
dose cohorts). 


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10. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
10.1. 
Pharmacodynamic Analyses 
 
As LSD1 inhibition results in a blockage of platelet maturation, platelet count changes 
can be viewed as a PD effect. From the time course of platelet, the platelet nadir and time 
to nadir will be computed for each subject. This analysis will only take into account the 
platelet data observed at the initial dose level and during the first 60 days on treatment. 
The platelet nadir will also be expressed as percent change from baseline platelet count. 
 
Pharmacodynamic parameters will be listed and summarized descriptively (mean, 
standard deviation, median, minimum, maximum, geometric mean, and the standard 
deviation, CV% and 95% confidence interval (CI) of log-transformed parameters) by 
dose cohort. 
 
If a subject has received the planned doses for at least 7 days out of first 10 days on 
study, this subject will be included in the descriptive statistics summary. Otherwise the 
subject will not be included. 
 
10.2. 
Biomarker Analyses 
 
If this data is analysed, it will be summarized in a separate report. 


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11. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
The primary goal of this analysis is to characterize the pharmacokinetic / 
pharmacodynamic relationship of GSK2879552 administered orally in participants with 
SCLC. 
11.1. 
Statistical Analyses / Methods 
 
Quantitative safety parameters and biomarkers of interest, as available, will be plotted 
graphically against summary exposure measures (e.g.; Cmax, AUC obtained on Day 1) as 
well as against dose. Only dose cohorts with repeat daily dosing will be included in the 
analysis of platelet as a PD effect (i.e. 0.25 mg – 3.0 mg daily dose cohorts). Where 
evidence of a signal is seen, linear and/or non-linear mixed effect models will be fitted to 
the data to estimate PK/PD parameters of interest; e.g. slope, baseline (E0), or exposure 
producing 50% of the maximum effect (EC50), and maximum effect (Emax). 


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12. 
REFERENCES 
GUI_137354 (2.0): Information for Authors: Reporting and Analysis Plans 
GUI_51487: Non-compartmental Analysis of Pharmacokinetic Data, CPMS Global 
Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics 53, 983-997. 
 
SOP_54838 (6.0): Development, Review and Approval of Reporting and Analysis Plans 


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13. 
APPENDICES 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
 
13.1.1. 
Exclusions from Per Protocol Population 
 
There will be no Per Protocol population used for any displays or statistical analysis. 


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13.2. 
Appendix 2: Schedule of Activities 
 
13.2.1. 
Protocol Defined Schedule of Events 
 
Refer to Protocol Amendment 4 Section 7.1. 


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13.3. 
Appendix 3: Assessment Windows 
 
No assessment windows will be applied. 


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13.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
 
13.4.1. 
Study Time Periods 
 
Assessments and events will be classified according to the time of occurrence relative to 
treatment start date. 
 
Study Phase 
Definition 
Pre-Treatment 
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date 
Post-Treatment 
Date > Study Treatment Stop Date 
 
Some datasets include the first dosing day as On-Treatment and some exclude the first 
dosing date as On-Treatment. The first dosing day (Day 1) is considered Pre-Treatment 
for ECOG, ECG, vital signs, liver events, lab tests, cardiac scan, and other safety 
domains. The first dosing day (Day 1) is considered to be On-Treatment for adverse 
events and concomitant medications. 
 
13.4.1.1. 
Study Phases for Concomitant Medication 
 
Study Phase 
Definition 
Prior 
If medication end date is not missing and is before 28 days prior to screening visit 
Concomitant 
Any medication that is not a prior 
NOTES: 
• 
Refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 


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13.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
 
13.5.1. 
Reporting Process 
 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: Compound: GSK2879552, Study:200858 
Analysis Datasets 
• 
Analysis datasets will be created according to Legacy GSK A&R dataset standards 
Generation of RTF Files 
• 
RTF files will be generated for SAC. 
13.5.2. 
Reporting Standards 
 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings: 
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings. 
• 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses. 
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables. 
• 
Unscheduled visits will be included in figures. 
• 
All unscheduled visits will be included in listings. 


