A Phase I/II Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
Phase: PHASE2
Conditions: Neoplasms
Sponsor: GlaxoSmithKline

2013N159121_10
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The GlaxoSmithKline group of companies
BET116183
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase I/II open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK525762 in subjects with relapsed, refractory 
hematologic malignancies
Compound Number:
GSK525762
Development Phase:
I/II
Effective Date:
15-MAR-2018
Protocol Amendment Number:  BET116183/09
Authors:
 (Biology, Epigenetics Management, USA)
 (Statistics, Oncology TA Group, USA)
(Biotransformation and Drug Disposition, PTS, UK)
 (Cancer Research Epigenetics Management, USA)
 (Clinical Pharmacology Modeling & Simulation, USA)
 (Global Clinical Safety & Pharmacovigilance, USA)
 (Global Clinical Operational Sciences, USA)
 (Precision Medicine and Diagnostics, USA)
 (Clinical Oncology, USA)
 (Pathology, PTS, UK)
 (Global Clinical Safety & Pharmacovigilance, USA)
 (Global Clinical Operational Sciences, USA)
 (Biology, Epigenetics Management, USA)
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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The GlaxoSmithKline group of companies
BET116183
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2013N159121_00
2013-MAY-20
Original
2013N159121_01
2013-AUG-15
Amendment No. 01
Country Specific Protocol Amendment: At the request of the Medicines and Healthcare 
products Regulatory Agency, United Kingdom, the duration of exposure on the study was 
revised in accordance with the Commission Directive 2005/28/EC.
2013N159121_02
2013-OCT-15
Amendment No.: 02
At the request of the Food and Drug Administration, United Stated, the dose limiting 
toxicity (DLT) in Section 3.2.3 was updated to require that it must clearly be established 
that an event is unrelated to treatment for the event to not be considered a DLT; the 
stopping rules related to safety were expanded in Section 11.4.1.  Additional changes 
include the clarification of exploratory endpoints to assess metabolites, correction of 
exclusion criteria number 12, and clarification of the Time and Events Table, Dietary 
Restrictions, and the futility analysis of Part 2.
2013N159121_03
2014-NOV-12
Amendment No. 03
The secondary objectives of Part 1 were updated to include evaluation of the clinical 
activity of GSK525762 (response rate and overall survival). Additional details for twice 
daily (BID) dosing during dose escalation included.
Eligibility criteria refined:

Clarification of eligibility for subjects with AML (Part 1 and 2).

Platelets count eligibility criteria were specified for each group of hematological
malignancies separately.

Exemption of exclusion due to prior allogeneic stem cell transplant added
DLT for hematological toxicities clarified and dose reduction algorithm for
thrombocytopenia added. Study statistic amended for part 2 (AML expansion cohort):
hypothesis and number of patients. Data from ongoing preclinical and clinical research
added. Time point of collection for samples for disease and efficacy assessments refined.
List of baseline assessments for each indication added. Minor clarifications, reformatting
of tables and typographical errors are also addressed in this amendment.
2013N159121_04
2015-APR-06
Amendment No. 04
An update to the QTc management guidelines and enhanced guidance for management 
and dose modifications for thrombocytopenia, specifically for subjects with AML, has 
been added. 
Separation of cohorts in Part 1 was included to determine MTD/RP2D separately in 
AML, MM, NHL cohorts. Eligibility criteria were refined to account for new platelet 
 
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management guidelines. Eligibility regarding prior allogeneic stem cell transplant and 
CNS disease were simplified.  Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2.  PD assessments have been removed from Part 2 and tumor biopsies 
were added in Part 2 for translational research.  The 100 mg dose strength was removed 
due to a change in manufacturing.  Minor clarifications, reformatting of tables and 
typographical errors were also addressed in this amendment.
2013N159121_05
2015-JUN-25
Amendment No. 05
Amendment 5 includes updated inclusion criteria and guidance on contraception use 
based on emerging data from embryo-fetal development preclinical studies of. Minor 
clarifications were made regarding the Echo and Holter monitoring requirements and the 
list of medications with risk for Torsades de Pointes and prohibited medications were 
updated. The AML response criteria were updated with modified Cheson 2003 
guidelines. Futhermore, the dosing schedule was updated to a continuous daily dosing 
schedule. Finally, after an internal QTc analysis and evaluation of cardiac safety data 
collected from all subjects in the BET115521 study up to and including the 100mg QD 
cohort available by 15 May 2015, the 48-hour telemetry requirement has been removed 
for all parts of the study and the frequency of Holter Monitoring was decreased in Part 1.  
Minor clarifications, reformatting of tables and typographical errors were also addressed 
in this amendment.
2013N159121_06
2015-JUL-08
Re-published Amendment 
No. 05
Protocol amendment 5 was re-published to correct an error in the first sentence of the 
Revision Chronology, dated 2015-JUN-25. The text has been revised to:
Amendment 5 includes updated inclusion criteria and guidance on contraception use 
based on emerging data from preclinical studies of embryo-fetal development.
2013N159121_07
2016-MAR-15
Amendment No. 06
Amendment 6 includes an update to introduce the crystalline besylate formulation within 
Part 1 and Part 2 of the study.  The meals and dietary restrictions for the crystalline 
besylate formulation were added.  Minor clarifications, reformatting of tables and 
typographical errors were also addressed in this amendment.
2013N159121_08
2016-JUN-23
Amendment No. 07
Study design was amended to include collection of additional safety data of GSK525762 
BID dosing (exploratory cohort) after determination of maximum tolerated dose with QD 
dose and to evaluate the preliminary efficacy of GSK525762 BID dosing. The secondary 
objectives of Part 1 were updated to include evaluation of clinical efficacy of 
GSK525762 (overall response rate). The endpoints for secondary objective of Part 2 
(determination of clinical activity of GSK525762) was updated to include TTP, DOR, 
PFS for MM and NHL. Eligibility criteria were clarified for MM and NHL for both Part 
1 and 2. Risk associated with drug interaction was updated. Permanent discontinuation 
from study treatment section was updated. Time and events tables were also updated in 
 
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line with study design modifications. Whole section of urine collection was removed. 
Tables of cautionary medications, prohibited medications and drugs affecting PK of 
GSK525762 were updated. Interim analysis was included for part 1. Minor clarifications, 
formatting and typographical errors were also addressed in this amendment.
2013N159121_09
2017-FEB-14
Amendment No. 8
The study population for the AML cohort in Part 2 was amended from a population of 
subjects with AML to a population of subjects with relapsed or refractory 
myelodysplastic syndrome (MDS) or hypoproliferative AML that has arisen from an 
antecedent MDS. The Part 2 primary and secondary objectives along with the eligibility 
criteria were updated to include this new population.   The safety assessments were 
updated to be in line with the Investigator Brochure. The dose limiting toxicity criteria 
were modified to remove the specific criteria for leukemia. The time and events tables 
were updated to reduce the cardiac monitoring (ecg, holter and troponin), remove mRNA 
and cytokine collection, add a Pain Assessment, addition of an exploratory translational 
research blood draw and to add Factor VII assay collection. The disease related 
events/outcomes section was removed and the pregnancy reporting timeframe was 
reduced to 24 hours. Fever was removed from the dose adjusting/stopping safety 
criteria. Aspirin and non-steroidal-anti-inflammatory drugs (NSAIDs) were added to the 
Cautionary medications. Response Criteria for MDS was added as an Appendix. Minor 
clarifications, formatting and typographical errors were also addressed in this 
amendment.
2013N159121_10
2018-MAR-15
Amendment No. 9
The study population for the NHL cohort in Part 2 was amended from a population of 
subjects with NHL to a population of subjects with cutaneous T-cell lymphoma (CTCL).  
The Part 2 primary and secondary objectives along with the eligibility criteria were 
updated to include this new CTCL population, and removal of expansion into multiple 
myeloma in Part 2.  Eligibility criteria for all populations were updated (ECOG, cardiac 
safety).  The time and events tables were updated to reduce the cardiac monitoring based 
on updated risk/benefit profile, and BID dosing was removed.  Medications affecting QT 
prolongation were re-categorized from prohibited to cautionary.  Liver chemistry 
monitoring, interruption stopping and follow-up criteria were updated as per latest 
criteria.  Response Criteria for CTCL was added as an Appendix, and a QOL 
questionnaire (SKINDEX-29) was added.  Minor clarifications, formatting and 
typographical errors were also addressed in this amendment.
 
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day 
Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
 
 MD, 
PhD
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 Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s):  Investigational New Drug (IND) # 
IND119332
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BET116183
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................16
PROTOCOL SYNOPSIS...............................................................................................21
1.
INTRODUCTION....................................................................................................32
1.1.
Background ................................................................................................32
1.2.
Study Population Rationale.........................................................................32
1.3.
Dose Rationale ...........................................................................................35
1.3.1.
QD Dose Cohort ..........................................................................35
1.3.1.1.
Starting Dose Calculations .........................................35
1.3.1.1.1.
Preclinical Considerations ......................35
1.3.1.1.2.
Human Pharmacokinetics and 
Equivalent Exposure for NOEL for 
QTc prolongation....................................36
1.3.1.1.3.
Clinical Considerations ...........................36
1.3.1.2.
Predicted therapeutic dose range...............................36
1.3.2.
Dose escalation steps..................................................................37
1.4.
Rationale for Study and Endpoints..............................................................37
1.5.
Benefit: Risk Assessment ...........................................................................38
1.5.1.
Risk Assessment .........................................................................38
1.5.2.
Benefit Assessment.....................................................................44
1.5.3.
Overall Benefit: Risk Conclusion..................................................44
1.6.
Communication Plan for Safety Evaluation .................................................44
2.
OBJECTIVES, ENDPOINTS, HYPOTHESES ........................................................45
3.
INVESTIGATIONAL PLAN.....................................................................................48
3.1.
Study Design/Schematic.............................................................................48
3.2.
Discussion of Design ..................................................................................49
3.2.1.
Part 1: Dose Escalation ...............................................................49
3.2.1.1.
Dose Escalation and Schedule...................................50
3.2.1.2.
Accelerated Dose Escalation in Part 1........................50
3.2.1.3.
3 + 3 Dose Escalation in Part 1 ..................................51
3.2.1.4.
Alteration of Schedule ................................................53
3.2.1.5.
Intra-Subject Dose Escalation ....................................54
3.2.1.6.
Toxicity Leading to Termination of Accelerated 
Titration ......................................................................54
3.2.2.
Dose Limiting Toxicity (DLT)........................................................54
3.2.3.
Maximum Tolerated Dose (MTD) and Recommended 
Phase 2 Dose (RP2D) .................................................................55
3.2.4.
Part 2: Disease Specific Expansion Cohorts................................55
4.
STUDY POPULATION...........................................................................................59
4.1.
Number of Subjects ....................................................................................59
4.2.
Eligibility Criteria .........................................................................................59
4.2.1.
Inclusion Criteria..........................................................................59
4.2.2.
Exclusion Criteria.........................................................................63
 
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4.2.3.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria .........................................................65
4.2.3.1.
Permanent Discontinuation from Study 
Treatment...................................................................65
4.2.3.2.
Subject Completion ....................................................66
4.2.4.
Treatment after the End of the Study ...........................................66
5.
TIME AND EVENTS TABLES ................................................................................66
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................81
6.1.
Study Visits.................................................................................................81
6.1.1.
Assessments ...............................................................................81
6.1.2.
Visit Windows ..............................................................................81
6.2.
Baseline Assessment..................................................................................82
6.2.1.
Baseline assessment for all Subjects...........................................82
6.2.2.
Baseline assessment for Subjects with MDS/AML.......................82
6.2.3.
Baseline assessment for Subjects with NHL (excepting 
CTCL)..........................................................................................82
6.2.4.
Baseline assessment for Subjects with CTCL..............................83
6.2.5.
Baseline assessment for Subjects with myeloma.........................83
6.3.
Safety Evaluations......................................................................................83
6.3.1.
Physical Examinations.................................................................83
6.3.2.
ECOG performance status...........................................................84
6.3.3.
Vital Signs....................................................................................84
6.3.4.
Left ventricular ejection fraction (LVEF) Evaluation......................84
6.3.5.
Electrocardiograms......................................................................84
6.3.6.
Clinical Laboratory Assessments .................................................85
6.3.7.
Troponin ......................................................................................87
6.4.
Efficacy.......................................................................................................87
6.4.1.
Disease Assessment ...................................................................87
6.5.
Pharmacokinetics .......................................................................................87
6.5.1.
Blood Sample Collection..............................................................87
6.5.2.
Plasma Sample Analysis .............................................................87
6.5.3.
Activity .........................................................................................87
6.6.
Translational Research...............................................................................88
6.6.1.
Tumor Specific Tissue Collection.................................................88
6.6.2.
Blood Sample Collection for Exploratory Translational 
Research .....................................................................................89
6.6.3.
Unscheduled Safety Biomarker Blood Samples...........................89
6.7.
Adverse Events (AE) and Serious Adverse Events (SAE)...........................89
6.7.1.
Definition of an AE.......................................................................89
6.7.2.
Definition of a SAE.......................................................................90
6.7.2.1.
Cardiovascular Events................................................91
6.7.2.2.
Death Events..............................................................92
6.7.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................92
6.7.4.
Time Period and Frequency of Detecting AEs and SAEs.............92
6.7.5.
Method of Detecting AEs and SAEs.............................................93
6.7.6.
Prompt Reporting of SAEs and Other Events to GSK ..................93
6.7.7.
Regulatory reporting requirements for SAEs................................94
6.8.
Pregnancy ..................................................................................................95
6.8.1.
Time period for collecting pregnancy information.........................95
 
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6.8.2.
Action to be taken if pregnancy occurs ........................................95
6.8.3.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ................................................................95
6.9.
Pharmacogenetics......................................................................................96
6.10.
Quality of Life/Patient-Reported Outcomes.................................................96
7.
STUDY TREATMENTS..........................................................................................96
7.1.
GSK525762 Investigational Product Dosage/Administration.......................96
7.2.
Handling and Storage of Study Treatment ..................................................98
7.3.
Meals and Dietary Restrictions ...................................................................99
7.4.
Treatment Assignment..............................................................................100
7.5.
Product Accountability ..............................................................................100
7.6.
Treatment Compliance..............................................................................100
7.7.
Dose Modifications ...................................................................................100
7.7.1.
Dose and Safety Management Guidelines.................................100
7.7.2.
Dose Adjustments for Toxicity....................................................107
7.8.
Guidelines for Events of Special Interest and Dose Modifications.............107
8.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................108
8.1.
Permitted Medications ..............................................................................108
8.2.
Cautionary/Prohibited Medications............................................................108
8.2.1.
Drugs Potentially Affecting GSK525762 Pharmacokinetics 
or affected by GSK525762.........................................................109
8.3.
Non-Drug Therapies .................................................................................110
8.4.
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study .........................................................................110
8.5.
Treatment of Study Treatment Overdose..................................................110
9.
LIFESTYLE REQUIREMENTS (CONTRACEPTION) AND/OR DIETARY 
RESTRICTIONS...................................................................................................111
9.1.
Contraception ...........................................................................................111
9.1.1.
Female Subjects........................................................................111
9.1.2.
Male Subjects............................................................................112
9.2.
Caffeine, Alcohol, and Tobacco ................................................................112
10. DATA MANAGEMENT .........................................................................................112
11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................113
11.1.
Sample Size Assumptions ........................................................................113
11.1.1.
Part I, Dose Escalation ..............................................................113
11.1.2.
Part 2, Expansion Cohort...........................................................113
11.1.3.
Sensitivity Analysis ....................................................................115
11.1.4.
Sample Size Re-estimation........................................................115
11.2.
Analysis Populations.................................................................................115
11.3.
Data Analysis Considerations ...................................................................115
11.3.1.
Analysis Datasets ......................................................................116
11.3.2.
Withdrawal.................................................................................116
11.3.3.
Missing Data..............................................................................116
11.3.4.
Derived and Transformed Data..................................................116
11.3.5.
Assessment Windows................................................................116
11.3.6.
Other Issues ..............................................................................116
11.4.
Interim Analysis ........................................................................................117
 
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11.4.1.
Other Stopping Criteria for Part 2...............................................117
11.5.
Final Analyses ..........................................................................................117
11.6.
Efficacy Analyses......................................................................................118
11.6.1.
Primary Analysis........................................................................118
11.6.2.
Secondary Analysis ...................................................................118
11.7.
Safety Analyses........................................................................................119
11.7.1.
Extent of Exposure ....................................................................120
11.7.2.
Adverse Events..........................................................................120
11.7.3.
Clinical Laboratory Evaluations..................................................120
11.8.
Pharmacokinetic Analyses........................................................................120
11.9.
Pharmacokinetic/Pharmacodynamic Analyses..........................................121
11.10. Translational Research Analyses..............................................................122
11.11. Pharmacogenetic Analyses ......................................................................122
11.12. Quality of Life Analyses ............................................................................122
12. STUDY CONDUCT CONSIDERATIONS .............................................................122
12.1.
Posting of Information on Clinicaltrials.gov................................................122
12.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................122
12.3.
Urgent Safety Measures ...........................................................................123
12.4.
Quality Control (Study Monitoring) ............................................................123
12.5.
Quality Assurance.....................................................................................123
12.6.
Study and Site Closure .............................................................................123
12.7.
Records Retention....................................................................................124
12.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Register and Publication....................125
13. COUNTRY SPECIFIC..........................................................................................125
14. REFERENCES.....................................................................................................126
15. APPENDICES......................................................................................................130
15.1.
Appendix 1: CKD-Epi Formula..................................................................130
15.2.
Appendix 2: NYHA Functional Classification System for Heart 
Failure ......................................................................................................131
15.3.
Appendix 3: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria......................................................................................132
15.4.
Appendix 4: Dose Adjustment/Stopping Criteria/Supportive Care.............137
15.5.
Appendix 5: Pharmacogenetic Research ..................................................139
15.6.
Appendix 6: Response Criteria for Multiple Myeloma................................143
15.7.
Appendix 7: Response Criteria for Non-Hodgkin’s Lymphoma (Part 
1) ..............................................................................................................145
15.8.
Appendix 8: Response Criteria for Acute Myeloid Leukaemia...................147
15.9.
Appendix 9: Response Criteria for Myelodysplastic Syndrome .................148
15.10. Appendix 10: Staging and Response Criteria for CTCL (mSWAT 
method) ....................................................................................................149
15.10.1. Staging of Subjects with CTCL ..................................................149
15.10.2. Response Assessment of Subjects with CTCL ..........................151
15.11. Appendix 11: Patient Reported Outcomes Assessments for CTCL 
(Skindex-29) .............................................................................................158
15.11.1. US English Skindex-29 ..............................................................158
15.12. Appendix 12: Pain Assessment ................................................................161
 
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15.13. Appendix 13: Updated PK data from protocols BET115521 and 
BET116183...............................................................................................162
15.14. Appendix 14: Protocol Changes for Amendment 1 (15-Aug-2013) 
from the Original Protocol  (20-May-2013) ................................................164
15.15. Appendix 15: Protocol Changes for Amendment 2 (15-OCT-2013) 
from the Protocol Amendment 1 (15-AUG-2013) ......................................165
15.16. Appendix 16: Protocol Changes for Amendment 3 (12-NOV-2014) 
from the Protocol Amendment 2 (15-OCT-2013).......................................195
15.17. Appendix 17: Protocol Changes for Amendment 4 (06-APR-2015) 
from the Protocol Amendment 3 (12-NOV-2014) ......................................241
15.18. Appendix 18: Protocol Changes for Amendment 5 (08-JUL-2015) 
from the Protocol Amendment 4 (06-APR-2015).......................................288
15.19. Appendix 19: Protocol Changes for Amendment 6 (15-MAR-2016) 
from the Protocol Amendment 5 (08-JUL-2015)........................................309
15.20. Appendix 20: Protocol Changes for Amendment 7 (23-JUN-2016) 
from the Protocol Amendment 6 (15-MAR-2016) ......................................314
15.21. Appendix 21: Protocol Changes for Amendment 8 (14-FEB-2017) 
from the Protocol Amendment 7 (23-JUN-2016) .......................................378
15.22. Appendix 22: Protocol Changes for Amendment 9 (15-Mar-2018) 
from the Protocol Amendment 8 (14-FEB-2017) .......................................429
 
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LIST OF TABLES
PAGE
Table 1
Hematological cancer cell line sensitivity to GSK525762, 3-day 
growth-death assay................................................................................34
Table 2
Accelerated Dose Escalation Procedures in Part 1 ................................51
Table 3
3 + 3 Dose Escalation Design ................................................................52
Table 4
Definitions for Adequate Organ Function................................................62
Table 5
Time and Events: Part 1.........................................................................67
Table 6
Time and Events: Part 1 Laboratory Assessments.................................70
Table 7
Disease Specific Assessments...............................................................72
Table 8
Time and Events: Part 1 Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling ..........................................76
Table 9
Time and Events: Part 2 Expansion Cohort............................................77
Table 10
Time and Events: Part 2 Laboratory Assessments.................................80
Table 11
Clinical Laboratory Tests........................................................................86
Table 12
Reporting of SAEs and Other Events to GSK.........................................94
Table 13
GSK525762 Amorphous Free Base Investigational Product 
Dosage/ Administration ..........................................................................97
Table 14
GSK525762 Besylate Investigational Product 
Dosage/Administration ...........................................................................98
Table 15
Dose Adjustment/Stopping Safety Criteria............................................101
Table 16
Dose Adjustment for Toxicity................................................................107
Table 17
Modified ISCL/EORTC Revisions to the tumor-node-metastasis-
blood (TNMB) Classification of MF/SS .................................................149
Table 18
Modified ISCL/EORTC Revisions to the Staging of MF/SS ..................151
Table 19
Global Response Score .......................................................................152
Table 20
Response in Skin .................................................................................153
Table 21
Modified Severity Weighted Assessment Tool (mSWAT) .....................154
Table 22
Response in Lymph Nodes ..................................................................155
 
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Table 23
Response in Viscera ............................................................................156
Table 24
Response in Blood...............................................................................157
Table 25
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following a Single Oral Administration of GSK525762 in Study 
BET115521 and BET116183................................................................163
Table 26
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following Repeat Daily Oral Administration of GSK525762 in 
Study BET115521 and BET116183......................................................163
 
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LIST OF FIGURES
PAGE
Figure 1
Survival of Multiple Myeloma (OPM-2) bearing mice ..............................34
Figure 2
Study Schema........................................................................................49
Figure 3
Dose Escalation Schema (Part 1) ..........................................................53
Figure 4
Diagram of Stopping Rules for MDS Cohort Expansion..........................57
Figure 5
Diagram of Stopping Rules for CTCL Cohort Expansion ........................58
 
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LIST OF ABBREVIATIONS
1,5 AG
1,5-Anhydroglucitol
ACLS
Advanced Cardiac Life Support
AE
Adverse Event
ALC
Absolute lymphocyte count
ALL
Acute Lymphoblastic Leukemia
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
AML
Acute Myeloid Leukemia
AMM
Agnogenic Myeloid Metaplasia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve over the dosing interval
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
BAL
Bronchoalveolar lavage
BCL
B-Cell Leukemia
BCRP
Breast Cancer Resistance Protein
BET
Bromodomain and extra-terminal
BID
Bis in die - Twice daily
BM
Bone marrow
BNP
B-type Natriuretic Peptide
BP
Blood pressure
BQL
Below the quantitative limit
BRD
Bromodomain
Cav
Average observed concentration
CBC
Complete blood count
CD4
Cluster of differentiation
CK
Creatine kinase
CKD-Epi
Chronic Kidney Disease Epidemiology Collaborative
CK-MB
Creatine kinase-MB (isozyme)
CL
Clearance
CL/F
Apparent clearance following oral administration
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CML
Chronic Myeloid Leukemia
CML-BP
Chronic Myelogenous Leukemia in Blast Phase
CMML
Chronic MyeloMonocytic Leukaemia
CNS
Central nervous system
COPD
Chronic Obstructive Pulmonary Disease
CPK
Creatine phosphokinase
 
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CPMS
Clinical Pharmacokinetics Modelling & Simulation
CR
Complete response
CRC
Colorectal cancer
CrCl
Creatinine clearance
CRp
As per CR but platelet count <100 x 109/L
CRP
C reactive protein
CRu
Complete Response/Unconfirmed
CT
Computerized Tomography
CTCL
Cutaneous T cell lymphoma
Cτ
Pre-dose (trough) concentration at the end of a dosing interval
D
Day
DBP
Diastolic blood pressure
DHEA
Dehydroepiandrosterone
DHL
Double hit lymphoma
DILI
Drug induced liver injury
dL
Deciliter
DLBCL
Diffuse large B cell lymphoma
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLT
Dose limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DOR
Duration of Response
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EORTC
European Organization of Research and Treatment of Cancer
EOT
End of treatment
FDA
Food and Drug Administration
FISH
Fluorescence in situ hybridization
FL
Follicular lymphoma
FLC
Free light chain (assay)
FLIPI
Follicular Lymphoma International Prognostic Index
FSH
Follicle Stimulating Hormone
Fu
Fraction unbound
GCP
Good Clinical Practice
GCSF
Granulocyte colony-stimulating factor
GI
Gastrointestinal
GLP
Good Laboratory Practice
GMCSF
Granulocyte-macrophage colony-stimulating factor
GSK
GlaxoSmithKline
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C Virus
HDL-C
High-density lipoprotein cholesterol
 
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HepC
Hepatitis C
hERG
Human ether à go-go-related gene (encoding the alpha subunit of the 
potassium ion channel Kv11.1)
HIV
Human Immunodeficiency Virus
HNSTD
Highest non-severely toxic dose 
hr
Hour(s)
HR
Heart rate
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IDSL
Integrated Data Standards Library
Ig
Immunoglobulin
IL
Interleukin
IMWG
International Myeloma Working Group
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ISCL
International Society for Cutaneous Lymphomas
ISS
International Staging System
IUD
Intrauterine device
IUS
Intrauterine system
IVRS
Interactive voice response system
Kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
LDL-C
Low-density lipoprotein cholesterol
LLN
Lower limit of normal
LMWH
Low molecular weight heparin
LVEF
Left ventricular ejection fraction
MDS
Myelodysplastic Syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MF
Mycosis fungoides
µL
Microliter
mg
Milligrams
Mins
Minute(s)
mL
Milliliter
MLL
Mixed-Lineage, Leukemia
MM
Multiple Myeloma
mmHg
Millimeter of mercury
mmol
Millimole
MPN
Myeloproliferative neoplasms
MR
Minimal Response
MRI
Magnetic Resonance Imaging
 
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mRNA
Messenger Ribonucleic acid
MSDS
Material Safety Data Sheet
msec
Milliseconds
mSWAT
Modified severity weighted assessment tool
MTD
Maximum tolerated dose
MUGA
Multi gated acquisition scan
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse 
Events
N-CRM
Neuenschwander continual reassessment method
NHL
Non-Hodgkin’s Lymphoma
NOAEL
No observed adverse effect level
NOEL
No observable effect level
NT-proBNP
N-terminal pro–B-Type natriuretic peptide
NYHA
New York Heart Association
OATP
Organic anion transporting polypeptide
ORR
Overall Response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
pcALCL
Primary cutaneous anaplastic large cell lymphoma
PCR
Polymerase chain reaction
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression Free Survival
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PI
Primary Investigator
PK
Pharmacokinetic
PR
Partial response
PS
Performance status
PT
Prothrombin time/ Preferred (coded) term
PTT
Partial thromboplastin time
QD
quaque die - Once daily
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid
Ro
Observed accumulation ratio
RP2D
Recommended Part 2 Dose
RR
Time interval from the onset of one QRS complex to the onset of the 
next QRS complex
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SCLC
Small cell lung cancer
sCR
Stringent complete response
 
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SCR
Screening Visit
SD
Stable disease/ Standard deviation
SOC
System Organ Class
SPD
Sum of products of the diameters
SPEP
Serum protein electrophoresis
SPM
Study Procedures Manual
SRT
Safety Review Team
SS
Sézary syndrome
STD 10
10% mortality over the duration of the study
T0
Time of transplant
t1/2
Apparent terminal half-life
Tmax
Time of maximum concentration
TNF
Tumor Necrosis Factor
TNMB
Tumor-node-metastasis-blood
TSH
Thyroid stimulating hormone
TTP
Time to Progression
UK
United Kingdom
ULN
Upper limit of normal
UPEP
Urine protein electrophoresis
USA
United States
V/F
Volume of distribution
VGPR
Very good partial response
W
Week
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
WinNonlin
 
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PROTOCOL SYNOPSIS

PRODUCT: GSK525762

PROTOCOL TITLE: A phase I/II open-label, dose escalation study to investigate 
the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 
in subjects with relapsed, refractory hematologic malignancies

PROTOCOL NO.: BET116183

U.S. IND NO.:  IND119332

EudraCT NO: 2013-000445-39

CLINICAL PHASE:  I/II

STUDY DESIGN AND DURATION:  This study is divided into 2 parts: Part 1 of 
the study is a dose escalation phase to select the recommended Part 2 dose (RP2D) 
based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after 
oral administration of GSK525762.  Eligible subjects with select relapsed refractory 
hematological malignancies (acute myeloid leukemia [AML], non-Hodgkin’s 
Lymphoma [NHL] and multiple myeloma [MM]), will be enrolled in once daily 
(QD) cohorts until a maximum tolerated dose (MTD) is established. Subjects may 
continue treatment in the study until disease progression, unacceptable toxicity, or 
withdrawal of consent.  Part 2 will explore clinical activity at the MTD or RP2D; 
separate expansion cohorts will be planned for myeloid malignancies (high-risk 
myelodysplastic syndrome [MDS] or acute myeloid leukemia [AML] that has 
evolved from an antecedent MDS, hereafter referred as the “myeloid cohort”), and 
cutaneous T-cell lymphomas (mycosis fungoides [MF], Sézary syndrome [SS], 
primary cutaneous anaplastic large cell lymphoma [pcALCL], and large cell 
transformation of underlying MF/SS; hereafter referred as the “cutaneous T cell 
lymphoma [CTCL] cohort”).

STUDY RATIONALE: Current data from GSK525762 preclinical development 
indicate a potential to inhibit the BET family of bromodomain (BRD) proteins and 
that this inhibition may have clinical utility in the treatment of various tumors, 
including hematological malignancies. Relapsed and/or refractory hematological 
malignancies such as MDS, AML, NHL, and MM have an overall poor outlook. This 
is the first study of this agent to be conducted in subjects with these relapsed and/or 
refractory hematological malignancies with few or no conventional treatment options 
that could be expected to provide any lasting benefit. Dose escalation initially 
focused on AML, NHL (without consideration to histologic subtype), and MM, 
based on preclinical data.  Emerging clinical data demonstrated delayed response in 
AML subjects, many of whom had evidence of antecedent MDS.  In the NHL cohort,
more robust clinical efficacy was observed in subjects with CTCL compared to other 
NHL subtypes.  As a result of these observations, dose expansion (Part 2) was 
modified to evaluate MDS and CTCL instead of AML and unselected NHL, 
respectively.
 
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
OBJECTIVES AND ENDPOINTS:
Part 1: 
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) 
administration, establishing the 
recommended Phase 2 dose (RP2D) 
of GSK525762 in adult subjects with 
acute myeloid leukemia (AML), 
multiple myeloma (MM), or non-
Hodgkin’s lymphoma (NHL).

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate clinical efficacy following 
QD administration in subjects with 
AML, MM, and NHL.

Objective response rate (ORR), as 
measured by standard response 
criteria

To characterize the Pharmacokinetic
(PK) of GSK525762, and relevant 
metabolites, as applicable, after 
single- and repeat-dose 
administration.

PK parameters for GSK525762 and 
relevant metabolites, as applicable,
following single- and repeat-dose 
administration of GSK525762, 
including Area under concentration-
time curve(AUC), Minimum observed 
concentration (Cmin), Pre-dose 
(trough) concentration at the end of a 
dosing interval (C), Maximum 
observed concentration (Cmax), Time 
of maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.
Exploratory

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC, following 
single and repeat-dose oral 
administration of GSK525762)

To evaluate the relationship between 
GSK525762 dose/exposure and 
pharmacodynamic response.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.
 
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Part 1 Objectives
Part 1 Endpoints

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess objective response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To investigate the mechanism of 
action and indicators of sensitivity and 
resistance to GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response.
Hypothesis

No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
Part 2:
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in high-
risk myelodysplastic syndrome (MDS) 
or acute myeloid leukemia (AML) that 
has evolved from an antecedent MDS 
(“myeloid cohort”).

For MDS cohort: ORR (defined as the 
percentage of subjects achieving Complete 
Response [CR], marrow CR, CRp [as per 
CR but platelet count <100 x 109/L], CRi 
[as per CR but platelet count <100 x 10
9/L 
or neutrophil count <1 x 10
9/L], or Partial 
Response [PR],) per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in CTCL

For CTCL: ORR4; defined as the 
percentage of subjects that have achieved 
a CR or PR, per global response criteria
and the modified severity weighted 
assessment tool (mSWAT), lasting more 
than 4 months 
Secondary

To evaluate the effect of GSK525762 
on disease-related symptoms, as 
reported by subjects (CTCL cohort 
only)

For CTCL: measure the effects of skin 
disease based on quality of life 
questionaire Skindex-29 

To characterize the PK of 
GSK525762, and relevant 
metabolites, as applicable, in 2
disease-specific cohorts of subjects 
with MDS/AML, or CTCL after repeat-
dose administration.

Population PK parameters for GSK525762, 
and relevant metabolites, as applicable,
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 2 disease-
specific cohorts of subjects with 

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
 
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Part 2 Objectives
Part 2 Endpoints
MDS/AML, or CTCL.
parameters, vital signs, and cardiac 
parameters) at RP2D.

To determine the clinical activity of 
GSK525762 in 2 disease-specific 
cohorts of subjects with MDS/AML, 
or CTCL.

Duration of response (DOR, time from 
onset of response to earlier date of disease 
progression or death due to any cause) for 
MDS/AML and CTCL

Progression free survival (PFS, time from 
the treatment start date to earlier date of 
disease progression or death due to any 
cause) for MDS/AMLand CTCL.

Overall survival (OS, the time from the 
treatment start date until death from any 
cause) for MDS/AML, and CTCL
Exploratory

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To evaluate the exposure response  
relationship between GSK525762 and 
safety/efficacy parameters in 
2 disease-specific cohorts of subjects 
with MDS/AML, or CTCL.

Relationship between GSK525762 
exposure markers and safety and efficacy 
parameters.

To investigate the mechanism of 
action and indicators of sensitivity and 
resistance to GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of tumor 
baseline genetic and genomic profiles with 
response; Leukemic Stem Cell studies; 
PDX model studies and other translational 
medicine studies.
Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Myelodysplastic syndrome and transformed MDS: A response rate of 30% relative to a 
10% response rate suggesting no activity in subjects with MDS/AML.  This will be 
conducted by testing the null hypothesis that P0≤0.10 versus the alternative that 
P1≥0.30, assuming the maximum response rate for an ineffective drug is 0.10 and the 
minimum response rate for an effective drug is 0.30.

CTCL: A response rate, lasting more than 4 months, of 40% relative to a 20% response 
rate suggesting no activity in subjects with CTCL.  This will be conducted by testing the 
null hypothesis that P0≤0.20 versus the alternative that P1≥0.40, assuming the maximum 
response rate for an ineffective drug is 0.20 and the minimum response rate for an 
effective drug is 0.40. 

STUDY DURATION:  Duration of study will depend on recruitment rates, and 
timing of subjects’ duration on study (withdrawal rates due to toxicity or 
progression).

SUBJECT SAMPLE:  Up to 138 subjects worldwide
 
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
INCLUSION/EXCLUSION CRITERIA:
Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply and after consultation with GlaxoSmithKline (GSK):
1. Written informed consent provided.
2. Males and females 18 years old or older.
3. Subjects must have a diagnosis of one of the following hematologic malignancies, 
which has relapsed or been refractory to treatment as follows:

(Part 1 only): Subjects with AML are eligible if they 
o have relapsed and/or refractory disease, OR
o are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

(Part 2 only): Subjects with MDS/AML (myeloid cohort) are eligible if they:
o Have high-risk (defined as intermediate [INT]-2 or higher by International 
Prognostic Scoring System [IPSS] criteria, or high/very high by IPSS-
Revised [IPSS-R] criteria) MDS that has relapsed after or been refractory 
to prior therapy with hypomethylating agent, OR
o Have AML that has arisen from an antecedent MDS (irrespective of 
IPSS/IPSS-R score; subjects without a documented history of antecedent 
MDS/ myeloproliferative neoplasms (MPN) must have AML with 
myelodysplasia-related changes or recurrent cytogenetic abnormalities per 
World Health Organization [WHO] criteria)

Subjects with secondary AML must have progressed despite, or 
failed to respond to, prior therapy with hypomethylating agent, AND

Subjects must have hypoproliferative disease, defined as either:

A peripheral white blood cell count of less than 20,000 
cells/µL in the absence of leukoreducing therapy (e.g., 
hydroxyurea, leukapheresis), OR

At least one bone marrow biopsy obtained within 28 days 
of first dose of GSK525762 must demonstrate a marrow 
blast percentage of no more than 30%
Note: If marrow blasts exceed 30% on any biopsy within 
28 days of first dose of GSK525762, enrolment will 
only be permitted after discussion with the medical 
monitor
 
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
(Part 1): Subjects with multiple myeloma are eligible if they have progressed 
despite therapy with an alkylating agent, proteasome inhibitor, and 
immunomodulatory agent, either as individual regimens or in combination

(Part 1 only): Subjects with NHL are eligible if they have received at least 
two prior lines of systemic therapy, including at least one line of 
immunochemotherapy with an anti-CD20 antibody (if their tumor expresses 
CD20)

(Part 2 only): Subjects will be eligible for enrolment into the CTCL cohort if 
they:
o
Have histologically- or cytology-proven diagnosis of CTCL (MF, 
SS, pcALCL, or large cell transformation of underlying MF/SS) 
that has failed to respond to, or progressed despite, at least one 
prior systemic therapy
4. Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) 
are allowed if 

At least 3 months have elapsed from the time of transplant, and

the subject has recovered from transplant-associated toxicities prior to the 
first dose of GSK525762, and

For subjects with a prior history of allogeneic transplant, 
o
the subject has been off systemic immunosuppressive medications 
(including but not limited to: cyclosporine, tacrolimus, mycophenolate 
mofetil, or corticosteroids) for at least 1 month prior to the first dose of 
GSK525762.  Topical steroids are permitted
o
there are no signs or symptoms of graft versus host disease, other than 
Grade 1 skin involvement
5. Eastern Cooperative Oncology Group (ECOG) performance status of:

1 for all Part 1 Cohorts (AML, MM, and NHL)

2 for all Part 2 cohorts (MDS/AML and CTCL)
6. Subject must be stable enough to be expected to complete dosing through the 
DLT observation period as assessed by 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. A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea [in questionable cases, a blood 
sample with simultaneous follicle stimulating hormone (FSH) >40 
MlU/mL and estradiol <40 pg/mL (<140 pmol/L) is confirmatory].  
Females on hormone replacement therapy (HRT) and whose menopausal 
 
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status is in doubt will be required to use one of the contraception methods 
defined in protocol 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.  For most forms of HRT, at 
least two to four weeks will elapse between the cessation of therapy and 
the blood draw; this interval depends on the type and dosage of HRT.  
Following confirmation of their post-menopausal status, they can resume 
use of HRT during the study without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraception methods 
for an appropriate period of time (as determined by the product label or 
investigator) prior to the start of dosing to sufficiently minimize the risk of 
pregnancy at that point.  Female subjects must agree to use contraception 
until at least 7 months after the last dose of study medication.

Negative serum pregnancy test ≤7 days prior to first study drug dose.

Female subjects who are lactating must discontinue nursing prior to the 
first dose of study treatment and must refrain from nursing throughout the 
treatment period and for 5 half-lives of GSK525762 or at least 28 days 
(whichever is longer) following the last dose of study treatment.
9. Male subjects with a female partner of childbearing potential or who is pregnant 
must agree to use one of the methods of contraception specified in Section 9.1.  
This method must be used from the time of the first dose of study medication until 
16 weeks after the last dose of study medication. In addition, male subjects whose 
partners are or become pregnant must use/continue to use condoms until 16 weeks 
after last dose of study medication.
10. Adequate organ system functions (at both screening and where applicable pre first 
dose) as defined in below.
11. Ability to comply with dietary and tobacco/alcohol abstinence requirements.
 
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Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Hemoglobin (only for myeloma and lymphoma)
≥8.0 g/dL
Coagulation assays (prothrombin time/ international 
normalized ratio [PT/INR] and activated partial 
thromboplastin time [aPTT] 1
1.2 X upper limit of normal (ULN)
Platelets (for subjects with lymphoma)
Platelets (for subjects with MM)
Platelets (for subjects with acute leukemia)
≥75,000 (transfusion independent)
≥50,000 (transfusion independent)
10,000 (transfusions permitted to bring platelet 
count to >10,000)
Hepatic
Total bilirubin
≤1.5 X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of 
Gilbert’s syndrome)
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST)
2.5 X ULN 
Renal
Creatinine3
OR
Calculated creatinine clearance [calculated by Chronic 
Kidney Disease Epidemiology Collaborative (CKD-Epi) 
method 2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN 
≥50 mL/min
≥50 mL/min
Cardiac
Ejection fraction
≥Lower limit of normal (LLN) by echocardiogram 
(ECHO) (minimum of 50%) or Multi Gated 
Acquisition (MUGA) scan
Troponin (T)
≤ULN
Thyroid
Thyroid stimulating hormone (TSH) 4
≥LLN and ≤ULN
1.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
2.
For MM subjects, adequate renal function is defined as serum creatinine ≤2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥30 mL/min
3.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
 
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Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Haematological malignancy associated with human immunodeficiency virus 
(HIV) infection or solid organ transplant or positive Hepatitis B Antigen or 
positive Hepatitis C antibody at screening or within 3 months prior to first dose
(subjects with positive Hepatitis C antibody may be enrolled, provided that the 
confirmatory test [e.g., Hepatitis C Virus [HCV] Ribonucleic acid [RNA]
polymerase chain reaction [PCR] is negative).
2. History or concurrent malignancy of solid tumours, except for below.
Exception:  Subjects who have been disease-free for 5 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated 
in situ carcinoma are eligible.  Subjects with second malignancies that are 
indolent or definitively treated may be enrolled even if less than 5 years have 
elapsed since treatment.  Consult the GSK Medical Monitor if unsure whether 
second malignancies meet requirements specified above.
3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno-
therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization). 
Note: the following are allowed:
Hydroxyurea for proliferative disease
Corticosteroids (topical and/or systemic)
Use of hematopoetic growth factors is permitted at the discretion of the 
investigator according to published guidelines (e.g., National 
Comprehensive Cancer Network (NCCN), American Society of Clinical 
Oncology (ASCO), American Society of Hematology (ASH), etc.).
Note: the following are NOT allowed:
Investigational anti-cancer drug within 2 weeks prior to the first dose of 
GSK525762.
Major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK525762.
Chemotherapy regimens with delayed toxicity within the last 4 weeks.  
Chemotherapy regimens given continuously or on a weekly basis with 
limited potential for delayed toxicity within the last 2 weeks.
Nitrosourea or mitomycin C within the last 6 weeks.
4. Evidence of severe or uncontrolled infection.
5. Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days 
prior to the first dose of GSK525762.  Low dose (prophylactic) anticoagulants 
(e.g., low molecular weight heparin (LMWH) or oral anticoagulants) is permitted.  
 
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In addition, INR must be monitored in accordance with local institutional 
practices, as appropriate.
6. Current use of a prohibited medication or planned use of a prohibited medication
during treatment with GSK525762.
7. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes).  Any serious and/or unstable pre-existing medical (aside from 
malignancy 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.
8. Symptomatic or untreated central nervous system (CNS) disease, 

Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are 
permitted to enrol if they have previously received appropriate therapy and
CNS remission has been documented.

Subject with primary CNS lymphoma (defined as isolated CNS lymphoma 
without systemic involvement) are excluded from study.
9. Cardiac abnormalities as evidenced by any of the following:

History or current clinically significant conduction abnormalities, 
uncontrolled arrhythmias or hypertension.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

Recent history (within the past 3 months) of acute coronary syndromes 
(including unstable angina and myocardial infarction), coronary angioplasty, 
or stenting.
10. Any of the following electrocardiogram (ECG) findings or assessments including:

Baseline QTcF interval ≥480 msec.

Clinically significant ECG assessments should be reviewed by the site 
cardiologist prior to study entry.
11. GSK525762 is a benzodiazepine class molecule.  Any serious known immediate 
or delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs 
chemically related to the investigational drug.
12. Evidence of hemoptysis within the last 7 days.
13. History of major gastrointestinal bleeding within the last 3 months or any 
evidence of active gastrointestinal bleeding.
14. Presence of gastrointestinal disease that would significantly affect compound 
absorption.
 
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
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN: Starting dose 
will be 5 mg, orally (tablets), once a day.  Dose escalations will be performed in 
Part 1 and dose adjustments are allowed to address tolerability and safety issues.  
Alternate dosing schedules e.g. intermittent dosing may be required to manage 
toxicities and may be considered based on investigator assessment and after 
consultation with GSK without requiring a protocol amendment.

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: There 
will be serial blood sampling for PK and pharmacodynamics (in some subjects) 
measurements in Part 1 of this study and more limited PK sampling in Part 2 of this 
study.  Single safety PK blood draws may be collected for subjects with severe 
adverse events or adverse events of concern.  In addition, pre-treatment and post-
treatment tumor tissue samples will be collected from selected subjects to be 
evaluated for target engagement and effects of GSK525762 on tumor biology.

EFFICACY MEASUREMENTS:  ORR, PFS and OS in AML, MDS, MM, and 
CTCL; time to progression (TTP) and duration of response in MM and CTCL. Rate 
of objective response lasting at least 4 months (ORR4) in CTCL

SAFETY MEASUREMENTS:  Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events will be 
performed.  Cardiac safety monitoring will be required, consisting of 12-lead ECGs 
prior to dosing on selected days and prior to drawing PK samples on serial PK 
sampling days (overnight stays in research facility may be necessary in Part 1).  
Laboratory testing includes, in addition to standard hematology, clinical chemistry, 
pancreatic, coagulation, and liver chemistry panels, testing for troponin, N-terminal 
prohormone B-type Natriuretic Peptide (NT pro-BNP), c-peptide, 1,5-
Anhydroglucitol (1, 5 AG), Hemoglobin A1c (HbA1c), and thyroid monitoring.  
Additional safety assessments may be necessary based on emerging data.

STATISICAL ANALYSIS: Subject demographic and safety data will be collected 
on electronic case report forms (eCRFs).  All data will be pooled and descriptive 
safety analyses summarized and listed by cohort at conclusion of Part 2 expansion 
cohorts.  Additional analyses may occur between Part 1 and Part 2; details will be 
included in the Reporting Analysis Plan (RAP).  Part 2 of the study is designed to 
evaluate preliminary efficacy.  Futility assessment will be conducted on an ongoing 
basis, starting with a minimum of 10 treated subjects assessed for response. The 
assessments are based on the predictive probability of success if the enrolment 
continues to the maximum of 32 subjects in the MDS cohort and 37 subjects in the 
CTCL cohort respectively.  Subjects enrolled in Part 1, at the Part 2 dose, for 
diseases under study in Part 2, will be included in Part 2 analysis.
 
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1.
INTRODUCTION
1.1.
Background
Bromodomains (BRDs) are small protein domains found in a variety of proteins that 
recognize and bind to acetylated histone tails.  This binding affects chromatin structure 
and facilitates the localisation of transcriptional complexes to specific genes, thereby 
regulating epigenetically controlled processes including gene transcription and 
Messenger Ribonucleic acid (mRNA) elongation.  The BRD and extra-terminal (BET) 
family of BRD proteins includes the BRD2, BRD3, BRD4 and BRDT [testes] proteins.
The investigational agent GSK525762 is a potent inhibitor of the BET family of proteins 
and prevents the binding required for macromolecular complex assembly and the 
subsequent transcriptional response [Nicodeme, 2010].
GSK525762 inhibits growth in a broad spectrum of human hematological cancer cell 
lines and solid cancer cell lines.  In cell line sensitivity studies, GSK525762 consistently 
exhibits broad anti-proliferative activity and induces cytotoxicity in the majority of these 
tumour derived cell lines including Acute Myeloid Leukemia (AML), Chronic Myeloid 
Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), B- Cell Leukemia (BCL), 
Multiple Myeloma (MM), and non-Hodgkin’s Lymphoma (NHL).  GSK525762 is orally 
active in vivo in both solid and haematological xenograft tumour models of disease, and 
exhibits tumour growth inhibition and a significant survival advantage compared to 
vehicle treated animals in a MM mouse model [GSK525762 IB, GlaxoSmithKline 
Document Number 2011N113741_06]. 
Recent published data studying another BET inhibitor [Dawson, 2011] have also shown 
therapeutic promise in pre-clinical models of hematologic malignancies and further 
support extending clinical evaluation of this novel therapeutic agent in a broad spectrum 
of hematological malignancies.
Parallel to study BET116183, GSK525762 is being investigated in solid tumors 
(GlaxoSmithKline [GSK] Study BET115521, NCT# NCT01587703)
1.2.
Study Population Rationale
Myelodysplastic syndromes (MDS) and AML are related neoplasms of myeloid cells 
characterized by an excess of immature myeloblasts in the bone marrow, as well as 
ineffective hematopoiesis leading to peripheral cytopenias.  MDS and AML exist along a 
spectrum defined by the percentage of marrow blasts, with > 20% delineating the 
boundary between the two diseases.  While AML may arise de novo, it may also evolve 
from an antecedent myelodysplasia or myeloproliferative syndrome.  Both AML and 
MDS are increasingly defined by genetic characteristics, with cytogenetic abnormalities 
and mutations in genes involved in RNA splicing and epigenetic regulation frequently 
observed in MDS as well as AML that transformed from MDS.  The only approved 
therapies for MDS are the hypomethylating agents 5-azacitidine and decitabine; these 
agents are frequently used in patients with AML who are not suitable candidates for 
aggressive induction chemotherapy (e.g., as a consequence of advanced age or other 
 
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comorbidity).  To date, there are no second-line agents for subjects who did not respond 
to or who have progressed despite hypomethylating agent therapy, and overall survival 
for patients who have failed prior therapy is typically measured in months (Prebet, 2011; 
Sekeres, 2014; Jabbour, 2010).
Non-Hodgkin’s lymphomas are a family of more than sixty malignancies arising from 
abnormal lymphoid, histiocytoid, or dendritic cell development (Swerdlow, 2016).  They 
constitute a spectrum of diseases that may be focal or systemic, indolent or aggressive, 
based on the underlying cell of origin and other biological factors.  Therapy is 
customized for each patient based on the disease subtype and location and typically 
involves radiation, systemic therapy, or both.  Recently, targeted systemic therapies have 
emerged and have been approved based on promising response data.  However, NHL is 
an incurable disease for most patients and thus new approaches are necessary in the face 
of inexorable progression and relapse.
Cutaneous T-cell lymphomas are a family of NHLs characterized by skin infiltration by 
cluster of differentiation 4 (CD4)-positive T-cells.  These diseases are characterized by 
erythroderma and/or tumor-phase growths on the skin, as well as intense pruritis as a 
consequence of upregulation of multiple pro-inflammatory cytokines [Ahern, 2012].  
Targeted systemic therapies remain the cornerstone of treatment for many patients, 
including those with limited-stage disease, both to control the disease itself as well as to 
reduce the overall symptomatic burden [Whittaker, 2016].  Recently, a role for BRD4 in 
the expression of lymphoma-associated genes has been demonstrated (Kohnken, 2017), 
making BET inhibition a rational approach for treatment of cutaneous T cell lymphoma
(CTCL).
Multiple myeloma is a neoplastic proliferation of plasma cells.  In almost all cases, 
myeloma is incurable; though novel therapies have emerged in the past decade and a half, 
most patients with multiple myeloma will die from their disease.  Thus, new therapies are 
necessary.
Relapsed and/or refractory hematological malignancies such as AML, MDS, NHL, and 
MM have an overall poor outlook.  These subjects are appropriate for clinical trials with 
new agents such as the BET inhibitor GSK525762. Preclinical studies have shown that 
small molecule based inhibition of BET protein binding to chromatin downregulates 
oncogene expression (e.g., down regulation of MYC oncogene expression and its 
downstream transcriptional functions) in several hematological cancer cell lines.  This 
down regulation results in significant anti-tumour activity both in vitro and in animal 
models of disease [Delmore, 2011; Mertz, 2011].  Down-regulation of c-Myc protein 
expression has been reported upon exposure to GSK525762 in MM MM1S cells 
[Delmore, 2011], Burkitt’s Lymphoma Raji cells and LP-1 myeloma cells [Mertz, 2011].  
Consistent with the published literature, GSK525762 inhibits proliferation and induces a 
cytotoxic response in cell lines across a wide range of hematological tumour types 
(Table 1). 
 
