Conditions: Myelodysplastic Syndrome Myelodysplastic Syndromes
Keywords: GSK2879552 Revised International Prognostic Scoring System (IPSS-R) azacitidine hypomethylating agents myelodysplastic syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is a Phase I/II, open-label, 2 arm study to evaluate the safety and clinical activity of GSK2879552 alone, or in combination with azacitidine in subjects with MDS. The study consisted of 2 parts. The objective of Part 1 is to determine the recommended phase 2 dose (RP2D) of GSK2879552 administered alone and in combination with azacitidine in adult subjects with high risk MDS previously treated with HMA. The objective of Part 2 is to evaluate clinical activity after treatment with GSK2879552, alone or in combination with azacitidine, in adult subjects with high risk MDS previously treated with HMA.

Detailed description:

Arms:
arm 1: Subjects will receive GSK2879552 2 milligrams (mg) once daily in each 28 day cycle. arm 2: Subjects will receive GSK2879552 starting at 1 mg once daily in each 28 day cycle and Azacitidine 75 mg/square meter (m2) from Day 1 to Day 7 of each 28 day cycle.

Interventions: intervention 1: GSK2879552 intervention 2: Azacitidine
Intervention descriptions: intervention 1: GSK2879552 will be administered orally as continuous daily dosing. intervention 2: Azacitidine will be administered at 75 mg/m2 from Day 1 to Day 7 of each 28 day cycle by intravenous (iv) infusion or subcutaneous (sc) injection.

Protocol document:
Prot_000.pdf: 
2016N275425_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
205744
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase I/II, open-label, 2 arm study to investigate the safety,
clinical activity, pharmacokinetics and pharmacodynamics of 
GSK2879552 administered alone or in combination with 
azacitidine, in adult subjects with IPSS-R high and very high risk 
myelodysplastic syndromes (MDS) previously treated with 
hypomethylating agents (HMA)
Compound Number:
GSK2879552
Development Phase:
I/II
Effective Date:
08-MAY-2017
Protocol Amendment Number: 01
Author (s):
Oncology Epigenetics Clinical, PA, USA
Oncology Epigenetics Clinical, PA, USA
Clinical Pharmacology Modeling & Simulation, PA, USA
Clinical Biomarkers and Translational Research, PA, USA
Biology, Epigenetics DPU, PA, USA
Discovery Biometrics, PA, USA
Biology, Epigenetics DPU, PA, USA
Global Clinical Safety & Pharmacovigilance, PA, USA
In Vivo In Vitro Translation, PA, USA
Oncology Epigenetics Clinical, PA, USA
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2016N275425_01
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The GlaxoSmithKline group of companies
205744
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N275425_00
2016-JUL-15
Original
2016N275425_01
2017-MAY-08
Amendment No. 1
Addition of 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. Minor clarifications, correction of typographical
errors, reformatting of tables, administrative and grammatical changes to text and Time
and Events tables/footnotes.


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary 
Medical 
Monitor 
 
MD, MPH
GlaxoSmithKline
1250 South 
Collegeville Road, 
UP4410
Collegeville, PA 
19426, USA
Secondary 
Medical 
Monitor
 
MD, 
PhD
GlaxoSmithKline
1250 South 
Collegeville Road, 
UP4410
Collegeville, PA 
19426, USA
 
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application. 
Regulatory Agency Identifying Number(s): IND number 121577 
PPD
PPD
PPD
PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205744
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205744......................................................10
2.
INTRODUCTION....................................................................................................18
2.1.
Rationale ....................................................................................................18
2.1.1.
Lysine Specific Demethylase 1 (LSD1) and Haematological 
Malignancy ..................................................................................18
2.1.2.
Rationale for subject population...................................................18
2.1.3.
Study Rationale ...........................................................................19
2.2.
Background ................................................................................................20
2.2.1.
GSK2879552...............................................................................20
2.2.2.
LSD1 inhibitor and azacitidine......................................................20
2.2.3.
Pre-Clinical PK and Safety of GSK2879552.................................21
2.2.3.1.
Pharmacokinetics and Product Metabolism in 
Animals ......................................................................21
2.2.3.2.
General Toxicology.....................................................21
2.2.4.
Pharmacokinetics and Pharmacodynamics of GSK2879552 in 
Human.........................................................................................22
2.2.5.
Clinical Safety of GSK2879552....................................................23
2.2.6.
Azacitidine ...................................................................................24
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................25
3.1.
Part 1..........................................................................................................25
3.2.
Part 2..........................................................................................................26
4.
STUDY DESIGN ....................................................................................................28
4.1.
Overall Design ............................................................................................28
4.2.
Treatment Schedule and Duration ..............................................................29
4.3.
Part 1..........................................................................................................30
4.3.1.
Arm A (Monotherapy) - Safety Evaluation....................................30
4.3.2.
Arm B (Combination) - Dose Escalation.......................................30
4.3.3.
Dose Limiting Toxicities ...............................................................31
4.3.4.
Dose Escalation Committee.........................................................31
4.4.
Part 2..........................................................................................................32
4.5.
Intra-subject Dose-Escalation .....................................................................32
4.6.
Intra-subject Monotherapy to Combination Arm Crossover .........................32
4.7.
Permanent Discontinuation of Study Treatment..........................................32
4.8.
Type and Number of Subjects.....................................................................33
4.9.
Design Justification.....................................................................................33
4.10.
Dose Justification........................................................................................34
4.10.1.
Arm A: GSK2879552 Monotherapy..............................................34
4.10.2.
Arm B: GSK2879552 and Azacitidine Combo..............................35
4.11.
Benefit:Risk Assessment ............................................................................35
4.11.1.
Risk Assessment .........................................................................36
4.11.2.
Benefit Assessment.....................................................................39
4.11.3.
Overall Benefit: Risk Conclusion..................................................39
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............39
5.1.
Inclusion Criteria.........................................................................................40


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5.2.
Exclusion Criteria........................................................................................42
5.3.
Screening and Baseline Failures ................................................................43
5.4.
Withdrawal/Stopping Criteria.......................................................................43
5.4.1.
Liver Chemistry Stopping Criteria ................................................44
5.4.1.1.
Study Treatment Restart or Rechallenge....................44
5.4.2.
QTc Stopping Criteria ..................................................................45
5.4.3.
Mental Status Stopping Criteria ...................................................45
5.5.
Safety Management....................................................................................46
5.5.1.
Events of Special Interest ............................................................46
5.5.1.1.
Hematologic Events....................................................46
5.5.1.2.
Mental Status Change................................................46
5.5.2.
Dose Adjustment for Non-Hematologic Toxicity ...........................47
5.5.3.
Dose Adjustment for Hematologic Toxicity...................................48
5.6.
Subject and Study Completion....................................................................49
6.
STUDY TREATMENT ............................................................................................49
6.1.
Investigational Product and Other Study Treatment....................................49
6.2.
Description of Investigational Product(s).....................................................49
6.2.1.
GSK2879552...............................................................................49
6.2.2.
Azacitidine ...................................................................................50
6.3.
Treatment Assignment................................................................................50
6.4.
Blinding.......................................................................................................50
6.5.
Packaging and Labeling..............................................................................50
6.6.
Preparation/Handling/Storage/Accountability..............................................50
6.7.
Compliance with Study Treatment Administration.......................................51
6.8.
Treatment of Study Treatment Overdose....................................................51
6.9.
Treatment after the End of the Study ..........................................................52
6.10.
Lifestyle and/or Dietary Restrictions............................................................52
6.10.1.
Caffeine, Alcohol and Tobacco Restrictions.................................52
6.11.
Concomitant Medications and Non-Drug Therapies....................................52
6.11.1.
Permitted Medication(s)...............................................................52
6.11.2.
Prohibited Medication(s) ..............................................................52
6.11.3.
Drugs that may alter the Pharmacokinetics of GSK2879552........53
6.11.4.
Drugs that may have their PK altered by GSK2879552................53
6.12.
Non-Drug Therapies ...................................................................................53
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................53
7.1.
Time and Events Table for Arm A – Part 1..................................................55
7.2.
Screening and Critical Baseline Assessments ............................................67
7.3.
Safety .........................................................................................................67
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........67
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................67
7.3.1.2.
Method of Detecting AEs and SAEs ...........................68
7.3.1.3.
Follow-up of AEs and SAEs........................................68
7.3.1.4.
Cardiovascular and Death Events ..............................68
7.3.1.5.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................69
7.3.1.6.
Regulatory Reporting Requirements for SAEs............69
7.3.2.
Pregnancy ...................................................................................69
7.3.3.
Physical Exams ...........................................................................69
7.3.4.
Vital Signs....................................................................................70


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7.3.5.
Electrocardiogram (ECG).............................................................70
7.3.6.
ECOG Performance Status..........................................................70
7.3.7.
Montreal Cognitive Assessment...................................................70
7.3.8.
Echocardiogram and/or Multi-gated Acquisition Scans ................70
7.3.9.
Clinical Safety Laboratory Assessments ......................................70
7.4.
Evaluation of Anti-Cancer Activity ...............................................................72
7.5.
Pharmacokinetics .......................................................................................72
7.5.1.
Blood Sample Collection..............................................................72
7.5.2.
Sample Analysis ..........................................................................72
7.6.
Translational Research...............................................................................72
7.6.1.
Biomarker Analysis ......................................................................73
7.7.
Genetics .....................................................................................................73
8.
DATA MANAGEMENT ...........................................................................................73
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................74
9.1.
Hypotheses.................................................................................................74
9.1.1.
Part 1:..........................................................................................74
9.1.2.
Part 2: Disease-Specific Expansion Cohorts................................74
9.2.
Sample Size Considerations.......................................................................75
9.2.1.
Sample Size Assumptions ...........................................................75
9.2.2.
Sample Size Sensitivity................................................................76
9.2.3.
Sample Size Re-estimation or Adjustment...................................76
9.3.
Data Analysis Considerations .....................................................................76
9.3.1.
Analysis Populations....................................................................76
9.3.2.
Interim Analysis ...........................................................................76
9.3.2.1.
Part 2 Cohort Expansion ............................................77
9.4.
Key Elements of Analysis Plan ...................................................................77
9.4.1.
Clinical Activity Analyses .............................................................78
9.4.2.
Safety Analyses...........................................................................79
9.4.2.1.
Extent of Exposure .....................................................80
9.4.2.2.
Adverse Events ..........................................................80
9.4.2.3.
Clinical Laboratory Evaluations ..................................80
9.4.2.4.
Other Safety Measures...............................................80
9.4.3.
Pharmacokinetic Analyses...........................................................80
9.4.3.1.
Pharmacokinetic Parameters......................................80
9.4.3.2.
Statistical Analysis of Pharmacokinetic Data ..............81
9.4.4.
Pharmacokinetic/Pharmacodynamic Analyses.............................81
9.4.4.1.
Translational Research Analyses ...............................81
9.4.4.2.
Novel Biomarker(s) Analyses .....................................82
10. STUDY GOVERNANCE CONSIDERATIONS........................................................82
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............82
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................82
10.3.
Quality Control (Study Monitoring) ..............................................................83
10.4.
Quality Assurance.......................................................................................83
10.5.
Study and Site Closure ...............................................................................83
10.6.
Records Retention......................................................................................84
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................85


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11. REFERENCES.......................................................................................................86
12. APPENDICES........................................................................................................89
12.1.
Appendix 1: Abbreviations and Trademarks................................................89
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................93
12.3.
Appendix 3: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines...................................................................................................96
12.4.
Appendix 4: Genetic Research ...................................................................99
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................100
12.5.1.
Definition of Adverse Events......................................................100
12.5.2.
Definition of Serious Adverse Events.........................................101
12.5.3.
Definition of Cardiovascular Events ...........................................102
12.5.4.
Recording of AEs and SAEs ......................................................103
12.5.5.
Evaluating AEs and SAEs..........................................................103
12.5.6.
Reporting of SAEs to GSK.........................................................105
12.6.
Appendix 6: ECOG Performance Status1..................................................106
12.7.
Appendix 7: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................107
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP) ..............................107
12.7.2.
Collection of Pregnancy Information ..........................................108
12.7.3.
References ................................................................................109
12.8.
Appendix 8: Montreal Cognitive Assessment............................................111
12.9.
Appendix 9: Country Specific Requirements.............................................112
12.10. Appendix 10: IWG CRITERIA FOR RESPONSE ......................................113
12.11. Appendix 11: Protocol Changes................................................................114
12.11.1. Protocol Changes for Amendment 1 (08-MAY-2017) from the 
original Protocol (15-Jul-2016)...................................................114


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1.
PROTOCOL SYNOPSIS FOR STUDY 205744
Rationale
Induction of differentiation may provide a new opportunity in Myelodysplastic 
syndromes (MDS) treatment. Preclinical studies have shown that GSK2879552 induces 
the expression of putative Lysine Specific Demethylase 1 (LSD1) target genes and has 
potent, predominantly cytostatic, anti-proliferative activity in Acute Myeloid Leukemia
(AML) cell lines. While there are no cell lines that represent MDS, the activity of 
GSK2879552 in myeloid cell lines suggests that myeloblasts may also be sensitive to 
growth inhibitory effects of GSK2879552.  
Changes in the expression of cell surface markers and genes associated with myeloid 
differentiation suggest that GSK2879552 treatment results in a pro-differentiation effect 
in preclinical studies. In the ongoing AML study (200200), increases in CD11b and 
CD86 expression were observed with GSK2879552 monotherapy at 2-4 mg. 
Hypomethlating Agent (HMA) and GSK2879552 are similar in that both can promote 
derepression of gene expression.  This mechanistic overlap leads to the hypothesis that 
MDS patients may respond better to a HMA when combined with GSK2879552.  The 
proposed Phase I/II study will evaluate the safety (Part 1) and clinical activity (Part 2) of 
GSK2879552 administered alone or in combination with azacitidine, in adult subjects 
with the Revised International Prognostic Scoring System (IPSS-R) high or very high risk 
MDS after failure of a HMA.
Objective(s)/Endpoint(s)
Part 1
Objectives
Endpoints
Primary
1. To determine the recommended phase 2 
dose (RP2D) of GSK2879552
administered alone and in combination 
with azacitidine in adult subjects with 
HR MDS previously treated with 
HMA.
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 evaluate clinical activity after 
treatment with GSK2879552, alone or 
in combination with azacitidine, in 
adult subjects with HR MDS previously 
treated with HMA.  
1. Clinical benefit rate (CBR) defined as 
% of subjects achieving CR, mCR, PR, 
cytogenetic response, hematologic 
improvement (HI) or SD. Objective 
response rate (ORR) defined as % of 
subjects achieving CR, mCR, PR, 
cytogenetic response, or HI [as per 
2006 IWG criteria]).


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Objectives
Endpoints
2. To measure the exposure to 
GSK2879552 alone and to 
GSK2879552 and azacitidine in 
combination, in patients with HR MDS 
previously treated with HMA.  
2. GSK2879552 and azacitidine 
concentrations pre-dose and post-dose.
3. To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival and overall 
survival.
3. Duration of response (DOR) defined as 
the time from first documented 
response to disease progression. 
Progression-free survival (PFS) defined 
as the time from first dosing day to 
disease progression or death from any 
cause. Overall survival (OS) defined as 
the time from first dosing day until 
death from any cause.
4. To evaluate frequency and time to 
progression to AML (per 2006 IWG 
criteria).
4. Proportion of subjects with disease 
progression to AML. Time to AML 
progression.
5. To evaluate platelet and RBC 
transfusion dependence.
5. Number of documented platelet and 
RBC transfusions per month prior to 
study entry and on study.
Exploratory
1. To investigate the mechanism of action 
and indicators of sensitivity and 
resistance to GSK2879552 alone and in 
combination with azacitidine.
1. Gene and/or protein expression studies 
of peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 
response.
Part 2
Objectives 
Endpoints 
Primary
1. To evaluate clinical activity after 
treatment with GSK2879552, alone or 
in combination with azacitidine, in 
adult subjects with HR MDS previously 
treated with HMA.  
1. Clinical benefit rate (CBR) defined as % 
of subjects achieving CR, mCR, PR, 
cytogenetic response, HI or SD. 
Objective response rate (ORR) defined 
as % of subjects achieving CR, mCR, 
PR, cytogenetic response, or HI [as per 
2006 IWG criteria]).


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Objectives 
Endpoints 
Secondary
1. To further evaluate the safety and 
tolerability of GSK2879552
administered alone or in combination 
with azacitidine. 
1. Changes in safety parameters: e.g. AEs 
and SAEs, changes in laboratory 
values, vital signs, electrocardiograms 
[ECGs], and physical examinations.
2. To characterize the population PK of 
GSK2879552, alone or in combination 
with azacitidine in patients with HR 
MDS previously treated with HMA. 
2. Population PK parameters for 
GSK2879552 such as clearance (CL/F).
3. To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival, and overall 
survival.
3. Duration of response (DOR) defined as 
the time from first documented 
response to disease progression. 
Progression free survival (PFS) defined 
as the time from first dosing day to 
disease progression or death from any 
cause. Overall survival (OS) defined as 
the time from first dosing day until 
death from any cause.
4. To evaluate frequency and time to 
progression to AML (per 2006 IWG 
criteria)
4. Proportion of subjects with disease 
progression to AML. Time to AML 
progression.
5. To evaluate platelet and RBC 
transfusion dependence.
5. Number of documented platelet and 
RBC transfusions per month within 3 
months prior to study entry and while 
on study.
Exploratory
1. To investigate the mechanism of action 
and indicators of sensitivity and 
resistance to GSK2879552 
administered alone or in combination 
with azacitidine to patients with HR 
MDS previously treated with HMA. 
1. Gene and/or protein expression studies 
of peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 
response.
2. To evaluate the relationship of 
exposure of GSK2879552, 
administered alone or in combination 
with azacitidine, and safety/efficacy 
parameters, based on Part 1 and 2 data 
combined.
2. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax or AUC (0-tau)) 
and safety/clinical activity.


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Objectives 
Endpoints 
3. To investigate the relationship between 
genetic variants in host DNA and the 
safety, tolerability, and efficacy of 
GSK2879552 alone or in combination 
with azacitidine based on Part 1 and 2 
data combined.
3. Pharmacogenomic (PGx) analysis using 
saliva samples.
Overall Design
This is a Phase I/II, open-label, 2 arm study to evaluate the safety and clinical activity of 
GSK2879552 alone, or in combination with azacitidine in adult subjects with MDS. 
Eligible subjects with IPSS-R high or very high risk MDS by World Health Organization 
(WHO) classification, who have failed a HMA will be enrolled into the study.  
This study consists of 2 Arms, i.e., monotherapy with GSK2879552 (Arm A) and 
combination therapy with GSK2879552 and azacitidine (Arm B).  Each Arm has Part 1 
for safety evaluation followed by Part 2 to evaluate clinical activity.  Both Arms will 
proceed in parallel and subjects will be randomized in Part 2 to receive either 
GSK2879552 alone or GSK2879552 in combination with azacitidine.  In Arm A, 
approximately 3-6 subjects will receive during Part 1 the Recommended Phase 2 Dose
(RP2D) of GSK2879552 determined in First Time In Humans (FTIH) study (200858), 
i.e., 2 mg once daily, to confirm the RP2D for MDS. In Arm B, a traditional 3+3 dose 
escalation procedure will be followed in Part 1 to determine the RP2D of GSK2879552 in 
combination with azacitidine. Bayesian Logistic Regression Model (BLRM) prediction 
on Dose-Limiting Toxicity (DLT) rate may also be provided at dose escalation meetings 
as the supplementary analysis to 3+3 design.  Once the RP2D of GSK2879552 for MDS 
is confirmed in both Arms, Part 2 enrolment will open. Each treatment cycle is 28 days 
and subjects experiencing disease progression on monotherapy (Arm A) will be allowed 
to cross over (to Arm B) to be treated with the combination at the RP2D.   
The statistical design and number of subjects to be enrolled in Part 2 is based on the 
predictive probability of success if enrollment continues until all planned subjects are 
recruited . The predictive probability design allows for evaluation of stopping rules after 
each subject once a minimum number of subjects are evaluable. The study will stop for 
futility, while also taking into account subject and study termination criteria as defined in 
the protocol. Final decisions on stopping enrolment will depend on the totality of the data 
collected.
Treatment Schedule and Duration
Treatment with GSK2879552 in both arms will be administered orally as continuous 
daily dosing until progression. Azacitidine will be administered at 75 mg/m2 on days 1-7 
of each 28 day cycle by intravenous (iv) infusion or subcutaneous (sc) injection (route of 
administration: by physicians choice). Subcutaneous administration will be required 
during the first cycle as pharmacokinetic (PK) information will be collected. 