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Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
13.5.3. 
Reporting Standards for Pharmacokinetic 
 
Pharmacokinetic Concentration Data 
PC Windows Non- 
Linear (WNL) File 
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
[Insert document name]. 
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
Yes, refer to GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to GUI_51487 


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13.6. 
Appendix 6: Derived and Transformed Data 
 
13.6.1. 
General 
 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing 
→ Study Day = Missing 
• 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
• 
Ref Date≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1 
 
13.6.2. 
Study Population 
 
Extent of Exposure 
• 
Number of days of exposure to study drug will be calculated based on the formula: 
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• 
Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 


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13.7. 
Appendix 7: Reporting Standards for Missing Data 
 
13.7.1. 
Premature Withdrawals 
 
Element 
Reporting Detail 
General 
• 
A subject will be considered to have completed the study if they complete screening 
assessments, at least 28 days of study treatment(s) and the post-treatment follow-up 
visit. 
• 
If subjects which prematurely discontinue, additional subjects may be enrolled as 
replacement subjects at the discretion of the Sponsor in consultation with the 
investigator. 
• 
Subjects who fail to take at least 75% of their scheduled doses in the first 28 days for 
reasons other than toxicity (e.g., dose limiting toxicities) will be replaced 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
• 
Withdrawal visits will be summarised as withdrawal visits. 
13.7.2. 
Handling of Missing Data 
 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
 
13.7.2.1. 
Handling of Missing and Partial Dates 
 
Imputed partial dates will not be used to derive study day, duration (e.g. duration of 
adverse events), or elapsed time variables. 
 
With the exception of exposure end date on the Exposure analysis dataset, imputed dates 
will not be stored on datasets. 
 
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. In addition, partial dates may be imputed for ‘slotting’ data to study time periods or 
for specific analysis purposes as outlined below. 
 
Dataset Date Missing 
Element 
Rule 
Adverse 
Events 
(AE) 
Start 
Date 
day, 
month, 
and year 
• No Imputation for completely missing dates 


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Dataset Date Missing 
Element 
Rule 
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 
 
Anti-Cancer Therapy and Radiotherapy: 
 
Start and end dates are generally not imputed. If start or end dates need to be imputed for 
an analysis (e.g., to calculate duration), the rules for imputation will be defined within the 
algorithm of the derived covariate. Additionally, post treatment anti-cancer therapy and 
radiotherapy start dates may be imputed to determine date of new anti-cancer therapy. In 
this case only, the date of new anti-cancer therapy (not all anti-cancer therapy and 
radiotherapy start dates) will be stored on appropriate efficacy datasets. Imputed partial 
dates will not be used to derive time since most recent prior therapy. In addition, the 
cancer therapy treatment status variable, and not any variables that use imputed partial 
dates, will be used to differentiate prior and follow-up anti-cancer therapy and 
radiotherapy. 
 
Dataset 
Date 
Missing 
Element 
Rule 
Anti-Cancer 
Therapy 
Start 
Date 
day, 
month, 
• 
No Imputation for completely missing dates 


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Dataset 
Date 
Missing 
Element 
Rule 
Radiotherapy 
and year 
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. 
End 
Date 
• 
No imputation for partial end dates will be 
performed 
 
Surgery: 
 
The date of surgery or procedure is generally not imputed. If the date of surgery or 
procedure needs to be imputed for an analysis (e.g., to calculate duration or elapsed time 
as covariates for efficacy analyses), the rules for imputation will be defined within the 
algorithm of the derived covariate. Additionally, post treatment surgery or procedure 
dates maybe imputed (where applicable) to determine date of new anti-cancer therapy. In 
this case only, the date of new anti-cancer therapy (not specific surgery or procedure 
date) will be stored on appropriate efficacy datasets. The category for surgical procedure 
variable, and not any variables that use imputed partial dates, will be used to differentiate 
prior, on, and follow-up surgical procedure data. The derived time in relation to treatment 
variables are not needed for reporting of data because the category for surgical procedure 
variable can be used. Therefore, imputed dates are not needed for derivation of time in 
relation to treatment. 
 
Dataset 
Missing 
Element 
Rule 
Surgical 
Procedures 
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 
 
 
Concomitant Medication and Blood and Blood Supportive Care Products: 
 
Start and end dates may be imputed for use in derivation of the reference variables 
concomitant medication start and end relative to treatment and blood and blood 
supportive care start and end relative to treatment, but should not be permanently stored 
in the analysis datasets. The reference variables will be used to differentiate before, 


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during and after for the concomitant medication or blood or blood supportive care start 
and end dates. The derived time in relation to treatment variables are not needed for 
reporting of these data. 
 