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Table 1
Hematological cancer cell line sensitivity to GSK525762, 3-day 
growth-death assay
Cell Line 
Tumor Type
% Sensitive Linesa
Total Lines 
Tested
Median gIC50
(M)
ALL
100
4
0.29
AML
96
25
0.10
Burkitt 
50
8
1.2
CML
100
4
0.32
CTCL
100
3
0.22
DLBCL
90
29
0.17
Erythroleukemia
100
2
0.38
FL
100
4
0.06
MCL
80
5
0.80
MM
100
12
0.06
a.
Cell lines defined as sensitive to GSK525762 if the gIC50 <1.0 M.  
Abbreviations:  ALL = Acute lymphoblastic leukemia; AML = Acute myeloid leukemia; CML = Chronic myeloid 
leukemia; CTCL = Cutaneous T cell lymphoma; DLBCL = Diffuse large B cell lymphoma; FL = Follicular lymphoma; 
gIC50 = Growth IC50, 6-day assay; MCL = Mantle cell lymphoma; MM = Multiple myeloma.
Ninety-one percent of hematological cancer cell lines tested (87/96) are sensitive to 
GSK525762, exhibiting growth IC50 (gIC50) values below 1.0M. Some of the most 
sensitive hematological cancer cell types include FL (median gIC50= 60 nM), MM 
(median gIC50= 60 nM), AML (median gIC50=  100 nM), and DLBCL (median gIC50=  
170 nM). Additionally, oral dosing of GSK525762 results in tumour growth inhibition 
and improved survival in a myeloma mouse xenograft model (OPM-2) of disease (Figure 
1).  Consistent with published reports, down-regulation of c-Myc protein expression was 
observed in OPM-2 xenografts following a single dose of GSK525762 or daily 
administration for up to 11 days. 
Figure 1
Survival of Multiple Myeloma (OPM-2) bearing mice
 
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These preclinical data highlight the potential of GSK525762 to provide benefit to 
subjects with relapsed and/or refractory hematological malignancies where significant 
unmet need still exists [GSK525762 IB, GlaxoSmithKline Document 
Number 2011N113741_06].
1.3.
Dose Rationale
1.3.1.
QD Dose Cohort
1.3.1.1.
Starting Dose Calculations
The proposed starting dose for this clinical study in subjects with hematologic 
malignancies is 5 mg once daily (QD) based on the following, assuming a 70 kg adult 
with a body surface area of 1.7 m2.  The dose of 5 mg daily was based on preclinical 
considerations described Section 1.3.1.1.1, preliminary human pharmacokinetics (PK; 
Section 1.3.1.1.2), clinical consideration including the aggressive nature of the relapsed 
and/or refractory tumor (Section 1.3.1.1.3), and the desire to minimise sub-therapeutic 
exposures. This starting dose is different from the ongoing solid tumor study (GSK Study 
BET115521, NCT# NCT01587703) in which the starting dose was 2 mg daily (see 
Section 1.3.1.1.3).  
1.3.1.1.1.
Preclinical Considerations
The following approaches have been considered to establish the starting dose for 
GSK525762:
1.
One tenth of the rat STD (Severely Toxic Dose) 10 as per International Conference 
on Harmonization (ICH) S9 guidance (based on dose):
a.
Based on the observed morbidity levels in the 30 mg/kg dose group following 1 
month of dosing, the Rat STD10 was defined as 30 mg/kg.  One tenth of the rat 
STD10 as per the ICH S9 guidance is 18 mg/m2 (this dose is also not severely 
toxic to dogs) which results in a starting human dose of 30 mg daily.
b.
Assuming that 30 mg/kg may not be tolerated for dosing periods greater than 1 
month without significant morbidity, a conservative Rat STD10 was defined as 10 
mg/kg.  One tenth of the rat STD10 is 6 mg/m2 (this dose is also not severely 
toxic to dogs) which results in a starting human dose of 10.2 mg daily.
2.
One sixth of the dog Highest Non Severely Toxic Dose (HNSTD) as per ICH S9 
guidance (based on dose):
a.
Based on tolerability, the HNSTD was defined as 1 mg/kg in the dog.  One sixth 
of the dog HNSTD is 3.33 mg/m2 which translates to a starting dose in man of 
5.7 mg.
b.
Based on feedback from the Food and Drug Administration (FDA), QTc 
prolongation was taken into consideration when defining the HNSTD.  The 
revised HNSTD was defined as 0.3 mg/kg in the dog.  One sixth of the dog 
HNSTD is 1 mg/m2, which translates to a starting dose in man of 1.7 mg that was 
rounded to 2 mg, based on tablet strength.
 
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1.3.1.1.2.
Human Pharmacokinetics and Equivalent Exposure for NOEL for QTc 
prolongation
Average plasma systemic exposure in dogs at the repeat dose that resulted in QTc 
prolongation No observable effect level (NOEL) (0.3 mg/kg) was as follows: Area under 
concentration-time curve (AUC) - 642 ng.hr/mL total and 167 ng.hr/mL free; Maximum 
observed concentration (Cmax) - 80 ng/mL total and 20.8 ng/ml free (fraction unbound 
[Fu] in plasma is 26%).  Extrapolating the free AUC to humans, the dose required for 
parity is given by Dose = AUC x Clearance (CL)/Fu, where Fu is fraction unbound in 
plasma in humans (18.6%).  The average clearance observed in the 2 first subjects in 
BET115521 who received 2 mg was 9.7 L/hr, a value similar to the value predicted from 
animal data using allometric scaling.  Using the above expression, the predicted starting 
dose would be 167 ng.hr/mL x 9.70 (L/hr)/0.186 = 8.7 mg.
Based on the Cmax observed in the two subjects who received a single 2 mg dose of 
GSK525762, the predicted free drug Cmax is about 50.4 ng/mL for a 8.7 mg dose.  This 
predicted free Cmax is higher than the observed free Cmax in dogs (27.8 ng/mL) at QTc 
NOEL. This does not impact the proposed starting dose using exposure at the NOEL for 
QTc prolongation as the preclinically observed QTc prolongation is not consistent with a 
direct hERG blockade (i.e., free Cmax levels).  Taking this into consideration, the human 
dose which matches the average free exposure that did not result in QTc prolongation 
(QTc NOEL) in the dog is 9 mg daily.
PK information obtained up to January 2017 is available in the Investigator’s Brochure 
Section 5.2. 
1.3.1.1.3.
Clinical Considerations
Relapsed and/or refractory hematologic malignancies have an aggressive and rapidly 
progressive course and patients with leukemia are unlikely to remain stable even for 3 
week for the Dose Limiting Toxicity (DLT) assessment to be done.  Therefore there is a 
need to minimise the number of patients exposed to sub-therapeutic doses without 
compromising safety.  The 5 mg starting dose provides adequate safety margins for 
toxicities that can be clinically monitored and are largely reversible (excluding testicular 
long-term effects on  male and female reproductive function, which is being evaluated), 
while minimizing the number of patients with aggressive hematologic cancers exposed to 
predicted sub-therapeutic doses. Moreover, the starting dose of 2 mg daily in the solid 
tumor trial (BET115521) has been successfully cleared. Taking all the above into 
consideration and the extensive clinical monitoring for QT prolongation, a starting dose 
of 5 mg QD is planned.
1.3.1.2.
Predicted therapeutic dose range
Cell lines of hematological origin were generally more sensitive than the cell lines of 
other solid tumor origins, namely small cell lung cancer (SCLC) and Colorectal cancer 
(CRC) cells.  The more sensitive cell lines had growth IC50 (gIC50) values as low as 50-
100 nM.  The potential therapeutic dose for GSK525762 in humans was derived using 
available preclinical PK, data from in vitro cell lines of hematological origin, and 
efficacy data from OPM-2 multiple myeloma tumour xenograft studies.  Based on 
 
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modeling, maximal efficacy of GSK525762 may require ≥50% target inhibition.  The 
predicted human effective daily dose is likely to be in the range of 25 to 100 mg 
assuming 50 to 100% oral bioavailability.
1.3.2.
Dose escalation steps
Human PK predictions suggest that exceeding the systemic exposure of the preclinical 
4 week maximum tolerated dose (MTD) (1 mg/kg in dogs and 10 mg/kg in rats) may be 
required to achieve ≥50% target inhibition in the majority of subjects.  The start of the 
predicted therapeutic range in humans is at parity with the 4 week MTD exposure range 
in preclinical species.  The toxicities observed at exposures greater than the preclinical 
MTD are amenable to clinical monitoring and are largely reversible (excluding testicular 
effects).  A stringent safety monitoring and evaluation process will be implemented and 
therefore semi-semi-log (≤2-fold) dose escalation above the preclinical MTD, conditional 
on acceptable safety and tolerability, is permitted until the clinical MTD is established. 
The MTD of GSK525762 may be different for AML/MDS, NHL, and MM.  To fully 
evaluate this, each dose escalation step will be evaluated separately for the three disease 
types.  Parallel cohorts will commence upon termination of accelerated dose titration 
(Section 3.2.1.2) and follow the 3 + 3 design described in Section 3.2.1.3.
1.4.
Rationale for Study and Endpoints
Safety and efficacy (Response Rate) are being assessed to address the primary objectives 
of the study.  The safety assessments along with PK will be important for determining the 
MTD.  The pharmacodynamic assessments will further support the recommended Phase 
II doses (RP2D) and expand the understanding regarding mechanism of action.
The BET116183 study has 2 parts.  Part 1 is a dose finding study, which will include 
subjects with hematologic malignancies to determine an MTD.  Part 2 is a cohort 
expansion, which will study the RP2D of GSK525762 to determine preliminary efficacy,
safety and tolerability in three separate cohorts of subjects with myeloid neoplasms 
(myelodysplastic syndrome [MDS] or MDS that has transformed to AML), and CTCL.
Originally, Part 2 of the study was designed to evaluate preliminary clinical efficacy in 
relapsed or refractory AML, MM, and NHL.  However, after an evaluation of data from 
the Part 1 AML cohort, the following observations prompted changes to the Part 2 
cohort; clinical responses were observed at doses of 60 mg and above, these responses 
occurred in subjects whose disease harbored complex karyotype and recurrent mutations 
in TP53 and in proteins that regulate gene expression, suggesting that these subjects had 
an antecedent MDS that transformed to AML.  Furthermore, most subjects with AML 
discontinued GSK525762 early in the course of their treatment as a consequence of their 
underlying AML or disease complications.  Responses tended to be delayed (at the four 
week mark or later, with many requiring more than 10 weeks to manifest).  Thus, most 
subjects were not remaining on study for long enough to achieve benefit.  In order to 
maximize time on-study, Part 2 was updated to enroll subjects with a more slowly-
progressing disease that maintained many of the clinical characteristics of the AML 
responses that were observed in Part 1 (i.e., MDS and MDS that has transformed to AML 
with a low burden of disease).
 
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The original study design included a dose expansion in non-Hodgkin’s lymphoma, 
enrolling subjects regardless of histological subtype.  Furthermore, this cohort enrolled
subjects with double- and triple-hit lymphoma (i.e., B-cell lymphomas with 
rearrangement and/or overexpression of myc and BCL2 and/or BCL6) in an exploratory 
sub-cohort.  However, interim analysis of the Part 1 data demonstrated limited activity in 
both B-cell lymphomas in general as well as double/triple hit lymphomas.  Responses, 
including very deep, durable responses, were achieved in subjects with CTCL and other 
T-cell lymphomas of the skin.  Therefore, Part 2 of the study was amended to restrict 
enrollment to these diseases, for which emerging clinical data suggested a reasonable rate 
of benefit.
1.5.
Benefit: Risk Assessment
The investigational agent GSK525762 is a potent inhibitor of the BET family of proteins 
that prevents BET binding to acetylated histone tails required for macromolecular 
complex assembly and the subsequent transcriptional response of many oncogenes 
[Nicodeme, 2010].  GSK525762 inhibits growth in a broad spectrum of human 
hematological and solid cancer cell lines.  In cell line sensitivity studies, GSK525762 
consistently exhibits broad antiproliferative activity and induces cytotoxicity in the 
majority of these tumor derived cell lines including AML, CML, ALL, NHL, and MM.
GSK525762 is orally active in vivo in both solid and hematological xenograft tumor 
models of disease, and exhibits tumor growth inhibition and a significant survival 
advantage compared to vehicle treated animals in a MM mouse model.  Recent published 
data studying BET inhibitors [Dawson, 2011] have also shown therapeutic promise in 
pre-clinical animal models of hematologic malignancies.  Considering the overall poor 
outlook of patients with relapsed and/or refractory hematological malignancy and the 
therapeutic promise of GSK525762, clinical evaluation of this novel therapeutic agent in 
a broad spectrum of hematological malignancies is justified.
1.5.1.
Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK525762 can be found in the Investigator’s Brochure (IB) [GlaxoSmithKline 
Document Number 2011N113741_06].  Toxicology studies performed in dogs, rats and 
mice suggest that the primary toxicities of GSK525762 are gastrointestinal, 
cardiovascular, pancreatic, hematologic and reproductive (see the GSK525762 IB 
[GlaxoSmithKline Document Number 2011N113741_06]).  The following Section 
outlines the risk assessment and mitigation strategy for this protocol.
 
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Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Gastrointestinal
Gastrointestinal effects contributed to the 
definition of severely toxic repeat dose in both 
rats and dogs. 30 mg/kg (rat) and 3 mg/kg 
(dog).
In life findings included reduced body weight 
gain / body weight loss, reduced food 
consumption, abnormal faeces.  Microscopic 
evidence of erosions or ulcerations with 
inflammation in multiple locations throughout 
the Gastrointestinal (GI) tract.  Recovery after 
3 weeks off dose.
Informed Consent Form (ICF) 
includes the risk of gastrointestinal 
effects.
Protocol includes medical history, 
physical examination (including 
weight) and clinical laboratory 
assessments to assess toxicity in 
the GI tract.  Subjects with a 
history of gastrointestinal bleeding 
in the past 3 months (Section 4.2) 
or active bleeding will be excluded.
Protocol also includes specific 
dose adjustment/stopping safety 
criteria for diarrhea and mucositis.
Lymphoid / 
Hematologic
Lymphoid / hematologic toxicity was observed 
in rats and dogs and the effects contributed to 
the definition of severely toxic repeat dose in 
rats (30 mg/kg).
The effects manifested as hypocellularity in 
bone marrow, thymus, spleen and lymph 
nodes; decreased spleen and thymic weight; 
mild hemolysis; variable and inconsistent 
changes in white cell /lymphocyte count, 
multiple red blood cells parameters and 
reticulocyte counts. Minimal bone marrow 
hypocellularity was still evident in male rats 
previously given 30/20 mg/kg/day for 13 
weeks following a 17 week off dose period.
Changes relating to coagulation were evident 
in both rats (considered non-adverse) and 
dogs (considered adverse at 3 mg/kg/day).  
These included a reduction in platelet counts 
(54%) and an increase in activated partial 
thromboplastin time (aPTT; 1.38X).
Full recovery of aPTT and a compensatory 
increase in platelet counts in dogs (1.27X) 
was evident following the 3 week off-dose 
period.
ICF includes the risk of lymphoid / 
hematologic toxicity.
Protocol includes laboratory 
assessments (complete blood 
count [CBC] and coagulation 
factors [international normalized 
ratio (INR), prothrombin time (PT), 
partial thromboplastin time (PTT)], 
exclusion criteria if there is 
evidence of clinically significant 
bleeding episodes, monitoring for 
bruising/infection and dose 
stopping/modifications criteria.
Anticoagulants at therapeutic 
doses (e.g., warfarin, direct 
thrombin inhibitors, etc) are 
PROHIBITED from seven days 
prior to the first dose of study drug 
through completion of the Final 
Study Visit.  Low dose 
(prophylactic) anticoagulants are 
permitted provided that the 
subject’s PT/PTT meet entry 
criteria.
 
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Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human 
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
A review of all available data as of November 
2017 (representing 271 subjects dosed up to 
100 mg in the BET115521 solid tumor study 
and up to 120 mg in the BET116183 heme 
malignancy study) demonstrated a clinically 
negligible effect on QT in humans.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose 
(1 mg/kg in dogs and 60 mg/kg in rats); no 
effects were observed in the 7 day repeat 
dose dog CV study; increase in mean BP up 
to 11 mmHg; decrease in mean BP up to 13 
mmHg.
QA interval (indirect measure of cardiac 
contractility).
Decreased QA interval at single non-tolerated 
doses in dog (no effect seen in rats); up to 10
msec. No effects were observed in the 7 day 
repeat dose dog CV study; No 
echocardiography changes in the 28 day dog 
toxicology study.
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], and 
cardiac ejection fraction) during 
the study, and dose 
stopping/modifications criteria for 
the management cardiac events.
Drugs with a risk of QT 
prolongation must be used with 
caution, (refer to Section 8.2).
Given the risks of long QTc 
associated arrhythmias, and of 
compound associated 
cardiomyopathy, subjects will be 
monitored closely for changes in 
QTc with 12-lead ECG, and for 
elevations in plasma Troponin.  
Inpatient 48-hour telemetry was 
originally required for all subjects 
following the first dose of study 
drug, as part of the cardiac 
monitoring. Evaluation of cardiac 
safety data from subjects treated 
up to and including the 100 mg QD 
cohort by the cut-off date of May 
15, 2015 demonstrated no 
significant QTc prolongation after 
single and repeat dose 
administration. Therefore, the 48-
hour telemetry requirement was 
removed and the frequency of 
Holter monitoring was reduced 
with Protocol Amendment 5 and 
removed in Protocol Amendment 8 
following additional analysis of all 
available data by the cut off of 10-
Jun-2016.
Specific stopping criteria and 
management guidelines are 
 
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provided for cardiac toxicities.
Electrolytes, including potassium 
and magnesium will be checked at 
baseline and at regular intervals or 
when clinically indicated. 
Appropriate medical management 
will be instituted to assure that 
electrolytes are kept within the 
normal range
Cardiovascular -
Troponin
Elevations in cardiac biomarkers relative to 4 
week Good Laboratory Practice (GLP) 
toxicology study control group in:

Cardiac troponin I (up to 15X in rat 
and 4.7X in dog)

Cardiac troponin T (up to 8.9X in rat) 

Myosin light chain III (up to 4.8X in 
rat)

NT-proANP (up to 1.54X in rat)
Changes were reversible and there was no 
evidence of compound related myocardial 
histopathological changes in either species 
after up to 3 months of dosing.
Protocol includes troponin 
monitoring (local laboratory 
monitoring for troponin I or T 
based on availability and troponin 
T at central laboratory) and dose 
stopping/modifications criteria for 
the management of cardiac 
toxicity.
.
Reproductive
GSK525762 has shown adverse degenerative 
effects on testes in rats, rabbits and dogs, 
with no observed adverse effect level 
(NOAEL) in rabbits. These changes were 
accompanied in rats and dogs by changes in 
sperm morphology, motility and number and 
hormonal changes (decreased testosterone 
and Inhibin B in rats and increased FSH in 
rats and dogs).  Reduced prostate weight and 
secretory content was also evident in the rat.  
An effect on spermatogenesis is anticipated. 
Full or partial reversibility of the testicular 
effects was observed in the 3 month rat and 
dogs studies following a 17 week off dose 
period.
GSK525762 has shown effects on female 
fertility (disrupted estrous cyclicity, delays to 
mating and/or reduced fertility index), embryo-
fetal toxicity and embryofetal developmental 
(decreased fetal body weight, fetal 
malformations or variations and / or pre- and 
ICF includes the risk of damage to 
reproductive organs such as testes 
or ovaries.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects and collecting 
testosterone (free and complete) 
for male subjects.
ICF includes the potential risk of 
reproductive effects.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects.
 
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Potential Risk of 
Clinical 
Significance
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Mitigation Strategy
post-implantation loss). A NOAEL has yet to 
be determined. There is a substantiated risk 
for adverse effects on embryofetal 
development and impacts on female fertility.
Pancreatic
A male rat-specific pancreatic change (islet 
cell fibrosis / fibroplasias and peri-islet 
haemorrhage, pigmented macrophages and 
inflammation) was observed at a dose of 
30 mg/kg/day in the 4 week study only. No 
effects were observed in the 3 month 
toxicology studies.
Following the 3 week off-dose period, these 
changes were decreased in incidence and/or 
severity.
An unrelated pancreatic lesion (acinar cell 
apoptosis, vacuolation and/or degranulation) 
was present in female dogs given 
3 mg/kg/day.
ICF includes the risk of pancreatic 
effects.
Protocol includes laboratory 
assessments (glucose -serum and 
urine, insulin and 1,5-
Anhydroglucitol (1,5-AG), c-petide, 
Hemoglobin A1c (HbA1c), 
amylase, lipase) as appropriate 
and monitoring for signs of gastric 
distress, abdominal pain, and 
clinical signs of malabsorption.
Protocol also includes dose 
stopping/modifications criteria for 
the management of 
hypo/hyperglycemia.
Liver/Gallbladder
Non-adverse liver changes were observed in 
preclinical toxicology studies including 
increases in bilirubin levels and transient 
increases in AST in rats. Hepatocellular 
necrosis was observed in a single rat at a 
non-tolerated dose (30 mg/kg/day).
GSK525762 has been demonstrated to 
undergo bioactivation in vitro which indicates 
potential for idiosyncratic heptotoxicity.  The 
precursor metabolite has been observed in 
clinical plasma samples.
ICF includes the risk of 
hepatic/gallbladder effects.
Protocol includes hepatic eligibility 
criteria, laboratory assessments 
during the study, dose 
stopping/modifications criteria for 
the management hepatic events.
Lung effects
Aggregates of foamy macrophages in 
peribronchiolar areas were evident in rats 
given ≥10 mg/kg/day for 28 days.  Following 
the 3 week off-dose period, these changes 
were decreased in incidence.  This finding is 
unlikely to affect pulmonary function. No 
effects were observed in the 3 month 
toxicology studies. For more information, see 
the GSK 525762 IB [GlaxoSmithKline 
Document Number 2011N113741_06].
ICF includes the risk of lung 
effects.
Kidney
Eosinophilic inclusions and/or tubular 
basophilia were observed in the kidneys of 
rats in preclinical toxicology studies up to 3 
months dosing. These changes were 
Protocol includes renal monitoring 
including urinalysis (assessment 
for protein) and creatinine.
 
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Potential Risk of 
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Mitigation Strategy
considered non-adverse.
Effect on Teeth
Effects (disruption of dentin formation) on 
incisors (teeth that continually grow in 
rodents) were evident in male rats given ≥10 
mg/kg/day GSK525762 and both male and 
female rats at 30 mg/kg/day in the 13 week 
study, which resulted in pale and broken teeth 
during the in-life phase of the study from 
Week 8.  These microscopic effects were 
lower in severity and incidence after a 
minimum of 3 week off dose period.  No 
effects were observed in molar teeth (non-
growing).
Unlikely to affect adults.
Drug Interactions
GSK525762 is a substrate for CYP3A4 
enzymes, and for P-gp and breast cancer 
resistance protein (BCRP) transporters. 
GSK525762 clearance is virtually solely via 
CYP3A4.  There is evidence of potential auto-
induction after repeat dosing in clinical studies 
since reduction in parent exposures (~25% at 
lower doses to ≥60% at doses ≥60 mg, 
mainly in BET115521 study) have been 
observed.
There is low potential for GSK525762 to 
inhibit cytochrome P450 (CYP) enzymes or to 
inhibit P-gp or BCRP based on in vitro data.  
GSK525762 was shown to be an inhibitor of 
organic anion transporting polypeptide 1B1 
(OATP1B1) and organic anion transporter 3 
(OAT3) in vitro.
GSK525762 was shown to be a moderate 
inducer of CYP3A4 in a human hepatocyte 
induction study.
Use of concomitant medications, 
herbal medicines and fruit juices 
that are strong or moderate 
CYP3A4 inhibitors or inducers 
should be avoided during the 
course of the study where possible 
as they may respectively decrease 
or increase exposure to 
GSK525762.
Potent inhibitors of breast cancer 
resistance protein (BCRP) and P-
glycoprotein transporters, such as 
cyclosporine, tacrolimus, or 
ketoconazole, should be avoided.
Use of concomitant medications 
that are sensitive substrates of 
OATP1B1 and OAT3 should be 
done with caution.
Medications that have a narrow 
therapeutic index and that are 
substrates of CYP3A4 should be 
administered with caution, as their 
metabolism may be affected by co-
administration with GSK525762 
and result in decreased exposure. 
These include alfentanil, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, 
and theophylline.
 
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1.5.2.
Benefit Assessment
Study BET116183 is an open-label, dose escalation study and the first study of this agent 
to be conducted in subjects with hematological malignancies that have not responded to 
or have relapsed following standard therapy.  GSK525762 has promising preclinical 
activity in the hematological cell lines, however it is unknown whether GSK525762 will 
have clinical efficacy in subjects with hematological malignancies, thus any potential 
beneficial effect for an individual subject attributable to GSK525762 is unknown.  Data 
obtained in Study BET116183 may assist in progressing the knowledge base on advanced 
hematological malignancies and their treatment, or help identify individuals more likely 
to benefit or have side-effects from GSK525762.  Study participants may benefit from the 
medical tests and screening performed during the study.
1.5.3.
Overall Benefit: Risk Conclusion
Current data from GSK525762 preclinical development indicate a potential to inhibit the 
BET family of BRD proteins and that this inhibition may have clinical utility in the 
treatment of various tumors, including hematological malignancies.  Taking into account 
the measures taken to minimise risk to subjects participating in the Phase I clinical trials, 
the potential risks identified in association with GSK525762 are justified by the 
anticipated benefits that may be afforded to subjects with the previously mentioned tumor 
types that have been shown in preclinical models to respond to GSK525762.
1.6.
Communication Plan for Safety Evaluation
This phase I/II study is intended to enroll subjects at two or more sites.  Safety data will 
be closely monitored and reviewed by the GSK medical monitor, and/or clinical 
scientist(s), responsible for all studies of GSK525762 (e.g., the BET115521 solid tumor 
study).  There will be 2 way communication between the local participating sites and the 
GSK clinical team via email, fax and phone.  The GSK team will review all safety data 
throughout the study, and safety findings from all studies with GSK525762 will be 
discussed with investigators from all participating sites on a monthly basis and 
appropriate action will be taken.  Urgent safety information will be shared with all the 
participating sites at the earliest possible time after the data becomes available.  Emerging 
safety and tolerability data from the currently ongoing phase I study in solid tumors will 
also be communicated to the participating investigators in this study as appropriate at the 
monthly meeting, or sooner if necessary.
 
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2.
OBJECTIVES, ENDPOINTS, HYPOTHESES
Part 1
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, 
tolerability and maximum 
tolerated dose (MTD) following 
once daily (QD) administration, 
establishing the recommended 
Phase 2 dose (RP2D) of 
GSK525762 in adult subjects 
with acute myeloid leukemia 
(AML), multiple myeloma (MM), 
or non-Hodgkin’s lymphoma 
(NHL).

Adverse Events (AEs), Serious 
Adverse Events (SAEs), Dose Limiting 
Toxicity (DLT), dose reductions or 
delays, withdrawals due to toxicities 
and changes in safety assessments 
(e.g., laboratory parameters, vital 
signs, and cardiac parameters).
Secondary

To evaluate clinical efficacy 
following QD administration in 
subjects with AML, MM, and 
NHL.

Objective response rate (ORR), as 
measured by standard response 
criteria

To characterize the 
Pharmacokinetic (PK) of 
GSK525762 after single- and 
repeat-dose administration.

GSK525762 PK parameters following 
single- (Day 1) and repeat-dose 
(Day 15) administration of 
GSK525762, including Area under 
concentration-time curve(AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.
Exploratory

To evaluate the relationship 
between GSK525762 exposure 
and cardiac and other safety 
parameters.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC), following 
single and repeat-dose oral 
administration of GSK525762

To evaluate the relationship 
between GSK525762 
dose/exposure and 
pharmacodynamic response.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.

To evaluate the relationship 

Assess objective response rate (ORR) 
 
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Part 1 Objectives
Part 1 Endpoints
between GSK525762 dose and 
exposure with clinical activity of 
GSK525762
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical l samples.

To investigate the mechanism of 
action and indicators of 
sensitivity and resistance to 
GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response.
Hypothesis

No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in 
high-risk myelodysplastic 
syndrome (MDS) or acute myeloid 
leukemia (AML) that has evolved 
from an antecedent MDS 
(“myeloid cohort”).

For MDS Cohort: ORR (defined as the 
percentage of subjects achieving 
Complete Response (CR), Marrow 
CR, CRp [as per CR but platelet count 
<100 x 109/L], CRi [as per CR but 
platelet count <100 x 109/L or 
neutrophil count <1 x 109/L], or Partial 
Response [PR] per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in 
CTCL.

For CTCL: ORR4; defined as the 
percentage of subjects that have 
achieved a CR or PR, per global 
response criteria and the modified 
severity weighted assessment tool 
(mSWAT), lasting more than 4 months
Secondary

To evaluate the effect of 
GSK525762 on disease-related 
symptoms, as reported by 
subjects (CTCL cohort only)

For CTCL: measure the effects of skin 
disease based on quality of life 
questionaire Skindex-29

To characterize the PK of 
GSK525762 in 3 disease specific 
cohorts of subjects with 
MDS/AML, or CTCL after repeat-
dose administration.

Population PK parameters for 
GSK525762 such as apparent 
clearance following oral administration 
(CL/F) and volume of distribution 
(V/F), and relevant covariates which 
may influence exposure (e.g., age, 
weight, or disease associated 
covariates).

To evaluate the safety and 

AEs, SAEs, dose reductions or delays, 
 
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Part 2 Objectives
Part 2 Endpoints
tolerability of RP2D of 
GSK525762 in 2 disease-specific 
cohorts of subjects with 
MDS/AML, or CTCL.
withdrawals due to toxicities and 
changes in safety assessments (e.g., 
laboratory parameters, vital signs, and 
cardiac parameters) at RP2D.

To determine the clinical activity of 
GSK525762 in2 disease-specific 
cohorts of subjects with 
MDS/AML, or CTCL.

Progression free survival (PFS, time 
from treatment start date to disease 
progression or death due to any 
cause, whichever is earlier) for 
MDS/AML, andCTCL.
Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for MDS/AML, and CTCL.

Duration of response (DOR, time from 
onset of response to disease 
progression or death due to any 
cause, whichever is earlier in 
responders) for MDS/AML, and CTCL

Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for MDS/AML, and CTCL
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and safety 
profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To evaluate the exposure 
response relationship between 
GSK525762 and safety/efficacy 
parameters in 2 disease-specific 
cohorts of subjects with 
MDS/AML, orCTCL.

Relationship between GSK525762 
exposure markers and safety and 
efficacy parameters.

To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response; Leukemic stem 
cell studies; PDX model studies and 
other translational medicine studies. 
 
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Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Myelodysplastic syndrome and transformed MDS (myeloid cohort): A response rate of 
30% relative to a 10% response rate suggesting no activity in subjects with MDS/AML.  
This will be conducted by testing the null hypothesis that P0≤0.10 versus the alternative 
that P1≥0.300, assuming the maximum response rate for an ineffective drug is 0.10 and 
the minimum response rate for an effective drug is 0.30.

CTCL: A response rate, lasting more than 4 months, of 40% relative to a 20% response 
rate suggesting no activity in subjects with CTCL.  This will be conducted by testing the 
null hypothesis that P0≤0.20 versus the alternative that P1≥0.40, assuming the maximum 
response rate for an ineffective drug is 0.20 and the minimum response rate for an 
effective drug is 0.40. 
3.
INVESTIGATIONAL PLAN
3.1.
Study Design/Schematic
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Section 5 Time and Events Tables 
are essential.
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD in 
subjects with myeloid malignancies, multiple myeloma, and non-Hodgkin’s Lymphoma, 
and the recommended Phase 2 dose (RP2D) for GSK525762 given once-daily (QD) 
orally.  Part 1 will be conducted in adult subjects with relapsed and/or refractory myeloid 
malignancies, multiple myeloma, and non-Hodgkin’s lymphomas.  Part 2 will be 
conducted in adult subjects with relapsed and/or refractory myeloid malignancies and 
cutaneous T-cell lymphoma (Figure 2).
 
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Figure 2
Study Schema
In both Parts 1 and 2, subjects may be evaluated for systemic BET inhibitory effects in 
blood (whole blood transcriptional). A subset of subjects in Part 1 may also be evaluated 
for plasma cytokine profiling..  In addition, pre-treatment and post-treatment bone 
marrow, skin, whole blood for PBMC isolation or lymph node samples will be collected 
from selected subjects to be evaluated for target engagement and effects of GSK525762 
on tumor biology.
All study treatment(s) including investigational product will be referred to as ‘study 
treatment(s)’ for ease of presentation throughout the protocol.  For EU regulatory 
purposes, the term ‘investigational product’ will only be used in Section 7 when 
describing the GSK compound under investigation.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
3.2.1.
Part 1: Dose Escalation
In Part 1, an accelerated dose titration will be employed with one subject per dose level 
until the first instance of a ≥ Grade 2 drug related non-hematological toxicity, (except for 
 
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a pre-specified Grade 3 non-serious non-hematological drug related adverse event that 
would allow continuation of accelerated dose escalation; Section 3.2.1.6). During 
accelerated dose titration, there will be a single cohort comprised of all eligible subjects; 
parallel cohorts will not be evaluated during this stage. 
Thereafter, subjects will be enrolled in a standard 3+3 design.  Separate dose escalation 
cohorts will be opened for subjects with AML, NHL, and MM.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the recommended dose from Neuenschwander continual 
reassessment method (N-CRM) design [Neuenschwander, 2009].  N-CRM design is a 
type of Bayesian adaptive dose escalation scheme.  The method is fully adaptive and 
makes use of all the DLT information available at the time of each dose assignment.  The 
DLT information of all subjects enrolled in the trial are used to update the dose-toxicity 
relationship and provide supportive information in addition to 3+3 design in the next 
escalation/de-escalation decision.
Dose escalation will continue until an MTD is determined or until a dose of 200 mg per 
day is reached.  After the MTD has been determined in Part 1 for each disease type, then 
the Part 2 dose expansion cohorts will be opened for that disease type. 
Due to the potentially different MTD in subjects with myeloid neoplasms, NHL, and MM 
(Section 1.3.2), each dose escalation step will be evaluated separately for the three 
disease types. 
3.2.1.1.
Dose Escalation and Schedule
A staggered dosing schedule will be implemented to monitor for safety including any 
delayed toxicity.  This approach allows repeat dosing in a step-wise fashion to detect 
changes in safety, such as cardiotoxicity.  Based on a low risk of drug accumulation and 
the aggressive nature of relapsed and/or refractory hematologic malignancies, a three 
week period will be used for DLT monitoring and dose escalation decision making.  
Alternative dosing regimens and/or schedule may be implemented based on emerging PK 
and safety data and without requiring a protocol amendment.
Extensive monitoring for cardiac safety signals will be performed including 12-lead ECG 
on the days indicated in the Time and Events Table. 
3.2.1.2.
Accelerated Dose Escalation in Part 1
One subject per dose level in the accelerated dose escalation schema will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 and continuing until one 
subject experiences ≥Grade 2 drug related non-hematological toxicity, or DLT (except 
for pre-specified Grade 3 non-serious non-hematological drug related adverse event, see 
Section 3.2.2) (Table 2).  Once this occurs, the accelerated dose escalation will terminate, 
and subjects will be enrolled in one of three disease-specific cohorts (AML, MM, or 
NHL) under a standard 3+3 design (Section 3.2.1.3).  
 
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Table 2
Accelerated Dose Escalation Procedures in Part 1
Dose Level
Change in Dose
Dose Level -1
Lower doses may be used if Dose Level 1 is not tolerated.  This may be 
achieved by reducing the dose or by alternate dosing (e.g. every other day)
Dose Level 1
Starting Dose at 5 mg once daily 
Subsequent dose levels
Increase by 2-fold after a subject clears the previous dose cohort
(No subjects with Grade 2 drug related toxicity AND no subjects with any 
DLTs in first 3 weeks of treatment)
End of Accelerated Titration 
Phase
Begin 3+3 Dose Escalation Phase
(1 subject Grade 2 drug related non-hematological toxicity in the first 3 
weeks of treatment) or Grade 3 drug related specific toxicity)
NOTE: Route/Administration/Duration: Oral QD (specific dosing instructions will be provided to each subject)
3.2.1.3.
3 + 3 Dose Escalation in Part 1
Due to the potentially different MTDs in myeloid neoplasms, MM, and NHL, dose 
escalation will be evaluated in three separate cohorts divided by disease subtype.  These 
cohorts will be evaluated in parallel with each other, and DLT/MTD determination will 
be made separately for each cohort.  
Upon termination of accelerated dose titration, two additional subjects with the final 
disease type will be enrolled, for a total of three subjects with that disease type at that 
dose level.  Three additional subjects with each of the two other disease subtypes will 
also be enrolled at that dose level, for a total of nine subjects at each dose level.
Subjects unable to receive at least 75% of scheduled doses for reasons other than toxicity 
(e.g., acute illness, disease progression) will not be evaluable for DLT purposes and will 
be replaced in the cohort.
For each cohort, if no DLTs are observed in any of the 3 subjects, then dosing will 
proceed to the next higher dose level (≤2fold increase in dose).  Subjects within each 
cohort will be entered in a staggered approach with at least 3 days between each subject 
to minimize the risk of inadvertently exceeding the MTD in multiple subjects.  Each 
disease cohort may initiate dosing independent of the other two (i.e., subjects with 
different diseases may start therapy <3days apart, but subjects with the same disease must 
be separated by at least three days). Escalation to the next dose level will not increase 
greater than 2 fold from the previous dose level.  If 2 or more DLTs in 6 subjects are 
observed at any dose level, the MTD will have been exceeded (Table 3).
 
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Table 3
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to the next dose level with increase 100% if there have been 
less than 2 subjects with Grade 2 toxicity  and no DLTs (first 3 weeks 
of treatment in any cohort)
Escalate to next dose level with an increase of 50% if, in the first 
3 weeks of any cohort, there have been:
- two or more subjects with Grade 2 toxicity
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded.  Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to 15 subjects
Once the MTD is reached and RP2D is determined, up to 12 additional subjects within 
each cohort may be enrolled at the MTD to evaluate safety, additional PK, and obtain 
clinical samples for pharmacodynamic biomarkers.  Additional subjects may be enrolled 
at the MTD, and at least 1 dose level below MTD, to confirm if the MTD is appropriate 
for AML, MM and NHL subjects. Up to an additional 6 subjects may be enrolled at any 
dose level below the MTD in order to obtain additional clinical specimens for 
pharmacodynamic biomarkers to better understand the dose/exposure/pharmacodynamic
relationship.  Additional cohorts (with daily exposure not exceeding MTD exposure) may 
also be initiated to explore alternative dosing schedules to optimize the PK, safety and 
tolerability profile.  The enrolment of additional subjects as described could be in parallel 
with Part 2 enrolment.  Although DLT will not be based on the additional subjects 
enrolled into the study to further evaluate safety, PK, to obtain tumor tissue for 
biomarkers, data from these additional subjects will be considered in defining final MTD 
and RP2D (Figure 3).
 
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Figure 3
Dose Escalation Schema (Part 1)
3.2.1.4.
Alteration of Schedule
Alterations may be made to the schedule of administration and/or PK/pharmacodynamic
sampling schedule based on the results of emerging PK and safety data.
Schedules that incorporate a recovery period may be explored (e.g., 2 weeks on, 1 week 
off).  This approach will be considered if the safety and PK data suggest that a 
therapeutic exposure cannot be achieved using the initial schedule without excessive 
toxicity.  The starting dose for the alternate schedule will be the highest completed dose 
level (at or below MTD) with the initial schedule.  Escalation can then proceed as 
described using 3 + 3 dose escalation.  If alternative dosing schedules are explored, PK 
sampling times and other safety assessments may be modified to reflect the new dosing 
schedule.
Subjects may need to undergo dose modification(s) to manage toxicities.  A dose 
adjustment may be made after consultation with the GSK medical monitor. The 
investigator should use clinical judgment to determine whether the dosing scheduling 
may be contributing to any potential toxicity necessitating dose adjustment, and make the 
appropriate change after consultation with the GSK Medical Monitor.
 
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In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling (pre-dose, 0.5, and 3 
hours) at the new dose level, after at least 7 days at the adjusted dose level.
3.2.1.5.
Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that a 
higher dose level cohort (accelerated phase or 3+3 phase) has been cleared, and after 
review of all safety data and approval by a GSK Medical Monitor and discussion with the 
investigator.  The subject on a lower dose level may be increased up to the highest dose 
level cleared.  In this case, the subject may begin daily dosing at the higher dose level as 
it will have already been demonstrated to be tolerable and monitoring will be performed 
as described in the protocol.
Subjects approved for intra-subject dose escalation may require additional limited PK 
sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by GSK 
Clinical Pharmacology, after at least 7 days at the adjusted dose level. Additional safety 
assessments may be specified at the time of dose escalation or schedule modification 
based on the safety profile in previous subjects at the higher dose level.
3.2.1.6.
Toxicity Leading to Termination of Accelerated Titration
The following events will result in an end to accelerated dose escalation:

Any Grade 2 or higher adverse event (except drug related Grade 3 fatigue, asthenia, 
and nausea that respond to standard medical care within 48hrs, Grade 3 or higher 
electrolyte abnormalities unrelated to underlying malignancy and corrected in 48 hrs) 
that is considered related to the study medication and which do not improve with 
standard medical care within 48hrs. Disease related events such as abnormalities in 
hematologic parameters for acute leukemia will not be considered.

Grade 2 QTcF prolongation (confirmed on triplicate ECGs by manual reading) 
Grade 2 alanine aminotransferase (ALT) increase (unless clearly attributed to the 
underlying disease).

Any grade adverse events that are considered in the judgment of the investigator and 
GSK Medical Monitor to be serious and related to the drug and requiring addition of 
additional subjects to better understand the toxicity.
3.2.2.
Dose Limiting Toxicity (DLT)
An event will be considered a DLT if it occurs within the first 3 weeks of treatment and 
meets one of the following criteria unless it can be clearly established that the event is 
unrelated to treatment.  As described in Section 3.2.1.3, subjects unable to receive at least 
75% of scheduled doses for reasons other than toxicity (e.g., acute illness, disease 
progression) will not be evaluable for DLT purposes and will be replaced in the cohort. 

Prolonged myelosuppression, as follows: 

For myeloma or lymphoma:
 
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
Grade 4 neutropenia persisting for ≥7 days or febrile neutropenia not 
responding to treatment within 24h 

Grade 4 thrombocytopenia lasting more than 7 day and not responding to 
transfusions, or Grade 3 thrombocytopenia associated with bleeding (>10mL) 

Drug-related Grade 3 or 4 non-hematologic toxicity (including QTcF prolongation) 
as described in the National Cancer Institute-Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v4.0 [NCI, 2009] (excluding abnormalities of alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) (see criteria below).  In 
addition, the DLT exceptions include: rash, diarrhea, fatigue, mucositis, nausea, and 
vomiting or new electrolyte disturbance that do respond to standard medical care 
within 72 hours.  Electrolyte disturbances associated with underlying malignancy are 
excluded.

Drug-related Grade 2 non-hematological toxicity (at any time during treatment) that 
in the judgment of the investigator and GSK Medical Monitor is dose-limiting.

Grade 2 Troponin T elevation (central laboratory >Upper Limit of Normal [ULN]), 
measured on two separate occasions within 48 hours in order to confirm elevation 
and with other clinical signs, symptoms, and/or laboratory tests consistent with
cardiac toxicity.  In the event a troponin T [central laboratory assessment] is not 
performed or a laboratory error occurs, considerations for a DLT criterion will 
involve review of two separate local troponin (I or T) assays done within 48 hours at 
a local investigator site.  Troponin I or T elevations greater than the upper limit of 
normal will be considered as a Grade 2 elevation).

Treatment delay of 14 days or greater due to unresolved drug-related toxicity 
(Treatment delays due to underlying malignancy are excluded).

ALT 3xULN + bilirubin ≥2xULN (>35% direct) or ALT between 3-5xULN with 
bilirubin <2xULN but with hepatitis symptoms or rash or ALT 5xULN.
3.2.3.
Maximum Tolerated Dose (MTD) and Recommended Phase 2 
Dose (RP2D)
The MTD will be exceeded if 2 or more subjects in a cohort of up to 6 subjects 
experience a DLT.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available pharmacodynamic data generated from 
all subjects in Part 1 for that disease type.  If necessary alternate schedules can be 
explored to determine additional biologically active doses even after a RP2D is defined.
3.2.4.
Part 2: Disease Specific Expansion Cohorts
Up to 32 subjects with myelodysplastic syndrome and up to 37 subjects with CTCL (as 
defined in Section 4.2.1), may be enrolled in an expansion cohort at the RP2D.  These will 
be conducted to gather more safety data and to further assess anti-tumor activity.  
Subjects in Part 2 will start with a continuous daily dosing schedule unless safety or PK 
data necessitate a different dosing schedule.  The final dose and regimen for Part 2 will 
be decided upon completion of dose escalation in Part 1.
 
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Plasma samples for PK evaluation will be collected in all subjects.  The Part 2 portion of 
the study will employ a Bayesian design that allows the trial to be monitored with the 
constraint of both Type I and Type II error rates.  Clinical response will be defined per 
standard evaluation criteria (see Appendix 6, Appendix 7 and Appendix 8).  Patient-
reported outcome questionaire, Skindex 29 (Appendix 11) will be used to gauge the 
effects of treatment with GSK525762 on the quality of life and other subjective measures 
in subjects with CTCL.
For each cohort, the first interim analysis will be conducted after at least 10 subjects 
become evaluable (have had at least one-post baseline disease assessment, have 
progressed or died, or have discontinued from study treatment) in the MDS and CTCL
cohorts respectively. The number of subjects may be increased up to a total of 32 for the 
MDS cohort and up to a total of 37 for the CTCL cohort, depending on the results 
observed; a separate decision will be made for each disease cohort.  The decision rules, 
specifying the number of subjects with a clinical response needed for continuing 
enrolment or, stopping for futility, are indicated in Figure 4 and Figure 5.  The 
methodology is based on the predictive probability of success if enrolment continues to 
maximum number of subjects for MDS and CTCL.  Subjects enrolled in Part 1 with the 
same type of disease as Part 2, and treated at the RP2D, will be included in the Part 2 
analysis.  These rules are intended as a guideline.  Actual decisions will depend on the 
totality of the data.
For MDS and CTCL cohorts: when 10 subjects are included in the first interim analysis, a
single responder in a cohort will be adequate to pursue further enrolment. The number of 
observed confirmed responses will guide further enrolment according to the rules 
summarized in Figure 4 and Figure 5. A maximum of 32 subjects with MDS and 37
subjects with CTCL will be enrolled at the RP2D.  All available data will be considered 
in making enrolment decisions.
 
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Figure 4
Diagram of Stopping Rules for MDS Cohort Expansion
Number of Responders
Number of Subjects
0
1
2
3
4
5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if 
there is no response in 10 subjects, then the predictive probability for success will be 1% or less 
(the futility criterion) and further enrollment in these cohorts may be stopped.
 
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Figure 5
Diagram of Stopping Rules for CTCL Cohort Expansion
Number of Subjects
0
1
2
3
4
5
6
7
8
9
10
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if there is no response in 
10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and further enrollment in 
this cohort may be stopped.
 
