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 Acute Myeloid Leukemia
Phase: PHASE1
Conditions: Leukaemia, Myelocytic, Acute
Sponsor: GlaxoSmithKline

2013N163643_05 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
200200 
 
1 
 
Division: Worldwide Development 
Information Type: Protocol Amendment 
Title: 
A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK2879552 given orally in subjects with 
relapsed/refractory acute myeloid leukemia 
Compound Number: GSK2879552 
Development Phase: 
I 
Effective Date: 
06-OCT-2017 
 
Protocol Amendment Number:  5 
Author (s):  
Cancer Research Epigenetics Management, USA 
Clinical Pharmacology, Science, Study Operations, USA  
Cancer Research Epigenetics Management, USA 
Clinical Pharmacology Modeling & Simulation, USA 
Biomarker discovery, Epigenetics DPU, USA 
Biology, Epigenetics DPU, USA 
Clinical Statistics, USA 
Biology, Epigenetics DPU, USA 
In Vitro/In Vivo Translation, USA 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
PPD

2013N163643_05 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
200200 
 
2 
 
Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2013N163643_00 
2014-MAY-02 
Original 
2013N163643_01 
2014-OCT-01 
Amendment No. 1 
DLT criteria are revised according to the regulatory agency request. PD sampling 
requirements and subject populations are also clarified. 
2013N163643_02 
2015-MAY-27 
Amendment No. 2 
Additional eligibility criteria and safety monitoring measures are put in place to address 
recent safety findings. 
2013N163643_03 
2016-MAY-09 
Amendment No. 3 
A combination arm with ATRA is added. One of the Dose Limiting Toxicities criteria 
has been revised according to the NCI criteria. Pharmacodynamic/exploratory sample 
collection and processing have been changed. Pharmacogenetic sample has been added. 
The criteria for Progressive Disease and Stable Disease have been added in the response 
criteria. Concomitant medications have been updated. 
2013N163643_04 
2017-MAY-02 
Amendment No. 4 
Add language to include a stopping rule that halts enrollment upon the occurrence of any 
encephalopathy, unless clearly attributable to central nervous system disease involvement 
or intercurrent illness.  
2013N163643_05 
2017-OCT-06 
Amendment No. 5 
Modify renal entrance criteria to align with regulatory agencies. Add additional dose 
adjustment language for hematologic toxicities. Optimize DLT criteria and safety 
management for retinoic acid syndrome. Add de-escalation language for both 
GSK2879552 and ATRA. Move PD secondary objective and endpoint to exploratory. 
Clarified definition of objective response rate (ORR). Included duration of response 
(DoR), time to response (TTR) and progression-free survival (PFS) as the secondary 
objectives in the expansion cohort. Updated statistical section to clarify data from Part 1 
and Part 2 may be combined for analyses if appropriate. Deleted “dose limiting toxicity” 
as the safety endpoint of expansion cohort.  Update and clarify inconsistencies within 
protocol: update dose escalation committee language to align with new standard 
language, define the “baseline” MOCA, baseline assessment of vitamin B12, TSH, free 
T3 or free T4 added at screening visit, define time window for informed consent, clarify 
urine metabolite and PK sample collections, add morphology to analysis of bone marrow 
aspirates, clarify use of azoles permitted on study and other administrative updates. 
 

PPD
PPD

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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 
 
Collegeville, PA 19426, USA 
Secondary 
Medical 
Monitor 
 
 MD, 
PhD 
GlaxoSmithKline 
1250 South Collegeville Rd 
Mailstop UP 4310 
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. 
Regulatory Agency Identifying Number(s): 
Compound Number 
IND Number 
GSK2879552 
121577 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol number 200200 
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 .................................................................................................... 26 
1.1. 
Background – LSD1 .................................................................................... 26 
1.2. 
Unmet Medical Needs for Relapsed/Refractory AML .................................. 26 
1.3. 
GSK2879552 .............................................................................................. 27 
1.3.1. 
GSK2879552 - Background ......................................................... 27 
1.3.2. 
LSD1 inhibitor and All-Trans Retinoic Acid ................................... 28 
1.3.3. 
Pre-Clinical PK and Safety of GSK2879552 ................................. 29 
1.3.4. 
Pharmacokinetics of GSK2879552 in Humans ............................ 30 
1.3.5. 
Clinical Safety of GSK2879552 .................................................... 31 
1.3.6. 
Combination Agent ...................................................................... 31 
1.3.6.1. 
All-Trans Retinoic Acid (ATRA)................................... 31 
1.4. 
Rationale .................................................................................................... 32 
1.4.1. 
Rationale for Study ...................................................................... 32 
1.4.1.1. 
Rationale for Combination with ATRA......................... 33 
1.4.2. 
Rationale for Population ............................................................... 34 
1.4.3. 
Rationale for Dose – GSK2879552 Monotherapy ........................ 34 
1.4.3.1. 
Predicted Effective Dose ............................................ 34 
1.4.3.2. 
Starting Dose .............................................................. 35 
1.4.4. 
Rationale for Dose – GSK2879552 and ATRA 
combination ................................................................................. 37 
1.4.4.1. 
Predicted Effective Dose ............................................ 37 
1.4.4.2. 
Starting Dose .............................................................. 37 
1.4.5. 
Benefit Risk Assessment ............................................................. 37 
1.4.5.1. 
Risk Assessment ........................................................ 38 
1.4.5.2. 
Benefit Assessment .................................................... 40 
1.4.5.3. 
Overall Risk Benefit Conclusion.................................. 40 
2. 
OBJECTIVES, ENDPOINTS AND HYPOTHESES ................................................. 41 
3. 
STUDY POPULATION ........................................................................................... 43 
3.1. 
Number of Subjects .................................................................................... 43 
3.2. 
Subject Selection Criteria ............................................................................ 43 
3.2.1. 
Inclusion Criteria .......................................................................... 43 
3.2.2. 
Exclusion Criteria ......................................................................... 45 
4. 
INVESTIGATIONAL PLAN ..................................................................................... 47 
4.1. 
Discussion of Study Design ........................................................................ 47 
4.2. 
Part 1: Dose-Escalation Phase ................................................................... 49 
4.2.1. 
GSK2879552 Mono-therapy ........................................................ 49 
4.2.2. 
GSK2879552 and ATRA combination .......................................... 53 
4.2.3. 
PK/PD Expansion Cohorts ........................................................... 55 
4.2.4. 
Alternative Dosing and PK/PD Sampling Schedules .................... 55 
4.2.5. 
Dose-Limiting Toxicity .................................................................. 56 

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4.2.6. 
Maximum Tolerated Dose and Recommended Phase 2 
Dose ............................................................................................ 56 
4.3. 
Part 2: Expansion Cohort ............................................................................ 56 
4.4. 
Intra-subject Dose-Escalation ..................................................................... 57 
4.5. 
Study Treatment ......................................................................................... 57 
4.5.1. 
Treatment Assignment ................................................................. 57 
4.6. 
Dosage and Administration of Study Treatment(s) ...................................... 57 
4.6.1. 
Meals and Dietary Restrictions .................................................... 57 
4.6.2. 
Blinding ........................................................................................ 58 
4.7. 
Safety Management Guidelines .................................................................. 58 
4.7.1. 
Liver Chemistry Stopping Criteria ................................................ 58 
4.7.1.1. 
Liver Chemistry Follow-up Procedures ....................... 58 
4.7.2. 
QTc Stopping Criteria .................................................................. 60 
4.7.3. 
Mental Status Stopping Criteria ................................................... 61 
4.8. 
Guidelines for Events of Special Interest and Dose Modifications ............... 62 
4.8.1. 
Events of Special Interest ............................................................ 62 
4.8.2. 
Dose Adjustment for Non-Hematologic Toxicity ........................... 62 
4.8.3. 
Dose Adjustment For Hematologic Toxicity .................................. 63 
4.8.4. 
Safety Management for ATRA Combination ................................ 64 
4.8.4.1. 
Retinoic Acid syndrome .............................................. 64 
4.8.4.2. 
Liver Function Test Elevation ..................................... 66 
4.8.4.3. 
Pseudotumor Cerebri (benign intracranial 
hypertension) .............................................................. 66 
5. 
INVESTIGATIONAL PRODUCT(S) ........................................................................ 66 
5.1. 
Description of Investigational Product(s) ..................................................... 66 
5.2. 
Preparation/Handling/Storage of Investigational Product ............................ 67 
5.3. 
Product Accountability ................................................................................ 68 
5.4. 
Treatment Compliance ................................................................................ 68 
5.5. 
Treatment of Investigational Product Overdose .......................................... 68 
6. 
COMPLETION OR WITHDRAWAL OF SUBJECTS ............................................... 69 
6.1. 
Screen and Baseline Failures ..................................................................... 69 
6.2. 
Subject Completion Criteria ........................................................................ 69 
6.3. 
Permanent Discontinuation from Study Treatment ...................................... 69 
6.4. 
Study Completion ....................................................................................... 71 
6.5. 
Treatment after the End of the Study .......................................................... 71 
7. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 71 
7.1. 
Time and Events Table(s) ........................................................................... 72 
7.2. 
Demographic/Medical History and Baseline Assessments .......................... 80 
7.2.1. 
Critical Baseline Assessments ..................................................... 80 
7.3. 
Safety Evaluations ...................................................................................... 81 
7.3.1. 
Physical Examinations ................................................................. 81 
7.3.2. 
ECOG Performance Status .......................................................... 81 
7.3.3. 
Montreal Cognitive Assessment ................................................... 81 
7.3.4. 
Vital Signs .................................................................................... 81 
7.3.5. 
Electrocardiogram ........................................................................ 82 
7.3.6. 
Echocardiogram and/or Multi-gated Acquisition Scans ................ 82 
7.3.7. 
Laboratory Assessments ............................................................. 82 
7.3.8. 
Pregnancy Testing and Reporting ................................................ 83 
7.4. 
Pharmacokinetics ....................................................................................... 84 

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7.4.1. 
Blood Sample Collection for Pharmacokinetics ............................ 84 
7.4.2. 
Urine Sample Collection for Pharmacokinetics ............................ 84 
7.4.3. 
Pharmacokinetic Sample Analysis ............................................... 84 
7.5. 
Pharmacodynamics .................................................................................... 85 
7.6. 
Translational Research ............................................................................... 85 
7.6.1. 
Tumor Biomarker Analysis ........................................................... 86 
7.6.2. 
RNA Expression Changes Pre and Post Treatment ..................... 86 
7.7. 
Evaluation of Anti-Cancer Activity ............................................................... 86 
7.8. 
Pharmacogenetics ...................................................................................... 86 
8. 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................... 87 
8.1. 
Definition of an AE ...................................................................................... 87 
8.2. 
Definition of an SAE .................................................................................... 88 
8.3. 
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs ....................................................................................... 89 
8.3.1. 
Cardiovascular Events ................................................................. 89 
8.4. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs ..................................................................................... 90 
8.5. 
Time Period and Frequency of Detecting AEs and SAEs ............................ 90 
8.5.1. 
Method of Detecting AEs and SAEs ............................................. 90 
8.5.2. 
Prompt Reporting of SAEs and Other Events to GSK .................. 91 
8.5.3. 
Regulatory reporting requirements for SAEs ................................ 91 
9. 
STUDY TREATMENT RESTART OR RECHALLENGE ......................................... 92 
9.1. 
Rechallenge Following Liver Event That Are Possibly Related To 
Study Treatment ......................................................................................... 92 
9.2. 
Restart Following Transient, Resolving Liver Events Not Related to 
Study Treatment ......................................................................................... 93 
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ......................... 94 
10.1. 
Permitted Medication(s) .............................................................................. 95 
10.2. 
Prohibited Medication(s) ............................................................................. 95 
10.2.1. 
Drugs that may alter the Pharmacokinetics of 
GSK2879552 ............................................................................... 95 
10.2.2. 
Drugs that may have their PK altered by GSK2879552 ................ 95 
10.3. 
Non-Drug Therapies ................................................................................... 96 
11. LIFESTYLE AND/OR DIETARY RESTRICTIONS .................................................. 96 
11.1. 
Contraception ............................................................................................. 96 
11.1.1. 
Female Subjects .......................................................................... 96 
11.1.2. 
Male Subjects .............................................................................. 97 
11.2. 
Caffeine, Alcohol and Tobacco Restrictions ................................................ 98 
12. DATA MANAGEMENT ........................................................................................... 98 
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 99 
13.1. 
Hypothesis(es) ............................................................................................ 99 
13.2. 
Part 1: Dose-Escalation Phase ................................................................... 99 
13.3. 
Part 2: Expansion Cohort ............................................................................ 99 
13.4. 
Sample Size Determination ........................................................................ 99 
13.4.1. 
Part 1: Dose-Escalation Phase .................................................... 99 
13.4.2. 
Part 2: Expansion Cohort ........................................................... 100 

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13.5. 
Sample Size Sensitivity ............................................................................. 102 
13.5.1. 
Sample Size Re-estimation ........................................................ 102 
13.6. 
Data Analysis Considerations ................................................................... 102 
13.6.1. 
Analysis Populations .................................................................. 102 
13.7. 
Interim Analysis ........................................................................................ 102 
13.7.1. 
Part 1: Dose-Escalation ............................................................. 102 
13.7.2. 
Part 2: Expansion Cohort ........................................................... 102 
13.8. 
Key Elements of Analysis Plan ................................................................. 103 
13.8.1. 
Anti-Cancer Activity Analyses .................................................... 103 
13.8.2. 
Safety Analyses ......................................................................... 104 
13.8.3. 
Pharmacokinetic Analyses ......................................................... 105 
13.8.3.1. Pharmacokinetic Parameters .................................... 105 
13.8.3.2. Statistical Analysis of Pharmacokinetic Data ............ 106 
13.8.4. 
Pharmacokinetic/Pharmacodynamic Analyses ........................... 106 
13.8.4.1. Translational Research Analyses ............................. 107 
13.8.4.2. Novel Biomarker(s) Analyses ................................... 107 
14. STUDY CONDUCT CONSIDERATIONS ............................................................. 107 
14.1. 
Posting of Information on Clinicaltrials.gov ................................................ 107 
14.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...................................................................................... 107 
14.3. 
Urgent Safety Measures ........................................................................... 108 
14.4. 
Quality Control (Study Monitoring) ............................................................ 108 
14.5. 
Quality Assurance ..................................................................................... 108 
14.6. 
Study and Site Closure ............................................................................. 109 
14.7. 
Records Retention .................................................................................... 109 
14.8. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................. 110 
15. REFERENCES ..................................................................................................... 111 
16. APPENDICES ...................................................................................................... 115 
16.1. 
Appendix 1: Simulation Results of N-CRM in Dose Escalation 
Phase ....................................................................................................... 115 
16.2. 
Appendix 2: NYHA Functional Classification System ................................ 116 
16.3. 
Appendix 3: CKD-EPI EQUATION ............................................................ 117 
16.4. 
Appendix 4: ECOG Performance Status1 .................................................. 118 
16.5. 
Appendix 5: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria ...................................................................................... 119 
16.6. 
Appendix 6: Response Criteria ................................................................. 122 
16.7. 
Appendix 7: Country Specific Requirements ............................................. 124 
16.8. 
Appendix 8: Montreal Cognitive Assessment ............................................ 125 
16.9. 
Appendix 9: Genetic Research ................................................................. 126 
16.10. Appendix 10: Protocol Amendment Changes ............................................ 129 
 

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LIST OF ABBREVIATIONS 
AE(s) 
Adverse Event(s) 
AML 
Acute Myeloid Leukemia 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate aminotransferase 
ATRA 
All-Trans Retinoic Acid 
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-τ) 
Area Under the Concentration-time curve over the dosing interval 
β-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  
CV 
Coefficient of Variance 
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 
FACTS 
 Fixed and Adaptive Clinical Trial Simulator  
FSH 
Follicle Stimulating Hormone 
FTIH 
First Time In Humans 

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GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate  
GGT 
Gamma Glutamyl Transferase 
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 
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 
MOCA 
Montreal Cognitive Assessment 
MPV 
Mean Platelet Volume 
MRI 
Magnetic Resonance Imaging  

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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 
PARP 
poly ADP ribose polymerase 
PCI 
Potential Clinical Importance 
PCR 
Polymerase Chain Reaction  
PD 
Progressive Disease or Pharmacodynamic 
PI 
Principal Investigator  
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time  
PTS 
Platform Technology and Science 
PTT 
Partial Thromboplastin Time  
QTc 
Corrected QT interval duration 
QTcF 
QT interval corrected for heart rate by Fridericia’s  formula 
RAP 
Reporting and Analysis Plan 
RBC 
Red Blood Cells 
RNA 
Ribonucleic acid 
Ro 
Accumulation ratio  
RP2D 
Recommended Phase 2 Dose 
SAE 
Serious Adverse Event(s) 
SCLC 
Small Cell Lung Cancer 
SD 
Standard Deviation  
SPM 
Study Procedures Manual 
STD 
Severely Toxic Dose 
t 
Time of last observed quantifiable concentration 
t1/2 
Terminal phase half-life 
τ 
Dosing interval 
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 
 

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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 acute myeloid leukemia 
PROTOCOL NUMBER 
200200 
CLINICAL PHASE 
I 
COMPOUND(S) 
GSK2879552 
STUDY RATIONALE 
GSK2879552 is a potent, selective, mechanism-based 
inactivator of LSD1/CoREST activity. Preclinical studies have 
shown that GSK2879552 induces the expression of putative 
LSD1 target genes and has potent, predominantly cytostatic, 
anti-proliferative activity in AML cell lines. Changes in the 
expression of cell surface markers suggest that GSK2879552 
treatment results in a pro-differentiation effect in both in vitro 
and in vivo studies.  The proposed Phase I study will evaluate 
the safety and tolerability, pharmacokinetics, 
pharmacodynamics, and clinical activity to determine the 
recommended Phase 2 Dose (RP2D) and regimen of 
GSK2879552, alone or in combination with ATRA, given 
orally in adult subjects with relapsed/refractory AML. 
 

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STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES 
PART 1: Escalation Cohort 
 
Objectives 
Endpoints 
Primary 
1. To determine the safety, 
tolerability, MTD and/or RP2D and 
regimen of GSK2879552, alone or 
in combination with ATRA, given 
orally in adult subjects with AML.   
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 PK of 
GSK2879552, alone or in 
combination with ATRA, after 
single- and repeat-dose oral 
administration. 
 
 
2. To evaluate clinical response after 
treatment with GSK2879552, alone 
or in combination with ATRA. 
 
 
 
 
 
3. To characterize the PK of ATRA in 
combination with 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. Objective response rate defined as the 
percentage of subjects achieving 
complete remission (CR), partial 
remission (PR), CRp (as per CR but 
platelet count <100 x 109/L)  and 
morphologic leukemia-free state per 
response criteria (Cheson, 2003). 
 
3. ATRA PK parameters following single 
and repeat-dose administration of 
ATRA and GSK2879552, including 
AUC, Cmax, tmax, t½ (terminal phase). 
Exploratory 1. To explore markers of 
differentiation (including 
morphology assessment) in 
response to GSK2879552, alone or 
in combination with ATRA. 
2. To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552, 
alone or in combination with ATRA. 
3. To evaluate the relationship 
between GSK2879552 exposure, 
alone or in combination with ATRA,   
and safety/efficacy/ PD parameters 
 
4. To characterize the metabolite 
profile of GSK2879552 after oral 
single and repeat-dosing in some 
subjects 
5. To determine the amount of 
GSK2879552 excreted in urine 
after oral single and repeat-dosing 
in some subjects treated with 
GSK2879552  
1. Change from baseline expression in 
cell surface markers in AML cells 
derived from bone marrow and/or 
peripheral blood. 
2. Analysis of morphology, DNA, RNA 
and/or protein markers in blasts cells in 
bone marrow aspirates and/or 
peripheral blood. 
 
 
3. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax, Cmin or AUC (0-
tau)) and safety/efficacy/PD 
parameters. PD parameters assessed 
by change from baseline in select 
biomarkers, e.g. CD86 and CD11b 
 
4. GSK2879552 metabolites in plasma 
and/or urine 
 
 
5. Concentration of GSK2879552 in urine 

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6. To investigate the relationship 
between genetic variants in 
candidate genes,PK and safety 
profile of GSK2879552, alone or in 
combination with ATRA. 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over time 
6. Pharmacogenomic (PGx) study using 
buccal samples 
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 alone or in 
combination with ATRA, at the 
respective RP2D given orally in 
adult subjects with AML.  
1. Objective response rate defined as the 
percentage  of subjects achieving 
complete remission (CR), partial 
remission (PR), CRp (as per CR but 
platelet count <100 x 109/L)  and 
morphologic leukemia-free state) per 
response criteria (Cheson, 2003) 
Secondary  
 
1. To evaluate the safety and 
tolerability of respective RP2D of 
GSK2879552, alone or in 
combination with ATRA. 
 
 
 
2. To characterize the population PK 
of GSK2879552, alone or in 
combination with ATRA. 
 
 
 
3. To evaluate clinical activity in 
terms of duration of response 
(DoR), time to response (TTR) and 
progression-free survival (PFS) 
1. AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and 
changes in safety assessments (e.g., 
laboratory parameters, vital signs, 
ECGs, physical examinations) 
 
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. Duration of response (DoR), defined 
as the time from first documented 
evidence of PR or better until 
disease progression (PD) or death, 
among responders, i.e. confirmed 
PR or better.  
 

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Time to Time to Response is defined 
as the time from first dose to the first 
documented evidence of response (PR 
or better). 
 
Progression-free survival (PFS), 
defined as the time from first dose 
until the earliest date of disease 
progression (PD), or death due to 
any cause. 
 
Exploratory 
1. To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552, 
alone or in combination with 
ATRA. 
2. To evaluate the exposure 
response (PK/PD) relationship 
between GSK2879552, alone or in 
combination with ATRA and 
safety/efficacy/PD parameters. 
 
3. To investigate the relationship 
between genetic variants in 
candidate genes, PK and safety 
profile of GSK2879552, alone or in 
combination with ATRA.  
 
1. Analysis of morphology, DNA, RNA 
and/or protein markers in blast cells 
from bone marrow aspirate and/or 
peripheral blood  sample  
2. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax or AUC (0-tau)) 
and safety/efficacy/PD parameters. PD 
parameters assessed by change from 
baseline in select biomarkers, e.g. 
CD86 and CD11b 
 
3. Pharmacogenomic (PGx) study using 
buccal samples 
 
 
Hypothesis 
Clinical response will be defined as Objective Response Rate (% of subjects achieving 
CR, PR, CRp or morphologic leukemia-free state) per response criteria. 
The null hypothesis is: H0: RR ≤10% 
The alternative hypothesis is: HA:  ≥30% 

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STUDY DESIGN 
This is a Phase I, open-label, multi-center, non-randomized, 2-
part study.  
Part 1 is a dose escalation phase to determine the MTD and/or 
RP2D for GSK2879552, alone or in combination with ATRA 
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 safety, tolerability, PK and PD. 
Once MTD and/or RP2D is identified, an expansion cohort 
(Part 2) of up to 30 subjects will be enrolled to further 
evaluate the efficacy and tolerability of GSK2879552, alone 
or in combination with ATRA in subjects with 
relapsed/refractory AML.  
The proposed treatment schedule of GSK2879552 is 
continuous daily dosing.  The starting dose for GSK2879552 
mono therapy arm will be 0.25 mg/day or the highest dose 
determined to be safe in the ongoing SCLC study, whichever 
is higher with a maximum of 1 mg/day (see Section 1.4.3.2 for 
details). The starting dose of GSK2879552 in combination 
with ATRA will be 1-2 dose levels below the highest dose 
determined to be safe in the GSK2879552 mono therapy arm 
in this study, i.e., 2 mg once daily. Alterations to the dose and 
schedule may be incorporated based on emerging PK, PD, and 
tolerability data.  Dose reduction and/or truncated dose 
scheduling may be considered for subjects with recurrent/ 
persistent toxicity or according to the institutional guideline. 
NUMBER OF SUBJECTS 
It is estimated that approximately 55 subjects will be enrolled 
into Part 1 dose-escalation and additional 25 subjects into 
PK/PD expansion cohorts in GSK2879552 mono therapy and 
combination with ATRA arm.  Up to 60 subjects will be 
enrolled in Part 2 (expansion cohort) of GSK2879552 alone 
and combination with ATRA arm.  A total of approximately 
140 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. ≥18 years of age and provided signed written informed 
consent. 

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2. Subjects must have relapsed/refractory acute myeloid 
leukemia by WHO classification for which no standard 
therapies are available or anticipated to result in a 
durable remission.  FAB subtype M3 will be excluded. 
3. Subjects  ≥ 60 years of age with AML who are not 
candidates for or have refused standard chemotherapy.  
4. Subjects who have previously received an autologous 
stem cell transplant are allowed if a minimum of 3 
months has elapsed from the time of transplant and the 
subject has recovered from transplant-associated 
toxicities prior to the first dose of GSK2879552. 
5. Subjects with a history of allogeneic stem cell 
transplant are eligible for study participation provided 
the following eligibility criteria are met: 
• 
transplant was >60 days prior to study enrollment. 
• 
subject has not taken immunosuppressive 
medications (including but not limited to: 
cyclosporine, tacrolimus, methotrexate, or 
mycophenolate mofetil) for at least 1 month 
• 
no signs or symptoms of graft versus host disease 
other than Grade 1 skin involvement 
• 
no active infection 
6. Eastern Cooperative Oncology Group (ECOG) 
performance status of 0-1. 
7.  Subjects must be stable and, in the opinion of the 
investigator, be expected to complete 4 week treatment 
period. 
8. Able to swallow and retain orally administered 
medication and does not have any clinically significant 
gastrointestinal abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of 
the stomach or bowels, 
9. 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).  
10. Adequate baseline organ function defined by:  
 

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System 
Laboratory Values 
Hematologic 
 
White blood cell count 
(absolute) 
≤30,000/uL 
Coagulation assays (PT/INR 
and aPTT)  
≤1.3 X ULN 
Hepatic 
 
Total bilirubin 
≤ 1.5 X ULN1 
ALT and AST 
≤2.5 × ULN  
Renal 
 
Calculated creatinine clearance 
by Chronic Kidney Disease 
Epidemiology Collaboration 
(CKD-EPI) equation  
(Appendix 3) or measured from 
24hr urine 
 
≥ 40 mL/min 
Cardiac 
Ejection fraction 
≥ LLN by Echocardiogram 
(ECHO) or MUGA 
Lipid (ATRA combination ONLY) 
Triglyceride (fasting) 
Cholesterol (fasting) 
≤ 300 mg/dL 
≤ 300 mg/dL 
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 
 
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. 
11. 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 (Section 11.1), during the study and for 
7 days (GSK2879552 mono therapy) or 30 days 
(combination with ATRA), following the last dose of 
study treatment. 
12. Men with a female partner of childbearing potential 
must have either had a prior vasectomy or agree to use 
effective contraception (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 

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for clearance of any altered sperm. 
Subjects meeting any of the following criteria must not be 
enrolled in the study: 
1. Active Human Immunodeficiency Virus (HIV), Hepatitis 
B Virus (HBV) or Hepatitis C Virus (HCV) infections at 
the time of screening. Subjects with laboratory evidence 
of HCV clearance (HCV RNA PCR is negative) may be 
enrolled. 
2. History of or concurrent malignancy of solid tumours, 
except for below. 
Exception:  Subjects who have been disease-free for 5 
years, or subjects with a history of completely resected 
non-melanoma skin cancer or successfully treated in situ 
carcinoma are eligible.  Subjects with second 
malignancies that are indolent or definitively treated may 
be enrolled even if less than 5 years have elapsed since 
treatment.  Consult GSK Medical Monitor if unsure 
whether second malignancies meet requirements specified 
above 
3. Currently receiving cancer therapy (chemotherapy, 
radiation therapy, immuno- therapy, biologic therapy, 
hormonal therapy, surgery, and/or tumour embolization)  
Note: HYDREA (hydroxyurea) will be allowed. 
4. Received major surgery, radiotherapy, or immunotherapy 
within 4 weeks of GSK2879552 administration.  
5. Prior treatment with temozolomide, dacarbazine or 
procarbazine  
6. Prior treatment with poly ADP ribose polymerase (PARP) 
inhibitors (e.g., olaparib, ABT-888) 
7. Screening Montreal Cognitive Assessment (MOCA) 
score of 22 or lower 
8. Evidence of severe or uncontrolled systemic diseases 
(e.g., severe/chronic infection, unstable or uncompensated 
respiratory, 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  
9. Current active liver or biliary disease (with the exception 
of Gilbert's syndrome or asymptomatic gallstones, liver 

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metastases or otherwise stable chronic liver disease per 
investigator’s assessment). 
10. Patients at risk of non-AML related major bleeding (e.g. 
recent GI hemorrhage or neurosurgery). 
11. Symptomatic or untreated CNS leukemia. Subjects are 
permitted to enroll if previously treated for CNS disease, 
free of symptoms at the time of screening, and have not 
required intrathecal chemotherapy at least 1 month prior 
to study Day 1. 
12. 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, 
Appendix 2). 
• 
History of acute coronary syndromes (including 
unstable angina and myocardial infarction), coronary 
angioplasty, or stenting within the past 3 months.  
• 
Baseline QTc interval using Fridericia’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. 
13. Administration of an investigational drug within 14 days 
or 5 half-lives, whichever is shorter with a minimum of 
14 days preceding the first dose of study treatment(s) in 
this study.  
14. Have a known immediate or delayed hypersensitivity 
reaction or idiosyncrasy to drugs chemically related to 
GSK2879552 or LSD1 inhibitors that contraindicates 
their participation. 
15. Lactating female. 
16. 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.  
17. Current use of a prohibited medication including 
anticoagulants or platelet inhibitors (Section 10.2) or 
expected to require any of these medications during 
treatment with the investigational drug. 

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18. Previous treatment with GSK2879552 
For ATRA Combination arm ONLY 
19. Known hypersensitivity to ATRA, parabens 
(preservatives in the gelatin capsule) or other retinoids. 
20. ATRA capsule contains sorbitol. Subjects with rare 
hereditary problems of fructose intolerance are excluded. 
21. History of seizure within 12 months or brain tumor 
(primary) 
22. History of taking mega-dose vitamin A (>25,000 USP 
U/day) within 3 months from the dosing start. 
STUDY TREATMENT DOSE/ROUTE/REGIMEN 
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. 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 and ATRA 
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 for GSK2879552 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 blood samples for PD, exploratory and biomarker 
will be collected at planned visits as listed in the Time and 
Event Table. 
For subjects in the highest dose of Part 1 PK/PD expansion 
cohort, additional blood samples for GSK2879552 metabolite 
profiling will be collected on Day 1 and Day 15 at the same 
time points as listed in the Time and Event Table (Section 
7.1). In addition, pre-dose urine sample will be collected on 
Day 1, and 24 hour urine sample will be collected starting 
from post-dose on Days 1 and 15 until dosing on Days 2 and 
16, respectively.  
For all subjects in Part 2 expansion cohorts, serial blood 
samples for analysis of GSK2879552 and ATRA 
concentrations will be collected on Days 1 and 15 at planned 
time points as listed in the Time and Event Table (Section 
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and every 4 week thereafter. Pre-dose blood samples for PD, 
exploratory and biomarker will be collected at planned visits 
as listed in the Time and Event Table. 
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 assessments will be made by physical examination 
and laboratory evaluation.  Bone marrow aspiration/biopsy 
will be performed as stated in the Time and Event Table 
(Section 7.1). Response criteria are listed in Appendix 6. 
Laboratory evaluation will include a complete blood count 
with differential and blood smear to measure blasts. 
TRANSLATIONAL 
RESEARCH 
Blood and/or bone marrow aspirates will be collected at 
various times, throughout the study in order to support 
research aimed at understanding the biological effect of 
GSK2879552 alone or in combination with ATRA in AML as 
well as identifying indicators of sensitivity or resistance 
STATISTICAL METHODS 
In Part 1 Dose Escalation Phase, No formal statistical 
hypotheses are being tested.  The sample size depends on the 
actual number of cohorts of subjects treated.  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.  
The primary goal of Part 2 is to detect a clinically meaningful 
response rate (defined as the percentage of subjects that have 
achieved a CR, CRp, PR or a morphologic leukemia-free 
state) of 30% relative to a 10% response rate suggesting no 
activity.  
Symbolically, the null hypothesis is: 
H0: RR≤10% 
The alternative hypothesis is: 
HA:RR≥30% 
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 
stages, once a minimum number of subjects are evaluable.  In 

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this particular study, we will stop only for futility. 
After 10 subjects have been enrolled to examine safety and 
efficacy, the number of observed confirmed objective 
responses will guide further enrolment according to the rules 
summarized in Figure 3. A maximum of 30 subjects will be 
enrolled at the respective RP2D for GSK2879552 mono 
therapy and in combination with ATRA. All available data 
will be considered in making enrollment decisions. 
Analysis Population 
All Treated 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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1. 
INTRODUCTION 
1.1. 
Background – LSD1 
LSD1 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. 
Multiple roles for LSD1 have been described in the literature.  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 plays a critical role in normal hematopoietic 
differentiation by mediating repression of a key gene expression program in 
hematopoietic progenitors [Saleque, 2007].  In AML, LSD1 knockdown or small 
molecule inhibition has a pro-differentiation effect both in vitro and in vivo [Harris, 
2012].  Sub-lethally irradiated (syngeneic) mice transplanted with LSD1 knockdown 
mouse derived MLL-AF9 AML cells showed a prolonged survival relative to mice 
engrafted with control cells [Harris, 2012]. In a separate study, LSD1 inhibition extended 
survival of mice transplanted with mouse derived MLL-AF9 leukemia cells.  In this 
study, mice were treated for 17 days with an LSD1 inhibitor and a survival benefit was 
apparent for weeks beyond the treatment duration [Kruger, 2013]. Together these studies 
suggest LSD1 is a regulator of expression programs and its role may depend on the 
complex in which it resides as well as the susceptibility of specific genes to 
transcriptional modulation. 
GSK2879552 is a potent, selective inhibitor of LSD1/CoREST. GSK2879552 causes an 
increase in histone 3 lysine 4 di-methylation (H3K4me2) at promoters of putative LSD1 
target genes and has predominantly cytostatic effect on small cell lung cancer (SCLC) 
and acute myeloid leukemia (AML) cell lines (Refer to the Investigator Brochure (IB) for 
GSK2879552 [GlaxoSmithKline Document Number 2013N168888_03). 
1.2. 
Unmet Medical Needs for Relapsed/Refractory AML 
Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a 
median age at diagnosis of 67 years old. No standard regimen exists for the treatment of 
patients with relapsed AML, particularly in patients with the first remission duration of 
less than 1 year.  For refractory AML patients, overall survival at 1 year is less than 10% 
and the median survival is a few months only [Schmid, 2006]. Older patients with AML 
have significant comorbidities, a poorer performance status, more unfavorable 
cytogenetic abnormalities, and a higher incidence of secondary AML than their younger 
counterparts [Klepin, 2009]. The median overall survival of elderly AML patients 
remains on the order of months with few long-term survivors [Dombret, 2008]. There is a 
clear unmet medical need for treatment options in relapsed/refractory AML and elderly 

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AML patients who are not eligible for chemotherapy.  Agents like decitabine, which alter 
the chromosomal methylation status, have been approved for the treatment of advanced 
myelodysplastic syndromes and AML in elderly patients who are not eligible for 
induction chemotherapy.  GSK2879552, which can induce differentiation in AML cell 
lines has the potential to be an effective treatment for AML. 
1.3. 
GSK2879552 
1.3.1. 
GSK2879552 - Background 
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 mechanism-based nature of the inhibition by which the enzyme-bound FAD 
cofactor becomes irreversibly covalently modified. For an irreversible inhibitor, the 
inhibition is predicted to be relieved upon new protein synthesis. In vitro results suggest 
that the half-life (t1/2) of LSD1 protein is greater than 24 hrs. The growth inhibitory 
effects of GSK2879552 were assessed in a diverse panel of cell lines representing a range 
of tumor types.  The activity was specific primarily to SCLC and AML cell lines 
suggesting that GSK2879552 is not a generally cytotoxic agent.    
GSK2879552 induces the expression of putative LSD1 target genes and has potent, 
predominantly cytostatic, anti-proliferative activity in sensitive SCLC (median EC50 = 25 
nM, range 2 – 240 nM)) and AML (median EC50 = 26 nM, range = 3 – 102 nM) cell 
lines.  In a 6 day assay, GSK2879552 has potent anti-proliferative activity in 20 of 29 cell 
lines representing multiple sub-types of AML (M0 - M7).   Eight of the 9 lines resistant 
in the 6 day assay were further characterized and are sensitive in an extended duration 10 
day assay, suggesting that prolonged LSD1 inhibition may result in greater efficacy. 
Treatment of bone marrow cells derived from AML patients revealed inhibition of AML 
blast colony formation, demonstrating that the anti-proliferative activity of GSK2879552 
may extend beyond established cell lines.  
Consistent with literature reports [Harris, 2012], a pro-differentiation effect was observed 
upon GSK2879552 treatment of AML cells both in vitro and in vivo.  In vitro, 
GSK2879552 treatment resulted in growth inhibition of AML cell lines as well as 
increased expression of differentiation associated cell surface markers (CD11b EC50 = 7.1 
nM and CD86 EC50 = 13 nM at 24 hours in SKM-1) across cell lines representing 
multiple subtypes of AML.   
In vivo studies using MV-4-11 AML cells engrafted into irradiated mice demonstrated an 
increase in expression of cell surface markers by 8 hours that continued to increase 
through 72 hours following daily administration of GSK2879552 (CD86, EC50 = 1.4 
mg/kg and CD11b, EC50 = 2.1 mg/kg at 24 hrs).  The pro-differentiation response 
observed in the MV-4-11 model provides evidence that GSK2879552 had biological 
efficacy in vivo, however, this did not translate into increased survival in this model.  In a 
MLL-AF9+ murine model of AML, treatment with GSK2879552 led to a significant 
delay in leukemia onset in treated mice relative to vehicle treated controls.   