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Alterations to the dose and schedule of GSK2879552 may be incorporated based on 
emerging safety, tolerability and PK data.  The dose and schedule of azacitidine may be 
also altered based on emerging safety, tolerability and PK data. Azacitidine dosing on 
Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case basis. 
Subjects may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent. Subjects experiencing disease progression on mono 
therapy (Arm A) will be allowed to cross over to be treated with the combination (Arm 
B) once the RP2D has been established.  All subjects will be followed after study 
treatment discontinuation until death, lost to follow-up or withdrawal of consent. The 
duration of the study will depend on recruitment rates, and timing of subject’s duration 
on study. Subjects may be allowed to continue on study treatment after disease 
progression if the Investigator, in consultation with the sponsor’s Medical Monitor, 
determines that continuing treatment will benefit the patient. 
Type and Number of Subjects
Approximately 3-12 subjects may be enrolled in Part 1 of each Arm. Later, 
approximately 28 subjects will be enrolled in Part 2 of each Arm with a total of 74 (Arm 
A: 6+28; Arm B: 12+28) subjects in the study. The number of subjects may change 
depending on the dose levels in Part 1.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. 18 years of age and provided signed written informed consent 
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects must have IPSS-R high or very high risk myelodysplastic syndromes (MDS)  
by WHO classification
3. Subjects must have failed hypomethylating treatment where “failure” is defined as: 
a) Progression (according to 2006 International Working Group [IWG] criteria) 
at any time after initiation of the hypomethylating treatment OR 
b) Failure to achieve complete or partial response or hematological improvement 
(HI) (according to 2006 IWG) after at least 4 cycles treatment OR 
c) Relapse after initial complete or partial response or HI (according to 2006 
IWG criteria). 
4. Subjects are not a candidate, or have failed allogeneic stem cell transplantation.  


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Subjects who underwent allo-transplant in the past are eligible under following 
conditions:
a) transplant was >2 year prior to enrolment, and 
b) no evidence of active Graft-versus-host disease (GVHD)
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
6. Subjects have a life expectancy of at least 12 weeks, in the opinion of the 
investigator.
7. 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.
8. 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 enrolment (except for alopecia).  
LABORATORY
9. Adequate baseline organ function defined by:
System
Laboratory Values
Coagulation
INR and aPTT
1.3 X ULN
Hematologic
PLT
>10,000
(transfusions permitted to bring platelet 
count to >10,000)
Hepatic
Total bilirubin
≤1.5 X ULNa
ALT 
2.5 ULN 
Renal
Creatinine
OR
Calculated creatinine clearance by 
Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation or 
measured from 24hr urine
≤1.5 X ULN
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by Echocardiogram (ECHO) or 
MUGA
a.
Isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of Gilbert’s syndrome


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GENDER and REPRODUCTIVE POTENTIAL
10. 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, 
during the study and for 7 days following the last dose of study treatment.
11. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception, 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.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. AML according to WHO criteria (i.e. bone marrow blasts >20%) 
2. Active hepatitis B or hepatitis C treatment
3. Baseline (pre-dose Day 1)Montreal Cognitive Assessment (MOCA) score of 22 or 
lower
CONCURRENT CONDITIONS/MEDICAL HISTORY 
4. History of or concurrent malignancy of solid tumours, except for below: 
Exception:  Subjects who have been disease-free for 2 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated in 
situ carcinoma are eligible.  Consult GSK Medical Monitor if unsure whether second 
malignancies meet requirements specified above
5. Prior treatment with temozolomide, dacarbazine or procarbazine
6. Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, 
ABT-888)
7. Currently receiving other anti-cancer therapy (chemotherapy, radiation therapy, 
immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization)
8. Received major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK2879552 administration
9. 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
10. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator’s 
assessment)
11. Patients with any major bleeding within the past 4 weeks. (e.g. recent GI hemorrhage 


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or neurosurgery).
12. Administration of an investigational drug within 14 days or 5 half-lives, whichever is 
shorter, preceding the first dose of study treatment(s) in this study. 
13. Cardiac abnormalities as evidenced by any of the following:

Clinically significant uncontrolled arrhythmias or uncontrolled hypertension.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA)

History of acute coronary syndromes (including unstable angina and 
myocardial infarction), coronary angioplasty, or stenting within the past 3
months 

Baseline QTc interval using 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
CONCOMITANT MEDICATIONS/OTHER RESTRICTIONS
14. Current use of a prohibited medication including anticoagulants or platelet inhibitors 
or expected to require any of these medications during treatment with the 
investigational drug 
15. 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 
16. Lactating female
CONTRAINDICATION
17. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates 
their participation
18. Known hypersensitivity to azacitidine or mannitol
Analysis
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 1 and in Part 2 where applicable. In some instances, analysis may 
also be generated based on the dose of GSK2879552. Data from Part 1 and Part 2 may be 
combined for some analyses such as safety and efficacy 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.


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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. 
2.
INTRODUCTION
2.1.
Rationale
2.1.1.
Lysine Specific Demethylase 1 (LSD1) and Haematological 
Malignancy
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 CoRepressor for 
Element-1-Silencing Transcription factor (CoREST) and HDACs (Histone Deacetylases) 
1 and 2 [You, 2001; Shi, 2003].  These data suggest that LSD1 localization and activity 
correlates with transcriptional repression and that inhibition of LSD1 will result in 
increased expression of LSD1 target genes.
LSD1 activity is essential for the maintenance of pluripotency in embryonic stem cells by 
regulating the balance between H3K4 and H3K27 methylation, thereby keeping 
differentiation associated genes silenced [Adamo, 2011].  LSD1 also plays a critical role 
in normal hematopoietic differentiation by mediating repression of a key gene expression 
program in hematopoietic progenitors [Saleque, 2007].
Within acute myeloid leukemia (AML), LSD1 is most highly expressed in less 
differentiated subtypes [Rhodes, 2007; Wouters, 2009; Radich, 2006]. Knockdown or 
inhibition of LSD1 has been shown to have a pro-differentiation effect [Harris, 2012] and 
sensitizes AML cells to all-trans retinoic acid (ATRA), a differentiation therapy used in 
Acute Promyelocytic Leukemia (APL) [Schenk, 2012]. 
2.1.2.
Rationale for subject population
Myelodysplastic syndromes (MDS) are clonal disorders of the bone marrow 
characterized by ineffective hematopoiesis with peripheral blood-cytopenia and a 
propensity to transform to acute myeloid leukemia (AML).  MDS may evolve into AML 
in up to 45% of patients [Greenberg, 1997].  Differentiation of hematopoietic stem cells 
is impaired in MDS.  Clonal expansion of the abnormal stem cells results in the 
production of cells which have lost the ability to differentiate into normal blood cells 
[Fenaux, 2014].  In MDS patients, myeloblasts often constitute more than 5% of the cells 
in the bone marrow.  The number of myeloblasts is one of the principal determinants of 


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disease severity, where the percentage of blasts of >20% constitutes a transformation to 
AML.  MDS occurs in 3-4 individuals per 100,000 in the US population.  Incidence rates 
increase with age. Individuals age 60 and above have a higher prevalence rate of 7-35 per 
100,000 [Rollinson, 2008].  The median age at diagnosis of MDS is 73 years [Mufti, 
2012]. 
Using the Revised International Prognostic Scoring System (IPSS-R), patients with MDS 
are grouped into 5 risk groups: very low, low, intermediate, high and very high risk.  
Patients with high and very high risk MDS have a median survival of 1.6 and 0.8 years 
respectively [Greenberg, 1997].  Allogeneic stem cell transplantation is the only curative   
treatment modality for patients with MDS, but due to advanced age, frequent co-
morbidities, and limited allogeneic graft sources, only a minority of high risk-MDS 
patients undergo allogeneic stem cell transplantation [Zeidan, 2014].  Remaining high 
and very high risk MDS patients can be treated with AML-like regimens, or with HMAs. 
There are two Hypomethlating Agent (HMA) drugs currently approved in the USA for 
treatment of MDS patients: azacitidine and decitabine.  While both drugs have 
demonstrated superior response rates and a longer time to AML transformation when 
compared with supportive care alone, they have not been directly compared with each 
other in a randomized trial. So far, a survival advantage has been only demonstrated for 
azacitadine.  Only 30-40% of patients with high risk MDS respond to treatment with 
HMA [Zeidan, 2014].  In addition, half of responders lost response within 20 months 
[Fenaux, 2009].   Patients failing azacitidine or decitabine have a poor outcome, with an 
estimated 1-year survival probability of 28% and 21-24 month survival probability of 
15% [Prebet, 2011; Duong, 2013].  The median overall survival after azacitidine or 
decitabine failure in patients with MDS is 5.6 and 4.3 months, respectively.  Alternative 
treatments (including best supportive care, low dose chemotherapy, intensive AML-like 
chemotherapy) are of little benefit in this setting [Prebet, 2011; Jabbour, 2010].  
Therefore, there is an urgent need for new treatment options in MDS patients who have 
been previously treated with a HMA.
2.1.3.
Study Rationale
Induction of differentiation may provide a new opportunity in MDS treatment. 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. While there are no cell lines that represent MDS, the activity of GSK2879552 in 
myeloid cell lines suggests that myeloblasts may also be sensitive to growth inhibitory 
effects of GSK2879552.  
Changes in the expression of cell surface markers and genes associated with myeloid 
differentiation suggest that GSK2879552 treatment results in a pro-differentiation effect 
in preclinical studies. In the ongoing AML study (200200), an increase of expression of 
differentiation markers CD11b and CD86 was observed with GSK2879552 monotherapy 
at 2-4 mg. HMA and GSK2879552 are similar in that both can promote de-repression of 
gene expression.  This mechanistic overlap leads to the hypothesis that MDS patients 
may respond better to HMA when combined with GSK2879552.  The proposed Phase I/II 
study will evaluate the safety (Part 1) and clinical activity (Part 2) of GSK2879552 


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administered alone or in combination with azacitidine, to adult subjects with IPSS-R high 
or very high risk MDS after failure of a HMA.
2.2.
Background
2.2.1.
GSK2879552
GSK2879552 is a potent, selective, mechanism-based, irreversible inhibitor of 
lysine-specific demethylase-1 (LSD1)/RE1 silencing transcription factor co-repressor 
(CoREST).  GSK2879552 had potent anti-proliferative activity in small cell lung 
carcinoma (SCLC) and acute myelogenous leukemia (AML) cell lines in vitro.  The anti-
proliferative effect was predominantly cytostatic, although there was evidence of 
cytotoxic effects in certain contexts.  
GSK2879552 treatment resulted in an increase in H3K4me2 at regions surrounding 
transcriptional start sites of putative LSD1 target genes and increased their expression in 
vitro in AML and SCLC cell lines.Gene expression analysis in vitro as well as in tumors 
from mice bearing human SCLC xenograft tumors suggests that while the onset of gene 
expression changes in response to treatment may be relatively rapid, multiple days of 
dosing may be required in order to achieve the maximal effect.
In AML cell lines, treatment with GSK2879552 resulted in increased expression of cell 
surface markers, CD86 and CD11b.  Decreased expression of CD71 as well as an 
increase in superoxide production in a subset of cell lines was also observed.  Together,
these findings suggest that treatment of AML cells with GSK2879552 may lead to a more 
differentiated phenotype.  CD86 and CD11b expression also increased in a dose-
dependent manner upon treatment with GSK2879552 in mice engrafted with MV-4-11 
cells, although there was no effect on survival for this model under the conditions of the 
study.  In a MLL-AF9+ retroviral murine model of AML, treatment with GSK2879552 
led to a significant delay in leukemia onset in treated mice relative to vehicle treated 
controls.
2.2.2.
LSD1 inhibitor and azacitidine
Given that there were no cell line models of MDS available, the activity of 
GSK2879552A in combination with 5-Aza-2’-deoxycytidine (DAC) was investigated in 
a panel of AML cell lines.  To evaluate the effect of combining DAC with GSK2879552 
on the inhibition of AML cell growth, 12 AML cell lines were pre-treated with up to 100 
nM DAC for 72 hours then exposed to a 20-point dose response of GSK2879552 for 6 
days. DAC pre-treatment resulted in increased sensitivity to GSK2879552 in four AML 
cell lines in a 6-day Growth/Death assay.  Greater than 5-fold potency shifts (EC50 or 
gIC50) and/or increased percent growth inhibition by greater than 30% were observed in 
comparison to LSD1 single agent activity.   These data suggest that there is a potential 
combination benefit to the use of HMA with an LSD1 inhibitor.


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2.2.3.
Pre-Clinical PK and Safety of GSK2879552
2.2.3.1.
Pharmacokinetics and Product Metabolism in Animals
The nonclinical intravenous (IV) pharmacokinetics of GSK2879552 was similar across 
species.  GSK2879552 had moderate to high blood clearance and volume of distribution 
in the mouse, rat and dog.  The oral bioavailability in the mouse, rat and dog was 
moderate to high following single oral administration of GSK2879552 in solution.  In the 
safety species (i.e. rat and dog), systemic exposure to GSK2879552 generally was similar 
between males and females, increased dose-proportionally and there was no evidence for 
accumulation after repeat dosing.  The renal clearance of GSK2879552 in the rat was 
similar to glomerular filtration rate (GFR).  Renal elimination was the primary route of 
excretion from both the intact and bile duct-cannulated rats following oral administration 
of [14C] GSK2879552.  In vitro plasma protein binding of GSK2879552 was low to 
moderate and GSK2879552 partitioned into blood cells (blood to plasma ratio was ~1 
across nonclinical species and humans) which is consistent with its high permeability.  
GSK2879552 had low in vitro intrinsic clearance, suggesting limited oxidative 
metabolism in any species tested.  
Consistent with its high permeability and moderate to high volume of distribution, 
following oral administration, [14C] GSK2879552-related material was rapidly and 
widely distributed into tissues and concentrations declined steadily over time.  
GSK2879552 is not a Pgp substrate and was distributed into central nervous system 
(CNS) tissues.  It also demonstrated strong but reversible affinity for melanin-containing 
tissues.
Preliminary in vitro assessments of metabolism, cytochrome P450 (CYP) inhibition and 
pregnane X receptor (PXR) activation potential indicated that GSK2879552 is unlikely to 
have the potential of being a perpetrator or victim of drug-drug interactions through the 
CYP enzymes.  The in vitro assessments indicated that GSK2879552 is unlikely to have 
the potential of being a perpetrator in drug-drug interactions through P-gp, BCRP, 
OATP1B1, OATP1B3, OCT2 (organic cation transporter 2) or MATE2-K (multidrug and 
toxin extrusion transporter 2-K) inhibition or being a victim in drug-drug interactions 
through P-gp, BCRP, OCT2, MATE1 (multidrug and toxin extrusion transporter 1), 
MATE2-K, OAT1, or OAT3 transporters.
2.2.3.2.
General Toxicology
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 (greater the suppression, the greater the rebound off-dose) 
peaking in approximately 10 days.  By 4 weeks after dosing, platelet counts returned to or 
near pre-treatment values in rats and dogs.


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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 pre-treatment 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 pre-treatment values in rats and dogs.
GSK2879552 caused a dose-dependent increase in circulating monocytes in rats and 
dogs.  In both species, monocytes remained elevated during the dosing period, did not 
decrease below pre-treatment values after cessation of dosing and returned to 
pre-treatment values by 4 weeks after dosing.
The decreases in circulating platelets, neutrophils and reticulocytes result from the 
pharmacologic activity of GSK2879552 on hematopoietic lineages in the bone marrow as 
evidenced by a shift to immaturity of progenitor cells in the megakaryocytic, granulocytic 
and erythroid lineages, while the increase in monocytes results from stimulation of 
monopoiesis.  Myelofibrosis and hyperostosis in rat (but not dog) was secondary to the 
marked regenerative response in the bone marrow in response to the peripheral blood 
cytopenias and likely represents a rodent-specific response.  Generally mild to moderate, 
reversible effects (reduced weight, cellularity or necrosis/hemorrhage) were observed in 
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 intercurrent deaths of dogs at 0.3 and 0.1 mg/kg/day, the NOAEL and the highest 
non-severely toxic dose (HNSTD) is 0.03 mg/kg/day [mean AUC0-t 22.0 ng.h/mL, mean 
Cmax 6.1 ng/mL (gender averaged based on Day 27 values)].  
2.2.4.
Pharmacokinetics and Pharmacodynamics of GSK2879552 in 
Human
GSK2879552 pharmacokinetics (PK) 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 accumulation following once daily oral administration. 


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Following single and repeated once daily administration of 0.25 mg to 4 mg of 
GSK2879552, Cmax and AUC tended to increase in a dose proportional fashion.
As LSD1 inhibition results in a blockage of platelet maturation, platelet count changes 
can be viewed as a PD effect and was evaluated in subjects with small cell lung cancer 
(study 200858). Following daily administration of 3 mg in 3 subjects, the median lowest 
platelet count was 10 G/L (range: 9 to 15), observed between Day 15 and Day 18. The 
median platelet nadir was 29 G/L (range: 22 to 93) in the 5 subjects who received 2 mg of 
GSK2879552 once daily. There is a steep relationship between platelet nadir and 
GSK2879552 dose, Cmax, or AUC. Following GSK2879552 dose interruption, platelet 
count started to recover within days with full recovery seen after a week interruption. But 
platelet count decreased once again, with a delay, following treatment restart.
Based on preclinical data, it is predicted that an increase in CD11b- and CD86-positive 
AML blasts will be consistent with a pro-differentiation mechanism and/or target 
engagement in subjects with AML (study 200200).  Using 10% additional CD11b or 
CD86 positive blasts in treatment samples compared with baseline as a threshold, CD11b 
and CD86 positive blasts increased in bone marrow aspirates at 1 or more time points in 8 
of 8 subjects and 2 of 8 subjects, respectively. Using these same criteria CD11b and 
CD86 positive blasts increased in peripheral blood of 7 of 9 subjects and 3 of 9 subjects, 
respectively.  An increase in CD11b and/or CD86 occurs as early as 2 days of treatment, 
and as late as the last assessment at 4 weeks.  A dose responsive increase could not be 
assessed with the 2 doses evaluated (2 mg and 4 mg).
2.2.5.
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_02]. 
In ongoing study 200858, 18 subjects with small cell lung cancer (SCLC) have been 
enrolled at 5 dose levels of daily doses (0.25 mg, 0.50 mg, 1 mg, 2 mg, and 3 mg) and 2 
intermittent dosing regimens (3 mg for 4 days on then either 3 days off or 10 days off).  
Thirteen subjects have completed the study.  Three subjects have prematurely 
discontinued; 2 subjects discontinued due to AEs (encephalopathy and asthenia) and 1 
subject withdrew consent.  The most frequently reported AEs (>20%) were 
thrombocytopenia, fatigue, anemia, constipation, decreased appetite, nausea, and back 
pain.  The most frequently reported (>20%) treatment-related AEs were 
thrombocytopenia, anemia, fatigue, decreased appetite and nausea.  Grade 4 AEs 
included thrombocytopenia/platelet count decreased (n=6), neutropenia (n=1), and 
increased gamma glutamyl transferase (n=1).  Four subjects (22%) have had serious 
adverse events (SAEs), including encephalopathy (n=3), asthenia (n=1), malaise (n=1), 
and pericardial effusion (n=1).  One event of encephalopathy was fatal.  The other 
2 subjects with SAEs of encephalopathy died due to disease progression.  Dose-limiting 
toxicities (DLTs) included thrombocytopenia/platelet count decreased (n=3) and 
encephalopathy (n=2).  In addition to the 1 death due to AE, 4 subjects have died due to 
disease under study. In the ongoing study 200200, 11 subjects with acute myeloblastic 
leukemia (AML) have been enrolled at 4 dose levels of daily doses (1 mg, 2 mg, 4 mg, or 


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8 mg of GSK2879552).  All subjects have completed the study.  The most frequently 
reported AEs (>20%) were fatigue, febrile neutropenia, nausea, anemia, decreased 
appetite, hypotension, rash, cellulitis, hypokalemia, and localized edema.  Treatment-
related AEs reported in at least 10% of subjects were nausea (n=4), decreased appetite 
(n=2), and thrombocytopenia (n=2).  All Grade 4 AEs were hematological, including 
thrombocytopenia (n=2) and neutropenia (n=1).  Treatment-related events that were 
Grade 3 or 4 included thrombocytopenia (n=2, Grade 4), anemia and nausea (1 subject 
each, Grade 3).  There have been no DLTs reported in Study 200200.  All 11 subjects in 
Study 200200 have experienced SAEs.  Febrile neutropenia was the most frequently 
reported SAE (n=6).  All cases of febrile neutropenia resolved.  No other SAE has been 
reported in more than 1 subject. No cases of encephalopathy were reported in the AML 
study.  Two subjects have died due to disease under study, including the subject with 
fatal pleural effusion.
2.2.6.
Azacitidine
Azacitidine (5-azacitidine, 5-aza, Vidaza) is a pyrimidine nucleoside analog of cytidine, 
which causes hypomethylation (demethylation) of DNA and has direct cytotoxicity on 
abnormal bone marrow hematopoietic cells. It is approved for the treatment of patients 
with MDS in the US. Available studies indicate overall response rates in patients with 
low or intermediate-1 risk MDS of approximately 50 percent, with survival benefits 
observed in responders versus nonresponders. In most centers azacitidine is administered 
in an outpatient setting at a dose of 75mg/m2 per day subcutaneously for 7 consecutive 
days every 28 days. Best responses may not occur until six cycles have been given. In the 
combined the Cancer and Leukemia Group B (CALGB) experience, the median number 
of cycles to first response was three, with 90 percent of responses seen by cycle six. More 
convenient dosing regimens, in which the agent is given for only five consecutive days, 
or with a "drug holiday" over the weekend, or as a 10-day cycle have also been adopted 
by clinicians.  Dose adjustment and growth factor support are necessary for some patients 
during treatment with azacitidine.
Most common adverse reactions (>30%) by SC route are: nausea, anemia, 
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, 
constipation, neutropenia and ecchymosis. Most common adverse reactions by IV route 
also included petechiae, rigors, weakness and hypokalemia. Azacitidine is available in 
lyophilized powder in 100 mg single-use vials. 
Azacitidine is rapidly absorbed and eliminated after SC administration with the peak 
plasma azacitidine concentration occurring in 0.5 hour and a mean half-life of 41 
minutes. The bioavailability of SC azacitidine relative to IV azacitidine is approximately 
89%, based on AUC. AUC and Cmax of SC administration of azacitidine were 
approximately dose proportional within the 25 to 100 mg/m2 dose range. Multiple dosing 
at the recommended dose-regimen does not result in drug accumulation. Urinary 
excretion is the primary route of elimination of azacitidine and its metabolites [Vidaza 
Prescribing Information 2015].