Dataset 
Date 
Missing 
Element 
Rule 
Concomitant 
Medication 
Blood and 
Blood 
Supportive 
Care 
Products 
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 
treat
▪
ment 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 
day, 
month, 
and year 
• 
No Imputation for completely missing dates 
day, 
• 
If partial end date contains year only, set end date 
= earliest of December 31 or date of last contact. 


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Dataset 
Date 
Missing 
Element 
Rule 
month 
day 
• 
If partial end date contains month and year, set 
end date = earliest of last day of the month or date 
of last contact (MSTONE.LCONTDT). 
Overall Response Rate and Duration of Response: 
 
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be temporarily imputed in order to define 
overall response rate or duration of response (i.e. start date for new anti-cancer therapy). 
Dates will only be imputed when a month and year are available but the day is missing. 
The imputed date(s) will not be stored on the anti-cancer therapy, radiotherapy, or 
surgical procedure datasets. The following rules will be used to impute the date when 
partial start dates are present on anti-cancer therapy radiotherapy, and/or surgical 
procedures datasets: 
 
Dataset 
Date 
Missing 
Element 
Rule 
Anti-Cancer 
Start 
day, month, 
• 
No Imputation for completely missing dates 
Therapy 
Date 
and year 
Where 
applicable: 
Radiotherapy 
Surgical 
Procedures 
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 


43 
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MID200858 
 
 
 
Dataset 
Date 
Missing 
Element 
Rule 
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 anti-cancer therapy is derived as the earliest date of new anti-cancer 
therapy (e.g., chemotherapy), radiotherapy (where applicable), or cancer related surgical 
procedure (where applicable) and will include imputed dates. 
 
13.8. 
Imputation of Missing Exposure End Dates 
 
For subjects who have missing end dates in their last exposure record potentially due to 
being lost to follow-up, the last contact date will be imputed as the last exposure date (i.e. 
date of last dose).  This imputation will only be used when needed, e.g. TBD. 


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13.9. 
Appendix 8: Values of Potential Clinical Importance 
 
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. 
 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to 
assign grades to the relevant laboratory parameters. 


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13.10. 
Appendix 9: Abbreviations & Trade Marks 
 
13.10.1. 
Abbreviations 
 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
AUC(0-) 
Area under the concentration-time curve from time zero (pre-dose) extrapolated 
to infinite time 
AUC(0-t) 
Area under the concentration-time curve from time zero (pre-dose) to last time 
of quantifiable concentration within a subject across all treatments 
AUC(0-) 
Area under the concentration-time curve over the dosing interval 
A&R 
Analysis and Reporting 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CR 
Complete response 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
C1D1 
Cycle 1 Day 1 
C1D15 
Cycle 1 Day 15 
DBF 
Database Freeze 
DBR 
Database Release 
DLBCL 
Diffuse Large B Cell Lymphoma 
DLT 
Dose-limiting toxicity 
DOB 
Date of Birth 
DP 
Decimal Places 
ECG(s) 
Electrocardiogram(s) 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
EZH2 
Enhancer of Zeste Homolog 2 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GCB 
Germinal Center B-cell like 
GCB-DLBCL 
Germinal Center B-cell-like Diffuse Large B-cell Lymphoma 
GSK 
GlaxoSmithKline 


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Abbreviation 
Description 
H3K27me3 
Tri-methylated Histone H3 lysine 27 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
INR 
International normalization ratio 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MM 
Multiple Myeloma 
MMRM 
Mixed Model Repeated Measures 
msec 
Millisecond 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
NHL 
Non-Hodgkin’s Lymphoma 
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PopPK 
Population PK 
PP 
Per Protocol 
PR 
Partial response 
QC 
Quality Control 
QTc 
Corrected QT interval duration 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System 
RBC 
Red blood cells 
SAC 
Statistical Analysis Complete 
SAE 
Serious adverse event(s) 
SD 
Stable disease 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
t1/2 
Terminal phase half-life 
τ 
Dosing interval 
TA 
Therapeutic Area 
tFL 
Transformed Follicular Lymphoma 
TFL 
Tables, Figures & Listings 
tmax 
Time of occurrence of Cmax 
WBC 
White blood cells 