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In the mouse MV-4-11 AML engraftment model, severe thrombocytopenia with bleeding 
resulted in increased morbidity. Macroscopic and histopatholgic examination suggested 
that the severity of the thrombocytopenia was likely due to the combined effects of 
irradiation, engraftment of injected AML cells into marrow and multiple other organs, 
and the effect of GSK2879552 on platelets.   
1.3.2. 
LSD1 inhibitor and All-Trans Retinoic Acid 
Retinoic acid regulates normal embryonic cell differentiation and development of many 
tissues including the brain, lungs, and other organs [Niederreither, 2008]. All-trans-
retinoic acid (ATRA) induced differentiation has been explored in cancers that appear to 
retain stem-like cells as well as those in which molecular features of differentiation have 
been characterized.  Sarcoma cells including osteosarcoma and rhabdomyosarcoma 
display morphological changes and alterations in molecular markers consistent with 
osteoblast and myogenic differentiation in response to ATRA [Luo, 2010; Barlow, 2006].  
The presence of cancer stem cells in glioblastoma has been associated with therapeutic 
resistance and tumor initiating potential.  Pre-clinical models have been developed to 
reveal this subpopulation and, in this setting, glioblastoma cells exposed to ATRA 
undergo reduced proliferation and self-renewal, differentiation into glial and neuronal 
lineages, and ultimately apoptosis [Karsy, 2010; Choschzick, 2014].  Despite the pre-
clinical data suggesting ATRA treatment can promote differentiation in a number of 
tumor models, ATRA therapy has not proven efficacious in solid tumors clinically.  
ATRA has been used successfully in hematological malignancies and is the current 
standard of care for acute promyelocytic lekemia (APL), a subtype of acute myeloid 
leukemia (AML).  ATRA therapy promotes complete remission in more than 90% of 
patients through differentiation of leukemic blasts, however, this efficacy has not 
translated to non-APL subtypes of AML.  The selective response to ATRA in APL is 
associated with the expression of PML-RAR, the fusion protein that results from 
chromosomal translocation t(15,17)(q22;q21).  In this setting, ATRA can induce 
expression changes in genes associated with myeloid differentiation through relief of 
repression of the myeloid expression program imposed by the PML-RAR fusion protein 
[Melnick, 1999; Johnson, 2015].  These data suggest that targeting a differentiation 
mechanism may also provide an effective therapy in AML if expression of myeloid gene 
programs can be achieved. 
Inhibition of LSD1 by GSK2879552 can promote differentiation in AML cells as 
evaluated by several measures including gene expression and cell surface marker changes 
consistent with myeloid differentiation.   LSD1 has been implicated in regulation of the 
ATRA driven response through increases in H3K4me2 at key genes involved in the 
ATRA pathway [Schenk, 2012; Sakamoto, 2014].  Given the overlapping mechanism 
associated with each single agent, and the potentiating effect of LSD1 inhibition on the 
ATRA pathway, treatment of AML may demonstrate greater response to ATRA when 
combined with GSK2879552.  

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1.3.3. 
Pre-Clinical PK and Safety of GSK2879552 
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 and a comparison of systemic exposures achieved in these studies are 
presented in the IB for GSK2879552 [GlaxoSmithKline Document 
Number2013N168888_03]. A summary of principal toxicological findings are discussed 
below. 
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. 

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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 maturation block of 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 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)].   
1.3.4. 
Pharmacokinetics of GSK2879552 in Humans 
GSK2879552 pharmacokinetics (PK) will be evaluated in a limited number of subjects in 
the first time in human study in small cell lung cancer patients (GSK study 200858, 
NCT# 02034123) prior to the initiation of this study.  PK 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. 
As of 20-NOV-2015, the PK of GSK2879552 was evaluated following administration of 
single (N=18) and repeated (N=16) oral administration of 0.25 mg to 3 mg of 
GSK2879552 in subjects with SCLC in Study 200858 and following single (N=11) and 
repeated (N=8) oral administration of 1 mg to 8 mg in subjects with AML in Study 
200200. GSK2879552 pharmacokinetics are characterized by a rapid absorption with 

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maximum concentration occurring typically within the first hour after dosing. 
GSK2879552 is eliminated slowly with an average terminal phase half-life of 12 to 
38 hours, leading to a moderate average increase in exposure of 72% for AUC at 2 mg 
daily. Following single and repeated administration of 0.25 mg to 4 mg of GSK2879552, 
Cmax and AUC tended to increase in a dose proportional fashion. 
1.3.5. 
Clinical Safety of GSK2879552 
Summary of findings from clinical studies conducted with GSK2879552 can be found in 
the Investigator Brochure for GSK2879552 [GlaxoSmithKline Document Number 
2013N168888_03].  
As of 20-NOV-2015, 11 subjects have been enrolled in Part 1 at once daily doses of 1 mg 
(n=1), 2 mg (n=2), 4 mg (n=7), and 8 mg (n=1). All 11 subjects (100%) had experienced 
AEs.  The most frequently reported AEs (>20%) were fatigue, febrile neutropenia, 
nausea, anemia, decreased appetite, hypotension, rash, cellulitis, hypokalemia, and local 
edema. All Grade 4 AEs were hematological and included thrombocytopenia and 
neutropenia. Treatment-related AEs reported in at least 10% of subjects were nausea, 
decreased appetite, and thrombocytopenia. The treatment-related thrombocytopenia AEs 
were Grade 4 in both subjects; one of these subjects also had Grade 3 febrile neutropenia 
and Grade 3 anemia. Other treatment-related events that were Grade 3 or 4 included 
anemia and nausea. There were no fatal AEs. 
All 11 subjects in Study 200200 have experienced SAEs. The most common SAE was 
febrile neutropenia. All cases of febrile neutropenia resolved. No other SAEs occurred in 
more than 1 subject. One subject had fatal pleural effusion secondary to disease under 
study, which was considered by the investigator to be not related to study treatment. 
1.3.6. 
Combination Agent 
1.3.6.1. 
All-Trans Retinoic Acid (ATRA) 
All-trans retinoic acid (ATRA, tretinoin) is indicated for the induction of remission in 
patients with acute promyelocytic leukemia (APL) at 45 mg/m2/day, or according to the 
French-American-British (FAB) classification the M3 subtype of acute myeloid leukemia 
(AML-M3). 
The most frequently reported adverse events of ATRA are similar to those described in 
patients taking high doses of vitamin A and included headache (86%), fever (83%), 
skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash 
(54%), mucositis (26%), pruritus (20%), and increased sweating (20%) [ATRA 
Prescribing Information, 2004].  
About 25% of patients with APL treated with ATRA have experienced the retinoic acid-
APL (RA-APL) syndrome. The syndrome generally occurs during the first month of 
treatment, with some cases reported following the first dose of ATRA. During ATRA 
treatment, about 40% of patients will develop rapidly evolving leukocytosis which is 
associated with a higher risk of life threatening complications. Retinoids have been 
associated with pseudotumor cerebri (benign intracranial hypertension), especially in 

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pediatric patients.  Up to 60% of patients experienced hypercholesterolemia and/or 
hypertriglyceridemia, which were reversible upon completion of treatment.  Elevated 
liver function test results occur in 50% to 60% of patients during treatment. However, the 
majority of these abnormalities resolve without interruption of ATRA or after completion 
of treatment. ATRA has teratogenic and embryotoxic effects and there is a high risk that 
severe fetal abnormalities may result with ATRA administration during pregnancy. Cases 
of thrombosis involving various sites have been reported rarely [ATRA Prescribing 
Information, 2004]. 
In a Phase I study conducted in subjects with solid tumor, ATRA was administered at 
doses ranging from 45 to 309 mg/m2 per day [Conley, 1997]. Hypertriglyceridemia was 
dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous 
dryness and headache. The recommended once-daily ATRA dose was 215 mg/m2.  In 
another Phase I study conducted in subjects with solid tumor, ATRA dose ranged from 
45 to 200 mg/m2 per day [Lee, 1993]. Skin toxicities were dose limiting in this study at 
175 mg/m2 or higher dose. Headache was one of the most common toxicities and 
nausea/vomiting were frequent at dose levels higher than 100 mg/m2. The recommended 
once daily ATRA dose was 150 mg/m2. In a Phase I study conducted in patients with 
head and neck squamous cell carcinoma with prior surgical resection [Park, 2000], 
ATRA was administered at 45, 90, or 150 mg/m2 either once daily or as divided doses. A 
similar toxicity profile was observed with headache, mucocutaneous dryness, and 
hypertriglyceridemia as the frequent toxicities. The maximum tolerable dose of ATRA in 
this population was established at 45 mg/m2/day, although the reason for the lower 
tolerance in this subject population is not clear.   
ATRA is available in a 10 mg soft gelatin capsule for oral administration. The 
recommended dose in APL is 45 mg/m2/day administered as two divided doses, as 
equally as feasible.  
Pharmacokinetics of ATRA 
ATRA (tretinoin) is rapidly absorbed following oral administration with peak 
concentration observed within 1 to 2 hours after dosing. ATRA is eliminated rapidly, 
with a terminal half-life of 0.5 to 2 hours following the first dose in patients with APL or 
CML. Cytochrome P450 3A4, 2C8 and 2E enzymes have been implicated in the 
oxidative metabolism of ATRA. There is evidence that ATRA induces its own 
metabolism. Plasma ATRA concentrations decrease on average to one-third of their day 1 
values during 1 week of continuous therapy. Mean ± SD peak ATRA concentrations 
decreased from 394 ± 89 to 138 ± 139 ng/mL, while area under the curve (AUC) values 
decreased from 537 ± 191 ng·h/mL to 249 ± 185 ng·h/mL following 45 mg/m2 daily 
dosing in 7 APL patients [ATRA Prescribing Information, 2004]. This reduction in 
exposure was reverted following a one week dose interruption [Russo, 1998].    
1.4. 
Rationale 
1.4.1. 
Rationale for Study 
Relapsed/refractory AML is an area of significant unmet need. Induction of 
differentiation is a clinically proven therapeutic mechanism in a subset of AML (APL-

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AML), and targeting LSD1 could provide a new opportunity in AML treatment by 
inducing differentiation in non-APL AML. Preclinical studies have shown that 
GSK2879552 induces the expression of putative LSD1 target genes and has potent, 
predominantly cytostatic, anti-proliferative activity in AML cell lines. Changes in the 
expression of cell surface markers suggest that GSK2879552 treatment results in a pro-
differentiation effect in both in vitro and in vivo studies.  The proposed Phase I study will 
evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics, and clinical 
activity to determine the recommended Phase 2 Dose (RP2D) and regimen of 
GSK2879552, alone or in combination with ATRA, given orally in adult subjects with 
relapsed/refractory AML.  
1.4.1.1. 
Rationale for Combination with ATRA 
Previous studies indicated that, when combined with ATRA, knockdown of LSD1 or 
treatment of AML cells with a non-selective LSD1 inhibitor, tranylcypromine, resulted in 
a greater anti-leukemic effect in vitro and in vivo.  The addition of LSD1 inhibitor 
potentiated ATRA induced cell surface marker changes, myeloid differentiation gene 
expression, and in vivo engraftment of AML cells.  These effects were observed in both 
ATRA sensitive and insensitive cells [Schenk, 2012].   
Several approaches were undertaken to evaluate the combination effects of GSK2879552 
with ATRA.  As described, growth inhibition by GSK2879552 alone is cytostatic and 
does not invoke cell death mediated by apoptosis.  Evaluation of proliferation in AML 
cell lines showed that ATRA alone has growth inhibitory effects.  Co-treatment of AML 
cell lines with fixed concentrations of ATRA (0, 1, 10, 100, or 1000 nM) with 
GSK2879552A (3000 nM-0.152 nM) decreased the EC50 associated with GSK2879552 
growth inhibition and resulted in cytotoxicity at earlier timepoints than ATRA alone in 
MOLM-13 cells and OCI-AML3 cells.  Overall, percent maximum inhibition increased 
in combination relative to GSK2879552 alone in 5 of 6 cell lines tested.  Using a similar 
study paradigm, caspase activation, a hallmark of apoptotic cell death was measured to 
further evaluate the mechanism of cytotoxicity invoked by the combination.  
GSK2879552 in combination with ATRA resulted in increased caspase activation when 
compared to activity of either single agent and supra -additive effects were observed in 5 
of 6 AML cell lines tested.  Five of 6 cell lines tested reached a supra-additive effect at 
100 nM and 1000 nM ATRA while 3 cell lines, HL-60, MV-4-11 and SIG-M5, reached a 
supra-additive effect at 10 nM ATRA.  Supra-additive effects occurred at GSK2879552A 
concentrations ≥ 37 nM except in SIG M5 cells where the supra-additive were only 
evident at lower doses of GSK2879552A (0.46 nM to 37 nM).   
In a separate study using samples derived from bone marrow of AML patients, AML 
blast colony forming ability was evaluated with the combination of GSK2879552 with 
fixed concentrations of ATRA (0-1000nM).  While each single agent did inhibit AML 
blast colony number to varying degrees in a 6 of 9 samples, co-treatment with 0.1 µM or 
1 µM ATRA in combination with GSK2879552 resulted in a greater anti-leukemic effect 
as revealed by a lower GSK2879552 IC50 or greater maximal inhibition of AML blast 
colony forming ability than either single agent alone.  Supra-additive effects were 
observed in 2 of 6 evaluable samples.   

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Finally, flow cytometric evaluation of cell surface markers of 2 AML cell lines (KG-1 
and KG-1a) revealed increased CD11b and CD86 expression above single agent activity 
in 1 of the 2 cell lines.  Taken together, these studies indicate that the combination of 
LSD1 inhibition with ATRA can enhance in vitro growth inhibition of AML cells beyond 
that achievable by either agent alone.  
In this study, a combination arm will be included to evaluate safety, tolerability, PK, PD 
and clinical activity of GSK2879552 in combination with ATRA.  
1.4.2. 
Rationale for Population 
Acute myeloid leukemia (AML) is a clonal disorder characterized by arrest of 
differentiation in the myeloid lineage coupled with an accumulation of immature 
progenitors in the bone marrow, resulting in hematopoietic failure. AML is defined as the 
involvement of more than 20% of the blood and/or bone marrow by leukemic 
myeloblasts (per WHO) and is the most common acute leukemia in adults, with estimated 
14,590 new cases and 10,370 deaths in US in 2013 [American Cancer Society, 2013]. 
The incidence of AML increases with age, with a median age at diagnosis of 67 years 
old. 
Approximately 60% to 70% of adults with AML can be expected to attain complete 
remission following appropriate induction therapy. More than 25% of adults with AML 
can be expected to survive 3 or more years and may be cured. However, no standard 
regimen exists for the treatment of patients with relapsed AML, particularly in patients 
with the first remission duration of less than 1 year.  For refractory AML patients, the 
chance to achieve a CR with standard treatment is 10% to 20% at best, and overall 
survival at 1 year is less than 10% with a median survival of 4 months only [Schmid, 
2006]. 
Remission rates in adult AML are also inversely related to age and the older patients have 
a median overall survival on the order of months with few long-term survivors [Dombret, 
2008]. A few population-based studies have reported 3-year survival rates of only 9-10% 
and 5-year survival of 3-8% in patients aged 60 years and older, compared with 5-year 
survival rates of up to 50% for younger patients [Alibhai, 2009; Juliusson, 2009]. These 
subjects tolerate intensive chemotherapy poorly, and often have AML with poor-
prognosis karyotypes.  There is a clear unmet medical need for treatment options in 
relapsed/refractory AML and elderly AML patients who are not eligible for 
chemotherapy. Hypomethylating agents have been approved for the treatment of 
advanced myelodysplastic syndromes and AML in elderly patients who are not eligible 
for induction chemotherapy which may highlight the potential for these agents. 
1.4.3. 
Rationale for Dose – GSK2879552 Monotherapy 
1.4.3.1. 
Predicted Effective Dose 
The potential therapeutic dose for GSK2879552 in humans with relapsed/refractory AML 
was derived using available preclinical PK, in vitro AML cell line data and in vivo PD 
and efficacy data from AML tumor xenograft studies.  

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In vitro, GSK2879552 showed inhibition of proliferation of AML cells with median 
EC50 = 26 nM (range = 3 - 102 nM).  In SKM-1 AML cell lines, GSK2879552 treatment 
results in increased expression of cell surface markers consistent with a pro-
differentiation mechanism (CD11b EC50 = 7.1 nM or 2.6 ng/mL and CD86 EC50 = 
13 nM or 4.7 ng/mL at 24 hours). GSK2879552 is a mechanism-based irreversible 
inhibitor of LSD1 suggesting that enzyme inhibition is predicted to be relieved upon new 
protein synthesis. In vitro results suggest that the t1/2 of LSD1 protein is greater than 24 
hrs, and therefore once daily regimen should be adequate even though the predicted half-
life of GSK2879552 is less than 4 hours.  
In vivo studies using MV-4-11 AML cells engrafted into mice revealed an increase in 
expression of both CD11b and CD86 cell surface markers by 8 hours that continued to 
increase through 72 hours following daily administration of GSK2879552 (CD86, dose 
for 50% effect, ED50 of 1.4 mg/kg at 24 hrs, and ED75 of 4.9 mg/kg at 24 hours). 
The anticipated effective daily doses in humans based on a predicted clearance of 
5.4 mL/min/kg are around 10 mg to 11 mg, computed to provide a free average steady-
state concentration of 26 nM (median in vitro EC50) and a free AUC similar to the one 
predicted for mice receiving 4.9 mg/kg (in vivo EC75 for CD86 in MV-4-11 model), 
respectively. A daily dose of 40 mg would provide a free average steady-state 
concentration of 102 nM, the maximum in vitro EC50 observed in AML cell lines. The 
prediction based on in vivo mouse data has taken into account the 25% difference in 
plasma protein binding between human and mouse and assume 100% oral bioavailability. 
1.4.3.2. 
Starting Dose 
Four approaches have been considered to establish the starting dose for GSK2879552 in 
AML patients assuming a 70 kg adult with a surface area of 1.7 m2.  
1. One tenth of the rat 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 
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.  

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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 free exposure in 
rats and dogs is predicted to be 1.6 mg and 0.6 mg, respectively. 
4. The highest dose determined to be safe in the ongoing first in human study of 
GSK2879552 in subjects with small cell lung cancer (GSK study 200858, NCT# 
02034123).  
The highest dose determined to be safe is the highest dose that has cleared the DLT 
observation period (first 4 weeks of treatment) without any observed DLT as defined in 
that study. It is expected that while the Grade 3 or 4 non-hematologic toxicities that 
constitute DLTs are likely to be similar in SCLC and AML subjects, the hematologic 
Grade 3 or 4 toxicities constituting the DLT criteria are likely to be observed earlier in 
SCLC subjects. Since AML subjects have disease-induced suppressed bone marrow 
function and pancytopenia, the definition of hematologic dose limiting toxicity is 
different in the AML study compared with the SCLC study:  Hematologic toxicities 
would be considered dose limiting if prolonged suppression is observed (See Section 
4.2.5). Therefore, a dose determined to be safe in SCLC subjects, i.e., without 
hematologic or non-hematologic DLTs, is expected to be safe for AML subjects and will 
allow for a starting dose that is likely to be nearer to MABEL dose. 
Taking all approaches into consideration, the target population of relapsed/refractory 
AML subjects and the nature of the dose-limiting toxicity in animals, a starting dose of 
0.25 mg daily (same starting dose as in the FTIH in SCLC study) is proposed. However, 
to minimize the number of subjects exposed to sub-therapeutic doses, a higher starting 
dose will be considered if the following conditions are met: 
• 
A higher dose has been established to be safe in the ongoing FTIH study of single 
agent GSK2789552 in small cell lung cancer (GSK study 200858; NCT# 02034123). 
Safety and PK data from all patients treated up to the highest safe dose level in the 
small cell lung cancer study has been reviewed by the 200858 study Investigators 
with GSK Medical Monitor, clinical team, safety physician and PK representative.  
• 
Safety and PK data mentioned above is summarized in a supplemental document, not 
requiring protocol amendment, with the rationale for starting at a higher dose.  The 
supplemental document will be submitted for review and approval by Investigators 
and site IRB/EC for the present study in AML subjects, and communicated to 
regulatory authorities as appropriate. 

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If all of the above conditions are met, the present study can start at a higher dose than 
0.25 mg daily, but not exceeding a starting dose of 1 mg once daily. In the absence of 
meeting all three conditions, the starting dose will remain 0.25 mg daily. 
1.4.4. 
Rationale for Dose – GSK2879552 and ATRA combination 
1.4.4.1. 
Predicted Effective Dose 
Effective doses for GSK2879552 in combination with ATRA are anticipated to be at or 
below the predicted single agent effective doses of 10 to 40 mg daily. 
ATRA dose of 45 mg/m2/day as two divided doses (as equally as feasible) would provide 
maximum concentrations around 500 nM, average steady-state concentrations around 
80 nM and concentrations above 100 nM for around 6 hours. ATRA concentrations at 
100 to 1000 nM ranges in combination with up to 2 µM GSK2879552 resulted in a 
greater anti-leukemic effect in in vitro studies.  
1.4.4.2. 
Starting Dose 
ATRA dose will be fixed at 45 mg/m2/day as two divided doses, as equally as feasible. 
The starting dose for GSK2879552 will be 2 mg. These starting doses were chosen based 
on the following considerations: 
• 
GSK2879552 and ATRA do not have overlapping toxicity profiles based on the 
nonclinical toxicology and clinical safety profile of GSK2879552 at doses up to 4 
mg daily. 
• 
GSK2879552 mono-therapy has been well tolerated in this study at up to 4 mg daily 
dose. 2 mg daily dose of GSK2879552 represents a 50% reduction from the highest 
cleared dose of 4 mg daily as of 20-NOV-2015. 
• 
A dose of 45 mg/m2/day for ATRA represents the recommended dose in APL as a 
single agent, well below the MTD of 150-215 mg/m2/day. 
• 
The risk of GSK2879552 altering ATRA PK is low. In-vitro data suggests that 
GSK2879552 has a very low potential to inhibit or induce CYP enzymes, and to 
inhibit Pgp, BCRP, OATP1B1 or OATP1B3 transporters.  
• 
The risk for ATRA to increase GSK2879552 exposure is very low. ATRA has only 
been reported to be an enzyme inducer. 
1.4.5. 
Benefit Risk Assessment 
Summaries of findings from non-clinical and clinical studies conducted with 
GSK2879552 can be found in the Investigator Brochure (IB) for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_03].  The following section 
outlines the risk assessment and mitigation strategy for this protocol 
 

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1.4.5.1. 
Risk Assessment 
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. Reduced platelet aggregation has been observed 
in rats following repeat dosing at a time when there was 
significant thrombocytopenia.   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, hypocellularity was not observed in the bone 
marrow of these animals. 
Informed Consent Form includes the risk of hematologic toxicity. 
Protocol specifies:  
- 
Exclusion criteria for non-AML related major bleeding (e.g. recent GI 
hemorrhage or neurosurgery) 
- 
Laboratory assessments (complete blood count [CBC])  
- 
Dose stopping/modification criteria 
Signs and symptoms of bleeding or infection will be closely monitored 
during the study. 
Encephalopathy 
Three (out of 18) 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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Potential Risk of 
Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
ATRA Combination ONLY 
RA-APL syndrome or 
respiratory 
compromise  
About 25% of patients with APL treated with ATRA have 
experienced the retinoic acid-APL (RA-APL) syndrome. 
Protocol provides the guideline for RA-APL syndrome management. 
  
Leukocytosis 
About 40% of patients may develop rapidly evolving 
leukocytosis  during ATRA treatment 
Subjects with an increased risk of a further rapid increase in WBC counts, 
i.e., WBC >30,000/uL, are excluded. 
Pseudotumor cerebri/ 
intracranial 
hypertension. 
ATRA may cause pseudotumor cerebri/intracranial 
hypertension. 
Concomitant administration of ATRA and agents known to cause 
pseudotumor cerebri/intracranial hypertension (e.g., tetracycline) will be 
prohibited. 
Hypercholesterolemia/ 
hypertriglyceridemia 
Up to 60% of patients experienced hypercholesterolemia 
and/or hypertriglyceridemia with ATRA treatment. 
Subjects with hypertriglyceridemia or hypercholesterolemia >300 mg/dL 
are excluded. 
Lipid panel will be checked weekly for the first 4 weeks and then q 4 weeks 
thereafter. 
Liver function test 
elevation 
Elevated liver function test results occur in 50% to 60% of 
patients during ATRA treatment. 
LFT is monitored twice weekly for the first 2 weeks, weekly for the next 2 
weeks and then q 4 weeks thereafter.  
Treatment stopping criteria based on elevation in LFT is in place and the 
safety management guideline is also provided.  
Hypervitaminosis A 
Chemically, ATRA is all-trans retinoic acid and is related to 
retinol (Vitamin A). 
Vitamin A or multivitamins including vitamin A are prohibited. 
Teratogenic effect 
There is a high risk that a severely deformed infant will 
result if ATRA is administered during pregnancy.  
Female subjects with child bearing potential will be required to use 2 
reliable forms of contraception methods simultaneously during the 
treatment and until 30 days after the last dose of ATRA or 7 days after the 
last dose of GSK2879552, whichever is later. Contraception counselling 
will be repeated monthly throughout ATRA treatment.   
Serum pregnancy test will be performed at screening and end of treatment 
visit, and urine pregnancy test at week 4 and every 4 weeks thereafter.  
Thrombosis 
Cases of fatal thrombotic complications have been reported 
rarely in patients concomitantly treated with ATRA and anti-
fibrinolytic agents. 
CBC and coagulation panel are monitored weekly for the first 4 weeks and 
then every 4 weeks thereafter. 
Concomitant administration of antifibrinolytic agents (such as tranexamic 
acid, aminocaproic acid, or aprotinin) will be prohibited. 

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1.4.5.2. 
Benefit Assessment 
This is an open-label, dose escalation and the first time in human study of this agent to be 
conducted in subjects with relapsed/refractory AML for which no standard therapies are 
anticipated to result in a durable remission.  GSK2879552 has promising preclinical 
activity in AML cell lines, however it is unknown whether GSK2879552 will have 
efficacy in subjects with AML, thus any potential beneficial effect for an individual 
subject attributable to GSK2879552 is unknown.  
ATRA is indicated for acute promyelocytic leukemia (APL). While there has been 
significant success in the utility of ATRA as a differentiation therapy in APL, ATRA has 
not been found to invoke a similar mechanism in other AML subtypes.  GSK2879552 
promotes differentiation in AML cell lines leading to the hypothesis that, through an 
overlapping mechanism, treatment of AML may demonstrate a greater response to ATRA 
when combined with GSK2879552.  Any potential beneficial effect for an individual 
subject attributable to the combination of ATRA with GSK2879552 in non-APL type 
AML is unknown. 
Data obtained in this study may assist in progressing the knowledge base on AML 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 
1.4.5.3. 
Overall Risk Benefit Conclusion 
Current data from GSK2879552 preclinical studies, alone or in combination with ATRA, 
indicate a potential for clinical activity by induction of differentiation in AML. Taking 
into account the measures taken to minimise risks to subjects participating in this Phase I 
clinical trial, the potential risks identified in association with GSK2879552, alone or in 
combination with ATRA, are justified by the anticipated benefits that may be afforded to 
subjects with relapsed/refractory AML, for whom there are currently no effective 
available therapies. 

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2. 
OBJECTIVES, ENDPOINTS AND HYPOTHESES 
PART 1: Escalation Cohort 
 
Objectives 
Endpoints 
Primary 
1. To determine the safety, tolerability, 
MTD and/or RP2D and regimen of 
GSK2879552, alone or in 
combination with ATRA, given orally 
in adult subjects with AML.   
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 PK of 
GSK2879552, alone or in 
combination with ATRA, after single- 
and repeat-dose oral administration. 
 
 
2. To evaluate clinical response after 
treatment with GSK2879552, alone or 
in combination with ATRA. 
 
 
 
 
3. To characterize the PK of ATRA in 
combination with 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. Objective response rate defined as the 
percentage of subjects achieving 
complete remission (CR), partial remission 
(PR), CRp (as per CR but platelet count 
<100 x 109/L)  and morphologic leukemia-
free state per response criteria (Cheson, 
2003) 
3. ATRA PK parameters following single and 
repeat-dose administration of ATRA and 
GSK2879552, including AUC, Cmax, 
tmax, t½ (terminal phase). 
Exploratory 
1. To explore markers of differentiation 
(including morphology) in response to 
GSK2879552, alone or in 
combination with ATRA. 
2. To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552, 
alone or in combination with ATRA. 
3. To evaluate the relationship between 
GSK2879552 exposure, alone or in 
combination with ATRA and 
safety/efficacy/PD parameters. 
 
 
 
 
 
4. To characterize the metabolite profile 
of GSK2879552 after oral single and 
repeat-dosing in some subjects 
5. To determine the amount of 
GSK2879552 excreted in urine after 
oral single and repeat dosing in some 
subjects treated with GSK2879552 
1. Change from baseline expression in cell 
surface markers in AML cells derived from 
bone marrow and/or peripheral blood. 
2. 
Analysis of morphology, DNA, 
RNA and/or protein markers in blasts cells 
in bone marrow aspirates and/or 
peripheral blood.    
  
3. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax, Cmin or AUC (0-
tau)) and safety/efficacy/PD parameters.  
PD parameters assessed by change from 
baseline in select biomarkers, e.g. CD86 
and CD11b 
 
4. GSK2879552 metabolites in plasma 
and/or urine 
 
5. Concentration of GSK2879552 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time 
6. Pharmacogenomic (PGx) study using 

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6. To investigate the relationship 
between genetic variants in candidate 
genes, PK and safety profile of 
GSK2879552, alone or in 
combination with ATRA. 
buccal samples. 
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, alone or in 
combination with ATRA at the 
respective RP2D given orally in 
adult subjects with AML.  
1. Objective response rate defined as the 
percentage of subjects achieving 
complete remission (CR), partial remission 
(PR), CRp (as per CR but platelet count 
<100 x 109/L)  and morphologic leukemia-
free state per response criteria (Cheson, 
2003). 
Secondary 
1. To evaluate the safety and 
tolerability of respective RP2D of 
GSK2879552, alone or in 
combination with ATRA. 
1. AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, ECGs, physical 
examinations). 
2. To characterize the population PK of 
GSK2879552, alone or in 
combination with ATRA.  
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 clinical activity in terms 
of duration of response, time to 
response (TTR) and progression-
free survival (PFS) 
3. Duration of response (DoR), defined as 
the time from first documented evidence 
of PR or better until disease progression 
(PD) or death, among responders, i.e. 
confirmed PR or better.Time to Time to 
Response is defined as the time from first 
dose to the first documented evidence of 
response (PR or better). 
Progression-free survival (PFS), defined 
as the time from first dose until the earliest 
date of disease progression (PD), or death 
due to any cause.  
Exploratory 
1.  To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552, 
alone or in combination with ATRA. 
2. To evaluate the exposure response 
(PK/PD) relationship between 
GSK2879552, alone or in 
combination with ATRA and 
1.    Analysis of morphology, DNA, RNA 
and/or protein markers in blast cells from 
bone marrow aspirate and/or peripheral 
blood  sample 
2. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax or AUC (0-tau)) and 
safety/efficacy/PD parameters. PD 

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safety/efficacy/PD parameters. 
 
 
3. To investigate the relationship 
between genetic variants in 
candidate genes, PK and safety 
profile of GSK2879552, alone or in 
combination with ATRA. 
  
parameters assessed by change from 
baseline in select biomarkers, e.g. CD86 
and CD11b 
3. Pharmacogenomic (PGx) study using 
buccal samples 
Hypothesis 
Clinical response will be defined as Objective Response Rate (% of subjects achieving CR, 
PR, CRp or morphologic leukemia-free state) per response criteria. 
The null hypothesis is: H0: RR ≤10% 
The alternative hypothesis is: HA:  ≥30% 
3. 
STUDY POPULATION 
3.1. 
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 55 subjects will be enrolled into Part 1 dose-escalation and 
additional 25 subjects may be enrolled into PK/PD expansion cohorts in GSK2879552 
mono therapy and combination with ATRA arm.  Up to 60 subjects will be enrolled in 
Part 2 (expansion cohort) of GSK2879552 alone and combination with ATRA arm.  A 
total of approximately 140 subjects will be enrolled in the study.  Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels.  
In Part 1, 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. 
3.2. 
Subject Selection Criteria 
3.2.1. 
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) for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_03] 
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. 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. ≥18 years of age and provided signed written informed consent. 