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3.
OBJECTIVE(S) AND ENDPOINT(S)
3.1.
Part 1
Objectives
Endpoints
Primary
1. To determine the recommended phase 2 
dose (RP2D) of GSK2879552
administered alone and in combination 
with azacitidine in adult subjects with 
HR MDS previously treated with 
HMA.
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 evaluate clinical activity after 
treatment with GSK2879552, alone or 
in combination with azacitidine, in 
adult subjects with HR MDS previously 
treated with HMA.  
1. Clinical benefit rate (CBR) defined as 
% of subjects achieving CR, mCR, PR, 
cytogenetic response, hematologic 
improvement (HI) or SD. Objective 
response rate (ORR) defined as % of 
subjects achieving CR, mCR, PR, 
cytogenetic response, or HI [as per 
2006 IWG criteria]).
2. To measure the exposure to 
GSK2879552 alone and to 
GSK2879552 and azacitidine in 
combination, in patients with HR MDS 
previously treated with HMA.  
2. GSK2879552 and azacitidine 
concentrations pre-dose and post-dose.
3. To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival and overall 
survival.
3. Duration of response (DOR) defined as 
the time from first documented 
response to disease progression. 
Progression-free survival (PFS) defined 
as the time from first dosing day to 
disease progression or death from any 
cause. Overall survival (OS) defined as 
the time from first dosing day until 
death from any cause.
4. To evaluate frequency and time to 
progression to AML (per 2006 IWG 
criteria).
4. Proportion of subjects with disease 
progression to AML. Time to AML 
progression.
5. To evaluate platelet and RBC 
transfusion dependence.
5. Number of documented platelet and 
RBC transfusions per month prior to 
study entry and on study.
Exploratory
1. To investigate the mechanism of action 
and indicators of sensitivity and 
resistance to GSK2879552 alone and in 
combination with azacitidine.
1. Gene and/or protein expression studies 
of peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 


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Objectives
Endpoints
response.
3.2.
Part 2
Objectives 
Endpoints 
Primary
1. To evaluate clinical activity after 
treatment with GSK2879552, alone or 
in combination with azacitidine, in 
adult subjects with HR MDS previously 
treated with HMA.  
1. Clinical benefit rate (CBR) defined as 
% of subjects achieving CR, mCR, PR, 
cytogenetic response, HI or SD. 
Objective response rate (ORR) defined 
as % of subjects achieving CR, mCR, 
PR, cytogenetic response, or HI [as per 
2006 IWG criteria]).
Secondary
1. To further evaluate the safety and 
tolerability of GSK2879552
administered alone or in combination 
with azacitidine. 
1. Changes in safety parameters: e.g. AEs 
and SAEs, changes in laboratory 
values, vital signs, electrocardiograms 
[ECGs], and physical examinations.
2. To characterize the population PK of 
GSK2879552, alone or in combination 
with azacitidine in patients with HR 
MDS previously treated with HMA. 
2. Population PK parameters for 
GSK2879552 such as clearance (CL/F).
3. To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival, and overall 
survival.
3. Duration of response (DOR) defined as 
the time from first documented 
response to disease progression. 
Progression free survival (PFS) defined 
as the time from first dosing day to 
disease progression or death from any 
cause. Overall survival (OS) defined as 
the time from first dosing day until 
death from any cause.
4. To evaluate frequency and time to 
progression to AML (per 2006 IWG 
criteria)
4. Proportion of subjects with disease 
progression to AML. Time to AML 
progression.
5. To evaluate platelet and RBC 
transfusion dependence.
5. Number of documented platelet and 
RBC transfusions per month within 3 
months prior to study entry and while 
on study.  


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Objectives 
Endpoints 
Exploratory
1. To investigate the mechanism of action 
and indicators of sensitivity and 
resistance to GSK2879552 
administered alone or in combination 
with azacitidine to patients with HR 
MDS previously treated with HMA. 
1. Gene and/or protein expression studies 
of peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 
response.
2. To evaluate the relationship of 
exposure of GSK2879552, 
administered alone or in combination 
with azacitidine, and safety/efficacy 
parameters, based on Part 1 and 2 data 
combined.
2. Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax or AUC (0-tau)) 
and safety/clinical activity.
3. To investigate the relationship between 
genetic variants in host DNA and the 
safety, tolerability, and efficacy of 
GSK2879552 alone or in combination 
with azacitidine based on Part 1 and 2 
data combined.
3. Pharmacogenomic (PGx) analysis using 
saliva samples.


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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase I/II, open-label, 2 arm study to evaluate the safety and clinical activity of 
GSK2879552 alone, or in combination with azacitidine in subjects with MDS. Eligible 
subjects with IPSS-R high or very high risk MDS by World Health Organization (WHO) 
classification, who have failed an HMA will be enrolled in the study.  
This study consists of 2 Arms, i.e., monotherapy with GSK2879552 (Arm A) and 
combination therapy with GSK2879552 and azacitidine (Arm B).  Each Arm has Part 1 
for safety evaluation followed by Part 2 to evaluate clinical activity.  Both Arms will 
proceed in parallel and subjects will be randomized in Part 2 to receive either 
GSK2879552 alone or GSK2879552 in combination with azacitidine.  In Arm A, 
approximately 3-6 subjects will receive during Part 1 the RP2D of GSK2879552 
determined in FTIH study (200858), i.e., 2 mg once daily to confirm the RP2D for MDS. 
In Arm B, traditional 3+3 dose escalation procedure will be followed in Part 1 to 
determine the RP2D of GSK2879552 in combination with azacitidine. Bayesian Logistic 
Regression Model (BLRM) prediction on DLT rate may also be provided at dose 
escalation meetings as the supplementary analysis to 3+3 design (See Section 4.3.2. for 
more details).  Once the RP2D of GSK2879552 for MDS is confirmed in both Arms, Part 
2 enrolment will open. Each treatment cycle is 28 days and subjects experiencing disease 
progression on monotherapy (Arm A) will be allowed to cross over (to Arm B) to be 
treated with the combination at RP2D.   
The statistical design and number of subjects to be enrolled in Part 2 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. This study 
will stop only for futility. Final decisions on stopping enrolment will depend on the 
totality of the data collected.


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Figure 1
Study Schematic
4.2.
Treatment Schedule and Duration
Treatment with GSK2879552 in both arms will be administered orally as continuous 
daily dosing until progression. Azacitidine will be administered at 75 mg/m2 on days 1-7 
of each 28 day cycle by intravenous (iv) infusion or subcutaneous (sc) injection (route of 
administration: by physicians choice). Subcutaneous administration will be required 
during the first cycle as PK information will be collected. 
Alterations to the dose and schedule of GSK2879552 may be incorporated based on 
emerging safety, tolerability, and PK data.  The dose and schedule of azacitidine may be 
also altered based on emerging safety, tolerability and PK data. Azacitidine dosing on 
Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case basis. 
Subjects may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent. Subjects experiencing disease progression on mono 
therapy (Arm A) will be allowed to cross over to be treated with the combination 
(Arm B) once the RP2D has been established.  All subjects will be followed after study 
treatment discontinuation until death, lost to follow-up or withdrawal of consent. The 
duration of the study will depend on recruitment rates, and timing of subject’s duration 
on study. Subjects may be allowed to continue on study treatment after disease 
progression if the Investigator, in consultation with the sponsor’s Medical Monitor, 
determines that continuing treatment will benefit the patient. 


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4.3.
Part 1
4.3.1.
Arm A (Monotherapy) - Safety Evaluation
Approximately 3-6 HR MDS subjects will receive GSK2879552 2 mg once daily to 
evaluate the safety and tolerability of GSK2879552. If the number of subjects with DLT 
is 0 (out of 3) or ≤ 1 (out of 6), RP2D for MDS will be considered defined. Subjects who 
fail to take at least 75% of their scheduled doses in the 4 weeks for reasons other than 
toxicity will be replaced.
If the 2 mg daily dose is not well tolerated, a reduced dose will be evaluated to determine 
RP2D for monotherapy in HR MDS.   Part 2 enrolment will begin when the RP2D is 
confirmed in both mono therapy and combination arm. See Section 4.10 for dose 
justification. 
4.3.2.
Arm B (Combination) - Dose Escalation
Using the 3 + 3 procedure, up to six subjects will be enrolled at each dose level.  
Evaluation of a cohort of at least three subjects completing one cycle of treatment 
(defined as first 28 days) is required prior to opening the next dose level. Subjects who 
fail to take at least 75% of their scheduled doses in the 4 weeks for reasons other than 
toxicity will be replaced.
Dose escalation will progress as described in Table 1.  Dose escalation decisions will take 
into account all available data, including the safety profile of prior cohorts.
Table 1
3 + 3 Dose Escalation Procedure
Number of Subjects with DLT
Action
0 out of 3 subjects
Escalate to next dose level 
1 out of 3 subjects
Accrue three additional evaluable subjects at current 
dose level for a total of six evaluable subjects
1 out of 6 subjects
Escalate to the next dose level 
2 or more out of 6 subjects
Maximum tolerated dose has been exceeded.  Either 
evaluate an intermediate dose lower than current dose
or expand a prior cohort up to 12 subjects. 
Two dose levels for GSK2879552 are planned to be explored with a fixed dose of 
azacitidine (Table 2).  In addition, alternate dose levels and schedules may also be 
explored based on emerging toxicity and PK data.  The dose escalation will complete 
when emerging DLTs prohibit further escalation, or when pre-specified RP2D is reached. 
The RP2D will not exceed the MTD and may be chosen based on both PK and safety 
data.
In Part 1 Arm B, to facilitate dose escalation/de-escalation decisions, a Bayesian logistic 
regression model (BLRM) may be utilized to predict the probability of DLT at the dose 
levels yet to be tested. Specifically, a BLRM for combination treatment will be fitted on 
the dose limiting toxicity data (i.e., absence or presence of DLT) accumulated throughout 


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the dose-escalation to model the dose-toxicity relationship of GSK2879552 and 
azacitidine when given in combination. 
Table 2
Planned Dose Levels
Dose Level
GSK2879552a
Azacitidineb
-1
0.5 mg once daily
75mg/m2
1
1 mg once daily
75 mg/m2
2
2 mg once daily
75 mg/m2
a.
Continuous daily dosing
b.
Days 1-7 of 28 days cycle via IV or SC administration
4.3.3.
Dose Limiting Toxicities
An event will be considered a DLT if it occurs within the first 28 days of treatment, and 
meets one of the following criteria unless it can be clearly established that the event is 
unrelated to treatment. Subjects unable to receive at least 75% of scheduled doses (of 
both agents, at the intended strength) for reasons other than toxicity (e.g., acute illness, 
disease progression) will not be evaluable for DLT purposes:

Grade 4 thrombocytopenia associated with clinically significant bleeding 

Any Grade 3 or greater non-hematologic toxicity

Fatigue, asthenia, nausea, vomiting or new electrolyte disturbance that respond to 
standard medical care within 72 hours are exceptions 

Any toxicity considered drug related  that in the judgment of the investigator and 
GSK Medical Monitor is dose-limiting

Drug related toxicities that prevent subjects from taking ≥75% of the intended 
doses during the first 28 days of treatment

Treatment delay of 14 days or greater due to unresolved drug-related toxicity 
4.3.4.
Dose Escalation Committee
A data review team, consisting (at a minimum) of the investigator(s), GSK medical 
monitor, clinical pharmacologist, clinical scientist, and statistician, will be responsible for 
determining whether dose escalation during Part 1 should continue as planned according 
to the 3+3 design rules together with the predicted DLT rates at all dose levels under a 
Bayesian logistic regression model (BLRM). Prior to the dose escalation decision, the 
data review team will review all available data on  adverse events including non-DLT 
toxicities, laboratory assessments and other safety evaluations.


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4.4.
Part 2
Part 2 of the study will be started once the dose escalation has been completed for both 
arms (A and B), and a dose has been selected for GSK2879552 monotherapy and 
combination of azacitidine with GSK2879552. Once deemed eligible, subjects will be 
randomly assigned at study entry to Arm A or Arm B in accordance with the 
randomization schedule generated by Clinical Statistics, prior to the start of the study, 
using validated internal software. 
4.5.
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.
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 may require additional limited PK 
sampling at the higher dose as determined by GSK Clinical Pharmacology.
4.6.
Intra-subject Monotherapy to Combination Arm Crossover
Subjects on monotherapy (Arm A) will be allowed to cross over (to Arm B) to be treated 
with the combination at RP2D at the time of progression. The crossover is allowed if a 
patient has not experienced intolerable toxicity on mono therapy, and has experienced 
disease progression (including AML) according to 2006 IWG criteria. In each case, 
approval for crossover has to be granted by GSK Medical Monitor. 
The study site is required to provide the safety and disease assessment data of the subject, 
and the completed crossover form (Refer to Study Procedure Manual) at least 48 hrs prior 
to the crossover. The medical monitor will review the data and provide the approval for 
crossover with a signed crossover form. 
The crossover to combination treatment Arm B should occur as quickly as possible and 
no later than within 4 weeks of disease progression. All assessments and samples 
required at the “crossover visit” as described in the Time and Event table (Section 7.1) 
must be completed at the time of crossover. The disease assessment and safety laboratory 
results at the time of crossover will be considered a new baseline as the subject starts 
combination treatment and continue on with the next visit (from the mono therapy).  
4.7.
Permanent Discontinuation of Study Treatment
Subjects will receive study treatment until disease progression (according to IWG), death, 
withdrawal of consent, or unacceptable toxicity, including meeting stopping criteria for 
liver chemistry.  The investigator may discuss with a GSK Medical Monitor continuing a 
subject who is receiving clinical benefit but has met the formal criteria for disease 
progression, if the following criteria are met: Investigator-determined clinical benefit 
(e.g. symptomatic improvement), lack of significant toxicity (no drug related non-


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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:

Substantial deviation(s) from the protocol

Request of the subject or proxy (withdrawal of consent by subject or proxy)

Investigator’s discretion

A clinically significant adverse event leading to an interruption of treatment for 
greater than 14 days.  If the investigator and GSK Medical Monitor conclude that 
the benefit: risk is positive and supports continued treatment in  a subject who has 
had a > 14 day treatment delay, then the subject may continue therapy with the 
approval of the GSK Medical Monitor on case by case basis. 

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.
Once a subject has permanently discontinued study treatment, the subject will not be 
allowed to re-enter this study.  All subjects who discontinue from study treatment will 
have safety assessments at the time of discontinuation and during post-study treatment 
monthly follow-up. 
4.8.
Type and Number of Subjects
Approximately 3-12 subjects may be enrolled in Part 1 of each Arm. Later, 
approximately 28 subjects will be enrolled in Part 2 of each Arm with a total of 74 (Arm 
A: 6+28; Arm B: 12+28) subjects in the study. The number of subjects may change 
depending on the dose levels in Part 1.
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels. 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor.
4.9.
Design Justification
The proposed study design will help to assess the GSK2879552 monotherapy safety and 
activity in MDS patients at doses which have been well tolerated in patients with SCLC 


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or with AML. The combination arm, in addition to safety assessments, will also provide 
the first clinical activity data of the combination of GSK2879552 with azacitidine in 
patients with HR MDS. Upon progression patients from the GSK2879552 mono therapy 
arm will, have the possibility to cross over to the combination arm to allow testing the 
hypothesis whether patients failing GSK2879552 might be rescued by combination 
treatment.
4.10.
Dose Justification
4.10.1.
Arm A: GSK2879552 Monotherapy
Dose limiting toxicities reported in the FTIH study in the SCLC population are 
thrombocytopenia and encephalopathy. Following 3 mg daily GSK2879552 
administration (n=3), platelets started to decrease within days after initiation of treatment 
with a similar rate of decrease and Grade 4 thrombocytopenia was observed by Day 15 in 
all 3 subjects. Following dose interruption, the platelet count fully recovered after 1 week 
in all 3 subjects, but decreased again, with a delay, following treatment restart. Therefore, 
2 mg once daily was determined to be the MTD and the RP2D. 
GSK has conducted a thorough investigation on three encephalopathy cases reported in 
the SCLC study at 2mg-3 mg. Based on the likelihood that prior treatment with 
temozolomide predisposed the first two patients to encephalopathy, that meningeal 
carcinomatosis was the primary cause in the third case of encephalopathy, and that there 
have not been any cases of encephalopathy in AML patients treated at higher doses 
(including 7 patients at 4 mg once daily and 1 patient at 8 mg once daily dosing), GSK 
concluded that it is unlikely that GSK2879552 alone was the cause of any case of 
encephalopathy. It is quite typical for advanced SCLC patients to have pre-existing brain 
injury from radiation therapy, brain metastases, or meningeal disease. None of those 
factors predisposing to brain injuries are typical for the MDS population and prior 
treatment with temozolomide, dacarbazine or procarbazine as well as poly ADP ribose 
polymerase (PARP) inhibitors are exclusion criteria in this protocol. 
Given all the above considerations, the proposed daily dose of 2 mg of GSK2879552, 
which is 25% of the 8 mg dose currently being tested in AML patients without 
occurrence of DLTs is expected to be tolerated by MDS subjects. The 2 mg dose is 
expected to achieve exposure where some clinical activity can be expected, while 
protecting subjects’ safety. Therefore, the daily dose of 2mg will be evaluated for safety 
in Part 1 of the monotherapy arm. If the 2 mg daily dose is not well tolerated, a reduced 
dose will be evaluated to determine RP2D for MDS. Once the RP2D is confirmed in Part 
1, clinical activity will be evaluated in the Part 2 expansion cohort. Treatment with 
GSK2879552 monotherapy will continue until intolerable toxicity, consent withdrawal, 
or progression. In the case of progression, the patients from arm A will be allowed to 
cross over to arm B, and to continue on the combination treatment arm of study.


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4.10.2.
Arm B: GSK2879552 and Azacitidine Combo
Azacitidine will be administered at a fixed dose of 75 mg/m2/day on Days 1-7 of each 28 
day-cycle, whereas GSK2879552 dose escalation will start at1 mg once daily. These 
starting doses were chosen based on the following considerations:

This is the first time that both agents are going to be co-administered to humans, 
therefore a careful escalation is warranted. 

Azacitidine is an approved agent with proven activity in MDS patients, therefore 
azacitidine will be administered at the approved dose to maximize patients 
chances of having a response to treatment. A 1 mg daily dose of GSK2879552 
represents a 50% reduction from the declared MTD in the SCLC study, and was 
very well tolerated in the SCLC study with no Grade 3 or 4 hematological AE. A 
1 mg daily dose was the starting dose in the AML study and was also well 
tolerated. 1 mg is 12.5% of the dose currently being tested in AML (8mg).

GSK2879552 and azacitidine may have an overlapping toxicity profile in respect 
to hematological toxicity with thrombocytopenia, neutropenia and anemia.

The risk for a pharmacokinetic interaction between GSK2879552 and azacitidine 
is considered low.
4.11.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK2879552 can be found in the Investigator’s Brochure (IB).  The following section 
outlines the risk assessment and mitigation strategy for this protocol:


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4.11.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
GSK2879552 
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.
Thrombocytopenia has been observed in study 
200858 including grade 4 thrombocytopenia. The 
extent of thrombocytopenia was dose-dependent with 
a steep relationship between platelet nadir and dose, 
Cmax, or AUC and  grade 3/4 events occurring at 
higher doses. To date, withdrawal of GSK2879552 
has resulted in the resolution of thrombocytopenia,  
but daily doses of 2mg did not cause clinically 
significant thrombocytopenia..  .
Informed Consent Form includes the risk of hematologic toxicity.
Protocol specifies: 
-
Exclusion criteria for - major bleeding (e.g. recent GI 
hemorrhage or neurosurgery)
-
Laboratory assessments (complete blood count [CBC] and 
coagulation panel) weekly for the first 4 weeks and monthly 
thereafter 
-
Dose stopping/modification criteria based on CBC
Signs and symptoms of bleeding or infection will be closely 
monitored and treated according to institutional standards during 
the study.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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
-
Montreal Cognitive Assessment (MOCA) at baseline (pre-dose 
Day 1) and weekly for the first 4 weeks and monthly thereafter.
-
Subjects with baseline (pre-dose Day 1) 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 (pre-dose Day 1)
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
Azacitidine
Hematologic toxicity
Azacitidine causes anemia, neutropenia and 
thrombocytopenia. 
Protocol specifies: 
-
Subjects with major bleeding (e.g. recent GI hemorrhage or 
neurosurgery) within the past 4 weeks are excluded.
-
Laboratory assessments (complete blood count [CBC] and 
coagulation panel) are performed weekly for the first 4 weeks 
and monthly thereafter 
-
Dose stopping/modification criteria based on CBC is provided.
Signs and symptoms of bleeding or infection will be closely 
monitored and treated according to institutional standards during 
the study.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity 
Azacitidine is potentially hepatotoxic in patients with 
severe pre-existing hepatic impairment.
-
Subjects with elevated liver function test (LFT), history 
of/concurrent malignancy or current active liver or biliary 
disease are excluded. 
-
LFT is monitored weekly for the first 4 weeks and monthly 
thereafter. 
-
Treatment stopping criteria based on elevation in LFT is in 
place. 
Renal impairment
Renal toxicity ranging from elevated serum 
creatinine to renal failure and death have been 
reported in patients treated with intravenous 
azacitidine in combination with other 
chemotherapeutic agents for nonMDS conditions. 
Renal tubular acidosis has been also reported in 
patients treated with azacitidine and etoposide. 
Patients with renal impairment may be at increased 
risk for renal toxicity. Also, azacitidine and its 
metabolites are primarily excreted by the kidney.
-
Subjects with inadequate renal function are excluded
-
Chemistry panel including serum creatinine, BUN and 
electrolytes are monitored weekly for the first 4 weeks and 
monthly thereafter.
-
Treatment stopping criteria based on serum bicarbonate, 
creatinine and or BUN is provided.
Teratogenic effect
Azacitidine caused congenital malformations in 
animals and may cause fetal harm when administered 
to a pregnant woman. In animal studies, pre-
conception treatment of male mice and rats resulted 
in increased embryofetal loss in mated females
-
Pregnancy test will be performed at screening and monthly 
thereafter.
-
Female subjects with child bearing potential must have a 
negative serum pregnancy test within 7 days of first dose of 
study treatment and agree to use effective contraception, during 
the study and for 7 days following the last dose of study 
treatment.
-
Lactating females will be excluded.
-
Male subjects with a female partner of childbearing potential 
must have either had a prior vasectomy or agree to use effective 
contraception from the administration of the first dose of study 
treatment until 3 months after the last dose of study treatment. 