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4.
STUDY POPULATION
4.1.
Number of Subjects
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study.  To 
complete Part 1, it is estimated 60 to 70 evaluable (as described in Section 11) subjects 
will be enrolled.  Part 2 will enroll up to 69 subjects (two disease-specific cohorts of 32
and 37 subjects, for the MDS and CTCL cohorts, respectively)
See Section 11.1 for sample size assumptions.
If a subject discontinues the study before completing Week 3 during Part 1 due to reasons 
other than toxicity, additional subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator to ensure an adequate population for DLT and MTD 
evaluations.
4.2.
Eligibility Criteria
4.2.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events 
(AEs), and other pertinent information on the GSK study treatment that may impact 
subject eligibility is provided in the GSK525762 Investigator Brochure 
[GlaxoSmithKline Document Number 2011N113741_06].
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential. Additional details 
regarding the enrollment and registration process for this study can be found in the Study 
Procedures Manual.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply and after consultation with GSK:
1. Written informed consent provided.
2. Males and females 18 years old or older.
3. Subjects must have a diagnosis of one of the following hematologic malignancies, 
which has relapsed or been refractory to treatment as follows. (Part 1 only) 
Subjects with AML, are eligible if they 
o have relapsed and/or refractory disease, OR
o are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

(Part 2 only): Subjects with MDS/AML are eligible if they:
 
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o Have high-risk (defined as intermediate [INT]-2 or higher by International 
Prognostic Scoring System [IPSS] criteria [Greenberg], or high/very high 
by IPSS-Revised [IPSS-R] criteria [Greenberg]) MDS that has relapsed 
after or been refractory to prior therapy with hypomethylating agent, OR
o Have AML that has arisen from an antecedent MDS (irrespective of 
IPSS/IPSS-R score; subjects without a documented history of antecedent 
MDS/MPN must have AML with myelodysplasia-related changes or 
recurrent cytogenetic abnormalities per World Health Organization 
[WHO] criteria)

Subjects with secondary AML must have progressed despite, or 
failed to respond to, prior therapy with hypomethylating agent, AND

Subjects must have hypoproliferative disease, defined as either:

A peripheral white blood cell count of less than 20,000 
cells/µL in the absence of leukoreducing therapy (e.g., 
hydroxyurea, leukapheresis), OR

At least one bone marrow biopsy obtained within 28 days 
of first dose of GSK525762 must demonstrate a marrow 
blast percentage of no more than 30%
Note: If marrow blasts exceed 30% on any biopsy within 
28 days of first dose, enrolment will only be permitted after 
discussion with the medical monitor

(Part 1): Subjects with multiple myeloma are eligible if they have progressed 
despite therapy with an alkylating agent, proteasome inhibitor, and 
immunomodulatory agent, either as individual regimens or in combination

(Part 1 Only): Subjects with NHL are eligible if they have received at least 
two prior lines of systemic therapy, including at least one line of 
immunochemotherapy with an anti-CD20 antibody (if their tumor expresses 
CD20)

(Part 2 only): Subjects will be eligible for enrolment into the CTCL cohort if 
they:
o
Have histologically- or cytology-proven diagnosis of CTCL 
(mycosis fungoides [MF], Sézary syndrome [SS], primary 
cutaneous anaplastic large cell lymphoma [pcALCL], or large cell 
transformation of underlying MF/SS) that has failed to respond to, 
or progressed despite, at least one prior systemic therapy
4. Subjects with a prior history of stem cell transplant (autologous and/or allogeneic) 
are allowed if:

At least 3 months has elapsed from the time of transplant and

the subject has recovered from transplant-associated toxicities prior to the 
first dose of GSK525762, and
 
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
For subjects with a prior history of allogeneic transplant, 
o
the subject has been off systemic immunosuppressive medications 
(including but not limited to: cyclosporine, tacrolimus, mycophenolate 
mofetil, or corticosteroids) for at least 1 month prior to the first dose of 
GSK525762.  Topical steroids are permitted.
o
there are no signs or symptoms of graft versus host disease, other than 
Grade 1 skin involvement.
5. Eastern Cooperative Oncology Group (ECOG) performance status of:
o
1 for all Part 1 Cohorts (AML, MM, and NHL) 
o
2 for all Part 2 cohorts (MDS/AML and CTCL)
6. Subject must be stable enough to be expected to complete dosing through the 
DLT observation period as assessed by 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. A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea [in questionable cases, a blood sample 
with simultaneous follicle stimulating hormone (FSH) >40 MlU/mL and 
estradiol <40 pg/mL (<140 pmol/L) is confirmatory].  Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the contraception methods defined in protocol 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.  For most forms of HRT, at least two to four weeks will 
elapse between the cessation of therapy and the blood draw; this interval 
depends on the type and dosage of HRT.  Following confirmation of their 
post-menopausal status, they can resume use of HRT during the study without 
use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraception methods 
(described in Section 9.1) for an appropriate period of time (as determined by 
the product label or investigator) prior to the start of dosing to sufficiently 
minimize the risk of pregnancy at that point.  Female subjects must agree to 
use contraception until at least 7 months after the last dose of study 
medication.

Negative serum pregnancy test ≤7 days prior to first study drug dose.

Female subjects who are lactating must discontinue nursing prior to the first 
dose of study treatment and must refrain from nursing throughout the 
treatment period and for 5 half-lives of GSK525762 or at least 28 days 
(whichever is longer) following the last dose of study treatment.
 
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9. Male subjects with a female partner of childbearing potential or a female partner 
who is pregnant must agree to use one of the methods of contraception specified
in Section 9.1.  This method must be used from the time of the first dose of study 
medication until 16 weeks after the last dose of study medication. In addition, 
male subjects whose partners are or become pregnant must use/continue to use 
condoms until 16 weeks after last dose of study medication.
10. Adequate organ system functions (at both screening and where applicable pre first 
dose) as defined in Table 4.
11. Ability to comply with dietary and tobacco/alcohol abstinence requirements as 
defined in Section 9.2.
Table 4
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Hemoglobin (only for myeloma and lymphoma)
≥8.0 g/dL
Coagulation assays (prothrombin time/ international 
normalized ratio [PT/INR] and activated partial 
thromboplastin time [aPTT]1
1.2 X upper limit of normal (ULN)
Platelets (for subjects with lymphoma)
Platelets (for subjects with MM)
Platelets (for subjects with acute leukemia)
≥75,000 (transfusion independent)
≥50,000 (transfusion independent)
10,000 (transfusions permitted to bring platelet 
count to >10,000)
Hepatic
Total bilirubin
≤1.5 X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of 
Gilbert’s syndrome)
Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST)
2.5 X ULN 
Renal3
Creatinine3
OR
Calculated creatinine clearance [calculated by Chronic 
Kidney Disease Epidemiology Collaborative (CKD-Epi) 
method 2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN 
≥50 mL/min
≥50 mL/min
Cardiac
Ejection fraction
≥Lower limit of normal (LLN) by echocardiogram 
(ECHO) (minimum of 50%) or Multi Gated 
Acquisition (MUGA) scan
Troponin (T)
≤ULN
Thyroid
Thyroid stimulating hormone (TSH) 4
≥LLN and ≤ULN
1.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2.
2.
See Appendix 1 for CKD-Epi formula.
3.
For MM subjects, adequate renal function is defined as serum creatinine ≤2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥ 30 mL/min.
4.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
 
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4.2.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Haematological malignancy associated with human immunodeficiency virus 
(HIV) infection or solid organ transplant or positive Hepatitis B Antigen or 
positive Hepatitis C antibody at screening (subjects with positive Hepatitis C 
antibody may be enrolled, provided that the confirmatory test [e.g. Heptatitis C 
Virus Hepatitis C Virus [HCV] Ribonucleic acid [RNA] polymerase chain 
reaction [PCR] is negative).
2. History or concurrent malignancy of solid tumours, except for below.
Exception:  Subjects who have been disease-free for 5 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated 
in situ carcinoma are eligible.  Subjects with second malignancies that are 
indolent or definitively treated may be enrolled even if less than 5 years have 
elapsed since treatment.  Consult the GSK Medical Monitor if unsure whether 
second malignancies meet requirements specified above.
3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno-
therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization).
Note: the following are allowed:
Hydroxyurea for proliferative disease
Corticosteroids (topical and/or systemic)
Use of hematopoetic growth factors is permitted at the discretion of the 
investigator according to published guidelines (e.g., National 
Comprehensive Cancer Network (NCCN), American Society of Clinical 
Oncology (ASCO), American Society of Hematology (ASH), etc.).
Note: the following are NOT allowed:
Investigational anti-cancer drug within 2 weeks prior to the first dose of 
GSK525762
Major surgery, radiotherapy, or immunotherapy within 4 weeks of 
GSK525762
Chemotherapy regimens with delayed toxicity within the last 4 weeks.  
Chemotherapy regimens given continuously or on a weekly basis with 
limited potential for delayed toxicity within the last 2 weeks.  
Nitrosourea or mitomycin C within the last 6 weeks
 
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4. Evidence of severe or uncontrolled infection.
5. Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days 
prior to the first dose of GSK525762.  Low dose (prophylactic) anticoagulants
(e.g., low molecular weight heparin (LMWH) or oral anticoagulants) is permitted.  
In addition, INR must be monitored in accordance with local institutional 
practices, as appropriate.
6. Current use of a prohibited medication or planned use of a forbidden medication 
during treatment with GSK525762.
7. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes).  Any serious and/or unstable pre-existing medical (aside from 
malignancy 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.
8. Symptomatic or untreated CNS disease,

Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are 
permitted to enrol if they have previously received appropriate therapy and 
CNS remission has been documented.

Subject with primary CNS lymphoma (defined as isolated CNS lymphoma 
without systemic involvement) are excluded from study.
9. Cardiac abnormalities as evidenced by any of the following:

History or current clinically significant conduction abnormalities, 
uncontrolled arrhythmias or hypertension.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA) [Appendix 2].

Recent history (within the past 3 months) of acute coronary syndromes 
(including unstable angina and myocardial infarction), coronary angioplasty, 
or stenting.
10. Any of the following ECG findings or assessments including:

Baseline QTcF interval ≥480 msec 

Clinically significant ECG assessments should be reviewed by the site 
cardiologist prior to study entry.
11. GSK525762 is a benzodiazepine class molecule.  Any serious known immediate 
or delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs 
chemically related to the investigational drug.
12. Evidence of hemoptysis within the last 7 days.
13. History of major gastrointestinal bleeding within the last 3 months or any 
evidence of active gastrointestinal bleeding excludes the subject (refer to 
Section 1.5).
 
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14. Presence of gastrointestinal disease that would significantly affect compound 
absorption.
4.2.3.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria
4.2.3.1.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry defined in 
Appendix 3 or for hematologic and other non-hematologic toxicity in Appendix 4.  After 
disease progression, subjects may be allowed to continue treatment with study drug if the 
investigator strongly believes, and the Sponsor Medical Monitor concurs, that the subject 
could continue to receive benefit, the subject is not experiencing serious toxicity, and 
there is no alternative treatment that could benefit the subject.  For subjects with CTCL, 
in cases where the definition of progressive disease (PD) or relapse is met but the clinical 
impression is questionable, documentation for a period of at least 4 weeks is also 
recommended to avoid a subject being removed prematurely from the study.
In addition study treatment will 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 dose delay of >14 days unless the investigator or GSK Medical Monitor agree that 
further treatment may benefit the subject

intercurrent illness that prevents further administration of study treatment(s)

subject is lost to follow-up

study is closed or terminated
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF).  If a subject dies 
while on study, the cause of death should be recorded in the eCRF.
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated.
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in the 
Section 5 Time and Events Tables.
All subjects who permanently discontinue study treatment without disease progression
will be followed for progression according to the protocol schedule until:
 
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
progression

death, or

subject has been followed for 2 years after stopping treatment
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy every 6 months until death or until the subject has been 
followed for 2 years.  Reporting of any pregnancies in female subjects and/or female 
partners of male subjects will also be collected until 7 months after the last dose of study 
drug.  Upon discontinuation, any samples previously collected for pharmacodynamic
and/or translational research will be retained and tested as defined in the protocol, unless 
consent is specifically withdrawn.
4.2.3.2.
Subject Completion
In Part 1, a subject will be considered to have completed the study if:

they complete screening assessments, the 21-day DLT observation period, and the 
end-of-treatment follow-up visit,

they progress or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
In Part 2, a subject will be considered to have completed the study if the subject is 
followed until death or the end of study.
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  A subject will be considered to have withdrawn from the 
study if the subject has not died and is lost to follow-up, has withdrawn consent, or at the 
investigator’s discretion is no longer being followed.  The End of Study eCRF should 
only be completed when a subject is no longer being followed.  The study may be 
considered completed for purposes 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.
4.2.4.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment.
5.
TIME AND EVENTS TABLES
This section consists of the Time and Events Table(s) and supplemental footnotes to 
describe assessment windows and sequencing of study-specific assessments and 
procedures
 
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Table 5
Time and Events: Part 1
From W10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W5
W6
W7
W
10
q3w
q6w
E
O
T
D
1
D
2
D
3
D
5
D
6
D
7
D
1
D
6
D
7
D
1
D
1
D
1
D1
D
1
D
1
D
1
D
1
Informed consent
(Unless otherwise 
noted, screening 
assessments to 
be completed 
within 14 days of 
first dose.)
X
Demography
X
Medical historya
X
Disease 
characteristics
X
Cardiology eval.
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug: For details see Table 8
Administer study drug (Administer 
about same time of day. No food or 
antacids 1h before and 2h after.)
Daily
Review subject diary 
(Not required when dosed in clinic.)
X
X
X
X
X
X
X
Safety
Pregnancy test/ testosterone b
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital Signs c//Pain Assessment
X
X
X
X
X
X
X
X
X
X
X
Height and weight (Height at Scr only)
X
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 6.7.4)
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 6
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
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Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W5
W6
W7
W
10
q3W
q6w
E
O
T
D
1
D
2
D
3
D
5
D
6
D
7
D
1
D
6
D
7
D
1
D
1
D
1
D1
D
1
D
1
D
1
D
1
Cardiac Monitoring
ECHO or MUGA (Within 35 days of 
first dose)
X
X
X
X
X
X
12-lead ECGs e
X
O
O
X
O
X
X
O
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 8
PK Blood samples for GSK525762
X
Xk
Xh
X
X
X
Xk
X
Xf
PD Tumor Sample 
Xg
Xh
Translational Research i
Pharmacogenomics (PGx) sample
X
Blood sample for exploratory 
translational research
X
Additional samples will be collected on the date of disease assessment/bone marrow biopsy and date of progression or when 
patient is discontinued from study/end of treatmentj
Tumor biopsy at progression
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for subjects 
who discontinue study medication due to any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have completed the study 2 years 
after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 
years after the last subject is enrolled in Phase 2.
a.
Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the medical 
history and disease status.
b.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter. Pregnancy 
testing not required for females of non-childbearing potential as defined in Section 4.2.1.
c.
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, respiratory rate and temperature
d.
12-lead ECGs : Screening ECGs within 14 days of first dose.  For timing of ECGs on “O” days, see Table 8 for QD. Otherwise, ECGs at approximately same time of day, and prior to 
dosing. 
e.
For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W. Reduce to q12w after 12 months on study.
f.
Pretreatment biopsy for pharmacodynamic tumor sample must be performed within 14 days of first dose.
g.
During 3+3 dose escalation, pharmacodynamic tumor sample collection will be mandatory unless infeasible to collect, and approval is obtained by the GSK medical monitor.  Subjects 
with MM will have bone marrow aspirates collected on W1 D3 within 3-6 hours after the dose.  Subjects with AML will have bone marrow aspirates or peripheral blood collection 
(provided that there are sufficient leukemic cells in the peripheral circulation) collected on W1 D3 within 3-6 hours after the dose. Subjects with NHL will have a tissue biopsy (lymph 
node or other affected organ/region) collected on W1D3 within 3-6 hours after the dose. Timing of tissue collection will be based on tumor type and may be modified based on 
 
 
 
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emerging data. For operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection remain as described. A PK sample will need to be 
obtained within 1 hour of the tissue sampling.  See Table 7 disease specific assessments for details).
h.
Refer to Section 6.6 for details on Translational Research and Appendix 5 for details on PGx Research.
i.
Refer to Table 7 Disease Specific Assessments for timepoints. 
j.
Assessment only completed for Part 1 QD subjects
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; MUGA=multi-gated acquisition scan; PGx=Pharmacogenetics; COPD=Chronic obstructive pulmonary disease; SPM=Study Procedures Manual; D=day; EOT=End-of-
Treatment; q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; W=week
 
 
 
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Table 6
Time and Events: Part 1 Laboratory Assessments
q3w and 
q6w Initiated 
from Wk 10
NB: Collect blood samples prior to dosing.  W1D1 samples not needed if SCR 
sample collected within 24h of first dose.
SCR
W1
W2
W3
W4
W5
W6
W7
W10
q3W
q6W
EOT
Assessment
Notes
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, 
NT pro-BNP
Troponin:  Collect 2 samples: 1 sample for local lab 
[troponin I or T], 1 sample for central lab [troponin T])
X
X
X
X
X
X
X
X
X
X
X
Hematology
Increase frequency as medically indicated 
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
Factor VII Assay
In addition to scheduled timepoints, perform if PT or INR 
or aPTT are 1.5XULN, or in case of bleeding event
X
X
X
Creatine phosphor-
kinase 
X
X
X
X
X
X
X
X
X
X
X
CK-MB
CK-MB at predose and 12-18 h post dose take on W1D1, 
and as clinically appropriate.
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
LDH
X
X
X
X
X
X
X
X
Fasting blood 
glucose and insulin
Will be performed at central lab if not available at local lab
X
X
X
X
X
X
X
X
X
c-peptide and 1, 5 
AG
Will be performed at central lab if not available at local lab; 
performed at baseline and repeated if necessary during 
the study.
X
HbA1c
Performed at baseline and repeated if necessary during 
the study.
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4. If TSH is abnormal W1D1, monitor 
TSH, free T3 and free T4 going forward
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
 
 
 
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q3w and 
q6w Initiated 
from Wk 10
NB: Collect blood samples prior to dosing.  W1D1 samples not needed if SCR 
sample collected within 24h of first dose.
SCR
W1
W2
W3
W4
W5
W6
W7
W10
q3W
q6W
EOT
Assessment
Notes
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Pregnancy test, 
females
Serum pregnancy test within 7 days of first dose; urine or 
serum test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at SCR; free testosterone 
thereafter
X
X
X
X
X
X
HBsAg, HepC 
antibody
If hepatitis C antibody positive, a confirmatory study (e.g., 
HCV RNA PCR) should be performed as per local 
standard
X
Abbreviations: 1,5 AG=1,5-Anhydroglucitol, NT-pro BNP=N-ternimal prohormone B-type Natriuretic Peptide; C=cycle; CK-MB=Creatine Kinase – MB (isoform); LDH=Lactate 
dehydrogenase; TSH=Thyroid stimulating hormone; HBsAg = Hepatitis B surface Antigen; HepC=Hepatitis C; HCV Hepatitis C Virus; RNA=Ribonucleic acid; PCR=polymerase chain 
reaction; D=day; EOT=End of Treatment Visit; q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; W=week
 
 
 
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Table 7
Disease Specific Assessments
Multiple Myeloma (MM) Assessments (Part 1)
q3w and q6w Initiated from Wk 10
Procedure
Notes
SCR
W4
W7
W10
q3W
q6W
EOT
D1
D1
D1
D1
D1
Disease Characteristics 
Including cytogenetics as appropriate 
X
Total Protein, CRP, 2 
microglobulin
X
X
X
X
X
SPEP, FLC assay, quantitative 
immunoglobulins ( IgG, IgA, IgM)
Not required for subjects with non-
secretory MM; 
X
X
X
X
X
UPEP
Only required if paraprotein is 
present in urine
X
X
X
X
Extramedullary Disease 
Assessment 
Only required for MM with 
extramedullary disease
X
X
X
X
Blood sample for exploratory 
translational research
A blood sample for exploratory 
translational research should be 
collected at EOT and/or date of 
progression and at timepoints as 
indicated
X
X
X
X
X
BM aspirate and biopsy 
Required for non-secretory MM, or as 
appropriate for other subjects
X
X
Response assessment
Every 6 weeks after wk4; Response 
criteria in Appendix 6
X
X
X
X
 
 
 
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NHL Assessments (Part 1)
q3w and q6w Initiated from Wk 10
Procedure
Notes
SCR
W4
W7
W10
q3W
q6W
q12W
EOT
D1
D1
D1
D1
D1
D1
Disease characteristics, including historya
immunophenotypes, cytogenetics  and 
prognostic markers b
X
2-microglobulin
X
X
B Symptoms
X
X
X
X
X
Lymph node and organ exam
X
X
X
X
X
Bone marrow/tissue biopsy c
X
X
Blood sample for exploratory translational 
research
X
X
Wk 16, wk 24, then 
q12wks
Xg
CT Scan d
X
X
Wk 16, wk 24, then 
q12wks
X
PET Scan d, e 
X
X
Response evaluation f
X
Wk 16, wk 24, then 
q12wks
X
a.
Including date of first diagnosis, disease stage, and complete history of diagnostic results and therapies.
b.
Examples of prognostic markers may include:  ALC, FLIPI-1, FLIPI-2 (includes β2-microglobulin), FcR gamma 3A.
c.
A sample will be required at screening only if clinically appropriate for the lymphoma subtype AND an appropriate previous sample is available. A follow-up bone marrow biopsy will 
be performed no later than 8 weeks following CR (as judged by investigator) in accordance with the response guidelines (Appendix 7) if a subject had involvement of the BM at the 
start of the study.
d.
Baseline/Screening Computerized Tomography (CT) and PET scans may be obtained within 35 days of first dose Follow-up CT scans at week 7 wk 16, wk 24 and then every 12 
weeks.
e.
Positron emission tomography (PET) or PET/CT scan if clinically indicated (e.g., confirmation of CR for Diffuse large B-cell lymphoma). 
f.
Evaluation of response for lymphoma at week 7, week 16, week 24 and then every 12 weeks. Assessments are described in Appendix 7 : Response Criteria for Lymphoma.
g.
A blood sample for exploratory translational research should be collected at EOT and/or date of progression
 
 
 
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CTCL Assessments (Part 2)
Procedure
SCR
W3
W7
W10
W16 and beyond
EOT
D1
D1
D1
Disease characteristics, including historya
and current staging
X
Skin assessment (e.g., medical 
photography)
X
X
Wk 16, wk 24, then 
q12wks
X
Cross-sectional imagingb
X
X
Wk 16, wk 24, then 
q12wks
X
Quantitative evaluation of disease in 
blood (e.g., flow cytometry)
X
X
Wk 16, wk 24, then 
q12wks
X
Gobal response scoringc
X
X
Wk 16, wk 24, then 
q12wks
X
Skindex 29 (Quality of life/symptom 
assessment)
X
X
X
X
Wk 16, wk 24, then 
q12wks
X
Tissue biopsyd
X
X
X
Blood sample for exploratory translational 
researche
X
X
X
Wk 16, wk 24, then 
q12wks
X
a.
Including date of first diagnosis, disease stage, and history of prior therapies
b.
CT, PET/CT, or magnetic resonance imaging (MRI) may be used, as per standard practice
c.
Global response score (refer to Appendix 10 for full description) takes into account status of disease as measured by assessment of skin, lymph nodes, viscera, and blood.  Any 
response or PR should be confirmed by repeat assessment no sooner than 4 weeks after the assessment demonstrating response.
d.
Punch biopsy of affected skin lesion should be performed at times indicated for translational research.  Pre- and post-dose biopsies should be collected from the same lesion.  The 
W3D1 biopsy should be collected within 3-6 hours after the dose
e.
Blood samples should be collected within 3-6 hours after the dose
 
 
 
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MDS and Leukaemia Assessments (Part 1 and Part 2)
q3w and q6w Initiated 
from Wk 10
Procedure
Notes
SCR
Week 
2
W3
Wk4
W5
W7
W10
q3W
q6W
EOT
D1
D1
D1
D1
D1
D1
D1
D1
Disease characteristics, 
including history, 
immuno-phenotype, 
cytogenetics and 
molecular studies as 
appropriate  and History a
X
Lymph node and spleen 
assessment 
Only as appropriate 
X
X
X
X
X
X
Response Assessmentb
X
X
X
X
Blood sample for 
exploratory translational 
research
X
X
X
X
Xf
Transfusion History c
X
X
X
X
X
X
X
X
Bleeding History
X
X
X
X
X
X
X
X
Hematology d, e
X
X
X
X
X
X
X
X
a.
Including date of diagnosis and complete history of diagnostic results and therapies.
b.
Bone marrow biopsy/aspirate should be obtained for response assessment at the timepoints indicated.  Subjects without marrow involvement may be assessed by other 
means (e.g., medical photography for leukemia cutis) after discussion with the medical monitor, provided that the same method is used for all assessments of that subject.  
Response criteria for AML are described in Appendix 8; response criteria for MDS are described in Appendix 9.  For subjects with AML, a peripheral blood sample can be 
taken at baseline if a bone marrow sample cannot be collected.  Subjects should be off cytokine support (granulocyte colony-stimulating factor [GCSF] or granulocyte-
macrophage colony-stimulating factor [GMCSF]) for a minimum of 7 days before obtaining bone marrow to document remission.
c.
Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly cumulative basis.
d.
Hematology includes complete blood count (CBC) with white blood cell count differential (including neutrophils, eosinophils, basophils, lymphocytes and monocytes) and 
platelets; hemoglobin, hematocrit, red blood cell count.  A CBC with differential and platelets, hemoglobin and hematocrit may be performed daily during in-patient care; once 
subject is discharged, assessments to continue weekly until disease response assessment.  This is collected at baseline/screening;, then weekly.  Platelet count achievement 
of 20,000/mL for 3 days is entered into the eCRF and the date of platelet count achievement of 100,000/mL is entered into the eCRF.
e.
A blood cell smear to measure peripheral blood blasts.
f.
A blood sample for exploratory translational research should be collected at EOT and/or date of progression
 
 
 
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Table 8
Time and Events: Part 1 Serial Electrocardiograms, Pharmacokinetics, and Biomarker Sampling
Procedure / time after dose
W1D1 
W1D2
W1D5
pre 
dose
0h
15 min 
± 5m
30 min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h ±2h
24h 
±1h
0h
0h
2h 
±15m
4h 
±15m
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
PK sample for GSK525762 b
X
X
X
X
X
X
X
X
X b
X
X
Procedure / time after dose
W2D6
W2D7 (if dose has been altered (including held and resumed) serial PK sampling 
should occur 4 to 7 days after dosing resumed)
W3D1
W7D1 ±4 days c
pre
dose
pre 
dose
0h
15 min 
± 5m
30 min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h 
±2h
24h 
±1h
0h
pre 
dose
0h
0.5-
2h
4 -
8h
Dose
X
X
X
12-lead ECG 
X
X
X
X
X
X
PK sample for GSK525762
X
X
X
X
X
X
X
X
X
Xb
X
X
X
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
A single ECG should be collected at each timepoint, within 10 min prior to PK draw.
b.
Sample to be obtained before dosing on Week 1, Day 2 or Week 3 Day 1
c.
If dose was escalated, the W7D1 visit may be performed +4 to +7 days.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
 
 
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Table 9
Time and Events: Part 2 Expansion Cohort
Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from 
Wk 10)
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Informed 
consent
(Unless otherwise noted, 
screening assessments to be 
completed within 14 days of first 
dose.)
X
Demography
X
Medical 
historya
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register 
subject
X
TREATMENT PHASE
Study Drug
Dispense study drug (Administer about same time of 
day.)
Continuous daily dosing (unless safety, PK or pharmacodynamic data 
necessitate a different dosing schedule), see Section 3.2.4
X
Review compliance (Not required when dosed in 
clinic.)
X
X
X
X
X
X
X
X
Safety
Pregnancy test/testosterone b
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
Vital Signs c//Pain Assessment
X
X
X
X
X
X
X
X
X
Weight and height (Height at SCR only)
X
X
X
X
X
X
X
Chest x-ray
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 6.7.4)
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 10
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from 
Wk 10)
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Tests
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO or MUGA (Within 35 days of first dose).  
X
X
X
X
X
X
12-lead ECGs d
X
X
X
X
X
X
X
X
X
PK and Blood pharmacodynamics
PK 
Blood 
sample
sf
Three samples to be collected  each 
sampling day: During the first 3 weeks 
collect a predose (within 60 minutes prior 
to dose), a single draw between 0.5 to 2 h 
postdose, and a  single draw between 4-
8h postdose (fasting requirements apply).  
Thereafter W7 and Q6W only a predose 
and 0.5 hour post dose sample are 
collected. PK sampling may be 
discontinued after 6 months on study
X
X
X
X
Translational Research
PGx sample
X
Tumor sample (e.g., bone marrow biopsy, skin 
punch biopsy, or peripheral blood collection [only for 
subjects with circulating disease])
X e
X f
(CTC
L 
only)
X f
(MDS/AML 
only)
Xg
Blood samples for exploratory translational research 
X
Xf(CT
CL 
only)
X f
(MDS/AML 
only)
Additional samples will be collected on the date of disease 
assessment/bone marrow biopsy and date of progression or when 
patient is discontinued from study/end of treatment
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have completed the 
study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects 
have died or 5 years after the last subject is enrolled in Phase 2.
 
 
 
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a.
Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the 
medical history and disease status
b.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter.  Pregnancy 
testing not required for females of non-childbearing potential as defined in Section 4.2.1
c.
Vital signs include SBP, DBP, heart rate, respiratory rate and temperature
d.
Screening ECGs within 35 days of first dose.  ECGs prior to dosing.  If QTcF increase >30msec, ECGs should be repeated every 2-3 days until the QTcF is within 30 msec of 
baseline.
e.
Pretreatment biopsy for tumor sample must be performed within 14 days of first dose.
f.
Subjects with MDS/AML should have bone marrow aspirates or peripheral blood collection (provided that there are sufficient leukemic cells in the peripheral circulation) collected 
on W4 D1 within 3-6 hours after the dose.  Subjects with CTCL will have a punch biopsy of the skin and blood sample collected on W3D1 within 3-6 hours after the dose. Any 
additional blood samples should be collected within 3-6 hours post-dose.  Timing of tissue collection will be based on tumor type and may be modified based on emerging data. 
For operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection remain as described. A PK sample will need to be obtained 
within 1 hour of the tissue sampling. For CTCL subjects the 4-8 hour PK sample required to be drawn can be utilized as the sample that is required after tissue sampling.  See 
Table 7 disease specific assessments for details).  
g.
Tumor samples for translational research are requested at end of treatment for subjects with progressive disease. 
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by 
Fridericia’s formula; PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; Wk=week
 
 
 
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Table 10
Time and Events: Part 2 Laboratory Assessments
NB: Collect blood samples prior to dosing.  W1D1 
samples not needed if SCR sample is within 24h of first 
dose. (Notes)
SCR
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
q3w and q6w 
Initiated from Wk 10
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP (1 sample for local lab [troponin I or 
T], 1 sample for central lab [troponin T]) 
X
X
X
X
X
X
X
X
X
Hematology
X
X X a
X X a
X a
X a
X a
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
Factor VII Assayb
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
LDH
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
Fasting blood glucose, c-peptide, insulin, 1,5 AG
(Will be performed at central lab if not available at local lab)
X
X
X
X
X
X
HbA1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Thyroid monitoring (TSH, free T3, free T4.  If TSH is 
abnormal W1D1, monitor TSH, free T3 and free T4 going 
forward)
X
X
X
X
X
X
X
HBsAg, HepC antibody (If hepatitis C antibody positive, a 
confirmatory study [e.g., HCV RNA PCR] should be 
performed as per local standard)
X
a. Assess platelet count as clinically appropriate but at minimum twice weekly for weeks 1 and 2; weekly for weeks 3 to 8.
b. In addition to scheduled timepoints, perform if PT or INR or aPTT are 1.5XULN, or in case of bleeding event
Abbreviations: NT-proBNP=N-terminal pro–B-type Natriuretic Peptide; 1,5 AG=1,5-Anhydroglucitol; Hb=Hemoglobin; TSH=Thyroid Stimulating Hormone; HBsAg = Hepatitis B surface 
Antigen HepC=Hepatitis C; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week
 
 
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written ICF must be obtained from the subject prior to any study-specific 
procedures or assessments.
Refer to the timing of each assessment in the Section 5 Time and Events Tables.  The 
timing and number of the planned study assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the assessments.
The change in timing or addition of time points for any of the planned study assessments 
listed above must be approved and documented by GSK, but this will not constitute a 
protocol amendment.  The institutional review board (IRB) or ethics committee (EC) will 
be informed of any safety issues that require alteration of the safety monitoring scheme. 
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  Detailed procedures for obtaining each assessment are provided in the 
SPM).
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed.
6.1.
Study Visits
6.1.1.
Assessments
See the Section 5 Time and Events Tables for details on the specific assessments.
6.1.2.
Visit Windows
Screening (baseline to pre-dose): All assessments should be completed within 14 days 
prior to screening unless otherwise noted in the Section 5 Time and Events Tables.  Note 
for females, pregnancy testing should be performed within 7 days prior to first dose.  
Also, clinical labs performed during screening within 24 hours of first dose do not need 
to be repeated on Day 1.
Visits during Week 1: Based on subject and clinic schedule, Week 1 Day 5 assessments 
can be 1 day.
Visits between Week 2 through Week 3 (inclusive): Based on subject and clinic 
schedule, assessments can be +3 days.
 
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Visits between Week 4 through Week 9 (inclusive): Clinic visits can be scheduled 4 
days.
Every 3-week and 6-week visits from Week 10 through Week 48 Clinic visits can be 
scheduled 7 days.
After Week 48: Every 3-week visits are no longer required, based on clinical judgment.  
Every 6-week clinic visits must include safety assessments from the “q3w” column in the 
Time and Events Table and can be scheduled 7 days.  Response assessments may be 
scheduled 7 days.
Discontinuation visit: should be within 14 days from last dose of study drugs.  If a 
subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of adverse events.
Discontinuation Survival Follow Up Visit: can be scheduled 7 days
6.2.
Baseline Assessment
Subjects diagnosed with refractory hematological malignancy (MM, NHL (excepting 
CTCL), CTCL, MDS and/or AML), will be assessed at baseline for general disease 
characteristics as noted in Section 6.2.1 and tumor type specific measures as noted in 
Section 6.2.2, Section 6.2.3 Section 6.2.4, and Section 6.2.5, respectively.
Baseline is defined as the assessment closest to first dose, (i.e., Week [W] 1 Day [D] 1
assessment) or screening if SCR sample collected within 24h of first dose.
6.2.1.
Baseline assessment for all Subjects

Primary tumor  type (immunophenotyping and histology if applicable)

History of other tumor types/medical history

Date of initial diagnosis of primary tumor type

Date of relapse/progression
6.2.2.
Baseline assessment for Subjects with MDS/AML

WHO classification

FAB classification (AML only)

Cytogenetics

IPSS/IPSS-R classification (MDS only)
6.2.3.
Baseline assessment for Subjects with NHL (excepting CTCL) 

Ann Arbor staging at initial diagnosis and screening

Number of sites with extranodal involvement at initial diagnosis 

Follicular Lymphoma International Prognostic Index (FLIPI) 1 and 2
 
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
FCgR3a genotype and other cytogenetics/molecular analysis applicable such as 
antigen gene receptor rearrangements, BCL2 rearrangements and translocations.

Fluorescence in situ hybridization (FISH), cytogenetics/molecular analysis, and/or 
IHC for MYC, BCL2, and/or BCL6 (only required to enrol in double- and triple-hit 
lymphoma sub-cohort)
6.2.4.
Baseline assessment for Subjects with CTCL

Modified International Society for Cutaneous Lymphomas (ISCL)/ European 
Organization of Research and Treatment of Cancer (EORTC) stage at initial 
diagnosis and screening (Appendix 10, Table 22)

Quality of life assessment (Skindex-29 [refer to Appendix 11])
6.2.5.
Baseline assessment for Subjects with myeloma

International staging system (ISS) stage at initial diagnosis and screening

Type (active or smoldering)

Presence of plasmacytoma

Cytogenetics

Presence of extramedullary disease

Laboratory assessment: Total protein, paraprotein, C reactive protein (CRP) and β2-
microglobulin; for secretory MM: serum protein electrophoresis (SPEP), urine 
protein electrophoresis (UPEP), IgG, IgA, IgM, free light chain (FLC) assay
6.3.
Safety Evaluations
Planned time points for all safety assessments are provided in the Section 5 Time and 
Events Tables.
6.3.1.
Physical Examinations
A complete physical examination will be performed by a qualified physician or designee 
according to local practice.  Height and weight will also be measured and recorded.  
Height only needs to be measured at baseline.
Cardiovascular medical history/risk factors will also be assessed at baseline by the 
Investigator.  Additional assessment by a cardiologist may be required at the discretion of 
the Investigator and/or Medical Monitor [prior to enrolment/first dose] if any 
cardiovascular risk factors or ECG/laboratory abnormalities are identified.”
 
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6.3.2.
ECOG performance status
The performance status assessment is based on the ECOG scale [Oken, 1982].
Grade
Descriptions
6.3.3.
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
respiration, and temperature.  The vital signs will be measured after resting for at least 5 
minutes in a supine or semi-recumbent position.  Pain will be assessed using a visual 
analog scale (see Appendix 12).
6.3.4.
Left ventricular ejection fraction (LVEF) Evaluation
For all subjects, evaluation of cardiac output will be performed at screening and at 
assessment times as outlined in Section 5.  While ECHO is the preferred modality of 
imaging, MUGA scans may be accepted as an alternative.  Subjects should have the same 
assessment modality performed at each time point listed in Section 5.  When possible, 
ECHOs/MUGAs should be evaluated and compared to baseline by the same reader. 
All ECHO/MUGA data may be transferred and reviewed by an independent cardiologist.
6.3.5.
Electrocardiograms
ECGs will be performed using a standard 12-lead ECG machine that automatically 
calculates the Heart Rate (HR) and measures PR, QRS, QT and QTcF intervals. In Part 1, 
the investigator will review the ECG data manually, and should not rely solely on the 
 
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automatic readings of the equipment, when making decisions regarding dosing of 
subjects.
Standard 12-lead ECGs (Safety ECGs) will be performed as part of the real-time 
assessment of subjects and may not be included in the primary QT analysis.  Safety ECGs 
should be reviewed by the investigator on an ongoing basis for safety purposes.  The 
dosing for each new week in the first cycle should not begin until the safety ECG has 
been reviewed and no significant abnormalities have been detected.
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.

QTc interval ≥530 msec OR interval increase from baseline 60 msec: 
Investigational product (IP) will be discontinued unless the benefits of 
therapy outweigh the risk of rechallenge in the opinion of the Investigator, 
the GSK Medical Monitor, as well as the GSK medical governance. In this 
situation, rechallenge may be permitted (see Section 7.7 for rechallenge 
guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
Baseline results are defined by the nearest timepoint prior to first dose. 
Abnormal ECGs should be evaluated manually prior to final decision making. ECG data 
may be transferred and reviewed by an independent central reviewer.
6.3.6.
Clinical Laboratory Assessments
All protocol required safety laboratory assessments, as defined in Section 5, are 
performed at the institution’s local laboratory.  All non-safety assessments (e.g., PK 
samples, biopsy, translational samples) will be assessed by a central laboratory.  Some 
laboratory assessments can vary throughout the day such as testosterone.  It is 
recommended but not mandated that laboratory assessments are collected at 
approximately the same time on each clinic day.  If abnormal testosterone levels are 
observed, repeat measurements should occur at the approximate baseline timing to ensure 
this is a trend and not a single outlying event.
 
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Table 11
Clinical Laboratory Tests
Serum Chemistry
Blood urea nitrogen
Magnesium 
Aspartate aminotransferase (AST)
Total and direct bilirubin
Sodium
Potassium
Alanine aminotransferase (ALT)
Uric acid
Creatinine
Chloride
Alkaline phosphatase (ALP)
Albumin
Fasting Glucose
Calcium
Total protein
Lactate dehydrogenase
Ionized calcium
Hematology
Platelet count
Automated White Blood Cell 
Red blood cell count
Differential:
White blood cell count (absolute)
Blast count
Neutrophils (absolute)
Hemoglobin
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Factor VII assay
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density 
lipoprotein cholesterol (HDL-C)
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3), Free Thyroxine 4 (Free T4),
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
HBsAg, HepC antibody
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
24-hour urine creatinine clearance (if needed)
Subjects should be instructed to fast (no food and only water allowed) for 8 hours prior to 
any fasting laboratory assessments (example: fasting glucose, fasting lipid panel, etc.).
Abnormal laboratory results that are considered by the investigator to be clinically 
significant should be recorded on the eCRF as AEs.  Laboratory results or other safety 
assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay, must be recorded as an 
associated AE or SAE.  In addition, these clinically significant abnormal laboratory 
results should be followed until the abnormality resolves or is determined to be stable.  
 
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6.3.7.
Troponin
Troponin T will be assessed at a central laboratory as a means of consistent evaluation 
across all subjects.  A second troponin sample will be assessed at a local laboratory for 
purposes of subject management.  Whenever possible, troponin T will be assayed by the 
local laboratory.  However, troponin I may be assessed at a local laboratory if troponin T 
is not available.  The same local laboratory test (troponin I or troponin T) should be used 
consistently for an individual subject throughout the study.
6.4.
Efficacy
6.4.1.
Disease Assessment
Response will be assessed as outlined in the Section 5 Time and Events Table 7 Table by 
the investigator using the appropriate criteria for MM, lymphoma, CTCL, AML, and 
MDS, as noted in Appendix 6, Appendix 7 Appendix 8, Appendix 9, and Appendix 10,
respectively.  
Subjects enrolled in Part 1 at RP2D and Part 2 are to be followed until death for 
assessment of overall survival (OS).
6.5.
Pharmacokinetics
6.5.1.
Blood Sample Collection
Blood samples to enable quantification of GSK525762, and relevant metabolites, as 
applicable, in plasma will be collected at the time points indicated in the Section 5 Time 
and Events Tables. The actual date and time of each blood sample collection will be 
recorded.  The timing of PK samples may be altered and/or PK samples may be obtained 
at additional time points to ensure thorough PK monitoring.
6.5.2.
Plasma Sample Analysis
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline.  Concentrations of 
GSK525762 will be determined in plasma samples using the currently approved 
analytical methodology.  In addition, selected metabolites of GSK525762 may also be 
quantified using approved analytical methodology. Raw data will be stored in the GLP 
Archives, GlaxoSmithKline.
In addition, plasma may be analyzed qualitatively for other circulating compound-related 
material and the results will be reported under a separate DMPK protocol.
6.5.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.
 
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6.6.
Translational Research
Blood and or tumor tissue specimens will be collected at various times, throughout the 
study in order to support research aimed at understanding the biological effect of 
GSK525762 and BET inhibition as well as identifying indicators of sensitivity or 
resistance to GSK525762.
Toward that end the successful collection of quality tumor specimens will be critical to 
furthering our understanding of BET biology and identifying the best way to treat 
patients with a BET inhibitor. Specifically, the evaluation of responders, responders at 
relapse, and non-responders for gene mutation status and/or pathway activation may lead 
to the discovery of potential new diagnostic markers or novel combinations. Similarly, 
pre- and post-dose tumor specimens will be evaluated for markers of target engagement, 
tumor response, and/or evaluated for changes in gene expression; thus supporting 
identification of a biologically effective dose and furthering our mechanistic 
understanding of BET inhibition in these settings. In certain settings such as myeloid 
malignancies, samples may be used to evaluate changes in leukemic stem cell 
populations or to generate PDX models.
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology. Biopsies may also be assessed for deoxyribonucleic 
acid (DNA), RNA or proteins which may be potential predictors of sensitivity or 
resistance to BET inhibition based on emerging data.
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies are 
mandatory. For subjects in Part 1 and 2, if tumor tissue is not accessible, discussion with 
the GSK medical monitor is required. 
6.6.1.
Tumor Specific Tissue Collection
The tissue collection and pharmacodynamic tests for Part 1 are disease specific and 
outlined below: 

For subjects with AML, changes in specific protein markers and/or mRNA 
expression signatures will be assessed in bone marrow and/or tumor cell-
enriched PBMCs isolated from whole blood.

For subjects with lymphomas, tissue biopsies will be required before and after 
treatment to evaluate changes in tumor-specific protein markers and/or gene 
expression signatures.

For subjects with MM, bone marrow will be evaluated for changes in tumor-
specific protein markers and/or gene expression signatures (for example, c-
Myc).
The tissue collection to support translational and mechanistic research for Part 2 is also 
disease specific and is similar to that described above.  
 
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Specific timing of post-treatment sample collection is defined in the T&E table. See 
Study Procedures Manual (SPM) and central lab manual for additional details.
6.6.2.
Blood Sample Collection for Exploratory Translational Research
Blood samples collected at time points described below and in the Time and Events 
tables for PK and pharmacodynamic testing may be required for all subjects.

Part 1 &2: At screening, date of bone marrow biopsy (Part 2 MDS cohort only), 
disease assessment (Table 7) and disease progression for isolating plasma for 
circulating biomarkers (eg, cfDNA) , PBMCs and neutrophils.
6.6.3.
Unscheduled Safety Biomarker Blood Samples
Unscheduled biomarker sample(s) may be collected based on emerging safety.  One to 
three samples may be collected in a day to address specific safety concerns.  Each sample 
would be up to 10 mL of whole blood to look at cytokines, gene signature (mRNA) or 
other plasma proteins.  The timing of the samples will be based on emerging safety data 
and would be discussed and determined by GSK medical monitor and study team review.
6.7.
Adverse Events (AE) and Serious Adverse Events (SAE)
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 6.7.1 and 
Section 6.7.2, respectively.
6.7.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse.  Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).
 
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“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE.
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
6.7.2.
Definition of a SAE
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:
a.
Results in death.
b.
Is life-threatening.
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out subject setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect.
 
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f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
Protocol-Specific SAEs are as follows:

All events of possible drug-induced liver injury with hyperbilirubinaemia 
defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 
3xULN and INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury.  If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then 
the event is still reported as an SAE.  If INR is obtained, include values on the 
SAE form.  INR elevations >1.5 suggest severe liver injury.

Any new primary cancers.

Significant cardiac dysfunction such as Grade 3 or higher decrease in LVEF 
and QTcF withdrawal criteria.

Grade 4 laboratory abnormalities (not disease related).

Drug related hepatobiliary event leading to permanent discontinuation of 
study treatment.
6.7.2.1.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep Venous Thrombosis
 
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
Revascularization
6.7.2.2.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
non-cardiovascular death.
This information should be recorded within one week of when the death is first reported.
6.7.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgment of the investigator, are to be recorded as an AE or 
SAE in accordance with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.
6.7.4.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the time the first dose of study treatment is administered until 
28 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice.
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact.  All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.7.6.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs 
(including laboratory abnormalities such as an increase in troponins) that are ongoing 
until resolution or stabilization of the event or until the subject is lost to follow-up.  At 
 
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any time after 28 days the investigator may report any adverse event that they believe 
possibly related to study treatment.
6.7.5.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?” 
“Have you had any (other) medical problems since your last visit/contact?” “Have you 
taken any new medicines, other than those provided in this study, since your last 
visit/contact?” 
6.7.6.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities and any other events meeting pre-
defined criteria will be reported promptly by the investigator to GSK as described in 
Table 12 once the investigator determines the event meets the protocol definition for that 
event.
 
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Table 12
Reporting of SAEs and Other Events to GSK
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
24 hours
Pregnancy 
Notification Form
24 hours
Pregnancy Follow 
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event 
electronic Case 
Report Form 
(eCRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool.  
Updated Liver 
Event eCRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks
24 hours1
Liver Event 
eCRF2
24 hours
Updated Liver 
Event eCRF2
ALT3xULN and 
<5xULN and bilirubin
<2xULN
24 hours1
Liver Event eCRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver event documents should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SPM.
6.7.7.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
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 
 
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regulatory authority, Institutional Review Board (IRB)/ Ethics Committee (EC) and 
investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/ EC, if appropriate according to local requirements.
6.8.
Pregnancy
6.8.1.
Time period for collecting pregnancy information
Reporting of any pregnancies in female subjects and/or female partners of male subjects 
will be collected after the start of dosing and until 7 months after the last dose of study 
drug.
6.8.2.
Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to GSK within 24 hours of learning of a subject's pregnancy.
The subject will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK.  Generally, 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 6.7.6.  While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will be withdrawn from 
the study.
6.8.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
GSK within 24 hours of learning of the partner’s pregnancy.  The 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 
 
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6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
Procedures for pregnancy report will be located in the SPM.
6.9.
Pharmacogenetics
An important objective of the clinical study is pharmacogenetics (PGx) research.  
Participation in PGx is optional, but all subjects who are eligible for the clinical study 
will be given the opportunity to participate.  Subjects may decline participation without 
effect on their medical care or care during the clinical study.  A separate consent 
signature is required for PGx research.
Subjects who provide consent will have a saliva sample taken for analysis.  The 
presence/absence of genetic variations in selected candidate genes in DNA from saliva 
will be analysed to determine their relationship with response (safety, tolerability, PK, 
and efficacy) to treatment with GSK525762.
Information regarding PGx research is included in Appendix 5.  The IRB/ EC and, where 
required, the applicable regulatory agency must approve the PGx assessments before 
these can be conducted at the site.  The approval(s) must be in writing and will clearly 
specify approval of the PGx assessments (i.e., approval of Appendix 5).  In some cases, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted.
6.10.
Quality of Life/Patient-Reported Outcomes
Patient-reported outcome, Skindex 29 (refer to Appendix 11) will be used to gauge the 
effects of treatment with GSK525762 on the quality of life and other subjective measures 
in subjects with CTCL.
7.
STUDY TREATMENTS
7.1.
GSK525762 Investigational Product Dosage/Administration
GSK525762 tablets will be provided to sites by GSK.  The contents of the label will be in 
accordance with all applicable regulatory requirements. An amorphous, free-base 
formulation of GSK525762 (Table 13) and a crystalline, besylate formulation (Table 14) 
will be utilized.  
In the BET115521 study, a sub-study was conducted to evaluate the PK characteristics of 
the new besylate formulation. This sub-study was an open-label, randomized, single dose, 
four period, cross over sub-study performed to investigate the relative bioavailability of
the besylate tablet compared to the amorphous free-base tablet, the effect of high-fat 
 
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high-calorie meal on the bioavailability of the besylate tablet and the dose proportionality 
of two doses of GSK525762 administered as besylate tablets. 
The sub-study results showed that the besylate salt-coated tablet is bioequivalent to the 
amorphous free-base uncoated tablet. In addition, there is a lack of effect of a high-fat 
high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered as 
besylate coated tablets while administration with food tended to slightly decrease Cmax. 
The fasting requirement is thus no longer necessary in subjects taking the besylate 
formulation in Part 2.  
Either amorphous or besylate tablets may be used in Part 1, based on the bioequivalence 
described above.  During the DLT observation period, subjects will only receive one or 
the other formulation; any individual cohort will only enrol subjects receiving a single 
formulation type.  Upon completion of the DLT observation window, subjects may be 
changed from amorphous to besylate tablets at the equivalent dose.
The besylate tablet will be utilized in Part 2.
Precaution will be taken to avoid direct contact with the study treatment.A Material 
Safety Data Sheet (MSDS) describing the occupational hazards and recommended 
handling precautions will be provided to site staff if required by local laws or will 
otherwise be available from GSK upon request.
Table 13
GSK525762 Amorphous Free Base Investigational Product Dosage/ 
Administration
Investigational Product
Product name:
GSK525762 Amorphous Free Base Tablets
Unit dose strength(s)/Dosage level(s):
1mg
10mg
30mg
Dosage form
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Physical description:
white to off-white, round, biconvex tablets with no markings
Route/
Administration/ Duration:
Oral; see the Section 5 Time and Events Tables for 
schedule and administration timings
Dosing instructions:
Dose with 240 mL water and should be taken within a 
similar time frame each morning.  No food or antacids for at 
least 1 h before and 2 h after dosing.  (If a subject vomits 
after taking study drug, the subject should be instructed not 
to retake the dose and should take the next scheduled 
dose.)
 