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2. Subjects must have relapsed/refractory acute myeloid leukemia by WHO 
classification for which no standard therapies are available or anticipated to result 
in a durable remission.  FAB subtype M3 will be excluded. 
3. Subjects  ≥ 60 years of age with AML who are not candidates for or have refused 
standard chemotherapy.  
4. Subjects who have previously received an autologous stem cell transplant are 
allowed if a minimum of 3 months has elapsed from the time of transplant and the 
subject has recovered from transplant-associated toxicities prior to the first dose 
of GSK2879552. 
5. Subjects with a history of allogeneic stem cell transplant are eligible for study 
participation provided the following eligibility criteria are met: 
• 
transplant was >60 days prior to study enrollment. 
• 
subject has not taken immunosuppressive medications (including but not 
limited to: cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil) 
for at least 1 month 
• 
no signs or symptoms of graft versus host disease other than Grade 1 skin 
involvement 
• 
no active infection 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. 
7.  Subjects must be stable and, in the opinion of the investigator, be expected to 
complete 4 week treatment period. 
8. Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such 
as malabsorption syndrome or major resection of the stomach or bowels, 
9. 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).  
10. Adequate baseline organ function defined by:  

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System 
Laboratory Values 
Hematologic 
 
White blood cell count (absolute) 
≤30,000/uL 
Coagulation assays (PT/INR and aPTT)  
≤1.3 X ULN 
Hepatic 
 
Total bilirubin 
≤ 1.5 X ULN1 
ALT and AST 
≤2.5 × ULN  
Renal 
 
Calculated creatinine clearance by Chronic 
Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Appendix 3) or measured 
from 24hr urine 
 
≥ 40 mL/min 
Cardiac 
Ejection fraction 
≥ LLN by Echocardiogram (ECHO) or 
MUGA 
Lipid (ATRA combination ONLY)  
Triglyceride (fasting) 
Cholesterol (fasting) 
≤ 300 mg/dL 
≤ 300 mg/dL 
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 
 
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. 
11. 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 (Section 11.1), during the study and for 7 days (GSK2879552 mono 
therapy) or 30 days (combination with ATRA), following the last dose of study 
treatment. 
12. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception (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. 
3.2.2. 
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: 

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1. Active Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or 
Hepatitis C Virus (HCV) infections at the time of screening. Subjects with laboratory 
evidence of HCV clearance (HCV RNA PCR is negative) may be enrolled. 
2. History of or concurrent malignancy of solid tumours, except for below. 
Exception:  Subjects who have been disease-free for 5 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated 
in situ carcinoma are eligible.  Subjects with second malignancies that are indolent or 
definitively treated may be enrolled even if less than 5 years have elapsed since 
treatment.  Consult GSK Medical Monitor if unsure whether second malignancies 
meet requirements specified above 
3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- 
therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization)  
Note: HYDREA (hydroxyurea) will be allowed. 
4. Received major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK2879552 administration.  
5. Prior treatment with temozolomide, dacarbazine or procarbazine  
6. Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, 
ABT-888) 
7. Screening Montreal Cognitive Assessment (MOCA) score of 22 or lower 
8. Evidence of severe or uncontrolled systemic diseases (e.g., severe/chronic infection, 
unstable or uncompensated respiratory, 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  
9. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator’s assessment). 
10. Patients at risk of non-AML related major bleeding (e.g. recent GI hemorrhage or 
neurosurgery). 
11. Symptomatic or untreated CNS leukemia. Subjects are permitted to enroll if 
previously treated for CNS disease, free of symptoms at the time of screening, and 
have not required intrathecal chemotherapy at least 1 month prior to study Day 1. 
12. 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, Appendix 2). 
• 
History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months.  

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• 
Baseline QTc interval using Fridericia’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. 
13. Administration of an investigational drug within 14 days or 5 half-lives, whichever is 
shorter with a minimum of 14 days preceding the first dose of study treatment(s) in 
this study. 
14. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates 
their participation. 
15. Lactating female. 
16. 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.  
17. Current use of a prohibited medication including anticoagulants or platelet inhibitors 
(Section 10.2) or expected to require any of these medications during treatment with 
the investigational drug. 
18. Previous treatment with GSK2879552 
For ATRA Combination arm ONLY 
19. Known hypersensitivity to ATRA, parabens (preservatives in the gelatin capsule) or 
other retinoids.  
20. ATRA capsule contains sorbitol. Subjects with rare hereditary problems of fructose 
intolerance are excluded. 
21. History of seizure within 12 months or  brain tumor (primary) 
22. History of taking mega-dose vitamin A (>25,000 USP U/day) within 3 months from 
the dosing start. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Discussion of Study Design 
This is a Phase I, open-label, multi-center, non-randomized, 2-part study. Part 1 is a dose 
escalation phase to determine the MTD and/or RP2D for GSK2879552, alone or in 
combination with ATRA, based on the safety, tolerability, pharmacokinetic, and 
pharmacodynamic profiles observed after oral administration of GSK2879552. Eligible 
subjects with relapsed/refractory acute myeloid leukemia or elderly subjects who are 
ineligible for or refuse induction therapy will be enrolled. Any dose level(s) may be 
expanded up to 12 subjects in order to collect additional data on safety, tolerability, PK 
and PD. 
Once MTD and/or RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects 
each will be enrolled to further evaluate the efficacy and tolerability of GSK2879552, 
alone or in combination with ATRA, in subjects with relapsed/refractory AML.  

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The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose for GSK2879552 mono therapy arm will be 0.25 mg/day or the highest dose 
determined to be safe in the ongoing SCLC study, whichever is higher with a maximum 
of 1 mg/day (see Section 1.4.3.2 for details). The starting dose of GSK2879552 in 
combination with ATRA will be 1-2 dose levels below the highest dose determined to be 
safe in the GSK2879552 mono therapy arm in this study, i.e., 2 mg once daily. 
Alterations to the dose and schedule may be incorporated based on emerging PK, PD, and 
tolerability data.  
Dose reduction and/or truncated dose scheduling may be considered for subjects with 
recurrent/ persistent toxicity or according to the institutional guideline. For example, once 
the disease control (CR, CRp, PR or a morphologic leukemia-free state) is attained, 
ATRA may be given in an intermittent schedule, e.g., 2 week on/2 weeks off. 
Subjects may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent. The duration of study will depend on recruitment 
rates, and timing of subjects’ duration on study. The study will end 2 years from the last 
subject first dose or earlier if all patients are off study drug. Patients may be allowed to 
continue on study drug after the end of the study if the Investigator, in consultation with 
the sponsor’s Medical Monitor, determines that continuing treatment will benefit the 
patient.  
Figure 1 
Study Schema 
Part 1: Dose Escalation
Part 2: Expansion
Determine safety, tolerability and 
RP2D
Neuenschwander
- Continual 
Reassessment 
Method
MTD
PK, PD and 
tolerability
Efficacy and tolerability
(n=max. 30)
Evaluate clinical activity at 
RP2D
• PK/PD expansion: Any dose level could be expanded up to 12 subjects during 
dose escalation.
• Alternative dosing schedule may be explored. 
 
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. 

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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 
the site personnel with administrative and detailed technical information that does not 
impact subject safety. 
4.2. 
Part 1: Dose-Escalation Phase 
4.2.1. 
GSK2879552 Mono-therapy 
In Cohort 1, a single subject will receive a dose of GSK2879552 0.25 mg once daily or 
the highest dose determined to be safe in FTIH in SCLC study (GSK study 200858), 
whichever is higher with a maximum of 1 mg/day.  
The subject in Cohort 1will be evaluated for dose limiting toxicities (DLTs) during the 
first 4 weeks of treatment (DLT observation window), and the safety and PK data will be 
reviewed prior to a dose escalation decision and starting Cohort 2.  If the first subject 
becomes unevaluable 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 DLT observation window 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 4 weeks for reasons other than toxicity will be replaced. 
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 
• 
Any Grade 2 or higher non-hematologic adverse event that is considered related 
to the study medication with the following exceptions: 
o Grade ≤ 3 fatigue, asthenia, and nausea that respond to standard medical care 
within 72hrs, significant electrolyte abnormalities unrelated to underlying 
malignancy and corrected within 24 hrs, and alopecia  
• 
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. 
The subsequent cohorts may revert to 1 subject per cohort in either of the following 2 
scenarios:  

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• 
2 additional subjects are added at the dose where the toxicity was seen in the 
initial subject and no additional toxicity meeting the above criteria is seen in 
either of the 2 new subjects. 
• 
No subjects treated at next higher dose level have toxicity meeting the above 
criteria. 
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. 
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 DLT or any Grade 2 or higher non-hematologic adverse event that is 
considered related to the study medication (with the exceptions as above) is observed.  
The maximum allowable dose increment will be determined based on the prior dose level 
data.  
Completion of Dose Escalation 
The dose escalation will complete when MTD and/or 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.  Up to 12 additional subjects will be enrolled at the dose to further 
define the safety and tolerability of the dose and schedule.  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 data. Quality control of critical safety data will be 
described in the Dose Escalation Plan, which includes ongoing study monitoring visits, 
Sponsor review of the clinical database, and confirmation by site investigators and/or 
delegate that the data is accurate and complete.  
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/de-escalation 
should continue as recommended by the N-CRM. The dose-escalation decision and 

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rationale for each cohort will be discussed with investigators during teleconference(s) and 
documented in writing, with copies maintained at each study site and in the study master 
file. 
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 
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. 
 
 
 

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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 possible 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 1 shows the median prior probability of experiencing a DLT at a given 
dose along with a 95% credible interval around the median. This table does not imply that 
all doses will be studied: 
 
Table 1 
Specified Prior Probability of DLT 
Dose level (mg) 
2.5% Quantile 
for Probability of 
Toxicity 
Median 
Probability of 
Toxicity 
97.5% Quantile 
for Probability of 
Toxicity 
0.25 mg 
0.005 
0.01 
0.2 
0.5 mg 
0.01 
0.02 
0.25 
1 mg 
0.02 
0.03 
0.3 
1.5 mg 
0.02 
0.04 
0.35 
2 mg 
0.03 
0.05 
0.4 
2.5 mg 
0.04 
0.06 
0.5 
3 mg 
0.05 
0.07 
0.6 
4 mg 
0.05 
0.08 
0.7 
5 mg 
0.06 
0.1 
0.78 
6 mg 
0.07 
0.13 
0.85 
8 mg 
0.08 
0.16 
0.95 
10 mg 
0.1 
0.2 
0.99 
12 mg 
0.12 
0.24 
0.99 
15 mg 
0.13 
0.28 
0.99 
20 mg 
0.14 
0.35 
0.99 
25 mg 
0.15 
0.42 
0.99 
 
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 5 mg.  Doses are 
the projected doses.  Actual doses used during the conduct of the trial may vary. 

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Figure 2 
Prior Distribution For The Probability of DLT Given Dose 
 
4.2.2. 
GSK2879552 and ATRA combination 
In Cohort 1, three subjects will receive GSK2879552 2 mg once daily dose with ATRA 
45 mg/m2/day as two divided doses.  After all three subjects complete the first 4 weeks of 
treatment, the safety data will be reviewed for DLT. Available PK and PD data will be 
also reviewed prior to a dose escalation decision and starting Cohort 2. Each cohort will 
enroll 3 or more subjects to obtain sufficient data. If any subject becomes unevaluable for 
reasons other than toxicity, a replacement subject will be enrolled. In addition, subjects 
who fail to take at least 75% of their scheduled doses of each drug in the first 4 weeks for 
reasons other than toxicity will be replaced. Starting with Cohort1, the dose escalation 
will use the N-CRM with prior DLT information of GSK2879552 and ATRA mono-
therapies and follow the same rule with regards to the number of subjects, maximum dose 
increment, and the completion of dose escalation as described in Section 4.2.1. The 
details of priors used in N-CRM model is described in Section 13.2.  
Starting at dose level 1, the following GSK2879552 dose levels are planned for 
evaluation in combination with ATRA..  
Dose level 
GSK2879552 
ATRA 
1 
2 mg/day 
45 mg/m2/day 
2 
4 mg/day 
45 mg/m2/day 
3 
8 mg/day 
45 mg/m2/day 
4 
12 mg/day 
45 mg/m2/day 
5 
20 mg/day 
45 mg/m2/day 
 

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A reduced dose of GSK2879552 or ATRA may be considered if the combination is not 
well tolerated at dose level 1. The initial dose level reductions allow for either drug to be 
reduced. Subsequent dose levels are based on the totality of data and upon discussion 
with the investigators. 
Dose level 
GSK2879552 
ATRA fixed at 45mg/m2 
-1 
1 mg/day 
-2 
0.5 mg/day 
 

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Dose level 
GSK2879552 
ATRA <30mg/m2 
1a 
2 mg/day 
-1a 
1 mg/day 
-2a 
0.5 mg/day 
 
4.2.3. 
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.  However, PD sample (peripheral blood and bone 
marrow aspirate) collection may be stopped early at the sponsor’s discretion. Subjects 
may be enrolled at previously completed dose levels for the purpose of obtaining 
additional data.  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.  
4.2.4. 
Alternative Dosing and PK/PD Sampling Schedules 
In Part 1 Dose Escalation phase, subjects will initially receive daily dosing of 
GSK2879552. If the terminal half-life is longer than 5 hours, some subjects may be 
requested to withhold Day 2 and Day 3 dosing to obtain blood samples for PK analysis at 
timed intervals up to 72 hours after dosing. Once their final PK sample on Day 4 is 
obtained, these subjects would begin repeat dosing on Day 4.  In Part 2, subjects will 
begin repeat dosing per RP2D and regimen from Day 1. 
Further alterations may be made to the dosing schedule and/or PK/PD sampling schedule 
of GSK2879552 or ATRA based on the results of emerging PK, PD, efficacy and safety 
data, and documented in the SPM. These changes will be communicated to IRB/EC, but 
would not constitute a protocol amendment. 
Schedules that incorporate a recovery period may be explored (e.g., 4 days on/3 days off). 
Alternatively, a drug holiday after continuous dosing may be explored for GSK2879552 
and/or ATRA. 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.  

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4.2.5. 
Dose-Limiting Toxicity 
An event will be considered a DLT if it occurs within the first 28 days of treatment (with 
exception of myelosuppression as stated below), and meets one of the following criteria 
unless it can be clearly established that the event is unrelated to treatment.  
Subjects unable to receive at least 75% of scheduled doses within the DLT period 
for reasons other than toxicity (e.g., acute illness, disease progression) will not be 
evaluable  
• 
Hematologic DLT: Myelosuppression (as defined by absolute neutrophil count 
(ANC) <500/µl  AND platelets ≤25,000/µl) with bone marrow hypoplasia 
(cellularity ≤ 5%) without evidence of leukemia (<5% blasts) for ≥ 42 days after 
drug cessation.  
• 
Grade ≥3 non-hematologic toxicity that is considered clinically significant and lasts 
>72 hours. Fatigue, asthenia, or nausea that respond to standard medical care within 
72 hours and new electrolyte disturbance that respond within 24 hours are 
exceptions. In addition, electrolyte disturbances associated with underlying 
malignancy are not considered DLT. 
• 
Grade 2 toxicity that in the judgment of the investigator and GSK Medical Monitor 
is dose-limiting. 
• 
Treatment delay of ≥42 days due to unresolved toxicity (without evidence of 
leukemia (<5% blasts)).  
4.2.6. 
Maximum Tolerated Dose and Recommended Phase 2 Dose 
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.  The RP2D 
may be different for mono-therapy and for the combination therapy with ATRA. 
Data considered for RP2D selection will include, but not be limited to: safety, available 
PK profile, and observed signs of clinical activity from Part 1. 
 
4.3. 
Part 2: Expansion Cohort 
Once the respective RP2D have been determined, an expansion cohort of up to 30 
subjects each, GSK2879552 mono-therapy or in combination with ATRA, will be 
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Additional expansion cohorts may be initiated to test the efficacy of i) GSK2879552 at 
RP2D in ≥60 years old treatment naïve subjects, and ii) GSK2879552 in combination 
with other agents (demonstrated synergy in pre-clinical studies) in relapsed/refractory or 
≥60 years old treatment naïve subjects.   
The statistical design and number of subjects to be enrolled in the dose expansion cohort 
is based on the predictive probability of success if enrollment continues until all planned 
subjects are recruited [Lee, 2008]. The predictive probability design allows for evaluation 
of stopping rules after each subject once a minimum number of subjects are evaluable.   
In this particular study, we will stop only for futility. Final decisions on stopping 
enrolment will depend on the totality of the data collected. 
4.4. 
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 a higher dose level cohort has been cleared 
without a DLT. 
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. 
Subjects approved for intra-subject dose escalation will require additional limited PK 
sampling at the higher dose as determined by GSK Clinical Pharmacology. 
4.5. 
Study Treatment 
4.5.1. 
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. 
4.6. 
Dosage and Administration of Study Treatment(s) 
See Section 5.1 for the dosage and administration of GSK2879552 and ATRA. 
4.6.1. 
Meals and Dietary Restrictions 
Subject should refrain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids, grapefruit juice, pomelos, or exotic citrus fruits, which may inhibit efflux 
transporters, from 1 day prior to the first dose of study treatment(s) until the last dose of 
study drug. 
GSK2879552 will be administered under fasting conditions, either 1 hour before or 
2 hours after a meal. Subjects should take their morning ATRA dose fasted, at the same 
time as GSK2879552. If ATRA concentrations are lower than anticipated following 
fasted administration, subjects may be asked to take their morning ATRA dose with food. 
Subject should take their evening ATRA dose with food. 

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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 study medication. 
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. 
4.6.2. 
Blinding 
This is an open-label study. 
4.7. 
Safety Management Guidelines 
4.7.1. 
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) ≥5 X (times) upper limit of normal (ULN) and 
bilirubin ≥2 Xs ULN (or ALT ≥5 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 ≥8 X ULN. 
3. ALT ≥5 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). 
4. ALT ≥5X ULN persists for ≥4 weeks. 
5. ALT ≥5 X ULN and cannot be monitored weekly for 4 weeks. 
Subjects with ALT ≥5 X ULN and <8 Xs 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 following section for details on weekly follow-up 
procedures for these subjects. 
4.7.1.1. 
Liver Chemistry Follow-up Procedures 
Refer to the diagram in Appendix 5 for a visual presentation of the procedures listed 
below. 
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 4.7.1: 
• 
Immediately withdraw the subject from study treatment.  

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• 
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 approval as described in Section 9. 
Safety Follow-Up Procedures for subjects with ALT ≥3 times 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 ≥5 times ULN and bilirubin ≥2 
times ULN (or ALT ≥5 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 ≥5 times 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). 
• 
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 120 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 

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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 ≥5 times ULN and bilirubin ≥2 times 
ULN (>35% direct) or ALT ≥ 5 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 HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]). NOTE: not required in China   
• 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 PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793. 
4.7.2. 
QTc Stopping Criteria 
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.   
• 
QT interval corrected for heart rate by Fridericia’s formula (QTcF = QT / 
CubeRootRR) >500 msec  
• 
Increase of QTcF by ≥60 msec from baseline 
• 
For patients with underlying bundle branch block, follow the discontinuation 
criteria listed below: 

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Baseline QTc with Bundle Branch Block 
Discontinuation QTc with Bundle Branch 
Block 
< 450 msec 
> 500 msec 
450 – 480 msec 
≥ 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. 
If the QTc prolongation resolves to Grade 1 or baseline, 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 7 for the French specific QTc 
stopping criteria. 
4.7.3. 
Mental Status Stopping Criteria 
Enrollment will be stopped upon the occurrence of any encephalopathy, unless 
clearly attributable to central nervous system disease involvement or intercurrent 
illness. 
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 (Pre-dose Day 1) 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 or to the MOCA score before the decrease. 
• 
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. 

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4.8. 
Guidelines for Events of Special Interest and Dose 
Modifications 
The severity of adverse events (AEs) will be graded utilizing the National Cancer 
Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version v4.03.  
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment(s) are provided in this section. 
4.8.1. 
Events of Special Interest 
Any signs of bleeding, bruising and infection will be monitored closely throughout the 
study. Platelet transfusion will be administered following institutional guidelines and 
practices. Neutropenia and anemia management and fungal or bacterial prophylaxis will 
also follow institutional guidelines. 
4.8.2. 
Dose Adjustment for Non-Hematologic Toxicity 
See Table 2 Dose Adjustment Guideline for drug related non-hematologic toxicities 
based on worst grade. 
Table 2 
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† 
Hold for 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. 
*Note: Exceptions to ≤ drug-related Grade 1 requirement may be made for rash, alopecia, quickly reversible (<72 
hours) laboratory abnormality (example: electrolyte changes). 
†In combination cohort, consider holding ATRA dosing first for skin related toxicity (dryness, rash), nausea, vomiting, 
pain, headache, and mucositis. With fever, consider holding LSD1 first to allow neutrophil count to recover. 
If the non-hematologic toxicity or event resolves to baseline or ≤ Grade 1 within 14 days 
of stopping therapy, treatment with GSK2879552 and/or ATRA 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 non-hematologic 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.  

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4.8.3. 
Dose Adjustment For Hematologic Toxicity 
Toxicity 
Dose Adjustment/ 
Stopping Criteria 
Management Guidelines 
At all thrombocytopenia grades, implement fall precautions to avoid bleeding due to trauma, e.g. 
trauma to head can cause a subdural hematoma. This risk increases with higher grades of 
thrombocytopenia 
Thrombocytopenia 
regardless of blast 
count 
Grade 1, 2 & 3 (platelets 
≥25,000/mm3) 
Continue dosing at same dose level with more frequent 
monitoring as necessary. 
 
Thrombocytopenia 
if blasts >5% 
Grade 4 (platelets  
<25,000/mm3) and/or 
any grade accompanied 
by severe bleeding 
related to 
thrombocytopenia 
 
If platelet count <25,000/mm3 but ≥10,000/mm3:  
1. Use clinical judgement to institute more frequent 
monitoring as necessary  
2. Institute platelet transfusion as appropriate. 
 
If platelet count <10,000/mm3: 
1. Continue treatment and start platelet transfusion 
as per institutional guidelines.  
2. If repeat platelet transfusions are not able to 
rescue platelet count, then consider irradiated, 
leukapherised or HLA-matched platelets as 
clinically appropriate 
3. If still unable to rescue platelet count, investigator 
may consider treatment interruption in discussion 
with medical monitor.   
4. Use of concomitant therapies (tranexamic acid) is 
permitted. Please note tranexamic acid is 
prohibited for subjects receiving GSK2879552 in 
combination with ATRA. 
5. Use of hydroxyurea in the setting of increased 
blast counts in conjunction with decreased 
platelet counts is permitted. 
 
Thrombocytopenia 
if blasts <5%  
 
 
 
 
 
 
 
 
 
 
Grade 4 (platelets  
<25,000/mm3) and/or 
any grade accompanied 
by severe bleeding 
related to 
thrombocytopenia 
 
If platelet count <25,000/mm3 but ≥10,000/mm3:  
1. Use clinical judgement to institute more frequent 
monitoring as necessary  
2. Institute platelet transfusion as appropriate. 
 
If platelet count <10,000/mm3 (or ≤25,000/mm3 with 
accompanying fever, sepsis, or minor bleeding): 
1. Treatment may be held for up to 4 weeks and 
resume* as soon as count recovery has occurred 
(i.e., neutrophils ≥0.5 and platelets ≥25 x 109/L). 
Use clinical judgement to institute more frequent 
monitoring as necessary. 
2. The treatment may be held for additional 1-2 
weeks if the neutrophil and platelet counts do not 
recover after the initial 2 weeks. 
3. After a total of 5-6 consecutive weeks, if there is 
no evidence of recovering blood counts, a repeat 
bone marrow examination should be performed 

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Toxicity 
Dose Adjustment/ 
Stopping Criteria 
Management Guidelines 
 
 
 
during that period (approximately -35-42 days 
after drug cessation) to evaluate for the possibility 
of hematologic DLT. 
4. If persistent for 6 weeks and not attributed to 
disease or requires platelet transfusions for 
bleeding in the absence of the disease, the 
subject will be withdrawn from the study.  
*If treatment resumes, the dose and schedule may be 
adjusted based on platelet count, i.e., dose can be 
reduced by at least 25% increments up to two times.   
 
4.8.4. 
Safety Management for ATRA Combination 
4.8.4.1. 
Retinoic Acid syndrome 
About 25% of patients with APL treated with ATRA have experienced the retinoic acid- 
(RA) syndrome characterized by fever, dyspnea, acute respiratory distress, weight gain, 
radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, and hepatic, 
renal, and multi-organ failure [ATRA Prescribing Information, 2004]. This syndrome has 
occasionally been accompanied by impaired myocardial contractility and episodic 
hypotension. The syndrome generally occurs during the first month of treatment, with 
some cases reported following the first dose of ATRA.   
Retinoic Acid Syndrome should be strongly suspected if the following signs or symptoms 
(without any other clear or established etiology) emerge during treatment with 
GSK2879552: 
• New or worsening progressive dyspnea or hypoxemia, with increasing demands 
for supplemental oxygen; respiratory distress refractory to treatment for the 
initially suspected cause 
• Radiologic evidence of new or worsened bilateral pulmonary involvement 
(infiltrates or opacities) with or without presence of infection, refractory to 
treatment with anti-infectives (antibiotics, antivirals, antifungals) 
• Radiologic evidence of new or worsened pleural or pericardial effusion that is 
refractory to treatment for an initially suspected cause 
• New or worsened peripheral edema, with rapid weight gain (e.g., >5 kg/11 pounds 
over 7 days) 
• Increase in serum creatinine (e.g., >2-fold from baseline) 
• The following symptoms or signs may be features of retinoic acid syndrome but if 
isolated and not accompanied by pulmonary or renal manifestations, may not 
require rapid initiation of retinoic acid syndrome treatment (unless sufficiently 
severe and prolonged): 
o Unexplained fever ≥38oC (100.4oF) 
o Rash of unknown origin 
o Bone pain 

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o Lymphadenopathy 
The measures below are recommended to be taken at the earliest manifestations of 
suspected retinoic acid syndrome: 
• Patients with severe or rapidly progressing retinoic acid syndrome should be 
hospitalized for continued observation 
• In case of uncertainty with the diagnosis, e.g., presence of less specific symptoms 
of moderate severity, patients should be closely monitored, as the condition may 
rapidly worsen 
• Corticosteroids should be promptly initiated (e.g., 10 mg of dexamethasone every 
12 hours until resolution of retinoic acid syndrome). Once resolved the 
corticosteroid dose can be progressively reduced over 1-2 weeks 
• GSK2879552 and/or ATRA may be withheld at the physician’s discretion. Due to 
the long half-life of GSK2879552 (about 16 hours), treatment interruption may 
not immediately reverse the symptoms of retinoic acid syndrome. If interrupted, 
GSK2879552 treatment may be reinitiated at the original or a reduced dose, once 
the signs and symptoms resolve and the patient’s clinical condition improves 
• In patients with elevated WBC counts, prompt initiation of hydroxyurea is 
suggested, or treated as per standard local practice (e.g., dose of 2 to 3g PO 2- or 
3-times daily for WBC >30x109/L) 
• In cases of severe leukocytosis, use of leukapheresis may be appropriate 
• For substantial fluid accumulation, initiation of furosemide may be appropriate, as 
per local standard practice 
• Patients with pericardial effusion (a less common manifestation of retinoic acid 
syndrome) can require urgent cardiac intervention due to it being a life-
threatening condition  
• Patients with increasing serum creatinine levels should be evaluated for tumor 
lysis syndrome 
• Patients experiencing a rapid increase in peripheral blood cells should be 
monitored for disseminated intravascular coagulopathy and hemorrhage  
• Imaging techniques such as standard or high-resolution computerized tomography 
(CT) scan and chest X-ray are useful for establishing a diagnosis of retinoic acid 
syndrome by identifying pulmonary infiltrates or effusions; noting that a CT scan 
is  more sensitive in detecting early radiological signs of retinoic acid syndrome-
associated changes 
 

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4.8.4.2. 
Liver Function Test Elevation 
If ALT ≥5 X ULN, ATRA dose should be held while GSK2879552 dosing continues 
• 
If resolved in 14 days, ATRA dose should resume at full dose 
• 
If not resolved in 14 days, GSK2879552 dose should be also held. 
o If resolved in another 14 days, resume GSK2879552 at a reduced dose by 
minimum 25% and ATRA at full dose 
o If not resolved in another 14 days, withdraw the subject from the study.  
 
4.8.4.3. 
Pseudotumor Cerebri (benign intracranial hypertension) 
Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual 
disturbances.  Subjects with these symptoms should be evaluated for pseudotumor 
cerebri, and, if present, appropriate care should be instituted including high dose steroid. 
ATRA dose should be held for moderate to severe pseudotumor cerebri.   
5. 
INVESTIGATIONAL PRODUCT(S) 
The term ‘study treatment’ is used throughout the protocol to describe investigational 
product(s) (IP) received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.  
5.1. 
Description of Investigational Product(s) 
Product 
name: 
GSK2879552 Capsule 
Formulation 
description*: 
GSK2879552 capsules contain 0.5 mg, 2 mg or 5 mg of GSK2879552 as 
parent.   
Dosage 
form: 
Capsule 
Unit dose 
strength(s) 
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: 
0.5 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. 
* NOTE: 0.25 mg strength of GSK2879552 capsule is no longer being used and is removed from the table.   

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GSK2879552 will be provided to sites by GSK, whereas ATRA will be locally supplied 
and prepared according to local standards.  The contents of the label will be in 
accordance with all applicable regulatory requirements. 
Product name: 
Tretinoin (ATRA) Capsule 
Formulation 
description: 
ATRA is supplied as a 10 mg capsule for oral administration.  
Dosage form: 
Capsule 
Unit dose strength(s) 
10 mg 
Route/Regimen 
Oral/The initial dosing regimen will be continuous oral twice daily 
dosing, i.e., morning and evening. ATRA dose may be divided evenly 
2-4 times a day, as needed. 
Subjects should take their morning dose fasted, at the same time as 
GSK2879552. If ATRA concentrations are lower than anticipated 
following fasted administration, subjects may be asked to take their 
morning ATRA dose with food. Subject can take their evening ATRA 
dose with food.  
5.2. 
Preparation/Handling/Storage of 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 Study Procedures Manual (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.  See package insert for ATRA storage conditions.  
Maintenance of a temperature log (manual or automated) is required at the clinical sites. 

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5.3. 
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. 
5.4. 
Treatment Compliance 
On clinic days, GSK2879552 and ATRA 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 IP 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 capsules dispensed to and taken by each subject must be 
maintained and reconciled with study treatment and compliance records.  Treatment start 
and stop dates, including dates for treatment delays and/or dose reductions will also be 
recorded in the eCRF. 
5.5. 
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. 
The MTD of ATRA in patients with myelodysplastic syndrome or solid tumors was 
195mg/m2/day. Overdosage with other retinoids has been associated with transient 
headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These 
symptoms have quickly resolved without apparent residual effects. There is no specific 
treatment in the case of an overdose, however, it is important that the patient be treated in 
a special hematological unit [ATRA Prescribing Information, 2004]. 
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. 

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6. 
COMPLETION OR WITHDRAWAL OF SUBJECTS 
6.1. 
Screen and Baseline Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and any Serious Adverse Events. 
Individuals who do not meet the criteria for participation in this study (screen 
failure) may be rescreened. Rescreened participants should be assigned the same 
participant number as for the initial screening if rescreening for same arm of study 
(monotherapy to monotherapy or ATRA combination to ATRA combination.)  If 
rescreening for a different arm of the study, (monotherapy to ATRA combination or 
ATRA combination to monotherapy) participants will need a new screening number.  
Please refer to the Study Procedures Manual for more details.  
 
6.2. 
Subject Completion Criteria 
In Part 1, a subject will be considered to have completed the study if: 
• 
they complete screening assessments, the 28-day DLT observation period, and taking 
a minimum of 75% of planned doses, 
• 
they progress or die while receiving study treatment, or 
• 
they are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study. 
In Part 2, a subject will be considered to have completed the study if: 
• 
they die while receiving study treatment, 
• 
they progress while receiving study treatment and are followed until death, or 
• 
they are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study. 
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  The End of Study eCRF should only be completed when 
a subject is no longer being followed.   
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 4.7.1.  
The investigator may discuss with a GSK Medical Monitor continuing a subject who is 
receiving benefit but has met the criteria for disease progression, if the following criteria 
are met: Investigator-determined clinical benefit (e.g. symptomatic improvement), lack of 

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significant toxicity (no drug related non-hematologic grade 3/4 AEs within the last 4 
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 
• 
A clinically significant hematologic adverse event leading to an interruption of 
treatment for greater than 28 days.  Subjects will be allowed up to a 28-day 
delay in dosing for hematologic toxicity to resolve or for scheduling difficulties.  
If the investigator and GSK Medical Monitor conclude that the benefit: risk 
supports continued treatment of a subject who has had a > 28 day treatment 
delay, then the subject may continue therapy with the approval of the GSK 
Medical Monitor. 
• 
A clinically significant non-hematologic adverse event leading to an interruption 
of treatment for greater than 14 days.  Subjects will be allowed up to a 14-day 
delay in dosing for non-hematologic toxicity to resolve or for scheduling 
difficulties.  If the investigator and GSK Medical Monitor conclude that the 
benefit: risk supports continued treatment of a subject who has had a > 14 day 
treatment delay, then the subject may continue therapy with the approval of the 
GSK Medical Monitor.  
• 
Persistent G4 thrombocytopenia for 4 weeks not attributed to disease or requires 
platelet transfusions for bleeding in the absence of the disease. 
• 
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.  
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).   

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6.4. 
Study Completion 
The study will be considered completed, having met the study objectives, when 80% or 
more subjects in Part 2 have withdrawn from the study. 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 assessments.  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. 
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. 
Detailed procedures for obtaining each assessment are provided in the Study Procedures 
Manual (SPM). 
Visit Window 
Informed consent should be signed within 35 days prior to dosing.  
 