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4.11.2.
Benefit Assessment
This is an open-label and the first time in human study of this agent to be conducted in 
subjects with MDS who have failed hypomethylating treatment 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 MDS, thus any potential beneficial effect for an individual 
subject attributable to GSK2879552 is unknown. 
Azacitidine is used for treating MDS in clinical practice. The preclinical data suggest a 
potential combination benefit for use of a HMA and GSK2879552.  GSK2879552 
promotes increased expression of genes associated with myeloid differentiation.  
Mechanistically, HMA and GSK2879552 are similar in that they both cause de-
repression of gene expression.  This mechanistic overlap leads to the hypothesis that 
MDS patients may respond better to HMA when combined with GSK2879552.  Any 
potential beneficial effect for an individual subject attributable to the combination of 
azacitidine with GSK2879552 in MDS is unknown.
Data obtained in this study may assist in progressing the knowledge base on MDS 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
4.11.3.
Overall Benefit: Risk Conclusion
Current data from GSK2879552 preclinical studies, alone or in combination with 5-Aza-
2’-deoxycytidine, indicate a potential for clinical activity by induction of differentiation 
in MDS. Taking into account the measures taken to minimise risks to subjects 
participating in this Phase I/II clinical trial, the potential risks identified in association 
with GSK2879552, alone or in combination with azacitidine, are justified by the 
anticipated benefits that may be afforded to subjects who failed HMA, for whom there 
are currently no effective available therapies.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB for GSK2879552 
[GlaxoSmithKline Document Number 2013N168888_02].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.


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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. 18 years of age and provided signed written informed consent
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Subjects must have IPSS-R high or very high risk myelodysplastic syndromes (MDS)  
by WHO classification
3. Subjects must have failed hypomethylating treatment where “failure” is defined as: 
a) Progression (according to 2006 IWG criteria) at any time after initiation of 
the hypomethylating treatment OR 
b) Failure to achieve complete or partial response or hematological 
improvement (HI) (according to 2006 IWG) after at least 4 cycles treatment 
OR 
c) Relapse after initial complete or partial response or HI (according to 2006 
IWG criteria). 
4. Subjects are not a candidate, or have failed allogeneic stem cell transplantation.  
Subjects who underwent allo-transplant in the past are eligible under following 
conditions: 
a) transplant was >2 year prior to enrolment, and 
b) no evidence of active GVHD 
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
6. Subjects must have a life expectancy of at least 12 weeks, in the opinion of the 
investigator.
7. 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.
8. 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).  


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LABORATORY
9. Adequate baseline organ function defined by:
System
Laboratory Values
Coagulation
INR and aPTT
1.3 X ULN
Hematologic
PLT
>10,000 
(transfusions permitted to bring platelet 
count to >10,000)
Hepatic
Total bilirubin
≤1.5 X ULNa
ALT 
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
a. 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
GENDER and REPRODUCTIVE POTENTIAL
10.
Women of childbearing potential must have a negative serum pregnancy test 
within 7 days of first dose of study treatment and agree to use effective contraception, 
as defined in Appendix 7 of this protocol, during the study and for 7 days following the 
last dose of study treatment.
11.
Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception, as defined in Appendix 7 of this 
protocol,  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.


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. AML according to WHO criteria (i.e. bone marrow blasts >20%)
2. Active hepatitis B or hepatitis C treatment
3. Baseline (pre-dose Day 1) Montreal Cognitive Assessment (MOCA) score of 22 or 
lower
CONCURRENT CONDITIONS/MEDICAL HISTORY 
4. History of or concurrent malignancy of solid tumours, except for below: 
Exception:  Subjects who have been disease-free for 2 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated in 
situ carcinoma are eligible.  Consult GSK Medical Monitor if unsure whether second 
malignancies meet requirements specified above
5. Prior treatment with temozolomide, dacarbazine or procarbazine
6. Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, 
ABT-888)
7. Currently receiving other anti-cancer therapy (chemotherapy, radiation therapy, 
immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization)
8. Received major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK2879552 administration
9. 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
10. Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator’s 
assessment)
11. Patients with any major bleeding current or within the past 4 weeks. (e.g. recent GI 
hemorrhage or neurosurgery).
12. Administration of an investigational drug within 14 days or 5 half-lives, whichever is 
shorter, preceding the first dose of study treatment(s) in this study. 
13. Cardiac abnormalities as evidenced by any of the following:

Clinically significant uncontrolled arrhythmias or uncontrolled hypertension.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA)

History of acute coronary syndromes (including unstable angina and myocardial 


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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
CONCOMITANT MEDICATIONS/OTHER RESTRICTIONS
14. Current use of a prohibited medication including anticoagulants or platelet inhibitors 
or expected to require any of these medications during treatment with the 
investigational drug 
15. Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, 
pomelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) 
until the last dose of study drug
16. Lactating female
CONTRAINDICATION
17. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates 
their participation
18. Known hypersensitivity to azacitidine or mannitol
5.3.
Screening 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 Serious Adverse Events (see Section 7.3.1.6).
5.4.
Withdrawal/Stopping Criteria
See Section 4.7. for the permanent discontinuation of study treatment.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 


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known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost to 
Follow-up”. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
See Figure 2 for liver stopping criteria algorithm.
Figure 2
Liver Chemistry Stopping and Increased Monitoring Algorithm
See Appendix 2 for Liver Safety Required Actions and Follow up Assessments.
5.4.1.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted


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
Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 3 for full guidance. 
5.4.2.
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:
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.
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
5.4.3.
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) Montreal 
Cognitive Assessment (MOCA) score (Section 7.3.7)


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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 (pre-dose Day 1).

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 (pre-dose Day 1).
5.5.
Safety Management
5.5.1.
Events of Special Interest
5.5.1.1.
Hematologic Events
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.
Transfusions are allowed throughout the study as clinically indicated. 
Erythropoietin is not allowed on study. 
The use of granulocyte stimulating growth factors is only allowed for treatment of febrile 
neutropenia and other life threatening infections.
5.5.1.2.
Mental Status Change
When a subject presents with a possible indication of early encephalopathy, the subject 
should be admitted and study treatment held immediately.  Below procedures should take 
place following the admission to support the diagnosis and/or exclude carcinomatous 
meningitis, unless contraindicated:

Brain MRI scan with contrast

Lumbar puncture with cytology analysis 

Electroencephalogram (EEG)

Metabolic panel 


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5.5.2.
Dose Adjustment for Non-Hematologic Toxicity
See Table 3 below. Dose Adjustment Guideline for drug related non-hematologic 
toxicities based on worst grade.
Table 3
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 GSK2879552 and/or azacitidine for up to 2 weeks for 
toxicity to resolve to baseline or ≤ Grade 1, then continue at the same dose 
OR dose reduce GSK2879552 and/or azacitidine by 25-50%.
G3 and 4
Hold GSK2879552 and/or azacitidine for up to 2 weeks for toxicity to 
resolve to baseline or ≤ Grade 1, then dose reduce GSK2879552 and/or 
azacitidine by 25-50%.
If no recovery to ≤Grade 1* or baseline after 14 days, patient should be 
withdrawn.
*Note: Some AEs, such as rash and alopecia, may not be required to recover to Grade 1 or baseline. 
Additional AEs may be considered non-clinically significant and qualify for this exception if agreed upon 
by the GSK medical monitor.
If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, azacitidine 
dose should be reduced by 50% on the next course. Similarly, if unexplained elevations 
of BUN or serum creatinine occur, the next cycle should be delayed until values return to 
normal or baseline and the dose should be reduced by 50% on the next treatment course. 
A full dose of azacitidine will be administered in the subsequent treatment courses, once 
serum bicarbonate level returns to ≥ 20mEq/L, and BUN and serum creatinine level 
returns to normal or baseline, and no other toxicities are apparent.
If the non-hematologic toxicity or event resolves to baseline or Grade 1 within 14 days 
of stopping therapy, treatment with GSK2879552 and/or azacitidine may be restarted 
with at least 25% dose reduction. For a non-DLT, the treatment with GSK2879552 
and/or azacitidine 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.  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 of both drugs once the 
toxicity resolves to Grade 1 or baseline. 


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5.5.3.
Dose Adjustment for Hematologic Toxicity
The dose of azacitidine and/or GSK2879552 may be adjusted based on neutrophil, 
platelet, WBC and bone marrow biopsy cellularity at baseline and nadir according to the 
guidelines below: 
No dose adjustments are needed for anemia.
For patients with baseline (start of treatment) WBC ≥3.0 x10
9
/L, ANC ≥1.5 x10
9
/L, and 
platelets ≥75.0 x10
9
/L, adjust the dose as follows, based on nadir counts for any given 
cycle:
Nadir Counts 
% Dose of  
Azacitidine/GSK2879552 to 
be administered 
Course
-
ANC (x109/L) 
Platelets (x109/L) 
<0.5 
<25.0 
50%/50-67%
0.5 –1.5 
25.0-50.0 
67%/67-100% 
>1.5 
>50.0 
100%/100% 
For patients whose baseline counts are WBC <3.0 x10
9
/L, ANC<1.5 x10
9
/L, or platelets 
<75.0 x10
9
/L, dose adjustments should be based on nadir counts and bone marrow biopsy 
cellularity at the time of the nadir as noted below, unless there is clear improvement in 
differentiation (percentage of mature granulocytes is higher and ANC is higher than at 
onset of that course) at the time of the next cycle, in which case the dose of the current 
treatment should be continued.
WBC or Platelet 
Nadir % decrease in 
counts from baseline 
Bone Marrow Biopsy Cellularity at Time of Nadir 
(%) 
30-60 
15-30 
<15 
% Dose of Azacitidine/GSK2879552 to be administered -
50 - 75 
>75 
100%/100% 
50%/33-67% 
33%/25-50% 
75%/50-100%
50/33-67% 
33%/25-50% 
If a nadir as defined in the table above has occurred, the next course of treatment should 
be given 28 days after the start of the preceding course, provided that both the WBC and 
the platelet counts are >25% above the nadir and rising. If a >25% increase above the 
nadir is not seen by day 28, counts should be reassessed every 7 days. If a 25% increase 
is not seen by day 42, then the patient should be treated with 50% of the scheduled dose.


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5.6.
Subject and Study Completion
A subject will be considered to have completed the study if they are followed until death.
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.  
The study will be considered completed for the purpose of a final analysis when 70% of 
subjects enrolled in Part 2 have progressed or died.  If available, subjects continuing on 
treatment at the time of final analysis may be offered the option to continue in a rollover 
trial.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products 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.
6.2.
Description of Investigational Product(s)
6.2.1.
GSK2879552
Product name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.5 mg or 2 mg of GSK2879552 as 
parent. 
Dosage form:
Capsule
Unit dose 
strength(s)
0.5 mg, 2 mg 
Route/
Regimen
Oral
The initial dosing regimen will be continuous oral daily dosing. 
Subjects should take their doses fasted (i.e. no food intake from 2 
hours before dosing until 1 hour after dosing) 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.
GSK2879552 will be provided to sites by GSK.


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6.2.2.
Azacitidine
Azacitidine is a pyrimidine nucleoside analog of cytidine, which causes hypomethylation 
(demethylation) of DNA and has direct cytotoxicity on abnormal bone marrow 
hematopoietic cells.
Azacitidine is supplied as white lyophilised powder for injection in a single use vial
Azacitidine will be locally supplied, and stored and prepared according to local standards.
6.3.
Treatment Assignment
In Part 1, subjects will be assigned to Arm A (GSK2879552 only) or Arm B 
(GSK2879552 in combination with azacitidine) according to the investigator discretion 
and/or the availability of the enrolment slot.
In Part 2, subjects will be assigned to Arm A (GSK2879552 only) or Arm B 
(GSK2879552 in combination with azacitidine) in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
6.4.
Blinding
This will be an open-label study 
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
Azacitidine is a cytotoxic drug and, as with other potentially toxic compounds, caution 
should be exercised when handling and preparing azacitidine suspensions. If 
reconstituted azacitidine comes into contact with the skin, immediately and thoroughly 
wash with soap and water. If it comes into contact with mucous membranes, flush 
thoroughly with water. Refer to Study Procedure Manual (SPM) for preparation 
instructions for azacitidine.
No special preparation of GSK2879552 is required.
GSK2879552 is to be stored at a temperature range of 2-8C (36-46F), protected from 
moisture.  Azacitidine vials are to be stored at 25º C (77º F); excursions permitted to 15º-
30º C (59º-86º F).  Maintenance of a temperature log (manual or automated) is required at 
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
The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 
6.7.
Compliance with Study Treatment Administration
On clinic days, GSK2879552 and azacitidine (if applicable) will be administered in the 
clinic after safety procedures including blood sampling for CBC and PK/PD samplings, if 
applicable, are completed.  When subjects self-administer GSK2879552 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.
6.8.
Treatment of Study Treatment 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.
One case of overdose with azacitidine was reported when a patient received a single IV 
dose of approximately 290 mg/m2. The patient experienced diarrhea, nausea, and 
vomiting and the events resolved without sequelae. In the event of azacitidine overdose, 
the patient should be monitored with appropriate blood counts and should receive 


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supportive treatment, as necessary. There is no known specific antidote for azacitidine 
overdose.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions
See Appendix 7 for the contraception requirements, when applicable. 
6.10.1.
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 sample during each serial PK sampling day 
(e.g., Part 1, Days 1, 7 and 15).
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits which may inhibit efflux 
transporters and CYP enzyme, from 1 day prior to the first dose of study treatment until 
the last dose of study drug.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
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 (excluding platelet inhibitors), as appropriate.
6.11.2.
Prohibited Medication(s)
Subjects should not receive other anti-cancer therapy (chemotherapy, radiation therapy, 
immunotherapy, biologic therapy, and hormone therapy other than for replacement) while 
on treatment in this study.  
Anticoagulants (e.g., warfarin, direct thrombin inhibitors, etc) or platelet inhibitors (e.g., 
aspirin, clopidogrel) are prohibited from 14 days prior to the first dose of study drug 
through completion of the Final Study Visit.
Erythropoietin is not allowed on study. 


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6.11.3.
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.
6.11.4.
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. 
Pharmacokinetics of  co-meds that are substrates of CYP enzymes is unlikely altered by 
GSK2879552. 
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 transporter 2 (OCT2) and 
multidrug and toxin extrusion transporter 2-K (MATE2-K).  Pharmacokinetics of co-
meds that are substrates of the above transporters are unlikely altered by GSK2879552. 
6.12.
Non-Drug Therapies
Transfusions are allowed as clinically indicated. 
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
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1

The timing and number of planned study assessments, including safety, PK, 
PD/biomarker 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. 

The change in timing or addition of time points for any planned study assessments 
must be documented in a Note to File which is approved by the relevant GSK 


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study team member and then archived in the study sponsor and site study files, but 
this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

In Arm B, all procedures planned on Day 7 will be conducted on Day 9, if 
azacitidine is administered on 5+2 schedule: Mon-Fri (Days 1-5) and Mon-Tue 
(Days 8-9) schedule instead of 7 consecutive daily dosing on Days 1-7.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECGs, vital signs, 
blood draws.  
If the blood draw is done first, there should be at least 15 minute interval before the vital 
signs and 12-lead ECGs measurements are taken
Detailed procedures for obtaining each assessment are provided in the Study Procedures 
Manual (SPM).
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.
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.
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
0.5 and 1 hours post dose sampling: 5 minutes
3 hours post dose sampling: 15 minutes
24 hours post dose sampling: 2 hour and should be done before the next dose 
administration.


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7.1.
Time and Events Table for Arm A – Part 1
SC
R
Cycle 1 (28 days)
C2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment 
Bi-Monthly 
Follow-Up16
D 1
D2
D4
D7
D 15
D22
Office Visit for Arm A 
(mono)
X
X
X1
X
X
X
X
C2: D1, 7, 15 and 22 
C3 and after: D1
X
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------ Daily or per dosing schedule --------------------
Azacitidine dosing
X14
Review subject dosing diary
X
X
Day 1
X
X
GSK2879552 Drug 
Dispensing 
X
Day 1
Complete physical exam
X
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
X
Vital Signs
X
X7
X
X
Day 1
X
X
Height and weight6
X
X7
X
Day 1
X
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
X
HIV, HBV and HCV Ab 
testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 15 and 22 
X
X


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SC
R
Cycle 1 (28 days)
C2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment 
Bi-Monthly 
Follow-Up16
D 1
D2
D4
D7
D 15
D22
C3 and after: D1
Chemistry Panel including 
LFT
X
X7
X12
X
X
Day 1
X
X
Coagulation Panel 
including a PTT and INR
X
X12
x
X
Day 1
X
X
PK Blood samples
X1
X1
X8
X2
X5
X8
C2: D1, 7, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
X
Blood samples for 
exploratory studies 
(peripheral blood)3, 11
X
X
X
X
Day 1
X
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X
as clinically indicated 
X18
X15
PGX samples (saliva 
sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS  Assessment
X


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1.
A blood sample will be collected for GSK2879552 PK analysis on D1 at pre-dose, 0.5, 1 hr, and 3 hrs post dose..An additional optional PK sample will be 
collected at 24 hours post Day 1 dose for GSK2879552 measurement.
2.
A blood sample will be collected for GSK2879552 PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. 
3.
Samples should be collected at pre-dose. 
4.
For women of child bearing potential only. Serum pregnancy test is required for screening, crossover and EOT visits. Urine pregnancy test is adequate 
during study visits.
5.
A blood sample will be collected for GSK2879552 PK analysis on D15 at pre-dose and 0.5-1 hr post dose. 
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 for GSK2879552 should be taken pre-dose. PK sample will not be collected beyond 48 weeks. 
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. Collection of exploratory sample (peripheral blood and/or BMA) time points may be terminated at the sponsor’s discretion 
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
13. PK blood sample should be collected prior to dosing on biopsy days. 
14. Azacitidine dosing can start on Day 1 of the next cycle after the cross over visit is completed. 
15. Optional for all subjects
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up 
will continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at the time of crossover, unless the sample 
collection is stopped per sponsor discretion; the PK blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is collected.  
The PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit.
18. A mandatory BM sample will be collected at the time of the crossover visit to establish the new baseline.  A window of 14 days is allowed for this BM 
assessment.   


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Time and Events Table for Arm A – Part 2
SC
R
Cycle 1 (28 days)
Cycle 2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment 
Bi-monthly 
Follow-Up16
D 1
D4
D 7
D 15
D22
Office Visit for Arm A 
(mono)
X
X
X
X
X
X
C2: D1, 7, 15 and 22 
C3 and after: D1
X
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ----------------------- Daily or per dosing schedule --------------------
Azacitidine dosing14
X14
Review subject dosing diary
X
X
Day 1
X
X
GSK2879552 Drug 
Dispensing 
X
Day 1
Complete physical exam
X
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
X
Vital Signs
X
X7
X
X
Day 1
X
X
Height and weight6
X
X7
X
Day 1
X
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
X
HIV, HBV  and HCV Ab 
X


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SC
R
Cycle 1 (28 days)
Cycle 2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment 
Bi-monthly 
Follow-Up16
D 1
D4
D 7
D 15
D22
testing
CBC
X
X7
X12
X
X
C2: D1, 712, 15 and 22 
C3 and after: D1
X
X
Chemistry Panel including 
LFT
X
X7
X12
X
X
Day 1
X
X
Coagulation Panel including 
a PTT and INR
X
X12
x
X
Day 1
X
X
PK Blood samples
X1
X8
X5
X2
X8
C2: D1, 7, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
X
Blood samples for 
exploratory studies 
(peripheral blood)3, 11
X
X
X
X
Day 1
X
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X
as clinically indicated 
X18
X15
PGX samples (saliva 
sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS Assessment
X


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1.
A blood sample will be collected for PK analysis on D1 at pre-dose, 0.5hr, 1 hr and 3 hrs post dose. . 
2.
A blood sample will be collected for PK analysis on D15 at pre-dose and between 0.5 to 1 hour.
3.
Samples should be collected at pre-dose. 
4.
For women of child bearing potential only. Serum pregnancy test is required for screening, crossover and EOT visits. Urine pregnancy test is adequate 
during study visits.
5.
A blood sample will be collected for PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. .
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 for GSK2879552 should be taken pre-dose around the same time as CBC.  PK sample will not be collected beyond 48 weeks.
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. Collection of exploratory sample (peripheral blood and/or BMA) time points  may be terminated at the sponsor’s discretion
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
13. PK corresponding blood sample should be collected prior to dosing
14. Azacitidine dosing can start on Day 1 of the next cycle after the cross over visit is completed.
15. Optional for all subjects
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up 
will continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection 
is stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is 
collected.  The PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
18. A mandatory BM sample will be collected at the time of the crossover visit to establish the new baseline.  A window of 14 days is allowed for this BM 
assessment.  