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Table 14
GSK525762 Besylate Investigational Product Dosage/Administration
Investigational Product
Product name:
GSK525762 Besylate Tablets
Unit dose strength(s)/Dosage level(s):
5mg
20mg
25mg
50mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
GSK
Physical description:
White to 
slightly 
colored, 
round, 
biconvex 
tablet.
Yellowish 
pink, 
round, 
biconvex 
tablet
White to 
slightly 
colored, 
round, 
biconvex 
tablet
White to 
slightly 
colored, oval 
shaped tablet
Route/
Administration/ Duration:
Oral; see Time and Event Tables for schedule and 
administration timings
Dosing instructions for Part 1:
Dose with 240mL water and should be taken at the same 
time each day, preferably in the morning.  No food or 
antacids for at least 1h before and 2h after dosing. (If a 
subject vomits after taking study drug, the subject should 
be instructed not to retake the dose and should take the 
next scheduled dose.)
Dosing Instructions for Part 2
Dose with 240mL water and should be taken at the same 
time each day, preferably in the morning.  (If a subject 
vomits after taking study drug, the subject should be 
instructed not to retake the dose and should take the next 
scheduled dose.)
7.2.
Handling and Storage of Study Treatment
Handling
Precaution will be taken to avoid direct contact with the study treatment.
  An MSDS describing the occupational hazards and recommended handling precautions 
will be provided to site staff if required by local laws or will otherwise be available from 
GSK upon request
 
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Adequate precautions must be taken to avoid direct contact with the IP.  Limited 
exposure and precautionary action (example: wearing gloves, washing hands post 
exposure, etc.) should be taken by site staff dispensing GSK525762 tablets.
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager.
Refer to the SPM for detailed procedures for the disposal and/or return of unused study 
treatment(s).
Storage
GSK525762 tablets must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the GSK525762 tablets will 
be limited to the investigator and authorized site staff.  GSK525762 must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK525762 tablets.
GSK525762 Amorphous free-base tablets are to be stored at up to 30°C (86°F) and 
protected from light and moisture.
GSK525762 Besylate Tablets are to be stored at up to 30°C (86°F) and protected from 
moisture.
7.3.
Meals and Dietary Restrictions
Subjects enrolled under Part 1 will fast for at least one hour prior to each dose of study 
drug (amorphous free or besylate). No food or antacid should be taken for 2 hours after 
dosing. Subjects should not eat a heavy meal in the morning prior to the 1 hour washout 
before dosing to minimize potential risk for food interaction.  On serial PK sampling 
days, subjects should fast overnight (i.e., at least 8 hours). After dosing, subjects will be 
asked to fast for an additional two hours.  These fasting requirements have been 
implemented in the protocol and informed consents to minimize PK variability.
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next scheduled dose.  Requirements for fasting before 
and after dosing may be modified based on emerging PK, pharmacodynamic and safety 
data.  Any change in fasting requirements will be communicated to each investigator and 
site staff in a future protocol amendment.  Should a twice daily regimen be required, 
additional consideration will be paid to this requirement once the escalation period is 
past.
Fasting will consist of avoiding the oral ingestion of calorie-containing products; 
however, ingestion of water is permitted.
Based on the results of the BET115521 sub-study showing a lack of effect of a high-fat 
high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered as 
besylate coated tablets, the fasting requirement is being lifted for subjects in Part 2 only 
 
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except on Serial PK sampling days (Week 1 and Week 3) or days in which required for 
fasting blood draws.  On these days, subjects should fast overnight (i.e., at least 8 hours). 
After dosing, subjects will be asked to fast for an additional two hours.  These fasting 
requirements have been implemented in the protocol and informed consents to minimize 
PK variability.
7.4.
Treatment Assignment
This is an open-labeled study.
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the GSK 
interactive voice response system (IVRS), by the investigator or authorized site staff.
7.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  Refer to the SPM for further detailed instructions on product accountability.
7.6.
Treatment Compliance
At each visit, an evaluation of subject compliance with taken medication will be 
performed.  The investigator will make every effort to bring non-compliant subjects into 
compliance.
Compliance with GSK525762 will be assessed through querying the subject during the 
site visits and documented in the source documents and eCRF.
A record of the number of GSK525762 tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the eCRF.
7.7.
Dose Modifications
7.7.1.
Dose and Safety Management Guidelines
The following dose modification criteria in Table 15 should be used to provide guidance, 
but not act as a replacement for sound clinical judgment.  The investigator should use 
clinical judgment to determine which drug may be contributing to the toxicity 
necessitating dose adjustment, and make the appropriate change for that drug.
 
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Table 15
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary
Grade 3 (platelets 
<50,000, ≥25,000/mm3)
After discussion with medical monitor and using sound 
clinical judgement, continue at same dose or dose reduce 
to previously cleared dose level. Monitor CBC at least 
twice a week, or more frequently if clinically indicated. 
Grade 4 (platelets  
<25,000/mm3)
and/or any grade 
accompanied by severe 
bleeding related to 
thrombocytopenia
For Lymphoma and Multiple Myeloma:
Interrupt study medication and monitor CBC every 2-3 
days. 
1.
If platelet counts recover to Grade 2 and are steady 
for at least 2 CBC measurements at least 3 days 
apart, or rising, discuss with the medical monitor. 
Based on clinical judgement, resume treatment at 
the same or previously cleared lower dose. 
2.
Platelet transfusion is allowed based on institutional 
guidelines.  If platelet transfusions are required, hold 
drug until platelet counts recover to Grade 2, and are 
steady for at least 2 CBC measurements at least 3 
days apart, or rising. Using clinical judgement and 
after consultation with the medical monitor, consider 
resuming treatment at same or the previously 
cleared lower dose. 
3.
Discontinue treatment if drug has to be held for >14 
days.
For Acute Myeloid Leukemia and Myelodysplastic 
Syndrome - if platelet count <25,000/mm3 but 
10,000/mm3: Use clinical judgement to institute more 
frequent monitoring as necessary.
For Acute Myeloid Leukemia and Myelodysplastic 
Syndrome - if platelet count <10,000/mm3 :
1.
Continue treatment and start platelet transfusion 
as per institutional guidelines. After platelet 
transfusion, assess platelet level within a couple of 
hours of transfusion. Institute more frequent 
monitoring as clinically indicated.
2.
If repeat platelet transfusions are not able to 
rescue platelet count to 10,000/mm3  (or to 
20,000/mm3in case of accompanying fever, 
sepsis, or minor bleeding) in 2 days, then interrupt 
treatment. If subsequent transfusions are able to 
increase the platelet count within 14 days of 
interruption, consider restarting therapy at the 
same or previously cleared dose after discussing 
with the medical monitor and approval by GSK 
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
medical governance.  If transfusions are unable to 
increase the platelet count within 14 days of 
interruption, therapy will be discontinued.
3.
Use of adjunctive therapies is permitted.
4.
Use of hydroxyurea is permitted in the setting of 
increased blast counts in conjunction with 
decreased platelet counts.
QTcF
If >30msec and < 60 
msec change from 
baseline  AND manual 
QTcF <530 (average of 
three ECGs over at 
least 15 minutes)

Continue current dose of GSK525762

Supplement electrolytes, particularly potassium 
and magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels >0.85 
mmol/L

Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider 24 hour or longer telemetry monitoring if clinically 
indicated.
If 60 msec change 
from baseline occurs
OR
QTcF 530 
(average of three ECGs 
over at least 15 
minutes)

Discontinue GSK525762 and notify the GSK Medical 
Monitor. 
(1) Supplement electrolytes to recommended levels:
a.
Maintain serum potassium > 4mol/L
b.
Maintain serum magnesium levels >0.85 
mmol/L
(2) Rule out other potential etiologies for prolonged 
QTcF such as cardiac ischemia
(3) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(4) Consider telemetry monitoring if clinically 
indicated.

This subject may consider restarting study treatment 
at a previous dose level if the following criteria for QTcF 
rechallenge are met:

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless under 
the following conditions: 
(1)
QTcF event reduced to <480 msec,
(2)
potassium and magnesium levels are within 
institutional normal range,
(3)
a favorable risk/benefit profile (in the medical 
judgement of the Investigator and the GSK 
Medical Monitor),
(4)
approval within GSK medical governance:
a.
agreement with SERM MD and PPL,
b.
review with Chair or co-Chair of the GSK 
QT panel,
c.
SERM VP and Clinical VP approval
d.
Head Unit Physician approval
(5)
Institutional IRB (or equivalent) approval (if 
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
required), and
(6)
The subject is re-consented regarding the 
possible increased risk of QTc prolongation. 

If approval for re-challenge is granted, the subject 
must be re-consented (with a separate informed 
consent specific to QTc prolongation).

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the subject 
should complete the following activities post-dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be monitored 
weekly for two weeks, and then next assessment at 4 
weeks post-dose.
(3) If QTcF results have not resolved to baseline by 4 
weeks post-dose, then continue every 4-5 weeks until 
resolution
Troponin
Troponin level >ULN

Contact the subject immediately for evaluation of 
symptoms and to obtain ECG.  Repeat troponin within 
24-48 hours or as soon as possible.

For asymptomatic subjects with repeat troponin values 
>ULN hold study medication(s), refer to a cardiologist 
and contact the GSK Medical Monitor.  If the repeat 
value is within the normal range, the subject may 
continue study medication with close follow-up for 
symptoms, ECG monitoring and further troponin 
measurements as clinically indicated.

If the subject is symptomatic or the troponin level 
approaches the threshold for MI according to local lab 
parameters, the study medication must be withdrawn 
and the subject will be referred immediately to a 
cardiologist for appropriate medical care.

May consider restarting study treatment at a reduced 
dose based on discussion with GSK Medical Monitor.
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
LVEF

Asymptomatic, 
absolute decrease 
of >10% in LVEF 
compared to 
baseline and the 
ejection fraction is 
below the 
institution’s lower 
limit of normal (LLN)

Interrupt investigational drug(s) and repeat evaluation 
of LVEF within 2 weeks

If LVEF recovers (defined as LLN and absolute 
decrease 10% compared to baseline) at any time 
during the next 4 weeks, after consultation and 
approval of the GSK medical monitor, the subject may 
be restarted on investigational drug(s) at a reduced 
dose.  Monitoring to be performed at 2 and 4 weeks 
after restarting investigational drug(s) and then per 
protocol specifications.

If LVEF does not recover within 4 weeks, permanently 
discontinue investigational drug(s).  Evaluation by a 
cardiologist will be conducted.  Ejection fraction should 
continue to be monitored at 2 weeks, 4 weeks and 
every 4 weeks until 16 weeks or resolution.

Grade 3 or 4

Permanently discontinue investigational drug(s).  
Evaluation by a cardiologist will be conducted.  
Ejection fraction should be monitored at 2 weeks, 4 
weeks and then every 4 weeks until 16 weeks or 
resolution.
Liver 

ALT >5X ULN

ALT >3X ULN and 
bilirubin >2X ULN 
(>35% direct 
bilirubin, bilirubin 
fractionation 
required) or INR 
>1.5 without 
evidence of biliary 
obstruction or 
progressive disease

ALT >3X ULN with 
the appearance 
hepatitis symptoms 
or rash

Discontinue study medications, notify the GSK Medical 
Monitor, and refer to follow-up procedures outlined in 
protocol, Liver chemistry follow-up procedures.  In the 
presence of known hepatic metastases, if there is 
evidence to suggest a drug induced effect, discontinue 
study medications, notify the GSK Medical Monitor, 
and refer to follow-up procedures outlined in protocol 
Liver Chemistry Follow-Up Procedures (see Appendix
3).
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate and 
severe intensity 
criteria; however 
for CRF reporting 
use NCI-CTCAE 
v4.0 [NCI, 2009] 
Grade 1-5) 

(Mild) Fasting blood 
glucose >150 mg/dL

Monitor fasting and preprandial glucose.

(Moderate to 
Severe) Fasting 
blood glucose any 
blood glucose 
>250 mg/dL

Hold investigational product and instruct subject to 
notify investigator immediately.

If a blood glucose >250 mg/dL is observed the subject 
should be monitored for ketoacidosis as clinically 
indicated.

If subject has evidence of ketoacidosisTreatment 
should be undertaken with awareness that the action of 
insulin or other antihyperglycemic agents (e.g., 
sulfonylureas, biguanides, etc.) may be substantially 
blocked by the action of the study medication.  The 
action of insulin or other antihyperglycemic agents 
should be restored as study medication is cleared.  If 
an antihyperglycemic agent is administered, then the 
subject should be observed closely for rebound 
hypoglycemia as the study medication is cleared.  
Intravenous insulin treatment is recommended.

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
GSK Medical monitor.
(Moderate to 
Severe) Fasting 
blood glucose 
<70 mg/dL

(Moderate to Severe) Hold investigational product 

Provide sugar containing liquids and monitor blood 
sugar closely.  Check for insulin and c-peptide levels.  
After blood sugar normalizes 

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
GSK Medical monitor
Diarrhea

Grade 1

Initiate supportive care including loperamide.

Grade 2

Initiate supportive care including loperamide.  Consider 
temporary discontinuation of study medications and 
discuss with GSK Medical Monitor.

Grade 3 or 4

Above plus consider IV hydration, hospital admission 
and prophylactic antibiotics as appropriate.  Consider 
temporary discontinuation of study medications and 
discuss with GSK Medical Monitor.

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with GSK Medical 
monitor.
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Mucositis
Grade 1-2

Encourage oral hygiene.  Offer topical supportive 
anesthetics.  Encourage adequate hydration.
Grade 3-4

(Above, plus systemic opiate administration as needed.  
Consider IV hydration and hospital admission as 
appropriate.

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with GSK Medical 
monitor.
Pneumonitis
Grade 1
(For all Grades) Obtain high resolution chest CT if 
possible.
Consider evaluation by pulmonologist.  Consider room 
air O2 saturation at rest via pulse oximetry reading (X 
2, 5 mins apart).  Repeat evaluations every 8-12 
weeks until return to within normal limits (wnl).  
Continue investigational drug(s) at current dose(s).
Grade 2
Consider evaluation by pulmonologist.  Consider 
pulmonary function tests including: spirometry, 
Diffusing Capacity of the Lung for Carbon Monoxide 
(DLCO), and room air O2 saturation at rest via pulse 
oximetry reading (X 2, 5 mins apart).  Repeat 
evaluations every 8-12 weeks until return to wnl.  
Consider a bronchoscopy with biopsy and/or 
bronchoalveolar lavage.  (BAL).
Treat only if symptomatic.  Consider corticosteroids if 
symptoms are troublesome and infectious origin is 
ruled out.  Taper as medically indicated.
Hold investigational drug(s) until recovery to <Grade 1, 
then reduce dose by at least 25%.  Discontinue 
investigational drug(s) if no recovery to <Grade 1 
within 4 weeks.  May consider escalation to pre-event 
dose after discussion with GSK Medical Monitor.
Grade 3 and 4

Permanently discontinue investigational drug

Evaluation by pulmonologist.  Required pulmonary 
function tests including: spirometry, DLCO, and room 
air O2 saturation at rest via pulse oximetry reading (X 
2, 5 mins apart).  Repeat evaluations at least every 8 
weeks until return to normal.  Bronchoscopy with 
biopsy and/or BAL is recommended.

Consider corticosteroids if infectious origin is 
ruled out. Taper as medically indicated.
*Baseline results are defined by the nearest time point prior to first dose. If W1D1 results are available, these are 
considered the baseline results. If screening occurred within 72h of fit dose, W1D1 samples are not needed and 
screening data are considered as baseline.
Abbreviations:  GSK=GlaxoSmithKline; QTcF= QT duration corrected for heart rate by Fridericia’s formula; 
ECG=Electrocardiogram; IRB=Institutional review board; EC=Ethics committee; ULN=Upper limit of normal; 
LLN=Lower limit of normal; LVEF= Left ventricular ejection fraction; ALT=Alanine Transferase; BAL=Bronchoalveolar 
lavage; DLCO=Diffusing Capacity of the Lung for Carbon Monoxide; IL=Interleukin
 
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7.7.2.
Dose Adjustments for Toxicity
Dose adjustments for toxicity, other than those described in Section 7.7.1, are indicated in 
Table 16.
Table 16
Dose Adjustment for Toxicity
Worst Grade
Action
1
No change in dose
2
For drug-related Grade 2 toxicities, continue dosing with no change or may consider holding 
for up to 1 week for toxicity to be <Grade 2.  Continue at the same dose (dose reduction is 
required if the grade 2 toxicity is considered a DLT).
3
Hold dose for one week intervals until drug-related Grade 2 then restart with no change 
for 1st episode.  Utilize an alternative, less frequent schedule or reduce by one dose level 
with 2nd episode.  If no recovery to ≤Grade 1* after a 21 day delay, subject should go off 
protocol therapy.
4
Permanently discontinue study medication except if the event is considered non-serious 
and patient is likely to benefit by being on the study then hold dose for one week intervals 
until drug-related Grade 1 then restart after dose reduction by one dose level.  If no 
recovery to ≤Grade 1* after a 21 day delay, subject should go off protocol therapy.
*NOTE: Exceptions to drug-related Grade 1 requirement may be made for Rash, alopecia, etc.  Exceptions to 
drug-related Grade 1, 2, 3 requirements would be quickly reversible (<48 hours) laboratory abnormality (example: 
electrolyte changes).
Abbreviations: DLT=Dose limiting toxicity.
Dose escalation decisions will take into account all available data, including PK data and 
the safety profile of prior cohorts, relevant data from Study BET116183, and will occur 
following review of these data by the investigator(s), GSK medical monitor, 
pharmacokineticist, and statistician.  The decision and rationale will be documented in 
written format and distributed to the investigator(s), GSK medical monitor, 
pharmacokineticist, and statistician.
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
[safety, PK and/or pharmacodynamics] findings at a given dose level, or to add cohorts to 
evaluate additional dose levels.  The study procedures for these additional subject(s) or 
cohort(s) will be the same as that described for other study subjects.
7.8.
Guidelines for Events of Special Interest and Dose 
Modifications
The severity of adverse events will be graded utilizing the NCI-CTCAE v4.0 
[NCI, 2009].  Additional details regarding diarrhea, rash and liver toxicity are outlined in
Appendix 4.
 
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8.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from signing informed consent until the end of the study (Final Study Visit).  
Any concomitant medication(s), including herbal preparations taken during the study will 
be recorded in the eCRF.  The minimum requirement is that drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates of 
administration should be recorded.  Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file.  Any such changes 
will be communicated to the investigative sites in the form of a letter.
8.1.
Permitted Medications
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  The only caveat is that subjects should not receive those 
medications listed as prohibited in Section 8.2.
Bisphosphonates will be allowed if subjects have been on a stable dose for at leat three 
months.
Supportive measures including erythropoietin, blood transfusions, and hematopoietic 
colony stimulating factors for treatment of cytopenias are permitted.  Erythropoiesis-
stimulating agents and colony-stimulating factors like filgrastim and pegfilgrastim may 
be used as clinically indicated.
8.2.
Cautionary/Prohibited Medications
The use of certain medications and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study medication (and for the 
duration of the study) will not be allowed.  If a prohibited medication is required for 
single use (such as for a procedure) while study treatment(s) is held, the GSK Medical 
Monitor can approve such use.
Subjects must not receive other anti-cancer therapy (including chemotherapy, 
immunotherapy, biologic therapy, or hormonal therapy, whether approved or 
investigational) while on treatment in this study.  Short courses of steroids may be co-
administered with permission from the GSK medical monitor.
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc.) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit.  Low dose (prophylactic) anticoagulants are permitted.
 
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Aspirin may not be administered at doses that exceed 100 mg per day.  Non-steroidal 
anti-inflammatory agents should be avoided except where they provide benefit over other 
analgesics; if administered, they should be used with caution and consideration should be 
given to co-administration with proton pump inhibitors.
Co-administration of medications that are associated with prolonged QT interval (please 
refer to crediblemeds.org for a complete list of these medications) is permitted as follows:

If a subject is taking a QT-prolonging medication prior to first dose of 
GSK525762, then the subject may continue to take this medication without 
additional monitoring, so long as the baseline QTcF meets criteria as described in 
Section 4.2.2

If a subject must initiate a QT-prolonging medication while receiving 
GSK525762, then additional ECG monitoring should be implemented, per local 
standard, until the QT-prolonging medication achieves therapeutic concentrations.  
Refer to Table 15 for QT management guidelines.
During Part 1, Antacids should not be consumed for at least 1h before and 2h after 
administration of GSK525762.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
8.2.1.
Drugs Potentially Affecting GSK525762 Pharmacokinetics or 
affected by GSK525762 
In vitro data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of potent inducers and moderate or potent inhibitors of CYP3A4 should 
be avoided during the course of the study where possible as they may respectively 
decrease or increase exposure to GSK525762. Note: any medication (including 
antibacterials, antifungals, or antivirals) which are necessary for the health, well-being, 
and standard clinical care of patients with hematologic malignancies are exempt from the 
restrictions below.
GSK525762 is a moderate CYP3A4 inducer. Medications that have a narrow therapeutic 
index and that are substrates of CYP3A4 should be administered with caution, as their 
metabolism may be affected by co-administration with GSK525762 and result in 
decreased exposure. These include alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline.
GSK525762 is a substrate for breast cancer resistance protein (BCRP) and P-glycoprotein 
(Pgp) transporters. Therefore, potent inhibitors of these transporters, such as 
cyclosporine, tacrolimus, or ketoconazole, should be avoided.
 
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8.3.
Non-Drug Therapies
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the post-study 
follow-up visit, except as follows:
NOTE: Palliative radiation and/or surgical intervention may be permitted (for example to 
address pain management) and should be discussed with the GSK medical monitor prior 
to invention to determine appropriate dosing and schedule.  Irradiated/resected lesions 
should not subsequently be utilized as the sole lesion(s) for response assessment 
determination.
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit.  Subjects enrolled in Part 1 of the study should abstain from 
coffee and tea from 24 hours prior to an extensive PK collection day (i.e. W1D1 and 
W2D7) until the end of PK collection on that day.
Herbal products include, but are not limited to:

St. John’s Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto, ginseng, and marijuana.
8.4.
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of Study
Refer to Section 4.2.3 and Section 5 for follow-up assessment of subjects who are to be 
followed up for disease progression and/or survival after permanent discontinuation from 
study treatment.
8.5.
Treatment of Study Treatment Overdose
In the event of a study drug overdose (defined as administration of more than the 
protocol-specified dose), the investigator should:

contact the GSK Medical Monitor immediately 

closely monitor the subject for AEs/SAEs and laboratory abnormalities.

obtain a plasma sample for PK analysis as soon as possible from the date of the last 
dose of study treatment if requested by the GSK Medical Monitor (determined on a 
case-by-case basis).
-
This plasma sample should be collected as soon as possible from the date of 
the last dose of on-study dosing.

document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the GSK Medical Monitor based on the clinical evaluation of the 
subject.
 
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9.
LIFESTYLE REQUIREMENTS (CONTRACEPTION) 
AND/OR DIETARY RESTRICTIONS
9.1.
Contraception
9.1.1.
Female Subjects
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value <40pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping medications and so must be sexually inactive by abstinence or 
use contraceptive methods with a failure rate of < 1%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are NOT acceptable methods of contraception.  
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1% failure 
rate as stated in the product label

Note: Hormonal IUDs may only be used if the following criteria are met:

Male condoms are required AND

Subjects are informed of the potential for reduced systemic hormone levels 
from the IUD when taking GSK525762

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject.  For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible 
 
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for ensuring subjects understand how to properly use these methods of 
contraception.
All Hormonal means of birth control such as oral, injectable, dermal, subdermal or 
topical contraceptives are NOT acceptable forms of birth control given that their efficacy 
has not been evaluated when given in combination with the investigational drugs.
9.1.2.
Male Subjects
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug(s):

Vasectomy (documentation of azoospermia), or
Condom use PLUS partner use of highly effective contraceptive (<1% rate of failure 
per year) such as intrauterine device or system, or hormonal birth control such as 
contraceptive subdermal implant, combined estrogen and progestogen oral 
contraceptive, injectable progestogen, contraceptive vaginal ring, or percutaneous 
contraceptive patches, or
Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Male subjects whose partners are pregnant, or whose partners become pregnant during 
participation in the study, must use condoms from the first dose of study medication and 
for 16 weeks after stopping study medication(s).
Male subjects should be advised not to donate sperm while on study and for 16 weeks 
after the last dose of study drug(s).”
9.2.
Caffeine, Alcohol, and Tobacco
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or pharmacodynamic sample during each 
extensive PK session in Part 1.
10.
DATA MANAGEMENT
Subject 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 
 
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and audit trails, will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled. Data for screen failures will be collected in source 
documentation at the site but will not be transmitted to GSK. 
11.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
11.1.
Sample Size Assumptions
No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
11.1.1.
Part I, Dose Escalation
The sample size in Part 1 is not driven by statistical considerations.  The total number of 
subjects will depend on the number of dose escalations needed.  However, the maximum 
anticipated number of subjects will be approximately 60-70.
Doses to be studied in Part 1 will be guided by calculating the posterior probability that 
the DLT rate falls within an acceptable range for each subsequent dose after each dose 
cohort observation period. The N-CRM method will be used to calculate posterior 
probabilities utilizing a pre-specified prior distribution.
Subjects in Part 1 treated at the RP2D may be included in the efficacy analysis as 
described in Section 11.6.1.
11.1.2.
Part 2, Expansion Cohort
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with MDS, 
and CTCL.

For MDS, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, marrow CR, or PR) of 30% relative 
to a 10% response rate suggesting no activity.  Historically, hypomethylating agent 
failure has conferred a poor prognosis, with a response rate to second-line therapy of 
10% or less (Prebet, 2011).  Investigational agents have demonstrated a response rate 
of approximately 30%, though no effects on overall survival have been reported 
(Seetharam, 2012; Kantarjian, 2010).  Because of the high unmet medical need of 
relapsed/refractory MDS, and because no agent to date has exceeded the 30% 
 
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response rate published above, 30% was chosen as a realistic goal for subjects with 
MDS.

For CTCL, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, or PR lasting more than 4 months) 
of 40% relative to a 20% response rate suggesting no activity.  Multiple clinical 
studies with active and approved agents have demonstrated a response rate of 30-
40% in a comparable patient population (Duvic, 2007; Piekarz, 2009; Whittaker, 
2010).  Therefore, a target response rate of 40% was chosen to represent the response 
rate of an active agent.  Conversely, an agent with a response rate of 20% is unlikely 
to be developed further; this is approximately the response rate of placebo described 
in the denileukin difitox package insert [ONTAK package insert, 2008]. Therefore, 
20% was chosen to represent the activity of a futile agent.  
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 
weak prior Beta distribution with a mean response rate equal to the target response rate is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution (e.g. Beta (0.03, 0.07)) and the observed data x, the 
posterior distribution of the response rate follows a beta distribution, i.e.
In the following case, 30% is the target response rate.
p Beta (0.03 + x, 0.07 + n-x) with posterior mean (0.03+ x)/(0.07 + n).
Futility analysis for each disease cohort will begin when response data is available for at 
least 10 subjects treated at the RP2D in Part 1 and Part 2. Each disease cohort may be 
stopped early for futility if the predictive probability of success (response rate  > 
historical response rate) is less than 1%.  Futility stopping rules are defined for each 
cohort in Section 3.2.4.
For the MDS cohort, starting with a cohort of 10 subjects and allowing for a maximum 
sample size of 32 subjects at the RP2D with stopping guidelines as described in Section 
3.2.4, this design will have a Type I Error () of 0.034 and 87% power. Futility analysis 
will be based on subjects who have at least one post-baseline disease assessment, have 
progressed or died, or have permanently discontinued from study treatment. The trial will 
be stopped early for futility if the predictive probability of success (that the response rate 
historical response rate) is less than 1%. If the true response rate is 10%, the average 
sample size is 20 and the probability of early termination for futility is 93%. If the true 
response rate is 30%, the average sample size is 31 subjects and the probability of early 
termination is 9%. 
 
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For the CTCL cohort, starting with a cohort of 10 subjects and allowing for a maximum 
sample size of 37 subjects at the RP2D with stopping guidelines as described in Section 
3.2.4, this design will have a Type I Error () of 0.049 and 85.2% power. Futility 
analysis will be based on subjects who have at least one post-baseline disease assessment, 
have progressed or died, or have permanently discontinued from study treatment. The 
trial will be stopped early for futility if the predictive probability of success (that the 
response rate historical response rate) is less than 1%. If the true response rate is 20%, 
the average sample size is 23 and the probability of early termination for futility is 92%. 
If the true response rate is 40%, the average sample size is 36 subjects and the probability 
of early termination is 11%.
11.1.3.
Sensitivity Analysis
No analysis of sample size sensitivity was performed.
11.1.4.
Sample Size Re-estimation
No sample size re-estimation will be performed.
11.2.
Analysis Populations
All Treated (Safety and Clinical Activity) 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 PK Concentration Population: This will consist of those subjects in All Subjects 
Population for whom a PK sample is obtained and analyzed.
The PK Parameter Population: This will consist of those subjects in All Subjects 
Population for whom a PK parameter is available.
The Pharmacodynamic Population: This will consist of those subjects in All Subjects 
Population who contribute pharmacodynamic/biomarker samples.
More details of the analysis populations will be specified in reporting and analysis plan 
(RAP).
11.3.
Data Analysis Considerations
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
 
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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.
11.3.1.
Analysis Datasets
The construction of analysis data sets will be performed in accordance with all applicable 
GlaxoSmithKline standards and procedures.
11.3.2.
Withdrawal
Reasons for subject withdrawal will be listed.
11.3.3.
Missing Data
Missing data will not be imputed.  Where appropriate, available data will be summarized 
over specified intervals (e.g., from start of treatment until withdrawal from study) using 
suitable summary statistics.
11.3.4.
Derived and Transformed Data
The PK parameters AUC, Cmax, and terminal half-life will be log-transformed prior to 
analysis.
11.3.5.
Assessment Windows
Safety assessments that occur prior to the administration of study drug will be considered 
screening assessments.  Safety assessments that occur after dosing has begun will be 
considered as having occurred while on treatment.
Disease assessments will be distinguished as belonging to either screening, continued 
therapy or post-study phases of the study.
11.3.6.
Other Issues
Data from participating centers will be pooled by tumor cohort prior to analysis.  It is 
anticipated that subject accrual may be limited across centers and summaries of data by 
center would likely not be informative.  Therefore, these summaries will not be provided.
Demographic and baseline characteristics will be summarized.
For PK analyses, assay values below the quantitative limit (BQL) will be handled as 
described in the GSK Clinical Pharmacokinetics Modelling & Simulation (CPMS) PK 
Methods.
There will be no adjustments for multiplicity.
 
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11.4.
Interim Analysis
Interim analysis on Part 1 may be conducted when 

Part1 is completed or 

All subjects enrolled in any or all of AML, MM, and NHL cohorts in Part 1 have 
had at least one post-baseline disease assessment or progressed or died or 
withdrawn from the study
For each disease type in Part 2, after at least 10 subjects in the MDS or cutaneous 
lymphoma cohorts become evaluable (have had at least one post baseline disease 
assessment, have progressed or died, or have permanently discontinued from study 
treatment) at the selected dose regimen for the Expansion Cohort, data will be reviewed 
for clinical benefit on an ongoing basis and the number of subjects with observed clinical 
benefit will be compared with the stopping guidelines provided in Section 3.2.4.  For the 
CTCL cohort, subjects with CTCL in Part 1 treated at the RP2D will be included in this 
analysis of efficacy.
The study will not stop due to efficacy.  The trial may continue to enrol the maximum 
planned sample size to provide a better an estimate on the distribution of the response 
rate in the target patient populations.
11.4.1.
Other Stopping Criteria for Part 2
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics).  Deaths, SAEs and Grade 3/4 adverse events will be carefully evaluated for 
causality.  
If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, and/or if deaths related to study drug are observed, enrollment may be 
terminated and/or a lower-dose cohort may be opened or expanded.  The final 
determination will be made by the Sponsor and investigators.
11.5.
Final Analyses
Final primary analysis will occur when at least 70% of subjects are dead, have withdrawn 
consent, or are lost to follow-up, or all subjects still in follow-up have had at least 5 years 
follow-up, whichever is earlier.
The 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 GSK525762.  Data from Part 1 and Part 2 may be 
combined for some analyses at the end of the trial, as appropriate.  More detail on the 
data displays will be provided in the RAP.
Final OS analysis may be conducted when all subjects have completed the study. 
 
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11.6.
Efficacy Analyses
11.6.1.
Primary Analysis
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria described in the Section 5 Time and Events Table 7 for MM, lymphoma and/or 
leukemias, as noted in Appendix 6, Appendix 7 and Appendix 8, respectively.  If the data 
warrant, the response data will be summarized by dose level.  In addition, any subject in 
Part 1 treated at the RP2D may be included in the analysis of efficacy described below.
The primary aim of Part 2 is to detect a possibly clinically meaningful response rate in 
each of the disease cohorts separately. Each disease type (MDS and CTCL) will be 
evaluated separately.
Overall Response rate is defined as 

MDS: The percentage of subjects who achieved CR, marrow CR, or PR, as defined 
in Appendix 9. A waterfall plot of percent change from baseline in bone marrow 
blasts and peripheral blasts will be provided.
CTCL: ORR4 is defined as percentage of subjects who achieved a CR or PR lasting at 
least 4 months.  Responses will be defined as per consensus guidelines [Olsen, 2011]
using mSWAT criteria (Appendix 10).  All subjects treated at RP2D with CTCL will be 
counted as the denominator. The estimate for ORR4 along with 95% exact confidence 
interval will be provided. 
For subjects in the CTCL cohort, scans, photographs and raw flow cytometry used for 
response assessments may be requested for independent review. Further details regarding 
collection, storage, and transmission of these will be provided in the SRM
All subjects who received at least one dose of treatment will be included in the evaluation 
for response.  Response rates and the associated 2-sided 95% exact confidence limits will 
be provided.
11.6.2.
Secondary Analysis
For the analysis of PFS if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is Not Evaluable) prior to the initiation of therapy. 
Otherwise, if the subject does not have a documented date of events, PFS will be 
censored at the date of the last adequate assessment. 
For the analysis of overall survival (OS), the last date of known contact will be used for 
those subjects who have not died at the time of analysis; such subjects will be considered 
censored. Further details on rules for censoring will be provided in the RAP. Sensitivity 
analyses of PFS and further details on censoring rules will be provided in the RAP.  
Progression free survival (PFS) and overall survival (OS) will be summarized using 
Kaplan-Meier method if data warrant.
 
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The duration of response is defined for responders (subjects with CR, marrow CR, or PR
for MDS cohort, or subjects with a CR or PR for CTCL cohort), as the time from the first 
documented evidence of response until the first documented disease progression or death 
due to any cause. Censoring rules for duration of response will be outlined in detail in the 
RAP.
If sample size permits, duration of response will be summarized descriptively using 
Kaplan-Meier medians and quartiles. Censoring rules for duration of response will follow 
the rules for PFS outlined in detail in the RAP
OS along with 95% confidence intervals for leukemia subjects in Part 1, MDS subjects in 
Part 2, and MM subjects treated in Part 1 and cutaneous lymphoma  subjects treated in 
Part 2, will be estimated using the Kaplan Meier method if data warrant.  OS analysis for 
AML will exclude subjects with AML subtype M3. All cause mortality will be used and 
censoring will be performed using the date of last known contact for those who are alive 
or lost to follow-up at the time of analysis.  
11.7.
Safety Analyses
Safety endpoints are described in Section 2.  The All Treated Population will be used for 
the analysis of safety data.  All serially collected safety endpoints (e.g., laboratory tests, 
vital signs, ECGs) will be summarized according to the scheduled, nominal visit at which 
they were collected and across all on-treatment time points using a “worst-case” analysis.  
Complete details of the safety analyses will be provided in the RAP.
A listing by subject including treatment administered, and compliance, will be generated 
with dates and times of treatment administered. 
All relevant safety data will be listed and summarized according to IDSL standards.  The 
reporting and analysis plan will list the Integrated Data Standards Library (IDSL) 
templates for the displays.  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 Section 5
Time and Events Tables.  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 the NCI-CTCAE v4.0 [NCI, 2009].  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.
 
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ECOG Performance Status assessments will be listed and summarized for Part 1 (for each 
dose cohort) and Part 2.
11.7.1.
Extent of Exposure
Extent of exposure of GSK 525762 will depend on tolerability of the subjects to the doses 
administered and the course of their disease.  The number of subjects exposed to 
GSK525762 will be summarized for each dose level administered according to the 
duration of therapy.
11.7.2.
Adverse Events
AEs will be coded and summarized by frequency and proportion of total subjects, 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 by the investigator according to the NCI-CTCAE v4.0 [NCI, 2009].
Events will be summarized by maximum toxicity grade for each initial dose level. 
Separate summaries will be given for all AEs, treatment-related AEs, serious AEs and 
AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI-CTCAE v4.0 [NCI, 2009] table, the maximum grade will be 
summarized.  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.
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by dose 
cohort according to IDSL standards.
11.7.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.0 [NCI, 2009] grade.  Laboratory test results 
outside the reference ranges that do not have associated NCI-CTCAE criteria will be 
summarized using proportions.  Summaries will include data from scheduled assessments 
only, and all data will be reported according to the nominal visit date for which it was 
recorded (i.e., no visit windows will be applied).  Unscheduled data will be included in 
“overall” and “any post-screening” summaries which will capture a worst case across all 
scheduled and unscheduled visits post first dose of study treatment.  Further details will 
be provided in the RAP.
11.8.
Pharmacokinetic Analyses
PK analyses will be the responsibility of GSK CPMS.  Plasma GSK525762 and relevant 
metabolite(s), as appropriate, concentration-time data from dose escalation (Part 1) will 
be analyzed by non-compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacology parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½).  Trough concentration (C) 
 
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samples collected on the specified days will be used to assess attainment of steady state.  
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from the ratio of AUC(0-) in Week 2 Day 7 / AUC(0-) in 
Week 1 Day 1.  The ratio of AUC(0-) on Week 2 Day 7 / Week 1 Day 1 AUC(0-∞) will 
be calculated to assess time invariance.  Plasma concentration-time data will be listed by 
dose, dosing regimen, and summarized using descriptive statistics (n, mean, standard 
deviation [SD], median, minimum and maximum) by planned relative assessment time.  
Mean and/ or median values will be plotted over time.  Individual plasma and urinary (if 
available) PK parameters values as well as a descriptive summary (mean, standard 
deviation, median, minimum, maximum, geometric mean, and the standard deviation, 
CV% and 95% confidence interval of log-transformed parameters [if applicable]) by day, 
dose and dose regimen cohort will be reported.
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) will be plotted as a 
function of the dose administered and dosing regimen.  If more than 2 dose cohorts are 
evaluated, dose proportionality of AUC and Cmax for GSK525762 will be assessed using 
the power model (details will be provided in the RAP).
Plasma concentration-time data from Parts 1 and 2 will be combined and may be 
combined with data from other studies and further analyzed using a population approach.  
A nonlinear mixed effects model will be used to determine population PK parameters 
(absorption rate, Ka, apparent clearance, CL/F and volume of distribution, V/F) and 
summary exposure measures (Cmax, AUC and Average observed concentration 
(Cav) = AUC/) and identify important covariates (e.g., age, weight, or disease related 
covariates). This analysis may be reported separately.
11.9.
Pharmacokinetic/Pharmacodynamic Analyses
Observed or predicted concentrations will be combined with safety, efficacy, and/or 
pharmacodynamic measures of interest to examine potential exposure response 
relationships.
The relationship between QTcF and concentration expressed as Cmax, Cav, and 
instantaneous time-matched concentration will be plotted graphically.  A linear mixed 
effects analysis of the slope of the QTcF-concentration responses adjusting for baseline 
will be evaluated as a means of estimating QTcF effect in lieu of a thorough QT study.
Other quantitative safety parameters and biomarkers of interest including changes in 
troponin levels will be plotted graphically against summary exposure measures (e.g., 
Cmax, C, and Cav).  Where evidence of a signal is seen, linear and non-linear mixed 
effect models will be fitted to the data to estimate PK/pharmacodynamic parameters of 
interest; slope, baseline (E0), exposure producing 50% of the maximum effect (EC50), 
and maximum effect (Emax).
Overall efficacy data and overall tumor burden may be described using 
categorical/continuous models with summary exposure parameters (e.g., Cmax, C, and 
Cav) as covariates derived from the population PK analysis.  Further model details will 
be provided in the RAP.  This analysis may be reported separately.
 
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11.10.
Translational Research Analyses
Exploratory analysis may be performed to examine potential relationships between 
anticancer activity and changes in markers of BET target inhibition or tumor biology or 
between anticancer activity and potential markers of sensitivity.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment.  All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data.  Further details on the translational research analyses will be addressed in the RAP.
11.11.
Pharmacogenetic Analyses
The results of PGx research investigations will be reported separately from the main 
clinical study report or as an amendment.  All endpoints of interest from all comparisons 
will be descriptively and/or graphically summarized as appropriate to the data.  Further 
details on the PGx research and analyses are found in Appendix 5 and will be addressed 
in the PGx RAP.
11.12.
Quality of Life Analyses
Skindex-29 inquires about how often during the previous four weeks the patient 
experienced the effect described in each item. It includes three domains: Emotional, 
Symptoms, and Functioning as well as an additional item about Treatment that is not 
scored. Details about the score derivation and analysis will be provided in the RAP.  See 
Appendix 11 for more details.  
12.
STUDY CONDUCT CONSIDERATIONS
12.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
12.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with ICH Good Clinical Practice 
(GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/ EC review and approval of study protocol and any subsequent amendments.
 
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
Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject, prior to participation in the 
study.
12.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 
Investigational Product (IP), and this new event is likely to affect the study of subjects, 
the Sponsor, and the investigator will take appropriate urgent safety measures to protect 
subjects against any immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/ EC is notified.
12.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
12.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site.  Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study.  In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
12.6.
Study and Site Closure
The end of the study date will be defined as the date of the last visit of the last subject 
enrolled.
 
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Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  GSK may also close sites which fail to recruit. When feasible, GSK 
will provide advance notice to the investigator or head of the medical institution of the 
impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/ EC promptly and provide the reason(s) for the suspension/termination.
12.7.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
 
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12.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Register 
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.
13.
COUNTRY SPECIFIC
At the request of the Medicines and Healthcare products Regulatory Agency, 
Amendment 1 applies to study centres in the United Kingdom. Protocol amendment 1 
removed “until commercial supply of GSK525762 becomes available” as a duration of 
exposure on the study in accordance with the Commission Directive 2005/28/EC.  
Modifications include an updated protocol synopsis as outlined in Section 15.14. The 
protocol amendment 1 may also apply to other countries if specifically requested.
 
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14.
REFERENCES
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Safety 2009; 8: 709–14.
Ahern K, Gilmore ES, Poligone B. Pruritus in cutaneous T-cell lymphoma: a review. J 
Am Acad Dermatol. 2012;67(4):760-768.
Cheson BD, Bennett JM, Kopecky KJ, et al..  International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 
15;21(24):4642-9.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood  2006; 8:419-426.
Cheson BD, Pfistner B, Juweid ME, et al.; International Harmonization Project on 
Lymphoma. Revised response criteria for malignantlymphoma. J Clin Oncol. 2007; 
25(5): 579-86.
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
CredibleMeds. List of drugs with a risk of Torsades de Pointes. Available at: http://www.
crediblemeds.org   Accessed 02 March 2016
Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin 
as an effective treatment for MLL-fusion leukaemia. Nature. 2011; 478: 529-533.
Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic 
strategy to target c-Myc. Cell 2011; 146: 904-17.
Devine BJ.  Case Number 25 Gentamycin Therapy: Clinical Pharmacy Case Studies.  
Drug Intel. Clin. Pharm.  1974; 8: 650-55.
Durie BGM, Harousseau J-L, Miguel JS, et. al. International uniform response criteria for 
multiple myeloma. Leukemia, 2006; 20: 1467-73.
Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral 
vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell 
lymphoma (CTCL). Blood. 2007 Jan 1;109(1):31-39.
Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations. 
Pharmacogenomics. 2008; 9: 1543-46.
GlaxoSmithKline Document Number 2011N113741_06 Version 6. GSK525762 
Investigator's Brochure. Report Date 06-Apr-2017.
 
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2013N159121_10
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BET116183
127
Green SJ and Dahlberg S. Planned Versus Attained Design in Phase II Clinical Trials. 
Stat Med. 1992; 11: 853-62.
Greenberg P, C Cox, MM LeBeau, P Fenaux, P Morel, et al. Blood 1997;89(6):2079-
2088
Greenberg PL, H Tuechler, J Schanz, G Sanz, G Garcia-Manero, et al. Blood 2012 
120:2454-2465
Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and 
hypersensitivity reactions to abacavir. Lancet. 2002; 359(9312): 1121–2.
Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: a systematic review. Hepatology. 2010; 2: 
2216–22.
Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol. 2004; 22: 1382-88.
Jabbour, Garcia-Manero, Batty, Shan, et al.  Outcome of Patients with Myelodysplastic 
Syndrome after Failure of Decitabine Therapy.  Cancer, 2010; 116(16): 3830-4.
James LP. Pharmacokinetics of Acetaminophen - Protein Adducts Liver Failure. Drug 
Metab Disp. 2009: 37: 1779-84.
Kantarjian H, Garcia-Manero G, O'Brien S, et al. Phase I clinical and pharmacokinetic 
study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. 
J Clin Oncol. 2010 Jan 10;28(2):285-91. Epub 2009 Nov 23.
Kohnken R, Wen J, Mundy-Bosse B, McConnell K, Keiter A, Grinshpun L, et al. 
Diminished microRNA-29b level is associated with BRD4-mediated activation of 
oncogenes in cutaneous T-cell lymphoma. Blood. 2017;131(7):771-781.
Kortuem KM, Zidich K, Schuster SR, Khan ML, Jimenez-Zepeda VH, Mikhael JR, et 
al. Activity of 129 single-agent drugs in 228 phase I and II clinical trials in multiple 
myeloma. Clinical lymphoma, myeloma & leukemia. 2014;14:284-90 e5. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 2008; 5(2): 93-106.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI,, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-612.
Liu CY, Chen PM, Chiou TJ, et al. UGT1A1*28 polymorphism predicts irinotecan-
induced severe toxicities without affecting treatment outcome and survival in patients 
with metastatic colorectal carcinoma. Cancer. 2008; 112: 1932-40.
 
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2013N159121_10
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BET116183
128
Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-
DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor 
abacavir. Lancet. 2002; 359: 727-32.
Mertz JA. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc 
Natl Acad Sci USA 2011; 108: 16669-74.
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4.0, 
DCTD, NCI, NIH, DHHS, May 28, 2009.
Neuenschwander, B, Branson, M, and Gsponer, T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2009; 27: 2420–39.
Nicodeme E, Jeffrey K, et al.  Suppression of inflammation by a synthetic histone mimic.  
Nature. 2010; 478: 1119-23.
NYHA. The Criteria Committee of the New York Heart Association (NYHA).  
Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th 
Ed. Boston, Mass:  Little, Brown & Co.; 1994; 253-56.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group, Am. J. Clin. 
Oncol. 1982; 5: 649-55.
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb 
multicenter trial of vorinostat in patients with persistent, progressive, or treatment 
refractory cutaneousT-cell lymphoma. J Clin Oncol. 2007;25: 3109-3115.
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end 
points and response criteria in mycosis fungoides and Sézary syndrome: a consensus 
statement of the International Society for Cutaneous Lymphomas, the United States 
Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organisation for Research and Treatment of Cancer. J Clin Oncol. 
2011;29(18):2598-2607.
ONTAK (denileukin diftitox) Product Information. October, 2008.
Papay JI, Clines D, Rafi R, et al. Drug-induced liver injury following positive drug
rechallenge. Regul Toxicol Pharmacol. 2009; 54: 84–90.
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II 
multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy 
for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410-5417.
Prebet T, Gore SD, Esterni B, Gardin C, et al.  Outcome of high-risk myelodysplastic 
syndrome after azacitidine treatment failure. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2011 Aug 20;29(24):3322–7
 
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Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood. 2011; 117:4691–95.
Seetharam M, Fan A, Tran M, Xu L, et al.   Treatment of Higher Risk Myelodsplastic 
Syndrome Patients Unresponsive to Hypomethylating Agents with ON 01910.NA 
Leukemia Research. 2012; Jan; 36(1): 98–103.
Sekeres MA and Cutler C. How We Treat Higher-Risk Myelodysplastic Syndromes 
Blood. 2014; Feb 6;123(6):829-36.
Swerdlow, Campo, Pileri, et al.  The 2016 revision of the World Health Organization 
Classification of Lymphoid Neoplasms. Blood 2016; 127(20):2375-2390.
Tefferi A. Chronic myeloid disorders: Classification and treatment overview. Semin 
Hematol. 2001; 38(1 Suppl 2): 1–4
Whittaker S, Hoppe R, Prince HM. How I treat mycosis fungoides and Sézary syndrome.
Blood. 2016;127(25):3142-3153.
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results 
from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-
cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491.
Wilke RA, Berg RL, Vidaillet HJ, et al. Impact of age, CYP2C9 genotype and 
concomitant medication on the rate of rise for prothrombin time during the first 30 days 
of warfarin therapy. Clin Med Res. 2005; 3(4): 207–13.
 
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15.
APPENDICES
15.1.
Appendix 1: CKD-Epi Formula
The CKD-Epi method is a commonly-used surrogate marker for actual creatinine 
clearance (CrCl) and employs creatinine measurements and a subject's age and gender to 
predict the clearance.
Females, serum creatinine >62 μmol/L: 144 (serum creatinine 0.0113/0.7)−1.209 0.993age
Females, serum creatinine ≤62 μmol/L: 144 (serum creatinine 0.0113/0.7)−0.329 0.993age
Males, serum creatinine >80 μmol/L: 141 (serum creatinine 0.0113/0.9)−1.209 0.993age
Males, serum creatinine ≤80 μmol/L: 141 (serum creatinine 0.0113/0.9)−0.411 0.993age
[Levey, 2009]
 
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15.2.
Appendix 2: NYHA Functional Classification System for 
Heart Failure
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994] 
provides a simple way of classifying the extent of heart failure.  It places subjects in one 
of four categories based on the level of limitation experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest.  If any physical activity is undertaken, discomfort 
is increased.
 