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Baseline disease assessment should be completed within 21 days prior to dosing start.  
ECHO/MUGA should be completed within 35 days prior to dosing start. 
Pregnancy testing should be completed 7 days prior to dosing start and all other 
screening assessments should be completed within 14 days prior to dosing start. 
Visits in the first 4 weeks will be allowed ± 1 day window. Bone marrow on Day 15 can 
be done between Day 8 and Day 21. 
Visits beyond the first 4 weeks will have ± 3 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, 8, and 10 hours post dose sampling: ±30 minutes 
24 hours post dose sampling: ±1 hour and should be done before the next dose 
administration. 
48 and 72 hours post dose sampling: ±3 hours. The 72 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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Table 3 
Time and Events, Part 1 Dose Escalation 
SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
SFU 
Q12W 
  
D 1 
D 2 
D 4 
D 8 
D 11 
D 15 
D 16 
D 18 
D22 
D25 
 
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 
 
 
  
 
Review subject dosing diary 
X 
X 
X 
 
every 4 wks 
X  
 
Study Drug Dosing14 
< -------------------------------------------------- Daily or per dosing schedule ------------------------------------------- 
 
Study Drug Dispensing  
X 
 
every 4 wks 
 
Complete physical exam 
X 
 
 
X 
 
Brief physical exam 
X11 
X 
 
every 4 wks 
 
Montreal Cognitive 
Assessment 
X 
X 
 
 
X 
 
X 
 
 
X 
 
Wk 4 and every 4 wks 
 
Performance status  
X 
X11 
X 
 
every 4 wks 
X 
 
Vital Signs 
X 
X11 
 
X 
X 
 
X 
 
 
 
 
every 4 wks 
X 
 
Height and weight10 
X 
X11 
X 
 
every 4 wks 
X 
 
ECHO or MUGA 
X 
 
 
x 
 
12-lead ECGs 
X 
X 
 
 
X 
 
 
 
 
 
 
every 4 wks 
X 
 
HIV, HBsAg and HCV Ab 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X11 
 
X 
X 
X 
X 
 
X 
X 
X 
Every week x 4(wk 4-7), wk 
8  then every 4 wks16 
X 
 
Chemistry Panel including 
liver function tests 
X 
 
 
X22 
X 
X22 
X 
 
 
X 
 
every 4 wks 
X 
 

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SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
SFU 
Q12W 
  
D 1 
D 2 
D 4 
D 8 
D 11 
D 15 
D 16 
D 18 
D22 
D25 
 
Fasting Lipid panel 
(triglyceride, cholesterol)22 
X 
 
 
 
X 
 
X 
 
 
X 
 
every 4 wks 
 
 
Coagulation Panel (PT, PTT, 
INR, fibrinogen) 
X 
 
 
 
X 
 
X 
 
 
X 
 
every 4 wks 
X 
 
Vitamin B12, TSH, Free T4 
or Free T323 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Fetal hemoglobin  
(Hgb F) 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Pregnancy test8 
X 
 
every 4 wks 
X 
 
PK Blood samples 
 
X1 
X1 
X4 
X2 
 
X3 
X3 
 
X4 
 
Every week x 4 (wk 4-7), wk 
8, then every 4 wks4  
  
 
Blood samples for PD6, 21 
(peripheral blood)  
X 
 
X 
X 
X 
bone marrow day6 
 
 
Wk 4, between Wk 6- 8, Wk 
12 and then every 12 wks. 
X 
 
Blood samples for 
exploratory studies6, 21 
(peripheral blood)  
X 
 
 
X 
 
 
 
 
 
 
Bone marrow aspirate for 
PD21 
X7 
 
 
 
 
X18  
 
 
Wk 4, between Wk 6- 8, Wk 
12 and then every 12 wks  
X17 
 
Bone marrow aspirate for 
exploratory studies  21 
X7 
 
 
 
 
X18  
 
 
Wk 4, between Wk 6- 8, Wk 
12 and then every 12 wks. 
X17 
 
Blood smear to measure 
blasts 
X 
 
 
X 
X 
 
X 
 
 
 
 
Every week x 4 (wk 4-7), 
Wk8, then every 4 wks 
 
Bone marrow 
aspirate/biopsy for disease 
assessment24, 25 
X20 
 
 
 
 
X18 
 
 
Wk 4, between Wk 6- 819, 
Wk 12 and then every 12 
wks.  
 
Telephone call for survival 
status26 
 
 
 
 
 
 
 
 
 
 
X 
PGX sample (buccal swab) 
X 
 
 
 
PK blood sample on bone 
marrow day 15 
 
 
 
 
 
X (bone marrow day) 
 
 
Wk 4, between Wk 6- 8, Wk 
12 and then every 12 wks 
 
Transfusion Asssessment13 
X 
 
 
 
X 
 
X 
 
 
X 
 
Every week x 4 (wk 4-7), wk 
8, then every 4 wks 
 

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SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
SFU 
Q12W 
  
D 1 
D 2 
D 4 
D 8 
D 11 
D 15 
D 16 
D 18 
D22 
D25 
 
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 
evaluation 
 
X5, 12 
X5 
 
 
 
X5 
X5 
 
 
 
 
 
Urine for PK 
X5, 12 
X5 
X5 
X5 
 
 
 
 
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, 10, and 24 hrs post dose. In the combination 
cohort, a blood sample for ATRA PK analysis will be also collected at the same time points except for the 0.25, 10 and 24 hour sample. Additional samples may be 
collected at 48 and 72 hrs post dose in subjects not receiving a dose on Days 2 and 3 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. In the combination cohort, a blood sample for ATRA 
PK analysis will be also collected at the same time points. 
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, 10, and 24 hrs post dose. In the combination 
cohort, a blood sample for ATRA PK analysis will be also collected at the same time points except for the 0.25, 10 and 24 hour sample. 
4. 
PK blood sample should be taken pre-dose around 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.  
5. 
On Days 1 and 15, 24hr urine will be collected in the highest dose cohort in PK/PD expansion cohorts starting from post-dose on Day 1 and 15, and for 24 hours, i.e., 
until dosing on Days 2 and 16, respectively. The 24hr urine will be measured and samples collected for PK and metabolite evaluation.  
6. 
Blood samples for PD and exploratory studies should be collected pre-dose. 
7. 
A fresh bone marrow aspirate is requested from all subjects. This requirement is mandatory for all subjects participating in the PK-PD cohorts. 
8. 
For women of child bearing potential only. Serum pregnancy test is required for screening and EOT 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 3 subjects. The plasma samples will 
be collected at following time points on Days 1 and 15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 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 and metabolite evaluation at pre-dose on D1 in the highest dose cohort in PK/PD expansion cohorts. 
13. Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly cumulative basis.   
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. PK blood sample should be collected pre-dose on the day of bone marrow biopsy. This sample should be collected if the bone marrow biopsy was performed on the 
non-planned visit days and the “PK blood sample” was not collected, 

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16. Twice weekly CBC monitoring may continue per institutional guidelines. 
17. Bone marrow aspirate at the time of progression is optional for all subjects. 
18. Between D8 and D21, timing to be optimized based on emerging data.  
19. The assessment of response should occur between 1 – 4 weeks of count recovery (ANC > 1000/µl and platelets > 100,000/µl). Subjects should be off cytokine 
support (GCSF or GMCSF) for a minimum of 7 days before obtaining bone marrow to document remission. 
20. Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing should be performed as part of disease assessment at 
baseline. Cytomorphology is the preferred method to determine bone marrow blast counts. However, if a bone marrow aspirate cannot be obtained for 
cytomorphology review, a bone marrow biopsy is strongly recommended to determine the bone marrow blast count. 
21. In PK/PD expansion cohorts, PD and/or exploratory sample (peripheral blood and BMA) collection may be stopped earlier at the sponsor’s discretion. 
22. ATRA combination arm only.  
23. Free T3 to be tested only when clinically indicated 
24. At any time point in the study, if a bone marrow aspirate is found to be hemodilute (no spicules) or uninterpretable, then a bone marrow biopsy is strongly 
recommended to be collected at the next disease assessment time point in addition to the aspirate to ensure the conduct of a disease assessment. 
25. BM slides may be evaluated for changes in morphology. 
26. The Survival FU visit should be completed every 12 weeks after documented disease progression (or after initiation of another anticancer treatment). Subjects should 
be contacted every 12 weeks (±2 weeks) until death occurs. 
 
 
 

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Table 4 
Time and Events Table: Part 2 – Expansion Cohort 
  
SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
SFU 
  
D 1 
D4 
D 8 
D11 
D 15 
D18 
D22 
D25 
Q12W 
Office Visit 
X 
X 
X 
X 
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 
 
 
every 4 wks 
X  
 
Study Drug Dispensing  
X 
 
 
 
 
 
every 4 wks 
 
Complete physical exam 
X 
 
 
 
 
 
X 
 
Brief physical exam 
X7 
X 
 
 
 
 
every 4 wks 
 
Montreal Cognitive Assessment 
X 
X 
X 
 
X 
X 
 
Wk 4 and every 4 wks 
 
ECOG PS 
X 
X7 
X 
 
 
 
 
every 4 wks 
X 
 
Vital Signs 
X 
X7 
 
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 
 
HIV, HBsAg and HCV Ab testing 
X 
 
 
 
 
 
 
CBC 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
Weekly x 4 wks (Wk 4-7), 
Wk 8 and every 4 wks12 
X 
 
Chemistry Panel including LFT 
X 
 
X18 
X 
X18 
X 
 
X 
 
every 4 wks 
X 
 
Fasting Lipid panel (triglyceride, cholesterol)18 
X 
X 
 
X 
X 
 
Every 4 wks 
 
Coagulation Panel including PT, PTT, INR, 
fibrinogen 
X 
 
 
X 
 
x 
 
X 
 
every 4 wks 
X 
 

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SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
SFU 
  
D 1 
D4 
D 8 
D11 
D 15 
D18 
D22 
D25 
Q12W 
Vitamin B12, TSH, Free T4 or Free T320 
X 
 
 
 
 
 
 
PK Blood samples 
 
X1 
X8 
X8 
 
X2 
 
 
 
Weekly x 4 wks (Wk 4-7), 
Wk 8 and every 4 wks8 
  
 
Fetal hemoglobin (Hgb F) 
 
X 
 
X 
 
X 
 
 
 
 
 
Pregnancy test4 
X 
 
 
 
 
 
every 4 wks 
X 
 
Blood samples for PD (peripheral blood)3, 19 
X 
 
X 
X 
bone marrow day14 
 
 
Wk 4, between Wk 6-8, Wk 
12, then every 12 wks 
X 
 
Blood samples for exploratory studies3, 19 
(peripheral blood) 
X 
 
X 
 
 
 
 
 
 
Bone marrow aspirate for PD19 
X 
 
 
 
X14 
 
 
Wk 4, between Wk 6-8, Wk 
12, then every 12 wks 
X5 
 
Bone marrow aspirate for exploratory studies 19 
X11 
 
 
 
X14 
 
 
Wk 4, between Wk 6-8, Wk 
12, then every 12 wks 
X5 
 
Blood smear to measure blasts 
X 
 
 
X 
 
X 
 
 
 
Every week x 4 (Wk 4-7), Wk 
8 then every 4 wks 
 
Bone marrow aspirate /biopsy for disease 
assessment 21, 22 
X16 
 
 
 
X14 
 
 
Wk 4, between Wk 6-813, Wk 
12, then every 12 wks 
 
Telephone call for survival status 23 
 
 
 
 
 
 
 
 
 
X 
PGX samples (buccal swab) 
X 
 
 
 
 
 
PK blood sample on bone marrow day15 
 
 
 
 
X (on bone marrow day) 
 
 
Wk 4, between Wk 6- 8, Wk 
12, then every 12 wks.  
 
Transfusion Assessment10 
X 
 
 
X 
 
X 
 
X 
 
Every week x 4 (wk 4-7), Wk 
8, then every 4 wks 
 
Adverse Events 
Continuous 
 
Con Meds 
Continuous 
 
 
1. 
A blood sample will be collected for PK analysis on D1 at pre-dose, 0.5, and 3 hrs post dose. . In the combination cohort, a blood sample for ATRA PK analysis will be 
collected at the same time points. 
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. In the combination cohort, a blood sample 
for ATRA PK analysis will be collected at the same time points. 

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3. 
Blood samples for PD, exploratory  studies should be collected pre-dose.  
4. 
For women of child bearing potential only. Serum pregnancy test is required for screening and EOT visits. Urine pregnancy test is adequate during study visits. 
5. 
Bone marrow aspirate at the time of progression is optional for all subjects. 
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 around the same time as CBC. PK sample will not be collected beyond 48 weeeks.  
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.  
10. Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly cumulative basis   
11. A fresh bone marrow aspirate at baseline is required in Part 2 
12. Twice weekly CBC monitoring may continue per institutional guidelines. 
13. The assessment of response should occur between 1 – 4 weeks of count recovery (ANC > 1000/µl and platelets > 100,000/µl). Subjects should be off cytokine 
support (GCSF or GMCSF) for a minimum of 7 days before obtaining bone marrow to document remission. 
14. Between D8 and D21, timing to be optimized based on emerging data. 
15. PK blood sample should be collected prior to dosing on biopsy days. This sample should be collected if the bone marrow biopsy was performed on the non-planned 
visit days and the “PK blood sample” was not collected within the time frame 
16. Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing should be performed as part of disease assessment at 
baseline. Cytomorphology is the preferred method to determine bone marrow blast counts. However, if a bone marrow aspirate cannot be obtained for 
cytomorphology review, a bone marrow biopsy is strongly recommended to determine the bone marrow blast count. 
17. Sample should be collected at pre-dose on the day of bone marrow aspirate collection.  
18. ATRA combination only 
19. PD and/or exploratory sample (peripheral blood and BMA) collection may be stopped earlier at the sponsor’s discretion 
20. Free T3 to be tested only when clinically indicated 
21. At any time point in the study, if a bone marrow aspirate is found to be hemodilute (no spicules) or uninterpretable, then a bone marrow biopsy is strongly 
recommended to be collected at the next disease assessment time point in addition to the aspirate to ensure the conduct of a disease assessment. 
22. BM slides may be evaluated for changes in morphology. 
23. The Survival FU visit should be completed every 12 weeks after documented disease progression (or after initiation of another anticancer treatment). Subjects should 
be contacted every 12 weeks (±2 weeks) until death occurs. 
 
 
 

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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 assessed as related to the eligibility criteria listed in Section 
3.2. 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 obtained 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, TSH, free T3 or free T4 (see Table 5 for full list of laboratory tests 
required at screening). Patients should have baseline thyroid function, vitamin B12, 
and metabolic panel within acceptable limits (FDA request May 2015).  
• 
Lipid panel (ATRA combination only): triglyceride and cholesterol  
• 
Serum beta-human chorionic gonadotropin (β-HCG) pregnancy test for female 
subjects of childbearing potential only  
• 
12-lead electrocardiogram (ECG) 
• 
Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan  
• 
Baseline disease assessment and bone marrow aspirates  
• 
Review of concomitant medications 
• 
Montreal Cognitive Assessment (MOCA) 
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 
CBC will be monitored twice weekly in the first 4 weeks, followed by once weekly x 4 
weeks and then every 4 wks thereafter. CBC may be monitored more frequently 
according to the institutional guideline. 
Planned time points for all safety assessments will include physical exam, vital signs, 
clinical laboratory tests including chemistry, hematology, and coagulation panel, ECGs 
and ECOG performance status. AEs and toxicities will be assessed throughout the study 
and will be graded according to NCI-CTCAE v. 4.03.  
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. 
Planned time points for all safety assessments are provided in the Time and Events Table 
(Section 7.1). 
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 4) 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 8.  
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. Refer to the SPM for details regarding 
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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 4.7.2 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. 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 5 should be performed 
according to the Time and Events Table (Section 7.1).   
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 30 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
Hematology, clinical chemistry, coagulation panel and additional parameters to be tested 
are listed in Table 5: 

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Table 5 
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 
Blast count 
 
 
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 
Phosphate 
Lactate Dehydrogenase (LDH) 
Thyroid Stimulating 
Hormone 
Free T4 or Free T3 
Vitamin B12 
 
 
 
Lipid 
Triglyceride 
Cholesterol 
 
 
Other tests 
Coagulation Panel including PT, PTT, INR, fibrinogen 
Fetal hemoglobin (Hgb F) 
Other screening tests 
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only) 
HIV, Hepatitis B surface antigen (HBsAg) and Hepatitis C antibody (HCV Ab) testing 
1. 
Direct bilirubin should be assessed only if total bilirubin is elevated beyond the upper limit of normal (ULN) 
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 β-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 7 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 

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as an adverse event (AE) or serious adverse event (SAE).  Spontaneous abortions must be 
reported as an SAE. 
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 and ATRA 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 the highest dose 
cohort of the PK/PD expansion in 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 PK analysis of GSK2879552 and metabolite profiling will be collected 
in the highest dose cohort of the PK/PD expansion in 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 urine sample collection will be recorded. 
Details on PK urine sample collection, processing, storage and shipping procedures are 
provided in the SPM. 
7.4.3. 
Pharmacokinetic Sample Analysis 
Plasma sample analysis will be performed under the management of Bioanalysis, 
Immunogenicity & Biomarkers (BIB), In Vitro/In Vivo Translation (IVIVT), Platform 
Technology and Science (PTS), GlaxoSmithKline for GSK2879552 and InVentiv Health 

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Clinical for ATRA.  Concentrations of GSK2879552 and ATRA will be determined in 
plasma samples using the currently approved bioanalytical methodology.  Raw data will 
be stored in the Good Laboratory Practices (GLP) Archives, GlaxoSmithKline and 
InVentiv Health Clinical.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 protocol. 
Urine sample analysis may be performed under the management of Bioanalysis, 
Immunogenicity & Biomarkers (BIB), In Vitro/In Vivo Translation (IVIVT), 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 protocol. 
7.5. 
Pharmacodynamics 
In Part 1 and Part 2 of the study, blast cell cell-surface markers such as CD11b and CD86 
that are indicative of AML sub-population will be assessed in peripheral blood and bone 
marrow aspirates when possible to determine the effects of GSK2879552 alone or in 
combination with ATRA. Change from baseline levels will be measured.  Details on PD 
sample collection, processing, storage and shipping procedures are provided in the SPM. 
7.6. 
Translational Research 
Blood and/or bone marrow aspirates will be collected at various times, throughout the 
study in order to support research aimed at understanding the biological effect of 
GSK2879552 alone or in combination with ATRA in AML as well as identifying 
indicators of sensitivity or resistance. 
• 
The successful collection of quality tumor specimens will be critical to furthering our 
understanding the mechanism of action of GSK2879552 alone or in combination 
with ATRA, and identifying the best way to treat patients with GSK2879552. 
Specifically, the evaluation of responders, responders at relapse, and non-responders 
for DNA methylation, gene alteration status, cell surface marker expression and/or 
pathway activation may lead to the discovery of potential new diagnostic markers or 
novel combinations. Similarly, pre- and post-dose tumor specimens will be evaluated 
for markers of target engagement, tumor response, and/or evaluated for changes in 
gene expression; thus supporting identification of a biologically effective dose and 
furthering our mechanistic understanding of LSD1 inhibition in these settings. 
Performance of these investigations maybe conditional on the results of the clinical trial 
and samples may be selected for analysis on the basis of the clinical outcome.  All 
samples will be retained for a maximum of 15 years after the last subject completes the 
study. 
Details on sample collection, processing, storage and shipping procedures are provided in 
the SPM. 

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7.6.1. 
Tumor Biomarker Analysis 
All subjects will be asked to submit peripheral blood and fresh bone marrow aspirate at 
baseline, during the study and at the end of treatment in order to conduct retrospective 
tests for the identification of potential markers of sensitivity or resistance through the 
assessment of DNA, RNA and/or protein.   
7.6.2. 
RNA Expression Changes Pre and Post Treatment 
Transcriptomic analysis may be performed for RNA isolated from peripheral blast cells 
or bone marrow aspirates pre and post treatment of GSK2879552 alone or in combination 
with ATRA. This will enable the evaluation of changes in RNA expression profiles that 
may correlate with biological response relating to AML or the action of GSK2879552. 
7.7. 
Evaluation of Anti-Cancer Activity 
Disease assessments will be made by physical examination and laboratory evaluation.  
Bone marrow aspiration and biopsy will be performed as stated in the Time and Event 
table (Section 7.1). Response criteria are listed in Appendix 6. Laboratory evaluation will 
include a complete blood count with differential and blood smear to measure blasts. BM 
slides may be evaluated for morphological changes indicative of differentiation or other 
potential cellular changes due to the drug. 
7.8. 
Pharmacogenetics 
An important objective of the clinical study is pharmacogenetics (PGx) research. 
Participation in PGx is optional, but all subjects who are eligible for the clinical study 
will be given the opportunity to participate. Subjects may decline participation without 
effect on their medical care or care during the clinical study. A separate consent signature 
is required for PGx research. 
Subjects who provide consent will have a buccal swab sample taken for analysis. The 
presence/absence of genetic variations in selected candidate genes in DNA from saliva 
will be analysed to determine their relationship with response (safety, tolerability, PK, 
and efficacy) to treatment with GSK2879552, alone or in combination with ATRA. 
Information regarding PGx research is included in Appendix 9. The IRB/ EC and, where 
required, the applicable regulatory agency must approve the PGx assessments before 
these can be conducted at the site. The approval(s) must be in writing and will clearly 
specify approval of the PGx assessments (i.e., approval of Appendix 9). In some cases, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted. 
 

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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 
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.  

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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.  
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) ≥5 times upper 
limit of normal (ULN) and bilirubin ≥2 times ULN (>35% direct) (or 
ALT ≥5 times ULN and international normalization ratio (INR) >1.5, if INR is 
measured). 

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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 
 
8.3. 
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry), 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 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 

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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., 
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 8.5. 
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?” 

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8.5.2. 
Prompt Reporting of SAEs and Other Events to GSK 
Serious adverse events (SAEs), pregnancies, and liver function abnormalities 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. 
 
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  
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy 
Follow-up Form 
Liver chemistry abnormalities: 
ALT ≥5 times ULN and 
bilirubin ≥2 times ULN 
(>35% direct) (or ALT 
≥5 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 ≥8 times ULN; ALT 
≥5 times ULN with 
hepatitis or rash or 5 
times ULN ≥4 weeks 
24 hoursa 
Liver Event eCRFb 
24 hours 
Updated Liver Event 
eCRFb 
ALT ≥5 times ULN and 
<8 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 serious adverse events (SAEs) by the investigator to GSK is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 

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comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review board (IRB)/ethics committee (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 to 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 to 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 (not including platelet inhibitors), as appropriate. 
Some azoles are well known to interact with ATRA; please follow your local institutional 
guidelines for choosing the best anti-fungal agent while the subject is on ATRA to 
minimize drug-drug interactions. 
 
10.2. 
Prohibited Medication(s) 
Subjects should not receive other anti-cancer therapy (chemotherapy, immunotherapy, 
biologic therapy, and hormone therapy other than for replacement) while on treatment in 
this study.   
Anticoagulants (e.g., warfarin, direct thrombin inhibitors, etc) or platelet inhibitor (e.g., 
aspirin, clopidogrel) are prohibited from 14 days prior to the first dose of study drug 
through completion of the Final Study Visit.  
In the combination arm with ATRA, antifibrinolytic agents (such as tranexamic Acid, 
aminocaproic acid, or aprotinin), agents known to cause pseudotumor cerebri/intracranial 
hypertension (e.g., tetracycline) and vitamin A or multivitamin including vitamin A will be 
prohibited while receiving ATRA. 
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 PK 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),uptake transporters organic anion transporting 
polypeptide 1B1 (OATP1B1) and OATP1B3,  organic cation transporters (OCT2) and 
multidrug and toxin extrusion transporters (MATE1 and MATE2-K) should be used with 
caution.   

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10.3. 
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%.  
Female subjects of childbearing potential receiving ATRA combination treatment 
must use two reliable forms of contraception simultaneously during treatment and 30 
days after the last dose of ATRA or 7 days after the last dose of GSK2879552, whichever 
is later. Contraceptive counselling should be repeated monthly while receiving ATRA 
and documented in the site source file. Hormonal contraceptives are NOT considered 
acceptable form of contraception for female subjects of childbearing potential 
receiving ATRA combination treatment. Intrauterine device or intrauterine system, 
male partner sterilization and double-barrier method as described below are acceptable 
forms of contraception for female subjects of childbearing potential receiving ATRA 
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Abstinence 
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.  
Complete abstinence from sexual intercourse for 7 days prior to first dose of study 
treatment, through the dosing period, and for at least7 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. – GSK2879552 monotherapy ONLY 
• 
Estrogenic vaginal ring if not contraindicated for this subject population or per local 
practice. – GSK2879552 monotherapy ONLY 
• 
Percutaneous contraceptive patches if not contraindicated for this subject population 
or per local practice. – GSK2879552 monotherapy ONLY 
• 
Implants of levonorgestrel if not contraindicated for this subject population or per 
local practice. – GSK2879552 monotherapy ONLY 
• 
Injectable progesterone if not contraindicated for this subject population or per local 
practice. – GSK2879552 monotherapy ONLY 
• 
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, 

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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. 
• 
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 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 which may inhibit efflux 
transporters, 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. 
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times. 
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy. 

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13. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
13.1. 
Hypothesis(es) 
13.2. 
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. 
Bayesian Prior for Combination Therapy Cohorts 
The underlying Bayesian model requires that a Bayesian prior for the DLT rates for the 
combination be pre-specified.  The monotherapy DLT rates on observed data from 
200200 study and a prior Phase I ATRA study [Lee, 1993] were incorporated in the DLT 
prior distribution calculation. Table 6 shows the prior DLT data at a given dose.  
Table 6 
Prior Monotherapy DLT Data 
GSK2879552 
Dose level (mg) 
 # of DLTs  
/ # Subjects 
ATRA Dose 
Level (mg) 
# of DLTs  
/ # Subjects 
1 mg 
0/1 
45 mg/m2 
1/6 
2 mg 
0/2 
60 mg/m2 
0/3 
4 mg 
0/4 
80 mg/m2 
0/3 
8 mg 
0/1 
 
 
Additional detail on the model will be provided in the RAP. 
13.3. 
Part 2: Expansion Cohort 
The primary goal of Part 2 is to detect a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR, CRp, PR or a morphologic leukemia-
free state ) of 30% in AML relative to a 10% response rate suggesting no activity.  
Symbolically, the null hypothesis is: 
H0: RR≤10% 
The alternative hypothesis is: 
HA:RR≥30% 
13.4. 
Sample Size Determination 
13.4.1. 
Part 1: Dose-Escalation Phase 
The total number of subjects to be enrolled into Part 1 will depend on the number of dose 
escalations required to establish the maximum tolerated dose of GSK2879552 alone or in 

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combination with ATRA; they are not driven by statistical considerations. To complete 
dose escalation, it is estimated that approximately 55 evaluable subjects will be enrolled .  
Monotherapy doses to be studied in Part 1 will be guided by calculating the posterior 
probability that the DLT rate falls within an acceptable range for each subsequent dose 
after each dose cohort observation period.  The N-CRM method will be used to calculate 
posterior probabilities utilizing a pre-specified prior distribution. 
Combination doses to be studied in Part 1 will be guided by calculating the posterior 
probability that the DLT rate is as close to, but below the target toxicity rate of 33% at 
adjacent dose combinations. The Bayesian logistic regression method will be used to 
calculate posterior probabilities utilizing the pre-specified prior distribution of the 
toxicity rates on combinations.  
13.4.2. 
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 
stages, once a minimum number of subjects are evaluable.  In this particular study, we 
will stop only for futility. 
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 
weak prior Beta distribution with a mean response rate equal to the target response rate is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows: 
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution and the observed data x, the posterior distribution of the 
response rate follows a beta distribution, i.e. 
In the following case, 30% is the target response rate. 
p ∼ Beta (0.03 + x, 0.07 + n-x) with the posterior mean (0.03+ x)/(0.07 + n). 
For each cohort, to test hypotheses: 
H0: RR≤10% 
HA: RR≥30% 

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When maximum sample size is 30, the design will have a Type I error (α) of 0.064 and 
89% power with the probability of early termination is 0.88 when the treatment is futile 
and probability of early termination 0.084 when the treatment is effective (true 
RR=0.3).Futility analysis for each dose expansion cohort will begin when response data 
is available for at least 10 evaluable subjects. The dose expansion cohort may be stopped 
early for futility if the predictive probability of success (response rate ≥ historical 
response rate) is less than 5%.  Futility stopping rules are described below. 
After 10 evaluable subjects have been enrolled to examine safety and efficacy, the 
number of observed objective responses will guide further enrolment according to the 
rules summarized in Figure 3. A maximum of 30 subjects will be enrolled at the RP2Ds 
for GSK2879552 and GSK2879552 2 in combination with ATRA, respectively. All 
available data will be considered in making enrollment decisions. If both cohorts enroll 
the maximum number of subjects, this will result in 60 subjects total. Data from part 1 
may be combined with data from part 2 in the analysis to achieve the above final and 
interim analysis sample sizes. 
Figure 3 
Diagram of Stopping Rules for Cohort Expansion: GSK2879552 
 
 
Number of Responses 
Number of Subjects 
0 
1 
2 
3 
4 
5 
≥6 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
30 
 
 
 
 
 
 
 
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is only one 
response in fifteen subjects, then the predictive probability for success will be 5.0% or less (the futility criterion) 
and the study will be stopped. 
 
 

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13.5. 
Sample Size Sensitivity 
There was no need to perform sample size sensitivity analysis. 
13.5.1. 
Sample Size Re-estimation 
Sample size re-estimation is not planned for this study. 
13.6. 
Data Analysis Considerations 
13.6.1. 
Analysis Populations 
All Treated 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. 
13.7. 
Interim Analysis 
13.7.1. 
Part 1: Dose-Escalation 
In Part 1, interim analyses to inform dose escalation will be performed following the 
completion of each monotherapy and combination dose cohort in part 1.  The primary 
driver for dose escalation decisions in Part 1 will be governed by an N-CRM model for 
the mono-therapy dose cohorts and a Bayesian copula regression for the combination 
dose cohorts. They will be used to predict the probability of DLT at the dose levels yet to 
be tested to further guide these decisions. Further details of the model will be provided in 
the RAP 
Interim analysis on Part 1 may also be conducted when all subjects enrolled in in Part 1 
have had at least one post-baseline disease assessments or progressed or died or 
withdrawn from the study. 
The goal of the interim analysis will be to further evaluate the RP2D for part 2. The 
totality of the data will be considered when making this evaluation. 
Additionally, safety, PK, PD/biomarker data may be examined during Part 1. Prior to 
determining GSK2879552 dose for the next monotherapy cohort, exploratory analysis 
maybe conducted to assess the relationship of GSK2879552 dose levels with safety, PK 
and PD parameters using all data from available cohorts.  
13.7.2. 
Part 2: Expansion Cohort 
After the initial 10 evaluable 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 

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with the stopping rules provided in Section 13.4.2. As noted in Section 13.4 data from 
Part 1 at the RP2D may be combined with data from part 2 to achieve the required 
number of subjects for the response rate analysis. 
13.8. 
Key Elements of Analysis Plan 
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Data will be listed and summarized mostly by doses.  Separate analyses will 
be provided for Part I and in Part II where applicable. In some instances, analysis may 
also be generated based on the dose of GSK2879552. Data from Part I and Part II may be 
combined for some analyses at the end of the trial, for subjects treated at the same dose 
level. 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. 
13.8.1. 
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. 
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 (RR) is defined as the percentage of subjects who achieved CR, CRp, PR 
or morphologic leukemia-free state (MLFS) among subjects who received at least one 
dose of treatment. Response rate and the associated 2-sided 95% exact confidence limits 
will be provided.  A waterfall plot of percent change from baseline in bone marrow blasts 
and peripheral blasts will be provided. 
As a secondary analysis, if data warrant, PFS, OS, DOR, and TTR will be evaluated 
using the Kaplain-Meier method.  Summaries of median time to event, quartiles and 95% 
CIs will be presented.  
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, CRp, PR, MLFS, or SD) prior to the 

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initiation of therapy. Otherwise, if the subject does not have a documented date of events, 
PFS will be censored at the date of the last adequate assessment. For the analysis of 
overall survival (OS), the last date of known contact will be used for those subjects who 
have not died at the time of analysis; such subjects will be considered censored. Further 
details on rules for censoring will be provided in the RAP. Sensitivity analyses of PFS 
and further details on censoring rules will be provided in the RAP.  Progression free 
survival (PFS) and overall survival (OS) will be summarized using Kaplan-Meier 
method. 
The duration of response is defined for the subject or subjects with a CR, CRp, MLFS, or 
PR, as the time from the first documented evidence of a CR, CRp,MLFS, or PR until the 
first documented disease progression or death due to any cause. Censoring rules for 
duration of response will be outlined in detail in the RAP. 
Time to Response is defined, for subjects with a CR, CRp, MLFS, or PR, as the time 
from first dose to the first documented evidence of responses (PR or better). 
If the data warrant, duration of response and time to response will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Only the subset of subjects who 
show a confirmed complete or partial tumor response will be included. Censoring rules 
for duration of response will follow the rules for PFS outlined in detail in the RAP. 
13.8.2. 
Safety Analyses 
The All Treated Subjects Population will be used for the analysis of safety data. All 
serially collected safety endpoints (e.g. laboratory tests, vital signs, electrocardiogram 
[ECGs]) will be summarized according to the scheduled, nominal visit at which they 
were collected and across all on-treatment time points using a “worst-case” analysis. 
Complete details of the safety analyses will be provided in the Reporting and Analysis 
Plan (RAP).  
Safety endpoints are described in Section 2. Complete details of the safety analyses will 
be provided in the RAP. 
A listing by subject including treatment administered, and compliance, will be generated 
with dates and times of treatment administered. The number of subjects exposed to study 
drug will be tabulated for Part 1 (for each dose cohort) and Part 2. 
All relevant safety data will be listed and summarized according to IDSL standards. The 
reporting and analysis plan will list the IDSL templates for the displays.  Adverse events 
will be coded and grouped by system organ class (SOC) and preferred (coded) term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA) system for adverse 
event coding. AEs will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. Adverse events 
will be summarized by maximum toxicity grade for each initial dose level.  All AEs will 
be listed. A summary of the number and percent of subjects reporting each AE at least 
once will be produced for all AEs, for drug-related AEs and for SAEs for Part 1 (for each 
dose cohort) and Part 2. A listing of those AEs identified as dose-limiting toxicities will 
also be produced for each dose cohort for Part 1. A listing showing the relationship of AE 

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verbatim text to group terms and body systems will also be produced. A listing of 
withdrawals due to AEs will be provided. Deaths and SAEs will be listed should they 
occur. 
Clinical laboratory evaluations will be performed on the days specified in the Time and 
Events Table. Clinical chemistry, coagulation, hematology and urinalysis values and 
change from baseline values will be listed for each subject and flagged high or low 
relative to their normal ranges, where applicable. The toxicity grade for laboratory data 
will be calculated using NCI CTCAE Version 4.03. The lab data will then be summarized 
according to the subject’s baseline grade and maximum grade for each cycle of therapy. 
A listing of subjects with potentially clinically important lab abnormalities will also be 
produced. A summary of lab values and change from (baseline) may be done for Part 1 
(for each dose cohort) and Part 2. 
Vital signs and ECG data will be listed and summarized for Part 1(for each dose cohort) 
and Part 2. Changes from baseline will be included in the listings and summary. 
ECOG Performance Status assessments will be listed and summarized for Part 1 (for each 
dose cohort) and Part 2. 
13.8.3. 
Pharmacokinetic Analyses 
13.8.3.1. 
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 and ATRA, as appropriate, 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-τ) after repeated administration 
• 
apparent terminal phase elimination rate constant (λz) 
• 
apparent terminal phase half-life (t½) 
 
GSK2879552 trough concentration (Cτ) samples collected on the specified days will be 
used to assess attainment of steady state. To estimate the extent of accumulation for 
GSK2879552 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 for 
GSK2879552.  

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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 may be pooled and analyzed qualitatively for 
circulating metabolites; 0-24 hour urine samples may also be analyzed for GSK2879552 
and compound related metabolites. These results will be performed under a separate 
protocol and reported separately. 
 