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Time and Events Table – Arm B (Combination with Azacitidine), Part 1
SC
R
Cycle 1 (28 days)
Subsequent Cycles
End of 
Treatment Visit 
Post Treatment 
Bi-Monthly 
Follow-Up16
D 1
D2
D4
D719
D 15
D22
Office Visit for Arm B 
(combo)
X
X
X
X
X
X
X
C2: D1- 719, 15 and 22 
C3 and after: D1-719
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------ Daily or per dosing schedule --------------------
Azacitidine dosing14
<--Days 1-7--->
Days 1-7
Review subject dosing diary
X
X
Day 1
X
GSK2879552 Drug 
Dispensing 
X
Day 1
Complete physical exam
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
Vital Signs
X
X7
X
X
Day 1
X
Height and weight6
X
X7
X
Day 1
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
HIV, HBsAg and HCV Ab 
testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 19, 15 and 22 
C3 and after: D1
X


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SC
R
Cycle 1 (28 days)
Subsequent Cycles
End of 
Treatment Visit 
Post Treatment 
Bi-Monthly 
Follow-Up16
D 1
D2
D4
D719
D 15
D22
Chemistry Panel including 
LFT
X
X7
X12
X
X
Day 1
X
Coagulation Panel including 
a PTT and INR
X
X12
x
X
Day 1
X
PK Blood samples
X1
X1
X8
X2
X5
X8
C2: D1, 719, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
Blood samples for 
exploratory studies 
(peripheral blood)3, 11
X
X
X
X
Day 1
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X18
as clinically indicated 
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS Assessment
X


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1.
A blood sample will be collected for GSK2879552 and azacitidine PK analysis on D1 at pre-dose, 0.5, 1 hr, and 3 hrs post dose.. An additional PK sample 
will be collected at 24 hours post Day 1 dose for GSK2879552 measurement in the combination arm.
2.
A blood sample will be collected for GSK2879552 and azacitidine PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose.
3.
Samples should be collected at 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.
A blood sample will be collected for GSK2879552 PK analysis on D15 at pre-dose and 0.5-1 hr post dose. 
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 for GSK2879552 should be taken pre-dose. PK sample will not be collected beyond 48 weeks. 
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. Collection of exploratory sample (peripheral blood and/or BMA) time points  may be terminated at the sponsor’s discretion
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7 or the last day of Azacitidine in the cycle.
13. PK corresponding blood sample should be collected prior to dosing
14. Azacitidine dosing on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case.
15. Optional for all subjects
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up 
will continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection 
is stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is 
collected.  The PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
18. A window of 14 days is allowed for BM exam. Subjects who progressed to AML and cross over to Arm B will be required to have bone marrow for disease 
assessment prior to the start of combination dosing  
19. All procedures scheduled on Day 7 visit (of any cycle) should move to Day 9, if azacitidine is given on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) instead 
of Days 1-7. 


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Time and Events Table - Arm B (Combination with Azacitidine), Part 2
SC
R
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post 
Treatment Bi-
monthly 
Follow-Up16
D 1
D4
D718
D 15
D22
Office Visit for Arm B 
(combo)
X
X
X
X
X
X
C2: D1- 718, 15 and 22 
C3 and after: D1-7
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------- Daily or per dosing schedule ---------------------
Azacitidine dosing14
<--Days 1-7--->
Days 1-7
Review subject dosing diary
X
X
Day 1
X
GSK2879552 Drug 
Dispensing 
X
Day 1
Complete physical exam
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
Vital Signs
X
X7
X
X
Day 1
X
Height and weight6
X
X7
X
Day 1
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
HIV, HBsAg and HCV Ab 
testing
X


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SC
R
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post 
Treatment Bi-
monthly 
Follow-Up16
D 1
D4
D718
D 15
D22
CBC
X
X7
X12
X
X
C2: D1, 712, 18, 15 and 22 
C3 and after: D1
X
Chemistry Panel including 
LFT
X
X7
X12
X
X
Day 1
X
Coagulation Panel including 
a PTT and INR
X
X12
x
X
Day 1
X
PK Blood samples
X1
X8
X5
X2
X8
C2: D1, 718, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
Blood samples for 
exploratory studies 
(peripheral blood)3, 11
X
X
X
X
Day 1
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease assessment17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X19
bone marrow if clinically 
indicated 
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
Survival Assessment
X


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1.
A blood sample will be collected for GSK2879552 and azacitidine PK analysis on D1 at pre-dose, 0.5hr, 1 hr and 3 hrs post dose..
2.
A blood sample will be collected for PK analysis on D15 at pre-dose and between 0.5 to 1 hour.
3.
Samples should be collected at 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.
A blood sample will be collected for GSK2879552 and azacitidine PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose.
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 for GSK2879552 should be taken pre-dose around the same time as CBC. PK sample will not be collected beyond 48 weeks.
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. Collection of exploratory sample (peripheral blood and/or BMA) time points may be terminated at the sponsor’s discretion
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
13. PK corresponding blood sample should be collected prior to dosing
14. Azacitidine dosing on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case.
15. Optional for all subjects.
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up 
will continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection 
is stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is 
collected.  The PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
18. All procedures scheduled on Day 7 visit (of any cycle) should move to Day 9, if azacitidine is given on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) instead 
of Days 1-7. 
19. A window of 14 days is allowed for BM exam. Subjects who progressed to AML and cross over to Arm B will be required to have bone marrow for disease 
assessment prior to the start of combination dosing  


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management [e.g. blood 
count] 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 within the timeframe defined in the Time and Events Schedule.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 


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event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 5.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.11.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 5.
7.3.1.4.
Cardiovascular and Death Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.


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7.3.1.5.
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.
7.3.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects or female partners of male subjects will be 
collected after the start of dosing and until 7 days post-last dose.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 7.
7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded. 
A brief physical examination will include, at a minimum assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).


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
Investigators should pay special attention to clinical signs related to previous 
serious illnesses
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 
measurement of vital signs.
7.3.5.
Electrocardiogram (ECG)
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.  
7.3.6.
ECOG Performance Status
The performance status will be assessed using the Eastern Cooperative Oncology Group 
(ECOG) scale (Appendix 6) as specified in the Time and Events Table (Section 7.1).
7.3.7.
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.
7.3.8.
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).
7.3.9.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4 should be performed 
according to the Time and Events Table (Section 7.1).  


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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 14 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 4:
Table 4
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)
Other tests
Coagulation Panel including aPTT and INR
Other screening tests
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing 
potential only)
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)


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7.4.
Evaluation of Anti-Cancer Activity
Disease assessments will be made by physical examination and laboratory evaluation, 
which includes a complete blood count with differential.  Bone marrow aspiration should 
be performed if clinically indicated, and to confirm the response. Response criteria are 
listed in Appendix 10.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK2879552, GSK2879552 
metabolite(s), as deemed appropriate, and azacitidine will be collected 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.
7.5.2.
Sample Analysis
Plasma sample analysis will be performed under the control of Bioanalysis, 
Immunogenicity & Biomarkers (BIB), In Vitro/In Vivo Translation (IVIVT), Platform 
Technology and Science (PTS), GlaxoSmithKline.  Concentrations of GSK2879552, 
GSK2879552 metabolite(s), as deemed appropriate, and azacitidine will be determined in 
plasma samples using the currently approved bioanalytical methodology.  Raw data will 
be archived at the bioanalytical site.  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.
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 azacitidine in MDS as well as identifying 
indicators of sensitivity or resistance.  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 drug combinations. Similarly, pre- and on-
treatment blood and bone marrow specimens will be evaluated for target engagement, 
therapeutic 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.


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Performance of these investigations may be 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.
7.6.1.
Biomarker Analysis
All subjects will be asked to submit peripheral blood samples at baseline, during the 
study, and at the end of treatment.  All subjects will also be asked to submit fresh bone 
marrow aspirate at baseline and during the study. There is an optional bone marrow 
aspirate collection at the end of treatment.  These samples will be used to conduct 
retrospective tests to understand the mechanistic activity of GSK2879552 alone and in 
combination with azacitidine, therapeutic response and the identification of potential 
markers of sensitivity or resistance through the assessment of DNA, RNA and/or protein.  
These studies may include but are not limited to DNA methylation, transcriptomic, and 
genomic analyses.  
7.7.
Genetics
A 2 mL saliva sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic saliva sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 4 for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the Time and 
Events Schedule (Section 7.1).
8.
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.


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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.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
9.1.1.
Part 1:
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, based upon the safety, PK and efficacy profiles of GSK2879552 plus 
azacitidine in subjects with relapsed/refractory HR MDS.
9.1.2.
Part 2: Disease-Specific Expansion Cohorts
The primary goal of Part 2 is to evaluate disease-specific clinical activity in subjects with 
GSK2879552, alone or in combination with azacitidine, in adult subjects with MDS. 
Clinical activity is defined as a clinical benefit rate (% of subjects achieving CR, PR, HI 
or SD [per 2006 IWG criteria]). This will be conducted by testing the null hypothesis that 
P0<=0.3 versus the alternative that P1 ≥0.5, Subjects in Part 1 and Part 2 treated with the 
same starting dose will be analyzed together.  
The Part 2 portion of the study will employ a Bayesian predictive adaptive design [Lee, 
2008] for Arm A and Arm B separately that allows the trial to be monitored more 
frequently at multiple stages. The criteria will be based on a historically unimportant 
response rate of 30% versus a response rate of interest of 50%.  Bayesian statistics will be 
employed to calculate the predictive probability that the response rate ≥50% and ≥30% at 
interim assuming a Beta prior for the Binomial distributed data.  Predictive probability 
calculates the probability that the response rate ≥50% or ≥30% at the end of Part 2 given 
the responses that are currently being observed at interim.  It predicts what is likely to 
happen at the end of Part 2 so it is more meaningful and straightforward than posterior 
probability.  A weak prior Beta (0.005, 0.005) is used, which is equivalent to the 
information present in 0.01 subjects. The first interim analysis may be conducted when at 
least 10 subjects are recruited for each Arm. Futility interim analysis decision rules for 
the 10th to 28th evaluable subjects, specifying the number of subjects with clinical activity 
(CR, PR, HI or SD) needed for continuing enrolment or stopping for futility when total 
sample size is up to 28, is presented in Table 5.  These rules are intended as a guideline.  
Actual decisions will depend on the totality of the data.


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Table 5
Decision Making Criteria for Futility
Number of Evaluable 
Subjects 
This Number of 
Responses  to Stop 
Early for Futility
Probability of 
continuing enrolling 
when CBR=0.3
Probability of 
continuing enrolling
when CBR=0.5 
10
1
0.8507
0.9893
12
2
0.7363
0.9783
14
3
0.6242
0.9655
16
3
0.6242
0.9655
18
4
0.5739
0.9620
20
5
0.5087
0.9566
22
6
0.4414
0.9500
24
8
0.2601
0.9103
26
9
0.2059
0.8927
28
11
0.0000
0.0000
For the separate interim looks in each cohort in Part 2, the enrollment for that cohort may 
be stopped due to futility if the predictive probability that the confirmed response rate 
≥30% (historical control) is small (e.g., less than a 2% chance for a total sample size of 
28 subjects).  Enrollment may also be stopped due to futility if the equivalent of less than 
2 responses is observed in the first 10 enrolled evaluable subjects in that cohort or less 
than 3 responses are observed in the first 12 evaluable subjects.  The evaluable subject is 
defined as a subject, who has either progressed, withdrew from the study, was lost to 
follow-up, or is ongoing and has completed at least one post treatment disease 
assessment.  For example, when there are 10 evaluable subjects available at the time of 
interim analysis with only one response, then the Arm may be stop for futility.  
Otherwise, the enrolment of the respective Arm will continue to the target sample size. 
When the total sample size in a treatment arm is 28 and at least 12 responders out of 28 
subjects are observed, we can claim null hypothesis is rejected. 
No formal hypotheses are set up to compare the activity between Arm A and Arm B.  The 
CBR and ORR will be reported for both arms separately at the end of Part 2.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Part 1: Dose Escalation
The total number of subjects to be enrolled in the dose escalation phase of Part 1 will 
depend on the number of subjects needed to characterize individual dose combination 
cohorts. The sample size is not driven by statistical considerations. However, it is 
anticipated that approximately 10-12 evaluable subjects will be enrolled.


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Part 2: Expansion Cohorts
To determine the maximum sample size for Arm A or Arm B, Bayesian predictive 
adaptive design will be used for testing hypotheses:
H0: CBR≤30%
HA: CBR≥50%
When maximum sample size is 28, the design will have a Type I error () of 0.099 and 
81% power with the probability of termination is 0.90 when the treatment is futile and 
probability of early termination 0.183 when the treatment is effective (true RR=0.5).
In Part 2, a maximum of 28 subjects will be enrolled in Arm A and Arm B expansion 
cohort, respectively. If both arms enroll the maximum number of subjects, this will result 
in 56 subjects total randomized to Arm A and Arm B with 1:1 randomization ratio.
Enrollment into Arm A or Arm B may be halted early based on results from interim 
analyses incorporating emerging response data. Response data from a minimum of 10 
evaluable subjects will be required per arm before it may discontinue enrollment for 
futility. 
9.2.2.
Sample Size Sensitivity
There was no need to perform sample size sensitivity analysis.
9.2.3.
Sample Size Re-estimation or Adjustment
Sample size re-estimation is not planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
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 Crossover Population will comprise the subset of subjects in Part 1 and Part 2 who 
had intra-subject Arm A to Arm B crossover. It will be the primary population when 
summarizing data in Part 1, Part 2 crossover phase.
9.3.2.
Interim Analysis
No formal interim analysis will be performed.  Review of all available safety and 
pharmacokinetic data will be performed after completion of each dosing cohort. 


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In Part 1, to further facilitate dose escalation/de-escalation decisions, an adaptive 
Bayesian logistic regression model (BLRM) may be utilized to predict the probability of 
DLT at the dose levels yet to be tested. 
Prior distribution of the parameter for azacitidine will be calculated based on the toxicity 
data observed in the first time in human (FTIH) study of GSK2879552 where 
GSK2879552 is administered alone; similarly, prior distribution of the parameter for 
Azacitidine will be determined based on data observed in the study where Azacitidine is 
administered alone; a non-informative prior will be assumed for the other parameters 
which accounts for the combination of the two compounds.  The model will be used only 
as a guide for what further doses to study in the presence of DLTs.  The primary 
considerations for dose escalation/de-escalation will be based on the rules described in 
Section 4.3.  Further details on the model as well as prior distributions will be included in 
the Reporting and Analysis Plan (RAP).
9.3.2.1.
Part 2 Cohort Expansion
Interim data will be evaluated to monitor efficacy and safety. Enrollment may be stopped 
early for futility, should various criteria occur based on accrued data. The decision 
criteria for early stop for futility based on Bayesian Adaptive design are described in 
Section 9.1.2. The decision will be made for each individual cohort. 
The study population used for decision-making at the interim analyses during Part 2 
(Expansion Cohort) will be termed All Evaluable Subjects defined in Section 9.1.2.  This 
will be the population for Bayesian adaptive design described in Section 9.1.2 and 
summaries of response if data warrant. Any evaluable subject from Part 1 of the study 
who has the same initial dose as in Part 2 will be included in this analysis.  Because 
subjects enroll at different times, not all subjects will have been on the study long enough 
to have a single or multiple disease assessments.  Since disease assessments and are to be 
completed every 4 weeks, subjects who have at least one post-baseline disease 
assessment or have progressed or died or permanently withdraw from the study will be 
included in this population. 
9.4.
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 unlikely be informative, therefore data from all participating centers will 
be pooled prior to analysis.


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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.
9.4.1.
Clinical Activity Analyses
The clinical benefit rate (CBR) is defined as the percentage of subjects with a  Complete 
Remission (CR), marrow complete remission (mCR) or a Partial Remission (PR) or a 
Hematologic Improvement (HI) or Stable Disease (SD) at any time as per disease-
specific criteria (Appendix 5 and Appendix 6).  Subjects with unknown or missing 
response will be treated as non-responders, i.e. these subjects will be included in the 
denominator when calculating the percentage. The number and types of responses, as 
outlined in IWG criteria [Cheson, 2006], will be listed and summarized separately, as 
appropriate.
The ORR will be reported at the interim and final analysis for each arm specified in Part 
2 as well as all evaluable subjects in Part 1 treated at or above RP2D. Part 1 and Part 2 
subjects who received the same dose within the same treatment arm may be combined 
together in the analysis. The estimates along with 95% exact confidence interval (CI) will 
be provided. 
The CBR and ORR differences between the two cohorts will be provided along with 
corresponding 95% CI.  A chi-square test will be used to test for differences between 
arms if data warrant.
Duration of response is defined as the subset of subjects who show a response (CR, 
mCR, PR, or HI), the time from first documented evidence of response until the first 
documented sign of disease progression or death. Duration of response will be 
summarized descriptively for each arm, if data warrant, using Kaplan-Meier medians and 
quartiles. Details on rules for censoring will be provided in the RAP.
For the analysis of Progression-free survival (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, mCR, PR, HI 
or SD) prior to the initiation of therapy.  Progressive disease (PD) will also be defined per 
standard criteria.  Otherwise, if the subject does not have a documented date of events, 
PFS will be censored at the date of the last adequate assessment. Further details on rules 
for censoring will be provided in the RAP.  PFS will be summarized by arm and dose 
using Kaplan-Meier quantile estimates along with 2-sided 95% CIs at the time of final 
analysis, if data warrant.
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. OS will be 


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summarized by arm and dose using Kaplan-Meier quantile estimates along with 2-sided 
95% CIs at the time of final analysis, if data warrant.
9.4.2.
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).
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 
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.


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9.4.2.1.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy. 
Extent of exposure of GSK2879552 and azacitidine will depend on tolerability of the 
subjects to the doses administered and the course of their disease. The number of subjects 
exposed to GSK2879552 and azacitidine will be summarized for each dose level 
administered.
9.4.2.2.
Adverse Events
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.
9.4.2.3.
Clinical Laboratory Evaluations
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 criterion will be 
summarized using proportions.  Further details will be provided in the Reporting and 
Analysis Plan (RAP).
9.4.2.4.
Other Safety Measures
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).
9.4.3.
Pharmacokinetic Analyses
9.4.3.1.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK. 


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Population Pharmacokinetics
Plasma concentration-time data for GSK2879552 from all Arms and Parts may be 
combined with data from other studies and may be 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 (e.g. Cmax, AUC and Cav = AUC/) and identify relevant 
covariates (e.g., age, weight, or disease related covariates). Results may be reported 
separately.
9.4.3.2.
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the PK concentration data will be the responsibility of Discovery 
Biometrics, GSK.
Plasma concentration-time data for GSK2879552, GSK2879552 metabolite(s) as deemed 
appropriate, and azacitidine will be listed by dose and arm and summarized using 
descriptive statistics (n, mean, standard deviation [SD], median, minimum and 
maximum) by planned relative assessment time. Mean and/ or median values may be 
plotted over time. 
9.4.4.
Pharmacokinetic/Pharmacodynamic Analyses
Observed or predicted concentrations will be combined with safety and/or efficacy, 
measures of interest to examine potential exposure response relationships.
Quantitative safety parameters will be plotted graphically against summary exposure 
measures (eg; Cmax, Ctrough, and Cav). Where evidence of a signal is seen, linear and 
non-linear mixed effect models will be fitted to the data to estimate PK/PD parameters of 
interest; e.g. slope, baseline (E0), or exposure producing 50% of the maximum effect 
(EC50), and maximum effect (Emax).
Overall efficacy data 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.
9.4.4.1.
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 disease biology 
or between therapeutic 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.


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9.4.4.2.
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.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research. 

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  


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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.


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
GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 


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ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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11.
REFERENCES
Adamo A, Sesé B, Boue S, Castaño J, Paramonov I, Barrero MJ, et al. (2011) LSD1 
regulates the balance between self-renewal and differentiation in human embryonic stem 
cells. Nat Cell Biol 13(6): 652-60
Cheson Bruce D, Peter L. Greenberg, John M. Bennett, Clinical application and proposal 
for modification of the InternationalWorking Group (IWG) response criteria in 
myelodysplasia.Blood.2006;108(2):419-25.
Duong VH, Lin K, Reljic T, Kumar A., Al Ali NH, Lancet JE, et al. Poor outcome of 
patients with myelodysplastic syndrome after azacitidine treatment failure. Clin 
Lymphoma Myeloma Leuk 2013;13(6):711-5.
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V., Finelli C., Giagounidis A., et al.  
Efficacy of azacitidine compared with that of conventional care regimens in the treatment 
of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. 
Lancet Oncol.2009;10:223-32.
GlaxoSmithKline Document Number 2013N168888_02. GSK2879552 Investigator's 
Brochure.  Report Date: 29-FEB-2016.
Greenberg P, Cox C., LeBeau MM., Fenaux P., Morel P., Sanz G.,et al. International 
scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997; 
89:2079-88.
Harris,W.J., Huang,X., Lynch,J.T., Spencer,G.J., Hitchin,J.R., Li,Y., et al. The histone 
demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. 
Cancer Cell.2012;21(4):473-87.
Jabbour E, Garcia-Manero G, Batty N, Shan J., Brien S., Cortes J., et al. Outcome of 
patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 2010; 
116:3830–3834.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA,et al. 
Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 1779-1784. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 2008; 5(2):93-106.
Mufti GJ., Potter V. Myelodysplastic syndromes: who and when in the course of disease 
to transplant. Hematology Am Soc Hematol Educ Program. 2012;2012:49-55.
NCI Common Terminology Criteria for Adverse Events, Version 4, DCTD, NCI, NIH, 
DHHS, 28 May 2009.