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15.3.
Appendix 3: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
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 ANY Liver Stopping Event
Actions
Immediately discontinue study treatment 
Report the event to GSK within 24 hours
Complete the liver event CRF and complete SAE data colle`/ction tool if the event also meets the criteria 
for an SAE2
Perform liver event follow up assessments 
Monitor the participant until liver chemistriesresolve, stabilize, or return to within baseline (see 
MONITORING below)
Do not restart/rechallenge participant with study treatment unless allowed per protocol and GSK 
Medical Governance approval is granted
If restart/rechallenge not allowed per protocol or not granted, permanently discontinue study 
treatment and may continue participant in the study for any protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:
Repeat liver chemistries(include ALT, AST, alkaline phosphatase, bilirubin) and perform liver event 
follow up assessments within 24 hrs
Monitor participants twice weekly until liver chemistries resolve, stabilize or return to within baseline
 
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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 participants weekly until liver chemistries resolve, stabilize or return to within baseline
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 
2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the 
threshold value stated will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM. 
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.
Liver Safety Drug Restart Guidelines
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant
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 participant
 
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If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then participant must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments
Rechallenge Following Liver Stopping Events that are Possibly Related to Study 
Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies (Andrade, 2009). Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality.  
Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity (Andrade, 2009) with initial liver injury (e.g. fever, rash,
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges (Papay, 2009; Hunt, 2010)

evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment (Hunt, 2010)
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a participant 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
participant who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available.  

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.   

If the rechallenge is approved by GSK Medical Governance in writing, the 
participant 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 participant must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  
 
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
Study treatment must be administered at the dose specified by GSK.

Participants 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, participant meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 6.7. 
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
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).

Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 7.7 will apply.

There is no evidence of alcoholic hepatitis.

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 
participant 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 participant 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.

Participants 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, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 6.7.
References:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. 
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.
 
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15.4.
Appendix 4: Dose Adjustment/Stopping Criteria/Supportive 
Care
Diarrhea
General considerations for diarrhea management
Rule out other or concomitant causes. These include medications (e.g., stool softeners, 
laxatives, antacids, etc.), infection by C. difficile or Candida species, partial bowel 
obstruction, malabsorption/lactose intolerance, fecal impaction, diets high in fiber or 
lactose.
For uncomplicated Grade 1 to 2 diarrhea (i.e., mild to moderate and defined as 
NCI-CTCAE v4.0 [NCI, 2009] Grade 1-2 with no complicating signs or symptoms):

Dietary modifications: stop all lactose containing products and eat small meals.  A 
BRAT (banana, rice, apples, toast) diet can be helpful.

Hydration: drink 8-10 large glasses of clear liquids per day (e.g., Gatorade or broth)

Consider administration of standard dose of loperamide (subjects should have 
loperamide available in order to start at the first signs of diarrhea):

Initial dose of 4 mg followed by 2 mg every four hours or after every 
unformed stool; maximum 16 mg/day.

Continuation of loperamide is suggested until diarrhea free for 12 hours

Consider a temporary investigational drug dose interruption until symptoms have 
resolved to baseline or Grade 1.  Re-treatment with GSK525762 may then be 
resumed at 100%.  Please refer to Section 7.7.2 for additional guidance.

If mild to moderate diarrhea persists for more than 24 hours, administer loperamide 
2 mg every two hours; maximum 16 mg/day.  Consider adding oral antibiotics.

If mild to moderate diarrhea persists after 48 hours total treatment with loperamide, 
start second-line agents (octreotide, budesonide or tincture of opium).  Consider 
adding oral antibiotics.
For Grade 3 to 4 diarrhea or complicated Grade 1 to 2 diarrhea (i.e., cramping, 
nausea/vomiting ≥ Grade 2, decreased performance status, fever, sepsis, Grade 3 or 4 
neutropenia, frank bleeding, dehydration):

The subject must call the investigator immediately for any complicated severe 
diarrhea event.

Discontinue GSK525762 treatment and hold until symptoms resolve to ≤Grade 1 or 
baseline.  Consider re-starting therapy at a reduced dose.

If loperamide has not been initiated, initiate loperamide immediately.  Initial dose 4 
mg followed by 2 mg every two hours or after every unformed stool; maximum 16 
mg/day.
 
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
For dehydration, use intravenous fluids as appropriate; if severe dehydration,
administer octreotide.

Administer antibiotics as needed (e.g., fluoroquinolones), especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3 to 4 neutropenia.

Intervention should be continued until the subject is diarrhea free for at least 24 
hours.

Intervention may require hospitalization for subjects most at risk for life-threatening 
complications.
 
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15.5.
Appendix 5: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the PK (absorption, distribution, metabolism, 
elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
PGx analysis include:
PGx Associations with Safety Events
Drug
Disease
Gene
Outcome
Abacavir
HIV 
[Hetherington, 2002; 
Mallal, 2002]
Human 
Leukocyte 
Antigen B 
(HLA-
B*5701)
Individuals with HLA-B*5701 variant may be at 
increased risk for experiencing hypersensitivity 
to abacavir.  Clinical assays are available for 
HLA-B*5701 but none has been validated.  
HLA-B*5701 screening would supplement but 
never replace abacavir clinical risk 
management strategies aimed at minimizing 
rare but serious outcomes associated with 
abacavir hypersensitivity.
Carbamazepine
Seizure, Bipolar 
disorders & 
Analgesia
[Chung, 2010; 
Ferrell, 2008]
HLA-B*1502
Independent studies indicated that patients 
carrying HLA-B*1502 are at higher risk of 
Stevens-Johnson Syndrome and toxic 
epidermal.  Regulators, including the US FDA 
and the Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*1502 prior to initiating 
treatment with carbamazepine.
Warfarin
Cardiovascular
[Wilke, 2005]
CYP2C9
SAEs experienced by some subjects on 
warfarin may be explained by variations in the 
CYP2C9 gene that influences the degree of 
anticoagulation achieved.
Irinotecan
Cancer 
[Innocenti, 2004; Liu, 
2008]
UGT1A1
Variations in the UGT1A1 gene can influence a 
patient’s ability to break down irinotecan, which 
can lead to increased blood levels of the drug 
and a higher risk of side effects.  A dose of 
irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another subject without this variation, 
raising the risk of certain side-effects.  A 
genetic blood test (Invader UGT1A1 molecular 
assay) is available that can detect variations in 
the gene.
 
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A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of saliva samples, may enable PGx analysis to be conducted if at any time it 
appears that there is a potential unexpected or unexplained variation in handling or 
response to GSK525762.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a possible genetic relationship to handling or response to 
GSK525762.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK525762 that may be attributable 
to genetic variations of subjects, the following objectives may be investigated

Relationship between genetic variants and the PK and/or pharmacodynamics of 
study treatment

Relationship between genetic variants and safety and/or tolerability of study 
treatment.

Relationship between genetic variants and efficacy of study treatment.
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives study treatment may take part in 
the PGx research.  Any subject who has received an allogeneic bone marrow transplant 
must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study.  Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
Study Assessments and Procedures
A saliva sample will be collected for the PGx research using an Oragene DNA self 
collection tube.  It is recommended that the saliva sample be taken at day 1, but may be 
taken at any time while the subject is participating in the clinical study after the subjects 
provided informed consent for the PGx research.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff.  Coded samples do not carry 
personal identifiers (such as name or social security number).  The saliva sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample.
The DNA extracted from the saliva sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
 
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the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK525762 has been completed and the study data reviewed.  In some cases, the 
samples may not be studied (e.g., no questions are raised about how people respond to 
GSK525762).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will use samples collected from the study for 
the purpose stated in this protocol and in the ICF.
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:

The sample is retained for PGx research.

Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records.  In either case, GSK will only keep study 
information collected/generated up to that point.
Pharmacogenetics Analyses
Specific genes sections of DNA may be selected from areas of the genome (e.g., 
candidate genes) known to encode the drug target, drug metabolizing enzymes, areas 
associated with mechanisms underlying adverse events, and those linked to study disease 
and, thus, linked to drug response.
These candidate genes that may be investigated in this study include the following: the 
GSK Absorption, Distribution, Metabolism and Excretion genes.  These play a central 
role in drug PK and pharmacodynamics.  In addition, continuing research may identify 
other enzymes, transporters, proteins or receptors that may be involved in response to 
GSK525762.  The genes that may code for these proteins may also be studied.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) located throughout the genome, often correlated with a 
candidate gene, may be studied to determine the.  This approach is often employed when 
potential genetic effects are not well understood.
The results of PGx investigations will be reported either as part of the main clinical study 
report or as a separate report.  All endpoints of interest from all comparisons will be 
 
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descriptively and/or graphically summarized as appropriate to the data.  In all cases, 
appropriate statistical methods will be used to analyze the genetic markers in the context 
of other clinical data.  Statistical methods may include, but are not limited to Hardy-
Weinberg Equilibrium testing, Comparison of Demographic and Baseline Characteristics 
by Genotype, Evaluation of Genotypic Effects, Evaluation of Treatment by Genotype and 
Gene-Gene Interaction, Linkage Disequilibrium, Multiple Comparison and Multiplicity 
and/or Power and Sample Size Considerations.  A detailed description of the analyses to 
be conducted will be documented in the PGx RAP.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any sample being taken 
for PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the cumulative the PGx research results in the clinical study report.
In general, GSK does not inform the investigator, subject or anyone else (e.g., family 
members, study investigators, primary care physicians, insurers, or employers) of the 
PGx research results unless required by law.  The information generated from PGx 
research is preliminary in nature, and the significance and scientific validity of the results 
are undetermined at such an early stage of research.
 
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15.6.
Appendix 6: Response Criteria for Multiple Myeloma
Consensus Recommendations [Rajkumar, 2011] for the Uniform Reporting of 
Clinical Trials:  Report of the International Myeloma Working Group (IMWG) 
Consensus Panel
Response Criteria [Durie, 2006]
sCR (stringent complete response):
Complete response as defined below plus:

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 2-4 color flow 
cytometry.
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

5% plasma cells in bone marrow.
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis  OR

90% or greater reduction in serum M-component plus urine M-component
< 100mg/24h.
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by 
90% or to < 200mg/24h, and

If the serum and urine M-protein are not measurable, a 50% decrease in the 
difference between involved and uninvolved free light chain levels is required in 
place of the M-protein criteria.  If serum and urine M-protein are not measurable, 
and serum free light chain assay is also not measurable, 50% reduction in bone 
marrow plasma cells is required in place of M-protein, provided baseline bone 
marrow plasma cell percentage was 30%, and

In addition to the above listed criteria, if present at baseline, a 50% reduction in the 
size of the soft tissue plasmacytomas is also required.
MR (minimal response):

25% but 49% reduction of serum M-protein and reduction in 24 hour urinary M-
protein by 50% to 89%, AND

If present at baseline, 25% to 49% reduction in the size of soft tissue plasmacytomas 
is also required.
 
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
No increase in size or number of lytic bone lesions (development of compression 
fracture does not exclude response).
SD (stable disease):

Not meeting criteria for CR, VGPR, PR, MR or Progressive Disease.
Progressive Disease:
Requires any one or more of the following:

Increase of 25% from lowest response value in any one or more of the following: 

serum M-component (absolute increase must be 0.5 g/dl), or

urine M-component (absolute increase must be 200 mg/24h), or

the difference between involved and uninvolved free light chain levels (absolute 
increase must be > 10mg/dl): only for subjects without measurable serum and 
urine M-protein levels, or

bone marrow plasma cell percentage (the absolute % must be 10%) – only for 
subjects without measurable serum and urine M-protein levels and without 
measurable disease by FLC level.

definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas.

development of hypercalcemia (corrected calcium >11.5 mg/dl or 2.65 mmol/l) 
that can be attributed solely to the plasma cell proliferative disorder.
All response categories (CR, sCR, VGPR, PR, MR and Progressive Disease) require two 
consecutive assessments made at any time before the institution of any new therapy; CR, 
sCR, VGPR, PR, MR, and SD categories also require no known evidence of progressive 
or new bone lesions if radiographic studies were performed.  VGPR and CR categories 
require serum and urine studies regardless of whether disease at baseline was measurable 
on serum, urine, both, or neither.  Radiographic studies are not required to satisfy these 
response requirements.  Bone marrow assessments need not be confirmed.  For 
Progressive Disease, serum M-component increases of more than or equal to 1 g/dL are 
sufficient to define relapse if starting M-component is ≥5 g/dL.
Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only 
measurable disease is by serum FLC levels:  CR in such subjects indicates a normal FLC 
ratio of 0.26 to 1.65 in addition to CR criteria listed above.  VGPR in such subjects 
requires a >90% decrease in the difference between involved and uninvolved FLC levels.
Clarifications to IMWG criteria for coding Progressive Disease: Bone marrow criteria for 
Progressive Disease are to be used only in subjects without measurable disease by M 
protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone marrow 
results, and does not refer to bone lesions, soft tissue plasmacytomas, or hypercalcemia 
and the “lowest response value” does not need to be a confirmed value.
 
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15.7.
Appendix 7: Response Criteria for Non-Hodgkin’s
Lymphoma (Part 1)
Non-Hodgkin’s Lymphoma Response Criteria
This study employs response criteria from the International Workshop to standardize 
response criteria for Non-Hodgkin’s Lymphomas [Cheson, 2007].  These criteria use the 
following categories of response: Complete Response (CR), Partial Response (PR), 
Stable Disease (SD), Relapse and Progression.  To be assigned a status of PR, Complete 
Response/Unconfirmed (CRu) or CR, changes in tumor assessment must be confirmed by 
repeat studies performed at least four weeks after the criteria for response are first met.  
Because the criteria for Partial Response (PR) requires a decrease by 50% in sum of 
products of the diameters (SPD) in the six largest dominant nodes or nodal masses, six 
dominant nodes and/or nodal masses must be identified if > six involved nodes/nodal 
masses are present.
Complete Response
To be assigned a status of complete response, all changes must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for CR were met.

Complete disappearance of all detectable clinical and radiographic evidence of 
disease and disappearance of all disease related B-symptoms if present prior to 
therapy, as well as normalization (normal limits of institutional labs) of those 
biochemical abnormalities (e.g., LDH) definitely attributed to NHL.

All lymph nodes and nodal masses must have regressed to normal size.  Nodes that 
were 1.1 to 1.5 cm in their greatest diameter prior to treatment must each have 
decreased to < 1.0 cm in their greatest diameter after treatment or by more than 75% 
in the sum of the products of the greatest perpendicular diameters (SPD) of all nodes 
initially measuring 1.1 to 1.5 cm.  Nodes that were > 1.5 cm in their greatest 
diameter prior to therapy must have decreased to < 1.5 cm in the greatest diameter.

The spleen, if considered to be enlarged before therapy on the basis of a scan, must 
have decreased in size and must not be palpable on physical examination.  Any 
macroscopic nodules in any organs (i.e., splenic, hepatic) detectable on imaging 
studies should no longer be present.  Similarly, other organs considered to be 
enlarged prior to therapy due to involvement of lymphoma (i.e., kidneys, liver, etc.) 
must have decreased in size.

If the bone marrow was involved by lymphoma prior to treatment, the biopsy must 
be cleared. The biopsy sample on which this determination is made must be adequate 
(with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is 
negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in subject outcome.
 
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Partial Response (PR)
To be assigned a status of partial response, all changes must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for PR were met.

A decrease of > 50% in the SPD (sum of the products of the diameters) of the six 
largest (or less) dominant nodes or nodal masses.

No increase in the size of the liver or the spleen.  No unequivocal progression in any 
nonmeasurable or nondominant site.

Splenic and hepatic nodules must regress by > 50% in SPD (sum of the products of 
the diameters).

With the exception of splenic and hepatic nodules, involvement of other organs is 
considered nonmeasurable disease.  However, all extra-nodal sites should be 
followed.

Bone marrow assessment is not relevant for determination of a PR because it is 
assessable and not measurable disease.

No new sites of disease.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
progressive disease taking as reference the smallest SPD since the treatment started.
Progression
For subjects who have not responded or have achieved PR.

Appearances of any new lesions/sites during or after therapy.

Increase of 50% in the SPD from nadir measurement of any previously involved 
abnormal node or nodal mass.
Relapse
For subjects who have achieved CR or CRu.

Appearance of any new lesions/sites during or after therapy.

Increase of 50% in the SPD from nadir measurement of any previously involved 
dominant node >1.0 cm in its short axis.
Response Assessment
CT scans remain the standard for evaluation of nodal disease.  Chest, abdominal, and 
pelvic CT scans should be done even if those areas were not initially involved because of 
the unpredictable pattern of relapse in NHL.
Confirmation Measurement/Duration of Response
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies that should be performed at least four (4) weeks after the criteria for 
response are first met.
 
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15.8.
Appendix 8: Response Criteria for Acute Myeloid Leukaemia
[Modified Cheson, 2003]
Complete remission (CR):  The subject must achieve a morphologic leukemia-free state 
(≤5% blasts) and have no evidence of extramedullary disease.  The subject must be free 
of all symptoms related to leukemia, have an absolute neutrophil count 1 x 10
9/L and 
platelet count 100 x 10
9/L, and be transfusion independent.
CRp: Marrow response as per CR but platelet count <100 x 10
9/L.
CRi: Marrow response as per CR but platelet count <100 x 10
9/L or neutrophil count <1 
x 10
9/L.
Partial remission (PR): A decrease from baseline of at least 50% in the number of bone 
marrow blasts, to between 5% and 25% of the bone marrow aspirate.
No response: Subject does not meet criteria for CR, CRp, CRi, or PR.
Recurrence: Morphologic relapse, defined as the reappearance of peripheral blasts or 
increase in bone marrow blasts ≥ 5% not attributable to any other cause (e.g., infection, 
growth factor support, bone marrow regeneration)
 
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15.9.
Appendix 9: Response Criteria for Myelodysplastic 
Syndrome
[Cheson , 2006]
Complete remission (CR):  Bone marrow ≤5% myeloblasts with normal maturation of 
all cell lines.  Persistent dysplasia may be noted.  The subject must have a haemoglobin 
concentration of ≥ 11 g/dL, an absolute neutrophil count 1 x 10
9/L, a platelet count 100 
x 10
9/L, and have 0% blasts in the peripheral blood.
Marrow CR: Bone marrow ≤5% myeloblasts and decrease by ≥ 50% over pretreatment
Partial remission (PR): Bone marrow blasts decreased by ≥ 50% over pretreatment but 
still >5%.  Cellularity and morphology not relevant
Stable disease: Failure to achieve at least PR, but no evidence of progression for > 8 
weeks
Disease progression: For patients with:
o
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts
o
5% - 10% blasts: ≥ 50% increase to > 10% blasts
o
10% - 20% blasts: ≥ 50% increase to > 20% blasts
o
20% - 30% blasts: ≥ 50% increase to > 30% blasts
AND
Any of the following: At least 50% decrement from maximum remission/response 
in granulocytes or platelets, reduction in haemoglobin by ≥ 2 g/dL, transfusion 
dependence
Relapse after CR or PR: At least one of the following: return to pretreatment bone 
marrow blast percentage, decrement of ≥ 50% from maximum remission/response levels 
in granulocytes or platelets, reduction in haemoglobin concentration by ≥ 1.5 g/dL or 
transfusion dependence
 
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15.10.
Appendix 10: Staging and Response Criteria for CTCL
(mSWAT method)
[Olsen, 2011]
15.10.1.
Staging of Subjects with CTCL
Table 17
Modified ISCL/EORTC Revisions to the tumor-node-metastasis-
blood (TNMB) Classification of MF/SS
TNMB 
Stages
Description of TNMB
Skin*
T1 Limited patches, papules, and/or plaques covering < 10% of the skin 
surface; may further stratify into T1a (patch only) v T1b (plaque ± patch)
T2 Patches, papules, or plaques covering ≥ 10% of the skin surface; may 
further stratify into T2a (patch only) v T2b (plaque ± patch)
T3 One or more tumors (≥ 1 cm diameter)
T4 Confluence of erythema covering ≥ 80% body surface area
Node†
N0 No clinically abnormal lymph nodes; biopsy not required
N1 Clinically abnormal lymph nodes; histopathology Dutch grade 1 or National 
Cancer Institute (NCI) LN0-2
N1a
Clone negative
N1b
Clone positive
N2 Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI 
LN3
N2a
Clone negative
N2b
Clone positive
N3 Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI 
 
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TNMB 
Stages
Description of TNMB
LN4; clone positive or negative
Nx Clinically abnormal lymph nodes without histologic confirmation or 
inability to fully characterize the histologic subcategories
Visceral
M0 No visceral organ involvement
M1 Visceral involvement (must have pathology confirmation and organ 
involved should be specified)
Blood
B0 Absence of significant blood involvement: ≤5% of peripheral blood 
lymphocytes are atypical (Sézary) cells
B0a
Clone negative
B0b
Clone positive
B1 Low blood tumor burden: > 5% of peripheral blood lymphocytes are 
atypical (Sézary) cells but does not meet the criteria of B2
B1a
Clone negative
B1b
Clone positive
B2
High blood tumor burden: ≥ 1,000/μL Sézary cells with positive clone‡; 
one of the following can be substituted for Sézary cells: CD4/CD8 ≥ 10, 
CD4+CD7- cells ≥ 40% or CD4+CD26- cells ≥ 30%
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, 
European Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; 
SS, Sézary syndrome; NCI, National Cancer Institute.
*Patch = any size lesion without induration or significant elevation above the surrounding 
uninvolved skin: pokiloderma may be present. Plaque = any size lesion that is elevated or 
indurated: crusting or poikiloderma may be present. Tumor = any solid or nodular lesion 
≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth.
 
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†Lymph node classification has been modified from 2007 ISCL/EORTC consensus 
revisions to include central nodes. Lymph nodes are qualified as abnormal if > 1.5 cm in 
diameter.
‡The clone in the blood should match that of the skin. The relevance of an isolated clone 
in the blood or a clone in the blood that does not match the clone in the skin remains to be 
determined.
Table 18
Modified ISCL/EORTC Revisions to the Staging of MF/SS
Stage
T
N
M
B
IA
1
0
0
0, 1
IB
2
0
0
0, 1
IIA
1-2
1, 2, X
0
0, 1
IIB
3
0-2, X
0
0, 1
IIIA
4
0-2, X
0
0
IIIB
4
0-2, X
0
1
IVA1
1-4
0-2, X
0
2
IVA2
1-4
3
0
0-2
IVB
1-4
0-3, X
1
0-2
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, 
European Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; 
SS, Sézary syndrome; X, clinically abnormal lymph nodes without histologic 
confirmation or inability to fully characterize histologic subcategories.
15.10.2.
Response Assessment of Subjects with CTCL
Refer to Table 19, Table 20, Table 22, Table 23, and Table 24 for definitions of response 
in each category.  All subjects achieving CR or PR should be confirmed by repeat 
assessment no sooner than 4 weeks after the prior assessment demonstrating response.
 
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Table 19
Global Response Score
Global
Score
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of 
all clinical evidence of 
disease
CR
All categories have CR/NI
PR
Regression of measurable 
disease
CR
All categories do not have a CR/NI and no 
category has a PD
PR
No category has a PD and if any category 
involved at baseline, at least one has a CR 
or PR
SD
Failure to attain CR, PR, or 
PD representative of all 
disease
PR
No category has a PD and if any category 
involved at baseline, no CR or PR in any
SD
CR/NI, PR, SD in any category and no 
category has a PD
PD
Progressive disease
PD in any category
Relapse
Recurrence disease in prior 
CR
Relapse in any category
Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, 
progressive disease; SD, stable disease.
Refer to Table 21 for definition of mSWAT
 
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Table 20
Response in Skin
Response
Definition
Complete 
response
100% clearance of skin lesions*
Partial response 50%-99% clearance of skin disease from baseline without new tumors 
(T3) in patients with T1, T2 or T4 only skin disease
Stable disease
< 25% increase to < 50% clearance in skin disease from baseline without 
new tumors (T3) in patients with T1, T2, or T4 only skin disease
Progressive 
disease†
≥ 25% increase in skin disease from baseline or
New tumors (T3) in patients with T1, T2 or T4 only skin disease or
Loss of response: in those with complete or partial response, increase of 
skin score of greater than the sum of nadir plus 50% baseline score
Relapse
Any disease recurrence in those with complete response
NOTE. Based on modified Severity Weighted Assessment Tool score.
*A biopsy of normal appearing skin is unnecessary to assign a complete response. 
However, a skin biopsy should be performed of a representative area of the skin if there 
is any question of residual disease (persistent erythema or pigmentary change) where 
otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of mycosis fungoides/Sézary syndrome (see histologic criteria for early 
mycosis fungoides7), the response should be considered a partial response only.
†Whichever criterion occurs first.
 
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Table 21
Modified Severity Weighted Assessment Tool (mSWAT)
Body Region
% BSA in Body 
Region
Assessment of Involvement in 
Patient's Skin
Patch*
Plaque†
Tumor‡
Head
7
Neck
2
Anterior trunk
13
Arms
8
Forearms
6
Hands
5
Posterior trunk
13
Buttocks
5
Thighs
19
Legs
14
Feet
7
Groin
1
Subtotal of lesion BSA
Weighting factor
×1
×2
×4
Subtotal lesion BSA × 
weighting factor
NOTE. mSWAT score equals summation of each column line.
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted 
Assessment Tool.
*Any size lesion without induration or significant elevation above the surrounding 
uninvolved skin; poikiloderma may be present.
 
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†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may 
be present.
‡Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the 
skin and/or vertical growth.
Table 22
Response in Lymph Nodes
Response
Definition
CR
All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by 
method used to assess lymph nodes at baseline or biopsy negative for 
lymphoma; in addition, lymph nodes that were N3 classification and ≤1.5 cm in 
their long axis and > 1 cm in their short axis at baseline, must now be ≤1 cm in 
their short axis or biopsy negative for lymphoma
PR
Cumulative reduction ≥ 50% of the SPD of each abnormal lymph node at 
baseline and no new lymph node > 1.5 cm in the diameter of the long axis or > 
1.0 cm in the diameter of the short axis if the long axis is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD†
≥ 50% increase in SPD from baseline of lymph nodes or
Any new node > 1.5 cm in the long axis or > 1 cm in the short axis if 1-1.5 cm 
in the long axis that is proven to be N3 histologically or
Loss of response: > 50% increase from nadir in SPD of lymph nodes in those 
with PR
Relapse
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be 
N3 histologically
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum 
linear dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable 
disease; PD, progressive disease.
*Peripheral and central lymph nodes.
†Whichever criterion occurs first.
 
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Table 23
Response in Viscera
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be 
enlarged on physical exam and should be considered normal by imaging; no 
nodules should be present on imaging of liver or spleen; any post treatment 
mass must be determined by biopsy to be negative for lymphoma
PR
≥ 50% regression in any splenic or liver nodules, or in measureable disease 
(SPD) in any organs abnormal at baseline; no increase in size of liver or spleen 
and no new sites of involvement
SD
Fails to attain the criteria for CR, PR, or PD
PD*
> 50% increase in size (SPD) of any organs involved at baseline or
New organ involvement or
Loss of response: > 50% increase from nadir in the size (SPD) of any previous 
organ involvement in those with PR
Relapse
New organ involvement in those with CR
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum 
linear dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable 
disease; PD, progressive disease.
*Whichever criterion occurs first.
 
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Table 24
Response in Blood
Response
Definition
CR†
B0
PR‡
> 50% decrease in quantitative measurements of blood tumor burden from 
baseline in those with high tumor burden at baseline (B2)
SD
Fails to attain criteria for CR, PR, or PD
PD§
B0 to B2 or
> 50% increase from baseline and at least 5,000 neoplastic cells/μL or
Loss of response: in those with PR who were originally B2 at baseline, > 50% 
increase from nadir and at least 5,000 neoplastic cells/μL
Relapse
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, 
progressive disease.
*As determined by absolute numbers of neoplastic cells/μL.
†If a bone marrow biopsy was performed at baseline and determined to unequivocally be 
indicative of lymphomatous involvement, then to confirm a global CR where blood 
assessment now meets criteria for B0, a repeat bone marrow biopsy must show no 
residual disease or the response should be considered a PR only.
‡There is no PR in those with B1 disease at baseline as the difference within the range of 
neoplastic cells that define B1 is not considered significant and should not affect 
determination of global objective response.
§Whichever occurs first.
 
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15.11.
Appendix 11: Patient Reported Outcomes Assessments for 
CTCL (Skindex-29)
15.11.1.
US English Skindex-29
Note: please refer to the SPM for additional translations of Skindex-29
 
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by third party copyright laws and therefore have been excluded.

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15.12.
Appendix 12: Pain Assessment
 
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15.13.
Appendix 13: Updated PK data from protocols BET115521 
and BET116183
As of 11-August-2014, the pharmacokinetics of GSK525762 has been evaluated in 19 
subjects in study BET115521 following single and repeated once daily administration of 
2 mg to 60 mg of GSK525762 and in 2 subjects in study BET116183 following single 
and repeated once daily administration of 5 and 10 mg of GSK525762. The summary 
statistics of the preliminary PK parameters are summarized in Table 25 and Table 26
after single and repeat once daily oral administration, respectively. GSK525762
pharmacokinetics are characterized by a rapid absorption with maximum concentration 
occurring mostly within the first hour after dosing. GSK525762 is eliminated rapidly 
with an average terminal phase half-life of 3 to 7 hours, leading to a lack of accumulation 
following once daily oral administration. Following single and repeated once daily 
administration of 2 mg to 60 mg of GSK525762, Cmax and AUC tended to increase in a 
dose proportional fashion.  
 
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Table 25
Summary Statistics of GSK525762 Preliminary PK Parameters Following a Single Oral Administration of 
GSK525762 in Study BET115521 and BET116183
2 mg
4 mg
5 mg
8 mg
10 mg
16 mg
30 mg
60 mg
Parameters
N=3
N=4
N=1
N=1
N=1
N=3
N=4
N=4
Cmax, ng/mL
51.0 (41%)
70.4 (29%)
90.6
120
117
176 (37%)
604 (30%)
940 (31%)
Tmax, h
0.5 (0.5 - 0.6)
1.2 (0.5 - 2.0)
0.62
1.1
2.0
2.0
2.0 (0.97 - 2.0)
1.0 (0.5 - 2.0)
AUC, ng.h/mL
172 (42%)
361 (35%)
467
434
1092
884 (40%)
4420 (63%)
3670 (54%)
t1/2z, h
3.3 (103%)
5.1 (36%)
4.01
2.95
5.74
6.9 (46%)
6.4 (37%)
6.1 (49%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) are presented. If N=1, individual data are presented. Cmax is the 
maximum concentration observed at time tmax. AUC is the area under the concentration-time curve from 0 to infinity. T1/2 is the terminal phase half-life. All data are from BET115521 
study except for the 5 mg and 10 mg doses that were evaluated in BET116183 study.  
Table 26
Summary Statistics of GSK525762 Preliminary PK Parameters Following Repeat Daily Oral Administration of 
GSK525762 in Study BET115521 and BET116183
2 mg
4 mg
5 mg
8 mg
10 mg
16 mg
30 mg
60 mg
Parameters
N=1
N=2
N=1
N=1
N=1
N=3
N=4
N=3
Cmax, ng/mL
52
47.6 ; 59.9
103
103
133
138 (25%)
603 (17%)
807 (36%)
Tmax, h
1.0
1.0 ; 4.0
0.5
0.5
0.5
1.5
0.9 (0.32 - 4.0)
1.0 (0.50 - 1.0)
AUC, ng.h/mL
160
225 ; 497
511
330
911
674 (21%)
3150 (55%)
2910 (56%)
t1/2z, h
4.27
3.69 ; 4.46
3.54
4.92
5.26
3.6 (7.8%)
5.2 (26%)
3.13 (40%)
Cmax Week 3 / Cmax Week 1
1.42
0.968 ; 0.609
1.14
0.857
1.14
0.780 (12%)
0.998 (24%)
1.12 (10%)
AUCWeek 3 / AUC Week 1
1.38
0.900 ; 1.64
1.10
0.759
0.834
0.774 (20%)
0.724 (12%)
0.779 (13%)
AUCweek 3 / AUCt Week 1
1.39
0.904 ; 1.67
1.11
0.763
0.890
0.792 (20%)
0.799 (11%)
0.807 (10%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) are presented. If N=1 or 2, individual data are presented. Cmax is 
the maximum concentration observed at time tmax. AUCis the area under the concentration-time curve from 0 to 24 hours, the end of the dosing interval. T1/2 is the terminal phase 
half-life. All data are from BET115521 study except for the 5 and 10 mg dose that were evaluated in BET116183 study.  
 
 
 
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15.14.
Appendix 14: Protocol Changes for Amendment 1 (15-Aug-
2013) from the Original Protocol  (20-May-2013)
Where the Amendment Applies
Amendment 1 applies to study centres in the United Kingdom, and may also apply to 
other countries if specifically requested. 
General Protocol Changes
The study duration has been modified at the request of the Medicines and Healthcare 
products Regulatory Agency (MHRA), United Kingdom.  MHRA requested the removal 
of “until commercial supply of GSK525762 becomes available” as a duration of exposure 
in accordance with the Commission Directive 2005/28/EC.  Changes are noted below 
with strikethrough of deleted words and an underlining of new language added to the 
amendment. In addition, the sponsor/medical monitor information page has updated 
information.
15.11.1
List of Changes

STUDY DESIGN AND DURATION:  This study is divided into 2 parts; Part 1 of 
the study is a dose escalation phase to select the recommended Part 2 dose (RP2D) 
based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after 
oral administration of GSK525762.  Eligible subjects with relapsed refractory 
hematological malignancies will be enrolled in the dosing cohorts until a maximum 
tolerated dose (MTD) is established.  Subjects may continue treatment in the study 
until disease progression, unacceptable toxicity, or withdrawal of consent 
commercial supply of GSK525762 becomes available to the subject.  An expansion 
cohort is planned in subjects with acute leukemias to further explore clinical activity 
at the MTD (Part 2).

Updated Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
Mailstop UP 4340
Collegeville, PA 19426, USA
Primary 
Medical 
Monitor
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4210
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
, 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
Mailstop UP 1450
Collegeville, PA 19426, USA
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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15.15.
Appendix 15: Protocol Changes for Amendment 2 (15-OCT-
2013) from the Protocol Amendment 1 (15-AUG-2013)
Where the Amendment Applies
Amendment 2 applies to all study centres. 
General Protocol Changes
At the request of the Food and Drug Administration, United Stated, the dose limiting 
toxicity (DLT) in Section 3.2.3 was updated to require that it must clearly be established 
that an event is unrelated to treatment for the event to not be considered a DLT; the 
stopping rules related to safety were expanded in Section 11.4.1.  Additional changes 
include the clarification of exploratory endpoints to assess metabolites, correction of 
exclusion criteria number 12, and clarification of the Time and Events Table, Dietary 
Restrictions, and the futility analysis of Part 2. Changes are noted below with 
strikethrough to identify deleted text and bold underlining to identify new or 
replacement text.
15.12.1
List of Changes
Previous Text:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4210
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
, 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
Mailstop UP 1450
Collegeville, PA 19426, USA
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Revised Text:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4210
Collegeville, PA 19426, USA
Secondary
Medical 
Monitor
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4210
Collegeville, PA 19426, USA
Primary 
Medical 
Monitor
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4210
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
, 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
Mailstop UP 1450
Collegeville, PA 19426, USA
Rationale for Change:

The Medical Monitor and contact information has been updated with changes in 
GSK staff.

Previous Text:
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD), 
establishing the recommended Phase 
2 dose (RP2D) of GSK525762 in 
adult subjects with relapsed and/or 
refractory hematologic malignancies.

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration.
o
GSK525762 PK parameters following 
single- (Day 1) and repeat-dose (Day 15) 
administration of GSK525762, including 
Area under concentration-time curve(AUC), 
Minimum observed concentration (Cmin), 
Pre-dose (trough) concentration at the end 
of a dosing interval (C), Maximum 
observed concentration (Cmax), Time of 
maximum concentration (tmax), Apparent 
terminal half-life (t1/2) (or t1/2, eff), time 
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Part 1 Objectives
Part 1 Endpoints
invariance and accumulation ratio.

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters.
o
Changes in cardiac QT duration corrected 
for heart rate by Fridericia’s formula (QTcF) 
and other safety parameters in relation to 
GSK525762 exposure markers (dose, 
concentration, Cmax, AUC, following single 
and repeat-dose oral administration of 
GSK525762

To evaluate the relationship between 
GSK525762 exposure and 
Pharmacodynamic (PD) response
o
Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.
Exploratory
o
To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
o
To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK525762

Pharmacogenomic (PGx) study using 
blood samples

Transcriptomics studies of blood and 
tumor cells; correlation of tumor 
baseline genetic and genomic profiles 
with response

Revised Text:

2.  
OBJECTIVES, ENDPOINTS, HYPOTHESIS
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD), 
establishing the recommended Phase 
2 dose (RP2D) of GSK525762 in 
adult subjects with relapsed and/or 
refractory hematologic malignancies.

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration.
o
GSK525762 PK parameters following 
single- (Day 1) and repeat-dose (Day 15) 
administration of GSK525762, including 
Area under concentration-time curve(AUC), 
Minimum observed concentration (Cmin), 
Pre-dose (trough) concentration at the end 
of a dosing interval (C), Maximum 
observed concentration (Cmax), Time of 
 
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Part 1 Objectives
Part 1 Endpoints
maximum concentration (tmax), Apparent 
terminal half-life (t1/2) (or t1/2, eff), time 
invariance and accumulation ratio.

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters.
o
Changes in cardiac QT duration corrected 
for heart rate by Fridericia’s formula (QTcF) 
and other safety parameters in relation to 
GSK525762 exposure markers (dose, 
concentration, Cmax, AUC, following single 
and repeat-dose oral administration of 
GSK525762

To evaluate the relationship between 
GSK525762 exposure and 
Pharmacodynamic (PD) response
o
Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.
Exploratory
o
To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
o
To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK525762
o
To generate samples (data 
reported separately) with which to 
characterize the metabolic profile 
of GSK525762 after single and 
repeat-dosing (In the PK/PD 
expansion cohort only)
o
To determine the amount of 
GSK525762 excreted in urine after 
oral single and repeat-dosing
o
Pharmacogenomic (PGx) study using blood 
samples
o
Transcriptomics studies of blood and tumor 
cells; correlation of tumor baseline genetic 
and genomic profiles with response
o
Samples to characterize the metabolites 
in plasma and/or urine
o
Concentration of GSK575762 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over time
Rationale for Change:
The exploratory endpoints of Part 1 were clarified in Section 2 to include the collection 
and characterization of metabolites in plasma and urine that were described elsewhere in 
the protocol.
 
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Previous Text:
Exclusion criteria
No evidence of pulmonary hemoptysis within the last 7 days.
Revised Text:
Exclusion criteria
No Evidence of pulmonary hemoptysis within the last 7 days.
Rationale for Change:
Exclusion criteria was corrected in the synopsis and Section 4.2.2.
 
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Previous Text (excerpt from Table in Section 1.5.1):
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human 
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose (no 
effects were observed in the 28 day 
toxicology studies); increase in mean BP up to 
11 mmHg; decrease in mean BP up to 13 
mmHg.
QA interval (indirect measure of cardiac 
contractility).
Increased QA interval at single non-tolerated 
doses; up to 10msec. No effects were 
observed in the 28 day toxicology studies).
ICF includes the risk of (fatal) 
arrhythmias
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring and cardiac 
ejection fraction) during the study, 
and dose stopping/modifications 
criteria for the management 
cardiac events.
Drugs with a risk of Torsades de 
Pointes are prohibited, (refer to 
Section 8.3).
All subjects will receive their first 
doses of study medication (Week 
1 Day 1) in the hospital
 
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Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human 
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose (no 
effects were observed in the 28 day 
toxicology studies); increase in mean BP up to 
11 mmHg; decrease in mean BP up to 13 
mmHg.
QA interval (indirect measure of cardiac 
contractility).
Increased QA interval at single non-tolerated 
doses; up to 10msec. No effects were 
observed in the 28 day toxicology studies).
ICF includes the risk of (fatal) 
arrhythmias
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring and cardiac 
ejection fraction) during the study, 
and dose stopping/modifications 
criteria for the management 
cardiac events.
Drugs with a risk of Torsades de 
Pointes are prohibited, (refer to 
Section 8.3).
All subjects will receive their first 
doses of study medication (Week 
1 Day 1 and Week 1 Day 2) 
Rationale for Change:
The Mitigation Strategy in Section 1.5.1 Risk Assessment was updated to include the 
complete Study Day details for clarification. 
 
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Previous Text:
3.2.3
Dose Limiting Toxicity (DLT)
A dose-limiting toxicity (DLT) is defined as a clinically significant AE or abnormal 
laboratory value assessed as unrelated to disease progression, intercurrent illness, or 
concomitant medications and occurring during the first 3 weeks after administration of 
the first dose that meets any of the following criteria:
Revised Text:
3.2.3
Dose Limiting Toxicity (DLT)
An event will be considered a DLT if it occurs within the first 3 weeks of treatment, 
and meets one of the following criteria unless it can be clearly established that the 
event is unrelated to treatment.   A dose-limiting toxicity (DLT) is defined as a 
clinically significant AE or abnormal laboratory value assessed as unrelated to disease 
progression, intercurrent illness, or concomitant medications and occurring during the 
first 3 weeks after administration of the first dose that meets any of the following criteria:
Rationale for Change:
The text was updated to clarify criteria for a DLT.
 
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Previous Text (Table 6, Table 9, Table 10 and Table 11):
Table 6
Time and Events: Part 1
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed 
consent
(Unless 
otherwise 
noted, 
screening 
assessment
s to be 
completed 
within 14 
days of first 
dose.)
X
Demography
X
Medical 
history
X
Disease 
characteristic
s
X
Cardiology 
evaluation
X
Prior therapy
X
Register 
subject
X
TREATMENT PHASE
Study Drug
Administer study drug
(Administer about same time 
of day. No food or antacids 
1h before and 2h after.)
X X X X X
X X X X X X X
Daily
Review subject diary
(Not required when dosed in 
clinic.)
X
X
X
X X
X
X
Safety
Pregnancy test/
testosterone
(Females: serum pregnancy 
test within 7 days of first 
dose; urine or serum test 
thereafter.  Males: complete 
and free testosterone at SCR; 
free testosterone thereafter.)
X X
X
X
X
X
Physical exam
X X
X
X
X
X X
X
X
X
ECOG PS
X X
X
X
X
X
Vital Signs
(SBP, DBP, heart rate, 
respiratory rate, temp.)
X X
X
X
X
X
X X
X
X
X
Height and weight
(Height at SCR only)
X X
X
X
X
X X
X
X
X
Chest x-ray
X
Pulmonary function test
(As appropriate [subjects with 
severe COPD, history of 
pneumonitis, alveolar 
hemorrhage, chest radiation])
X
Adverse events
continuous from signing of informed consent
 
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Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X X X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
(Within 35 days of first dose)
X
X
X
X
X
X
12-lead ECGs
(Screening ECGs within 14 
days of first dose.  Triplicate 
ECGs prior to dosing.  For 
timing of ECGs on O days, 
see Table 9 and Table 10. 
Otherwise, triplicate ECGs at 
approximately same time of 
day, and prior to dose on 
dosing days. If QTcF increase 
>30msec, ECGs performed 
daily through W2.)
X O O
O X
X
X
X O X X X X X O X
X
X
Holter monitoring
(At least 24 h, on dosing days 
start predose.)
X X
X
X
X
X
Telemetry
(Starting predose and for at 
least 48 h)
X X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK Blood samples
X X
X
X
X X X
X
X
a
Blood samples for biomarkers 
(PD)
X X X
X
Blood samples for plasma 
cytokines
X X X
X
PK Urine samples
(only for subjects in PK/PD
expansion)
X
X
PD Tumor Sample b
X
b
,
c
Tissue and Timing to be based on tumor type and emerging data.  A PK sample 
will need to be obtained within 1 hour of the tissue sampling.  Details described in 
the SPM.
 
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Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Translational Research d
Pharmacogenomics (PGx) 
blood sample
X
Blood samples for circulating 
biomarkers (cfDNA etc.)
collected at: screening; date 
of 
X
Additional samples will be collected on the date of disease assessment/bone 
marrow biopsy and date of progression
Archival tumor tissue
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer 
therapy every 6 months.  Disease assessment will be collected for subjects who discontinue study medication due to 
any reason other than progression or death.  Individual subjects will be considered to have completed the study 2 
years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the 
Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in 
Phase 2.
a.
For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W.
b.
PD tumor samples will be collected when feasible (see Table 8 disease specific assessments for details).
c.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
d.
Refer to Section 6.6 for details on Translational Research and Appendix 5 for details on PGx Research.
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by 
Fridericia’s formula; ECOG PS=Eastern Cooperative Oncology Group Performance Status; PGx=Pharmacogenetics; 
COPD=Chronic obstructive pulmonary disease; SPM=Study Procedures Manual; D=day; EOT=End-of-Treatment; 
q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; W=week
 
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Table 9
Time and Events: Part 1 Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling, Week 1 and  Week 2
Procedure
W1D1
W1D5
pre 
dose
15 
min 
± 5m
30 
min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h 
±2h
24h 
±1h
30 min 
±10m
3h 
±30m
12-lead ECG, in 
triplicate, 5 
minutes apart 
and within 10 
min prior to PK 
draw
X
X
X
X
X
X
X
X
X
X
X
PK sample a
X
X
X
X
X
X
X
X
X a
X
X
Blood sample for 
biomarkers
X
X
X
X
X
Plasma cytokine 
sample
X
X
X
X
X
Urine PK 
sampling (Only 
at MTD or RP2D 
in 6 subjects)
X
The frequency of sampling of plasma cytokines may be changed (likely reduced) based on data from the first few 
subjects assessed.
a.
Pharmacokinetic sample to be obtained before dosing on Week 1, Day 2.
Table 10
Time and Events: Part 1 Serial Electrocardiograms and
Pharmacokinetics, Week 3 and Week 7
Procedure
W2D7 + 2 days
W7D1 ±4 days
(if dose was 
escalated, +4 to +7 
days)
pre 
dose
15 
min 
± 
5m
30 
min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h 
±2h
24h 
±1ha
pre 
dose
0.5-
2h
4 -
8h
12-lead ECG, in 
triplicate, 5 
minutes apart 
and within 10 
min prior to PK 
draw
X
X
X
X
X
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling (Only 
at MTD in 6 
subjects)
0-2h
2-24h
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
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Table 11
Time and Events: Part 2
Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Informed 
consent
Unless 
otherwise noted, 
screening 
assessments to 
be completed 
within 14 days 
of first dose.
X
Demogra
phy
X
Medical 
history
X
Disease 
characteri
stics
X
Cardiolog
y 
evaluatio
n
X
Prior 
therapy
X
Register 
subject
X
TREATMENT PHASE
Study 
Drug
Dispense 
study 
drug
Administer 
about same 
time of day.  No 
food or antacids 
1h before and 
2h after.
X
X
X
X
X
X
X
Review 
complianc
e
Not required 
when dosed in 
clinic.
X
X
X
X
X
Safety
Pregnanc
y 
test/testo
sterone
Females: serum 
pregnancy test 
within 7 days of 
first dose; urine 
or serum test 
thereafter.  
Males: complete 
and free 
testosterone at 
SCR; free 
testosterone 
thereafter.
X
X
X
X
X
X
Physical 
exam
X
X
X
X
X
X
X
X
X
ECOG 
PS
X
X
X
X
X
X
X
X
X
Vital 
Signs
X
X
X
X
X
X
X
X
X
Weight 
Height at SCR 
X
X
X
X
X
X
X
 
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Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
and 
height
only
Chest x-
ray
X
Pulmonar
y function 
test
X
Adverse 
events
continuous from signing of informed consent
Concomit
ant 
medicatio
ns
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
Cardiac 
Monitorin
g
ECHO
Within 35 days 
of first dose
X
X
X
X
X
X
X
12-lead 
ECGs 
(triplicate)
Screening 
ECGs within 35 
days of first 
dose.  Triplicate 
ECGs prior to 
dosing.  If QTcF 
increase 
>30msec, ECGs 
performed daily 
through W2.
X
X
X
X
X
X
X
X
X
Holter 
monitorin
g
At least 24 h, on 
dosing days 
start predose.
X
X
Tumor 
PD 
Assessm
ent 
PD 
Tumor 
sample 
X 
a
1 biopsy between W1D2 and 
W4D1, timing to be optimized 
based on emerging data.  PK 
sample to be obtained within 1 hr 
of tumor sample collection.
 
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Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
PK and Blood PD
PK Blood 
samples
Three samples 
to be collected  
each sampling 
day for each 
type of analysis: 
Predose within 
60 minutes prior 
to dose, single 
draw between 
2-4 h postdose, 
single draw 
between 6-8h 
postdose
X
X
X
X
Blood 
sample 
for 
biomarker
X
X
X
Blood 
samples 
for 
plasma 
cytokines
X
X
Translational Research
PGx 
blood 
sample
X
Blood 
samples 
for 
circulating 
biomarker
s (cfDNA 
etc.)
X
Additional samples will be collected on the date of disease assessment/bone 
marrow biopsy and date of progression
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer 
therapy every 6 months.  Disease assessment will be collected for subjects who discontinue study medication due to 
any reason other than progression or death.  Individual subjects will be considered to have completed the study 2 
years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the 
Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in 
Phase 2.
1.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; 
ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; PD=Pharmacodynamics; 
PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 
weeks; SCR=Screening; Wk=week
 
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Revised Text:
Table 6
Time and Events: Part 1
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed 
consent
(Unless 
otherwise 
noted, 
screening 
assessment
s to be
completed 
within 14 
days of first 
dose.)
X
Demography
X
Medical 
history
X
Disease 
characteristic
s
X
Cardiology 
evaluation
X
Prior therapy
X
Register 
subject
X
TREATMENT PHASE
Study Drug
Administer study drug
(Administer about same time 
of day. No food or antacids 
1h before and 2h after.)
X X X X X
X X X X X X X
Daily
Review subject diary
(Not required when dosed in 
clinic.)
X
X
X
X X
X
X
Safety
Pregnancy test/
testosterone
(Females: serum pregnancy 
test within 7 days of first 
dose; urine or serum test 
thereafter.  Males: complete 
and free testosterone at SCR; 
free testosterone thereafter.)
X X
X
X
X
X
Physical exam
X X
X
X
X
X X
X
X
X
ECOG PS
X X
X
X
X
X
Vital Signs
(SBP, DBP, heart rate, 
respiratory rate, temp.)
X X
X
X
X
X
X X
X
X
X
Height and weight
(Height at SCR only)
X X
X
X
X
X X
X
X
X
Chest x-ray
X
Pulmonary function test
(As appropriate [subjects with 
severe COPD, history of 
pneumonitis, alveolar 
hemorrhage, chest radiation])
X
Adverse events
continuous from signing of informed consent
 
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Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X X X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
(Within 35 days of first dose)
X
X
X
X
X
X
12-lead ECGs
(Screening ECGs within 14 
days of first dose.  Triplicate 
ECGs prior to dosing.  For 
timing of ECGs on “O” days, 
see Table 9 and Table 10. 
Otherwise, triplicate ECGs at 
approximately same time of 
day, and prior to dose on 
dosing days. If QTcF increase 
>30msec, ECGs performed 
daily through W2.)
X O O
O X
X
X
X O X X X X X O X
X
X
Holter monitoring
(At least 24 h, on dosing days 
start predose.)
X X
X
X
X
X
Telemetry
(Starting predose and for at 
least 48 h)
X X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK Blood samples for 
GSK525762
X X
X
X
X X X
X
X
a
PK blood samples for 
metabolite evaluation (only 
at MTD or RP2D in 6 
subjects)
X X
X X
Blood samples for biomarkers 
(PD)
X X X
X
X
Blood samples for plasma 
cytokines
X X X
X
PK Urine samples
(only at MTD or RP2D in 6 
subjects for subjects in 
PK/PD expansion)
X X X
X X
X
PD Tumor Sample b
X
b
,
c
Tissue and Timing to be based on tumor type and emerging data.  A PK sample 
will need to be obtained within 1 hour of the tissue sampling.  Details described in 
the SPM.
 