Population Pharmacokinetics 
Plasma concentration-time data from Part 2 (Expansion Cohort) will be combined with 
data from Part 1 and possibly with data from other studies 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/τ) and 
identify relevant covariates (e.g., age, weight, or disease related covariates). Results may 
be reported separately. 
13.8.3.2. 
Statistical Analysis of Pharmacokinetic Data 
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK. 
Plasma concentration-time data for GSK2879552 and ATRA 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-τ], steady state) for GSK2879552 
and ATRA, if appropriate, 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).  
13.8.4. 
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 

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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 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. 
13.8.4.1. 
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. 
13.8.4.2. 
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 any novel 
biomarkers. 
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: 

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• 
Institutional review board (IRB)/ethics committee (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 Institutional review board 
(IRB)/ethics committee (EC) is notified. 
14.4. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, Good Clinical Practice (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 electronic case report form (eCRF) will serve as the source document. 
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 International Conference on Harmonization Good Clinical 
Practice (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 

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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, International Conference on Harmonization Good Clinical Practice (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 
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. 

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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. 
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Alibhai SM, Leach M, Minden MD, Brandwein J. Outcomes and quality of care in acute 
myeloid leukemia over 40 years. Cancer. 2009; 115(13):2903-11 
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Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714. 
Barlow JW et al. Differentiation of rhabdomyosarcoma cell lines using retinoic acid.  
Pediatr Blood Cancer. 2006;47(6):773-84 
Choschzick I et al. Phase I clinical trial of all-trans-retinoic acid with correlation of its 
pharmacokinetics and pharmacodynamics. Neuroscience, 2014, 279; 44–64 
Conley BA et al. Phase I clinical trial of all-trans-retinoic acid with correlation of its 
pharmacokinetics and pharmacodynamics. Cancer Chemother Pharmacol. 
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Dombret H et al. Acute myeloid leukemia in the elderly.  Semin Oncol. 2008; 35(4):430-
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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 
GlaxoSmithKline Document Number 2013N168888_03. GSK2879552 Investigator's 
Brochure.  Report Date: 8-FEB-2017. 
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 
Harris WJ et al. The histone demethylase KDM1Asustains the oncogenic potential of 
MLL-AF9 leukemia stem cells. Cancer cell. 2012; 21(4):473-487 
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. 
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Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
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Hurwitz JL, McCoy F, Scullin P, Fennell DA. Oncologist. New advances in the second-
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
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Research Communications. 2012;421:665-70 
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Sakamoto K et al. Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is 
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Schramm A, König K, Diehl L, Mestdagh P, Vandesompele J, Speleman F, Jastrow H, 
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16. 
APPENDICES 
16.1. 
Appendix 1: 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 below.  Doses are the projected doses. 
The specified prior probabilities discussed in Section 3.2 were used to determine an 
explicit equation for the prior distribution using the FACTS software.  The parameters 
(s.d.) of the explicit distribution are α= -1.6278(1.3652), ln(β)= -0.0116 (0.4136), and 
ρ=0.2429  where α and ln(β) are distributed as bivariate normal with correlation ρ. 
 
Dose level 
S1: Steep Dose-tox 
curve 
S2: Moderate dose-tox 
curve 
S3: Shallow dose-tox curve 
 
True DLT 
rate 
% of trials 
selecting 
dose as 
MTD  (%) 
True DLT 
rate 
% of trials 
selecting 
dose as 
MTD (%) 
True DLT 
rate 
% of trials 
selecting 
dose as 
MTD (%) 
0.25 mg 
0.02 
0 
0.02 
0 
0.01 
0 
0.5 mg 
0.05 
0.1 
0.05 
0.3 
0.02 
0 
1 mg 
0.07 
0.9 
0.07 
0.3 
0.03 
0 
1.5 mg 
0.12 
5 
0.1 
1.3 
0.04 
0.1 
2 mg 
0.16 
13.8 
0.11 
1.7 
0.05 
0.2 
2.5 mg 
0.23 
21.7 
0.12 
3.9 
0.06 
0.4 
3 mg 
0.25 
34.9 
0.15 
9 
0.07 
0.6 
4 mg 
0.35 
21.1 
0.18 
18 
0.08 
3.4 
5 mg 
0.6 
2.5 
0.22 
18.3 
0.1 
4.5 
6 mg 
0.8 
0 
0.25 
23.3 
0.13 
10.8 
8 mg 
0.9 
0 
0.3 
16.9 
0.16 
18.1 
10 mg 
0.95 
0 
0.4 
5.6 
0.2 
17.8 
12 mg 
0.95 
0 
0.5 
1.1 
0.24 
15.6 
15 mg 
1 
0 
0.6 
0.3 
0.28 
15.1 
20 mg 
1 
0 
0.66 
0 
0.35 
5.8 
25 mg 
1 
0 
0.72 
0 
0.42 
7.6 
 
The average sample size over the 1000 clinical trials simulated under Scenarios 1-3 was 
23, 27, and 30 respectively. 

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16.2. 
Appendix 2: 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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16.3. 
Appendix 3: 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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16.4. 
Appendix 4: ECOG Performance Status1 
Reference: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.

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16.5. 
Appendix 5: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria 
 

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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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16.6. 
Appendix 6: Response Criteria 
Overall efficacy will be assigned according to a criteria slightly modified from the 
standard response criteria for Acute Myeloid Leukemia [Cheson, 2003]. 
AML International Working Group Response Assessment 
Response Criteria 
Time of 
Assessment 
Neutrophils 
(uL) 
Platelets 
(uL) 
Bone Marrow 
Blasts (%) 
Other 
Early Treatment 
Assessment 
7-10 days 
after therapy 
 
 
 
 
Morphologic 
leukemia-free state 
Varies by 
protocol 
NA 
NA 
<5 
Flow Cytometry EMD 
Morphologic CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Transfusion EMD 
Cytogenetic CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Cytogenetics – normal, 
EMD 
Molecular CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Molecular – negative, 
EMD 
Partial remission 
Varies by 
protocol 
>1,000 
>100,000 
>50 or decrease 
to 5-25 
Blasts < 5% if Auer rod 
positive 
Abbreviations: EMD, extramedullary disease; CR, complete remission. 
 
Morphologic Complete Remission (CR) requires that the subject is independent of 
transfusions and that the following be present: 
Peripheral blood counts 
• 
Absolute neutrophil count >1.0 Gi/L  
• 
Platelet count >100 Gi/L  
• 
Note: Reduced hemoglobin concentration or hematocrit has no bearing on remission 
status 
• 
Leukemic blasts must not be present in the peripheral blood 
Bone Marrow Aspirate and Biopsy 
• 
Maturation of all cell lines must be present 
• 
<5% blasts in an aspirate with marrow spicules 
• 
Auer rods must not be detectable 
• 
Extramedullary leukemia, such as CNS or soft tissue involvement must not be 
present 
If there is a question of residual leukemia in the bone marrow, another bone marrow 
aspirate should be repeated in approximately one week. 

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Partial Remission (PR) requires that all of the criteria for complete remission be 
satisfied except that: 
• 
Decrease of at least 50% in bone marrow blasts to 5% to 25% in bone marrow 
aspirate and normalization of blood counts as described for CR 
• 
If all other criteria for CR are met, then a value of <5% blasts with Auer rods present 
or abnormal morphology is considered partial remission 
Relapse/Recurrence 
Peripheral blood counts 
• 
Reappearance of blasts in the blood as demonstrated by doubling of peripheral blasts 
which should be confirmed by bone marrow examination 
Bone marrow aspirate 
• 
Presence of >5% blasts, not attributable to another cause (i.e. bone marrow 
regeneration) 
• 
Molecular and/or genetic relapse is characterized by reappearance of a cytogenetic or 
molecular abnormality 
• 
If there are no circulating blasts and the bone marrow contains 5% to 20% blasts, 
then a repeat bone marrow performed ≥1 week later documenting more than 
5% blasts is necessary to meet the criteria for relapse 
A subject who does not achieve PR, or better is considered primary refractory. 
Progressive Disease 
Presence of > 50% increase in bone marrow blasts to a level of at least 50% and/or a 
doubling of the percentage of peripheral blood blasts to a level of at least 50% 
Stable Disease 
The absence of a complete or partial response, CRp, morphologic leukemia-free state and 
no progressive disease 
Reference: 
Cheson BD et al. Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 
2003;21(24):4642-9. 
 

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16.7. 
Appendix 7: 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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16.8. 
Appendix 8: 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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16.9. 
Appendix 9: Genetic Research 
Genetics – Background 
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study. 
 
Genetic Research Objectives and Analyses 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:  
• 
Response to medicine, including GSK2879552 or any concomitant medicines; 
• 
AML disease susceptibility, severity, and progression and related conditions  
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate. 
Study Population 
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research. 

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

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If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records.  
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.  
• 
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.   
• 
Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.  
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files. 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.  
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 
References 
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464 
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486. 

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16.10. 
Appendix 10: Protocol Amendment Changes 
AMENDMENT 5 
Where the Amendment Applies 
Protocol Amendment 5 applies to all sites participating in the conduct of the study 
Summary of Amendment  
Move PD secondary objective and endpoint to exploratory. Modify renal entrance criteria 
to align with Canadian regulatory agency. Add de-escalation language for both 
GSK2879552 and ATRA. Add additional dose adjustment language for hematologic 
toxicities. Optimize DLT criteria and safety management for retinoic acid syndrome. 
Update and clarify inconsistencies within protocol: update dose escalation committee 
language to align with new standard language, define the “baseline” MOCA, define time 
window for informed consent, clarify urine metabolite and PK sample collections, add 
morphology to analysis of bone marrow aspirates, and other administrative updates. 
Section wise amendment is shown under ‘Revised text’. The deletion of the previous text 
is shown by ‘Strike Off’ and addition of text by ‘Underline’. To minimize the size of the 
section, location of the change is mentioned with paragraph number and line number. 
 List of Specific Changes 
Section: Authors: 
Rationale for change: 
Sponsor contact information has been updated with changes in GSK staff. 
REVISED TEXT: 
Biomarker discovery, Epigenetics DPU, PA, USA 
Cancer Research Epigenetics Management, USA 
Clinical Pharmacology, Science and Study Operations, 
USA  
Cancer Research Epigenetics Management, USA 
Clinical Pharmacology Modeling & Simulation, USA 
Global Clinical Safety & Pharmacovigilance, UP, PA, USA 
Biomarker discovery, Epigenetics DPU, USA 
Biology, Epigenetics DPU, USA 
Discovery Biometrics, USA 
Biology, Epigenetics DPU, USA 
Global Clinical Operational Sciences, RTP, NC, USA  
Drug Metabolism and Pharmacokinetics, PA In Vitro/In 
Vivo Translation, USA 
 
 
 
Discovery Biometrics, PA, USA 
PPD
PPD
PPD

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Section: Sponsor/Medical Monitor Information Page 
Rationale for change: 
Sponsor medical monitor contact information has been updated with changes in GSK 
staff. 
REVISED TEXT: 
Role 
Name 
Day Time 
Phone Number 
After-hours 
Phone/Cell/ 
Pager Number 
GSK Address 
Primary 
Medical 
Monitor 
 
 
MD, PhD 
 
 MD 
GlaxoSmithKline 
1250 South Collegeville Rd 
Mailstop UP 4310 
Collegeville, PA 19426, USA 
  
 
Section: Protocol Synopsis/ Study Objectives, Endpoints and Hypotheses 
Changes made to both Part 1 Dose Escalation and Part 2 Dose Expansion 
Rationale for change: 
Secondary PD endpoints were moved to exploratory to …. 
REVISED TEXT: 
Secondary Objective #3 
To evaluate the relationship between GSK2879552 exposure, alone or in combination 
with ATRA, and safety/efficacy/PD parameters 
Secondary Endpoint #3 
Relationship between GSK2879552 exposure markers (e.g. dose, concentration, Cmax, 
Cmin or AUC (0-tau)) and safety/efficacy/PD parameters. PD parameters assessed by 
change from baseline in select biomarkers, e.g. CD86 and CD11b 
 
Exploratory Objective #1  
To explore markers of differentiation (including morphology assessment) in response to 
GSK2879552, alone or in combination with ATRA. 
 
Exploratory Objective #3  
PPD
PPD
PPD
PPD
PPD
PPD

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To evaluate the relationship between GSK2879552 exposure, alone or in combination 
with ATRA, and safety/efficacy/ PD parameters 
 
Exploratory Endpoint #2 
Analysis of morphology, DNA, RNA and/or protein markers in blasts cells in bone 
marrow aspirates and/or peripheral blood. 
 
Exploratory Endpoint #3  
Relationship between GSK2879552 exposure markers (e.g. dose, concentration, Cmax, 
Cmin or AUC (0-tau)) and safety/efficacy/PD parameters. PD parameters assessed by 
change from baseline in select biomarkers, e.g. CD86 and CD11b 
 
Section: Protocol Synopsis/ Inclusion/ Exclusion 
Rationale for change: Creatinine was removed from renal criteria and the criteria for 
CKD-EPI reduced as per Canadian regulatory request. 
REVISED TEXT: 
Criteria #10 under Subjects eligible for enrolment in the study must meet all of the 
following criteria: 
Renal 
 
Creatinine  
OR 
Calculated creatinine clearance 
by Chronic Kidney Disease 
Epidemiology Collaboration 
(CKD-EPI) equation  
(Appendix 3) or measured 
from 24hr urine 
 
≤1.5XULN 
≥ 50 40 mL/min 
 
Section: Protocol Synopsis/ Inclusion/ Exclusion 
Rationale for change: Clarify the definition of “baseline”. 
Criteria #7 under Subjects meeting any of the following criteria must not be enrolled in 
the study: 
7. Baseline Screening Montreal Cognitive Assessment (MOCA) score of 22 or lower 

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Section: Protocol Synopsis/ Clinical Activity Assessment 
Rationale for change: Provide the option of performing a bone marrow biopsy if an 
aspirate was unevaluable at a prior timepoint. 
REVISED TEXT: 
Second sentence 
Bone marrow aspiration/biopsy will be performed as stated in the Time and Event Table 
(Section 7.1). 
 
Section 1.3.5: Clinical Safety of GSK2879552 
Rationale for change: Updated version 3 of the IB available at time of publication. 
REVISED TEXT: 
First paragraph, first sentence: 
[GlaxoSmithKline Document Number 2013N168888_02 2013N168888_03].  
Section 1.4.5: Benefit Risk Assessment 
Rationale for change: Updated version 3 of the IB available at time of publication. 
REVISED TEXT: 
First paragraph, first sentence: 
[GlaxoSmithKline Document Number 2013N168888_02 2013N168888_03].  
 
Section 2. Objectives, Endpoints and Hypothesis 
Changes made to both Part 1 Dose Escalation and Part 2 Dose Expansion 
Rationale for change:  
REVISED TEXT:Secondary PD endpoints were moved to exploratory to …. 
Secondary Objective #3 
To evaluate the relationship between GSK2879552 exposure, alone or in combination 
with ATRA, and safety/efficacy/PD parameters 
Secondary Endpoint #3 

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Relationship between GSK2879552 exposure markers (e.g. dose, concentration, Cmax, 
Cmin or AUC (0-tau)) and safety/efficacy/PD parameters. PD parameters assessed by 
change from baseline in select biomarkers, e.g. CD86 and CD11b 
 
Exploratory Objective #1  
To explore markers of differentiation (including morphology assessment) in response to 
GSK2879552, alone or in combination with ATRA. 
 
Exploratory Objective #3  
To evaluate the relationship between GSK2879552 exposure, alone or in combination 
with ATRA, and safety/efficacy/ PD parameters 
 
Exploratory Endpoint #2 
Analysis of morphology, DNA, RNA and/or protein markers in blasts cells in bone 
marrow aspirates and/or peripheral blood. 
 
Exploratory Endpoint #3  
Relationship between GSK2879552 exposure markers (e.g. dose, concentration, Cmax, 
Cmin or AUC (0-tau)) and safety/efficacy/PD parameters. PD parameters assessed by 
change from baseline in select biomarkers, e.g. CD86 and CD11b 
 
Section 3.2.1: Inclusion Criteria 
Rationale for change: Updated version 3 of the IB available at time of publication. 
REVISED TEXT: 
First paragraph, first sentence: 
[GlaxoSmithKline Document Number 2013N168888_03 ].  
 
Section 3.2.1: Inclusion Criteria  
Rationale for change: Creatinine was removed from renal criteria and the criteria for 
CKD-EPI reduced as per Canadian regulatory request. 
REVISED TEXT: 
Inclusion criteria #10 Adequate baseline organ function as defined by: 

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Renal 
 
Creatinine  
OR 
Calculated creatinine clearance by Chronic 
Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Appendix 3) or measured 
from 24hr urine 
 
≤1.5X ULN 
 
≥ 50 40 mL/min 
 
Section 3.2.2: Exclusion Criteria 
Rationale for change: Clarify the definition of “baseline”. 
REVISED TEXT: 
Exclusion criteria #78 
8. Baseline Screening Montreal Cognitive Assessment (MOCA) score of 22 or lower 
 
Section 4.2.1: GSK2879552 Monotherapy 
Rationale for change: The text was updated to align with new written standards for 
assurance of increased data integrity during dose escalation decisions.  
REVISED TEXT: 
Dose Escalation Committee 
First paragraph, third sentence 
Quality control of critical safety data will be described in the Dose Escalation Plan, 
which includes ongoing study monitoring visits, Sponsor review of the clinical database, 
and confirmation by site investigators and/or delegate that the data is accurate and 
complete.  
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/de-escalation 
should continue as recommended by the N-CRM. The dose-escalation decision and 
rationale for each cohort will be discussed with investigators during teleconference(s) and 
documented in writing, with copies maintained at each study site and in the study master 
file. 
 
 

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Section 4.2.2: GSK2879552 and ATRA combination 
Rationale for change: Language was added for reduced dose levels for both GSK2879552 
or ATRA for situations where dose level 1 is not tolerated.  
REVISED TEXT: 
Second paragraph, first sentence 
Starting at dose level 1, the following GSK2879552 dose levels are planned for 
evaluation in combination with ATRA 45 mg/m2/day.  
Dose level 
GSK2879552 
ATRA 
1 
2 mg/day 
45 mg/m2/day 
2 
4 mg/day 
45 mg/m2/day 
3 
8 mg/day 
45 mg/m2/day 
4 
12 mg/day 
45 mg/m2/day 
5 
20 mg/day 
45 mg/m2/day 
 
A reduced dose of GSK2879552 or ATRA may be considered if the combination is not 
well tolerated at dose level 1. The initial dose level reductions allow for either drug to be 
reduced. Subsequent dose levels are based on the totality of data and upon discussion 
with the investigators. 
 
Dose level 
GSK2879552 
ATRA fixed at 45mg/m2 
-1 
1 mg/day 
-2 
0.5 mg/day 
 

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Dose level 
GSK2879552 
ATRA <30mg/m2 
1a 
2 mg/day 
-1a 
1 mg/day 
-2a 
0.5 mg/day 
 
Dose level 1: GSK2879552 2 mg/day 
Dose level 2: GSK2879552 4 mg/day 
Dose level 3: GSK2879552 8 mg/day 
Dose level 4: GSK2879552 16 mg/day 
Dose level 5: GSK2879552 32 mg/day 
 
Section 4.2.5: Dose-Limiting Toxicity  
Rationale for change: The text was updated to clarify criteria for a DLT. 
REVISED TEXT: 
Second paragraph, first sentence: 
An event will be considered a DLT if it occurs within the first 4 weeks 28 days of 
treatment (with exception of myelosuppression as stated below), and meets one of the 
following criteria unless it can be clearly established that the event is unrelated to 
treatment.  
Subjects unable to receive at least 75% of scheduled doses within the DLT period 
for reasons other than toxicity (e.g., acute illness, disease progression) will not be 
evaluable  
Hematologic DLT:  
• 
Myelosuppression (as defined by absolute neutrophil count (ANC) <500/µl  
AND platelets ≤25,000/µl) with bone marrow hypoplasia (cellularity ≤ 5%) 
without evidence of leukemia (<5% blasts) for ≥ 28 42 days after drug 
cessation. If a subject meets above criteria at the time of drug cessation within 
the DLT observation period, the dose escalation decision will be delayed until 
28 days have elapsed post drug cessation.  

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• 
Grade ≥3 or 4 non-hematologic toxicity that is considered clinically significant and 
lasts >72 hours. Fatigue, asthenia, or nausea that respond to standard medical care 
within 72 hours and new electrolyte disturbance that respond within 24 hours are 
exceptions. In addition, electrolyte disturbances associated with underlying 
malignancy are not considered DLT. 
• 
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 ≥42 28 days or greater due to unresolved toxicity.  
Section 4.7.3: Mental Status Stopping Criteria 
Rationale for change: Clarify the definition of «baseline» MOCA. 
REVISED TEXT: 
Second paragraph, second bullet: 
• 
A decrease of 3 points or more from baseline (Pre-dose Day 1) MOCA score  
 
Third paragraph, first bullet: 
• 
A reversible cause other than study treatment is identified and both MOCA score and 
symptoms return to baseline or to the MOCA score before the decrease. 
 
Section 4.8.3: Dose Adjustment for Hematologic Toxicity 
Rationale for change: Previous protocol did not define management guidelines for 
thrombocytopenia with >5% blasts. Text also added for fall precautions resulting from 
INDSRs on the study. 
REVISED TEXT: 
 

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Toxicity 
Dose Adjustment/ 
Stopping Criteria 
Management Guidelines 
At all thrombocytopenia grades, implement fall precautions  to avoid bleeding due to trauma, e.g. 
trauma to head can cause a subdural hematoma. This risk increases with higher grades of 
thrombocytopenia 
Thrombocytopenia 
regardless of blast 
count 
Grade 1, 2 & 3 (platelets 
≥25,000/mm3) 
Continue dosing at same dose level with more frequent 
monitoring as necessary. 
 
Thrombocytopenia 
if blasts >5% 
Grade 4 (platelets  
<25,000/mm3) and/or 
any grade accompanied 
by severe bleeding 
related to 
thrombocytopenia 
 
If platelet count <25,000/mm3 but ≥10,000/mm3:  
3. Use clinical judgement to institute more frequent 
monitoring as necessary  
4. Institute platelet transfusion as appropriate. 
 
If platelet count <10,000/mm3: 
6. Continue treatment and start platelet transfusion 
as per institutional guidelines.  
7. If repeat platelet transfusions are not able to 
rescue platelet count, then consider irradiated, 
leuko-pherised or HLA-matched platelets as 
clinically appropriate 
8. If still unable to rescue platelet count, investigator 
may consider treatment interruption in discussion 
with medical monitor.   
9. Use of concomitant therapies (tranexamic acid) is 
permitted. Please note tranexamic acid is 
prohibited for subjects receiving GSK2879552 in 
combination with ATRA. 
10. Use of hydroxyurea in the setting of increased 
blast counts in conjunction with decreased 
platelet counts is permitted. 
1.  
Thrombocytopenia 
if blasts <5%  
 
 
 
 
 
 
 
 
 
 
 
Grade 4 (platelets  
<25,000/mm3) and/or 
any grade accompanied 
by severe bleeding 
related to 
thrombocytopenia 
 
If platelet count <25,000/mm3 but ≥10,000/mm3:  
3. Use clinical judgement to institute more frequent 
monitoring as necessary  
4. Institute platelet transfusion as appropriate. 
 
If platelet count <10,000/mm3 (or ≤25,000/mm3 with 
accompanying fever, sepsis, or minor bleeding): 
5. Treatment may be held for up to 4 weeks and 
resume* as soon as count recovery has occurred 
(i.e., neutrophils ≥0.5 and platelets ≥25 x 109/L). 
Use clinical judgement to institute more frequent 
monitoring as necessary. 
6. The treatment may be held for additional 1-2 
weeks if the neutrophil and platelet counts do not 
recover after the initial 2 weeks. 
7. After a total of 5-6 consecutive weeks, if there is 
no evidence of recovering blood counts, a repeat 
bone marrow examination should be performed 
during that period (approximately -35-42 days 
after drug cessation) to evaluate for the possibility 

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Toxicity 
Dose Adjustment/ 
Stopping Criteria 
Management Guidelines 
 
 
 
 
 
of hematologic DLT. 
8. If persistent for 6 weeks and not attributed to 
disease or requires platelet transfusions for 
bleeding in the absence of the disease, the 
subject will be withdrawn from the study.  
*If treatment resumes, the dose and schedule may be 
adjusted based on platelet count, i.e., dose can be 
reduced by at least 25% increments up to two times.   
 
The treatment may be held for 2 weeks if 
• 
≤5% myeloblasts in bone marrow AND 
• 
neutrophil and platelet count did not recover to neutrophils ≥0.5 x 109/L and platelets 
≥25 x 109/L 
The treatment may resume as soon as count recovery has occurred (i.e., neutrophils ≥0.5 
and platelets ≥25 x 109/L). 
The treatment may be held for additional 1-2 weeks if the neutrophil and platelet count 
did not recover after 2 weeks. If there is no evidence of recovering blood counts, a repeat 
bone marrow examination should be performed during that period (approximately 14-28 
days after drug cessation) to evaluate for the possibility of hematologic DLT. 
When the treatment resumes post remission, the dose may be adjusted based on platelet 
count, i.e., dose can be reduced by at least 25% increments up to twice when the platelet 
count <25 x 109/L (G4 thrombocytopenia) and it is not attributed to the disease. If a 
subject has persistent G4 thrombocytopenia for 4 weeks not attributed to disease or 
requires platelet transfusions for bleeding in the absence of the disease, the subject will 
be withdrawn from the study.  
 
Section 4.8.4.1: Retinoic Acid-APL Syndrome 
Rationale for change: The text was updated with detailed management guidelines and 
signs and symptoms of differentiation syndrome which has been shown to occur in 
patients with APL treated with ATRA. 
REVISED TEXT: 
About 25% of patients with APL treated with ATRA have experienced the retinoic acid- 
APL (RA APL) syndrome characterized by fever, dyspnea, acute respiratory distress, 
weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, 

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and hepatic, renal, and multi-organ failure [ATRA Prescribing Information, 2004]. This 
syndrome has occasionally been accompanied by impaired myocardial contractility and 
episodic hypotension. The syndrome generally occurs during the first month of treatment, 
with some cases reported following the first dose of ATRA.   
Retinoic Acid Syndrome should be strongly suspected if the following signs or symptoms 
(without any other clear or established etiology) emerge during treatment with 
GSK2879552: 
• New or worsening progressive dyspnea or hypoxemia, with increasing demands 
for supplemental oxygen; respiratory distress refractory to treatment for the 
initially suspected cause 
• Radiologic evidence of new or worsened bilateral pulmonary involvement 
(infiltrates or opacities) with or without presence of infection, refractory to 
treatment with anti-infectives (antibiotics, antivirals, antifungals) 
• Radiologic evidence of new or worsened pleural or pericardial effusion that is 
refractory to treatment for an initially suspected cause 
• New or worsened peripheral edema, with rapid weight gain (e.g., >5 kg/11 pounds 
over 7 days) 
• Increase in serum creatinine (e.g., >2-fold from baseline) 
• The following symptoms or signs may be features of retinoic acid syndrome but if 
isolated and not accompanied by pulmonary or renal manifestations, may not 
require rapid initiation of retinoic acid syndrome treatment (unless sufficiently 
severe and prolonged): 
o Unexplained fever ≥38oC (100.4oF) 
o Rash of unknown origin 
o Bone pain 
o Lymphadenopathy 
The measures below are recommended to be taken at the earliest manifestations of 
suspected retinoic acid syndrome: 
• Patients with severe or rapidly progressing retinoic acid syndrome should be 
hospitalized for continued observation 
• In case of uncertainty with the diagnosis, e.g., presence of less specific symptoms 
of moderate severity, patients should be closely monitored, as the condition may 
rapidly worsen 
• Corticosteroids should be promptly initiated (e.g., 10 mg of dexamethasone every 
12 hours until resolution of retinoic acid syndrome). Once resolved the 
corticosteroid dose can be progressively reduced over 1-2 weeks 
• GSK2879552 and/or ATRA may be withheld at the physician’s discretion. Due to 
the long half-life of GSK2879552 (about 16 hours), treatment interruption may 
not immediately reverse the symptoms of retinoic acid syndrome. If interrupted, 
GSK2879552 treatment may be reinitiated at the original or a reduced dose, once 
the signs and symptoms resolve and the patient’s clinical condition improves 
• In patients with elevated WBC counts, prompt initiation of hydroxyurea is 
suggested, or treated as per standard local practice (e.g., dose of 2 to 3g PO 2- or 
3-times daily for WBC >30x109/L) 

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• In cases of severe leukocytosis, use of leukapheresis may be appropriate 
• For substantial fluid accumulation, initiation of furosemide may be appropriate, as 
per local standard practice 
• Patients with pericardial effusion (a less common manifestation of retinoic acid 
syndrome) can require urgent cardiac intervention due to it being a life-
threatening condition  
• Patients with increasing serum creatinine levels should be evaluated for tumor 
lysis syndrome 
• Patients experiencing a rapid increase in peripheral blood cells should be 
monitored for disseminated intravascular coagulopathy and hemorrhage  
• Imaging techniques such as standard or high-resolution computerized tomography 
(CT) scan and chest X-ray are useful for establishing a diagnosis of retinoic acid 
syndrome by identifying pulmonary infiltrates or effusions; noting that a CT scan 
is  more sensitive in detecting early radiological signs of retinoic acid syndrome-
associated changes 
High dose steroids should be immediately initiated at the first suspicion of the RA-APL 
syndrome irrespective of the leukocyte count, e.g., dexamethasone 10 mg intravenously 
administered every 12 hours for 3 days or until the resolution of symptom. . The first 
signs of the syndrome include:  
unexplained fever 
dyspnea and/or weight gain 
abnormal chest auscultatory findings or radiographic abnormalities 
Prophylactic treatment with steroid may be considered per institutional guideline when 
leukocyte counts double in number to >10,000/uL from baseline leukocyte <10,000/uL. 
Prophylactic treatment with hydroxyurea and steroid may be considered per institutional 
guideline when leukocyte counts double in number from baseline leukocyte 10,000- 
30,000 /uL. 
In cases of moderate and severe RA-APL syndrome, temporary interruption of ATRA 
treatment should be considered. 
 
Section 6.1: Screen and Baseline Failures 
Rationale for change: Text was updated to allow for rescreening of potential subjects. 
REVISED TEXT: 
Second paragraph: 
Individuals who do not meet the criteria for participation in this study (screen 
failure) may be rescreened. Rescreened participants should be assigned the same 

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participant number as for the initial screening if rescreening for same arm of study 
(monotherapy to monotherapy or ATRA combination to ATRA combination.)  If 
rescreening for a different arm of the study, (monotherapy to ATRA combination or 
ATRA combination to monotherapy) participants will need a new screening number.  
Please refer to the Study Procedures Manual for more details.  
 
Section 7: Study Assessments and Procedures 
Rationale for change: Text was updated to widen the window for signing of the informed 
consent. 
REVISED TEXT: 
Seventh paragraph: 
Visit Window 
Informed consent should be signed within 35 days prior to dosing.  
 
Section 7.1: Time and Events Table (Table 3 – Time and Events, Part 1 Dose 
Escalation) 
Rationale for change: The Time and Events Tables were updated to clarify vitamin B12, 
TSH, free T3 or free T4 requirement at screening, addition of allowance for bone marrow 
biopsies when bone marrow aspirate is inevaluable, urine metabolite collection. 
REVISED TEXT: 
Modified rows: 
SC
R 
First Treatment Phase (28 days) 
Continuatio
n Phase 
EO
T 
  
D 1 
D 2 
D 
4 
D 
8 
D 
11 
D 
15 
D 
16 
D 
18 
D2
2 
D2
5 
Vitamin B12, 
TSH, Free T4 
or Free T323 
X 
 
 
 
 
 
 
 
 
 
 
 
Blood 
samples for 
PD6, 21 
(peripheral 
blood)  
X 
 
X 
X 
X 
bone marrow day6 
 
 
Wk 4, 
between Wk 
6- 819, Wk 12 
and then 
every 12 
wks. 
X 
Bone marrow 
aspirate for 
PD21 
X7 
 
 
 
 
X18  
 
 
Wk 4, 
between Wk 
6- 819, Wk 12 
and then 
every 12 wks  
X17 
Bone marrow 
X7 
X18  
 
Wk 4, 
X17 

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SC
R 
First Treatment Phase (28 days) 
Continuatio
n Phase 
EO
T 
  
D 1 
D 2 
D 
4 
D 
8 
D 
11 
D 
15 
D 
16 
D 
18 
D2
2 
D2
5 
aspirate for 
exploratory 
studies  21 
between Wk 
6- 819, Wk 12 
and then 
every 12 
wks. 
Bone marrow 
aspirate/biops
y for disease 
assessment24, 
25 
X20 
 
 
 
 
X18 
 
 
Wk 4, 
between Wk 
6- 819, Wk 12 
and then 
every 12 
wks.  
Highest Dose in PK/PD expansion cohort ONLY 
Urine for PK 
 
X5, 
12 
X5 
 
 
 
X5 
X5 
 
 
 
 
 
Modified footnotes #6, 9, 20, 23, 24, 25: 
6. 
Blood samples for PD and exploratory biomarkers studies should be collected pre-dose. 
9. 
Additional samples will be collected for metabolite evaluation in the highest dose cohort in PK/PD expansion 
cohorts, in at least 6 3 subjects. The plasma samples will be collected at following time points on Days 1 and 
15: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hrs post dose  
20. Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing 
should be performed as part of disease assessment at baseline. Cytomorphology is the preferred method to 
determine bone marrow blast counts. However, if a bone marrow aspirate cannot be obtained for 
cytomorphology review, a bone marrow biopsy is allowed strongly recommended to determine the bone 
marrow blast count. 
23. Free T3 to be tested only when clinically indicated 
24. At any time point in the study, if a bone marrow aspirate is found to be hemodilute (no spicules), then a bone 
marrow biopsy is strongly recommended to be collected at the next disease assessment time point in 
addition to the aspirate to ensure the conduct of a disease assessment. 
25. BM slides may be evaluated for changes in morphology. 
 
Section 7.1: Time and Events Table (Table 4 – Time and Events, Part 2 Dose 
Expansion) 
REVISED TEXT: 
Modified rows: 
SC
R 
First Treatment Phase (28 days) 
Continuatio
n Phase 
EO
T 
  
D 
1 
D 
2 
D 
4 
D 
8 
D 
11 
D 
15 
D 
16 
D 
18 
D2
2 
D2
5 
Vitamin B12, 
TSH, Free T4 
or Free T320 
X 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate/biops
y for disease 
X16 
 
 
 
 
X14 
 
 
Wk 4, 
between Wk 
6- 813, Wk 12 

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SC
R 
First Treatment Phase (28 days) 
Continuatio
n Phase 
EO
T 
  
D 
1 
D 
2 
D 
4 
D 
8 
D 
11 
D 
15 
D 
16 
D 
18 
D2
2 
D2
5 
assessment21, 
22 
and then 
every 12 
wks.  
 
Modified footnotes:#3,16; Added:#20,21 & 22 
3. 
Blood samples for PD, exploratory biomarkers studies should be collected pre-dose.  
16. Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing 
should be performed as part of disease assessment at baseline. Cytomorphology is the preferred method to 
determine bone marrow blast counts. However, if a bone marrow aspirate cannot be obtained for 
cytomorphology review, a bone marrow biopsy is allowed strongly recommended to determine the bone 
marrow blast count. 
20. Free T3 to be tested only when clinically indicated 
21. At any time point in the study, if a bone marrow aspirate is found to be hemodilute (no spicules), then a bone 
marrow biopsy is strongly recommended to be collected at the next disease assessment time point in 
addition to the aspirate to ensure the conduct of a disease assessment. 
22. BM slides may be evaluated for changes in morphology. 
 