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Prebet T, Gore SD, Esterni B, Gardin C., Itzykson R., Thepot S., et al. Outcome of high-
risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 2011; 
29:3322–27.
Pierre Fenaux, Lionel Adès,  Raphael Itzykson,  Myelodysplastic syndromes. The 
Lancet.2014;383( 9936):p2239–52.
Radich,J.P., Dai,H., Mao,M., Oehler,V., Schelter,J., Druker,B., et al. Gene expression 
changes associated with progression and response in chronic myeloid leukemia. Proc. 
Natl. Acad. Sci. U. S. A. 2006; 103(8):2794-99.
Rhodes,D.R., Kalyana-Sundaram,S., Mahavisno,V., Varambally,R., Yu,J., Briggs,B.B., 
et al . Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer 
gene expression profiles. Neoplasia.2007;9(2):166-80.
Rollinson DE., Howlader N., Smith MT., Strom SS., Merritt WD., Ries LA., et al. 
Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in 
the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 
2008;112 (1):45-52.
Saleque, S., Kim, J., Rooke, H.M., Orkin, S.H.  Epigenetic regulation of hematopoietic 
differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1.  
Mol Cell 2007; 27: 262-272.
Schenk,T., Chen,W.C., Gollner,S., Howell,L., Jin,L., Hebestreit,K, et al. . Inhibition of 
the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation 
pathway in acute myeloid leukemia. Nat. Med. 2012;18(4):605-11.
Shi, Y., Sawada, J., Sui, G., Affar el, B., Whetstine, J.R., Lan, F.,et al. . Coordinated 
histone modifications mediated by a CtBP co-repressor complex. Nature.2003;
422(6933):735–8.
Stone RM. How I treat patients with myelodysplastic syndromes. Blood. 2009 
;113(25):6296-303
Vardiman, James W. , Thiele Juergen, Arber Daniel A., Brunning Richard D., Borowitz 
Michael J., Porwit Anna, et al "The 2008 revision of the World Health Organization 
(WHO) classification of myeloid neoplasms and acute leukemia: rationale and important 
changes." Blood.2009;114(5):937-51.
Vidaza Prescribing Information, VIDAZA (azacitidine for injection), for subcutaneous or 
intravenous use Initial U.S. Approval: 2004, Revised date 12/2015.
Wouters,B.J., Lowenberg,B., Erpelinck-Verschueren,C.A., van Putten,W.L., Valk,P.J., 
and Delwel,R. . Double CEBPA mutations, but not single CEBPA mutations, define a 
subgroup of acute myeloid leukemia with a distinctive gene expression profile that is 
uniquely associated with a favorable outcome. Blood.2009; 113 (13):3088-91.


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You A, Tong, J.K., Grozinger, C.M., and Schreiber, S.L. CoREST is an integral 
component of the CoREST- human histone deacetylase complex. Proc. Natl. Acad. Sci. 
USA.2001; 98(4): 1454–58.
Zeidan AM, Kharfan-Dabaja MA, Komrokji RS. Beyond hypomethylating agents failure 
in patients with myelodysplastic syndromes. Current Opinion in Hematol.  2014; 
21(2):123-30.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE(s)
Adverse Event(s)
AML
Acute Myeloid Leukemia
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
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-)
Area Under the Concentration-time curve over the dosing interval
-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood Urea Nitrogen
Cav
Average concentration
CBC
Complete Blood Count
CfDNA
Circulating cell free DNA
CKD-EPI 
equation
The Chronic Kidney Disease Epidemiology collaboration equation 
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
Cτ
Pre-dose (trough) concentration at the end of the dosing interval
CO2
Carbon dioxide
CoREST
CoRepressor for Element-1-Silencing Transcription factor
CPMS
Clinical Pharmacokinetic Modeling and Simulation
CR
Complete Response
CRM
Continual Reassessment Method
CT
Computed Tomography 
CV
Coefficient of Variance
DAC
5-Aza-2’-deoxycytidine
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)


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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
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate 
GGT
Gamma Glutamyl Transferase
GI
Gastrointestinal 
GLP
Good Laboratory Practices
GSK
GlaxoSmithKline
GVHD
Graft-versus-Host-Disease
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 
HMA
Hypomethlating Agent
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
IPSS-R
The Revised International Prognostic Scoring System
IRB
Institutional Review Board
IU
International Unit
IV
Intravenous 
IWG
International Working Group
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


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MATE-1
Multidrug And Toxin Extrusion Transporter 1
uM 
Micromole
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MOCA
Montreal Cognitive Assessment
MPV
Mean Platelet Volume
MRI
Magnetic Resonance Imaging 
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum Tolerated Dose
MUGA
Multigated  (radionuclide) angiogram
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
N-CRM
The Neuenschwander -Continuous Reassessment Method 
ng
Nanogram 
nM
Nanomole
NOAEL
No Observed Adverse Effect Level
NSAIDs
Non-Steroidal Anti-Inflammatory Drug 
NYHA
New York Heart Association
PARP
poly ADP ribose polymerase
PCI
Potential Clinical Importance
PCR
Polymerase Chain Reaction 
PD
Progressive Disease or Pharmacodynamic
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)
sc
subcutaneous
SCLC
Small Cell Lung Cancer
SD
Standard Deviation 
SPM
Study Procedures Manual
STD
Severely Toxic Dose


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


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to 
be related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study 
treatment

Report the event to GSK within 24 
hours

Complete the liver event CRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2

Perform liver event follow up 
assessments 

Monitor the subject until liver 
chemistries resolve, stabilize, or return 
to within baseline (see MONITORING
below)

Do not restart/rechallenge subject with 
study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (refer to Appendix 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained approximately 48h after 
last dose5

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with differential 
to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications


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3 for more details)

If restart/rechallenge is not granted, 
permanently discontinue study treatment 
and may continue subject in the study for 
any protocol specified follow up 
assessments
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) 
and perform liver event follow up 
assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin)
and perform liver event follow up 
assessments within  24-72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct high pressure 
liquid chromatography (HPLC) assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that subject if ALT 
3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is 
not required and the threshold value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such 
as fever, rash or eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or 
if unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for 
sample handling and shipping are in the SRM.


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Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity and who can be monitored 
weekly for 4 weeks

Notify the GSK medical monitor within 24 
hours of learning of the abnormality to discuss 
subject safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return 
to within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN 
and bilirubin <2xULN, monitor subjects twice 
monthly until liver chemistries normalize or 
return to within baseline.
1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest 
and prior to first dose of study treatment
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 


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12.3.
Appendix 3: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
1.
Rechallenge Following Liver Stopping Events that are Possibly Related to Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies.Andrade, 2009 Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT >3xULN, bilirubin 
>2xULN (direct bilirubin >35% of total), or INR>1.5

serious adverse event or fatality has earlier been observed with drug rechallenges 
Papay, 2009, Hunt, 2010

evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment3)
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.
Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a 
subject who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available.  

Ethics Committee or Institutional Review Board approval for rechallenge with 
study treatment must be obtained, as required.   


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
If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until 
stable liver chemistries have been demonstrated and then standard laboratory 
monitoring may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board 
as required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Appendix 5.
2.
Restart Following Transient Resolving Liver Stopping Events NOT Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

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.  


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
The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the 
study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume 
as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board 
as required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Appendix 5.
References:
1.
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
2.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.
3.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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12.4.
Appendix 4: Genetic Research
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and 
IRB/IEC allow, a saliva sample will be collected for DNA analysis

DNA samples will be used for research related to GSK2879552 or GSK2879552 
in combination with azacitidine or any concomitant medicines, or MDS and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests) related to GSK2879552 or GSK2879552 in combination with 
azacitidine or study treatments of this drug class, and MDS. Genetic research may 
consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire genome (as appropriate)

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

DNA samples will be analyzed for describe planned analyses. Additional analyses 
may be conducted if it is hypothesized that this may help further understand the 
clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to GSK2879552 or GSK2879552 in combination 
with azacitidine or study treatments of this class. The results of genetic analyses 
may be reported in the clinical study report or in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK2879552 or GSK2879552 in 
combination with azacitidine or study treatments of this class or MDS continues 
but no longer than 15 years or other period as per local requirements.


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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 


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the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.


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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology, if available.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.


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12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.6.
Appendix 6: 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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12.7.
Appendix 7: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
This appendix is optional and should ONLY be included if study treatment is supplied 
and information on pregnancies is to be collected for female subjects or for female 
partners of male study subjects. Female subjects with non-reproductive potential are 
defined as below:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable 
cases a blood sample with simultaneous follicle stimulating hormone (FSH) and 
estradiol levels consistent with menopause (refer to laboratory reference ranges for 
confirmatory levels)].  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal 
status prior to study enrolment.
12.7.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 


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personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
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 that subjects understand how to properly use these methods of contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential.
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
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 that subjects understand how to properly use these methods of contraception.
12.7.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who 
becomes pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK 
within 2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 
to 8 weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for procedure.


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
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator will be reported to 
GSK as described in Appendix 5. While the investigator is not obligated to 
actively seek this information in former study participants, he or she may learn of 
an SAE through spontaneous reporting.
Any female subject who becomes pregnant while participating 

will be withdrawn from the study

Investigator will attempt to collect pregnancy information on any female partner 
of a male study subject who becomes pregnant while participating in this study.   

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate 
form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of 
fetal status (presence or absence of anomalies) or indication for procedure.
12.7.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 


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FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Investigator Brochure for GSK2879552 [GlaxoSmithKline Document Number 
2013N168888_02]. Report Date: 29-FEB-2016.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.8.
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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12.9.
Appendix 9: Country Specific Requirements
No country-specific requirements exist.


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12.10.
Appendix 10: IWG CRITERIA FOR RESPONSE
Category
Response Criteria
Complete Remission
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell 
linesa
Persistent dysplasia will be noteda,b
Peripheral blood (Response must be maintained for at least 4 weeks)
Hgb ≥ 11 g/dL
Platelets ≥ 100 Gi/L
Neutrophils ≥  1.0 Gi/Lb
Blasts 0%
Partial Remission
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥ 50% over pre-treatment but still > 
5%
Cellularity and morphology not relevant
Marrow CRb
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-
treatmentb
Peripheral blood: if HI responses, they will be noted in addition to 
marrow CRb
HI
Erythroid (HI-E):
hgb increase of > 1.5 g/dL
decrease of > RBC transfusions/8weeks versus pretreatment requirement 
in previous 8 weeks; only RBC transfusions given for a pretreatment 
Hgb of < 9.0 g/dL count
Platelet (HI-P):
increase of > 30,000/mL (starting with > 20,000/mL)
increase from < 20,000/mL to >20,000/mL by > 100%
Neutrophil (HI-N):
increase of > 100% and > 500/uL
Stable Disease
Failure to achieve at least PR, but no evidence of progression > 8 wks
Disease Progression
For subjects with:

Less than 5% BM blasts: ≥ 50% increase in blasts to > 5% blasts

5%-<10% BM blasts: ≥ 50% increase to > 10% blasts

10%-<20% BM blasts: ≥ 50% increase to > 20% blasts

20%-30% BM blasts: ≥ 50% increase to > 30% blasts
Any of the following:

At least 50% decrement from maximum remission/response in 
granulocytes or platelets

Reduction in Hgb by 2 g/dL

Transfusion dependence
Non-evaluable
Subject does not meet any of the above criteria
BM = bone marrow ; CR = complete remission; Hgb = hemoglobin;; PR = partial remission
a.
Dysplastic changes should consider the normal range of dysplastic changes (modification).
b.
Modification to IWG response criteria [Cheson, 2006].


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12.11.
Appendix 11: Protocol Changes
12.11.1.
Protocol Changes for Amendment 1 (08-MAY-2017) from the 
original Protocol (15-Jul-2016)
Where the Amendment applies
Amendment 1 applies to all sites.
Summary of Amendment Changes with Rationale
Addition of 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. Minor clarifications, correction of typographical 
errors, reformatting of tables, administrative and grammatical changes to text and Time 
and Events tables/footnotes.
List of Specific Changes: (bold indicates text added and strikethrough indicates text 
removed)
General change: Abbreviations were defined at first instance throughout the 
document.
List of Authors
Rationale for Change
The list of authors was updated based on internal GSK team personnel changes.
Revised Text
Oncology, Clinical, PA, USA
Biomarker discovery, Epigenetics DPU, PA, USA
Oncology Epigenetics Clinical, PA, USA
Clinical Pharmacology Modeling & Simulation, PA, USA
Clinical Biomarkers and Translational Research, PA, USA
Biology, Epigenetics DPU, PA, USA
Discovery Biometrics, PA, USA
Biology, Epigenetics DPU, PA, USA
Oncology Epigenetics Clinical, PA, USA
Global Clinical Safety & Pharmacovigilance, PA, USA 
In Vivo In Vitro Translation, PA, USA
Oncology Epigenetics Clinical, PA, USA
Discovery Biometrics, PA, USA
PPD


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Sponsor Signatory
Rationale for Change
Designation of the sponsor was updated. 
Revised Text
 MD, Ph.D.
Senior Vice President, Epigenetics DPU Head SVP. TA I lead, Oncology R&D
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Rationale for Change
The medical monitoring information was updated to reflect the current contact 
information for medical monitoring. 
Revised Text
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary 
Medical 
Monitor 
MD, MPH
 
MD, PhD
GlaxoSmithKline
1250 South Collegeville 
RoadRd
Mailstop UP 44310
Collegeville, PA 19426, 
USA
  
Secondary 
Medical 
Monitor
MD, 
PhD
 
MD, MPH
GlaxoSmithKline
1250 South Collegeville 
Road Rd
Mailstop UP 44310
Collegeville, PA 19426, 
USA
 
Investigator Protocol Agreement Page
Rationale for Change
Investigator address and Phone number details were added.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Revised Text
Investigator Name: _________________________
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
Synopsis
Rationale for Change: References were removed from the synopsis section as 
synopsis need to be a stand alone document. Also, study stopping criteria was modified 
for clarification.
Revised Text
Overall Design
2nd and 3rd paragraph
Bayesian Logistic Regression Model (BLRM) prediction on Dose-Limiting Toxicity
(DLT) rate may also be provided at dose escalation meetings as the supplementary 
analysis to 3+3 design (See Section 4.3.2. for more details).  Once the RP2D of 
GSK2879552 for MDS is confirmed in both Arms, Part 2 enrolment will open. Each 
treatment cycle is 28 days and subjects experiencing disease progression on monotherapy 
(Arm A) will be allowed to cross over (to Arm B) to be treated with the combination at 
the RP2D.   
The statistical design and number of subjects to be enrolled in Part 2 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. The study will 
stop only for futility, while also taking into account subject and study termination
criteria as defined in the protocol. Final decisions on stopping enrolment will depend 
on the totality of the data collected.


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Type and Number of Subjects
Point 9, 10, 11 and Diagnostic assessment
GENDER and REPRODUCTIVE POTENTIAL
10. Women of childbearing potential must have a negative serum pregnancy test within 7 
days of first dose of study treatment and agree to use effective contraception, as defined 
in Appendix 7 of this protocol, during the study and for 7 days following the last dose of 
study treatment.
11. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception, as defined in Appendix 7 of this 
protocol, 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.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. AML according to WHO criteria (i.e. bone marrow blasts >20%) [Vardiman, 2009].
2. Active hepatitis B or hepatitis C treatment
3. Baseline (pre-dose Day 1) Montreal Cognitive Assessment (MOCA) score of 22 or 
lower
4.11.1 Risk Assessment
Rationale for change
Text was added to clarify the term Baseline to mean pre-dose Day 1
LABORATORY
9. 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


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Revised Text
Potential Risk of 
Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
GSK2879552 
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
-
Montreal Cognitive Assessment 
(MOCA) at baseline (pre-dose Day 1)
and weekly for the first 4 weeks and 
monthly thereafter.
-
Subjects with baseline (pre-dose Day 1)
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 (pre-dose 
Day 1) 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
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
5.2
Exclusion Criteria
Rationale for Change
Text was added to clarify the term Baseline to mean pre-dose Day 1
Revised Text
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
1. AML according to WHO criteria (i.e. bone marrow blasts >20%)
2. Active hepatitis B or hepatitis C treatment
3. Baseline (pre-dose Day 1) Montreal Cognitive Assessment (MOCA) score of 22 or 
lower


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5.4.3 Mental Status Stopping Criteria
Rationale for Change
Stopping criteria were updated based on the FDA mandated language resulting from a 
recent Dear Investigator Letter (DIL) of encephalopathy dated 24 Apr 17 reported in 
LSD1 study 200858
Revised Text
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) Montreal 
Cognitive Assessment (MOCA) score (Section 7.3.7)

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 (pre-dose Day 1).

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 (pre-dose Day 1).
6.
STUDY TREATMENT
6.2.1
GSK2879552
Rationale for Change
Only two doses were to be used in the study – 0.5 mg and 2 mg. Table was updated to 
remove 5 mg dose. 


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Revised Text
Product name:
GSK2879552 Capsule
Formulation 
description:
GSK2879552 capsules contain 0.5 mg or 2 mg, 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 (i.e. no food intake from 2 hours before dosing 
until 1 hour after dosing) 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.
7.1
Time and Events Table for Arm A – Part 1
Rationale for Change
Table was updated for correction of superscripts in tables, simplification/clarification of 
wording in footnotes and correction of numbering in footnotes to match tables.
Revised Text


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SC
R
Cycle 1 (28 days)
C2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment Bi-
Monthly 
Follow-Up16
D 1
D2
D4
D7
D 15
D22
Office Visit for Arm A (mono)
X
X
X1
X
X
X
X
C2: D1, 7, 15 and 22 
C3 and after: D1
X
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------ Daily or per dosing schedule --------------------
Azacitidine dosing
X14
Review subject dosing diary
X
X
Day 1
X
X
GSK2879552 Drug 
Dispensing
X
Day 1
Complete physical exam
X
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
X
Vital Signs
X
X7
X
X
Day 1
X
X
Height and weight6
X
X7
X
Day 1
X
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
X
HIV, HBV and HCV Ab 
testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 15 and 22 
C3 and after: D1
X
X


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SC
R
Cycle 1 (28 days)
C2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment Bi-
Monthly 
Follow-Up16
D 1
D2
D4
D7
D 15
D22
Chemistry Panel including 
LFT
X
X7
X12
X
X
Day 1
X
X
Coagulation Panel including a 
PTT and INR
X
X12
x
X
Day 1
X
X
PK Blood samples
X1
X1
X8
X2
X5
X8
C2: D1, 7, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
X
Blood samples for exploratory 
studies (peripheral blood)3, 11
X
X
X
X
Day 1
X
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X17
as clinically indicated 
X18
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS  Assessment
X
1.
A blood sample will be collected for GSK2879552 PK analysis on D1 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, a blood sample for 
azacitidine PK analysis will be collected at the same time points. An additional optional PK sample will be collected at 24 hours post Day 1 dose for GSK2879552 
measurement in the combination arm, but it is optional in mono therapy arm.


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2.
A blood sample will be collected for GSK2879552 PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, a blood sample for 
azacitidine PK analysis will be collected at the same time points.
3.
Samples should be collected at pre-dose. 
4.
For women of child bearing potential only. Serum pregnancy test is required for screening, crossover and EOT visits. Urine pregnancy test is adequate during 
study visits.
5.
A blood sample will be collected for GSK2879552 PK analysis on D15 at pre-dose and 0.5-1 hr post dose. 
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 for GSK2879552 should be taken pre-dose. PK sample will not be collected beyond 48 weeks. 
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.
Collection of exploratory sample (peripheral blood and/or BMA) time points may be terminated at the sponsor’s discretion 
12.
Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
13.
PK blood sample should be collected prior to dosing on biopsy days. 
14.
Azacitidine dosing can start on Day 1 of the next cycle after the cross over visit is completed. 
152.
Optional for all subjects
163.
Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up will 
continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
174.
The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at the time of crossover, unless the sample 
collection is stopped per sponsor discretion; the PK blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is collected.  The PK 
corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
185.
A mandatory BM sample will be collected at the time of the crossover visit to establish the new baseline.  A window of 14 days is allowed for this BM 
assessment.   