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Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Translational Research d
Pharmacogenomics (PGx) 
blood sample
X
Blood samples for circulating 
biomarkers (cfDNA etc.)
collected at: screening; date 
of 
X
Additional samples will be collected on the date of disease assessment/bone 
marrow biopsy and date of progression
Archival tumor tissue
X
Tumor biopsy at 
progression
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer 
therapy every 6 months.  Disease assessment will be collected for subjects who discontinue study medication due to 
any reason other than progression or death.  Individual subjects will be considered to have completed the study 2 
years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the 
Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in 
Phase 2.
a.
For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W.
b.
PD tumor samples will be collected when feasible (see Table 8 disease specific assessments for details).
c.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
d.
Refer to Section 6.6 for details on Translational Research and Appendix 5 for details on PGx Research.
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by 
Fridericia’s formula; ECOG PS=Eastern Cooperative Oncology Group Performance Status; PGx=Pharmacogenetics; 
COPD=Chronic obstructive pulmonary disease; SPM=Study Procedures Manual; D=day; EOT=End-of-Treatment; 
q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; W=week
 
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Table 9
Time and Events: Part 1 Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling, Week 1 and Week 2
Procedure
W1D1 – W1D2
W1D5
pre 
dose
15 
min 
± 5m
30 
min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h 
±2h
24h 
±1h
30 min 
±10m
3h 
±30m
12-lead ECG, in 
triplicate, 5 
minutes apart 
and within 10 
min prior to PK 
draw
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
GSK525762a
X
X
X
X
X
X
X
X
X a
X
X
PK sample for 
metabolite (only 
at MTD or RP2D 
in 6 subjects)a
X
X
X
X
X
X
X
X
X a
Blood sample for 
biomarkers (PD)
Xb
X
X
X
X
Plasma cytokine 
sample
Xb
X
X
X
X
Urine PK 
sampling (Only 
at MTD or RP2D 
in 6 subjects)
X
0-2 h
2-24 h
The frequency of sampling of plasma cytokines may be changed (likely reduced) based on data from the first few 
subjects assessed.
b.
Pharmacokinetic sample to be obtained before dosing on Week 1, Day 2.
c.
May be collected within 14 days prior to first dose.
 
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Table 10
Time and Events: Part 1 Serial Electrocardiograms and
Pharmacokinetics, Week 3 2 and Week 7
Procedure
W2D
4
W2D
6
W2D7 + 2 days
W7D1 ±4 days
(if dose was 
escalated, +4 to 
+7 days)
pre
dose
pre
dose
pre 
dos
e
15 
mi
n ± 
5m
30 
min 
±5
m
1h 
±10
m
2h 
±15
m
4h 
±15
m
8h 
±1
h
12h 
±2
h
24h 
±1
h
pre 
dos
e
0.5
-2h
4 
-
8
h
12-lead 
ECG, in 
triplicate, 5 
minutes 
apart and 
within 10 
min prior to 
PK draw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood 
sample for 
biomarker
s
X
Blood 
samples 
for plasma 
cytokines
X
Urine PK 
sampling 
(Only at 
MTD in 6 
subjects)
0-2h
2-24h
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
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Table 11
Time and Events: Part 2
Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Informed 
consent
Unless 
otherwise noted, 
screening 
assessments to 
be completed 
within 14 days 
of first dose.
X
Demogra
phy
X
Medical 
history
X
Disease 
characteri
stics
X
Cardiolog
y 
evaluatio
n
X
Prior 
therapy
X
Register 
subject
X
TREATMENT PHASE
Study 
Drug
Dispense 
study 
drug
Administer 
about same 
time of day.  No 
food or antacids 
1h before and 
2h after.
X
X
X
X
X
X
X
Review 
complianc
e
Not required 
when dosed in 
clinic.
X
X
X
X
X
Safety
Pregnanc
y 
test/testo
sterone
Females: serum 
pregnancy test 
within 7 days of 
first dose; urine 
or serum test 
thereafter.  
Males: complete 
and free 
testosterone at 
SCR; free 
testosterone 
thereafter.
X
X
X
X
X
X
Physical 
exam
X
X
X
X
X
X
X
X
X
ECOG 
PS
X
X
X
X
X
X
X
X
X
Vital 
Signs
X
X
X
X
X
X
X
X
X
Weight 
Height at SCR 
X
X
X
X
X
X
X
 
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Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
and 
height
only
Chest x-
ray
X
Pulmonar
y function 
test
X
Adverse 
events
continuous from signing of informed consent
Concomit
ant 
medicatio
ns
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
Cardiac 
Monitorin
g
ECHO
Within 35 days 
of first dose
X
X
X
X
X
X
X
12-lead 
ECGs 
(triplicate)
Screening 
ECGs within 35 
days of first 
dose.  Triplicate 
ECGs prior to 
dosing.  If QTcF 
increase 
>30msec, ECGs
performed daily 
through W2.
X
X
X
X
X
X
X
X
X
Holter 
monitorin
g
At least 24 h, on 
dosing days 
start predose.
X
X
Tumor 
PD 
Assessm
ent 
PD 
Tumor 
sample 
X 
a
1 biopsy between W1D2 and 
W4D1, timing to be optimized 
based on emerging data.  PK 
sample to be obtained within 1 hr 
of tumor sample collection.
 
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Part 2 
Procedur
e
Notes
S
C
R
Cycle 1
Cycl
e 2
Cycle 
3
Cycle 
4
Further Cycles
EO
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
PK and Blood PD
PK Blood 
samples
Three samples 
to be collected  
each sampling 
day for each 
type of analysis: 
Predose within 
60 minutes prior 
to dose, single 
draw between 
0.5 to 2 2-4 h 
postdose, single 
draw between 4
6-8h postdose
X
X
X
X
Blood 
sample 
for 
biomarker 
(PD)
X
X
X
Blood 
samples 
for 
plasma 
cytokines
X
X
Translational Research
PGx 
blood 
sample
X
Blood 
samples 
for 
circulating 
biomarker
s (cfDNA 
etc.)
X
Additional samples will be collected on the date of disease assessment/bone 
marrow biopsy and date of progression
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer 
therapy every 6 months.  Disease assessment will be collected for subjects who discontinue study medication due to 
any reason other than progression or death.  Individual subjects will be considered to have completed the study 2 
years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the 
Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in 
Phase 2.
1.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; 
ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; PD=Pharmacodynamics; 
PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 
weeks; SCR=Screening; Wk=week
Rationale for Changes:
The Time and Events tables were updated to clarify pharmacodynamic and translational 
research sample collection in Table 6, Week 1 serial ECGs and sample collection in 
Table 9, blood sample collection for biomarkers in Table 10, and remove triplicate ECG 
in Table 11.
 
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Previous Text:
6.3.5
Electrocardiograms
ECGs will be performed using a standard 12-lead ECG machine that automatically 
calculates the Heart Rate (HR) and measures PR, QRS, QT and QTcF intervals.  In 
Part 1, the investigator will review the ECG data manually, and should not rely solely on 
the automatic readings of the equipment, when making decisions regarding dosing of 
subjects.

During Part 1, a single 12-lead ECG should be performed at Screening and at all 
other time points that are not associated with a Serial PK sampling day.  Triplicate 
ECGs should be performed for all time points on Serial PK sampling days.  During 
Part 2, single 12-lead ECGs should be performed at the time points indicated in the 
Section 5 Time and Events Tables.
Revised Text:
6.3.5
Electrocardiograms
ECGs will be performed using a standard 12-lead ECG machine that automatically 
calculates the Heart Rate (HR) and measures PR, QRS, QT and QTcF intervals.  In 
Part 1, the investigator will review the ECG data manually, and should not rely solely on 
the automatic readings of the equipment, when making decisions regarding dosing of 
subjects.

During Part 1, triplicate a single 12-lead ECG should be performed at Screening and 
at all other time points indicated in the Section 5 Time and Events Tablesthat are 
not associated with a Serial PK sampling day.  Triplicate ECGs should be performed 
for all time points on Serial PK sampling days.  During Part 2, single 12-lead ECGs 
should be performed at the time points indicated in the Section 5 Time and Events 
Tables.
Rationale for Change:
The corrections were made for consistency with the Time and Events Table 5.
Previous Text:
6.6.2
Tumor Tissue Collection for PD Cohort
Subjects who consent to tumor PD assessments will also be required to provide pre- and 
post-treatment tumor specimens as appropriate in order to assess tumor PD response.    
The PD tests and tissue required are disease specific as outlined below.

For subjects with leukemias, changes in specific protein markers and/or mRNA 
expression signatures will be assessed in bone marrow or tumor cell-enriched 
PBMCs isolated from whole blood.
 
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
For subjects with lymphomas, lymph node biopsies (or bone marrow, if 
appropriate) samples will be required before and after treatment to evaluate 
changes in tumor-specific protein markers and/or gene expression signatures.

For subjects with MM, bone marrow will be evaluated for changes in tumor-
specific protein markers and/or gene expression signatures (for example, c-
Myc).
Revised Text:
6.6.2
Tumor Tissue Collection for PD Cohort
Subjects who consent to tumor PD assessments will also be required to provide pre- and 
post-treatment tumor specimens as appropriate in order to assess tumor PD response.    
The PD tests and tissue required are disease specific as outlined below.

For subjects with leukemias, changes in specific protein markers and/or mRNA 
expression signatures will be assessed in bone marrow and/or tumor cell-
enriched PBMCs isolated from whole blood.

For subjects with lymphomas, lymph node biopsies (or bone marrow, if 
appropriate) samples will be required before and after treatment to evaluate 
changes in tumor-specific protein markers and/or gene expression signatures.

For subjects with MM, bone marrow will be evaluated for changes in tumor-
specific protein markers and/or gene expression signatures (for example, c-
Myc).

Rationale for Change:
Section 6.6.2 was modified for clarification of sample collection.
Previous Text:
7.3
Meals and Dietary Restrictions
Subjects will fast for at least one hour prior to each dose of study drug.  After dosing, 
subjects will be asked to fast for an additional two hours.  These fasting requirements 
have been implemented in the protocol and informed consents to minimize PK 
variability.
Revised Text:
7.3
Meals and Dietary Restrictions
Subjects will fast for at least one hour prior to each dose of study drug.  Subjects should 
not eat a heavy meal in the morning prior to the 1 hour washout before dosing to 
minimize potential risk for food interaction.  On serial PK sampling days, subjects 
should fast overnight (i.e., at least 8 hours). After dosing, subjects will be asked to fast 
for an additional two hours.  These fasting requirements have been implemented in the 
protocol and informed consents to minimize PK variability.
 
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Rationale for Change:
The change was made to minimize the potential food interactions with the study drug.
Previous Text:
11.1.2
Part 2, Expansion Cohort
The primary goal of Part 2 is to detect a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR, CRp, PR or a morphologic leukemia-
free state ) of 20% in AML relative to a 5% response rate suggesting no activity.
Symbolically, the null hypothesis is:
H0: RR≤5%
The alternative hypothesis is:
HA:RR≥20%
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate ≥20% and 5% at interim and final analysis using a weak/non-informative 
prior.
To determine a maximal sample size for Part 2, a traditional, 2-stage Green-Dahlberg 
design [Green, 1992] was evaluated.  To test the hypotheses (RR=20% versus RR=5%) 
by Green-Dahlberg design, 40 subjects would be needed to minimize the Type I (< 5%) 
and Type II error rate (i.e., Power > 85%).
Using this sample size, a Bayesian design was evaluated.  A Bayesian analysis expresses 
uncertainty about a parameter in terms of probability.  A prior is defined to characterize 
the level of knowledge about a parameter before the data are collected.  Once the data are 
collected, a posterior distribution is formed using the prior and the likelihood (i.e., the
data).  A very weak prior Beta (0.02, 0.08) with a mean response rate of 20% is assumed.  
Thus, the posterior distribution for the response rate will be primarily driven by the data 
and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior and the likelihood of the observed data x, the posterior distribution of 
the response rate follows a beta distribution, i.e.,
p Beta (0.02 + x, 0.08 + n-x) with the posterior mean (0.02+ x)/(0. 1 + n).
Starting with a cohort of 20 subjects and allowing for a maximum sample size of 40, this 
Bayesian design will have a type I error rate () of 5% and 89% power.  For the interim 
analysis at N=20, if the predictive probability that the response rate ≥20% (H1) is small 
(i.e., less than 2% chance) or equivalent to observe one or no response in the first 
evaluable 20 subjects, the enrollment will be stopped due to futility.  Otherwise, the 
enrolment will continue to the target sample size of 40.  For the final analysis, if the 
 
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posterior probability that the response rate of >5% (H0) is large (i.e., greater than 95% 
chance), or equivalent to observe at least 5 responses in 40 subjects, sufficient statistical 
evidence has been provided in favor of declaring response rate >20%.
Revised Text:
11.1.2
Part 2, Expansion Cohort
The primary goal of Part 2 is to detect a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR, CRp, PR or a morphologic leukemia-
free state ) of 20% in AML relative to a 5% response rate suggesting no activity.
Symbolically, the null hypothesis is:
H0: RR≤5%
The alternative hypothesis is:
HA:RR≥20%
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate ≥20% and 5% at interim and final analysis using a weak/non-informative 
prior.
To determine a maximal sample size for Part 2, a traditional, 2-stage Green-Dahlberg 
design [Green, 1992] was evaluated.  To test the hypotheses (RR=20% versus RR=5%) 
by Green-Dahlberg design, 40 subjects would be needed to minimize the Type I (< 5%) 
and Type II error rate (i.e., Power > 85%).
Using this sample size, a Bayesian design was evaluated.  A Bayesian analysis expresses 
uncertainty about a parameter in terms of probability.  A prior is defined to characterize 
the level of knowledge about a parameter before the data are collected.  Once the data are 
collected, a posterior distribution is formed using the prior and the likelihood (i.e., the 
data).  A very weak prior Beta (0.02, 0.08) with a mean response rate of 20% is assumed.  
Thus, the posterior distribution for the response rate will be primarily driven by the data 
and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior and the likelihood of the observed data x, the posterior distribution of 
the response rate follows a beta distribution, i.e.,
p Beta (0.02 + x, 0.08 + n-x) with the posterior mean (0.02+ x)/(0. 1 + n).
Starting with a cohort of 20 subjects and allowing for a maximum sample size of 40, this 
Bayesian design will have a type I error rate () of 5% and 89% power.  For the interim 
analysis at N=20, if the predictive probability that the response rate ≥20% (H1) is small 
(i.e., less than 2% chance) or equivalent to observe one or no response in the first 
evaluable 20 subjects, the enrollment will be stopped due to futility.  Futility analysis 
 
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will be based on subjects who have at least one post-baseline disease assessment.  
Otherwise, the enrolment will continue to the target sample size of 40.  For the final 
analysis, if the posterior probability that the response rate of >5% (H0) is large (i.e., 
greater than 95% chance), or equivalent to observe at least 5 responses in 40 subjects, 
sufficient statistical evidence has been provided in favor of declaring response rate >20%.
Rationale for Change:
To clarify that futility analysis of response in the expansion cohort will require a 
population of subjects with at least one response assessment.
Previous Text:
11.1
Analysis Populations
All Subjects (Safety and Clinical Activity) 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.
Revised Text:
11.1
Analysis Populations
All Subjects Treated (Safety and Clinical Activity) 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.
Rationale for Change: 
The change was made for clarification of the analysis population.
Previous Text:
11.14.1
Other Stopping Criteria for Part 2
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics.
If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, enrollment may be terminated and/or a lower-dose cohort may be opened or 
expanded.  The final determination will be made by the Sponsor and investigators.
Revised Text:
11.14.1
Other Stopping Criteria for Part 2
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a GSK medical monitor, GSK Global Safety 
representative, and GSK clinical study representative (including a representative from 
Biostatistics). Deaths, SAEs and Grade 3/4 adverse events will be carefully evaluated 
for causality.  
 
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If clinically significant adverse events or toxicities are observed in more than one third of 
the subjects, and/or if deaths related to study drug are observed, enrollment may be 
terminated and/or a lower-dose cohort may be opened or expanded.  The final 
determination will be made by the Sponsor and investigators.
Rationale for Change:
The stopping criteria in Part 2 was updated to clarify that deaths related to study drug are 
included in the evaluation for stopping the study. 
Previous Text:
15.4  Appendix 4: Dose Adjustment/Stopping Criteria/Supportive Care
Fever
Safety monitoring cytokine blood samples may be collected (based on Section 7.7.1 of 
the protocol).  These samples include (but not limited to) assessments for TNF-alpha, IL-
1, IL-6, IL-10 as outlined in the SPM.
Assess or inquire if the subject is experiencing in combination with fever: swelling, 
redness, extreme fatigue or nausea.
Diarrhea
General considerations for diarrhea management
Rule out other or concomitant causes.  These include medications (e.g., stool softeners, 
laxatives, antacids, etc.), infection by C. difficile or Candida species, partial bowel 
obstruction, malabsorption/lactose intolerance, fecal impaction, diets high in fiber or 
lactose.
For uncomplicated Grade 1 to 2 diarrhea (i.e., mild to moderate and defined as 
NCI-CTCAE v4.0 [NCI, 2009] Grade 1-2 with no complicating signs or symptoms):

Dietary modifications: stop all lactose containing products and eat small meals.  A 
BRAT (banana, rice, apples, toast) diet can be helpful.

Hydration: drink 8-10 large glasses of clear liquids per day (e.g., Gatorade or broth)

Consider administration of standard dose of loperamide (subjects should have 
loperamide available in order to start at the first signs of diarrhea):

Initial dose of 4 mg followed by 2 mg every four hours or after every unformed 
stool; maximum 16 mg/day.

Continuation of loperamide is suggested until diarrhea free for 12 hours

Consider a temporary investigational drug dose interruption until symptoms have 
resolved to baseline or Grade 1.  Re-treatment with GSK525762 may then be 
resumed at 100%.  Please refer to for additional guidance.
 
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Revised Text:
15.4  Appendix 4: Dose Adjustment/Stopping Criteria/Supportive Care
Fever
Safety monitoring cytokine blood samples may be collected (based on Section 7.7.1 of 
the protocol).  These samples include (but not limited to) assessments for TNF-alpha, IL-
1, IL-6, IL-10 as outlined in the SPM.
Assess or inquire if the subject is experiencing in combination with fever: swelling, 
redness, extreme fatigue or nausea.
Diarrhea
General considerations for diarrhea management
Rule out other or concomitant causes.  These include medications (e.g., stool softeners, 
laxatives, antacids, etc.), infection by C. difficile or Candida species, partial bowel 
obstruction, malabsorption/lactose intolerance, fecal impaction, diets high in fiber or 
lactose.
For uncomplicated Grade 1 to 2 diarrhea (i.e., mild to moderate and defined as 
NCI-CTCAE v4.0 [NCI, 2009] Grade 1-2 with no complicating signs or symptoms):

Dietary modifications: stop all lactose containing products and eat small meals.  A 
BRAT (banana, rice, apples, toast) diet can be helpful.

Hydration: drink 8-10 large glasses of clear liquids per day (e.g., Gatorade or broth)

Consider administration of standard dose of loperamide (subjects should have 
loperamide available in order to start at the first signs of diarrhea):

Initial dose of 4 mg followed by 2 mg every four hours or after every unformed 
stool; maximum 16 mg/day.

Continuation of loperamide is suggested until diarrhea free for 12 hours

Consider a temporary investigational drug dose interruption until symptoms have 
resolved to baseline or Grade 1.  Re-treatment with GSK525762 may then be 
resumed at 100%.  Please refer to Section 7.7.2 for additional guidance.
Rationale for Change:
Section 7.2.2 was added for reference to the guidance.
 
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15.16.
Appendix 16: Protocol Changes for Amendment 3 (12-NOV-
2014) from the Protocol Amendment 2 (15-OCT-2013)
Where the Amendment Applies
Amendment 3 applies to all study centres. 
General Protocol Changes
Amendment No. 3: The secondary objectives of Part 1 were updated to include 
evaluation of the clinical activity of GSK525762 (response rate and overall survival).  
Additional details of twice daily (BID) dosing during dose escalation were included.  
Eligibility criteria refined: 1) Clarification of eligibility for subjects with AML (Part 1 
and 2). Platelets count eligibility criteria were specified for each group of hematological 
malignancies separately. 3) Exemption of exclusion due to prior allogeneic stem cell 
transplant added. DLT for hematological toxicities clarified and dose reduction algorithm 
for thrombocytopenia added.  Study statistic amended for part 2 (AML expansion 
cohort): hypothesis and number of patients. Data from ongoing preclinical and clinical 
research added. Time point of collection for samples for disease and efficacy assessments 
refined. List of baseline assessments for each indication added.  Minor clarifications, 
reformatting of tables and typographical errors are also addressed in this amendment.
15.13.1
List of Changes
Title Page
Rationale for Change: Clarification of indication, addition of twice daily dosing 
cohort to protocol
Revised Text (strikethrough=deleted text; underline=new text):
Description
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD and the 
recommended Phase 2 dose (RP2D) for GSK525762 given in subjects with acute 
leukemia and multiple myeloma/non-Hodgkin’s Lymphoma, once-daily orally and twice 
daily orally.  Part 1 will be conducted in adult subjects with relapsed and/or refractory 
hematological malignancies.  An expansion cohort (Part 2) is planned to further explore 
clinical activity of GSK525762 in subjects with specific subtypes of acute leukemias 
based on emerging data.
Title Page, Authors 
Rationale for Change: The sponsor information were updated based on internal GSK 
team personnel changes.
Revised Text
Global Clinical Safety & Pharmacovigilance, USA
Precision Medicine and Diagnostics, USA
Global Clinical Operational Sciences, USA
Biology, Epigenetics Management, USA
Global Clinical Safety & Pharmacovigilance, USA
Global Formulation Development, PTS, USA
 
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PPD
PPD
PPD
PPD
PPD

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Biotransformation and Drug Disposition, PTS, UK
Molecular Medicine Unit, USA
Cancer Research Epigenetics Management, USA
Clinical Pharmacology Modeling & Simulation, USA
Cancer Research Epigenetics Management, USA
Global Clinical Operational Sciences, USA
Global Clinical Operational Sciences, USA
Quantitative Sciences-Genetics, USA
Clinical Oncology, USA
Global Clinical Operational Sciences , UK
SA Pathology, PTS, UK
Global Clinical Safety & Pharmacovigilance, USA
Global Clinical Safety & Pharmacovigilance, USA
EpiNova DPU, UK
Global Clinical Safety & Pharmacovigilance, USA
Biology, Epigenetics Management, USA
Statistics, Oncology TA Group, USA
Sponsor/medical monitor Information Page
Rationale for Change: The sponsor and medical monitoring information has been 
updated based on internal GSK team personnel changes.
Revised Text: 
Medical Monitor and Sponsor Contact Information
Role
Name
Day 
Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
 
, MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
 
MD, PhD
GlaxoSmithKline
1250 South Collegeville Road
UP4410
Collegeville, PA 19426, USA
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Sponsor Registered Address:
Rationale for Change: Global Update of business address for GSK
Revised Text: 
GlaxoSmithKline
Iron Bridge Research & Development Limited
980 Great West Road 
Stockley Park West, Uxbridge,
Brentford
Middlesex, UB11 1BU, TW8 9GS
UK
Telephone:
ABBREVIATIONS
Rationale for Change: Abbreviations added as part of the protocol amendment and 
clarification
Revised Text: 
BID
Bis in die - Twice daily
N-CRM
Neuenschwander continual reassessment method
QD
quaque die - Once daily
TRADEMARK INFORMATION
Rationale for Change: Omission
Revised Text: 
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
WinNonlin
PROTOCOL SYNOPSIS
Rationale for Change: Twice daily dosing will be assessed in a formal separate 
cohort. No formal MTD analysis in separate cohorts for the different indication will be 
conducted.  
Revised Text:
STUDY DESIGN AND DURATION
This study is divided into 2 parts; Part 1 of the study is a dose escalation phase to select 
the recommended Part 2 dose (RP2D) based on the safety, pharmacokinetic, and 
pharmacodynamic profiles observed after oral administration of GSK525762.  Eligible 
subjects with relapsed refractory hematological malignancies will be enrolled in the once 
 
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daily (QD) and twice daily (BID) dosing cohorts until a maximum tolerated dose (MTD) 
is established. Subjects may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent.  An expansion cohort is planned in 
subjects with acute myeloid leukemias to further explore clinical activity at the MTD or 
RP2D (Part 2).
STUDY RATIONALE
Rationale for Change: Clarification of indication
Revised Text:
Current data from GSK525762 preclinical development indicate a potential to inhibit the 
BET family of BRD proteins and that this inhibition may have clinical utility in the 
treatment of various tumors, including hematological malignancies. Relapsed and/or 
refractory hematological malignancies such as Acute Myeloid Leukemia (AML), Adult
Acute Lymphoblastic Leukemia (ALL), non-Hodgkin’s Lymphoma (NHL), Multiple 
Myeloma (MM) and high-risk Myelodysplastic Syndromes (MDS) have an overall poor 
outlook. This is the first study of this agent to be conducted in subjects with these 
relapsed and/or refractory hematological malignancies for which no standard therapies 
are anticipated to result in a durable remission.
OBJECTIVES AND ENDPOINTS
Rationale for Change: Objectives and Endpoints were updated to reflect the addition 
of a BID dosing cohort; to clarify the target indications and to clarify specimens required 
and analysed for the exploratory research. Overall response rate and overall survival were 
added as secondary endpoints. The statistical hypothesis was updated in accordance with 
the changes.
 
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Revised Text:
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) and/or 
twice daily (BID) dosing schedules,
establishing the recommended Phase 
2 dose (RP2D) of GSK525762 in 
adult subjects with relapsed and/or 
refractory AML and other hematologic 
malignancies.

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration following 
QDand/or BID dosing schedules.
o
GSK525762 PK parameters following 
single- (Day 1) and repeat-dose (Day 15) 
administration of GSK525762, including 
Area under concentration-time curve(AUC), 
Minimum observed concentration (Cmin), 
Pre-dose (trough) concentration at the end 
of a dosing interval (C), Maximum 
observed concentration (Cmax), Time of 
maximum concentration (tmax), Apparent 
terminal half-life (t1/2) (or t1/2, eff), time 
invariance and accumulation ratio.

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters following 
QD and/or BID dosing schedules.
o
Changes in cardiac QT duration corrected 
for heart rate by Fridericia’s formula (QTcF) 
and other safety parameters in relation to 
GSK525762 exposure markers (dose, 
concentration, Cmax, AUC, following single 
and repeat-dose oral administration of 
GSK525762

To evaluate the relationship between 
GSK525762 exposure and
Ppharmacodynamic (PD) response
following QD and/or BID dosing 
schedules.
o
Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762
o
Assess overall response rate (RR) 
according to disease specific assessments 
for leukemia, multiple myeloma, and non-
Hodgkin’s lymphoma.
 
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Part 1 Objectives
Part 1 Endpoints
Exploratory
o
To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
following QD and/or BID dosing 
schedules.
o
Pharmacogenomic (PGx) study using blood 
or buccal samples
o
To investigate the mechanism of 
action and indicators of sensitivity 
and resistance to GSK525762.
o
Transcriptomics and protein studies of 
blood and tumor cells; correlation of tumor 
baseline genetic and genomic profiles with 
response
o
To generate samples (data reported 
separately) with which to characterize 
the metabolic profile of GSK525762 
after single and repeat-dosing (In the 
PK/PD expansion cohort only).
o
Samples to characterize the metabolites in 
plasma and/or urine
o
To determine the amount of 
GSK525762 excreted in urine after 
oral single and repeat-dosing.
o
Concentration of GSK5725762 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time
Hypothesis

No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in 
relapsed or refractory acute myeloid 
leukemia (r/r AML).

Objective response rate (% of subjects 
achieving Complete Response (CR), 
Partial Response (PR), CRp (as per CR 
but platelet count <100 x 109/L) or 
morphologic leukemia-free state) per
response criteria.
Secondary

To characterize the PK of 
GSK525762 in subjects with relapse 
refractory hematology malignancies
r/r AML after repeat-dose 
administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 
(i.e., PK/PD) relationship between 
GSK525762 and safety/efficacy 
parameters in acute leukemia. r/r 
AML.
o
PK/PD relationship between GSK525762 
exposure markers and safety and efficacy 
parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in acute 
leukemia r/r AML.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.
 
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Part 2 Objectives
Part 2 Endpoints

To evaluate the relationship between 
GSK525762 exposure and PD 
response in acute leukemia r/r AML.
o
Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.
o
To determine the clinical activity of 
GSK525762 in r/r AML.
o
Overall survival (OS, the time from the 
treatment start date until death from any 
cause)
Exploratory
o
To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
o
Pharmacogenomic (PGx) study using or 
buccal blood samples

To investigate the mechanism of 
action and indicators of sensitivity and 
resistance to GSK525762
o
Transcriptomics and protein studies of 
blood and tumor cells; correlation of tumor 
baseline genetic and genomic profiles with 
response; Leukemic Stem Cell studies; 
PDX model studies and other translational 
medicine studies
Hypothesis
o
The primary goal of Part 2 is to detect a clinically meaningful response rate of 2030% 
relative to a 510% response rate suggesting no activity in subjects with acute leukemia.  
This will be conducted by testing the null hypothesis that P0≤0.05010 versus the 
alternative that P1≥0.200 30, assuming the maximum response rate for an ineffective 
drug is 0.0510 and the minimum response rate for an effective drug is 0.20.3
Inclusion Criteria
Rationale for Change: Clarification of AML eligibility and that GSK should be 
consulted prior to enrolment. Platelet count eligibility criteria for MM was amended 
based on discussion with investigators and GSK to reflect standard of care. Mistake in 
Table reference was corrected.
Revised Text:
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply and after consultation with GSK:
Inclusion criteria number 3: In Part 1, subjects must have relapsed and/or refractory 
hematologic malignancies (leukemias, myeloproliferative neoplasms, lymphomas, and 
myelomas) for which no standard therapies are available or anticipated to result in 
remission.    In Part 2, subjects must have a diagnosis of relapsed and/or refractory Acute 
Myeloid Leukemia (AML).
AMLIn Part 2, subjects must have Acute Myeloid Leukemia (AML).
Subjects with AML (Part 1 and Part 2), are eligible if they 
o
have relapsed and/or refractory disease, OR
 
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o
are 65 years of age who areand not candidates for or have refused standard 
chemotherapy. 
Inclusion criteria number 10: Adequate organ system functions (at both screening and 
where applicable pre first dose) as defined in below.
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Platelets (only for subjects with lymphoma or)
Platelets (for subjects with MM)
Platelets (for subjects with acute leukemia)
≥ 75,000
≥ 50,000 (transfusion independent)
No restrictions
For MM subjects, calculated creatinine clearance criteria is <2.5mg/dL or 1424-hour urine creatinine clearance of ≥ 30 
mL/min
Exclusion Criteria
Rationale for Change: Clarification of exclusion criteria to allow participation of 
subjects where prior allogeneic stem cell transplantation does not impact the study data. 
Clarification of use of anticoagulants.
Revised Text:
Exclusion criteria number 4: Subjects with prior allogeneic stem cell transplant are 
excluded unless

transplant was >60 days prior to study enrollment.

subject has not taken immunosuppressive medications (including but not limited to: 
cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil) for at least 1 month

no signs or symptoms of graft versus host disease other than Grade 1 skin involvement

no active infection
Exclusion criteria number 5: Current uUse of anticoagulants (e.g., warfarin, heparin) at 
therapeutic levels within 147 days prior to the first dose of GSK525762.  Low dose 
(prophylactic) low molecular weight heparin (LMWH) is permitted.  In addition, INR 
must be monitored in accordance with local institutional practices, as appropriate.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN
Rationale for Change: To include BID dosing cohort.
Revised Text:
Starting dose will be 5 mg, orally (tablets), once a day.  Dose escalations will be 
performed in Part 1 and dose adjustments are allowed to address tolerability and safety 
issues.  BID dosing will be explored in a parallel cohort. Alternate dosing schedules 
(Twice daily [BID] ore.g. intermittent dosing) may be consideredrequired to manage 
toxicities and may be considered based on investigator assessment and after consultation 
with GSK; and may be implemented if the safety, pharmacokinetic (PK), and 
 
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pharmacodynamic (PD) data suggest that a sufficient therapeutic exposure cannot be 
achieved using the initialprotocol schedule and after a protocol amendment.

PHARMACOKINETIC/PHARMACODYNAMIC, EFFICACY and 
SAFETY MEASUREMENTS:

Rationale for Change: Clarification that PK and PD sampling in Part 1 and 
Part 2 differ. Response assessment for haematologic malignancies differs by 
indication; therefore language was replaced with a broader term that 
encompasses all indications. Analyte name for safety measurement was 
clarified.

Revised Text:

There will be serial blood sampling for PK and PD measurements in Part 1 of 
this study and more limited PK sampling in Part 2 of this study.  Single safety 
PK blood draws may be collected for subjects with severe adverse events or 
adverse events of concern.  In addition, pre-treatment and post-treatment tumor 
tissue samples will be collected from selected subjects to be evaluated for target 
engagement and effects of GSK525762 on tumor biology.

CR, PR, CRp or morphologic leukemia-free state Type and duration of response 
in AML, MM and NHL.

Routine physical examinations, vital sign measurements, echocardiograms, and 
monitoring of adverse events will be performed.  Stringent cardiac safety 
monitoring will be required, consisting of at least 48 hours of telemetry 
following the first dose (overnight stays in research facility necessary), 24 hours 
of Holter monitoring and triplicate 12-lead ECGs prior to dosing on selected 
days and prior to drawing PK samples on serial PK sampling days.  Laboratory 
testing includes, in addition to standard hematology, clinical chemistry, 
pancreatic, coagulation, and liver chemistry panels, testing for troponin, N-
terminal prohormone B-type Natriuretic Peptide (NT pro-BNP), c-peptide, 1,5-
Anhydroglucitol (1, 5 AG), Hemoglobin A1c (HbA1c), and thyroid monitoring.  
Additional safety assessments may be necessary based on emerging data.

STATISTICAL ANALYSIS:

Rationale for Change: Clarification of when futility assessment will be 
conducted. 

Revised Text:

Subject demographic and safety data will be collected on electronic case report 
forms (eCRFs).  All data will be pooled and descriptive safety analyses 
summarized and listed by cohort at study conclusion.  Part 2 of the study is 
designed to evaluate preliminary efficacy.  A fFutility assessment will be 
conducted after data are available from the first 20 on an ongoing basis, starting 
with a minimum of 10 treated subjects assessed for response. The assessments 
are based on the predicted probability of success with a maximum of 32 subjects 
treated and assessed for response. subjects in Part 2.
 
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Section 1.1. Background
Rationale for Change: Transparency of clinical development for the reader of the 
protocol.
Revised Text:
Paragraph 5:
Parallel to study BET116183, GSK525762 is being investigated in solid tumors (GSK 
Study BET115521, NCT# NCT01587703)
Section 1.2. Study Population Rationale
Rationale for Change: Availability of updated information.
Revised Text:
Paragraph 2, 3, 4:
Eighty-seven percent of hematological cancer cell lines tested (73/84) are highly sensitive 
to GSK525762, with growth IC50 (gIC50) < 1.0 M, and GSK525762 results in net cell 
death in 61% (51/84) of those cell lines.  Some of the most sensitive hematological 
cancer cell types were derived from AML (median gIC50 = 0.15 M), ALL (median 
gIC50 = 0.22 M), MM (median gIC50 = 0.12 M), and BCL (median gIC50 = 0.32 
M) [GSK525762 IB, GlaxoSmithKline Document Number 2011N113741_02].
Ninety percent of hematological cancer cell lines tested (94/104) are highly sensitive to 
GSK525762, exhibiting growth IC50 (gIC50) values below 1.0µM. Some of the most 
sensitive hematological cancer cell types include CML (median gIC50= 40 nM), MM 
(median gIC50= 49 nM), CTCL (median gIC50= 77 nM), and AML (median gIC50= 94 
nM).
OralAdditionally, oral dosing of GSK525762 results in tumour growth inhibition and 
improved survival in thea myeloma mouse xenograft model (OPM-2) of disease 
(Figure 2).  Consistent with published reports, down-regulation of c-Myc protein 
expression was observed in OPM-2 xenografts following a single dose of GSK525762 or 
daily administration for up to 11 days. 
 
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Superseded and Updated Figure 1: 
 
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Section 1.3. Dose Rationale
Rationale for Change: A BID dosing cohort was added to the study. In alignment 
with that, information was added on BID dosing including the rationale for BID. To 
facilitate reading of the protocol, new paragraphs were added and all paragraph 
numbering was updated to implement a parallel paragraph structure for QD and BID 
dosing. Minor clarifications in the QD cohort section were added. New or updated 
information based on clinical or preclinical studies was added.
Revised Text:
Section 1.3.1. QD Dose Cohort
Section 1.3.1.1. Starting Dose Calculations
The proposed starting dose for this clinical study in subjects with hematologic 
malignancies is 5 mg once daily (QD) based on the following, assuming a 70 kg adult 
with a body surface area of 1.7 m2.   This is different from the ongoing solid tumor study 
(BET115521) in which the starting dose was 2 mg daily.  This dose level has been 
successfully cleared and a dose of 4 mg is currently being evaluated. The dose of 5 mg 
daily was based on preclinical considerations described Section 1.3.1.1.1below,),
preliminary human pharmacokinetics (PK; Section 1.3.1.1.2), clinical consideration such 
asincluding the aggressive nature of the relapsed and/or refractory tumor (Section 
1.3.1.1.3), and the desire to minimise sub-therapeutic exposures. This starting dose is 
different from the ongoing solid tumor study (GSK Study BET115521, NCT# 
NCT01587703) in which the starting dose was 2 mg daily (see Section 1.3.1.1.3)
Section 1.3.1.1.1. Preclinical Considerations
The following approaches have been considered to establish the starting dose for 
GSK525762:
Section 1.3.1.1.2. Human PKPharmacokinetics and Equivalent Exposure for NOEL for 
QTc prolongation
Paragraph 3
Updated PK information obtained after first subject first dose is presented in Appendix 
13 (Section 15.13)
Section 1.3.1.1.3 Clinical Considerations
Relapsed and/or refractory hematologic malignancies have an aggressive and rapidly 
progressive course and patients with leukemia are unlikely to remain stable even for 3 
week for the Dose Limiting Toxicity (DLT) assessment to be done.  Therefore there is a 
need to minimise the number of patients exposed to sub-therapeutic doses without 
compromising safety.  The 5 mg starting dose provides adequate safety margins for 
toxicities that can be clinically monitored and are largely reversible (excluding testicular 
effectslong-term effects on  male and female reproductive function, which is being 
evaluated), while minimizing the number of patients with aggressive hematologic cancers 
exposed to predicted sub-therapeutic doses. Moreover, the starting dose of 2 mg daily in 
 
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the solid tumor trial (BET115521) has been successfully cleared and a dose of 4 mg daily 
is currently being explored.
Taking all the above into consideration and the extensive clinical monitoring for QT 
prolongation, a starting dose of 5 mg QD is planned.
Starting Dose Based on Dose Level Cleared in the Solid Tumor Study
The key safety findings from the ongoing solid tumor study (BET115521) will be shared 
with the investigators in this hematologic malignancies study (as described in Section ). 
Currently, the dose level of 2 mg has been cleared. In the event a dose level of 4 mg or 
higher is cleared in the solid tumor study, and the next dose level to be tested is higher 
than 5 mg, then GSK would consider amending this protocol to start at the same dose that 
the solid tumor protocol is testing at that time.
Section 1.3.1.2. Predicted therapeutic dose range
Cell lines of hematological origin were generally more sensitive than the cell lines of 
other solid tumor origins, namely small cell lung cancer (SCLC) and Colorectal cancer 
(CRC) cells.  The more sensitive cell lines had growth IC50 (gIC50) values as low as 50-
100 nM.  The potential therapeutic dose for GSK525762 in humans was derived using 
available preclinical PK, data from in vitro cell lines of hematological origin, and 
efficacy data from OPM-2 multiple myeloma tumour xenograft studies.  Based on 
modeling, maximal efficacy of GSK525762 may require ≥ 50% target inhibition.  The 
predicted human effective daily dose is likely to be 25 to 50 mgin the range of 25 to 100 
mg assuming 50 to 100% oral bioavailability.
Section 1.3.2. BID Dose Cohort 
Section 1.3.2.1. Preclinical Rationale for BID
Recent clinical and pre-clinical pharmacokinetic and pharmacodynamic data suggests a 
potential benefit of a twice daily (BID) dosing regimen compared to QD dosing 
[GSK525762 IB, GlaxoSmithKline Document Number 2011N113741_03]. In mice, 
GSK525762 has a short half-life of about 1.5 hours. Single dose pharmacodynamic 
experiments were performed in three SCLC and one CRC cell line xenograft model. 
Dose-dependent changes in gene expression were observed in all models at early time 
points post-dose; however, expression returned to pre-treatment levels within 8-12 hours. 
Additionally, in a subcutaneous multiple myeloma cell line xenograft study, c-Myc 
protein levels were significantly reduced 2 and 5 hours post-dose, and returned to 
baseline by 8 hours.
QD and BID dosing have been further explored in a number of in vivo xenograft efficacy 
studies. In a subcutaneous, patient-derived model of SCLC, BID dosing at 12.5mg/kg 
resulted in improved tumor growth inhibition compared to 25 mg/kg QD (74% versus 
60%, respectively).  Improved efficacy with BID dosing was also observed in a cell line 
xenograft model of CRC. BID dosing at 12.5mg/kg resulted in 48% tumor growth 
inhibition, whereas 25mg/kg QD dosing resulted in 34% inhibition.  In a third model, a 
cell line xenograft of SCLC, there was no significant difference in tumor growth 
 
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inhibition resulting from 12.5mg/kg BID versus 25mg/kg QD dosing. Thus, we observe 
equivalent or improved efficacy with BID dosing in all xenograft models tested.
Section 1.3.2.2. Clinical Rationale for BID
Pharmacokinetics of GSK525762 has been evaluated in subjects for studies BET115521 
and BET116183 following single and repeated daily administration of GSK525762 
(Section 15.13). 
GSK525762 pharmacokinetics are characterized by a rapid absorption with maximum 
concentration occurring mostly within the first hour after dosing. GSK525762 is 
eliminated rapidly with an average terminal phase half-life of 3 to 7 hours, leading to a 
lack of accumulation following once daily oral administration. Following single oral 
administration and repeated once daily administration of 2 mg to 60 mg of GSK525762, 
Cmax and AUC tended to increase in a dose proportional fashion.
Based on the pharmacokinetics of GSK525762 observed to date, and evidence of a short 
half-life of about 5 hours, trough concentrations are predicted to be below the average in 
vitro IC50 (0.08 uM to 1.3 uM) for the tumor types selected for this study. Furthermore, 
based on the pharmacokinetics to date, it is predicted that even 100 mg QD doses would 
result in the trough concentrations below the average in vitro IC50.  Dividing the daily 
dose into two doses administered about 12 hours apart would allow the trough 
concentration to be above the lower in vitro IC50 for doses around 30 mg BID.  
Section 1.3.2.3. Starting Dose for BID
The maximum starting dose for BID will be 20 mg provided the 40 mg QD dose cohort 
has been cleared. A lower BID starting dose will be considered depending on emerging 
safety, PK, and PD data
Section 1.3.3. Dose escalation steps (QD and BID)
The MTD in subjects with leukemia may differ from the MTD in subjects with multiple 
myeloma and lymphoma therefore AML subjects will be enrolled initially to determine 
the MTD for AML. Once the 40 mg dose cohort is cleared in AML, the MTD 
determination of MM and NHL subjects will begin at the 40 mg dose level.
Section 1.4 Rationale for Study and Endpoints
Rationale for Change: Clarification
Revised Text:
Paragraph 2
The BET116183 study has 2 parts.  Part 1 is a dose finding study, which will include 
subjects with relapsed refractory hematologic malignancies to determine an MTD.  Part 2 
is a cohort expansion, which will study the RP2D of GSK525762 to determine 
preliminary efficacy, safety and tolerability in subjects with specific acute myeloid 
leukemias.
 
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Section 1.5.1. Risk Assessment
Rationale for Change: New information available.
Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Reproductive
GSK525762 has shown adverse and 
potentially irreversible effects on testes in rats, 
rabbits and dogs, with no NOAEL in rabbits.
An effect on spermatogenesis is anticipated.
In definitive four-week oral toxicology studies, 
sperm retention and degenerative effects 
occurred in male dogs and rats. Degenerative 
changes were also observed in rabbits dosed 
dermally for 14 days.
GSK525762 has not been tested in 
reproductive toxicology studies but there is a 
theoretical risk that GSK525762 may also 
impact female reproductive organs (ovaries) 
and the development of an unborn baby (see 
the GSK 525762 IB [GlaxoSmithKline 
Document Number ] for references
2011N113741_02
In a dose range rat embryofetal development 
study, GSK525762 has been shown to impact 
fetal development at doses ≥1 mg/kg/day, 
including embryo-fetal toxicity, leading to a 
complete loss of litters at 30 mg/kg/day and 
developmental toxicity including fetal
malformations at doses ≥1 mg/kg/day. These 
adverse reproductive effects occur in rats at 
systemic exposures approximately 3-fold 
below the exposure observed in patients 
given 2 mg/day on the ongoing dose 
escalation Phase 1 clinical trial BET115521.
The findings from the dose-range reproductive 
toxicity study in rats with GSK525762 are 
consistent with literature reports that BRD2, 
BRD3, BRD4 and BRDT have crucial roles in 
reproductive function and embryofetal 
development (see the GSK 525762 IB 
[GlaxoSmithKline Document 
Number 2011N113741_03). for references).
Based on the findings in this reproductive 
toxicity study in rats with GSK525762, there is 
a substantiated risk for adverse effects on 
embryofetal development. There is a 
theoretical risk that GSK525762 may also 
impact female reproductive organs (ovaries). 
ICF includes the risk of damage to 
reproductive organs such as testes 
or ovaries.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects and collecting 
testosterone (free and complete) 
for male subjects.
ICF includes the potential risk of 
reproductive effects.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
A rat female fertility study is ongoing to 
evaluate this risk.
Section 1.5.2. Benefit Assessment
Rationale for Change: Clarification
Revised Text:
Study BET116183 is an open-label, dose escalation study and the first study of this agent 
to be conducted in subjects with relapsed and/or refractory hematological malignancies 
for which no standard therapies are anticipated to result in a durable remission.  
GSK525762 has promising preclinical activity in the hematological cell lines, however it 
is unknown whether GSK525762 will have clinical efficacy in subjects with
hematological malignancies, thus any potential beneficial effect for an individual subject 
attributable to GSK525762 is unknown.  Data obtained in Study BET116183 may assist 
in progressing the knowledge base on advanced hematological malignancies and their 
treatment, or help identify individuals more likely to benefit or have side-effects from 
GSK525762.  Study participants may benefit from the medical tests and screening 
performed during the study
Section 1.6. Communication Plan for Safety Evaluation
Rationale for Change: Clarification of process and functions/people involved
Revised Text:
This phase I/II study is intended to enroll subjects at two or more sites.  Safety 
evaluationsdata will be closely monitored and reviewed by a GSK Safety Review Team 
that includes the GSK medical monitor, and/or clinical scientist(s), and GSK safety 
physician responsible for both the BET116183 study and other ongoing clinical all 
studies of GSK525762 (e.g., the BET115521 solid tumor study).  There will be a 2 way 
communication between the local participating sites and the GSK clinical team via email, 
fax and phone.  The GSK team will review all safety data throughout the study, and 
safety findings from all studies with GSK525762 will be discussed with investigators 
from all participating sites on a monthly basis and appropriate action will be taken.  
Urgent safety information will be shared with all the participating sites at the earliest 
possible time after the data becomes available.  Emerging safety and tolerability data 
from the currently ongoing phase I study in solid tumors will also be communicated to 
the participating investigators in this study as appropriate at the monthly meeting, or 
sooner if necessary.
 