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Abbreviation 
Description 
WT 
Wild-type 
13.10.2. 
Trademarks 
 
Trademarks of the GlaxoSmithKline 
Group of Companies 
NONE 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
SAS 
WinNonlin 


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13.11. 
Appendix 10: List of Data Displays 
 
13.11.1. 
Data Display Numbering 
 
The following numbering will be applied for RAP generated displays: 
 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.7 
N/A 
Efficacy 
2.1 
N/A 
Safety 
3.1 to 3.32 
N/A 
Pharmacokinetic 
4.1 to 4.6 
N/A 
Pharmacodynamic 
5.1 
N/A 
PK/PD 
6.1 to 6.6 
6.1 to 6.6 
Section 
Listings 
ICH Listings 
1 to 29 
Other Listings 
30 to 35 
 
13.11.2. 
Mock Example Shell Referencing 
 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in a separate document. 
 
Section 
Figure 
Table 
Listing 
Pharmacokinetic 
N/A 
PK_T1 
PK_L1 
Pharmacodynamic 
N/A 
PD_T1 
PD_L1 
PKPD 
PKPD_F1 
PKPD_T1 
N/A 
 
13.11.3. 
Deliverables 
 
Delivery [Priority] [1] 
Description 
SAC [1] 
Final Statistical Analysis Complete 
NOTES: 
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


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49 
 
 
 
13.11.4. 
Study Population Tables 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
All Treated 
Subjects 
ES1 
Summary of Subject Disposition (Part 1) 
SAC [1] 
1.2. 
Enrolled 
NS1 
Summary of Number of Participant by Country and Site ID (Part 
1) 
SAC [1] 
Demographic and Baseline Characteristics 
1.3. 
All Treated 
Subjects 
DM1 
Summary of Demographic Characteristics (Part 1) 
SAC [1] 
1.4. 
Enrolled 
DM11 
Summary of Age Ranges (Part 1) 
SAC [1] 
1.5. 
All Treated 
Subjects 
DM5 
Summary of Race and Racial Combinations (Part 1) 
SAC [1] 
Medical History and Concomitant Medications 
1.6. 
All Treated 
Subjects 
MH1 
Summary of Current/Past Medical Conditions (Part 1) 
SAC [1] 
1.7. 
All Treated 
Subjects 
CM1 
Summary of Concomitant Medications (Part 1) 
SAC [1] 


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13.11.5. 
Efficacy Tables 
 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Clinical Response 
2.1. 
All Treated 
Subjects 
RE1a 
Summary of Independent Radiologist-Assessed and 
Investigator-Assessed Best Response With Confirmation 
(RECIST 1.1 Criteria) (Part 1) 
SAC [1] 
 
13.11.6. 
Safety Tables 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1. 
All Treated 
Subjects 
OEX5 
Summary of Exposure to GSK2879552 (Part 1) 
SAC [1] 
3.2. 
All Treated 
Subjects 
ODMOD1 
Summary of Dose Reductions (Part 1) 
SAC [1] 
3.3. 
All Treated 
Subjects 
ODMOD8 
Summary of Dose Escalations (Part 1) 
SAC [1] 
3.4. 
All Treated 
Subjects 
ODMOD2 
Summary of Dose Interruptions (Part 1) 
SAC [1] 
Adverse Events (AEs) 
3.5. 
All Treated 
Subjects 
OAE7 
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term (Part 1) 
SAC [1] 


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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
3.6. 
All Treated 
Subjects 
AE3 
Summary of All Adverse Events by Frequency (Part 1) 
SAC [1] 
3.7. 
All Treated 
Subjects 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participants and Occurrences) (Part 1) 
SAC [1] 
3.8. 
All Treated 
Subjects 
OAE7 
Summary of Encephalopathy Adverse Event of Special Interest 
by Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.9. 
All Treated 
Subjects 
OAE7 
Summary of Thrombocytopenia Adverse Event of Special 
Interest by Maximum Grade by System Organ Class and 
Preferred Term (Part 1) 
SAC [1] 
3.10. 
All Treated 
Subjects 
OAE7 
Summary of Hemorrhages Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.11. 
All Treated 
Subjects 
OAE7 
Summary of Diarrhea Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.12. 
All Treated 
Subjects 
OAE7 
Summary of Nausea & Vomiting Adverse Event of Special 
Interest by Maximum Grade by System Organ Class and 
Preferred Term (Part 1) 
SAC [1] 
3.13. 
All Treated 
Subjects 
OAE7 
Summary of Constipation Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.14. 
All Treated 
Subjects 
OAE7 
Summary of Infections Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 