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Time & Events Table for Arm A - Part 2
SCR
Cycle 1 (28 days)
Cycle 2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment Bi-
monthly 
Follow-Up16
D 1
D4
D 7
D 15
D22
Office Visit for Arm A (mono)
X
X
X
X
X
X
C2: D1, 7, 15 and 22 
C3 and after: D1
X
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ----------------------- Daily or per dosing schedule --------------------
Azacitidine dosing14
X14
Review subject dosing diary
X
X
Day 1
X
X
GSK2879552 Drug 
Dispensing 
X
Day 1
Complete physical exam
X
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
X
Vital Signs
X
X7
X
X
Day 1
X
X
Height and weight6
X
X7
X
Day 1
X
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
X
HIV, HBV  and HCV Ab testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 15 and 22 
X
X


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SCR
Cycle 1 (28 days)
Cycle 2 and beyond
Crossover 
Visit
End of 
Treatment 
Visit 
Post 
Treatment Bi-
monthly 
Follow-Up16
D 1
D4
D 7
D 15
D22
C3 and after: D1
Chemistry Panel including LFT
X
X7
X12
X
X
Day 1
X
X
Coagulation Panel including a 
PTT and INR
X
X12
x
X
Day 1
X
X
PK Blood samples
X1
X8
X5
X2
X8
C2: D1, 7, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
X
Blood samples for exploratory 
studies (peripheral blood)3, 11
X
X
X
X
Day 1
X
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X17
as clinically indicated 
X18
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS Assessment
X
1.
A blood sample will be collected for PK analysis on D1 at pre-dose, 0.5hr, 1 hr and 3 hrs post dose. In the combination cohort, a blood sample for azacitidine PK 


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analysis will be collected at the same time points.
2.
A blood sample will be collected for PK analysis on D15 at pre-dose and between 0.5 to 1 hour.
3.
Samples should be collected at pre-dose. 
4.
For women of child bearing potential only. Serum pregnancy test is required for screening, crossover and EOT visits. Urine pregnancy test is adequate during 
study visits.
5.
A blood sample will be collected for PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, a blood sample for azacitidine PK 
analysis will be collected at the same time points.
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 for GSK2879552 should be taken pre-dose around the same time as CBC. PK sample will not be collected beyond 48 weeks
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. Collection of exploratory sample (peripheral blood and/or BMA) time points  may be terminated at the sponsor’s discretion
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
13. PK corresponding blood sample should be collected prior to dosing
14. Azacitidine dosing can start on Day 1 of the next cycle after the cross over visit is completed.
15. Optional for all subjects
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up will 
continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection is 
stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is collected.  The 
PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
18. A mandatory BM sample will be collected at the time of the crossover visit to establish the new baseline.  A window of 14 days is allowed for this BM assessment.  


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Time and Events Table – Arm B (Combination with Azacitidine), Part 1
SCR
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post Treatment Bi-
Monthly Follow-
Up16
D 1
D2
D4
D719
D 15
D22
Office Visit for Arm B (combo)
X
X
X
X
X
X
X
C2: D1- 719, 15 and 22 
C3 and after: D1-719
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------ Daily or per dosing schedule --------------------
Azacitidine dosing14
<--Days 1-7--->
Days 1-7
Review subject dosing diary
X
X
Day 1
X
GSK2879552 Drug Dispensing 
X
Day 1
Complete physical exam
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
Vital Signs
X
X7
X
X
Day 1
X
Height and weight6
X
X7
X
Day 1
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
HIV, HBsAg and HCV Ab 
testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 19, 15 and 22 
C3 and after: D1
X


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SCR
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post Treatment Bi-
Monthly Follow-
Up16
D 1
D2
D4
D719
D 15
D22
Chemistry Panel including LFT
X
X7
X12
X
X
Day 1
X
Coagulation Panel including a 
PTT and INR
X
X12
x
X
Day 1
X
PK Blood samples
X1
X1
X8
X2
X5
X8
C2: D1, 719, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
Blood samples for exploratory 
studies (peripheral blood)3, 11
X
X
X
X
Day 1
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease 
assessment17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X18
as clinically indicated 
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
OS/PFS Assessment
X
1.
A blood sample will be collected for GSK2879552 and azacitidine. PK analysis on D1 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, a 
blood sample for azacitidine PK analysis will be collected at the same time points. An additional PK sample will be collected at 24 hours post Day 1 dose for 
GSK2879552 measurement in the combination arm, but it is optional in mono therapy arm.
2.
A blood sample will be collected for GSK2879552 and azacitidine. PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, a 


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blood sample for azacitidine PK analysis will be collected at the same time points.
3.
Samples should be collected at 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.
A blood sample will be collected for GSK2879552 PK analysis on D15 at pre-dose and 0.5-1 hr post dose. 
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 for GSK2879552 should be taken pre-dose. PK sample will not be collected beyond 48 weeks. 
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. Collection of exploratory sample (peripheral blood and/or BMA) time points  may be terminated at the sponsor’s discretion
12. Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7 or the last day of Azacitidine in the cycle.
13. PK corresponding blood sample should be collected prior to dosing
14. Azacitidine dosing on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case.
15. Optional for all subjects
16. Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up will 
continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
17. The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection is 
stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is collected.  The 
PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
18. A window of 14 days is allowed for BM exam. Subjects who progressed to AML and cross over to Arm B will be required to have bone marrow for disease 
assessment prior to the start of combination dosing  
19. All procedures scheduled on Day 7 visit (of any cycle) should move to Day 9, if azacitidine is given on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) instead of Days 
1-7. 


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Time and Events Table - Arm B (Combination with Azacitidine), Part 2
SCR
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post Treatment 
Bi-monthly 
Follow-Up16
D 1
D4
D718
D 15
D22
Office Visit for Arm B (combo)
X
X
X
X
X
X
C2: D1- 718, 15 and 22 
C3 and after: D1-7
X
Informed consent
X
Demography
X
Medical history
X
Disease characteristics
X
GSK2879552 Dosing9
< ------------------------- Daily or per dosing schedule ---------------------
Azacitidine dosing14
<--Days 1-7--->
Days 1-7
Review subject dosing diary
X
X
Day 1
X
GSK2879552 Drug Dispensing 
X
Day 1
Complete physical exam
X
X
Brief physical exam
X7
X
Day 1
Montreal Cognitive 
Assessment
X
X
X
X
X
Day 1
ECOG PS
X
X7
X
Day 1
X
Vital Signs
X
X7
X
X
Day 1
X
Height and weight6
X
X7
X
Day 1
X
ECHO/MUGA
X
12-lead ECGs
X
X7
X
Day 1
X
HIV, HBsAg and HCV Ab 
testing
X
CBC
X
X7
X12
X
X
C2: D1, 712, 18, 15 and 22 
C3 and after: D1
X


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SCR
Cycle 1 (28 days)
Subsequent Cycles
End of Treatment 
Visit 
Post Treatment 
Bi-monthly 
Follow-Up16
D 1
D4
D718
D 15
D22
Chemistry Panel including LFT
X
X7
X12
X
X
Day 1
X
Coagulation Panel including a 
PTT and INR
X
X12
x
X
Day 1
X
PK Blood samples
X1
X8
X5
X2
X8
C2: D1, 718, 15 and 22 
D1 of C3-C128
Pregnancy test4
X
Day 1
X
Blood samples for exploratory 
studies (peripheral blood)3, 11
X
X
X
X
Day 1
X
Bone marrow aspirate for 
exploratory studies 11
X
At time of disease assessment17
X15
Disease assessment
X
Day 1
X
Bone marrow for disease 
assessment
X19
bone marrow if clinically indicated 
X15
PGX samples (saliva sample)
X
PK blood sample 
(corresponding with 
exploratory BMA)13
X17
X17
Transfusion Need 
Assessment10
X
X
X
X
D1
Adverse Events
Continuous
Con Meds
Continuous
Survival Assessment
X
1.
A blood sample will be collected for GSK2879552 and azacitidine. PK analysis on D1 at pre-dose, 0.5hr, 1 hr and 3 hrs post dose. In the combination cohort, 
a blood    sample for azacitidine 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 and between 0.5 to 1 hour.


2016N275425_01
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3.
Samples should be collected at 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.
A blood sample will be collected for GSK2879552 and azacitidine. PK analysis on D7 at pre-dose, 0.5, 1 hr, and 3 hrs post dose. In the combination cohort, 
a blood sample for azacitidine PK analysis will be collected at the same time points.
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 for GSK2879552 should be taken pre-dose around the same time as CBC. PK sample will not be collected beyond 48 weeks
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.
Collection of exploratory sample (peripheral blood and/or BMA) time points may be terminated at the sponsor’s discretion
12.
Safety laboratory blood samples (CBC, chemistry and coagulation panel) should be collected post dose on Day 7.
132.
PK corresponding blood sample should be collected prior to dosing
143.
Azacitidine dosing on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) may be allowed on a case by case.
154.
Optional for all subjects
165.
Subjects are followed every 2 months to collect the survival, PFS data and the start of new treatment via chart review, or phone call contact. The follow-up will 
continue until death, lost to follow-up, withdrawal of consent or up to 12 months from end of treatment visit, whichever occurs first.
176.
The exploratory BM sample is collected whenever the bone marrow is done for disease assessment and/or at time of crossover, unless the sample collection 
is stopped per sponsor discretion; the PK corresponding blood sample will be collected pre-dose at the crossover visit if the exploratory BM sample is collected.  The 
PK corresponding blood sample will not be collected if a regularly scheduled PK sample is already being collected during the visit. 
187.
All procedures scheduled on Day 7 visit (of any cycle) should move to Day 9, if azacitidine is given on Mon-Fri (Days 1-5) and Mon-Tue (Days 8-9) instead of 
Days 1-7. 
198.
A window of 14 days is allowed for BM exam. Subjects who progressed to AML and cross over to Arm B will be required to have bone marrow for disease 
assessment prior to the start of combination dosing  


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7.7
Genetics
Rationale for Change
Text was updated to reflect use of saliva, in place of blood for genetic sample collection.
Revised Text
2nd paragraph
A 2 mL saliva sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic saliva blood sample may 
be requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
11.
References
Rationale for Change
Format of references was updated as per the GSK protocol template standards..
Revised Text
Adamo A, Sesé B, Boue S, Castaño J, Paramonov I, Barrero MJ, et al Izpisúa Belmonte 
JC. (2011) LSD1 regulates the balance between self-renewal and differentiation in human 
embryonic stem cells. Nat Cell Biol 13(6): 652-60
Cheson Bruce D, Peter L. Greenberg, John M. Bennett. Clinical application and proposal 
for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood. 2006;108(2):419-25. BLOOD, 15 JULY 2006
Duong VH, Lin K, Reljic T, Kumar A., Al Ali NH, Lancet JE, et al. Poor outcome of 
patients with myelodysplastic syndrome after azacitidine treatment failure. Clin 
Lymphoma Myeloma Leuk 2013;13(6):711-5
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V., Finelli C., Giagounidis A., et al.  
Efficacy of azacitidine compared with that of conventional care regimens in the treatment 
of higher-risk myelodysplastic syndromes: a randomized, open-label, phase III study. 
Lancet Oncol. 2009; 10:223-232.
Greenberg P, Cox C., LeBeau MM., Fenaux P., Morel P., Sanz G., et al. International 
scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997; 
89:2079-88.


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Harris,W.J., Huang,X., Lynch,J.T., Spencer,G.J., Hitchin,J.R., Li,Y., et al Ciceri,F., 
Blaser,J.G., Greystoke,B.F., Jordan,A.M., Miller,C.J., Ogilvie,D.J., and Somervaille,T.C.
(2012). The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 
leukemia stem cells. Cancer Cell.2012; 21(4):473-487.
Jabbour E, Garcia-Manero G, Batty N, Shan J., Brien S., Cortes J., et al. Outcome of 
patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer 2010; 
116:3830–3834.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. Davern 
TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 
1779-1784. 
Prebet T, Gore SD, Esterni B, Gardin C., Itzykson R., Thepot S., et al. Outcome of 
high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 
2011; 29:3322–3327.
Prof Pierre Fenaux, MD, Lionel Adès, MD, Raphael Itzykson, MD, Myelodysplastic 
syndromes. Published Online: 20 March 2014. The Lancet.2014; Volume 383, No
(9936):p2239–2252, 28 June 2014.
Radich,J.P., Dai,H., Mao,M., Oehler,V., Schelter,J., Druker,B., et al Sawyers,C., 
Shah,N., Stock,W., Willman,C.L., Friend,S., and Linsley,P.S. (2006). Gene expression 
changes associated with progression and response in chronic myeloid leukemia. Proc. 
Natl. Acad. Sci. U. S. A. 2006; 103(8): 2794-2799.
Rhodes,D.R., Kalyana-Sundaram,S., Mahavisno,V., Varambally,R., Yu,J., Briggs,B.B., 
et al Barrette,T.R., Anstet,M.J., Kincead-Beal,C., Kulkarni,P., Varambally,S., Ghosh,D., 
and Chinnaiyan,A.M. (2007). Oncomine 3.0: genes, pathways, and networks in a 
collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2): 9, 166-180.
Rollinson DE., Howlader N., Smith MT., Strom SS., Merritt WD., Ries LA., et al. 
Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in 
the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 
2008;112 (1):45-52.
Schenk,T., Chen,W.C., Gollner,S., Howell,L., Jin,L., Hebestreit,K., et al Klein,H.U., 
Popescu,A.C., Burnett,A., Mills,K., Casero,R.A., Jr., Marton,L., Woster,P., 
Minden,M.D., Dugas,M., Wang,J.C., Dick,J.E., Muller-Tidow,C., Petrie,K., and 
Zelent,A. (2012). Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-
retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med.2012;18(4):
605-611.
Shi, Y., Sawada, J., Sui, G., Affar el, B., Whetstine, J.R., Lan, F., et al Ogawa, H., Luke, 
M.P., Nakatani, Y., and Shi, Y. (2003). Coordinated histone modifications mediated by a 
CtBP co-repressor complex. Nature. 2003; 422 (6933): 735–738.


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Stone RM. How I treat patients with myelodysplastic syndromes. Blood. 2009 Jun 18
;113(25):6296-303
Vardiman, James W., Thiele Juergen, Arber Daniel A., Brunning Richard D., 
Borowitz Michael J., Porwit Anna, et al "The 2008 revision of the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale 
and important changes." Blood.2009;114(5): (2009): 937-951. 
Wouters,B.J., Lowenberg,B., Erpelinck-Verschueren,C.A., van Putten,W.L., Valk,P.J., 
and Delwel,R. (2009) . Double CEBPA mutations, but not single CEBPA mutations, 
define a subgroup of acute myeloid leukemia with a distinctive gene expression profile 
that is uniquely associated with a favorable outcome. Blood. 2009;113(13): 3088-3091.
You A, Tong, J.K., Grozinger, C.M., and Schreiber, S.L.(2001) . CoREST is an integral 
component of the CoREST- human histone deacetylase complex. Proc. Natl. Acad. Sci. 
USA.2001;98(4): 1454–1458.


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12.
Appendices
12.1
Abbreviations and Trademarks
Rationale for Change
Abbreviation and Trademarks table were updated as required by GSK protocol template 
standards.
Revised Text
Abbreviations
aPTT
Activated Partial Thromboplastin Time
DAC
5-Aza-2’-deoxycytidine
GVHD
Graft-versus-Host-Disease
MATE-1
Multidrug And Toxin Extrusion Transporter 1
PI
Principal Investigator 
sc
Subcutaneous
Trademark Information
Trademarks of the 
GlaxoSmithKline group of 
companies
Trademarks not owned by the 
GlaxoSmithKline group of 
companies
NONE
WinNonlin NONE

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205744 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
Title 
: Reporting and Analysis Plan for a phase I/II, open-label, 2 
arm study to investigate the safety, clinical activity, 
pharmacokinetics and pharmacodynamics of GSK2879552 
administered alone or in combination with Azacitidine, in 
adult subjects with IPSS-R high and very high risk 
myelodysplastic syndromes (MDS) previously treated with 
hypomethylating agents (HMA) 
Compound Number  : GSK2879552 
Effective Date  
: 21-Jun-2018 
 
Description: 
 
The purpose of this RAP is to describe the planned reporting and outputs to be 
included in the synoptic Clinical Study Report for Protocol 205744 and/or 
regulatory disclosure. 
 
This RAP is intended to describe details for reporting the safety, clinical activity, 
pharmacokinetic and pharmacodynamics analyses for the study.  
 
The study was terminated early, therefore a streamlined reporting will be taken as 
described in this document.  
 
 
 
 
 
 
 
 
 
 
 
 


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205744 
 
2 
 
RAP Author(s): 
Approver 
Date 
Approval 
Method 
 Employee of PAREXEL Ltd. 
working on behalf of GlaxoSmithKline 
15-Jun-2018 
Email 
Principal Statistician, Biostatistics 
 Employee of PAREXEL 
Ltd. working on behalf of GlaxoSmithKline 
Manager, Biostatistics 
23-May-2018 
Email 
 Employee of PAREXEL Ltd. 
working on behalf of GlaxoSmithKline 
22-May-2018 
Email 
Manager, Statistical Programming 
 Employee of PAREXEL 
Ltd. working on behalf of GlaxoSmithKline 
18-Jun-2018 
Email 
Programming Leader, Statistical Programming 
 Employee of 
PAREXEL Ltd. working on behalf of 
GlaxoSmithKline 
21-Jun-2018 
Email 
Associate Data Management Lead, Data 
Management 
 
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205744 
 
3 
 
RAP Team Approvals: 
Approver 
Date 
Approval 
Method 
 GlaxoSmithKline 
Lead Statistician, Statistics 
05-Jun-2018 
Email 
 GlaxoSmithKline 
Programming Manager, Statistical 
Programming 
22-May-2018 
Email 
 GSK 
Sr. Clinical Development Manager (Oncology 
CPSSO) 
24-Apr-2018 
Email 
 GSK 
Clinical Development, Oncology ES Clinical 
19-Apr-2018 
Email 
 GSK 
Director (Clinical Pharmacology, Modelling 
and Simulation) 
16-May-2018 
Email 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 
15-Jun-2018 
Email 
Senior Director (Oncology, Clinical Statistics) 
 
15-Jun-2018 
Email 
Programming Manager (Oncology, Clinical 
Programming) 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
CONFIDENTIAL 
 
 
 
205744 
 
 
4 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION - STUDY 
OBJECTIVE(S) AND ENDPOINT(S) ........................................................................ 5 
2.1.1. 
Part 1: Dose Confirmation and Escalation...................................... 5 
2.1.2. 
Part 2: Expansion Cohorts (This part of the study was not 
initiated) ......................................................................................... 6 
3. 
PLANNED REPORTING .......................................................................................... 8 
4. 
ANALYSIS POPULATIONS ..................................................................................... 8 
5. 
CONSIDERATIONS FOR REPORTING ................................................................... 8 
5.1. 
Study Population Reporting .......................................................................... 8 
5.2. 
Efficacy Reporting ......................................................................................... 8 
Objective response rate and Clinical benefit rate .......................................... 9 
Progression-free Survival ............................................................................ 10 
Duration of Response ................................................................................. 11 
Overall Survival........................................................................................... 11 
AML Progression ........................................................................................ 11 
Documented Platelet and RBC Transfusions .............................................. 12 
5.3. 
Safety Reporting ......................................................................................... 12 
5.4. 
Pharmacokinetic Reporting ......................................................................... 12 
5.5. 
Data Display Numbering ............................................................................. 12 
5.6. 
Mock Example Shell Referencing ............................................................... 12 
5.7. 
Deliverables ................................................................................................ 13 
5.7.1. 
Study Population Tables .............................................................. 14 
5.7.2. 
Efficacy Tables: Clinical Activity ................................................... 15 
5.7.3. 
Safety Tables ............................................................................... 16 
5.7.4. 
Pharmacokinetic Table ................................................................ 17 
5.7.5. 
ICH Listings ................................................................................. 18 
5.8. 
Appendix 13: Example Mock Shells for Data Displays ................................ 21 
5.8.1          Investigator-Assessed Responses Listing ................................ 21 
 


 
CONFIDENTIAL 
 
 
 
205744 
 
 
5 
 
1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the streamlined 
analyses to be included in the synoptic Clinical Study Report and/or regulatory disclosure 
for Protocol GSK205744: 
Revision Chronology: 
Version 01 
15-Jul-2016 
Original 
Amendment 1 
08-MAY-2017 Addition of 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 
inter-current illness. Minor clarifications, 
correction of typographical errors, reformatting of 
tables, administrative and grammatical changes to 
text and Time and Events tables/footnotes. 
 
Given the premature termination of the study, the study objectives and the statistical 
analyses planned (or described) in the protocol are no longer appropriate. Consequently, 
the reporting and analysis plan will be abbreviated to the tables and listings described in 
this document.  
A streamlined final reporting will be conducted after all required database cleaning 
activities have been completed and final database release and database freeze has been 
declared by Data Management. 
This is an open label study so there will be no special criteria for unblinding. 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION - STUDY 
OBJECTIVE(S) AND ENDPOINT(S) 
2.1.1. 
Part 1: Dose Confirmation and Escalation 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
 To determine the recommended 
phase 2 dose (RP2D) of 
GSK2879552 administered alone 
and in combination with 
Azacitidine in adult subjects with 
HR MDS previously treated with 
HMA. 
 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 Objectives 
Secondary Endpoints 
 To evaluate clinical activity after 
treatment with GSK2879552, 
alone or in combination with 
 Clinical benefit rate (CBR) defined as % 
of subjects achieving CR, mCR, PR, HI 
or SD. Objective response rate (ORR) 


 
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205744 
 
 
6 
 
Objectives 
Endpoints 
Azacitidine, in adult subjects with 
HR MDS previously treated with 
HMA. 
defined as % of subjects achieving CR, 
mCR, PR, or HI [as per 2006 IWG 
criteria]). 
 To measure the exposure to 
GSK2879552 alone and to 
GSK2879552 and Azacitidine in 
combination, in patients with HR 
MDS previously treated with 
HMA. 
 GSK2879552 and Azacitidine 
concentrations pre-dose and post-dose. 
 To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival and 
overall survival. 
 Duration of response (DOR) defined as 
the time from first documented response 
to disease progression. Progression-free 
survival (PFS) defined as the time from 
first dosing day to disease progression or 
death from any cause. Overall survival 
(OS) defined as the time from first dosing 
day until death from and cause. 
 To evaluate frequency and time to 
progression to AML (per 2006 
IWG criteria). 
 Proportion of subjects with disease 
progression to AML. Time to AML 
progression. 
 To evaluate platelet and RBC 
transfusion dependence. 
 Number of documented platelet and RBC 
transfusions per month prior to study 
entry and on study. 
Exploratory Objectives 
Exploratory Endpoints 
 To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552 
alone and in combination with 
Azacitidine. 
 Gene and/or protein expression studies of 
peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 
response. 
 