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Section 2. OBJECTIVES, ENDPOINTS, HYPOTHESES
The same changes were implemented in Section 2 of the protocol as documented in 
the change section of the protocol synopsis under ‘OBJECTIVES AND 
ENDPOINTS’
Section 3. Study Design/Schematic
Rationale for Change: Clarification of the study population and addition of a BID 
dosing cohort.
Revised Text:
Paragraph 2
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD in 
subjects with acute leukemia and multiple myeloma/non-Hodgkin’s Lymphoma, and the 
recommended Phase 2 dose (RP2D) for GSK525762 given once-daily (QD) orally and 
twice daily (BID) orally.  Part 1 will be conducted in adult subjects with relapsed and/or 
refractory hematological malignancies.  An expansion cohort (Part 2) is planned to 
further explore clinical activity of GSK525762 in subjects with specific subtypes of acute 
leukemias based on emerging data (Figure 3).
Figure 3. Study Schema
Rationale for Change: The figure was updated to reflect the addition of a separate 
BID dosing cohort.
Superseded and Revised Figure:
 
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Section 3.2.1. Part 1 Dose Escalation
Rationale for Change: Addition of BID dosing cohort and clarification of dose 
escalation design taking into account different indications. 
Revised Text:
Thereafter, subjects will be enrolled in a standard 3+3 design. Separate dose escalation 
cohorts will be opened for QD and BID dosing.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predicted dose from N-CRMNeuenschwander continual 
reassessment method (N-CRM) design [Neuenschwander, 2009].  N-CRM design is a 
type of Bayesian adaptive dose escalation scheme.  The method is fully adaptive and 
makes use of all the DLT information available at the time of each dose assignment.  The 
DLT information of all subjects enrolled in the trial are used to update the dose-toxicity 
relationship and provide supportive information in addition to 3+3 design in the next 
escalation/de-escalation decision.
Dose escalation will continue until an MTD is determined or until a dose of 100200 mg 
per day is reached.  After the MTD has been determined in Part1, then Part 2 dose 
expansion cohorts will be opened.
Due to the potentially different MTD in subjects with acute leukemia compared to 
myeloma/lymphoma (Section 1.3.3), MTD will initially be established in subjects with 
AML and subjects with MM/NHL may be enrolled at dose levels cleared in subjects with 
AML.
 
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Section 3.2.1.1. Dose Escalation and Schedule
Rationale for Change: Clarification of the duration of telemetry.
Revised Text:
Table 1. Three Week DLT monitoring: Dosing Schedule and Cardiac 
Monitoring
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
Dose
off
off
ECG, Holter
48h Telemetry*
ECG,
Telemetry
ECG,
Holter
ECG
* 48h Telemetry: start predose d1, remove  on d3
Please refer to Time and Events Section 5 for more details 
Section 3.2.1.2. Accelerated Dose Escalation in Part 1
Rationale for Change: Simplification by document cross referencing and clarification 
of prerequisite for accelerated dose escalation.
Revised Text:
One subject per dose level in the accelerated dose escalation schema will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 and continuing until one 
subject experiences ≥ Grade 2 drug related non-hematological toxicity, or DLT (except 
for pre-specified Grade 3 non-serious non-hematological drug related adverse event, see 
Section 3.2.2 (based on National Cancer Institute- Common Terminology Criteria for 
Adverse Events Version 4.0 [NCI-CTCAE v4.0] [NCI, 2009]) that would allow 
continuation of accelerated dose escalation;  (Table 2).  Once this occurs, the accelerated 
dose escalation will terminate, and subjects will be enrolled under a standard 3+3 design 
(i.e., 3 subject cohorts, see Section 3.2.1.3).
Table 2
Accelerated Dose Escalation Procedures in Part 1
Row 3
Dose Level
Change in Dose
Subsequent dose levels
Increase by 2-fold after a subject clears the previous dose cohort
(No subjects with Grade 2 drug related toxicity AND no subjects with any 
DLTs in first 3 weeks of treatment)
NOTE: Route/Administration/Duration: Oral QD or BID (specific dosing instructions will be provided to each 
subject)
 
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Section 3.2.1.3.
3 + 3 Dose Escalation in Part 1
Rationale for Change: The process of dose escalation with respect to the different 
indications was clarified and the figure was updated to include the BID dosing cohort
Revised Text:
Paragraph 3
Once the MTD is reached and RP2D is determined, up to 12 additional subjects may be 
enrolled at the MTD to evaluate safety, additional PK, and obtain tumor tissue for PD 
biomarkers.  Additional subjects may be enrolled at the MTD, and at least 1 dose level 
below MTD, to confirm if the MTD is appropriate for AML subjects. Should AML 
patients have lower tolerability to GSK525762, then a lower MTD/RP2D could be 
selected for AML subjects.and NHL/MM subjects. Up to an additional 6 subjects may be 
enrolled at any dose level below the MTD in order to obtain additional tumour tissue for 
PD biomarkers to better understand the dose/exposure/PD relationship.  Additional 
cohorts (with daily exposure not exceeding MTD exposure) may also be initiated to 
explore alternative dosing schedules to optimize the PK, safety and tolerability profile.  
The enrolment of additional subjects as described could be in parallel with Part 2 
enrolment.  Although DLT will not be based on the additional subjects enrolled into the 
study to further evaluate safety, PK, to obtain tumor tissue for biomarkers, data from 
these additional subjects will be considered in defining final MTD and RP2D (Figure 4).
Superseded and updated Figure
Figure 4. Dose Escalation Schema (Part 1)
 
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Section 3.2.1.5. BID dosing
Rationale for Change: Updated to reflect addition of BID dosing cohort to protocol 
and information how BID dosing will be implemented.
Revised Text:
Schedules that use a shorter recovery period, e.g., twiceTwice daily (BID) dosing, 
maywill also be explored initially in subjects with AML as described in Section 1.3.2.  
This approach will be considered if the safety, PK, and emerging PD data suggest that a 
sufficient therapeutic exposure cannot be achieved using the initial schedule.  If a shorter 
recovery period is used, the .  The initial dose level for BID will be 50%a maximum of 
the highest completed20 mg (ie 2x 20mg 12 hours apart, total daily dose of 40mg) or a 
dose level (at or below MTD) with the initial schedulelower than 20 mg depending on 
emerging safety, PK and PD data and dosing will be separated by approximately 12 
hours.  Escalation can then proceed as described using the 3 + 3 dose escalation.  
Alternative schedules with intense supportive careSubjects may need to undergo dose 
modification(s) to manage toxicities.  A dose adjustment (e.g., QD at the same dose level
or lower BID dose level) may alsobe made after consultation with GSK medical monitor. 
The investigator should use clinical judgment to determine whether the dosing scheduling 
may be exploredcontributing to any potential toxicity necessitating dose adjustment, and 
make the appropriate change after consultation with the GSK Medical Monitor.
 
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Section 3.2.1.6. Intra-Subject Dose Escalation
Rationale for Change: Requirement for additional PK samples for intra-subject dose 
escalation added.
Revised Text:
Paragraph 2
Subjects approved for intra-subject dose escalation will require additional limited PK 
sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by GSK 
Clinical Pharmacology.  Additional safety assessments may be specified at the time of 
dose escalation or schedule modification based on the safety profile in previous subjects 
at the higher dose level.
Section 3.2.2. Dose Limiting Toxicity (DLT)
Rationale for Change: DLT criteria for myelosuppression were differentiated by 
indication and refined to account for the differences due to the underlying disease.
Revised Text:
An event will be considered a DLT if it occurs within the first 3 weeks of treatment and 
meets one of the following criteria unless it can be clearly established that the event is 
unrelated to treatment.   

Prolonged myelosuppression, as defined by the National Cancer Institute (NCI) 
criteria specific for leukemia, i.e., marrow cellularity <5% on day 42 or later 
(6 weeks) from start of therapy without evidence of leukemia which can occur 
outside of the 3 week DLT window.follows: 

For leukemia:

At 6 weeks, bone marrow biopsy that demonstrates no evidence of residual 
leukemia AND EITHER:
Marrow aplasia, defined as <5% cellularity by trephine biopsy, OR
Peripheral cytopenias, defined as ANC ≤500/uL and/or platelets ≤25,000/uL (if 
baseline ANC and/or platelets were > 500/uL and/or 25,000/uL, respectively)

For myeloma or lymphoma:

Grade 4 neutropenia persisting for ≥7 days or febrile neutropenia in patients 
with myeloma or lymphoma.not responding to treatment within 24h 

Grade 4 thrombocytopenia in patients with myeloma or lymphoma.lasting 
more than 7 day and do not respond to transfusions or Grade 3 associated 
with bleeding (>10mL) 
 
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Section 3.2.4. Part 2 AML Expansion Cohort
Rationale for Change: Section was updated to reflect that analysis of Part 2 data will 
include analysis of Part 1 data; hence fewer subjects are required for Part 2. Decision 
steps for interim and final analysis were updated based on the updated number of subjects 
required for analysis. 
Revised Text:
Up to 4032 subjects with specific relapsed and/or refractory acute myeloid leukemias
(and/or other subsets), determined based on emerging data (preclinical and clinical data 
from Part 1), may be enrolled in an expansion cohort at the RP2D.  This will be 
conducted to gather more safety data and to further assess anti-tumor activity.  Subjects 
in Part 2 will start with a continuous daily dosing schedule unless safety, PK or PD data 
necessitate a different dosing schedule.  The final dose and regimen for Part 2 will be 
decided upon completion of dose escalation in Part 1.
The PhasePart 2 portion of the study will employ a Bayesian design that allows the trial 
to be monitored with the constraint of both Type I and Type II error rates.  Clinical 
response will be defined as CR, CRp, PR, or morphologic leukemia-free state.
The interim analysis will be conducted after efficacy data at a dose level based on RP2D 
are available on a minimum of 10 patients. An initial total of 20 subjects will be recruited 
at a dose level based on RP2D.  The number of subjects will be increased up to a total of
40 32 depending on the results observed.  The decision rules, specifying the number of 
subjects with a clinical response needed for continuing enrolment or, stopping for futility 
are indicated in Table 4.  The methodology is based on the predictive probability of 
success if enrolment continues to 4032 subjects [Lee, 2008].  These rules are intended as 
a guideline.  Actual decisions will depend on the totality of the data.
For the interim analysis at N=17, if observe one or no response in the first evaluable 17 
subjects, the enrollment will be stopped due to futility.  Otherwise, the enrolment will 
continue.  For the final analysis at N=32, if observe at least 7 responses in 32 evaluable 
subjects, sufficient statistical evidence has been provided in favor of declaring response 
rate >30%.
 
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Table 4
Part 2 Decision Making Criteria at Interim Analysis and Final 
Analysis
Number of 
Evaluable Subjects 
Enrolled
This Number Of Objective 
Responses To Stop Early For 
Futility/Not Reject Null 
Hypothesis At The End Of Study
This Number of Objective 
Responses to Continue 
Enrolment/Reject Null Hypothesis 
at the End of Study
2010
10
21
17
1
2
20
1
2
22
2
3
26
3
4
29
4
5
31
5
6
4032
46
57
Section 4.1. Number of Subjects
Rationale for Change: Section was updated to reflect that analysis of Part 2 data will 
include analysis of Part 1 data; hence fewer subjects are required for Part 2.
Revised Text:
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study.  To 
complete Part 1, it is estimated 20 to 30 evaluable subjects will be enrolled.  Part 2 will 
enroll up to 4032 subjects with specific relapsed and/or refractory acute myeloid 
leukemias. See Section 11.1 for sample size assumptions.
Section 4.2. Eligibility Criteria
Section 4.2.1 Inclusion Criteria
The changes that were implemented in Section 4.2.1 of the protocol are documented 
in the change section of the protocol synopsis under ‘Inclusion Criteria’
Changes in Section 4.2.1 that are not documented in the change section of the 
synopsis are documented below.
Revised Text:
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential. Additional details 
regarding the enrollment and registration process for this study can be found in the Study 
Procedures Manual.
 
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Section 4.2. Exclusion Criteria
The changes that were implemented in Section 4.2.2 of the protocol are documented 
in the change section of the protocol synopsis under ‘Exclusion Criteria’
Section 4.2.3.1. Permanent Discontinuation from Study Treatment
Rationale for Change: Implemented based on MHRA feedback on a similar protocol
Revised Text:
Paragraph 2
In addition study treatment maywill be permanently discontinued for any of the following 
reasons:

Substantial deviation(s) from the protocol
Section 4.2.3.2. Subject Completion
Rationale for Change: Clarification of definition of completion for Part 1 and Part 2 
separately.
Revised Text:
A subject will be considered to haveFor Part 1 (dose-escalation phase) subjects who are 
not treated with the RP2D, a completed subject is one who has completed the study 2 
years after the last treatment or if the subject dies or is still in follow-up at the time the 
study is closed or terminated, whichever is sooner.  
For Part 1 AML subjects who are treated at RP2D and for Part 2 (expansion cohorts) 
subjects, a completed subject is one who has discontinued study treatment and was 
followed to death or has died while receiving study treatment.  
Section 5. TIME AND EVENTS TABLES
Table 6. Time and Events: Part 1
Rationale for Change: The table was simplified by moving text into the table 
reference section and providing cross references instead. W6 D1 was added to allow for 
increased frequency of hematological assessments. Sampling for PK and PD were revised 
based on ongoing research.
Revised Text:
A column for W6 D1 Visit has been added 
In the heading row ‘Study Drug’, text added ‘QD or BID details’ and referred to Table 9 
and Table 10
For Pregnancy test/ testosterone row, the following text has been deleted and superscript 
‘a’ was added instead:  Females: serum pregnancy test within 7 days of first dose; urine 
or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone 
thereafter.)
 
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For Vital Signs row, the following text has been deleted and superscript ‘b’ added: (SBP, 
DBP, heart rate, respiratory rate, temp.) b
For Pulmonary function test, the following text has been deleted and superscript ‘c’ 
added: (As appropriate [subjects with severe COPD, history of pneumonitis, alveolar 
hemorrhage, chest radiation]) c
For Adverse events row, following text was revised: AEs & SAEs continuous from first 
dose; SAEs (If study related) from signing of informed consent (see Section 6.7.5.)
In the heading row ‘Laboratory assessments’, text revised: For details please see Table 7
following tables
For Laboratory assessments tests: W5, D1 and W6, D1 visit added
For 12-lead ECGs row, the following text has been deleted and superscript ‘d’ added: 
(Screening ECGs within 14 days of first dose.  Triplicate ECGs prior to dosing.  For 
timing of ECGs on “O” days, see  and . d Otherwise, triplicate ECGs at approximately 
same time of day, and prior to dose on dosing days. If QTcF increase >30msec, ECGs 
performed daily through W2.)
In Telemetry the following text edit were made: ‘Telemetry (Starting predose d1 and for 
at leastmin 48 h, remove on d3)’.
For PK Blood samples for GSK525762 following visit were added: W1-D3 (with 
referring to Superscript “f”).
For PK blood samples for metabolite evaluation (only at MTD or RP2D in 6 subjects) 
following visit were added: W3 D1
Specific parameter mentioned in PD Blood samples for biomarkers assessment as 
“mRNA”.
PD Tumor Sample (with referring to Superscript “f”]) to be drawn: this was applicable 
for entire study duration (part 1) was replaced with applicability to limiting to Screening 
visit [with referring to Superscript “g”] and W1 D3 visit. Following text was deleted: 
Tissue and Timing to be based on tumor type and emerging data.  A PK sample will need 
to be obtained within 1 hour of the tissue sampling.  Details described in the SPM
Translational Research heading was referred to superscript “h”
The following text has been updated in the investigation: Blood samples for Translational 
Medicine studycirculating exploratory biomarkers (cfDNA etc.)
Footnote text was revised as:
a.
Females: serum pregnancy test within 7 days of first dose; urine or serum test 
thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter.
b.
Vital signs include SBP, DBP, heart rate, respiratory rate and temperature
c.
Pulmonary tests as appropriate: subjects with severe COPD, history of 
pneumonitis, alveolar hemorrhage, chest radiation
ad.
12-lead ECGs : Screening ECGs within 14 days of first dose.  Triplicate ECGs 
prior to dosing.  For timing of ECGs on “O” days, see Table 9 for QD and Table 10 for 
 
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BID. Otherwise, triplicate ECGs at approximately same time of day, and prior to dose on 
dosing days. If QTcF increase >30msec, ECGs performed daily through W2.)
be.
For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W.
cf.
During 3+3 dose escalation, PD tumor samplessample collection will be 
mandatory unless infeasible to collect, and approval is obtained by the GSK medical 
monitor.  Subjects with MM or AML will have bone marrow aspirates collected when 
feasible (on W1 D3 approximately 2-4 hours after the dose.  Subjects with NHL will have 
a lymph node biopsy collected on W1D3 approximately 3-5 hours after the dose. Timing 
of tissue collection will be  based on tumor type and may be modified based on emerging 
data.  A PK sample will need to be obtained within 1 hour of the tissue sampling.  Details 
described in the SPM see Table 8 disease specific assessments for details).
dg.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of 
first dose.
eh.
Refer to Section 6.6 for details on Translational Research and Appendix 5 for 
details on PGx Research.
Table 7. Time and Events: Part 1 Laboratory Assessments
Rationale for Change: W6 D1 was added to allow for increased frequency of 
hematological assessments. Sampling for hematology was increased for enhanced patient 
monitoring.
Revised Text:
Sub headings “Assessment and Notes” added.
For Hematology parameter following note added: Increase frequency as medically 
indicated and following Visits are added: W2 D1, W2 D6, W5 D1, W6 D1.
BNP-9 was replaced by NT pro-BNP and was amended as N-ternimal prohormone, 
throughout the table.
Following abbreviations was expanded in footnote: NT-pro BNP=N-ternimal 
prohormone B-type Natriuretic Peptide;
Table 8. Time and Events: Disease Specific Assessments: Part 1 (Multiple 
Myeloma [MM] Assessments)
Rationale for Change: Sampling time points for disease assessments and time point 
for efficacy assessments were specified in alignment with standard of care and after 
discussion with internal and external experts.
 
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Revised Text:
For BM aspirate for disease assessment and Bone marrow biopsy for disease assessment  
the following information was deleted: 1 or 2 sample collections between W1D2 and 
W4D1, timing to be optimized based on emerging data.  PK sample to be obtained within 
1 hr of aspirate).
For Efficacy assessment: The following information “Efficacy assessments for MM are 
described in Appendix 6 : Response Criteria for Multiple Myeloma” was replaced with 
“Every 6 weeks after wk4; Response criteria in Appendix 6”. Additionally, the following 
Visit assessments are added: W4 D1 and q6W D1.
Footnote was deleted: a. An extra specimen will be collected for PD assessments from 
consenting subjects when feasible.
Table 8. Time and Events: Disease Specific Assessments: Part 1 
(Lymphoma Assessments)
Rationale for Change: Sampling time points for disease assessments, requirement for 
flow cytometry, time points for CT scans and time point for efficacy assessments were 
revised in alignment with standard of care and after discussion with internal and external 
experts.
Revised Text:
Flow cytometry assessments removed.
For Bone marrow/tissue biopsy for disease assessment the following information was 
deleted:  : 1 or 2 biopsies between W1D2 and W4D1, timing to be optimized based on 
emerging data. PK sample to be obtained within 1 hr of biopsy. e); instead assessment 
was added between W4 and q3W.
For CT Scan assessments: information added to Q6W D1 – Q12W D1: Wk 16, wk 24 , 
then q12wks
For Efficacy assessment: The following information “Efficacy assessments for 
lymphoma are described in Appendix 7: Response Criteria for Lymphoma” was removed 
and Footnote point “f” is referred. Following Visit was added: W7 D1, information added 
to Q6W D1 – Q12W D1: Wk 16, wk 24 , then q12wks.
Footnote referred for PET Scan assessments: “d” and “e”
Following text in footnote is revised: 
a. Including date of first diagnosis of MDS, sAML/MDS or de novo AML disease stage, and complete 
history of diagnostic results and therapies.
b. Prognostic markers include:  ALC, FLIPI-1, FLIPI-2 (includes ß2-microglobulin), FcR gamma 3A.
c. Immunohistochemistry or flow cytometry for immunophenotyping.
c. A sample will be required only if clinically appropriate for the lymphoma subtype at screening unless an 
appropriate previous sample is available. A follow-up bone marrow biopsy will be performed no later than 
8 weeks following CR (as judged by investigator) in accordance with the response guidelines (Appendix 7)
if a subjects had involvement of the BM sample were positive at the start of the study.
e. An extra specimen will be collected for PD assessments from consenting subjects when feasible.
d. Baseline/Screening CT and PET scans may be obtained within 35 days of first dose, similar to the 
requirement for obtaining ECHO. Follow-up CT scans at week 7 wk 16, wk 24 and then every 12 weeks.
 
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e. PET or PET/CT scan only if clinically indicated (e.g., confirmation of CR for Diffuse large B-cell 
lymphoma).
f. Efficacy assessments for lymphoma at week 7 , wk 16, wk 24 and then every 12 weeks.. Assessments are 
described in Appendix 7 : Response Criteria for Lymphoma
Table 8. Time and Events: Disease Specific Assessments: Part 1 
(Leukaemia Assessments)
Rationale for Change: Sampling time points for disease assessments and time point 
for efficacy assessments were specified in alignment with standard of care and after 
discussion with internal and external experts.
Revised Text:
For BM biopsy and or aspirate the following information was deleted:: 1 or 2 sample 
collections between W1D2 and W4D1, timing to be optimized based on emerging data. 
PK sample to be obtained within 1 hr of bone marrow sample collection.
For Efficacy assessment: The following information “Efficacy assessments for leukemia 
are described in Appendix 8 Response Criteria for Leukaemias” was deleted. Week 4 
Day 1 and q3W Day 1 visits are added.
Following text in footnote is revised: 
b. This bone marrow sample is required for disease assessment, but a peripheral blood 
sample can be taken if the bone marrow sample could not be collected.  See the study 
procedures manual (SPM) for sample handling. An extra specimen will be collected for 
PD assessments from consenting subjects when feasible.
g. Efficacy assessments for leukemia at wk 4 and every 3 weeks thereafter. Assesments 
are described in Appendix 8: Response Criteria for Leukaemias.
Table 9: Time and Events: Part 1 (QD cohorts) Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling
Rationale for Change: Two tables were combined and timing of dose was added as 0h 
for simplification and to ensure better compliance. Sampling time points for PK, mRNA
and cytokines were revised based on ongoing research. 
Revised Text:
Table title deleted: Table 9. Time and Events: Part 1 Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling, Week 1. And Table 10. Time and Events: 
Part 1 Serial Electrocardiograms and Pharmacokinetics, Week 2 and Week 7.
Table renamed: Time and Events: Part 1 (QD cohorts) Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling.
 
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Procedure / time after 
dose
W1D1 – W1D2
W1D2
W1D5
pr
e 
do
se
0
h
15 
min 
± 
5m
30 
min
±5
m
1h 
±1
0m
2h 
±1
5m
4h 
±1
5m
8h 
±1
h
12h 
±12
h
24
h 
±1
h
0h
0
h
30 
min 
±10
m
3h 
±30
m
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
GSK525762ab
X
X
X
X
X
X
X
X
X 
ab
X
X
PK sample for metabolite
b,c
X
X
X
X
X
X
X
X
X 
ab
Blood sample for 
biomarkers (PDmRNA)
Xb
Xd
X
X
X
X
X
Plasma cytokine sample
Xb
Xd
X
X
X
X
X
Urine PK sampling c
X 
0-2 h
2-24 12 24h
Procedure / time 
after dose
W2
D4
W2
D6
W2D7 + 2 days
W3D
1
W7D1 ±4 days e
(if dose was 
escalated, +4 to 
+7 days)
pr
e
do
se
pr
e
do
se
pr
e 
do
se
0
h
15 
min 
± 
5m
30 
min 
±5
m
1h 
±1
0m
2h 
±1
5m
4h 
±1
5m
8
h 
±
1
h
1
2
h 
±
1
h
2
4
h 
±
1
h
0
h
pre 
do
se
0
h
0.
5-
2
h
4 
-
8
h
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
GSK525762
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
metabolite c 
X
X
X
X
X
X
X
X
X
Blood sample 
biomarkers (mRNA)
X
X
Plasma cytokines 
samples
X
X
X
X
X
X
Urine PK sampling c
0-2h
2-24h1224h
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
In triplicate, 5 minutes apart and within 10 min prior to PK draw; For time points with a ±5 minute it is 
acceptable for the first ECG to be out of the minus 5-min window to allow scheduling in this short time 
frame, as long as PK sample is collected after the last ECG and at least within +5 minutes of the window.
b.
Sample to be obtained before dosing on Week 1, Day 2.
c.
only at MTD or RP2D in 6 subjects
d.
May be collected within 14 days prior to first dose.
e.
if dose was escalated, +4 to +7 days
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
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Table 10 added: Time and Events: Part 1 (BID Cohorts) Serial 
Electrocardiograms, Pharmacokinetics and Biomarker Sampling
Rationale for Change: Addition of BID dosing cohort to study.
W1D1
W1D2
W1
D3
W1
D4
W1D5
Timepoint; 
Hours after AM 
dose (hours after 
PM dose)
Pre-Dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
12h±1h
12h (0h)
15 min ± 5m
30 min ±5m
13h (1h) ±10m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h
AM & PM
AM & PM
AM & PM
AM
30 min ±5m
3h ±15m
PM
Dose
X
X
X
X
XX
XX
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK GSK525762
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biomarker sample 
(mRNA) c
X
d
X
X
X
X
X
X
X
X
Cytokine/APP
X
d
X
X
X
X
X
X
X
X
Urine PK b
X
0-2
2-24
W2D
4
W2D
6
W2D7
W3D1
W7D1±4 days e
Time point; 
Hours after AM 
dose (hours 
after PM dose)
pre AM dose
AM & PM
pre AM dose
AM & PM
Pre dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
12h±1h
12h (0h)
15 min ± 5m
30 min ±5m
13h (1h) ±5m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h
AM & PM
pre dose
0h
0.5-2h
4 - 8h
12h
Dose
X
X
X
X
X
X
XX
X
X
12-lead ECG a
X
X
X
X X X X X X X
♦♦♦♦♦
♦
X
X
X
X
PK GSK525762
X
X
X
X X X X X X X
♦♦♦♦♦
♦
X
X
X
X
Biomarker 
sample (mRNA) c
X
X
♦
X
Cytokine/APP
X
X X X
X
Urine PK b
0-2
2-12 ( ♦ 2-24)
a.
in triplicate, 5 minutes apart and within 10 minutes prior to PK draw; For timpoint with a ±5 minute it is 
acceptable for the first ECG to be out of the minus 5-min window to allow scheduling in this short 
time frame, as long as PK sample is collected after the last ECG and at least within +5 minutes of the 
window.
b.
only at MTD or RP2D in 6 subjects,
c.
Blood sample for PD biomarker
d.
May be collected within 14 days prior to first dose
e.
if dose was escalated, +4 to +7 days
APP=acute phase protein; ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose; 
♦=optional assessment, for subjects staying overnight only
 
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Table 11. Time and Events: Part 2
Rationale for Change: Clarification of study drug dispensing and AE reporting in line 
with existing text in protocol body. W1D3 was added to allow for more frequent 
hematology testing. Telemetry was added in alignment with Part 1. Additional time point 
for PK/PD was added based on ongoing research and in alignment with Part 1.
Revised Text:
Column for W1D3 was added
For dispensing study drug row, the following information was updated between Cycle 1, 
W1 D1 to Cycle 4 W10 D1 continuous daily dosing (unless safety, PK or PD data 
necessitate a different dosing schedule), see Section 3.2.4
For Adverse events row, the following text was revised: AEs & SAEs continuous from 
first dose; SAEs (If study related) continuous from signing of informed consent (see 
Section 6.7.5.)
Assessment added: Telemetry (Starting predose d1, for min 48 h, remove on d3) see 
Section 6.3.7.
For PD Tumor sample (biopsy), the following information was deleted: 1 biopsy between 
W1D2 and W4D1, timing to be optimized based on emerging data.  PK sample to be 
obtained within 1 hr of tumor sample collection); instead visit added on W1D3. For 
screening visit footnote “d” added, for W1D3 footnote “e” added.
For PK Blood samples W1D3 visit was added. 
Assessment updated in Translational Research: Blood samples for circulating biomarkers 
(cfDNA etc.) Translational Medicine study.
Footnote point “b” was added: Vital signs include SBP, DBP, heart rate, respiratory rate 
and temperature
Table 12. Time and Events: Part 2 Laboratory Assessments
Rationale for Change: To allow more frequent hematology assessments for patient 
monitoring.
Revised Text:
Point “a” of footnote added and are referred for Hematology parameters from Cycle 1, 
W1D1 – Cycle 3, W7D1: Assess platelet count as clinically appropriate but at minimum 
twice weekly for weeks 1 and 2; weekly for weeks 3 to 8.
 
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Table 13. Disease Specific Assessments: Part 2
Rationale for Change: Sampling time points for BM sample and time point for 
efficacy assessments were specified in alignment with standard of care and after 
discussion with internal and external experts.
Revised Text:
For BM biopsy and or aspirate the following information was deleted: for disease 
characteristics and/or PD assessment. 1 or 2 sample collections between W1D2 and 
W4D1, timing to be optimized based on emerging data.  PK sample to be obtained within 
1 hr of bone marrow sample collection.
For Efficacy assessment: The following information was deleted “Efficacy assessments 
for leukemia are described in Appendix 8 : Response Criteria for Leukaemias.”. Instead 
visits W4D1, W7D1, W10 D1, q3WD1 were added
Following text added in footnote: 
b.
This bone marrow sample is required, but a peripheral blood sample can be taken 
if the bone marrow sample could not be collected.  W1D3 sample will be collected 
approximately 2-4 hours after dose. PK sample to be obtained within 1 hour of aspirate
See SPM for sample handling.
g.
Efficacy assessments for leukemia are described in Appendix 8: Response Criteria 
for Leukaemias.
Section 6.2. Baseline Assessment
Rationale for Change: Key baseline assessments were omitted from the body text in 
prior versions and were added for completeness.
Revised Text:
Subjects diagnosed with refractory hematological malignancy for MM, lymphoma and/or 
leukemias, will be treated and assessed at baseline for appropriate general disease 
characteristics as noted in Section 6.2.1 and tumor type specific measures as noted in 
Appendix 6 Section 6.2.2, Appendix 7 Section 6.2.3 and Appendix 8 Section 6.2.4, 
respectively.
Baseline is defined as the assessment closest to first dose, ie W1D1assessment or 
screening if SCR sample collected within 72h of first dose.
6.2.1
Baseline assessment for all Subjects

Primary tumor  type (immunophenotyping and histology if applicable)

History of other tumor types/medical history

Date of initial diagnosis of primary tumor type

Date of relapse/progression

Details of any metastatic disease
 
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6.2.2
Baseline assessment for Subjects with leukemia
AML:

WHO classification

FAB classification

Source of AML

Cytogenetics
CLL

Modified Rai staging at initial diagnosis and screening

Binet stage at initial diagnosis and screening

Indication  of active disease: evidence of bone marrow failure, splenomegaly, 
lymphadenopathy, lymphocytosis, B-symptoms

Cytogenetics
6.2.3
Baseline assessment for Subjects with lymphoma

Ann Arbor staging at initial diagnosis and screening

Number of sites with extranodal involvement at initial diagnosis 

Follicular Lymphoma International Prognostic Index (FLIPI) 1 and 2

FCgR3a genotype and other cytogenetics/molecular analysis applicable such as 
antigen gene receptor rearrangements, BCL2 rearrangements and translocations.
6.2.4
Baseline assessment for Subjects with myeloma

International staging system (ISS) stage at initial diagnosis and screening

Type (active or smoldering)

Presence of plasmacytoma

Cytogenetics

Presence of extramedullary disease

Laboratory assessment: Total protein, paraprotein, CRP and β2-microglobulin; 
for secretory MM: SPEP, UPEP, IgG, IgA, IgM, FLC assay
Section 6.3.5. Electrocardiograms
Rationale for Change: Text was moved for better visibility. Clarification of definition 
of baseline was added.
 
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Revised Text:
If QTcF > 480 msec, or uncorrected QT > 600 msec (Grade 3 or 4), or any change from baseline*
of ≥60 msec even if not exceeding 480 msec, (all measurements based on an averaged manual 
overread of three ECGs over at least 15 minutes) discontinue study medications and notify the 
GSK Medical Monitor. Subject may restart if QTcF <480 after discussion with medical monitor
Baseline QTcF value
Discontinuation QTcF
<450 msec
>480 msec or ≥60 msec over baseline a
May restart if QTcF <480 after discussion with medical monitor, see* Baseline results are defined by the nearest time 
point prior to first dose. For this trial the Baseline QTcF value is determined by the mean of the triplicate W1D1 
predose QTcF results. If these results are not available, then the mean QTcF of the screening triplicate ECG results 
would be used.
Section 6.3.7. Telemetry
Rationale for Change: Flexible language to allow removal of telemetry requirement 
after all data is collected up to MTD and analyzed for QT safety. 
Revised Text:
Paragraph 2 and 3 added
At the end of Part 1, an analysis of data collected on the QT interval up to, and including, 
the MTD expansion will be carried out. If the analysis by the GSK Cardiac Safety Panel 
of internal and external experts indicates that telemetry is no longer required for 
monitoring the QT interval, then the study can progress to the next stage without 
telemetry. 
Removal of the telemetry requirement will be conveyed to the sites in the first instance 
through a separate document (or “note to file”) that will note - i) a summary of the 
analysis, and ii) the decision to proceed without telemetry monitoring in the next stage of 
this study. This will allow the sites to submit the necessary documentation to the 
IECs/IRBs for approval and to start the next stage of this study without telemetry. 
However, this process will be permitted only if there are no other cardiac monitoring 
changes to be implemented. If additional cardiac monitoring changes are required, a 
protocol amendment will be necessary before the next stage of the study can start.
Section 6.4.1. Disease Assessment
Rationale for Change: Overall survival was added as secondary endpoint, therefore 
longer follow up is required.
Revised Text:
Paragraph 2
Subjects enrolled in Part 1 at RP2D and Part 2 are to be followed until death for 
assessment of overall survival (OS).
 
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Section 6.5.3. Urine Collection
Rationale for Change: Flexibility added for shorter interval depending on if subject is 
hospitalized for treatment or not. Sample time point added based on ongoing research.
Revised Text:
Urine samples for quantitative analysis of GSK525762 will be collected over a dosing 
interval (12 or 24 hours) in two samples (first sample collected 0-2hr and second sample 
collected 2-24hr) immediately following dosing on Week 1 Day 1 and Week 2 Day 7.  
Urine samples will be collected from at least 6 subjects in Part 1 at the MTD.  Additional 
sampling may be instituted based on emerging data.
Section 6.7.6. Method of Detecting AEs and SAEs
Rationale for Change: Language not required for study in adults
Revised Text:
Care must be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?” or for pediatric studies, “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or for 
pediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for pediatric studies, ”Has your child needed to take any 
medicines, other than those provided in this study, since his/her last visit/contact?”
Section 7.3. Meals and Dietary Restrictions
Rationale for Change: Language added for consistency and in alignment with existing 
language in T&E
Revised Text:
Subjects will fast for at least one hour prior to each dose of study drug. No food or 
antacid should be taken for 2 hours after dosing. Subjects should not eat a heavy meal in 
the morning prior to the 1 hour washout before dosing to minimize potential risk for food 
interaction.  On serial PK sampling days, subjects should fast overnight (i.e., at least 8 
hours). After dosing, subjects will be asked to fast for an additional two hours.  These 
fasting requirements have been implemented in the protocol and informed consents to 
minimize PK variability.
 
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Section 7.7.1. Dose and Safety Management Guidelines
Rationale for Change: Additional guidance for investigators on dose adjustment for 
thrombocytopenia. Clarification of definition of baseline.
Revised Text:
Table 18
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 
Grade 3 (<50,000, 
≥25,000)
Grade 4 (<25,000)
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary
After discussion with medical monitor and using 
sound clinical judgement, continue at same dose or 
adjust dose (e.g. consider reduced daily dosing or 
dosing on alternate days). Monitor CBC at least twice 
a week, more frequently if necessary 
Temporarily interrupt study medication and monitor 
CBC every 2-3 days. If platelet counts recover to 
Grade 2 discuss with medical monitor resuming 
treatment at the same or adjusted dose based on 
sound medical judgement. Platelet transfusion is 
allowed based on institutional guidelines. In case of 
platelet transfusion, hold drug for at least 7 days from 
day of transfusion, and if platelet counts recover to 
Grade 2 consider initiating treatment at a lower dose 
using sound clinical judgement and after consulting 
with the GSK medical monitor. Discontinue treatment if 
drug has to be held for >14 days or greater than 2 
dose reductions required.
Table footnote:
Note added in the Table footnote for QTcF parameters“
*Baseline results are defined by the nearest time point prior to first dose. If W1D1 results are available, these are 
considered the baseline results. If screening occurred within 72h of fit dose, W1D1 samples are not needed and 
screening data are considered as baseline.
Section 7.7.2. Dose Adjustments for Toxicity
Rationale for Change: Correction
Revised Text:
Heading of the table replaced “GSK525762” by “Action”
 
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Section 8. 8. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES
Rationale for Change: Correction in alignment with T&E
Revised Text:
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment signing informed consent until 
the end of the study (Final Study Visit).  
Section 8.2.1. Cautionary Medications
Rationale for Change: Original data source not valid anymore and therefore updated.
Footnote Text for Table 20 revised:
Data Source: [www.QTdrugs.org, 2008]CredibleMeds, 2014.
Section 8.2.2. Drugs Potentially Affecting GSK525762 Pharmacokinetics
Rationale for Change: Text was removed as no data is currently available to support 
claim
Revised Text:
The precise in vivo metabolic liability for GSK525762 has yet to be assessed.  In vitro
data suggests that GSK525762 has a negligible turnover and low potential to inhibit the 
major human CYP isoforms (IC50’s ≥ 33 µM) with no evidence for time dependent 
inhibition of CYP2D6 or CYP3A4.
Section 8.3. Prohibited Medications
Rationale for Change: Original data source not valid anymore and therefore updated
Footnote Text for Table 22 revised:
1. Data Source: [www.QTdrugs.org, 2008][CredibleMeds, 2014]
The above table is not exhaustive and prohibited drugs are defined by the online version 
at the time of screening of the subject.
Section 11.1.1. Part I, Dose Escalation
Rationale for Change: Higher number due to the addition of BIC cohort
Revised Text:
The sample size in Part 1 is not driven by statistical considerations.  The total number of 
subjects will depend on the number of dose escalations needed.  However, the maximum 
anticipated number of subjects will be approximately 3060.
Section 11.1.2. Part 2, Expansion Cohort
Rationale for Change: The response rates for the hypothesis were raised to reflect 
standard of care after discussion with internal and external experts in this indication. 
Calculation were updated also taking into account the revised sample size with AML 
subjects from Part 1 being included in the analysis of part 2.
 
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Revised Text:
The primary goal of Part 2 is to detect a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR, CRp, PR or a morphologic leukemia-
free state ) of 2030% in AML relative to a 510% response rate suggesting no activity.
Symbolically, the null hypothesis is:
H0: RR≤510%
The alternative hypothesis is:
HA:RR≥2030%
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate ≥20% and 530% at interim and final analysis using a weak/non-
informative prior.
To determine a maximal sample size for Part 2, a traditional, 2-stage Green-Dahlberg 
design [, 1992] was evaluated.  To test the hypotheses (RR=20% versus RR=5%) by 
Green-Dahlberg design, 40 subjects would be needed to minimize the Type I (< 5%) and 
Type II error rate (i.e., Power > 85%).
Using this sample size, a Bayesian design was evaluated. A Bayesian analysis expresses 
uncertainty about a parameter in terms of probability.  A prior is defined to characterize 
the level of knowledge about a parameter before the data are collected.  Once the data are 
collected, a posterior distribution is formed using the prior and the likelihood (i.e., the 
data).  A very weak prior Beta (0.0203, 0.0807) with a mean response rate of 2030% is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior and the likelihood of the observed data x, the posterior distribution of 
the response rate follows a beta distribution, i.e.,
p Beta (0.0203 + x, 0.0807 + n-x) with the posterior mean (0.0203+ x)/(0. 1 + n).
Starting with a cohort of 2010 subjects and allowing for a maximum sample size of 32 
subjects at the RP2D with stopping guidelines as described in Section 4.2.3.240, this 
Bayesian design will have a tType I error rateError () of 5%0.04 and 8987% power.  For 
the interim analysis at N=20, if the predictive probability that the response rate ≥20% 
(H1) is small (i.e., less than 2% chance) or equivalent to observe one or no response in 
the first evaluable 20 subjects, the enrollment will be stopped due to futility. Futility 
analysis will be based on subjects who have at least one post-baseline disease assessment.  
Otherwise, the enrolment will continue to the target The trial will be stopped early for 
futility if the predictive probability of success (that the response rate ≥30%) is less than 
1%. If the true response rate is 10%, the average sample size of 40.  For the final analysis, 
if the posterior probability that the response rate of >5% (H0) is large (i.e., greater than 
 
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95% chance), or equivalent to observe at least 5 responses in 40 subjects, sufficient 
statistical evidence has been provided in favor of declaring response rate >20%.
The design property, by utilizing the decision rule specified in Section , is 20 and sample 
size of 40 subjects are shown ().  The probability of early termination of the trial is 
calculated by applying method of Lee et al [, 2008].  The the probability of early 
termination (PET) for futility is 74% under93%. If the null hypothesizedtrue response 
rate, is 30%, the average sample size is 31 subjects and the risk to incorrectly stop the 
trial early if the drug is effective is approximately 1%.PET is 9%. 
Table 23
Bayesian Design Performance
If True Response Rate to
GSK525762 is: (%)
Probability of Early Termination
Probability of Rejecting the Null 
Hypothesis
5%
0.74
0.041 (Type I error)
20%
0.069
0.89 (Power)
Section 11.1.3. Sensitivity Analysis
Rationale for Change: No sample size sensitivity analysis was performed 
Revised Text:
The Bayesian design property, with a varying underlying true response rate between 5% 
and 20% and a maximum sample size of 40.  When the true response rate is close to 20% 
(P1), the probability of stopping the trial for futility is low.  As the true response rate 
decreases, the probability of stopping the trial for futility increases.
Table 24
Bayesian Design Performance by Response Rates
If True Response Rate to
GSK525762 is: (%)
Probability of Early Termination
Probability of Rejecting the Null 
Hypothesis
10%
0.39
0.33
15%
0.18
0.68
No analysis of sample size sensitivity was performed.
Section 11.4. Interim Analysis
Rationale for Change: Language amended in alignment with amended decision 
making criteria (Section 3.2)
Revised Text:
Paragraph 2, 3 and 4
One interim analysis For Part 2, after the initial 10 subjects have enrolled at the selected 
dose regimen for the Expansion Cohort, data will be performed for Part 2 of the study.  
The primary analysis of this includes boundariesreviewed for early decisionclinical 
benefit on futility.  This procedure controls the Type Ian ongoing basis and II error rates 
at the nominal level.  One formal interim analysisthe number of subjects with observed 
clinical benefit will be conducted for the study.
 
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Atcompared with the interim analysis, the predictive probability given by Bayesian 
statistics will be used for decision making.  Based on the available data at each interim 
and a non-informative Beta (0.02, 0.08) prior, the posterior distribution of the response 
rate follows a beta distribution, i.e., p ~ Beta(0.02+x, 0.08+n-x) where p denotes the 
response rate for GSK525762, x represents the numbers of responses observed stopping 
guidelines provided in the current n patients.
For the interim analysis, if the predictive probability that the trial is declared successful 
(prob( response rate ≥20% )) is small (decision rule, less than Section 3.2.4%), the trial 
will be terminated due to futility.  It is calculated that at least 2 responses in 20 patients 
are needed to further progress the study.5.
Section 11.5. Final Analysis
Rationale for Change: In alignment with OS added as secondary endpoint
Revised Text:
Paragraph 2
Final OS analysis will occur when at least 70% of subjects are dead, have withdrawn 
consent, or are lost to follow-up, or all subjects still in follow-up have had at least 5 years 
follow-up, whichever is earlier.
Section 11.6.1. Primary Analysis
Rationale for Change: The response rates for the hypothesis testing were raised to 
reflect standard of care after discussion with internal and external experts in this 
indication. M3 AML will be assessed separately as this subtype of AML has a different 
course of disease.
Revised Text:
Paragraph 2 and 3
The primary aim of Part 2 is to detect a clinically meaningful response rate of 2030% 
relative to a 510% response rate suggesting no activity.
Response rate is defined as the percentage of subjects who achieved CR, CRp, PR and a 
morphologic leukemia-free state among subjects who received at least one dose of 
treatment in the target population.  Response rate and the associated 2-sided 95% exact 
confidence limits will be provided.  A waterfall plot of percent change from baseline in 
bone marrow blasts and peripheral blasts will be provided. Response rates of subjects 
with AML M3 will be summarised separately.
Section 11.6.2. Secondary Analysis (new section added)
Rationale for Change: Overall survival as added as a clinically meaningful secondary 
endpoint. M3 subtype, if enrolled, will be excluded because the course of the disease 
differs and could confound interpretation.
 
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Revised Text:
OS along with 95% confidence intervals for MM, lymphoma and/or leukemias subjects 
treated at RP2D, will be estimated using the Kaplan Meier method. OS analysis for 
AML will exclude subjects with AML subtype M3.  All cause mortality will be used and 
censoring will be performed using the date of last known contact for those who are alive 
or lost to follow-up at the time of analysis.
Section 11.8. Pharmacokinetic Analysis
Rationale for Change: Addition to account for the implementation of a BID as well as 
QD dosing regimen.
Revised Text:
Paragraph 3 and 4
Plasma concentration-time data will be listed by dose, dosing regimen, and summarized 
using descriptive statistics (n, mean, standard deviation [SD], median, minimum and 
maximum) by planned relative assessment time.  Mean and/ or median values will be 
plotted over time.  Individual plasma and urinary (if available) PK parameters values as 
well as a descriptive summary (mean, standard deviation, median, minimum, maximum, 
geometric mean, and the standard deviation, CV% and 95% confidence interval of log-
transformed parameters [if applicable]) by day, dose and dose regimen cohort will be 
reported.
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) will be plotted as a 
function of the dose administered. and dosing regimen.  If more than 2 dose cohorts are 
evaluated, dose proportionality of AUC and Cmax for GSK525762 will be assessed using 
the power model (details will be provided in the RAP).
Section 14. REFERENCES
Rationale for Change: Original data source for QT drugs was not valid anymore and 
therefore reference was updated. Investigator brochure reference was updated with the 
most recent version. Cross references were updated accordingly.
Revised Text:
CredibleMeds. List of drugs with a risk of Torsades de Pointes. Available at: http://www.
crediblemeds.org   Accessed 18-Aug-2014 
www.QTdrugs.org. At: http://www.azcert.org (revised 25-Mar-2008).
GlaxoSmithKline Document Number 2011N113741_03 Study ID Version 3. GSK
525762 Investigator's Brochure. Report Date 27-Mar-2014.
GlaxoSmithKline Document Number 2011N113741_02 Study ID Version 2. GSK
525762 Investigator's Brochure. Report Date 16-Apr-2013.
 
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Section 15.4Appendix 4: Dose Adjustment/Stopping Criteria/Supportive 
Care
Rationale for Change: Correction
Revised Text:
Diarrhea, For Grade 3 to 4 diarrhea or complicated Grade 1 to 2 diarrhea
Point 2: Discontinue GSK1120212GSK525762 treatment and hold until symptoms 
resolve to ≤Grade 1 or baseline.  Consider re-starting therapy at a reduced dose.
Section 15.7 Appendix 7: Response Criteria for Lymphoma
Rationale for Change: Updated to be in alignment with lymphoma guidelines
Revised Text:
Point 4: If the bone marrow was involved by lymphoma prior to treatment, the biopsy 
must be cleared. The biopsy sample on which this determination is made must be 
adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate by 
morphology, it should be negative by immunohistochemistry. A sample that is negative 
by immunohistochemistry but that demonstrates a small population of clonal 
lymphocytes by flow cytometry will be considered a CR until data become available 
demonstrating a clear difference in subject outcome.
Section 15.8.1
Acute Leukemias, MDS, Chronic Myelogenous Leukemia in 
Blast Phase (CML-BP), Chronic MyeloMonocytic Leukaemia 
(CMML)
Rationale for Change: Clarifications and alignment with respective leukemia 
guidelines
Revised Text:
Partial remission: Count recovery as per CR, with 6 to 25% abnormal cells in the 
marrow or 50% decrease in bone marrow blasts. (AML only: If all other criteria for CR 
are met, then a value of <5% blasts with Auer rods present or abnormal morphology is 
considered partial remission).
CRp: AsMarrow response as per CR but platelet count <100 x 10
9/L.
Section 15.8.2.
CLL
Rationale for Change: Alignment with respective CLL guidelines
Revised Text:
Complete Response:
Peripheral blood: Absolute lymphocyte count (ALC) <4 x 10
9/L with Hb >11 g/dL, 
ANC 1.5 x 10
9/L and platelet count >100 x 10
9/L (without need for growths factors 
or transfusions).
 
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Tumor: disappearance of all palpable lymph nodes, spleen, and liver without the 
appearance of new lesions. Absence of constitutional symptoms.
Bone Marrow: <30% lymphocytes in normocellular marrow; if lymphoid nodules are 
seen, response is deemed as nodular CR.(nPR). If all CR criteria are fulfilled but 
subject has drug-related cytopenia, consider CR with incomplete bone marrow 
recovery (CRi).
Progressive Disease or Relapse of Disease
Peripheral blood: A 50% increase in ALC over baseline in first course, or lowest 
prior thereafter, with a sustained level >105 x 10
9/L.
Tumor: An increase in the product of two perpendicular diameters of a measured 
lesion by 50% over the size present at entry on study or for subjects who respond, 
the size at the time of maximum regression and/or the appearance of new areas of 
malignant disease.  Transformation to a more aggressive histology (e.g., Richter’s 
syndrome).   Deterioration in performance status or increasing symptoms do not 
constitute progression; however, their appearance should initiate a new evaluation 
for extent of disease.
Section 15.10 Appendix 13: Updated PK data from protocols 
BET115521and BET116183 (new section added)
Rationale for Change: New data available
Added Text:
As of 11-August-2014, the pharmacokinetics of GSK525762 has been evaluated in 19 
subjects in study BET115521 following single and repeated once daily administration of
2 mg to 60 mg of GSK525762 and in 2 subjects in study BET116183 following single 
and repeated once daily administration of 5 and 10 mg of GSK525762. The summary 
statistics of the preliminary PK parameters are summarized in Table 24 and Table 25 
after single and repeat once daily oral administration, respectively. GSK525762 
pharmacokinetics are characterized by a rapid absorption with maximum concentration 
occurring mostly within the first hour after dosing. GSK525762 is eliminated rapidly 
with an average terminal phase half-life of 3 to 7 hours, leading to a lack of accumulation 
following once daily oral administration. Following single and repeated once daily 
administration of 2 mg to 60 mg of GSK525762, Cmax and AUC tended to increase in a 
dose proportional fashion.  
 