Section 7.2: Demographic/Medical History and Baseline Assessments 
REVISED TEXT: 
Baseline (Screening) assessments obtained will include: 
Fifth paragraph, fourth bullet: 
• 
Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters, 
vitamin B12, TSH, free T3 or free T4 (see Table 5 for full list of laboratory tests 
required at screening). Patients should have baseline thyroid function, vitamin B12, 
and metabolic panel within acceptable limits (FDA request May 2015).  
Fifth paragraph, last bullet: 
• 
Montreal Cognitive Assessment (MOCA) 
 
Section 7.3.7: Laboratory Assessments 
REVISED TEXT: 
Added to Table 5: List of Clinical Laboratory Tests, under Clinical Chemistry 
Free T4 or Free T3 and Vit B12 
 

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Section 7.6: Translational Research 
REVISED TEXT: 
Last sentence: 
Details on PD sample collection, processing, storage and shipping procedures are 
provided in the SPM. 
 
Section 7.7: Evaluation of Anti-cancer therapy 
REVISED TEXT: 
Last sentence: 
BM slides may be evaluated for morphological changes indicative of differentiation or 
other potential cellular changes due to the drug. 
 
Section 8.3: Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs or SAEs 
REVISED TEXT: 
First paragraph, first sentence: 
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. 
 
Section 10.1: Permitted Medication(s) 
REVISED TEXT: 
Second paragraph added: 
Some azoles are well known to interact with ATRA; please follow your local institutional 
guidelines for choosing the best anti-fungal agent while the subject is on ATRA to 
minimize drug-drug interactions. 
 
Section 10.2: Prohibited Medication(s) 

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REVISED TEXT: 
First paragraph, first sentence: 
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.   
 
Section 10.2.2: Drugs that may have their PK altered by GSK2879552 
REVISED TEXT: 
Second paragraph: 
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 organic cation transporters 
(OCT2) and multidrug and toxin extrusion transporters (MATE1 and MATE2-K) should 
be used with caution.  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.  
 
Section 16.6: Appendix 6: Response Criteria 
REVISED TEXT: 
Overall efficacy will be assigned according to a criteria slightly modified from the 
standard response criteria for Acute Myeloid Leukemia [Cheson, 2003]. 
AML International Working Group Response Assessment 

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Response Criteria 
Time of 
Assessment 
Neutrophils 
(uL) 
Platelets 
(uL) 
Bone Marrow 
Blasts (%) 
Other 
Early Treatment 
Assessment 
7-10 days 
after therapy 
 
 
 
 
Morphologic 
leukemia-free state 
Varies by 
protocol 
NA 
NA 
<5 
Flow Cytometry EMD 
Morphologic CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Transfusion EMD 
Cytogenetic CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Cytogenetics – normal, 
EMD 
Molecular CR 
Varies by 
protocol 
>1,000 
>100,000 
<5 
Molecular – negative, 
EMD 
Partial remission 
Varies by 
protocol 
>1,000 
>100,000 
>50 or decrease 
to 5-25 
Blasts < 5% if Auer rod 
positive 
Abbreviations: EMD, extramedullary disease; CR, complete remission. 
 
Morphologic Complete Remission (CR) requires that the subject is independent of 
transfusions and that the following be present: 
Peripheral blood counts 
• 
Absolute neutrophil count >1.0 Gi/L  
• 
Platelet count >100 Gi/L  
• 
Note: Reduced hemoglobin concentration or hematocrit has no bearing on remission 
status 
• 
Leukemic blasts must not be present in the peripheral blood 
Bone Marrow Aspirate and Biopsy 
• 
Maturation of all cell lines must be present 
• 
<5% blasts in an aspirate with marrow spicules 
• 
Auer rods must not be detectable 
• 
Extramedullary leukemia, such as CNS or soft tissue involvement must not be 
present 
If there is a question of residual leukemia in the bone marrow, another bone marrow 
aspirate should be repeated in approximately one week. 
Partial Remission (PR) requires that all of the criteria for complete remission be 
satisfied except that: 
• 
Decrease of at least 50% in bone marrow blasts to 5% to 25% in bone marrow 
aspirate and normalization of blood counts as described for CR 

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• 
If all other criteria for CR are met, then a value of <5% blasts with Auer rods present 
or abnormal morphology is considered partial remission 
Relapse/Recurrence 
Peripheral blood counts 
• 
Reappearance of blasts in the blood as demonstrated by doubling of peripheral blasts 
which should be confirmed by bone marrow examination 
Bone marrow aspirate 
• 
Presence of >5% blasts, not attributable to another cause (i.e. bone marrow 
regeneration) 
• 
Molecular and/or genetic relapse is characterized by reappearance of a cytogenetic or 
molecular abnormality 
• 
If there are no circulating blasts and the bone marrow contains 5% to 20% blasts, 
then a repeat bone marrow performed ≥1 week later documenting more than 
5% blasts is necessary to meet the criteria for relapse 
A subject who does not achieve PR, or better is considered primary refractory. 
Progressive Disease 
Presence of > 50% increase in bone marrow blasts to a level of at least 50% and/or a 
doubling of the percentage of peripheral blood blasts to a level of at least 50% 
Stable Disease 
The absence of a complete or partial response, CRp, morphologic leukemia-free state and 
no progressive disease 
Reference: 
Cheson BD et al. Revised recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 
2003;21(24):4642-9. 
[Modified Cheson, 2003] 
Complete remission (CR): The subject must achieve a morphologic leukemia-free state 
(≤ 5% blasts) and have no evidence of extramedullary disease. The subject must be free 
of all symptoms related to leukemia, have an absolute neutrophil count ≥1 x 109/L and 
platelet count ≥100 x 109/L, and be transfusion independent. 

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CRp: Marrow response as per CR but platelet count <100 x 109/L. 
CRi: Marrow response as per CR but platelet count <100 x 109/L or neutrophil count <1 
x 109/L. 
Partial remission (PR): A decrease from baseline of at least 50% in the number of bone 
marrow blasts, to between 5% and 25% of the bone marrow aspirate. 
No response: Subject does not meet criteria for CR, CRp, CRi, or PR. 
Recurrence: Morphologic relapse, defined as the reappearance of peripheral blasts or 
increase in bone marrow blasts ≥ 5% not attributable to any other cause (e.g., infection, 
growth factor support, bone marrow regeneration) 
 

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AMENDMENT 4 
Where the Amendment Applies 
Protocol Amendment 4 applies to all sites participating in the conduct of the study 
Summary of Amendment  
Add language to include a stopping rule that halts enrollment upon the occurrence of any 
encephalopathy, unless clearly attributable to central nervous system disease involvement 
or intercurrent illness.  
List of Specific Changes 
Section 4.7.3 Mental Stopping Criteria 
REVISED TEXT: (Added)   
Enrollment will be stopped upon the occurrence of any encephalopathy, unless 
clearly attributable to central nervous system disease involvement or intercurrent 
illness. 

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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  
A combination arm with ATRA is added. One of the Dose Limiting Toxicities criteria 
has been revised according to the NCI criteria. Pharmacodynamic/exploratory sample 
collection and processing have been changed. Pharmacogenetic sample has been added. 
The criteria for Progressive Disease and Stable Disease have been added in the response 
criteria. Concomitant medications have been updated. 
Section wise amendment is shown under ‘Revised text’. The deletion of the previous text 
is shown by ‘Strike Off’ and addition of text by ‘Underline’. To minimize the size of the 
section, location of the change is mentioned with paragraph number and line number. 
 List of Specific Changes 
Section: Medical Monitor Information Page / Sponsor Contact Information: 
REVISED TEXT: 
Role 
Name 
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/ 
Pager 
Number 
GSK Address 
Primary 
Medical 
Monitor 
MD, PhD 
GlaxoSmithKline 
1250 South Collegeville Rd 
Mailstop UP 4310 
Collegeville, PA 19426, USA 
  
 
Section: List Of Abbreviations 
REVISED TEXT: (added) 
ATRA 
All-Trans Retinoic Acid 
 
Section: Protocol Synopsis 
REVISED TEXT: 
Last sentence: The proposed Phase I study will evaluate the safety and tolerability, 
pharmacokinetics, pharmacodynamics, and clinical activity to determine the 
recommended Phase 2 Dose (RP2D) and regimen of GSK2879552, alone or in 
combination with ATRA, given orally in adult subjects with relapsed/refractory AML. 
 
PPD
PPD

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Section: Protocol Synopsis- Study Objectives, Endpoints And Hypotheses and 
Section 2: Objectives, Endpoints And Hypotheses 
REVISED TEXT: 
PART 1: Escalation Cohort 
 
Objectives 
Endpoints 
Primary 
1. To determine the safety, 
tolerability, MTD and/or 
RP2D and regimen of 
GSK2879552, alone or in 
combination with ATRA, 
given orally in adult subjects 
with AML 
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 PK of 
GSK2879552, alone or in 
combination with ATRA, 
after single- and repeat-dose 
oral administration. 
 
 
2. To evaluate clinical response 
after treatment with 
GSK2879552, alone or in 
combination with ATRA. 
 
3. To evaluate the relationship 
between GSK2879552 
exposure, alone or in 
combination with ATRA, and 
safety/efficacy/ PD 
parameters 
 
 
4. To characterize the PK of 
ATRA in combination with 
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. Objective response rate (% of 
subjects achieving CR, PR, CRp 
or morphologic leukemia-free 
state) per response criteria. 
3. Relationship between 
GSK2879552 exposure markers 
(e.g. dose, concentration, Cmax, 
Cmin or AUC (0-tau)) and 
safety/efficacy/PD parameters. 
PD parameters assessed by 
change from baseline in select 
biomarkers, e.g. CD86 and 
CD11b 
4. ATRA PK parameters following 
single and repeat-dose 
administration of ATRA and 
GSK2879552, including AUC, 
Cmax, tmax, t½ (terminal phase). 
Exploratory 1. To explore markers of 
differentiation assess 
feasibility of a select gene 
panel for use as a PD assay 
for in response to 
GSK2879552, alone or in 
combination with ATRA. 
1. Change from baseline expression 
in select genes cell surface 
markers in AML cells derived 
from bone marrow and/or 
peripheral blood. 
 
 

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2. To investigate the mechanism 
of action and indicators of 
sensitivity and relationship 
between tumor genomic 
profile, and response or 
resistance to GSK2879552, 
alone or in combination with 
ATRA. 
3. To assess RNA expression 
profile in tumor cells for 
identifying mechanisms of 
rational combination and 
potential resistance 
mechanism. 
4. To discover circulating 
markers of response and 
resistance  and correlation 
with clinical outcome 
 
3. To characterize the metabolite 
profile of GSK2879552 after 
oral single and repeat-dosing 
in some subjects 
4. To determine the amount of 
GSK2879552 excreted in 
urine after oral single and 
repeat-dosing in some 
subjects treated with 
GSK2879552  
5. To investigate the relationship 
between genetic variants in 
candidate genes,PK and 
safety profile of 
GSK2879552, alone or in 
combination with ATRA. 
2. Analysis of DNA, RNA and/or 
protein markers in blasts cells in 
bone marrow aspirates and/or 
peripheral blood. tumor samples 
to discover determinants of 
response 
 
 
3. Transcriptomic (RNA) profile of 
blast cells in bone marrow 
aspirates and peripheral blood 
pre- and post-treatment with 
GSK2879552. 
 
4. Analysis of circulating 
biomarkers (e.g. circulating cell 
free DNA [cfDNA], protein and 
RNA) and correlation with 
response 
3. GSK2879552 metabolites in 
plasma and/or urine 
 
 
4. Concentration of GSK2879552 in 
urine measured with an 
investigational bio-analytical 
method and extrapolated to total 
amount excreted in urine over 
time 
5. Pharmacogenomic (PGx) study 
using buccal samples 
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. 
 

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Part 2: Expansion Cohort 
 
Objectives 
Endpoints 
Primary 
1. To evaluate clinical activity 
of GSK2879552 alone or in 
combination with ATRA, at 
the respective RP2D given 
orally in adult subjects with 
AML.  
1. Objective response rate (% of 
subjects achieving CR, PR, CRp 
or morphologic leukemia-free 
state) per response criteria. 
Secondary  
 
1. To evaluate the safety and 
tolerability of respective 
RP2D of GSK2879552, alone 
or in combination with 
ATRA. 
 
 
 
2. To characterize the population 
PK of GSK28795522, alone 
or in combination with 
ATRA. 
 
 
 
3. To evaluate the exposure 
response (PK/PD) 
relationship between 
GSK2879552, alone or in 
combination with ATRA and 
safety/efficacy/PD 
parameters. 
 
 
4. To evaluate duration of 
response and best overall 
response 
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, ECGs, 
physical examinations) 
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. Relationship between 
GSK2879552 exposure markers 
(e.g. dose, concentration, Cmax or 
AUC (0-tau)) and 
safety/efficacy/PD parameters. 
PD parameters assessed by 
change from baseline in select 
biomarkers, e.g. CD86 and 
CD11b 
4. Duration of response and best 
overall response  
Exploratory 1. To investigate the mechanism 
of action and indicators of 
sensitivity and resistance to 
assess the feasibility of 
measuring expression changes 
of a select gene panel for use 
as a PD assay for 
GSK2879552, alone or in 
combination with ATRA. 
2. To investigate the relationship 
between genetic variants in 
candidate genes, PK and 
1. Change from baseline expression 
in select genes in AML cells 
derived from bone marrow and 
peripheral blood  
2. Analysis of  DNA, RNA and/or 
protein markers in blast cells from 
bone marrow aspirate and/or 
peripheral blood tumor samples to 
discover determinants of response  
 
3. Pharmacogenomic (PGx) study 
using buccal samples 

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safety profile of 
GSK2879552, alone or in 
combination with ATRA. 
tumor genomic profile, and 
response or resistance to 
GSK2879552. 
3. To assess RNA expression 
profile in tumor cells for 
identifying mechanisms of 
rational combination and 
potential resistance. 
4. To discover circulating 
markers of response and 
resistance and correlation 
with clinical outcome..  
 
 
4. Transcriptomics (RNA) profile of 
blast cells in bone marrow 
aspirates and peripheral blood 
pre- and post-treatment with 
GSK2879552. 
 
Analysis of circulating 
biomarkers (e.g. circulating cell 
free DNA [cfDNA], protein and 
RNA) and correlation with 
response. 
Hypothesis 
Clinical response will be defined as Objective Response Rate (% of 
subjects achieving CR, PR, CRp or morphologic leukemia-free state) per 
response criteria. 
The null hypothesis is: H0: RR ≤10% 
The alternative hypothesis is: HA:  ≥30% 
 
Section: Protocol Synopsis- Study Design 
REVISED TEXT: 
This is a Phase I, open-label, multi-center, non-randomized, 2-part study. Part 1 is a dose 
escalation phase to determine the MTD and/or RP2D for GSK2879552, alone or in 
combination with ATRA 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 safety, tolerability, PK and PD. 
Once MTD and/or RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects 
will be enrolled to further evaluate the efficacy and tolerability of GSK2879552, alone or 
in combination with ATRA in subjects with relapsed/refractory AML.  
The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose for GSK2879552 mono therapy arm will be 0.25 mg/day or the highest dose 
determined to be safe in the ongoing SCLC study, whichever is higher with a maximum 
of 1 mg/day (see Section 1.4.3.2 for details). The starting dose of GSK2879552 in 
combination with ATRA will be 1-2 dose levels below the highest dose determined to be 
safe in the GSK2879552 mono therapy arm in this study, i.e., 2 mg once daily. 
Alterations to the dose and schedule may be incorporated based on emerging PK, PD, and 
tolerability data. Dose reduction and/or truncated dose scheduling may be considered for 
subjects with recurrent/ persistent toxicity or according to the institutional guideline. 
 
Section: Protocol Synopsis- Number Of Subjects 
 
Revised: 
It is estimated that approximately 3055 subjects will be enrolled into Part 1 dose-
escalation and additional 4025 subjects into PK/PD expansion cohorts in GSK2879552 
mono therapy and combination with ATRA arm the study.  Up to 3060 subjects will be 

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enrolled in Part 2 (expansion cohort) of GSK2879552 alone and combination with ATRA 
arm.  A total of approximately 100140 subjects will be enrolled in the study.  Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. 
 
Section: Protocol Synopsis- Inclusion/Exclusion Criteria And Protocol Section 3.2.1: 
Inclusion criteria 
Point number 10. (Inclusion criteria) 
 
REVISED TEXT: 
 
TSH, T4 
Vitamin B12 
BUN 
Na, K2, Ca, Cl, CO2 
Glucose (fasting) 
WNL 
≥ LLN 
≤1.5 X ULN 
WNL 
≤1.25 X ULN 
Lipid (ATRA combination ONLY) 
Triglyceride (fasting) 
Cholesterol (fasting) 
≤ 300 mg/dL 
≤ 300 mg/dL 
2. 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 
 
 
REVISED TEXT: Point number 11: 
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 (Section 
11.1), during the study and for 7 days (GSK2879552 mono therapy) or 30 days 
(combination with ATRA), following the last dose of study treatment. 
 
Section: Protocol Synopsis- Inclusion/Exclusion Criteria And Protocol Section 3.2.2: 
Exclusion Criteria  
 
REVISED TEXT- Point number 18, 19, 20, 21, 22 (Exclusion criteria)-Addition 
18. Previous treatment with GSK2879552 
For ATRA Combination arm ONLY 
19. Known hypersensitivity to ATRA, parabens (preservatives in the gelatin capsule) or 
other retinoids. 
20. ATRA capsule contains sorbitol. Subjects with rare hereditary problems of fructose 
intolerance are excluded. 
21. History of seizure within 12 months or brain tumor (primary) 
22. History of taking mega-dose vitamin A (>25,000 USP U/day) within 3 months from 
the dosing start. 
 

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Section: Protocol Synopsis- Pharmacokinetic/ Pharmacodynamic Assessment(S) 
REVISED TEXT: (Paragraph 1, 2 And 3) 
For all subjects in the dose escalation cohorts in Part 1, serial blood samples for analysis 
of GSK2879552 and ATRA 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 for GSK2879552 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 blood samples for PD, exploratory and 
biomarker will be collected at planned visits as listed in the Time and Event Table. 
 
For subjects in the highest dose of Part 1 PK/PD expansion cohort, additional blood 
samples for GSK2879552 metabolite profiling will be collected on Day 1 at pre-dose and 
Day 15 at the same time points as listed in the Time and Event Table (Section 7.1). In 
addition, pre-dose urine sample will be collected on Day 1, and 24 hour urine sample will 
be collected starting from prepost-dose on Days 1 and 15 until dosing on Days 2 and 16, 
respectively. 
 
Sentence 1: For all subjects in Part 2 expansion cohorts, serial blood samples for analysis 
of GSK2879552 and ATRA concentrations will be collected on Days 1 and 15 at planned 
time points as listed in the Time and Event Table (Section 7.1). 
 
Section: Protocol Synopsis- Clinical Activity Assessment 
 
REVISED TEXT: 
Sentence 1: Disease assessments will be made by physical examination and laboratory 
evaluation.  Bone marrow aspiration and biopsy will be performed as stated in the Time 
and Event Table (Section 7.1).  
 
Section: Protocol Synopsis- Translational Research 
REVISED TEXT: 
Blood and/or bone marrow aspriates will be collected at various times, throughout the 
study in order to support research aimed at understanding the biological effect of 
GSK2879552 alone or in combination with ATRA in AML as well as identifying 
indicators of sensitivity or resistance. Comparative examination of baseline cancer cell 
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 AML and medically related conditions.  Comparative examination of post-dosing 
cancer cell profiles in conjunction with pre-dosing cancer cell profiles may yield known 
or novel candidate biomarkers/profiles and new insights which relate to the action of 
GSK2879552. 
 
Section: Protocol Synopsis- Statistical Methods 
REVISED TEXT: (Paragraph 4) 
Sentence 2: A maximum of 30 subjects will be enrolled at the respective RP2D for 
GSK2879552 mono therapy and in combination with ATRA. All available data will be 
considered in making enrollment decisions. 
 
 

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Section 1.1: Background – LSD1 
REVISED TEXT: (Paragraph 3) 
GSK2879552 is a potent, selective inhibitor of LSD1/CoREST. GSK2879552 causes an 
increase in histone 3 lysine 4 di-methylation (H3K4me2) at promoters of putative LSD1 
target genes and has predominantly cytostatic effect on small cell lung cancer (SCLC) 
and acute myeloid leukemia (AML) cell lines (Refer to the Investigator Brochure (IB) for 
GSK2879552 [GlaxoSmithKline Document Number 2013N168888_012013N168888_0 
2013N168888_02). 
 
Section 1.3.1: GSK2879552 – Background 
REVISED TEXT: (Paragraph 1-2nd line) 
GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 767 nM, kinact = 0.1 min-1Ki = 1.7 µM, kinact = 0.1 min-1) 
 
REVISED TEXT: (Paragraph 4- Added text) 
In a MLL-AF9+ murine model of AML, treatment with GSK2879552 led to a significant 
delay in leukemia onset in treated mice relative to vehicle treated controls.   
 
REVISED TEXT: (Paragraph 5- 3rd line) 
Macroscopic and histopatholgic examination suggested that the severity of the 
thrombocytopenia is was likely due to the combined effects of irradiation, engraftment of 
injected AML cells into marrow and multiple other organs, and the effect of 
GSK2879552 on platelets. 
 
Section 1.3.2: LSD1 inhibitor and All-Trans Retinoic Acid (added) 
 
Revised (Added text) 
Retinoic acid regulates normal embryonic cell differentiation and development of many 
tissues including the brain, lungs, and other organs [Niederreither, 2008]. All-trans-
retinoic acid (ATRA) induced differentiation has been explored in cancers that appear to 
retain stem-like cells as well as those in which molecular features of differentiation have 
been characterized.  Sarcoma cells including osteosarcoma and rhabdomyosarcoma 
display morphological changes and alterations in molecular markers consistent with 
osteoblast and myogenic differentiation in response to ATRA [Luo, 2010; Barlow 2006].  
The presence of cancer stem cells in glioblastoma has been associated with therapeutic 
resistance and tumor initiating potential.  Pre-clinical models have been developed to 
reveal this subpopulation and, in this setting, glioblastoma cells exposed to ATRA 
undergo reduced proliferation and self-renewal, differentiation into glial and neuronal 
lineages, and ultimately apoptosis [Karsy, 2010; Choschzick, 2014].  Despite the pre-
clinical data suggesting ATRA treatment can promote differentiation in a number of 
tumor models, ATRA therapy has not proven efficacious in solid tumors clinically. 
 
ATRA has been used successfully in hematological malignancies and is the current 
standard of care for acute promyelocytic lekemia (APL), a subtype of acute myeloid 
leukemia (AML).  ATRA therapy promotes complete remission in more than 90% of 
patients through differentiation of leukemic blasts, however, this efficacy has not 

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translated to non-APL subtypes of AML.  The selective response to ATRA in APL is 
associated with the expression of PML-RAR, the fusion protein that results from 
chromosomal translocation t(15,17)(q22;q21).  In this setting, ATRA can induce 
expression changes in genes associated with myeloid differentiation through relief of 
repression of the myeloid expression program imposed by the PML-RAR fusion protein 
[Melnick, 1999; Johnson 2015].  These data suggest that targeting a differentiation 
mechanism may also provide an effective therapy in AML if expression of myeloid gene 
programs can be achieved. 
 
Inhibition of LSD1 by GSK2879552 can promote differentiation in AML cells as 
evaluated by several measures including gene expression and cell surface marker changes 
consistent with myeloid differentiation. LSD1 has been implicated in regulation of the 
ATRA driven response through increases in H3K4me2 at key genes involved in the 
ATRA pathway [Schenck, 2012; Sakamoto, 2014].  Given the overlapping mechanism 
associated with each single agent, and the potentiating effect of LSD1 inhibition on the 
ATRA pathway, treatment of AML may demonstrate greater response to ATRA when 
combined with GSK2879552. 
 
Section 1.3.3: Pre-Clinical PK and Safety of GSK2879552 (General toxicology) 
REVISED TEXT: (Paragraph 1) 
Sentence 4: Summaries of principal findings following single and repeat dosing of 
GSK2879552 and a comparison of systemic exposures achieved in these studies are 
presented in the IB for GSK2879552 [GlaxoSmithKline Document Number 
2013N168888_012013N168888_0 2013N168888_02]. 
 
Section 1.3.4: Pharmacokinetics of GSK2879552 in Humans 
REVISED TEXT: (Paragraph 2-added and deleted previous paragraph 2) 
As of 20-NOV-2015, the PK of GSK2879552 was evaluated following administration of 
single (N=18) and repeated (N=16) oral administration of 0.25 mg to 3 mg of 
GSK2879552 in subjects with SCLC in Study 200858 and following single (N=11) and 
repeated (N=8) oral administration of 1 mg to 8 mg in subjects with AML in Study 
200200. GSK2879552 pharmacokinetics are characterized by a rapid absorption with 
maximum concentration occurring typically within the first hour after dosing. 
GSK2879552 is eliminated slowly with an average terminal phase half-life of 12 to 38 
hours, leading to a moderate average increase in exposure of 72% for AUC at 2 mg daily. 
Following single and repeated administration of 0.25 mg to 4 mg of GSK2879552, Cmax 
and AUC tended to increase in a dose proportional fashion. 
 
As of 29-April-2014, the pharmacokinetics of GSK2879552 has been evaluated in 1 
small cell lung cancer subject in GSK study 200858 following single and repeated daily 
oral administration of 0.25 mg of GSK2879552. GSK2879552 pharmacokinetics are 
characterized by a rapid absorption with maximum concentration occurring 0.5 to 1 hour 
after dosing followed by a bi-exponential decline. The maximum concentration was 4.55 
ng/mL after a single dose and 3.61 ng/mL after repeated administration. GSK2879552 

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preliminary terminal phase half-life was around 20 to 23 hours but estimated over a short 
time interval. The area under the curve from zero to 24 hours was 13.2 ng.h/mL after a 
single dose and 28.5 ng.h/mL after repeated daily dosing, leading to a 2.16-fold 
accumulation in this subject following once daily oral administration. 
 
Section 1.3.5: Clinical Safety of GSK2879552 
REVISED TEXT: (Paragraph 1- deleted and Paragraph 1,2 and 3 added) 
As of 29-April-2014, no AEs have been reported in a single subject receiving 
GSK2879552 0.25 mg once daily in small cell lung cancer study. A trend in slight 
decrease in platelet count was observed with a nadir reached on Day 11 (121 x 109/L vs. 
163 x 109/L at baseline) followed by full recovery with a platelet count of 173 x 109/L 
observed on Day 28. A trend in slight decrease in ANC beyond Day 21 was observed 
after initial drop from the pre-treatment level.  Otherwise laboratory test results and vital 
signs have been unremarkable. 
Summary of findings from clinical studies conducted with GSK2879552 can be found in 
the Investigator Brochure for GSK2879552 [GlaxoSmithKline Document Number 
2013N168888_02]. 
  
As of 20-NOV-2015, 11 subjects have been enrolled in Part 1 at once daily doses of 1 mg 
(n=1), 2 mg (n=2), 4 mg (n=7), and 8 mg (n=1). All 11 subjects (100%) had experienced 
AEs.  The most frequently reported AEs (>20%) were fatigue, febrile neutropenia, 
nausea, anemia, decreased appetite, hypotension, rash, cellulitis, hypokalemia, and local 
edema. All Grade 4 AEs were hematological and included thrombocytopenia and 
neutropenia. Treatment-related AEs reported in at least 10% of subjects were nausea, 
decreased appetite, and thrombocytopenia. The treatment-related thrombocytopenia AEs 
were Grade 4 in both subjects; one of these subjects also had Grade 3 febrile neutropenia 
and Grade 3 anemia. Other treatment-related events that were Grade 3 or 4 included 
anemia and nausea. There were no fatal AEs. 
 
All 11 subjects in Study 200200 have experienced SAEs. The most common SAE was 
febrile neutropenia. All cases of febrile neutropenia resolved. No other SAEs occurred in 
more than 1 subject. One subject had fatal pleural effusion secondary to disease under 
study, which was considered by the investigator to be not related to study treatment. 
 
Section 1.3.6: Combination Agent (added) 
Section 1.3.6.1: All-Trans Retinoic Acid (ATRA) (added) 
All-trans retinoic acid (ATRA, tretinoin) is indicated for the induction of remission in 
patients with acute promyelocytic leukemia (APL) at 45 mg/m2/day, or according to the 
French-American-British (FAB) classification the M3 subtype of acute myeloid leukemia 
(AML-M3). 
The most frequently reported adverse events of ATRA are similar to those described in 
patients taking high doses of vitamin A and included headache (86%), fever (83%), 
skin/mucous membrane dryness (77%), bone pain (77%), nausea/vomiting (57%), rash 
(54%), mucositis (26%), pruritus (20%), and increased sweating (20%) [ATRA 
Prescribing Information, 2004].  
About 25% of patients with APL treated with ATRA have experienced the retinoic acid-
APL (RA-APL) syndrome. The syndrome generally occurs during the first month of 

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treatment, with some cases reported following the first dose of ATRA. During ATRA 
treatment, about 40% of patients will develop rapidly evolving leukocytosis which is 
associated with a higher risk of life threatening complications. Retinoids have been 
associated with pseudotumor cerebri (benign intracranial hypertension), especially in 
pediatric patients.  Up to 60% of patients experienced hypercholesterolemia and/or 
hypertriglyceridemia, which were reversible upon completion of treatment.  Elevated 
liver function test results occur in 50% to 60% of patients during treatment. However, the 
majority of these abnormalities resolve without interruption of ATRA or after completion 
of treatment. ATRA has teratogenic and embryotoxic effects and there is a high risk that 
severe fetal abnormalities may result with ATRA administration during pregnancy. Cases 
of thrombosis involving various sites have been reported rarely [ATRA Prescribing 
Information, 2004]. 
In a Phase I study conducted in subjects with solid tumor, ATRA was administered at 
doses ranging from 45 to 309 mg/m2 per day [Conley, 1997]. Hypertriglyceridemia was 
dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous 
dryness and headache. The recommended once-daily ATRA dose was 215 mg/m2.  In 
another Phase I study conducted in subjects with solid tumor, ATRA dose ranged from 
45 to 200 mg/m2 per day [Lee, 1993]. Skin toxicities were dose limiting in this study at 
175 mg/m2 or higher dose. Headache was one of the most common toxicities and 
nausea/vomiting were frequent at dose levels higher than 100 mg/m2. The recommended 
once daily ATRA dose was 150 mg/m2. In a Phase I study conducted in patients with 
head and neck squamous cell carcinoma with prior surgical resection [Park, 2000], 
ATRA was administered at 45, 90, or 150 mg/m2 either once daily or as divided doses. A 
similar toxicity profile was observed with headache, mucocutaneous dryness, and 
hypertriglyceridemia as the frequent toxicities. The maximum tolerable dose of ATRA in 
this population was established at 45 mg/m2/day, although the reason for the lower 
tolerance in this subject population is not clear.   
ATRA is available in a 10 mg soft gelatin capsule for oral administration. The 
recommended dose in APL is 45 mg/m2/day administered as two divided doses, as 
equally as feasible.  
 
Pharmacokinetics of ATRA 
ATRA (tretinoin) is rapidly absorbed following oral administration with peak 
concentration observed within 1 to 2 hours after dosing. ATRA is eliminated rapidly, 
with a terminal half-life of 0.5 to 2 hours following the first dose in patients with APL or 
CML. Cytochrome P450 3A4, 2C8 and 2E enzymes have been implicated in the 
oxidative metabolism of ATRA. There is evidence that ATRA induces its own 
metabolism. Plasma ATRA concentrations decrease on average to one-third of their day 1 
values during 1 week of continuous therapy. Mean ± SD peak ATRA concentrations 
decreased from 394 ± 89 to 138 ± 139 ng/mL, while area under the curve (AUC) values 
decreased from 537 ± 191 ng·h/mL to 249 ± 185 ng·h/mL following 45 mg/m2 daily 
dosing in 7 APL patients [ATRA Prescribing Information 2004]. This reduction in 
exposure was reverted following a one week dose interruption [Russo, 1998]. 
 
Section 1.4.1: Rationale for Study 
REVISED TEXT: 
Last sentence: The proposed Phase I study will evaluate the safety and tolerability, 
pharmacokinetics, pharmacodynamics, and clinical activity to determine the 

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recommended Phase 2 Dose (RP2D) and regimen of GSK2879552, alone or in 
combination with ATRA, given orally in adult subjects with relapsed/refractory AML. 
 
Section 1.4.1.1: Rationale for Combination with ATRA (added) 
REVISED TEXT: 
Previous studies indicated that, when combined with ATRA, knockdown of LSD1 or 
treatment of AML cells with a non-selective LSD1 inhibitor, tranylcypromine, resulted in 
a greater anti-leukemic effect in vitro and in vivo.  The addition of LSD1 inhibitor 
potentiatied ATRA induced cell surface marker changes, myeloid differentiation gene 
expression, and in vivo engraftment of AML cells.  These effects were observed in both 
ATRA sensitive and insensitive cells [Schenk, 2012]. 
 
Several approaches were undertaken to evaluate the combination effects of GSK2879552 
with ATRA.  As described, growth inhibition by GSK2879552 alone is cytostatic and 
does not invoke cell death mediated by apoptosis.  Evaluation of proliferation in AML 
cell lines showed that ATRA alone has growth inhibitory effects.  Co-treatment of AML 
cell lines with fixed concentrations of ATRA (0, 1, 10, 100, or 1000 nM) with 
GSK2879552A (3000 nM-0.152 nM) decreased the EC50 associated with GSK2879552 
growth inhibition and resulted in cytotoxicity at earlier timepoints than ATRA alone in 
MOLM-13 cells and OCI-AML3 cells.  Overall, percent maximum inhibition increased 
in combination relative to GSK2879552 alone in 5 of 6 cell lines tested.  Using a similar 
study paradigm, caspase activation, a hallmark of apoptotic cell death was measured to 
further evaluate the mechanism of cytotoxicity invoked by the combination.  
GSK2879552 in combination with ATRA resulted in increased caspase activation when 
compared to activity of either single agent and supra -additive effects were observed in 5 
of 6 AML cell lines tested.  Five of 6 cell lines tested reached a supra-additive effect at 
100 nM and 1000 nM ATRA while 3 cell lines, HL-60, MV-4-11 and SIG-M5, reached a 
supra-additive effect at 10 nM ATRA.  Supra-additive effects occurred at GSK2879552A 
concentrations ≥ 37 nM except in SIG M5 cells where the supra-additive were only 
evident at lower doses of GSK2879552A (0.46 nM to 37 nM). 
 
In a separate study using samples derived from bone marrow of AML patients, AML 
blast colony forming ability was evaluated with the combination of GSK2879552 with 
fixed concentrations of ATRA (0-1000nM).  While each single agent did inhibit AML 
blast colony number to varying degrees in a 6 of 9 samples, co-treatment with 0.1 µM or 
1 µM ATRA in combination with GSK2879552 resulted in a greater anti-leukemic effect 
as revealed by a lower GSK2879552 IC50 or greater maximal inhibition of AML blast 
colony forming ability than either single agent alone.  Supra-additive effects were 
observed in 2 of 6 evaluable samples. 
 