2.1.2. 
Part 2: Expansion Cohorts (This part of the study was not 
initiated) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
 To evaluate clinical activity after 
treatment with GSK2879552, 
alone or in combination with 
Azacitidine, in adult subjects with 
HR MDS previously treated with 
HMA. 
 Clinical benefit rate (CBR) defined as % 
of subjects achieving CR, mCR, PR, HI 
or SD.  Objective response rate (ORR) 
defined as % of subjects achieving CR, 
mCR, PR, or HI [as per 2006 IWG 
criteria]). 
Secondary Objectives 
Secondary Endpoints 
 To further evaluate the safety and 
tolerability of GSK2879552 
 Changes in safety parameters: e.g. AEs 
and SAEs, changes in laboratory values, 


 
CONFIDENTIAL 
 
 
 
205744 
 
 
7 
 
Objectives 
Endpoints 
administered alone or in 
combination with Azacitidine. 
vital signs, electrocardiograms [ECGs], 
and physical examinations. 
 To characterize the population PK 
of GSK2879552, alone or in 
combination with Azacitidine in 
patients with HR MDS previously 
treated with HMA. 
 Population PK parameters for 
GSK2879552 such as clearance (CL/F). 
 To evaluate duration of response, 
duration of clinical benefit, 
progression-free survival, and 
overall survival. 
 Duration of response (DOR) defined as 
the time from first documented response 
to disease progression. Progression free 
survival (PFS) defined as the time from 
first dosing day to disease progression or 
death from any cause. Overall survival 
(OS) defined as the time from first dosing 
day until death from any cause. 
 To evaluate frequency and time to 
progression to AML (per 2006 
IWG criteria) 
 Proportion of subjects with disease 
progression to AML. Time to AML 
progression. 
 To evaluate platelet and RBC 
transfusion dependence. 
 Number of documented platelet and RBC 
transfusions per month within 3 months 
prior to study entry and while on study. 
Exploratory Objectives 
Exploratory Endpoints 
 To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK2879552 
administered alone or in 
combination with Azacitidine to 
patients with HR MDS previously 
treated with HMA. 
 Gene and/or protein expression studies of 
peripheral blood and/or bone marrow 
aspirates; correlation of baseline 
epigenetic and genomic profiles with 
response. 
 To evaluate the relationship of 
exposure of GSK2879552, 
administered alone or in 
combination with Azacitidine, and 
safety/efficacy parameters, based 
on Part 1 and 2 data combined. 
 Relationship between GSK2879552 
exposure markers (e.g. dose, 
concentration, Cmax or AUC (0-tau)) and 
safety/clinical activity. 
 To investigate the relationship 
between genetic variants in host 
DNA and the safety, tolerability, 
and efficacy of GSK2879552 
alone or in combination with 
azacitidine based on Part 1 and 2 
data combined. 
 Pharmacogenomic (PGx) analysis using 
saliva samples. 
 


 
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8 
 
3. 
PLANNED REPORTING 
Only Part 1 of the study was initiated so the scope of the planned reporting will be 
limited to Part 1.  Summaries for primary and secondary endpoints for Part 1 will be 
reported.  Other relevant Part 1 data will be listed.  There are no data to report for Part 2.  
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
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. 
 Study Population 
 Safety 
 Clinical Activity 
Pharmacokinetic 
Population 
 This population will consist of all subjects 
in the All Treated Subject Population for 
whom a blood sample for 
pharmacokinetics is obtained and 
analysed. 
 Pharmacokinetic 
analysis 
 
5. 
CONSIDERATIONS FOR REPORTING 
The reporting will be based on the All Treated Subjects population, unless otherwise 
specified. All summaries will be presented by treatment group initially treated and overall 
unless otherwise specified. All subjects in the study belong to one treatment group so all 
summaries will display only one group. 
5.1. 
Study Population Reporting 
Patient disposition, demographic characteristics and race will be summarized using IDSL 
standard reporting shells as indicated in Section 5.7.1. 
5.2. 
Efficacy Reporting 
Secondary efficacy (clinical activity) endpoints will be summarized using IDSL standard 
reporting shells as indicated in Section 5.7.2.  The following are considerations for 
handling and/or reporting secondary efficacy endpoints: 
Clinical benefit rate and objective response rate in monotherapy group will be displayed 
using the All Treated Subjects Population and based on the disease assessment data up to 
crossover and prior to new anti-cancer therapy.  
For the time to event efficacy endpoints (including DOR, PFS and Time to AML), 
crossover will be considered as censor situation (if no progressions before crossover) 
using the All Treated Subjects Population. The number of subjects with progression to 
AML will apply the same AML definition as the one used in time to event endpoint. 


 
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205744 
 
 
9 
 
OS is defined as the time from first treatment dose until death due to any reason 
regardless of crossover using the All Treated Subjects Population. 
Platelet and RBC transfusions will apply the same rule as CBR and ORR to present 
summaries by treatment group using the All Treated Subjects Population.  
Objective response rate and Clinical benefit rate 
This study employs response criteria from IWG criteria [Cheson, 2006] for response 
definition. The Clinical Benefit Rate (CBR) is defined as the percentage of subjects 
achieving a confirmed Complete Remission (CR) or Partial Remission (PR) or Marrow 
Complete Remission (mCR) or confirmed Hematologic Improvement (HI) or Stable 
Disease (SD) prior to new anti-cancer therapy and crossover on the All Treated Subjects 
Population.   
Objective response rate is defined as the percentage of subjects who achieved CR or PR 
or mCR or HI prior to new anti-cancer therapy on the All Treated Subjects Population.  
Subjects with Not Evaluable or missing response will be treated as non-responders; i.e. 
they will be included in the denominator when calculating the percentage. 
The CBR and ORR will be reported for combined treatment group in Part 1 with the 
same drug and the same dose. Confirmed and unconfirmed response summaries will be 
provided. The number and types of responses, as outlined in IWG criteria [Cheson, 2006, 
also presented in the table below], will be produced, along with two-sided 95% exact 
confidence interval (CI). 
The CBR and ORR differences between the two cohorts will be provided along with 
corresponding two-sided 95% exact confidence interval (CI). A chi-square test will be 
used to test for differences between arms if the data warrant. Otherwise, a fisher’s exact 
test will be employed if sample sizes are small at the beginning of trial. 
IWG CRITERIA FOR RESPONSE 
Category 
Response Criteria 
Complete Remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all 
cell 
linesa 
Persistent dysplasia will be noteda,b 
Peripheral blood (Response must be maintained for at least 4 
weeks) 
Hgb ≥ 11 g/dL 
Platelets ≥ 100 Gi/L 
Neutrophils ≥ 1.0 Gi/Lb 
Blasts 0% 
Partial Remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pre-treatment 
but still > 


 
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5% 
Cellularity and morphology not relevant 
Marrow CRb 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over 
pretreatmentb 
Peripheral blood: if HI responses, they will be noted in 
addition to 
marrow CRb 
HI 
Erythroid (HI-E): 
hgb increase of > 1.5 g/dL 
decrease of > RBC transfusions/8weeks versus pretreatment 
requirement 
in previous 8 weeks; only RBC transfusions given for a 
pretreatment 
Hgb of < 9.0 g/dL count 
Platelet (HI-P): 
increase of > 30,000/mL (starting with > 20,000/mL) 
increase from < 20,000/mL to >20,000/mL by > 100% 
Neutrophil (HI-N): 
increase of > 100% and > 500/uL 
Stable Disease 
Failure to achieve at least PR, but no evidence of progression 
> 8 wks 
Disease Progression 
For subjects with: 
 Less than 5% BM blasts: ≥ 50% increase in blasts to > 5% 
blasts 
 5%-<10% BM blasts: ≥ 50% increase to > 10% blasts 
 10%-<20% BM blasts: ≥ 50% increase to > 20% blasts 
 20%-30% BM blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
 At least 50% decrement from maximum remission/response 
in granulocytes or platelets 
 Reduction in Hgb by  2 g/dL 
 Transfusion dependence 
Non-evaluable 
Subject does not meet any of the above criteria 
BM = bone marrow ; CR = complete remission; Hgb = hemoglobin;; PR = partial remission 
a. Dysplastic changes should consider the normal range of dysplastic changes (modification). 
b. Modification to IWG response criteria [Cheson, 2006]. 
Progression-free Survival  
Progression-free survival (PFS) is defined as the time from first treatment dose until the 
first documented sign of disease progression or death. For the analysis of Progression-
free survival (PFS), if the subject received subsequent anti-cancer therapy or crossed over 
from monotherapy to combination therapy prior to the date of documented events, PFS 
will be censored at the last adequate assessment prior to the initiation of anti-cancer 
therapy and crossover. If the subject missed more than one visit prior to the date of 
documented events, PFS will be censored at the last adequate assessment prior to 
missing. Otherwise, if the subject does not have a documented date of events, PFS will be 


 
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censored at the date of the last adequate assessment. The description of PFS could be 
summarized as Table 1 using the All Treated Subjects Population.  
Table 1 
Progression-free Survival 
Situation  
Date of Progression or Censoring  
Outcome  
No baseline disease 
assessments  
Date of first dose  
Censored  
No post-baseline disease 
assessments  
Date of first dose  
Censored  
Crossover before progression 
Date of disease assessment prior to 
crossover 
Censored  
Progression documented 
between scheduled visits  
Date of disease assessment  
Progressed  
No progression  
Last date of disease assessment  
Censored  
New anticancer treatment 
started  
Date of disease assessment prior to 
initiation of anti-cancer therapy  
Censored  
Death before first PD 
assessment  
Date of death  
Progressed  
Death between adequate 
assessment visits  
Date of death  
Progressed  
Death or progression after 
more than one missed visit  
Date of disease assessment prior to 
missed visits 
Censored  
 
Duration of Response  
Duration of response is defined as the subset of subjects (responders) who show a 
response (CR, mCR, PR, or HI), the time from first documented evidence of response 
until the first documented sign of disease progression or death. If no disease progression 
or death, the DOR will be censored at last disease assessment.  The same censoring and 
event rules for PFS will be applied for DOR using the All Treated Subjects Population. 
Overall Survival  
Overall survival (OS) is defined as the time from first treatment dose until death due to 
any reason. 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.  
AML Progression 
The proportion of subjects with disease progression to Acute Myeloblastic Leukemia 
(AML) is defined as the percentage of patients experiencing AML on the All Treated 
Subjects Population. The number of patients experiencing progression due to AML will 
be summarized using the All Treated Subjects Population as well.  Time to AML 
progression is defined as the time from first treatment dose until AML progression or 
crossover if using the All Treated Subjects Population.  For the analysis of time to AML, 


 
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if the subject did not experience AML, time to AML will be censored at the last treatment 
prior to the initiation of anti-cancer therapy or crossover.  
Documented Platelet and RBC Transfusions 
The number and percentage of documented platelet and RBC transfusions per month 
prior to study entry and during the treatment period will be produced on the All Treated 
Subjects Population. The number of transfusions will be summarized on the data up to 
crossover for monotherapy treatment on the All Treated Subjects Population. 
5.3. 
Safety Reporting 
Safety parameters specified as primary and secondary endpoints will be summarized 
using IDSL standard reporting shells as indicated in Section 5.7.3. 
5.4. 
Pharmacokinetic Reporting 
GSK GSK2879552 concentrations pre-dose and post-dose will be summarized using 
IDSL standard reporting shell as indicated in Section 5.7.4. 
5.5. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.5 
 
Efficacy 
2.1 to 2.8 
 
Safety 
3.1 to 4.10 
 
Section 
Listings 
ICH Listings 
1 to 32 
 
5.6. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated. 
Section 
Figure 
Table 
Listing 
Study Population 
 
 
POP_Ln 
Safety 
 
SAFE_Tn 
SAFE_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Pharmacokinetic 
 
PK_Tn 
PK_Ln 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 


 
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5.7. 
Deliverables 
Delivery [Priority] [1] 
Description 
SAC [X] 
Final Statistical Analysis Complete 
NOTES:  
1. Indicates priority (i.e. order) in which displays will be generated for the reporting effort 


 
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5.7.1. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
All treated 
ES1  
 
Summary of Participant Disposition for the Participant 
Conclusion Record 
 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.2. 
All treated 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
SAC [1] 
Demographic and Baseline Characteristics 
1.3. 
All treated 
DM1  
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC [1] 
1.4. 
All treated 
DM11 
Summary of Age Ranges 
EudraCT 
SAC [1] 
1.5. 
All treated 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT 
SAC [1] 
 
 
 
 
 


 
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5.7.2. 
Efficacy Tables: Clinical Activity 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Efficacy Tables: Clinical Activity 
2.1.  
All treated 
RE1a 
Summary of Investigator-Assessed Best Response (Without 
Confirmation) (IMWG 2016) 
FDAAA, EudraCT 
Notes:  
Summarize by arm; Do not include 
Total. 
Best Response: Complete response 
(CR), molecular Complete 
Remission (mCR), Partial Response 
(PR), Cytogenetic Response, 
Hematologic Improvement (HI), or 
Stable Disease (SD), Not Evaluable 
(NE). 
Add a category of 'Missing' if 
summarize for Unconfirmed 
response. 
Objective Response Rate (ORR): % 
of subjects achieving CR, mCR, PR, 
Cytogenic Response, or HI. 
Clinical Benefit Rate (CBR): % 
subjects achieving CR, mCR, PR, 
Cytogenic Response, HI, or SD. 
Include: ORR and CBR (No p-
value) in one table. 
SAC [1] 


 
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Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.2.  
All treated 
RE1a 
Summary of Investigator-Assessed Best Response (With 
Confirmation) (IMWG 2016) 
FDAAA, EudraCT 
Note: See comments above for 
table 2.1. 
SAC [1] 
2.3.  
All treated 
TTE1 
Summary of Progression-free Survival 
FDAAA, EudraCT 
SAC [1] 
2.4.  
All treated 
TTE1a 
Summary of Duration of Response 
FDAAA, EudraCT 
SAC [1] 
2.5.  
All treated 
TTE1 
Summary of Overall Survival 
FDAAA, EudraCT 
SAC [1] 
2.6.  
All treated 
TTE1a 
Summary of Time to AML  
FDAAA, EudraCT 
SAC [1] 
2.7.  
All treated 
BPA1 
Summary of Documented Platelet Transfusions 
FDAAA, EudraCT 
SAC [1] 
2.8.  
All treated 
BPA1 
Summary of Documented RBC Transfusions 
FDAAA, EudraCT 
SAC [1] 
 
5.7.3. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1. 
All treated 
AE15 
Summary of Common (>=X%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) 
FDAAA, EudraCT 
X% will be set to 0% so table will 
include all Non-serious AEs 
SAC [1] 
3.2. 
All treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
 
SAC [1] 
3.3. 
All treated 
DL1 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
FDAAA, EudraCT 
SAC [1] 
Laboratory Parameters 


 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.4. 
All treated 
LB1 
Summary of Chemistry Changes from Baseline  
FDAAA, EudraCT 
SAC [1] 
3.5. 
All treated 
LB1 
Summary of Haematology Changes from Baseline  
FDAAA, EudraCT 
SAC [1] 
3.6. 
All treated 
LB1 
Summary of Coagulation Changes from Baseline  
FDAAA, EudraCT 
SAC [1] 
3.7. 
All treated 
LB1 
Summary of Urinalysis Changes from Baseline  
FDAAA, EudraCT 
SAC [1] 
3.8. 
All treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
FDAAA, EudraCT 
SAC [1] 
Vital Signs 
3.9. 
All treated 
Vs1 
Summary of Change from Baseline in Vital Signs 
FDAAA, EudraCT  
SAC [1] 
ECG 
3.10. 
All treated 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
FDAAA, EudraCT  
SAC [1] 
 
5.7.4. 
Pharmacokinetic Table 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 
4.1.  
PK 
PK01 
Summary of GSK2879552 Plasma Pharmacokinetic 
Concentration-Time Data (Part 1) 
 
SAC [1] 
 
 


 
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5.7.5. 
ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
All treated 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC [1] 
2.  
All treated 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
SAC [1] 
Protocol Deviations 
3.  
All treated 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
SAC [1] 
4.  
All treated 
IE3  
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC [1] 
Populations Analysed 
5.  
All treated 
SP3 
Listing of Participants Excluded from Any Population 
ICH E3 
 
SAC [1] 
Demographic and Baseline Characteristics 
6.  
All treated 
DM2  
Listing of Demographic Characteristics 
ICH E3 
SAC [1] 
7.  
All treated 
DM9  
Listing of Race 
ICH E3 
SAC [1] 
Exposure and Treatment Compliance 
8.  
All treated 
EX3  
Listing of Exposure Data 
ICH E3 
SAC [1] 
Prior and Concomitant Medications 
9.  
All treated 
AC6 
Listing of Prior Anti-Cancer Therapy 
ICH E3 
SAC [1] 
10.  
All treated 
AC7 
Listing of Prior Anti-Cancer Radiotherapy 
ICH E3 
SAC [1] 
11.  
All treated 
OSP3 
Listing of Prior Anti-Cancer Related Surgical Procedures 
ICH E3 
SAC [1] 
12.  
All treated 
CM3 
Listing of Concomitant Medications 
ICH E3 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
13.  
All treated 
BP4 
Listing of Prior Blood Products or Blood Supportive 
Products 
ICH E3 
SAC [1] 
14.  
All treated 
BP4 
Listing of Blood Products or Blood Supportive Products On 
Treatment 
ICH E3 
SAC [1] 
Adverse Events 
15.  
All treated 
AE8  
Listing of All Adverse Events 
ICH E3 
SAC [1] 
16.  
All treated 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
SAC [1] 
Serious and Other Significant Adverse Events 
17.  
All treated 
AE8  
 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC [1] 
18.  
All treated 
AE8  
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC [1] 
19.  
All treated 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
SAC [1] 
20.  
All treated 
AE8  
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
SAC [1] 
21.  
All treated 
AE8  
Listing of Other Significant Adverse Events 
ICH E3 
SAC [1] 
All Laboratory 
22.  
All treated  
LB5  
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance/Outside Normal Range 
ICH E3 
SAC [1] 
23.  
All treated 
LB5  
Listing of Laboratory Values of Potential Clinical Importance 
ICH E3 
SAC [1] 
24.  
All treated 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC [1] 
25.  
All treated 
UR2A 
Listing of Urinalysis Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
 
SAC [1] 
26.  
All treated 
OAE4 
Listing of Dose Limit Toxicity 
FDAAA, EudraCT 
SAC [1] 


 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Efficacy 
27.  
All treated 
EFF_L1 
Listing of Investigator-Assessed Responses (with and without 
confirmation) (IMWG 2016) 
ICH E3 
SAC [1] 
28.  
All treated 
TTE9 
Listing of Duration of Response 
ICH E3 
SAC [1] 
29.  
All treated 
TTE9 
Listing of Progression-Free Survival 
ICH E3 
SAC [1] 
30.  
All treated 
TTE9 
Listing of Overall Survival 
ICH E3 
SAC [1] 
31.  
All treated 
TTE9 
Listing of Time to Response 
ICH E3 
SAC [1] 
Pharmacokinetic 
32 
PK  
PK07 
Listing of GSK2879552 Plasma PK Concentration-Time Data  
ICH E3 
 
SAC [1] 


 
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5.8. 
Appendix 13: Example Mock Shells for Data Displays 
5.8.1          Investigator-Assessed Responses Listing 
Example: EFF_L1  
Protocol: GSK2879552                                                                             Page 1 of 1 
Population: All Treated                                                           (Data as of: DDMMMYYYY) 
Listing 27 
Listing of Investigator-Assessed Responses (with and without confirmation) 
 
 
 
 
 
Centre/ 
Subj. 
 
 
 
 
Age(y)/ 
Sex/ 
Race 
 
 
 
 
 
Cycle 
 
 
 
 
 
Visit 
 
 
 
 
 
New Lesion 
 
 
 
 
Response assessment 
(without confirmation)/ 
(with confirmation)  
 
 
 
 
 
 
 
65/ 
F/ 
White - 
White/Caucasian/
European 
Heritage  
 
UNSCHEDULED 
N 
Stable disease/ 
 
 
 
 
 
 
 
 
 
3 
DAY 1 
 
N 
Stable disease/ 
Stable disease 
 
 
 
 
 
 
 
 
4 
DAY 1 
 
N 
Partial response/ 
Stable disease 
 
 
 
 
 
 
 
 
5 
DAY 1 
N 
Complete response/ 
Partial response 
 
 
 
PPD


 
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Example:    [Insert IDSL Or Example Shell Reference]  
 
 
 
 
 
 
 
 
 
                 Page 1 of n 
Protocol:     [Insert Protocol Number] 
Population: [Insert Population] 
Table [Insert Table Number] 
[Insert Title]