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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
3.15. 
All Treated 
Subjects 
OAE7 
Summary of Neutropenia Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.16. 
All Treated 
Subjects 
OAE7 
Summary of Fatigue Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.17. 
All Treated 
Subjects 
OAE7 
Summary of Anemia Adverse Event of Special Interest by 
Maximum Grade by System Organ Class and Preferred Term 
(Part 1) 
SAC [1] 
3.18. 
All Treated 
Subjects 
OAE7 
Summary of Treatment-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term (Part 1) 
SAC [1] 
3.19. 
All Treated 
Subjects 
AE3 
Summary of Treatment-Related Adverse Events by Frequency 
(Part 1) 
SAC [1] 
Serious and Other Significant Adverse Events 
3.20. 
All Treated 
Subjects 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
(Part 1) 
SAC [1] 
3.21. 
All Treated 
Subjects 
AE3 
Summary of Serious Adverse Events by Frequency (Part 1) 
SAC [1] 
Laboratory: Chemistry 
3.22. 
All Treated 
Subjects 
OLB9C 
Summary of Clinical Chemistry Toxicity Grade Change from 
Baseline Grade (Part 1) 
For gradable Clinical chemistry tests. 
By dose, and overall. Include Worst- 
case. 
SAC [1] 
3.23. 
All Treated 
Subjects 
OLB11B 
Summary of Clinical Chemistry Laboratory Changes from 
Baseline With Respect to the Normal Range (Part 1) (Part 1) 
For non-gradable lab tests. By dose, 
and overall. 
SAC [1] 


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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hematology 
3.24. 
All Treated 
Subjects 
OLB9C 
Summary of Haematology Toxicity Grade Change from Baseline 
Grade (Part 1) 
For gradable Haematology tests. By 
dose, and overall.  Include Worst-case. 
SAC [1] 
3.25. 
All Treated 
Subjects 
OLB11B 
Summary of Clinical Chemistry Laboratory Changes from 
Baseline With Respect to the Normal Range (Part 1) 
For non-gradable lab tests. By dose, 
and overall. 
SAC [1] 
Laboratory: Hepatobiliary (Liver) 
3.26. 
All Treated 
Subjects 
OLB9C 
Summary of Clinical Liver Function Test Toxicity Grade Change 
from Baseline Grade (Part 1) 
For gradable Clinical chemistry tests. 
By dose, and overall. Include Worst- 
case. 
SAC [1] 
3.27. 
All Treated 
Subjects 
OLB11B 
Summary of Clinical Liver Function Test Laboratory Changes 
from Baseline With Respect to the Normal Range (Part 1) 
For non-gradable lab tests. By dose, 
and overall. 
SAC [1] 
3.28. 
All Treated 
Subjects 
OLIVER10 
Summary of Hepatobiliary Laboratory Abnormalities (Part 1) 
SAC [1] 
ECG 
3.29. 
All Treated 
Subjects 
EG1 
Summary of ECG Findings (Part 1) 
SAC [1] 
3.30. 
All Treated 
Subjects 
EG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category (Part 1) 
SAC [1] 
3.31. 
All Treated 
Subjects 
EG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category (Part 1) 
SAC [1] 
ECOG 
3.32. 
All Treated 
Subjects 
PS4A 
Summary of Change in ECOG 'Performance Status' from 
Baseline (Part 1) 
SAC [1] 