Finally, flow cytometric evaluation of cell surface markers of 2 AML cell lines (KG-1 
and KG-1a) revealed increased CD11b and CD86 expression above single agent activity 
in 1 of the 2 cell lines.  Taken together, these studies indicate that the combination of 
LSD1 inhibition with ATRA can enhance in vitro growth inhibition of AML cells beyond 
that achievable by either agent alone.  
In this study, a combination arm will be included to evaluate safety, tolerability, PK, PD 
and clinical activity of GSK2879552 in combination with ATRA. 
 

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Section 1.4.3: Rationale for Dose - GSK2879552 Monotherapy (addition in title) 
 
Section 1.4.4: Rationale for Dose – GSK2879552 and ATRA combination (added as 
new title) 
 
Section 1.4.4.1: Predicted Effective Dose (added) 
REVISED TEXT: (added) 
Effective doses for GSK2879552 in combination with ATRA are anticipated to be at or 
below the predicted single agent effective doses of 10 to 40 mg daily. 
 
ATRA dose of 45 mg/m2/day as two divided doses (as equally as feasible) would provide 
maximum concentrations around 500 nM, average steady-state concentrations around 80 
nM and concentrations above 100 nM for around 6 hours. ATRA concentrations at 100 to 
1000 nM ranges in combination with up to 2 µM GSK2879552 resulted in a greater anti-
leukemic effect in in vitro studies. 
 
Section 1.4.4.2: Starting dose (added) 
REVISED TEXT: (added) 
ATRA dose will be fixed at 45 mg/m2/day as two divided doses, as equally as feasible. 
The starting dose for GSK2879552 will be 2 mg. These starting doses were chosen based 
on the following considerations: 
• GSK2879552 and ATRA do not have overlapping toxicity profiles based on the 
nonclinical toxicology and clinical safety profile of GSK2879552 at doses up to 4 
mg daily. 
• GSK2879552 mono-therapy has been well tolerated in this study at up to 4 mg 
daily dose. 2 mg daily dose of GSK2879552 represents a 50% reduction from the 
highest cleared dose of 4 mg daily as of 20-NOV-2015. 
• A dose of 45 mg/m2/day for ATRA represents the recommended dose in APL as a 
single agent, well below the MTD of 150-215 mg/m2/day. 
• The risk of GSK2879552 altering ATRA PK is low. In-vitro data suggests that 
GSK2879552 has a very low potential to inhibit or induce CYP enzymes, and to 
inhibit Pgp, BCRP, OATP1B1 or OATP1B3 transporters. 
•  The risk for ATRA to increase GSK2879552 exposure is very low. ATRA has 
only been reported to be an enzyme inducer. 
 
Section 1.4.5: Benefit Risk assessment 
REVISED TEXT: 
Summaries of findings from non-clinical and clinical studies conducted with 
GSK2879552 can be found in the Investigator Brochure (IB) for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_012013N168888_0 
2013N168888_02].  The following section outlines the risk assessment and mitigation 
strategy for this protocol. 
 
Section 1.4.5.1: Risk Assessment 
REVISED TEXT: (in row 2 and addition after row 2) 

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Potential Risk 
of Clinical 
Significance 
Data/Rationale for Risk 
4. Mitigation Strategy 
Mental status 
change 
Encephalopath
y 
TwoThree (out of 16 18) 
subjects enrolled in 200858 
study experienced 
encephalopathy. 
- 
No change from the previous 
version 
ATRA Combination ONLY 
RA-APL 
syndrome or 
respiratory 
compromise  
About 25% of patients with 
APL treated with ATRA 
have experienced the 
retinoic acid-APL (RA-
APL) syndrome. 
Protocol provides the guideline for RA-
APL syndrome management. 
Leukocytosis 
About 40% of patients may 
develop rapidly evolving 
leukocytosis  during ATRA 
treatment 
Subjects with an increased risk of a 
further rapid increase in WBC counts, 
i.e., WBC >30,000/uL, are excluded. 
Pseudotumor 
cerebri/ 
intracranial 
hypertension. 
ATRA may cause 
pseudotumor 
cerebri/intracranial 
hypertension. 
Concomitant administration of ATRA 
and agents known to cause 
pseudotumor cerebri/intracranial 
hypertension (e.g., tetracycline) will be 
prohibited. 
5. Hyperchole
sterolemia/ 
hypertriglyceri
demia 
Up to 60% of patients 
experienced 
hypercholesterolemia and/or 
hypertriglyceridemia with 
ATRA treatment. 
Subjects with hypertriglyceridemia or 
hypercholesterolemia >300 mg/dL are 
excluded. 
Lipid panel will be checked weekly for 
the first 4 weeks and then q 4 weeks 
thereafter. 
Liver function 
test elevation 
Elevated liver function test 
results occur in 50% to 60% 
of patients during ATRA 
treatment. 
LFT is monitored twice weekly for the 
first 2 weeks, weekly for the next 2 
weeks and then q 4 weeks thereafter.  
Treatment stopping criteria based on 
elevation in LFT is in place and the 
safety management guideline is also 
provided.  
Hypervitamino
sis A 
Chemically, ATRA is all-
trans retinoic acid and is 
related to retinol (Vitamin 
A). 
Vitamin A or multivitamins including 
vitamin A are prohibited. 
Teratogenic 
effect 
There is a high risk that a 
severely deformed infant 
will result if ATRA is 
administered during 
pregnancy.  
Female subjects with child bearing 
potential will be required to use 2 
reliable forms of contraception methods 
simultaneously during the treatment and 
until 30 days after the last dose of 
ATRA or 7 days after the last dose of 
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Contraception counselling will be 
repeated monthly throughout ATRA 
treatment.   
Serum pregnancy test will be performed 
at screening and end of treatment visit, 
and urine pregnancy test at week 4 and 
every 4 weeks thereafter.  
6. Thrombosis 7. Cases of fatal 
thrombotic complications 
have been reported rarely in 
patients concomitantly 
treated with ATRA and anti-
fibrinolytic agents. 
CBC and coagulation panel are 
monitored weekly for the first 4 weeks 
and then every 4 weeks thereafter. 
Concomitant administration of 
antifibrinolytic agents (such as 
tranexamic acid, aminocaproic acid, or 
aprotinin) will be prohibited. 
 
Section 1.4.5.2.: Benefit Assessment 
REVISED TEXT: (addition of Paragraph 2) 
ATRA is indicated for acute promyelocytic leukemia (APL). While there has been 
significant success in the utility of ATRA as a differentiation therapy in APL, ATRA has 
not been found to invoke a similar mechanism in other AML subtypes.  GSK2879552 
promotes differentiation in AML cell lines leading to the hypothesis that, through an 
overlapping mechanism, treatment of AML may demonstrate a greater response to ATRA 
when combined with GSK2879552.  Any potential beneficial effect for an individual 
subject attributable to the combination of ATRA with GSK2879552 in non-APL type 
AML is unknown. 
 
Section 1.4.5.3.: Overall Risk Benefit Conclusion 
REVISED TEXT: 
Current data from GSK2879552 preclinical studies, alone or in combination with ATRA, 
indicate a potential for clinical activity by induction of differentiation in AML. Taking 
into account the measures taken to minimise risks to subjects participating in this Phase I 
clinical trial, the potential risks identified in association with GSK2879552, alone or in 
combination with ATRA, are justified by the anticipated benefits that may be afforded to 
subjects with relapsed/refractory AML, for whom there are currently no effective 
available therapies. 
 
Section 3.1: Number of subjects 
REVISED TEXT (Paragraph 1) 
Sentence 3:  It is estimated that approximately 30 55 subjects will be enrolled into Part 1 
dose-escalation and additional 40 25 subjects will be enrolled into PK/PD expansion 
cohorts in GSK2879552 mono therapy and combination with ATRA arm.  Up to 30 60 
subjects will be enrolled in Part 2 (expansion cohort) of GSK2879552 alone and 
combination with ATRA armthe study.  A total of approximately 100140 subjects will be 

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enrolled in the study.  Additional subjects/cohorts may be enrolled to allow for evaluation 
of additional dose levels. 
 
Section 3.2.1 Inclusion criteria 
REVISED TEXT: (Paragraph 1) 
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) for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_012013N168888_0 
2013N168888_02. 
 
Section 4.1: Discussion of study design 
REVISED TEXT (In paragraph 1, 2, 3 and addition of paragraph 4) 
Sentence 1: This is a Phase I, open-label, multi-center, non-randomized, 2-part study. 
Part 1 is a dose escalation phase to determine the MTD and/or RP2D for GSK2879552, 
alone or in combination with ATRA, based on the safety, tolerability, pharmacokinetic, 
and pharmacodynamic….. 
Once MTD and/or RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects 
each will be enrolled to further evaluate the efficacy and tolerability of GSK2879552, 
alone or in combination with ATRA, in subjects with relapsed/refractory AML.  
The proposed treatment schedule of GSK2879552 is continuous daily dosing.  The 
starting dose for GSK2879552 mono therapy arm will be 0.25 mg/day or the highest dose 
determined to be safe in the ongoing SCLC study, whichever is higher with a maximum 
of 1 mg/day (see Section1.4.3.2 for details). The starting dose of GSK2879552 in 
combination with ATRA will be 1-2 dose levels below the highest dose determined to be 
safe in the GSK2879552 mono therapy arm in this study, i.e., 2 mg once daily. 
Alterations to the dose and schedule may be incorporated based on emerging PK, PD, and 
tolerability data.  
Dose reduction and/or truncated dose scheduling may be considered for subjects with 
recurrent/ persistent toxicity or according to the institutional guideline. For example, once 
the disease control (CR, CRp, PR or a morphologic leukemia-free state) is attained, 
ATRA may be given in an intermittent schedule, e.g., 2 week on/2 weeks off. 
 
Section 4.2: Part 1: Dose-Escalation Phase (given the section number) 
Section 4.2.1: GSK2879552 Mono-therapy  
Revised section 
Sentence 2: If the first subject becomes inevaluable unevaluable for reasons other than 
toxicity, another subject will be recruited. 
 

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Under: Completion of Dose Escalation: 
REVISED TEXT: 
Sentence 5 (added): Up to 12 additional subjects will be enrolled at the dose to further 
define the safety and tolerability of the dose and schedule. If necessary, alternate 
schedules can be explored to determine additional biologically active doses even after a 
RP2D is defined. 
 
Section 4.2.2: GSK2879552 and ATRA combination (new addition) 
REVISED TEXT: (addition) 
In Cohort 1, three subjects will receive GSK2879552 2 mg once daily dose with ATRA 
45 mg/m2/day as two divided doses.  After all three subjects complete the first 4 weeks of 
treatment, the safety data will be reviewed for DLT. Available PK and PD data will be 
also reviewed prior to a dose escalation decision and starting Cohort 2. Each cohort will 
enroll 3 or more subjects to obtain sufficient data. If any subject becomes unevaluable for 
reasons other than toxicity, a replacement subject will be enrolled. In addition, subjects 
who fail to take at least 75% of their scheduled doses of each drug in the first 4 weeks for 
reasons other than toxicity will be replaced. Starting with Cohort1, the dose escalation 
will use the N-CRM with prior DLT information of GSK2879552 and ATRA mono-
therapies and follow the same rule with regards to the number of subjects, maximum dose 
increment, and the completion of dose escalation as described in Section 4.2.1. The 
details of priors used in N-CRM model is described in Section 13.2  
Following GSK2879552 dose levels are planned for evaluation in combination with 
ATRA 45 mg/m2/day. A reduced dose of ATRA may be considered if the combination is 
not well tolerated at dose level 1. 
• Dose level 1: GSK2879552 2 mg/day 
• Dose level 2: GSK2879552 4 mg/day 
• Dose level 3: GSK2879552 8 mg/day 
• Dose level 4: GSK2879552 16 mg/day 
Dose level 5: GSK2879552 32 mg/day 
 
Section 4.2.4: Alternative Dosing and PK/PD Sampling Schedules 
REVISED TEXT (Paragraph 2 and 3) 
Further alterations may be made to the dosing schedule and/or PK/PD sampling schedule 
of GSK2879552 or ATRA based on the results of emerging PK, PD, efficacy and safety 
data, and documented in the SPM. These changes will be communicated to IRB/EC, but 
would not constitute a protocol amendment. 
Sentence 1: Schedules that incorporate a recovery period may be explored (e.g., 4 days 
on/3 days off). Alternatively, a drug holiday after continuous dosing may be explored for 
GSK2879552 and/or ATRA.  
 

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Section 4.2.5: Dose-Limiting Toxicity 
REVISED TEXT: (paragraph 1 and point 1) 
An event will be considered a DLT if it occurs within the first 4 weeks of treatment (with 
exception as belowof myelosuppression), and meets one of the following criteria unless it 
can be clearly established that the event is unrelated to treatment: 
• Prolonged grade 4 neutropenia (≤0.5 x 109/L) or thrombocytopenia (≤25 x 
109/L)Myelosuppression with bone marrow hypoplasia (cellularity < 5%) , 28-
days after ceasing study treatment without evidence of leukemia (<5% blasts at 
the time of drug cessation and bone-marrow biopsy confirmed absence of 
leukemia 21-28 days later) for > 28 days. If a subject meets above criteria at the 
time of drug cessation within DLT observation period, the dose escalation 
decision will be delayed until 28 days have elapsed post drug cessation. 
Section 4.2.6: Maximum Tolerated Dose and Recommended Phase 2 Dose 
REVISED TEXT: (paragraph 2) 
Sentence 3 added: The RP2D may be different for mono-therapy and for the 
combination therapy with ATRA. 
 
Section 4.3: Part 2: Expansion Cohort 
REVISED TEXT: (paragraph 1 and addition of paragraph 3) 
Once the respective RP2D hasve been determined, an expansion cohort of up to 30 
subjects each, GSK2879552 mono-therapy or in combination with ATRA, will be 
enrolled in order to better characterize the clinical activity and safety profile of the RP2D. 
 
The statistical design and number of subjects to be enrolled in the dose expansion cohort 
is based on the predictive probability of success if enrollment continues until all planned 
subjects are recruited [Lee, 2008]. The predictive probability design allows for evaluation 
of stopping rules after each subject once a minimum number of subjects are evaluable.   
In this particular study, we will stop only for futility. Final decisions on stopping 
enrolment will depend on the totality of the data collected. 
 
 
Section 4.6: Dosage and Administration of Study Treatment(s) 
 
REVISED TEXT: 
See Section5.1 for the dosage and administration of GSK2879552 and ATRA. 
 
Section 4.6.1 Meals and Dietary Restrictions 
 
REVISED TEXT: (paragraph 2) 
GSK2879552 Study treatment(s) will be administered under fasting conditions, either 1 
hour before or 2 hours after a meal. Subjects should take their morning ATRA dose 
fasted, at the same time as GSK2879552. If ATRA concentrations are lower than 

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anticipated following fasted administration, subjects may be asked to take their morning 
ATRA dose with food. Subject should take their evening ATRA dose with food. 
 
Section 4.8.2: Dose Adjustment for Non-Hematologic Toxicity 
 
REVISED TEXT: (Addition at the footer of the table for G2 and G3 and G4) 
†In combination cohort, consider holding ATRA dosing first for skin related toxicity 
(dryness, rash), nausea, vomiting, pain, headache, and mucositis. With fever, consider 
holding LSD1 first to allow neutrophil count to recover. 
 
REVISED TEXT: (paragraph 2) 
Sentence 1: If the non-hematologic toxicity or event resolves to baseline or ≤ Grade 1 
within 14 days of stopping therapy, treatment with GSK2879552 and/or ATRA may be 
restarted with at least 25% dose reduction.  
 
Section 4.8.4: Safety Management for ATRA Combination (addition of new section 
and sub sections) 
 
REVISED TEXT: (addition of subsection 4.8.4.1) 
Retinoic Acid-APL syndrome 
About 25% of patients with APL treated with ATRA have experienced the retinoic acid-
APL (RA-APL) syndrome characterized by fever, dyspnea, acute respiratory distress, 
weight gain, radiographic pulmonary infiltrates, pleural and pericardial effusions, edema, 
and hepatic, renal, and multi-organ failure [ATRA Prescribing Information, 2004]. This 
syndrome has occasionally been accompanied by impaired myocardial contractility and 
episodic hypotension. The syndrome generally occurs during the first month of treatment, 
with some cases reported following the first dose of ATRA.   
High dose steroids should be immediately initiated at the first suspicion of the RA-APL 
syndrome irrespective of the leukocyte count, e.g., dexamethasone 10 mg intravenously 
administered every 12 hours for 3 days or until the resolution of symptom. The first signs 
of the syndrome include:  
• unexplained fever 
• dyspnea and/or weight gain 
• abnormal chest auscultatory findings or radiographic abnormalities 
 
Prophylactic treatment with steroid may be considered per institutional guideline when 
leukocyte counts double in number to >10,000/uL from baseline leukocyte <10,000/uL. 
Prophylactic treatment with hydroxyurea and steroid may be considered per institutional 
guideline when leukocyte counts double in number from baseline leukocyte 10,000- 
30,000 /uL. 
In cases of moderate and severe RA-APL syndrome, temporary interruption of ATRA 
treatment should be considered. 
 
REVISED TEXT: (addition of subsection 4.8.4.2) 
 
Liver Function Test Elevation  
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• If resolved in 14 days, ATRA dose should resume at full dose 
• If not resolved in 14 days, GSK2879552 dose should be also held. 
o If resolved in another 14 days, resume GSK2879552 at a reduced dose by 
minimum 25% and ATRA at full dose 
o If not resolved in another 14 days, withdraw the subject from the study.  
 
REVISED TEXT: (addition of subsection 4.8.4.3) 
Pseudotumor Cerebri (benign intracranial hypertension) 
Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual 
disturbances.  Subjects with these symptoms should be evaluated for pseudotumor 
cerebri, and, if present, appropriate care should be instituted including high dose steroid. 
ATRA dose should be held for moderate to severe pseudotumor cerebri. 
 
 
Section 5: Investigational Product(S) 
 
REVISED TEXT: (paragraph 1) 
The term ‘study treatment’ is used throughout the protocol to describe investigational 
product(s) (IP) received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. 
 
REVISED TEXT: (Section 5.1: Description of Investigational Product(s)) 
 
Product 
name: 
GSK2879552 Capsule 
Formulation 
description*: 
GSK2879552 capsules contain 0.25 mg, 0.5 mg, 2 mg or 5 mg of 
GSK2879552 as parent.   
Unit dose 
strength(s) 
0.25 mg, 0.5 mg, 2 mg and 5 mg 
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.   
 
NOTE: 0.25 mg strength of GSK2879552 capsule is no longer being used and is removed 
from the table.   
 
GSK2879552 will be provided to sites by GSK, whereas ATRA will be locally supplied 
and prepared according to local standards.  The contents of the label will be in 
accordance with all applicable regulatory requirements. 
 

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Product name: 
Tretinoin (ATRA) Capsule 
Formulation 
description: 
ATRA is supplied as a 10 mg capsule for oral administration.  
Dosage form: 
Capsule 
Unit dose 
strength(s) 
10 mg 
Route/Regimen 
Oral/The initial dosing regimen will be continuous oral twice 
daily dosing, i.e., morning and evening. ATRA dose may be 
divided evenly 2-4 times a day, as needed. 
Subjects should take their morning dose fasted, at the same time 
as GSK2879552. If ATRA concentrations are lower than 
anticipated following fasted administration, subjects may be 
asked to take their morning ATRA dose with food. Subject can 
take their evening ATRA dose with food.  
 
Section 5.2: Preparation/Handling/Storage of GSK2879552, GSK Investigational 
Product 
 
REVISED TEXT: (below storage, paragraph 2) 
GSK2879552 is to be stored at a temperature range of 2-8°C (36-46°F), protected from 
moisture.  See package insert for ATRA storage conditions. 
Section 5.4: Treatment Compliance 
 
REVISED TEXT: (paragraph 1 and 2) 
1st sentence of paragraph 1: On clinic days, GSK2879552 and ATRA should be taken 
in the clinic after safety procedures including blood sampling for CBC and PK/PD 
samplings, if applicable, are completed.   
 
1st sentence of paragraph 2: Compliance with GSK2879552 IP 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. 
 
Section 5.5: Treatment of Investigational Product Overdose 
 
REVISED TEXT (addition of paragraph 2) 
The MTD of ATRA in patients with myelodysplastic syndrome or solid tumors was 195 
mg/m2/day. Overdosage with other retinoids has been associated with transient headache, 
facial flushing, cheilosis, abdominal pain, dizziness and ataxia. These symptoms have 
quickly resolved without apparent residual effects. There is no specific treatment in the 
case of an overdose, however, it is important that the patient be treated in a special 
hematological unit [ATRA Prescribing Information, 2004]. 
 

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Section 6.2: Subject Completion Criteria 
 
REVISED TEXT: (full section) 
A subject will be considered to have completed the study if they have received at least 
one dose of the study drug and completed at least one post-treatment follow-up visit. 
 
In Part 1, a subject will be considered to have completed the study if: 
• they complete screening assessments, the 28-day DLT observation period, and 
taking a minimum of 75% of planned doses, 
• they progress or die while receiving study treatment, or 
• they are receiving ongoing study treatment at the time of the Sponsor’s decision 
to close the study. 
In Part 2, a subject will be considered to have completed the study if: 
• they die while receiving study treatment, 
• they progress while receiving study treatment and are followed until death, or 
• they are receiving ongoing study treatment at the time of the Sponsor’s decision 
to close the study. 
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  The End of Study eCRF should only be completed when 
a subject is no longer being followed. 
 
Section 6.3: Permanent Discontinuation from Study Treatment (5th point – 5th line) 
REVISED TEST: (5th point – 5th line) 
If the investigator and GSK Medical Monitor conclude that the benefit: risk rupports 
supports continued 
 
Section 6.4: Study Completion 
 
REVISED TEXT: (paragraph 1) 
First sentence: The study will be considered completed, having met the study objectives, 
approximately 2 years from the last subject’s first dosing or when 80% or more all 
subjects in Part 2 have withdrawn from the study, whichever occurs first. 
 
Section 7: STUDY ASSESSMENTS AND PROCEDURES 
 
REVISED TEXT: (below ‘Visit Window-4 paragraph) 
Visits in the first 4 weeks will be allowed ± 1 day window. Bone marrow on Day 15 can 
be done between Day 8 and Day 21. 

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Section 7.1: Time and Events Table(s) 
 
REVISED TEXT: (Table 3) 
SC
R 
First Treatment Phase (28 days) 
Continuation Phase 
EO
T 
  
D 1 
D 2 
D 4 
D 8 
D 11 
D 15 
D 16 
D 18 
D22 
D25 
Chemistry Panel including 
liver function tests 
X 
 
 
X22 
X 
X22 
X 
 
 
X 
 
every 4 wks 
X 
Vitamin B12, TSH, T4 
X 
 
Fasting Lipid panel 
(triglyceride, cholesterol)22 
X 
 
 
 
X 
 
X 
 
 
X 
 
every 4 wks 
 
Blood samples for PD6, 21 
(peripheral blood)  
X 
 
X 
X 
X 
bone marrow day6 
 
 
Wk 4, between Wk 6- 819, Wk 
12 and then every 12 wks. 
X 
Blood samples for 
exploratory studies6, 21 
(peripheral blood)  
X 
 
X 
X 
X 
bone marrow day21 
 
 
Wk 4 and Wk 24   
X 
Blood samples for 
circulating biomarkers and 
DNA6(plasma and cell 
pellet) 
 
X 
 
 
 
bone marrow day21 
 
 
 
X 
Bone marrow aspirate for 
PD21,22 
X7 
 
 
 
 
X18  
 
 
Wk 4, between Wk 6- 819, Wk 
12 and then every 12 wks  
X17 
Bone marrow aspirate for 
exploratory studies  21 
DNA, and RNA) 
X7 
 
 
 
 
X18  
 
 
Wk 4, between Wk 6- 819, Wk 
12 and then every 12 wks. Wk 
4 and 24 
X17 
PGX sample (buccal swab) 
X 
 
 
Blood for metabolite 
evaluation  
 
X9 
X9 
 
 
 
X9 
X9 
 
 
 
 
  
Urine for metabolite 
evaluation 
 
X5, 
12 
X5 
 
 
 
X5 
X5 
 
 
 
 
 
 
 

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REVISED TEXT: (footer of table) 
Point 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, 10, and 
24 hrs post dose. In the combination cohort, a blood sample for ATRA PK analysis will be also collected at the same time points except 
for the 0.25, 10 and 24 hour sample. Additional samples may be collected at 48 and 72 hrs post dose in subjects not receiving a dose on 
Days 2 and 3 to better characterize the terminal half-life of GSK2879552, if needed. 
Point 2: A blood sample will be collected for PK analysis on D8 at following time points: pre-dose, 0.5, 3 hrs post dose. In the 
combination cohort, a blood sample for ATRA PK analysis will be also collected at the same time points. 
Point 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, 10, and 
24 hrs post dose. In the combination cohort, a blood sample for ATRA PK analysis will be also collected at the same time points except 
for the 0.25, 10 and 24 hour sample. 
Point 5: On Days 1 and 15, 24hr urine will be collected in the highest dose cohort in PK/PD expansion cohorts starting from prepost-dose 
on Day 1 and 15, and for 24 hours, i.e., until dosing on Days 2 and 16, respectively. The 24hr urine will be measured and samples 
collected for PK and metabolite evaluation. 
Point 6: Blood samples for PD and exploratory and circulating biomarkers should be collected pre-dose 
Point 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 pre-dose on Day 1 and at following time points on Days 1 and 15: pre-dose, 0.25, 0.5, 
1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hrs post dose  
Height will be measured at screening only 
Point 19: Sample should be collected at pre-dose on the day of bone marrow aspirate collection. 
Point 20: Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing should be performed 
as part of disease assessment at baseline. Cytomorphology is the preferred method to determine bone marrow blast counts. However, if a 
bone marrow aspirate cannot be obtained for cytomorphology review, a bone marrow biopsy is allowed to determine the bone marrow 
blast count 
Point 21: In PK/PD expansion cohorts, PD and/or exploratory sample (peripheral blood and BMA) collection may be stopped earlier at 
the sponsor’s discretion. 
Point 22: ATRA combination arm only. 
 
 
 
 
 

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Table 4: Time and Events Table: Part 2 – Expansion Cohort 
  
SC
R 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
  
D 1 
D4 
D 8 
D11 
D 15 D18 
D22 
D25 
Vitamin B12, TSH, T4 
X 
Fasting Lipid panel (triglyceride, 
cholesterol)18 
X 
 
 
X 
 
X 
 
X 
 
Every 4 wks 
 
Blood samples for PD (peripheral 
blood)3, 19 
X 
 
X 
X 
bone marrow day14  
 
Wk 4, between Wk 6-8, 
Wk 12, then every 12 
wks 
X 
Blood samples for exploratory 
markers studies3, 19 (peripheral 
blood) 
X 
 
X 
X 
bone marrow day14  
 
Wk 4, between Wk 6- 8, 
Wk 12, then every 12 
wks. (on bone marrow 
day) 
 
Blood samples for circulating 
biomarkers3 and DNA (plasma and 
cell pellet) 
 
 
 
 
bone marrow day14  
 
 
X 
Bone marrow aspirate for PD19 
X 
 
 
 
X14 
 
 
Wk 4, between Wk 6-8, 
Wk 12, then every 12 
wks 
X5 
Bone marrow aspirate for 
exploratory studies DNA, and RNA) 
19  
X11 
 
 
 
X14 
 
 
Wk 4, between Wk 6-8, 
Wk 12, then every 12 
wks 
X5 
PGX samples (buccal swab) 
X 
 
 
 
 
 
REVISED TEXT: (footer of table) 
Point 1: A blood sample will be collected for PK analysis on D1 at pre-dose, 0.5, and 3 hrs post dose. . In the combination cohort, a blood 
sample for ATRA PK analysis will be collected at the same time points. 
Point 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. In the 
combination cohort, a blood sample for ATRA PK analysis will be collected at the same time points 
Point 3: Blood samples for PD, exploratory and circulating biomarkers should be collected pre-dose 

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Point 16: Baseline disease assessment should be completed within 21 days prior to dosing start. Cytogenetics testing should be performed 
as part of disease assessment at baseline. Cytomorphology is the preferred method to determine bone marrow blast counts. However, if a 
bone marrow aspirate cannot be obtained for cytomorphology review, a bone marrow biopsy is allowed to determine the bone marrow 
blast count. 
Point 18 (addition): ATRA combination only 
Point 19 (addition): PD and/or exploratory sample (peripheral blood and BMA) collection may be stopped earlier at the sponsor’s 
discretion

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Section 7.2: Demographic/Medical History and Baseline Assessments 
 
REVISED TEXT:  
Point 4: Clinical laboratory tests:  hematology, clinical chemistry, coagulation 
parameters vitamin B12, thyroid (TSH, T4) 
Point 5 (addition): Lipid panel (ATRA combination only): triglyceride and cholesterol 
 
Section 7.3.7: Laboratory Assessments 
 
REVISED TEXT: (addition under clinical chemistry panel)] 
Lipid 
Triglyceride 
cholesterol 
 
 
 
 
Section 7.4.1: Blood Sample Collection for Pharmacokinetics 
REVISED TEXT: (first paragraph) 
First sentence: Blood samples for pharmacokinetic (PK) analysis of GSK2879552 and 
ATRA will be collected at the time points indicated in the Time and Events Schedule 
(Section 7.1). 
 
Section 7.4.3: Pharmacokinetic Sample Analysis 
Plasma sample analysis will be performed under the management of Bioanalytical 
Science and ToxicokineticsBioanalysis, Immunogenicity & Biomarkers (BIB), Drug 
Metabolism and Pharmacokinetics (DMPK). In Vitro/In Vivo Translation (IVIVT), 
Platform Technology and Science (PTS), GlaxoSmithKline for GSK2879552 and 
InVentiv Health Clinical for ATRA.  Concentrations of GSK2879552 and ATRA will be 
determined in plasma samples using the currently approved bioanalytical methodology.  
Raw data will be stored in the Good Laboratory Practices (GLP) Archives, 
GlaxoSmithKline and InVentiv Health Clinical. 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 Bioanalysis, 
Immunogenicity & Biomarkers (BIB), In Vitro/In Vivo Translation (IVIVT)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. 
 
Section 7.5: Pharmacodynamic: 
REVISED TEXT: 
In Part 1 and Part 2 of the study, blast cell cell-surface markers such as CD11b and CD86 
that are indicative of AML sub-population will be assessed in peripheral blood and bone 
marrow aspirates when possible to determine the effects of GSK2879552 alone or in 
combination with ATRA. Change from baseline levels will be measured.  In addition, the 
above samples may be utilized for the development of a gene signature panel indicative 
of AML modulation in response to GSK2879552 as a potential PD marker. Changes in 

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the gene levels from baseline will be assessed. The PD outcome may be correlated to 
clinical outcome. 
Section 7.6: Translational Research 
REVISED TEXT: 
Comparative examination of baseline cancer cell 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 AML and medically related 
conditions.  Comparative examination of post-dosing cancer cell profiles in conjunction 
with pre-dosing cancer cell profiles may yield known or novel candidate 
biomarkers/profiles and new insights which relate to the action of GSK2879552. 
 
Blood and/or bone marrow aspirates will be collected at various times, throughout the 
study in order to support research aimed at understanding the biological effect of 
GSK2879552 alone or in combination with ATRA in AML as well as identifying 
indicators of sensitivity or resistance. 
The successful collection of quality tumor specimens will be critical to furthering our 
understanding the mechanism of action of GSK2879552 alone or in combination with 
ATRA, and identifying the best way to treat patients with GSK2879552. Specifically, the 
evaluation of responders, responders at relapse, and non-responders for DNA 
methylation, gene alteration  status, cell surface marker expression and/or pathway 
activation may lead to the discovery of potential new diagnostic markers or novel 
combinations. Similarly, pre- and post-dose tumor specimens will be evaluated for 
markers of target engagement, tumor response, and/or evaluated for changes in gene 
expression; thus supporting identification of a biologically effective dose and furthering 
our mechanistic understanding of LSD1 inhibition in these settings.The candidate 
biomarkers may be identified by application of: 
• DNA/gene, RNA and protein analysis of tumor cells. 
• Circulating cell free-DNA analysis of blood/plasma and other circulating markers like 
cytokines in blood. 
RNA transcriptome analysis of blast cells in peripheral blood or bone marrow aspirates 
pre and post treatment 
 
Section 7.6.1: Tumor Biomarker Analysis  
REVISED TEXT:  
All subjects will be asked to submit peripheral blood and fresh bone marrow aspirate at 
baseline, during the study and at the end of treatment in order to conduct retrospective 
tests for the identification of potential markers of sensitivity or resistance through the 
assessment of DNA, RNA and/or protein. 
 
Section 7.6.2: Circulating Cell Free DNA (cfDNA) and Additional Circulating 
Biomarker Analysis (full section deleted) 
REVISED TEXT: 
Tumor-specific circulating nucleic acid (cfDNA) found  in the plasma or serum of cancer 
subjects can harbor many genetic alterations (mutations, microsatellite alterations, 
aberrant methylation), which are generally consistent with the tumor. Thus, correlation of 
clinical outcome with molecular aberrations identified in the cfDNA may serve as a 
useful tool for the identification of sensitive and resistance markers.  Proteins including 

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cytokines and angiogenic factors circulating in the plasma may also be explored as 
markers of sensitivity and resistance.   
Blood samples pre-treatment, on study and at the end of study will be collected from all 
subjects. 
 
Section 7.6.2: RNA Expression Changes Pre and Post Treatment (according to 
current document) 
REVISED TEXT:  
First sentence: Transcriptomic analysis may be performed for RNA isolated from 
peripheral blast cells or bone marrow aspirates pre and post treatment of GSK2879552 
alone or in combination with ATRA. 
 
Section 7.8: Pharmacogenetics (added new section) 
 
REVISED TEXT: 
An important objective of the clinical study is pharmacogenetics (PGx) research. 
Participation in PGx is optional, but all subjects who are eligible for the clinical study 
will be given the opportunity to participate. Subjects may decline participation without 
effect on their medical care or care during the clinical study. A separate consent signature 
is required for PGx research. 
 
Subjects who provide consent will have a buccal swab sample taken for analysis. The 
presence/absence of genetic variations in selected candidate genes in DNA from saliva 
will be analysed to determine their relationship with response (safety, tolerability, PK, 
and efficacy) to treatment with GSK2879552, alone or in combination with ATRA. 
 
Information regarding PGx research is included in Appendix 9. The IRB/ EC and, where 
required, the applicable regulatory agency must approve the PGx assessments before 
these can be conducted at the site. The approval(s) must be in writing and will clearly 
specify approval of the PGx assessments (i.e., approval of Appendix 9). In some cases, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study. If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted 
 
Section 10.2: Prohibited Medications 
 
REVISED TEXT: (addition of paragraph 3) 
In the combination arm with ATRA, antifibrinolytic agents (such as tranexamic Acid, 
aminocaproic acid, or aprotinin), agents known to cause pseudotumor cerebri/intracranial 
hypertension (e.g., tetracycline) and vitamin A or multivitamin including vitamin A will 
be prohibited while receiving ATRA. 
 