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13.11.7. 
Pharmacokinetic Tables 
 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
4.1. 
PK 
PK01 
Summary of GSK2879552 Plasma Pharmacokinetic 
Concentration-Time Data (Part 1) 
SAC [1] 
4.2. 
PK 
PK06 
Summary of Derived GSK2879552 Plasma Pharmacokinetic 
Parameters (non-transformed and log-transformed) (Part 1) 
SAC [1] 
4.3. 
PK 
PK_T1 
Summary of Statistical Analysis to Assess the Dose 
Proportionality for AUC(0-∞) and Cmax Using Power Model – 
Day 1 (Part 1) 
SAC [1] 
4.4. 
PK 
PK_T1 
Summary of Statistical Analysis to Assess the Dose 
Proportionality for AUC(0-) and Cmax Using Power Model – 
Day 15 (Part 1) 
SAC [1] 
4.5. 
PK 
PK_T2 
Summary of Statistical Analysis to Assess the Accumulation for 
AUC(0-) on Day 15 vs AUC(0-) on Day 1 by Dose (Part 1) 
SAC [1] 
4.6. 
PK 
PK_T2 
Summary of Statistical Analysis to Assess the Time Invariance 
based on AUC(0-∞) on D1 and AUC(0-) on Day 15 by Dose 
(Part 1) 
SAC [1] 


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13.11.8. 
Pharmacodynamic Tables 
 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
5.1. 
All Treated 
Subjects 
PD_01 
Summary of Platelet Nadir by Dose (Part 1) 
SAC [1] 


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13.11.9. 
PK/PD Tables 
 
PD/PD: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
6.1. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir and Dose (Part 1) 
SAC [1] 
6.2. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir as Percent Change from Baseline and 
Dose (Part 1) 
SAC [1] 
6.3. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir and D1 Cmax (Part 1) 
SAC [1] 
6.4. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir as Percent Change from Baseline and 
D1 Cmax (Part 1) 
SAC [1] 
6.5. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir and D1 AUC(0-inf) (Part 1) 
SAC [1] 
6.6. 
PD 
PKPD_T1 
Summary of Emax model parameters describing the relationship 
between Platelet Nadir as Percent Change from Baseline and 
D1 AUC(0-inf) (Part 1) 
SAC [1] 


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13.11.10. PK/PD Figures 
 
PK/PD: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
6.1. 
PD 
PKPD_F1 
Relationship between Platelet Nadir and Dose (Individual Data 
and Emax model)  (Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 
6.2. 
PD 
PKPD_F1 
Relationship between Platelet Nadir as Percent Change from 
Baseline  and Dose (Individual Data and Emax model)  (Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 
6.3. 
PD 
PKPD_F1 
Relationship between Platelet Nadir and Day 1 Cmax (Individual 
Data and Emax model)  (Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 
6.4. 
PD 
PKPD_F1 
Relationship between Platelet Nadir as Percent Change from 
Baseline and Day 1 Cmax (Individual Data and Emax model) 
(Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 
6.5. 
PD 
PKPD_F1 
Relationship between Platelet Nadir and Day 1 AUC(0-inf) 
(Individual Data and Emax model)  (Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 
6.6. 
PD 
PKPD_F1 
Relationship between Platelet Nadir as Percent Change from 
Baseline and Day 1 AUC(0-inf) (Individual Data and Emax 
model)  (Part 1) 
S&P to provide dataset to CPMS, 
who will then be able to produce 
these plots 
SAC [1] 


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13.11.11. ICH Listings 
 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Study Population 
1. 
All Treated 
Subjects 
SD2 
Listing of Study Treatment Discontinuation (Part 1) 
SAC [1] 
2. 
All Treated 
Subjects 
DV2 
Listing of Important Protocol Deviations (Part 1) 
SAC [1] 
3. 
All Treated 
Subjects 
DM2 
Listing of Demographic Characteristics (Part 1) 
SAC [1] 
Safety 
4. 
All Treated 
Subjects 
OEX8b 
Listing of Exposure to Study Treatment (Part 1) 
SAC [1] 
5. 
All Treated 
Subjects 
ODMOD10A 
Listing of Dose Reductions (Part 1) 
SAC [1] 
6. 
All Treated 
Subjects 
ODMOD11A 
Listing of Dose Interruptions (Part 1) 
SAC [1] 
7. 
All Treated 
Subjects 
ODMOD15A 
Listing of Dose Escalations (Part 1) 
SAC [1] 
8. 
All Treated 
Subjects 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Part 1) 
SAC [1] 
9. 
All Treated 
Subjects 
OAE3 
Listing of Subject Numbers for Individual Adverse Events (Part 
1) 
SAC [1] 
10. 
All Treated 
Subjects 
OAE4 
Listing of All Adverse Events (Part 1) 
SAC [1] 


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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
11. 
All Treated 
Subjects 
OAE4 
Listing of Fatal Serious Adverse Events (Part 1) 
SAC [1] 
12. 
All Treated 
Subjects 
OAE4 
Listing of Non-Fatal Serious Adverse Events (Part 1) 
SAC [1] 
13. 
All Treated 
Subjects 
OAE4 
Listing of Dose-Limiting Toxicity (Part 1) 
SAC [1] 
14. 
All Treated 
Subjects 
OLB7 
Listing of Clinical Chemistry Laboratory Data (Part 1) 
SAC [1] 
15. 
All Treated 
Subjects 
OLB7 
Listing of Haematology Laboratory Data (Part 1) 
SAC [1] 
16. 
All Treated 
Subjects 
EG3 
Listing of ECG Values (Part 1) 
SAC [1] 
17. 
All Treated 
Subjects 
EG5 
Listing of Abnormal ECG Findings (Part 1) 
SAC [1] 
18. 
All Treated 
Subjects 
VS4 
Listing of Vital Signs (Part 1) 
SAC [1] 
19. 
All Treated 
Subjects 
OLVEF2A 
Listing of Left Ventricular Ejection Fraction Results (Part 1) 
SAC [1] 
20. 
All Treated 
Subjects 
PS5A 
Listing of ECOG Performance Status (Part 1) 
SAC [1] 
21. 
All Treated 
Subjects 
DM2 
Listing of Montreal Cognitive Assessment (MOCA) (Part 1) 
SAC [1] 
PK 
22. 
PK 
PK07 
Listing of GSK2879552 Plasma PK Concentration-Time Data 
(Part 1) 
SAC [1] 


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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
23. 
PK 
PK13 
Listing of GSK2879552 Plasma PK Parameters Data (Part 1) 
SAC [1] 
Efficacy 
24. 
All Treated 
Subjects 
LA2 
Listing of Investigator/Independent Radiologist/etc.-Assessed 
Target Lesion Assessments (RECIST 1.1 Criteria) (Part 1) 
SAC [1] 
25. 
All Treated 
Subjects 
LA3 
Listing of Investigator/Independent Radiologist/etc.-Assessed 
Non Target Lesion Assessments (RECIST 1.1 Criteria) (Part 1) 
SAC [1] 
26. 
All Treated 
Subjects 
RE5 
Listing of Investigator/Independent Radiologist/etc.-Assessed 
Tumour Responses with confirmation (RECIST1.1 Criteria) 
(Part 1) 
SAC [1] 
27. 
All Treated 
Subjects 
RE12 
Listing of Subject Accountability and Best Response (With and 
Without Confirmation)  (RECIST1.1 Criteria) (Part 1) 
SAC [1] 
28. 
All Treated 
Subjects 
LA2 
Listing of Investigator/Independent Radiologist/etc.-Assessed 
Lesion Assessments (RECIST 1.1 Criteria) (Part 1) 
SAC [1] 
29. 
All Treated 
Subjects 
LA6 
Listing of Investigator/Independent Radiologist/etc.-Assessed 
Baseline Target Lesions Previously Irradiated (RECIST 1.1 
Criteria) (Part 1) 
SAC [1] 


61 
CONFIDENTIAL 
MID200858 
 
 
 
13.11.12. Non-ICH Listings 
 
 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title 
Programming Notes 
Deliverable 
[Priority] 
Study Population 
30. 
All Treated 
Subjects 
AC6 
Listing of Prior Anti-Cancer Therapy (Part 1) 
SAC [1] 
31. 
All Treated 
Subjects 
OSP3 
Listing of Prior Anti-Cancer Surgical Procedures (Part 1) 
SAC [1] 
Safety 
32. 
All Treated 
Subjects 
SAFE_L1 
Listing of Echocardiogram Scan Results (Part 1) 
SAC [1] 
33. 
All Treated 
Subjects 
SAFE_L2 
Listing of Liver Function Tests for Subjects Meeting Potential 
Hy’s Law (Part 1) 
SAC [1] 
PD 
34. 
All Treated 
Subjects 
PD_L1 
Listing of Platelet PD Parameters 
SAC [1] 
Efficacy 
35. 
All Treated 
Subjects 
LA5 
Listing of Investigator-Assessed Lesion Assessments (Part 1) 
SAC [1]