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Section 10.2.2: Drugs that may have their PK altered by GSK2879552 
 
REVISED TEXT: (paragraph 2) 
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 OATP, BCRP 
OCT and MATE should be avoided when possible or monitored carefully.  Examples of 
such drugs are dofetillide, pilsicainide and procainamide. shown in Table 6.  
 
Table6 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, pitavastatin,pravastatin, 
rosuvastatin,simvastatin 
HMG-CoA Reductase Inhibitors 
glyburide, repaglinide 
Antidiabetics 
bosentan, ambrisentan 
Pulmonary hypertension 
dofetillide, pilsicainide, procainamide 
Antiarrythmic 
 
Section 11.1.1: Female Subjects 
REVISED TEXT: (addition of 2 paragraphs from the last sentence) 
Female subjects of childbearing potential receiving ATRA combination treatment must 
use two reliable forms of contraception simultaneously during treatment and 30 days after 
the last dose of ATRA or 7 days after the last dose of GSK2879552, whichever is later. 
Contraceptive counselling should be repeated monthly while receiving ATRA and 
documented in the site source file. 
 
Hormonal contraceptives are NOT considered acceptable form of contraception for 
female subjects of childbearing potential receiving ATRA combination treatment. 
Intrauterine device or intrauterine system, male partner sterilization and double-barrier 
method as described below are acceptable forms of contraception for female subjects of 
childbearing potential receiving ATRA combination treatment. 
 
REVISED TEXT: ( under-Contraceptive Methods with a Failure Rate of ≤1%) 
(Point 1 to 5) 
• Oral contraceptives (either combined or progesterone only) if not contraindicated for 
this subject population or per local practice. – GSK2879552 monotherapy ONLY 
• Estrogenic vaginal ring if not contraindicated for this subject population or per local 
practice. – GSK2879552 monotherapy ONLY 
• Percutaneous contraceptive patches if not contraindicated for this subject population 
or per local practice. – GSK2879552 monotherapy ONLY 
• Implants of levonorgestrel if not contraindicated for this subject population or per 
local practice. – GSK2879552 monotherapy ONLY 
• Injectable progesterone if not contraindicated for this subject population or per local 
practice. – GSK2879552 monotherapy ONLY 

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Section 13.2: Part 1: Dose-Escalation Phase 
REVISED TEXT: (addition of text after paragraph 1) 
Bayesian Prior for Combination Therapy Cohorts 
The underlying Bayesian model requires that a Bayesian prior for the DLT rates for the 
combination be pre-specified.  The monotherapy DLT rates on observed data from 
200200 study and a prior Phase I ATRA study [Lee, 1993] were incorporated in the DLT 
prior distribution calculation. Table 6 shows the prior DLT data at a given dose.  
Table 6 
Prior Monotherapy DLT Data 
GSK2879552 
Dose level (mg) 
 # of DLTs  
/ # Subjects 
ATRA Dose 
Level (mg) 
# of DLTs  
/ # Subjects 
1 mg 
0/1 
45 mg/m2 
1/6 
2 mg 
0/2 
60 mg/m2 
0/3 
4 mg 
0/4 
80 mg/m2 
0/3 
8 mg 
0/1 
 
 
Additional detail on the model will be provided in the RAP. 
 
Section 13.4.1: Part 1: Dose-Escalation Phase 
REVISED TEXT: 
The total number of subjects to be enrolled into Part 1 will depend on the number of dose 
escalations required to establish the maximum tolerated dose of GSK2879552 alone or in 
combination with ATRA; they are not driven by statistical considerations. To complete 
dose escalation, it is estimated that approximately 55 evaluable subjects will be enrolled .  
Monotherapy doses to be studied in Part 1 will be guided by calculating the posterior 
probability that  the DLT rate falls within an acceptable range for each subsequent dose 
after each dose cohort observation period.  The N-CRM method will be used to calculate 
posterior probabilities utilizing a pre-specified prior distribution. 
Combination doses to be studied in Part 1 will be guided by calculating the posterior 
probability that  the DLT rate is as close to, but below the target toxicity rate of 33% at 
adjacent dose combinations. The Bayesian logistic regression method will be used to 
calculate posterior probabilities utilizing the pre-specified prior distribution of the 
toxicity rates on combinations.No formal statistical hypothesis will be tested in Part I. 
The sample size depends on the actual number of cohorts of subjects treated. 
 
Section 13.4.2: Part 2: Expansion Cohort 
REVISED TEXT (after paragraph 1) 
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 

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weak prior Beta distribution with a mean response rate equal to the target response rate is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows: 
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution and the observed data x, the posterior distribution of the 
response rate follows a beta distribution, i.e. 
In the following case, 30% is the target response rate. 
p ∼ Beta (0.03 + x, 0.07 + n-x) with the posterior mean (0.03+ x)/(0.07 + n). 
For each cohort, to test hypotheses: 
H0: RR≤10% 
HA: RR≥30% 
When maximum sample size is 30, the design will have a Type I error (α) of 0.064 and 
89% power with the probability of early termination is 0.88 when the treatment is futile 
and probability of early termination 0.084 when the treatment is effective (true 
RR=0.3).Futility analysis for each dose expansion cohort will begin when response data 
is available for at least 10 evaluable subjects. The dose expansion cohort may be stopped 
early for futility if the predictive probability of success (response rate ≥ historical 
response rate) is less than 5%.  Futility stopping rules are described below. 
After 10 evaluable subjects have been enrolled to examine safety and efficacy, the 
number of observed confirmed objective responses will guide further enrolment 
according to the rules summarized in Figure 3. A maximum of 30 subjects will be 
enrolled at the RP2Ds for GSK2879552 and GSK2879552 2 in combination with ATRA, 
respectively. All available data will be considered in making enrollment decisions. If both 
cohorts enroll the maximum number of subjects, this will result in 60 subjects total. 
 
Section 13.7.1: Part 1: Dose-Escalation 
REVISED TEXT: 
In Part 1, interim analyses to inform dose escalation will be performed following the 
completion of each monotherapy and combination dose cohort in part 1.  The primary 
driver for dose escalation decisions in Part 1 will be governed by an N-CRM model for 
the mono-therapy dose cohorts and a Bayesian copula regression for the combination 
dose cohorts. They will be used to predict the probability of DLT at the dose levels yet to 
be tested to further guide these decisions. Further details of the model will be provided in 
the RAP 
No formal interim analysis will be performed for Part 1 of the study. 
Interim analysis on Part 1 may be conducted when  
• Part1 is completed or  
• All subjects enrolled in in Part 1 have had at least one post-baseline disease 
assessment s or progressed or died or withdrawn from the study 
Additionally, sSafety, PK, PD/biomarker data may will be examined during Part 1. Prior 
to determining GSK2879552 dose for the next monotherapy cohort, exploratory analysis 
maywill be conducted to assess the relationship of GSK2879552 dose levels with safety, 
PK and PD parameters using all data from available cohorts 
 
 

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Section 13.7.2: Part 2: Expansion Cohort 
REVISED TEXT: 
After the initial 10 evaluable subjects have enrolled… 
 
Section 13.8.1: Anti-Cancer Activity Analyses 
REVISED TEXT: 
Response rate (RR) is defined as the percentage of subjects who achieved CR, CRp, PR 
and or a morphologic leukemia-free state (MLFS) among subjects who received at least 
one dose of treatment. 
 
Addition of text after paragraph 3: 
As a secondary analysis, if data warrant, PFS, OS, DOR, and TTR will be evaluated 
using the Kaplain-Meier method.  Summaries of median time to event, quartiles and 95% 
CIs will be presented.  
 
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, CRp, PR, MLFS, or SD) prior to the 
initiation of therapy. Otherwise, if the subject does not have a documented date of events, 
PFS will be censored at the date of the last adequate assessment. For the analysis of 
overall survival (OS), the last date of known contact will be used for those subjects who 
have not died at the time of analysis; such subjects will be considered censored. Further 
details on rules for censoring will be provided in the RAP. Sensitivity analyses of PFS 
and further details on censoring rules will be provided in the RAP.  Progression free 
survival (PFS) and overall survival (OS) will be summarized using Kaplan-Meier 
method. 
 
The duration of response is defined for the subject or subjects with a CR, CRp, MLFS, or 
PR, as the time from the first documented evidence of a CR, CRp, ,MLFS, or PR until the 
first documented disease progression or death due to any cause. Censoring rules for 
duration of response will be outlined in detail in the RAP. 
 
Time to Response is defined, for subjects with a CR, CRp, MLFS, or PR, as the time 
from first dose to the first documented evidence of responses. 
 
If the data warrant, duration of response and time to response will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Only the subset of subjects who 
show a confirmed complete or partial tumor response will be included. Censoring rules 
for duration of response will follow the rules for PFS outlined in detail in the RAP. 
 

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Section 13.8.2.1: Extent of Exposure 
REVISED TEXT:  
The number of subjects administered study treatment will be summarized according to 
the duration of therapy.  
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. 
 
Section 13.8.2.2: Adverse Events 
REVISED TEXT:  
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 
National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), 
(version 4.03). 
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, serious adverse events (SAEs) and AEs leading to discontinuation of study 
treatment.  Adverse events (AEs), if listed in the NCI-CTCAE (version 4.03) will be 
summarized by the maximum grade.  Otherwise, the AEs will be summarized by 
maximum intensity. 
AEs of special interest will be outlined in the RAP. 
The incidence of deaths and the primary cause of death will be summarized. 
 
Section 13.8.2.3: Clinical Laboratory Evaluations 
REVISED TEXT: 
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to National Cancer Institute-Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE) (version 4.03).  Laboratory test results outside the 
reference ranges that do not have an associated NCI-CTCAE criteria will be summarized 
using proportions.  Further details will be provided in the Reporting and Analysis Plan 
(RAP) 
 
Section 13.8.2.4: Other Safety Measures 
REVISED TEXT 
Data for vital signs and electrocardiograms (ECGs) will be summarized based on 
predetermined criteria identified to be of potential clinical concern (PCI).  Further details 
will be provided in the Reporting and Analysis Plan (RAP). 
 

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Section 13.8.3.1: Pharmacokinetic Parameters 
REVISED TEXT: (Under Non-compartmental Pharmacokinetic Analyses) 
Paragraph 1, first sentence- Pharmacokinetic analysis of GSK2879552 and ATRA, as 
appropriate, in Part 1 will be conducted by non-compartmental methods. 
Paragraph 2- GSK2879552 tTrough concentration (Cτ) samples collected on the 
specified days will be used to assess attainment of steady state. To estimate the extent of 
accumulation for GSK2879552 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 for 
GSK2879552. 
 
REVISED TEXT: (under Metabolic Profiling) 
In a subset of subjects, plasma samples maywill be pooled and analyzed qualitatively for 
circulating metabolites; 0-24 hour urine samples may also be analyzed for GSK2879552 
and compound related metabolites. These results will be performed under a separate 
DMPK protocol and reported separately. 
 
REVISED TEXT: (under Population Pharmacokinetics) 
First line: Plasma concentration-time data from Part 2 (Expansion Cohort) will be 
combined with data from Part 1 and possibly with data from other studies and analyzed 
using a population approach. 
 
Section 13.8.3.2: Statistical Analysis of Pharmacokinetic Data 
REVISED TEXT: 
Paragraph 1: Statistical analyses of the PK parameters data will be the responsibility of 
Clinical Statistics Discovery Biometrics, GSK. 
Paragraph 2, first sentence: Plasma concentration-time data for GSK2879552 and 
ATRA will be listed by dose and… 
Paragraph 3, first sentence: Cmax and AUC (AUC[0-∞], single dose, and AUC[0-τ], 
steady state) for GSK2879552 and ATRA, if appropriate, will be plotted… 
 
Section 13.8.4.2: Novel Biomarker(s) Analyses 
Revised section: paragraph 2 
Additional exploratory analyses may be performed to further characterize the any novel 
biomarkers 
 

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Section 15: Reference: 
REVISED TEXT  
Changes in one reference: 
GlaxoSmithKline Document Number 2013N168888_012. GSK2879552 Investigator's 
Brochure.  Report Date: 29-FEB-201601-MAR-2015 
 
Addition of new references: 
Vesanoid (ATRA) Prescribing Information, July 2004 
 
Barlow JW et al. Differentiation of rhabdomyosarcoma cell lines using retinoic acid.  
Pediatr Blood Cancer. 2006;47(6):773-84 
 
Conley BA et al. Phase I clinical trial of all-trans-retinoic acid with correlation of its 
pharmacokinetics and pharmacodynamics. Cancer Chemother Pharmacol. 
1997;39(4):291-9 
 
Choschzick I et al. Phase I clinical trial of all-trans-retinoic acid with correlation of its 
pharmacokinetics and pharmacodynamics. Neuroscience, 2014, 279; 44–64 
 
Johnson DE and Redner RL. An ATRActive future for differentiation therapy in AML. 
Blood Rev. 2015 Jul;29(4):263-8 
 
Karsy M et al. All-trans retinoic acid modulates cancer stem cells of glioblastoma 
multiforme in an MAPK-dependent manner. Anticancer Res, 2010 Dec;30(12):4915-20 
 
Lee SH et al. Phase I Trial of All-Trans Retinoic Acid in Patients with Treated Head and 
Neck Squamous Carcinoma. Clin Cancer Res. 2000;6(3):847-54.  
 
Luo P et al, Retinoid-suppressed phosphorylation of RARalpha mediates the 
differentiation pathway of osteosarcoma cells. Oncogene. 2010;13;29(19):2772-83.  
 
Melnick A and Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and 
their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999 May 
15;93(10):3167-215 
 
Park SH et al. Phase I trial of all-trans retinoic acid in patients with treated head and neck 
squamous carcinoma. Clin Cancer Res. 2000 Mar;6(3):847-54. 
 
Russo D et al. All-trans retinoic acid (ATRA) in patients with chronic myeloid leukemia 
in the chronic phase. Leukemia 1998; 12: 449-454 
 

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Sakamoto K et al. Sensitivity of MLL-rearranged AML cells to all-trans retinoic acid is 
associated with the level of H3K4me2 in the RARa promoter region. Blood Cancer 
Journal 2014; 4: 1-8. 
 
Schenk T et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-
retinoic acid differentiation pathway in acute myeloid leukemia. Nature Medicine 2012; 
18 (4): 605-611. 
 
Section 16.6: Appendix 6: Response Criteria 
REVISED TEXT: 
Paragraph 1: Overall efficacy will be assigned according to a criteria slightly modified 
from the standard response criteria for Acute Myeloid Leukemia [Cheson, 2003]. 
Addition: 
Progressive Disease 
Presence of > 50% increase in bone marrow blasts to a level of at least 50% and/or a 
doubling of the percentage of peripheral blood blasts to a level of at least 50% 
Stable Disease 
The absence of a complete or partial response, CRp, morphologic leukemia-free state and 
no progressive disease. 
 
Section 16.9: Appendix 9: Genetic Research (Addition of new appendix) 
Genetics – Background 
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study. 
 
Genetic Research Objectives and Analyses 
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:  
Response to medicine, including GSK2879552 or any concomitant medicines; 
AML disease susceptibility, severity, and progression and related conditions  

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Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives. 
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate. 
 
Study Population 
 
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research. 
 
Study Assessments and Procedures 
 
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.   
A saliva swab sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
saliva sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the saliva sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The saliva sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.   
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).  
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product. 
Subjects can request their sample to be destroyed at any time. 
 
 
 

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Informed Consent 
 
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any saliva being taken. 
 
Subject Withdrawal from Study 
 
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected: 
Continue to participate in the genetic research in which case the genetic DNA sample 
is retained 
Discontinue participation in the genetic research and destroy the genetic DNA sample  
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records.  
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis.  
If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.   
Genetic data that has been analyzed at the time of withdrawn consent will continue to 
be stored and used, as appropriate.  
 
Screen and Baseline Failures 
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files. 
 
Provision of Study Results and Confidentiality of Subject’s Genetic Data 
 
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.  
 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 

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validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care. 
 
References: 
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464 
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486. 
 

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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  
This amendment is initiated to modify eligibility criteria and add additional safety 
monitoring measures in response to recent safety findings.  
List of Specific Changes 
Section 1.3.1 
GSK2879552 – Background, 1st paragraph 
PREVIOUS TEXT 
GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 767 nM, kinact = 0.1 min-1).   
REVISED TEXT 
GSK2879552 is a potent, selective, mechanism-based inactivator of LSD1/CoREST 
activity (Ki = 1.7 µM 767 nM, kinact = 0.1 min-1).   
Section 1.4.4 
Benefit Risk Assessment, 1st paragraph 
PREVIOUS TEXT 
Summaries of findings from non-clinical studies conducted with GSK2879552 can be 
found in the Investigator Brochure (IB) and supplement for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_00; GlaxoSmithKline Document 
Number 2014N197022_00].   
REVISED TEXT 
Summaries of findings from non-clinical studies conducted with GSK2879552 can be 
found in the Investigator Brochure (IB) and supplement for GSK2879552 
[GlaxoSmithKline Document Number 2013N16888_012013N168888_00; 
GlaxoSmithKline Document Number 2014N197022_00].   
Section 1.4.4.1 
Risk Assessment 
PREVIOUS TEXT 

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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. Reduced platelet 
aggregation has been observed in rats 
following repeat dosing at a time when 
there was significant thrombocytopenia.   
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, 
hypocellularity was not observed in the 
bone marrow of these animals. 
Informed Consent Form includes the 
risk of hematologic toxicity. 
Protocol specifies:  
- 
Exclusion criteria for non-AML 
related major bleeding (e.g. recent 
GI hemorrhage or neurosurgery) 
- 
Laboratory assessments (complete 
blood count [CBC])  
- 
Dose stopping/modification criteria 
Signs and symptoms of bleeding or 
infection will be closely monitored 
during the study. 
REVISED TEXT 
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. Reduced platelet 
aggregation has been observed in rats 
following repeat dosing at a time when 
there was significant 
thrombocytopenia.   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, 
hypocellularity was not observed in the 
bone marrow of these animals. 
Informed Consent Form includes the risk 
of hematologic toxicity. 
Protocol specifies:  
- 
Exclusion criteria for non-AML 
related major bleeding (e.g. recent 
GI hemorrhage or neurosurgery) 
- 
Laboratory assessments (complete 
blood count [CBC])  
- 
Dose stopping/modification criteria 
Signs and symptoms of bleeding or 
infection will be closely monitored during 
the study. 
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 

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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 3.2.1 
Inclusion Criteria 
PREVIOUS TEXT 
10. Adequate baseline organ function defined by:  
System 
Laboratory Values 
Hematologic 
 
White blood cell count (absolute) 
≤30,000/uL 
Coagulation assays (PT/INR and aPTT)  
≤1.3 X ULN 
Hepatic 
 
Total bilirubin 
≤ 1.5 X ULN1 
ALT and AST 
≤2.5 × ULN  
Renal 
 
Creatinine 
OR 
Calculated creatinine clearance by Chronic 
Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Appendix 3) or measured 
from 24hr urine 
≤1.5 X ULN 
 
≥ 50 mL/min 
Cardiac 
Ejection fraction 
≥ LLN by Echocardiogram (ECHO) or 
MUGA 
2. 
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 
 
REVISED TEXT 
10. Adequate baseline organ function defined by:  

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System 
Laboratory Values 
Hematologic 
 
White blood cell count (absolute) 
≤30,000/uL 
Coagulation assays (PT/INR and aPTT)  
≤1.3 X ULN 
Hepatic 
 
Total bilirubin 
≤ 1.5 X ULN1 
ALT and AST 
≤2.5 × ULN  
Renal 
 
Creatinine 
OR 
Calculated creatinine clearance by Chronic 
Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation (Appendix 3) or measured 
from 24hr urine 
≤1.5 X ULN 
 
≥ 50 mL/min 
Cardiac 
Ejection fraction 
≥ LLN by Echocardiogram (ECHO) or 
MUGA 
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 3.2.2 
Exclusion Criteria 
NEW TEXT added 
23. Prior treatment with temozolomide, dacarbazine or procarbazine  
24. Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., 
olaparib, ABT-888) 
25. Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower 
Section 4.7 Safety Management Guideline 
NEW SECTION added 
Section 4.7.3 
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  

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• 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. 
Section 7 
Study Assessments and Procedures 
PREVIOUS TEXT 
Visit Window 
Baseline disease assessment should be completed within 21 days prior to dosing start.  
REVISED TEXT 
Visit Window 
Baseline disease assessment should be completed within 21 days prior to dosing start.  
ECHO/MUGA should be completed within 35 days prior to dosing start. 

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Section 7.1 Time and Events Tables, Table 3 and Table 4 
NEW TEXT added 
Table 3 
Time and Events, 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 
D22 
D25 
Montreal 
Cognitive 
Assessment 
X 
X 
 
 
X 
 
X 
 
 
X 
 
Wk 4 and 
every 4 wks 
Vitamin 
B12, TSH, 
T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Table 4 
Time and Events, Part 2 Expansion Cohort 
  
SCR 
First Treatment Phase (28 days) 
Continuation Phase 
EOT 
  
D 1 
D4 
D 
8 
D11 
D 
15 
D18 
D22 
D25 
Montreal Cognitive 
Assessment 
X 
X 
 
X 
 
X 
 
X 
 
Wk 4 and every 4 wks 
Vitamin B12, TSH, T4 
X 
 
 
 
 
 
 
Section 7.2 Demographic/Medical History and Baseline Assessments, 4th 
paragraph 
PREVIOUS TEXT 
Baseline (Screening) assessments obtained 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 (β-HCG) pregnancy test for female 
subjects of childbearing potential only  
• 
12-lead electrocardiogram (ECG) 
• 
Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan  
• 
Baseline disease assessment and bone marrow aspirates  
• 
Review of concomitant medications 

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REVISED TEXT 
Fasting will be required for screening clinical laboratory tests. 
Baseline (Screening) assessments obtained 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 (β-HCG) pregnancy test for female 
subjects of childbearing potential only  
• 
12-lead electrocardiogram (ECG) 
• 
Echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan  
• 
Baseline disease assessment and bone marrow aspirates  
• 
Review of concomitant medications 
• 
Montreal Cognitive Assessment 
Section 7.3 Safety Evaluations 
NEW SECTION added 
Section 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 8. 

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Section 7.3.7 
Laboratory Assessments, Table 5 
PREVIOUS TEXT 
Table 5 
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) 
 
 
Blast count 
 
 
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 
Phosphate 
Lactate Dehydrogenase (LDH) 
 
 
Other tests 
Coagulation Panel including PT, PTT, INR, fibrinogen 
Fetal hemoglobin (Hgb F) 
Other screening tests 
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only) 
HIV, Hepatitis B surface antigen (HBsAg) and Hepatitis C antibody (HCV Ab) testing 
 

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REVISED TEXT 
Table 5 
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) 
 
 
Blast count 
 
 
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 
Phosphate 
Lactate Dehydrogenase (LDH) 
Thyroid Stimulating 
Hormone 
T4 
Vitamin B12 
 
 
 
Other tests 
Coagulation Panel including PT, PTT, INR, fibrinogen 
Fetal hemoglobin (Hgb F) 
Other screening tests 
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only) 
HIV, Hepatitis B surface antigen (HBsAg) and Hepatitis C antibody (HCV Ab) testing 
 

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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 DLT criteria following the 
regulatory review. PD sampling requirements and subject populations are also clarified.  
List of Specific Changes 
SPONSOR/MEDICAL MONITOR INFORMATION PAGE 
PREVIOUS TEXT 
Medical Monitor and Sponsor Contact Information: 
Role 
Name 
Day Time Phone 
Number 
After-hours 
Phone/Cell/ 
Pager 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 
REVISED TEXT 
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 4401 
Collegeville, PA 19426, USA 
Primary 
Secondary
Medical 
Monitor 
 
MD, PhD 
GlaxoSmithKline 
1250 South Collegeville Rd 
Mailstop UP 4210 
Collegeville, PA 19426, USA 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Role 
Name 
Day Time Phone 
Number 
After-hours 
Phone/Cell/ 
Pager Number 
GSK Address 
Secondary
Tertiary 
Medical 
Monitor 
MD 
GlaxoSmithKline 
1250 South Collegeville Rd 
Mailstop UP 4401 
Collegeville, PA 19426, USA 
 
 
Section 4.2.1 
PK/PD Expansion Cohorts 
PREVIOUS TEXT 
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.  Subjects may be enrolled at previously completed 
dose levels for the purpose of obtaining additional data.  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.  
REVISED TEXT 
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.  However, PD sample (peripheral blood and bone 
marrow aspirate) collection may be stopped early at the sponsor’s discretion. Subjects 
may be enrolled at previously completed dose levels for the purpose of obtaining 
additional data.  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.  
 
Section 4.2.3 
Dose Limiting Toxicity 
PREVIOUS TEXT 
An event will be considered a DLT if it occurs within the first 4 weeks of treatment (with 
exception as below), and meets one of the following criteria unless it can be clearly 
established that the event is unrelated to treatment: 
• 
Prolonged grade 4 neutropenia (≤0.5 x 109/L) or thrombocytopenia (≤25 x 109/L), 28-
days after ceasing study treatment without evidence of leukemia (<5% blasts at the time 
of drug cessation and bone-marrow biopsy confirmed absence of leukemia 21-28 days 
later). If a subject meets above criteria at the time of drug cessation within DLT 
observation period, the dose escalation decision will be delayed until 28 days have 
elapsed post drug cessation. 
• 
Drug related Grade 3 or 4 non-hematologic toxicity. Fatigue, asthenia, or nausea that 
respond to standard medical care within 72 hours and new electrolyte disturbance that 
PPD
PPD

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respond within 24 hours are exceptions. In addition, electrolyte disturbances associated 
with underlying malignancy are not considered DLT. 
• 
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 28 days or greater due to unresolved drug-related toxicity.  
REVISED TEXT 
An event will be considered a DLT if it occurs within the first 4 weeks of treatment (with 
exception as below), and meets one of the following criteria unless it can be clearly 
established that the event is unrelated to treatment: 
• 
Prolonged grade 4 neutropenia (≤0.5 x 109/L) or thrombocytopenia (≤25 x 109/L), 28-
days after ceasing study treatment without evidence of leukemia (<5% blasts at the time 
of drug cessation and bone-marrow biopsy confirmed absence of leukemia 21-28 days 
later). If a subject meets above criteria at the time of drug cessation within DLT 
observation period, the dose escalation decision will be delayed until 28 days have 
elapsed post drug cessation. 
• 
Drug related Grade 3 or 4 non-hematologic toxicity. Fatigue, asthenia, or nausea that 
respond to standard medical care within 72 hours and new electrolyte disturbance that 
respond within 24 hours are exceptions. In addition, electrolyte disturbances associated 
with underlying malignancy are not considered DLT. 
• 
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 28 days or greater due to unresolved drug-related toxicity.  
 
Section 7 
STUDY ASSESSMENTS AND PROCEDURES 
PREVIOUS TEXT 
Visit Window 
Baseline disease assessment should be completed within 21 days prior to dosing start. 
Baseline fresh bone marrow aspirates can be collected up to 28 days prior to dosing.  
REVISED TEXT 
Visit Window 
Baseline disease assessment should be completed within 21 days prior to dosing start. 
Baseline fresh bone marrow aspirates can be collected up to 28 days prior to dosing.  
 

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Section 7.1 Time and Events Table 
PREVIOUS TEXT 
Table 7 
Time and Events, 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 
D22 
D25 
Blood 
samples for 
PD6 
(peripheral 
blood)  
X 
 
X 
X 
X 
bone marrow day21 
 
 
Wk 4  
Blood 
samples for 
exploratory6 
(peripheral 
blood)  
X 
 
X 
X 
X 
bone marrow day21 
 
 
Wk 4,  between 
Wk 6- 8, Wk 12, 
then every 12 
wks (on bone 
marrow days) 
Blood 
samples for 
circulating 
biomarkers 
and DNA6 
(plasma and 
cell pellet) 
 
X 
 
 
 
bone marrow day21 
 
 
 
X 
Bone 
marrow 
aspirate for 
PD 
X7 
 
 
 
 
X18  
 
 
Wk 4  
X17 
Bone 
marrow 
aspirate for 
Exploratory 
(DNA and 
RNA) 
X7 
 
 
 
 
X18  
 
 
Wk 4, between 
Wk 6- 8, Wk 12 
and then every 
12 wks.  
X17 
7. 
Archival bone marrow aspirates are requested from all subjects. If archival specimen is not available, a fresh 
bone marrow aspirate may be performed.  Subjects enrolled in multi-subject cohorts during dose escalation 
and select PK/PD expansion cohorts must submit fresh bone marrow aspirates at screening. Samples 
collected up to 4 weeks prior to dosing are acceptable. 
 

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Table 8 
Time and Events Table: Part 2 – Expansion Cohort 
  
SC
R 
First Treatment Phase (28 days) 
Continuation 
Phase 
EOT 
  
D 
1 
D4 
D 8 
D11 
D 15 
D18 
D22 
D
25 
Blood samples for 
PD3 (peripheral 
blood) 
X 
 
X 
X 
bone marrow day17 
 
 
Wk 4 
Blood samples for 
exploratory 
markers3 (peripheral 
blood) 
X 
 
X 
X 
bone marrow day17 
 
 
Wk 4, between 
Wk 6- 8, Wk 12, 
then every 12 
wks. (on bone 
marrow day) 
Blood samples for 
circulating 
biomarkers3 and 
DNA (plasma and 
cell pellet) 
 
X 
 
 
bone marrow day17 
 
 
 
X 
Bone marrow 
aspirate for PD 
X11 
 
 
 
X14 
 
 
Wk 4 
X5 
Bone marrow 
aspirate for 
Exploratory (DNA 
and RNA) 
X11 
 
 
 
X14 
 
 
Wk 4, between 
Wk 6-8, Wk 12, 
then every 12 wks 
X5 
 

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REVISED TEXT 
Table 9 
Time and Events, Part 1 Dose Escalation 
SC
R 
First Treatment Phase (28 days) 
Continuati
on Phase 
EO
T 
  
D 
1 
D 
2 
D 
4 
D 
8 
D 
11 
D 
15 
D 
16 
D 
18 
D2
2 
D2
5 
Blood samples for 
PD6, 22 (peripheral 
blood)  
X 
 
X 
X 
X 
bone marrow day21 
 
 
Wk 4  
Blood samples for 
exploratory6,(periph
eral blood)  
X 
 
X 
X 
X 
bone marrow day21 
 
 
Wk 4,  
between 
Wk 6- 8, 
Wk 12, then 
every 12 
wks (on 
bone 
marrow 
days) and 
Wk 24   
X 
Blood samples for 
circulating 
biomarkers and 
DNA6 (plasma and 
cell pellet) 
 
X 
 
 
 
bone marrow day21 
 
 
 
X 
Bone marrow 
aspirate for PD22 
X7 
 
 
 
 
X18  
 
 
Wk 4  
X17 
Bone marrow 
aspirate for 
Exploratory (DNA 
and RNA) 
X7 
 
 
 
 
X18  
 
 
Wk 4, 
between 
Wk 6- 8, 
Wk 12 and 
then every 
12 wks.  
and wk 24 
X17 
7. 
A fresh bone marrow aspirate is requested from all subjects. This requirement is mandatory for all subjects 
participating in the PK-PD cohorts. Archival bone marrow aspirates are requested from all subjects. If 
archival specimen is not available, a fresh bone marrow aspirate may be performed.  Subjects enrolled in 
multi-subject cohorts during dose escalation and select PK/PD expansion cohorts must submit fresh bone 
marrow aspirates at screening. Samples collected up to 4 weeks prior to dosing are acceptable. 
22. In PK/PD expansion cohorts, PD sample (peripheral blood and BMA) collection may be stopped earlier at the 
sponsor’s discretion. 

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Table 10 
Time and Events Table: Part 2 – Expansion Cohort 
  
SCR 
First Treatment Phase (28 days) 
Continuation 
Phase 
E
OT 
  
D 
1 
D4 
D 8 
D
11 
D 
15 
D18 
D22 
D25 
Blood samples for 
PD3 (peripheral blood) 
X 
 
X 
X 
bone marrow 
day17 
 
 
Wk 4 
Blood samples for 
exploratory markers3 
(peripheral blood) 
X 
 
X 
X 
bone marrow 
day17 
 
 
Wk 4, between Wk 
6- 8, Wk 12, then 
every 12 wks. (on 
bone marrow day) 
Blood samples for 
circulating 
biomarkers3 and DNA 
(plasma and cell 
pellet) 
 
X 
 
 
bone marrow 
day17 
 
 
 
X 
Bone marrow aspirate 
for PD 
X11 
 
 
 
X14 
 
 
Wk 4 
X5 
Bone marrow aspirate 
for Exploratory (DNA 
and RNA) 
X11 
 
 
 
X14 
 
 
Wk 4, between Wk 
6-8, Wk 12, then 
every 12 wks 
X5 
 
Section 7.6.1 
Tumor Biomarker Analysis 
PREVIOUS TEXT 
All subjects will be asked to submit a most recent bone marrow aspirate specimen at 
baseline in order to conduct retrospective tests for the identification of potential markers 
of sensitivity or resistance.  If archival specimen is not available, a fresh biopsy may be 
performed.  Subjects enrolled in multi-subject cohorts during dose escalation, select 
PK/PD expansion cohorts and Part 2 expansion cohort must submit fresh bone marrow 
aspirates at screening. Samples collected up to 4 weeks prior to dosing are acceptable.   
This exploratory work may include protein measurements, mRNA measurements as well 
as DNA (mutation, DNA copy number, translocation) and epigenetic (DNA methylation, 
microRNA) measurements. Results of previous cytogenetic work performed on the 
subject will also be collected. Similar studies will also be performed on cancer specimen 
collected at progression or end of treatment when feasible to identify mechanisms of 
resistance.

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REVISED TEXT 
All subjects will be asked to submit peripheral blood and fresh bone marrow aspirate at 
baseline, during the study and at the end of treatment a most recent bone marrow aspirate 
specimen at baseline in order to conduct retrospective tests for the identification of 
potential markers of sensitivity or resistance through the assessment of DNA, RNA and 
protein.  If archival specimen is not available, a fresh biopsy may be performed.  Subjects 
enrolled in multi-subject cohorts during dose escalation, select PK/PD expansion cohorts 
and Part 2 expansion cohort must submit fresh bone marrow aspirates at screening. 
Samples collected up to 4 weeks prior to dosing are acceptable.   
This exploratory work may include protein measurements, mRNA measurements as well 
as DNA (mutation, DNA copy number, translocation) and epigenetic (DNA methylation, 
microRNA) measurements. Results of previous cytogenetic work performed on the 
subject will also be collected. Similar studies will also be performed on cancer specimen 
collected at progression or end of treatment when feasible to identify mechanisms of 
resistance. 
 
Section 13.6.1 
Analysis Populations 
PREVIOUS TEXT 
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. 
REVISED TEXT 
All Treated 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 Treated 
Subjects Population and for whom a PK sample is obtained and analyzed. 
The Pharmacodynamic Population: This will consist of those subjects in All Treated 
Subjects Population and who contribute PD/Biomarker samples. 
 

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Section 13.8.2 
Safety Analysis 
PREVIOUS TEXT 
The All Subjects Population will be used for the analysis of safety data. 
REVISED TEXT 
The All Treated Subjects Population will be used for the analysis of safety data.