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Table 24. Summary Statistics of GSK525762 Preliminary PK Parameters 
Following a Single Oral Administration of GSK525762 in Study 
BET115521 and BET116183
2 mg
4 mg
5 
mg
8 
mg
10 
mg
16 mg
30 mg
60 mg
Parameter
s
N=3
N=4
N=1
N=1
N=1
N=3
N=4
N=4
Cmax, 
ng/mL
51.0 
(41%)
70.4 
(29%)
90.
6
120
117
176 
(37%)
604 (30%)
940 (31%)
Tmax, h
0.5 (0.5 -
0.6)
1.2 (0.5 -
2.0)
0.6
2
1.1
2.0
2.0
2.0 (0.97 -
2.0)
1.0 (0.5 -
2.0)
AUC, 
ng.h/mL
172 (42%)
361 (35%)
467
434
1092
884 
(40%)
4420 (63%)
3670 
(54%)
t1/2z, h
3.3 
(103%)
5.1 (36%)
4.0
1
2.9
5
5.74
6.9 
(46%)
6.4 (37%)
6.1 (49%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) 
are presented. If N=1, individual data are presented. Cmax is the maximum concentration observed at time tmax. AUC 
is the area under the concentration-time curve from 0 to infinity. T1/2 is the terminal phase half-life. All data are from 
BET115521 study except for the 5 mg and 10 mg doses that were evaluated in BET116183 study.  
 
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Table 25. Summary Statistics of GSK525762 Preliminary PK Parameters 
Following Repeat Daily Oral Administration of GSK525762 in 
Study BET115521 and BET116183
2 
mg
4 mg
5 
m
g
8 
mg
10 
mg
16 mg
30 mg
60 mg
Parameters
N=
1
N=2
N=
1
N=
1
N=
1
N=3
N=4
N=3
Cmax, ng/mL
52
47.6 ; 
59.9
10
3
103
133
138 
(25%)
603 (17%)
807 (36%)
Tmax, h
1.0
1.0 ; 4.0
0.5
0.5
0.5
1.5
0.9 (0.32 -
4.0)
1.0 (0.50 -
1.0)
AUC, ng.h/mL
160
225 ; 497
51
1
330
911
674 
(21%)
3150 
(55%)
2910 
(56%)
t1/2z, h
4.2
7
3.69 ; 
4.46
3.5
4
4.9
2
5.2
6
3.6 
(7.8%)
5.2 (26%)
3.13 
(40%)
Cmax Week 3 / Cmax 
Week 1
1.4
2
0.968 ; 
0.609
1.1
4
0.8
57
1.1
4
0.780 
(12%)
0.998 
(24%)
1.12 
(10%)
AUCWeek 3 / AUC 
Week 1
1.3
8
0.900 ; 
1.64
1.1
0
0.7
59
0.8
34
0.774 
(20%)
0.724 
(12%)
0.779 
(13%)
AUCweek 3 / AUCt 
Week 1
1.3
9
0.904 ; 
1.67
1.1
1
0.7
63
0.8
90
0.792 
(20%)
0.799 
(11%)
0.807 
(10%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median 
(min-max) are presented. If N=1 or 2, individual data are presented. Cmax is the maximum concentration 
observed at time tmax. AUCis the area under the concentration-time curve from 0 to 24 hours, the end of 
the dosing interval. T1/2 is the terminal phase half-life. All data are from BET115521 study except for the 5 
and 10 mg dose that were evaluated in BET116183 study.
 
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15.17.
Appendix 17: Protocol Changes for Amendment 4 (06-APR-
2015) from the Protocol Amendment 3 (12-NOV-2014)
Where the Amendment Applies
Amendment 4 applies to all study centres. 
General Protocol Changes
Amendment 4:  An update to the QTc management guidelines and enhanced guidance for 
management and dose modifications for thrombocytopenia, specifically for subjects with 
AML, has been added. Separation of cohorts in Part 1 was included to determine 
MTD/RP2D separately in AML, MM, NHL cohorts. Eligibility criteria were refined to 
account for new platelet management guidelines. Eligibility regarding prior allogeneic 
stem cell transplant and CNS disease were simplified.  Inclusion of dose expansion 
cohorts for MM and NHL has been added in Part 2.  PD assessments have been removed 
from Part 2 and tumor biopsies were added in Part 2 for translational research.  The 100 
mg dose strength was removed due to a change in manufacturing.  Minor clarifications, 
reformatting of tables and typographical errors were also addressed in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
15.14.1
List of Changes
Title Page, Authors
Rationale for change: Additional authors contributed to the amendment.
Revised Text (strikethrough=deleted text; underline=new text):
Added Authors:
Oncology Stats and Programming, USA
Global Clinical Operational Sciences, USA
RD PCPS Qsci Clinical Statistics, USA
PROTOCOL SYNOPSIS
Revised Text:
Added EudraCT No.:

EudraCT NO: 2013-000445-39
 
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STUDY DESIGN AND DURATION
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data.
Revised Text:

STUDY DESIGN AND DURATION:  This study is divided into 2 parts: Part 1 of 
the study is a dose escalation phase to select the recommended Part 2 dose (RP2D) 
based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after 
oral administration of GSK525762.  Eligible subjects with relapsed refractory 
hematological malignancies will be enrolled in once daily (QD) and twice daily 
(BID) dosing cohorts until a maximum tolerated dose (MTD) is established. Subjects 
may continue treatment in the study until disease progression, unacceptable toxicity, 
or withdrawal of consent.  Part 2 will explore clinical activity at the MTD or RP2D; 
separate expansion cohorts will be planned for acute myeloid leukemia (AML), non-
Hodgkin’s Lymphoma (NHL, including an exploratory sub-cohort of subjects with 
myc and BCL2 and/or BCL6 rearrangements/overexpression [double- and triple-hit 
lymphoma]),), and multiple myeloma (MM). An expansion cohort is planned in 
subjects with acute myeloid leukemias to further explore clinical activity at the MTD 
or RP2D (Part 2).
OBJECTIVES AND ENDPOINTS:
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data.
Revised Text:
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) and/or 
twice daily (BID) dosing schedules, 
establishing the recommended Phase 
2 dose (RP2D) of GSK525762 in 
adult subjects with relapsed and/or 
refractory acute leukemia (AML), and 
other hematologic malignancies
multiple myeloma (MM), or non-
Hodgkin’s lymphoma (NHL).

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762 
following QD and/or BID dosing 
schedules.

Pharmacogenomic (PGx) study using 
blood or buccal clinical samples.
 
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Part 2
Part 2 Objectives
Part 2 Endpoints
Primary
To evaluate clinical efficacy after 
treatment with GSK525762 in relapsed or 
refractory acute myeloid leukemia (r/r
AML).

For AML: Objective response rate (% of 
subjects achieving Complete Response 
(CR), Partial Response (PR), CRp (as per 
CR but platelet count <100 x 109/L) or 
morphologic leukemia-free state) per
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in multiple 
myeloma (MM)

For MM: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, VGPR, or PR) per 
response criteria

To evaluate clinical efficacy after 
treatment with GSK525762 in non-
Hodgkin’s Lymphoma (NHL)

For NHL: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, or PR) per response 
criteria
Secondary
To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts of subjects with r/r AML, MM 
or NHL after repeat-dose 
administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).
16
To evaluate the exposure 
response (i.e., PK/PD) 
relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with r/r AML, 
MM or NHL.

PK/PD relationship between 
GSK525762 exposure markers and 
safety and efficacy parameters.
17
To evaluate the safety and 
tolerability of RP2D of 
GSK525762 in 3 disease-specific 
cohorts of subjects with r/r AML, 
MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.
18
To evaluate the relationship 
between GSK525762 exposure 
and PD response in 3 disease-
specific cohorts of subjects with
r/r AML, MM or NHL.

Dose related change in molecular 
markers (e.g., gene transcription 
and/or expression of proteins 
regulated by BRD proteins) in tumor 
tissue and/or peripheral blood 
samples.

To determine the clinical activity 
of GSK525762 in 3 disease-
specific cohorts of subjects with
r/r AML, MM or NHL.

Overall survival (OS), the time from 
the treatment start date until death 
from any cause)
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762 

Pharmacogenomic (PGx) study using 
or buccal clinical blood samples
 
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Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Acute leukemia: A response rate of 30% relative to a 10% response rate suggesting no 
activity in subjects with acute leukemia.  This will be conducted by testing the null 
hypothesis that P0≤0.10 versus the alternative that P1≥0.30, assuming the maximum 
response rate for an ineffective drug is 0.10 and the minimum response rate for an 
effective drug is 0.30.

Multiple myeloma: A response rate of 20% relative to a 5% response rate suggesting no 
activity in subjects with multiple myeloma..  This will be conducted by testing the null 
hypothesis that P0≤0.05 versus the alternative that P1≥0.20, assuming the maximum 
response rate for an ineffective drug is 0.05 and the minimum response rate for an 
effective drug is 0.20.

Non-Hodgkin’s lymphoma (non double hit (DH) lymphoma): A response rate of 30% 
relative to a 10% response rate suggesting no activity in subjects with non-Hodgkin’s 
lymphoma.  This will be conducted by testing the null hypothesis that P0≤0.10 versus 
the alternative that P1≥0.30, assuming the maximum response rate for an ineffective 
drug is 0.10 and the minimum response rate for an effective drug is 0.30. Subjects with 
DHL will be evaluated separately for efficacy, but no hypothesis testing will be conducted 
on the DHL cohort.
Subject Sample:
Rationale for Change: The approximate number of subjects planned for enrollment 
has been increased to account for the additional expansion cohorts for MM and NHL in 
Part 2.
Revised Text:
Up to 100180 subjects worldwide
INCLUSION/EXCLUSION CRITERIA:
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data. Eligibility criteria were 
refined with to account for new platelet management guidelines. Eligibility regarding 
prior allogeneic stem cell transplant and CNS disease were simplified.
Revised Text:
Inclusion Criteria
3
In Part 1, subjects must have relapsed and/or refractory hematologic malignancies 
(leukemias, myeloproliferative neoplasms, lymphomas, and myelomas) for which 
no standard therapies are available or anticipated to result in remission.  
In Part 2, subjects must have Acute Myeloid Leukemia (AML), Multiple 
Myeloma (MM), or non-Hodgkin’s Lymphoma (NHL).
Subjects with AML (Part 1 and Part 2), are eligible if they 
have relapsed and/or refractory disease, OR
 
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are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

In Part 2, the NHL cohort will separately enrol subjects with double- and triple 
hit lymphoma, so that a minimum of 10 subjects with this subset of disease will 
be enrolled. To be eligible for this sub-cohort, tumor sample from the subject 
must demonstrate rearrangement and/or overexpression of MYC and either BCL2 
and/or BCL6 genes. Evaluation of double- or triple-hit status may be performed 
via appropriate local testing, and the determination of double- or triple-hit 
diagnosis will be at the discretion of the investigator and GSK Medical Monitor.
4
Subjects who have previously received an autologous with a prior history of stem 
cell transplant are allowed if 

At least a minimum of 3 months has have elapsed from the time of transplant, 
(T0) and

the subject has recovered from transplant-associated toxicities prior to the 
first dose of GSK525762, and.

For subjects with a prior history of allogeneic transplant, 
2. the subject has been off systemic immunosuppressive medications 
(including but not limited to: cyclosporine, tacrolimus, mycophenolate 
mofetil, or corticosteroids) for at least 1 month prior to the first dose of 
GSK525762.  Topical steroids are permitted
3. there are no signs or symptoms of graft versus host disease, other than 
Grade 1 skin involvement
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Platelets (for subjects with lymphoma)
Platelets (for subjects with MM)
Platelets (for subjects with acute leukemia)
≥ 75,000 (transfusion independent)
≥ 50,000 (transfusion independent)
10,000 (transfusions permitted to bring platelet 
count to >10,000)No restrictions
1.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
2.
Refer Cockcroft Gault formula
3.
For MM subjects, adequate renal function is defined as serum creatinine ≤2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) calculated creatinine clearance criteria is <2.5mg/dL or 
24-hour urine creatinine clearance of ≥ 30 mL/min
4.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
Exclusion Criteria
3
Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno-
therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization). 
Note: the following are allowed:
Hydroxyurea for proliferative disease
 
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Corticosteroids for leukemia
Use of hematopoetic growth factors is permitted at the discretion of the 
investigator according to published guidelines (e.g., National 
Comprehensive Cancer Network (NCCN), American Society of Clinical 
Oncology (ASCO), American Society of Hematology (ASH), etc.).
4
Evidence of severe of uncontrolled infection.Subjects with prior allogeneic stem 
cell transplant are excluded unless

transplant was >60 days prior to study enrolment.

subject has not taken immunosuppressive medications (including but not 
limited to: cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil) 
for at least 1 month

no signs or symptoms of graft versus host disease other than Grade 1 skin 
involvement

no active infection
8
Symptomatic or untreated CNS disease, leptomeningeal or brain metastases or 
spinal cord compression, other compressive mass, uncontrolled painful lesion, 
bone fracture, etc (e.g., change in mental status, focal weakness).
Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are 
permitted to enrol if they were have previously received appropriate therapy 
and CNS remission has been documented.treated for CNS leukemia or brain 
metastases and have had stable central nervous system (CNS) disease 
(verified with consecutive imaging studies) for >2 months, are asymptomatic 
and off corticosteroids, or are on stable dose of corticosteroids for at least 1 
month prior to study Day 1.
Subject with primary CNS lymphoma (defined as isolated CNS lymphoma 
without systemic involvement) are excluded from study.
12
Evidence of pulmonary hemoptysis within the last 7 days.
Statistical Analysis
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data and hypothesis testing was 
added or modified for AML, MM, and NHL (non-DHL) cohorts.
Revised Text:

STATISICAL ANALYSIS: Subject demographic and safety data will be collected 
on electronic case report forms (eCRFs).  All data will be pooled and descriptive 
safety analyses summarized and listed by cohort at study conclusion.  Part 2 of the 
study is designed to evaluate preliminary efficacy.  Futility assessment will be 
conducted  on an ongoing basis, starting with a minimum of 10 treated subjects 
assessed for response. The assessments are based on the predictivepredicted
probability of success (response rate > historical response rate) with a maximum of 
32 subjects treated per cohort (for AML and non DH NHL cohorts) or 37 subjects 
treated (MM cohort) and assessed for response. Additionally at least 10 DHL 
 
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subjects will be treated.  No hypothesis testing will be conducted for the DHL 
cohort. For additional details, please refer to the reporting and analysis plan (RAP).
Section 1.2 Study Population Rationale
Rationale for Change: The correction is a minor clarifying point.
Revised Text:
First paragraph fourth sentence:

This down regulation results in significant anti-tumour activity both in vitro and 
in animal models of advanced disease [Delmore, 2011; Mertz, 2011].
Section 1.3.1.2. Predicted therapeutic dose range
Rationale for Change: The correction is a minor clarifying point.
Revised Text:

Third sentence:

The potential therapeutic dose for GSK525762 in humans was derived using 
available preclinical PK, data from in vitro cell lines of hematological origin, 
and efficacy data from OPM-2 multiple myeloma tumour xenograft studies.  
Section 1.3.3. Dose escalation steps (QD and BID)
Rationale for Change: The MTD of GSK525762 may be different for AML, NHL, 
and MM and revisions were made to reflect these potential differences.
Revised Text:
Second paragraph:
The MTD of GSK525762 may be different for AML, NHL, and MM.  To fully evaluate 
this, each dose escalation step will be evaluated separately for the three disease types.  
Parallel cohorts will commence upon termination of accelerated dose titration (Section 
3.2.1.2) and follow the 3 + 3 design described in Section 3.2.1.3. The MTD in subjects 
with leukemia may differ from the MTD in subjects with multiple myeloma and 
lymphoma therefore once the 40 mg dose cohort is cleared in AML, the MTD 
determination of MM and NHL subjects will begin at the 40 mg dose level.ML subjects 
will be enrolled initially to determine the MTD for AML. Once the 40 mg dose cohort is 
cleared in AML, the MTD determination of MM and NHL subjects will begin at the 40 
mg dose level.
Section 1.4. Rationale for Study and Endpoints
Rationale for Change: The MTD of GSK525762 may be different for AML, NHL, 
and MM and revisions were made to reflect these potential differences.
 
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Revised Text:
Second paragraph:
The BET116183 study has 2 parts.  Part 1 is a dose finding study, which will include 
subjects with relapsed refractory hematologic malignancies to determine an MTD.  Part 2 
is a cohort expansion, which will study the RP2D of GSK525762 to determine 
preliminary efficacy, safety and tolerability in three separate cohorts of subjects with 
acute myeloid leukemias, multiple myeloma and non-Hodgkin’s lymphoma.
Section 1.5.2. Benefit Assessment
Rationale for Change: The correction is a minor clarifying point.
Revised Text:

Study BET116183 is an open-label, dose escalation study and the first study of 
this agent to be conducted in subjects with relapsed and/or refractory
hematological malignancies for which no standard therapies are anticipated to 
result in a durable remission.
Section 2. Objectives, Endpoints, Hypotheses
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data.
Revised Text:
Part 1
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) and/or 
twice daily (BID) dosing schedules, 
establishing the recommended 
Phase 2 dose (RP2D) of 
GSK525762 in adult subjects with 
relapsed and/or refractory acute 
leukemia (AML) and other 
hematologic malignancies multiple 
myeloma (MM), or non-Hodgkin’s 
lymphoma (NHL).

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Exploratory
o
To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and safety 
profile of GSK525762 following QD 
and/or BID dosing schedules.
o
Pharmacogenomic (PGx) study using blood 
or buccal clinical samples
 
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Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in 
relapsed or refractory acute myeloid 
leukemia (r/r AML).

For AML: Objective response rate (% of 
subjects achieving Complete Response 
(CR), Partial Response (PR), CRp (as per 
CR but platelet count <100 x 109/L) or 
morphologic leukemia-free state) per
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in multiple 
myeloma (MM)

For MM: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, VGPR, or PR) per 
response criteria

To evaluate clinical efficacy after 
treatment with GSK525762 in non-
Hodgkin’s Lymphoma (NHL)

For NHL: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, or PR) per response 
criteria
Secondary

To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts subjects with r/r AML, 
MM or NHL after repeat-dose 
administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure 
response (i.e., PK/PD) 
relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with r/r AML, 
MM or NHL.
o
PK/PD relationship between GSK525762 
exposure markers and safety and efficacy 
parameters.

To evaluate the safety and 
tolerability of RP2D of 
GSK525762 in 3 disease-specific 
cohorts of subjects with r/r AML, 
MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.

To evaluate the relationship 
between GSK525762 exposure 
and PD response in 3 disease-
specific cohorts of subjects with
r/r AML, MM or NHL.
o
Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To determine the clinical activity of 
GSK525762 in 3 disease-specific 
cohorts of subjects with r/r AML, MM 
or NHL.
o
Overall survival (OS , the time from the 
treatment start date until death from any 
cause)
Exploratory
o
To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 

Pharmacogenomic (PGx) study using 
or buccal clinical blood samples
 
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Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Acute leukemia: A response rate of 30% relative to a 10% response rate suggesting no 
activity in subjects with acute leukemia.  This will be conducted by testing the null 
hypothesis that P0≤0.10 versus the alternative that P1≥0.30, assuming the maximum 
response rate for an ineffective drug is 0.10 and the minimum response rate for an 
effective drug is 0.30.

Multiple myeloma: A response rate of 20% relative to a 5% response rate suggesting no
activity in subjects with multiple myeloma..  This will be conducted by testing the null 
hypothesis that P0≤0.05 versus the alternative that P1≥0.20, assuming the maximum 
response rate for an ineffective drug is 0.05 and the minimum response rate for an 
effective drug is 0.20.

Non-Hodgkin’s lymphoma (non DHL): A response rate of 30% relative to a 10% 
response rate suggesting no activity in subjects with non-Hodgkin’s lymphoma.  This will 
be conducted by testing the null hypothesis that P0≤0.10 versus the alternative that 
P1≥0.30, assuming the maximum response rate for an ineffective drug is 0.10 and the 
minimum response rate for an effective drug is 0.30. No hypothesis testing will be 
conducted on the DHL cohort.
Section 3.1. Study Design/Schematic
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data.
Revised Text:
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD in 
subjects with acute leukemia and multiple myeloma/non-Hodgkin’s Lymphoma, and the 
recommended Phase 2 dose (RP2D) for GSK525762 given once-daily (QD) orally and 
twice daily (BID) orally.  Part 1 will be conducted in adult subjects with relapsed and/or 
refractory hematological malignancies.  An eExpansion cohorts cohort (Part 2) are is
planned to further explore clinical activity of GSK525762 in subjects with specific 
subtypes of acute myeloid leukemias, multiple myeloma, and non-Hodgkin’s lymphomas
based on emerging data (Figure 3).
Figure 3
Study Schema
In the figure below the heading Part 2: (n=32 for AML & NHLMM, 37 for MMNHL
cohort)
 
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Revised figure

Section 3.2.1. Part 1: Dose Escalation
Rationale for Change: The MTD of GSK525762 may be different for AML, NHL, 
and MM and revisions were made to reflect these potential differences.
Revised Text:
In Part 1, an accelerated dose titration will be employed with one subject per dose level 
until the first instance of a ≥ Grade 2 drug related non-hematological toxicity, (except for 
a pre-specified Grade 3 non-serious non-hematological drug related adverse event that 
would allow continuation of accelerated dose escalation; Section 3.2.1.7). During 
accelerated dose titration, there will be a single cohort comprised of all eligible subjects;
parallel cohorts will not be evaluated during this stage. 
Thereafter, subjects will be enrolled in a standard 3+3 design.  Separate dose escalation 
cohorts will be opened for subjects with AML, NHL, MM, as well as for QD and BID 
dosing.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predicted recommended dose from Neuenschwander 
continual reassessment method (N-CRM) design [Neuenschwander, 2009].  N-CRM 
design is a type of Bayesian adaptive dose escalation scheme.  The method is fully 
adaptive and makes use of all the DLT information available at the time of each dose 
assignment.  The DLT information of all subjects enrolled in the trial are used to update 
 
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the dose-toxicity relationship and provide supportive information in addition to 3+3 
design in the next escalation/de-escalation decision.
Dose escalation will continue until an MTD is determined or until a dose of 200 mg per 
day is reached.  After the MTD has been determined in Part1, then Part 2 dose expansion 
cohorts will be opened. 

Due to the potentially different MTD in subjects with AML, NHL, and MM
acute leukemia compared to myeloma/lymphoma (Section 1.3.3), each dose 
escalation step will be evaluated separately for the three disease types. MTD will 
initially be established in subjects with AML and subjects with MM/NHL may 
be enrolled at dose levels cleared in subjects with AML.
Section 3.2.1.1. Dose Escalation and Schedule
Rationale for Change: The MTD of GSK525762 may be different for AML, NHL, 
and MM and revisions were made to reflect these potential differences.
Revised Text:
Table 1
Three Week DLT monitoring: Dosing Schedule and Cardiac 
Monitoring (QD and BID)
Section 3.2.1.2. Accelerated Dose Escalation in Part 1

Last sentence of first paragraph:

Once this occurs, the accelerated dose escalation will terminate, and subjects 
will be enrolled in one of three disease-specific cohorts (AML, MM, or NHL)
under a standard 3+3 design (i.e., 3 subject cohorts, see Section 3.2.1.3).
Section 3.2.1.3. 3 + 3 Dose Escalation in Part 1
Rationale for Change: The MTD of GSK525762 may be different for AML, NHL, 
and MM and revisions were made to reflect these potential differences.
Revised Text:

Due to the potentially different MTDs in acute leukemia, MM, and NHL, dose 
escalation will be evaluated in three separate cohorts divided by disease subtype.  
These cohorts will be evaluated in parallel with each other, and DLT/MTD 
determination will be made separately for each cohort.

Upon termination of accelerated dose titration, two additional subjects with the 
final disease type will be enrolled, for a total of three subjects with that disease 
type at that dose level.  Three additional subjects with each of the two other 
disease subtypes will also be enrolled at that dose level, for a total of nine 
subjects at each dose level.

Two additional subjects will be enrolled to the dose level at which accelerated 
dose titration ends, for a total of at least 3 subjects at that dose level. For each 
cohort, Iif no DLTs are observed in any of the 3 subjects, then dosing will 
 
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proceed to the next higher dose level (≤2 fold increase in dose).  Subjects within 
each cohort will be entered in a staggered approach with at least 3 days between 
each subject to minimize the risk of inadvertently exceeding the MTD in 
multiple subjects.  Each disease cohort may initiate dosing independent of the 
other two (i.e., subjects with different diseases may start therapy <3 days apart, 
but subjects with the same disease must be separated by at least three days).  
Escalation to the next dose level will not increase greater than 2 fold from the 
previous dose level.  If 2 or more DLTs in 6 subjects are observed at any dose 
level, the MTD will have been exceeded (Table 3).   

Once the MTD is reached and RP2D is determined, up to 12 additional subjects 
within each cohort may be enrolled at the MTD to evaluate safety, additional 
PK, and obtain tumor tissue clinical samples for PD biomarkers.  Additional 
subjects may be enrolled at the MTD, and at least 1 dose level below MTD, to 
confirm if the MTD is appropriate for AML, MM and NHL/MM subjects. Up to 
an additional 6 subjects may be enrolled at any dose level below the MTD in 
order to obtain additional tumour tissue clinical specimens for PD biomarkers to 
better understand the dose/exposure/PD relationship.  Additional cohorts (with 
daily exposure not exceeding MTD exposure) may also be initiated to explore 
alternative dosing schedules to optimize the PK, safety and tolerability profile.  
The enrolment of additional subjects as described could be in parallel with Part 2 
enrolment.  Although DLT will not be based on the additional subjects enrolled 
into the study to further evaluate safety, PK, to obtain tumor tissue for 
biomarkers, data from these additional subjects will be considered in defining 
final MTD and RP2D (Figure 4).
Section 3.2.1.5. BID dosing
Rationale for Change: These corrections are minor clarifying points.
Revised Text:

First sentence in the first paragraph:

Twice daily (BID) dosing, will may also be explored, initially in subjects with 
AMLacute leukemia, as described in Section 1.3.2.
Section 3.2.2. Dose Limiting Toxicity (DLT)
Rationale for Change: These corrections are to correct typographical errors.
Revised Text:

Point number 6:

ALT >3xULN + bilirubin ≥2xULN (>35% direct) or ALT between 3-5xULN with 
bilirubin < 2xULN but with hepatitis symptoms or rash or ALT >5xULN.
 
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Section 3.2.4. Part 2: Disease Specific Expansion Cohorts
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has
been added in Part 2 based upon emerging pre-clinical data and hypothesis testing was 
added or modified for AML, MM, and NHL (non-DHL) cohorts.
Revised Text:
3.2.4. Part 2: AML Disease Specific Expansion Cohorts
Up to 32 subjects (per cohort) with specific relapsed and/or refractory acute myeloid 
leukemia or leukemias (and/or other subsets), determined based on emerging data 
(preclinical and clinical data from Part 1), non-Hodgkin’s lymphoma (non-DHL), and up 
to 37 subjects with multiple myeloma may be enrolled in an expansion cohort at the 
RP2D.  ThisThese will be conducted to gather more safety data and to further assess anti-
tumor activity.  Subjects in Part 2 will start with a continuous daily dosing schedule 
unless safety, PK or PD data necessitate a different dosing schedule.  The final dose and 
regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
At least 10 subjects with tumor that is positive for rearrangements or overexpression of 
MYC plus BCL-2 and/or BCL-6 genes (double- and triple-hit lymphoma) will be 
enrolled.  These subjects will be evaluated separately for efficacy, but hypotheses will not 
be tested.  See Section 11.1 for description of the plan for analysis of the NHL cohorts.
Plasma samples for PK evaluation will be collected in all subjects.  Plasma samples and 
tumor biopsies other clinical samples (e.g. lymph node or bone marrow biopsies) will be 
collected pre- and post- study drug treatment as defined in the Time and Events Table in 
Section 5 for the PD evaluation.
The Part 2 portion of the study will employ a Bayesian design that allows the trial to be 
monitored with the constraint of both Type I and Type II error rates.  Clinical response 
will be defined as CR, CRp, PR, or morphologic leukemia-free state per standard 
evaluation criteria (see Appendix 6, Appendix 7 and Appendix 8).
The For each cohort, an interim analysis will be conducted after efficacy data at a dose 
level based on RP2D are available on a minimum of 10 patients subjects in the AML and 
NHL (non-DHL) cohorts and a minimum of 13 subjects in the MM cohort. The number 
of subjects will may be increased up to a total of 32 for the AML and NHL(non-DHL) 
cohorts and up to a total of 37 for the MM cohort depending on the results observed; a 
separate decision will be made for each disease cohort.  The decision rules, specifying the 
number of subjects with a clinical response needed for continuing enrolment or, stopping 
for futility, are indicated in Figure 5 and Figure 6Table 4.  The methodology is based on 
the predictive probability of success (response rate > historical response rate) if 
enrolment continues to 32 subjects for AML and NHL (non-DHL) and 37 subjects for 
MM [Lee, 2008].  These rules are intended as a guideline.  Actual decisions will depend 
on the totality of the data.
For AML and NHL (non-DHL) cohorts: Ten subjects will be enrolled in each cohort at 
the RP2D to examine safety and efficacy.  If zero responses are observed in either cohort, 
then that cohort will be terminated and no further subjects will be enrolled due to futility. 
 
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A single response in a cohort will be adequate to pursue further enrolment. The number 
of observed confirmed responses will guide further enrolment according to the rules 
summarized in Figure 5. A maximum of 32 subjects per cohort will be enrolled at the 
RP2D.  All available data will be considered in making enrolment decisions.
Figure 5
Diagram of Stopping Rules for AML and NHL (non-DHL) Cohort 
Expansion
Number of Responders
Number of 
Subjects
0
1
2
3
4
5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no response in 
10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the study may be 
stopped.
 
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For the MM cohort: Thirteen subjects will be enrolled in each cohort at the RP2D to 
examine safety and efficacy.  If zero responses are observed in either cohort, then that 
cohort will be terminated and no further subjects will be enrolled due to futility. A single 
response in a cohort will be adequate to pursue further enrolment. The number of 
observed confirmed responses will guide further enrolment according to the rules 
summarized in Figure 6. A maximum of 37 subjects will be enrolled at the RP2D.  All 
available data will be considered in making enrolment decisions.
Figure 6
Diagram of Stopping Rules for MM Cohort Expansion
Number of 
Subjects
0
1
2
3
4
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no response in 
13 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the study may be 
stopped.
 
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For the interim analysis at N=17, if one or no response is observed in the first evaluable 
17 subjects, the enrollment will be stopped due to futility.  Otherwise, the enrolment will 
continue.  For the final analysis at N=32, if observe at least 7 responses in 32 evaluable 
subjects, sufficient statistical evidence has been provided in favor of declaring response 
rate >30%.
Table 4
Part 2 Decision Making Criteria at Interim Analysis and Final 
Analysis
Number of 
Evaluable Subjects 
Enrolled
This Number Of Objective 
Responses To Stop Early For 
Futility/Not Reject Null 
Hypothesis At The End Of Study
This Number of Objective 
Responses to Continue 
Enrolment/Reject Null Hypothesis 
at the End of Study
10
0
1
17
1
2
20
1
2
22
2
3
26
3
4
29
4
5
31
5
6
32
6
7
Section 4.1. Number of Subjects
Rationale for Change: The number of subjects were modified based on the 
clarification of BID dose expansion, separate dose cohorts for AML, MM, and NHL, and 
the addition of MM and NHL cohorts in Part 2.
Revised Text:
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study.  To 
complete Part 1, it is estimated 20 to 30 60 to 70 evaluable subjects will be enrolled.  
Part 2 will enroll up to 32111 subjects (three disease-specific cohorts of 32 to 37 subjects 
each, depending on disease subtype, and one disease-specific cohort of 10 subjects) with 
specific relapsed and/or refractory acute myeloid leukemias. See Section 11.1 for sample 
size assumptions.
Section 4.2.1. Inclusion Criteria
Rationale for Change: Inclusion of dose expansion cohorts for MM and NHL has 
been added in Part 2 based upon emerging pre-clinical data. Eligibility criteria were 
refined with to account for new platelet management guidelines. Eligibility regarding 
prior allogeneic stem cell transplant were simplified.
 
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Revised Text:
Inclusion criteria 3: In Part 1, subjects must have relapsed and/or refractory hematologic 
malignancies (leukemias, myeloproliferative neoplasms, lymphomas, and myelomas) for 
which no standard therapies are available or anticipated to result in remission.  
In Part 2, subjects must have Acute Myeloid Leukemia (AML), Multiple 
Myeloma (MM), or non-Hodgkin’s Lymphoma (NHL).
Subjects with AML (Part 1 and Part 2), are eligible if they 
have relapsed and/or refractory disease, OR
are 65 years of age and not candidates for or have refused standard 
chemotherapy.

In Part 2, the NHL cohort will separately enrol subjects with double- and triple 
hit lymphoma, so that a minimum of 10 subjects with this subset of disease will 
be enrolled. To be eligible for this sub-cohort, tumor sample from the subject 
must demonstrate rearrangement and/or overexpression of MYC and either 
BCL2 and/or BCL6 genes. Evaluation of double- or triple-hit status may be 
performed via appropriate local testing, and the determination of double- or 
triple-hit diagnosis will be at the discretion of the investigator and GSK Medical 
Monitor.
Inclusion criteria 4: Subjects with a prior history of who have previously received an 
autologous stem cell transplant (autologous and/or allogeneic) are allowed if 
At least 3 a minimum of months has elapsed from the time of transplant (T0)
and
the subject has recovered from transplant-associated toxicities prior to the first 
dose of GSK525762, and
For subjects with a prior history of allogeneic transplant, 
4. the subject has been off systemic immunosuppressive medications 
(including but not limited to: cyclosporine, tacrolimus, mycophenolate 
mofetil, or corticosteroids) for at least 1 month prior to the first dose of 
GSK525762.  Topical steroids are permitted
5. there are no signs or symptoms of graft versus host disease, other than 
Grade 1 skin involvement.
Inclusion criteria 10: Adequate organ system functions (at both screening and where 
applicable pre first dose) as defined in Table 4 Table 5.
 
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Table 45
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Platelets (for subjects with lymphoma)
Platelets (for subjects with MM)
Platelets (for subjects with acute leukemia)
≥75,000 (transfusion independent)
≥ 50,000 (transfusion independent)
10,000 (transfusions permitted to bring platelet 
count to >10,000) No restrictions
a.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
b.
See Appendix 1 for Cockcroft Gault formula
c.
For MM subjects, adequate renal function is defined as serum creatinine ≤2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) calculated creatinine clearance criteria is <2.5mg/dL or 
24-hour urine creatinine clearance of ≥ 30 mL/min
d.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
Section 4.2.2. Exclusion Criteria
Rationale for Change: Eligibility criteria regarding CNS disease and subject 
completion were simplified.
Revised Text:
Exclusion criteria 3: Currently receiving cancer therapy (chemotherapy, radiation 
therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour 
embolization).
Note: the following are allowed:
Hydroxyurea for proliferative disease
Corticosteroids for leukemia
Use of hematopoetic growth factors is permitted at the discretion of the 
investigator according to published guidelines (e.g., National 
Comprehensive Cancer Network (NCCN), American Society of Clinical 
Oncology (ASCO), American Society of Hematology (ASH), etc.).
Exclusion criteria 4: Evidence of severe of uncontrolled infection.Subjects with prior 
allogeneic stem cell transplant are excluded, unless.

transplant was >60 days prior to study enrolment.

subject has not taken immunosuppressive medications (including but not 
limited to: cyclosporine, tacrolimus, methotrexate, or mycophenolate mofetil) 
for at least 1 month

no signs or symptoms of graft versus host disease other than Grade 1 skin 
involvement

no active infection
Exclusion criteria 8: Symptomatic or untreated CNS disease leptomeningeal or brain 
metastases or spinal cord compression, other compressive mass, uncontrolled painful 
lesion, bone fracture, etc (e.g., change in mental status, focal weakness),
 
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Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are 
permitted to enrol if they were have previously received appropriate therapy 
and CNS remission has been documented.treated for CNS leukemia or brain 
metastases and have had stable central nervous system (CNS) disease 
(verified with consecutive imaging studies) for >2 months, are asymptomatic 
and off corticosteroids, or are on stable dose of corticosteroids for at least 1 
month prior to study Day 1.
Subject with primary CNS lymphoma (defined as isolated CNS lymphoma 
without systemic involvement) are excluded from study.

Exclusion criteria 12: Evidence of pulmonary hemoptysis within the last 7 days.
4.2.3.2. Subject Completion

Second paragraph:

For subjects treated at the RP2D (subset of Part 1 and all of Part 2) Part 1 AML 
subjects who are treated at RP2D and for Part 2 (expansion cohorts) subjects, a 
completed subject is one who has discontinued study treatment and was 
followed to death or has died while receiving study treatment.
Section 5. TIME AND EVENTS TABLES
Rationale for Change: The changes were made to clarify or correct disease 
assessments and revised tissue collection schedule for translational research.  The specific 
details of assessments during BID administration were added.
Revised Text:
Table 56
Time and Events: Part 1
PK blood samples for metabolite evaluation: Week 2 D6 deleted
Blood samples for plasma cytokines: W3D1 added
PK Urine samples: SCR and Week 2 D6 deleted
Pharmacogenomics (PGx) blood sample : Screening deleted and W1D1 added
Translational Research: Archival tumor tissue deleted
In footnote second sentence:
Disease assessment will be collected for subjects who discontinue study medication due 
to any reason other than progression or death (as described in Table 7).
In foot note:
Point number f: During 3+3 dose escalation, PD tumor sample collection will be 
mandatory unless infeasible to collect, and approval is obtained by the GSK medical 
monitor.  Subjects with MM or AML will have bone marrow aspirates collected on W1 
 
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D3 approximately 2-4 hours after the dose.  Subjects with NHL will have a lymph node 
biopsy collected on W1D3 approximately 3-5 hours after the dose. Timing of tissue 
collection will be based on tumor type and may be modified based on emerging data. For 
operational reasons sampling can be delayed by up to 2 days as long as the hours post-
dose for collection remain as described. A PK sample will need to be obtained within 1 
hour of the tissue sampling.  Details described in the SPM see Table 8 disease specific 
assessments for details).
Table 67
Time and Events: Part 1 Laboratory Assessments
Revised Text:
Troponin, NT pro-BNP Assessment Notes
W1D1, W1D2: troponin local lab sample 3X/24h; central troponin lab sample 1X/24h. 
Unscheduled troponin collect 2 samples: 1 for local, 1 for central lab; NT pro-BNP 
should be obtained on same day as electrocardiogram is performed.
 
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Revised Text:
Table 78
Disease Specific Assessments: Part 1 and 2
Multiple Myeloma (MM) Assessments
Procedure
Notes
S
C
R
Week 1
Week 
2
W
3
W
4
W7
W
10
q
3
W
q6
W
E
O
T
D
1
D
2
D5
D
1
D
6
D
1
D
1
D1
D1
D
1
D1
Disease 
Characteristics 
Including cytogenetics 
as appropriate 
X
Total Protein, CRP, 
2 microglobulin
X
X
X
X
X
SPEP, UPEP FLC 
assay, quantitative 
immunoglobulins 
(IgG, IgA, IgM)
Not required for 
subjects with non-
secretory MM; UPEP 
performed if protein 
present in urine.
X
X
X
X
X
Calculated 
Quantitative 
paraproteinUPEP
Only required if 
paraprotein is present 
in urine
X
X
X
X
CRP, β2 
microglobulin
X
X
X
X
FLC assay
Not required for 
subjects with non-
secretory MM
X
X
X
X
Extramedullary 
Disease Assessment 
Only required for MM 
with extramedullary 
disease
X
X
X
X
BM aspirate and 
biopsy for disease 
assessment
Required for non-
secretory MM, or as 
appropriate for other 
MMsubjects
X
X
Bone marrow biopsy 
for disease 
assessment
X
Efficacy Response
assessment
Every 6 weeks after 
wk4; Response criteria 
in Appendix 6
X
X
X
 
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Lymphoma Assessments
Procedure
Not
es
SC
R
Week 1
Week 2
W4
W7
W1
0
q3
W
q6
W
q1
2W
E
O
T
D
1
D2
D
5
D1
D6
D
1
D
4
D1
D1
D1
D1
D1
Disease characteristics, 
including historya
immunophenotypes, 
cytogenetics  and History 
aprognostic markersb
X
Lymphoma prognostic 
markers b
X
2-microglobulin
X
X
B Symptoms
X
X
X
X
X
Lymph node and organ 
exam
X
X
X
X
X
Bone marrow/tissue 
biopsy for disease 
assessment c
X
X
CT Scan d
X
X
Wk 16, 
wk 24, 
then
q12wks
X
PET Scan d, e 
X
X
Efficacy Response 
evaluation f
X
Wk 16, 
wk 24, 
then 
q12wks
a.
Including date of first diagnosis, disease stage, and complete history of diagnostic results and therapies.
b.
Examples of prognostic markers may include:  ALC, FLIPI-1, FLIPI-2 (includes ß2-microglobulin), FcR gamma 3A.
c.
A sample will be required only if clinically appropriate for the lymphoma subtype at screening only if clinically 
appropriate for the lymphoma subtype ANDunless an appropriate previous sample is available. A follow-up bone 
marrow biopsy will be performed no later than 8 weeks following CR (as judged by investigator) in accordance with 
the response guidelines (Appendix 7) if a subjects had involvement of the BM at the start of the study.
d.
Baseline/Screening CT and PET scans may be obtained within 35 days of first dose Follow-up CT scans at week 
7 wk 16, wk 24 and then every 12 weeks.
e.
PET or PET/CT scan only if clinically indicated (e.g., confirmation of CR for Diffuse large B-cell lymphoma). 
f.
Efficacy assessmentsEvaluation of response for lymphoma at week 7 , wk week 16, wk week 24 and then every 
12 weeks.. Assessments are described in Appendix 7 : Response Criteria for Lymphoma
 
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Leukaemia Assessments
Procedure
Notes
SC
R
Week 1
Week 2
W3
Wk
4
W5
W
7
W1
0
q
3
W
q
6
W
E
O
T
D1
D2
D5
D1
D6
D1
D1
D1
D
1
D1
D
1
D
1
Disease 
characteristics, 
including 
history,
immuno-
phenotypes
phenotype, 
cytogenetics 
and molecular 
studies as 
appropriate and 
History a
X
Lymph node 
and spleen 
assessment 
Only as 
appropriate 
X
X
X
X
X
X
BM biopsy and 
aspirate
FISH, 
cytogenetics, 
FLT3, IgVH, 
Zap-70 as 
appropriate
Xb
Xc
Xc
X
BM biopsy and 
or aspirate
FISH, 
cytogenetics, 
FLT3, IgVH, 
Zap-70 as 
appropriate
X b
X c
X
Transfusion 
History d
X
X
X
X
X
X
X
X
Bleeding 
History
X
X
X
X
X
X
X
X
Hematology e, f
X
X
X
X
X
X
X
X
Efficacy
Response 
assessment g
X
X
X
X
a.
Including date of first diagnosis of MDS, sAML/MDS or de novo AML and complete history of diagnostic 
results and therapies.
b.
This bone marrow sample is required for baseline disease assessment , but a peripheral blood sample can 
be taken if the bone marrow sample could not be collected.  See the study procedures manual (SPM) for sample 
handling.
c.
Bone marrow biopsy and aspirate obtained for the assessment of response.  The assessment of response 
should occur between 1 – 4 weeks of count recovery (ANC > 1000/l and platelets > 100,000/l), Subjects should 
be off cytokine support (GCSF or GMCSF) for a minimum of 7 days before obtaining bone marrow to document 
remission.
d.
Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly 
cumulative basis.
e.
Hematology includes complete blood count (CBC) with white blood cell count differential (including 
neutrophils, eosinophils, basophils, lymphocytes and monocytes) and platelets; hemoglobin, hematocrit, red blood 
cell count.  A CBC with differential and platelets, hemoglobin and hematocrit may be performed daily during in-
patient care; once subject is discharged, assessments to continue weekly until disease response assessment.  
This is collected at baseline/screening; daily during chemotherapy treatment, then weekly.  Platelet count 
achievement of 20,000/mL for 3 days is entered into the eCRF and the date of platelet count achievement of 
 
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100,000/mL is entered into the eCRF.
f.
A blood cell smear to measure peripheral blood blasts.
g.
Efficacy Response assessments for leukemia at wk 4, wk 10 and every 36 weeks thereafter. Assessments 
are described in Appendix 8: Response Criteria for Leukaemias.
Revised Text:
Table 89
Time and Events: Part 1 (QD cohorts) Serial 
Electrocardiograms, Pharmacokinetics, and Biomarker Sampling
Procedure / time after 
dose
W1D1 
W1D2
W1D5
pr
e 
do
se
0
h
15 
min 
± 
5m
30 
min 
±5
m
1h 
±1
0m
2h 
±1
5m
4h 
±1
5m
8h 
±1
h
12h 
±1h
2h
24
h 
±1
h
0h
0
h
30 
min 
±10
m
3h 
±30
m
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
GSK525762 b
X
X
X
X
X
X
X
X
X b
X
X
PK sample for metabolite 
b,c
X
X
X
X
X
X
X
X
X b
Blood sample for 
biomarkers (mRNA)
Xd
X
X
X
X
X
Plasma cytokine sample
Xd
X
X
X
X
X
Urine PK sampling  c
X 
0-2 h
2-24h
Urine metabolite 
samplingc
X
0-2 h
2-24h
Procedure / time 
after dose
W2
D4
W2
D6
W2D7
W3D
1
W7D1 ±4 days e
pr
e
do
se
pr
e
do
se
pr
e 
do
se
0
h
15 
min 
± 
5m
30 
min 
±5
m
1h 
±1
0m
2h 
±1
5m
4h 
±1
5m
8
h 
±
1
h
1
2
h 
±
1
h
2
4
h 
±
1
h
0
h
pre 
do
se
0
h
0.
5-
2
h
4 
-
8
h
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
GSK525762
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample for 
metabolite c 
X
X
X
X
X
X
X
X
X
Blood sample 
biomarkers (mRNA)
X
X
Plasma cytokines 
samples
X
X
X
X
X
X
Urine PK sampling c
0-2h
2-24h
Urine metabolite 
samplingc
0-2h
2-24h
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
The ECGs are taken iIn triplicate, 5 minutes apart and within 10 min prior to PK draw; .  For timepoint with a ±5 
minute it is acceptable for the first ECG to be out of the minus 5-min window to allow scheduling in this 
short time frame, as long as PK sample is collected after the last ECG and at least within +5 minutes of 
 
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the window.
b.
Sample to be obtained before dosing on Week 1, Day 2.
c.
Urine PK sample is collected only at MTD or RP2D in 6 subjects
d.
May be collected within 14 days prior to first dose. 
e.
Iif dose was escalated, the W4D1 visit may be performed +4 to +7 days.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
Revised Text:
Table 910
Time and Events: Part 1 (BID Cohorts) Serial 
Electrocardiograms, Pharmacokinetics and Biomarker Sampling
W1D1
W1D2
W1
D3
W1
D4
W1D5
Timepoint; 
Hours after AM 
dose (hours after 
PM dose)
Pre-Dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
Predose     
12h±1h 15 min
12h (0h)
12 h 15 min ± 
5m
12h 30 min 
±5m
13h (1h) ±10m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h 
prior to dosing
AM & PM
AM & PM
AM & PM
AM
30 min ±5m
3h ±15m
PM
Dose
X
X
X
X
XX
XX
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
♦
X
♦
X
X
X
X
PK GSK525762 b
X
X
X
X
X
X
X
X
X
X
X
X
♦
X
♦
X
X
X
X
Biomarker sample 
(mRNA) c
X
d
X
X
X
X
♦
X
♦
X
♦
X
X
Cytokine/APP
X
d
X
X
X
X
♦
X
♦
X
♦
X
X
Urine PK bf
X
0-2
2-12
2-24
W2D
4
W2D
6
W2D7
W3D1
W7D1 ±4 days e
Time point; 
Hours after AM 
dose (hours 
after PM dose)
pre AM dose
AM & PM
pre AM dose
AM & PM
Pre dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
Predose
12h±1h 5min
12h (0h)
12h 15 min 
±512h 30 min 
±5m
13h (1h) 
±5m10m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h
Prior to dosing
AM & PM
pre dose
0h
0.5-2h
4 - 8h
12h
Dose
X
X
X
X
X
X
XX
X
X
12-lead ECG a
X
X
X
X X X X X X
X
♦♦♦♦♦
♦
X
X
X
X
PK GSK525762
X
X
X
X X X X X X
X
♦♦♦♦♦
♦
X
X
X
X
Biomarker 
sample (mRNA) c
X
X
♦
X
Cytokine/APP
X
X X X
X
Urine PK bf
0-2
2-12
2-12 ( ♦ 2-24)
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 minutes prior to PK draw;. For time points 
with a ±5 minute it is acceptable for the first ECG to be out of the minus 5-min window to allow 
 
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scheduling in this short time frame, as long as PK sample is collected after the last ECG and at least 
within +5 minutes of the window.
b.
only at MTD or RP2D in 6 subjects, PK blood sample collected overnight may be kept refrigerated at 4C in 
the event the laboratory is closed.
c.
Blood sample for PD biomarker.
d.
May be collected within 14 days prior to first dose
e.
Iif dose was escalated, the W4D1 visit may be performed +4 to +7 days.
f.
Urine PK sample is collected only at MTD or RP2D in 6 subjects.
APP=acute phase protein; ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose; 
♦=optional assessment where feasible (e.g., for subjects staying overnight only).
Revised Text:
Table 1011
Time and Events: Part 2 Expansion Cohort
Part 2 Procedure 
(Notes)
SCR
Cycle 1
Cycl
e 2
Cycle 
3
Cycl
e 4
Further 
Cycles
E
O
T
W
1
W
1
W
2
W3
W4
W7
W10
q3W
q6W
D
1
D
3
D
1
D1
D1
D1
D1
D1
D1
Tumor PD Assessment 
PD Tumor sample (biopsy)
X d
X 
e
PK and Blood PD
PK Blood 
samples
Three samples to be 
collected  each 
sampling day for 
each type of 
analysis: Predose 
within 60 minutes 
prior to dose, single 
draw between 0.5 to 
2 h postdose, single 
draw between 4-8h 
postdose 
W7 and Q6W only 
predose
X
X
e
X
X
X
PD Blood 
sample for 
biomarker 
(mRNA)
X
X
X
Blood 
samples for 
plasma 
cytokines
X
X
Translational Research
PGx blood sample
X
Tumor sample (biopsy)
X d
X 
e
X
f
Blood samples for Translational 
Medicine study
X
Additional samples will be collected on the date of disease 
assessment/bone marrow biopsy and date of progression
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer 
therapy every 6 months.  Disease assessment will be collected for subjects who discontinue study medication due to 
any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have 
completed the study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of 
death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last 
subject is enrolled in Phase 2.
1.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and 
free testosterone at SCR; free testosterone thereafter.
2.
Vital signs include SBP, DBP, heart rate, respiratory rate and temperature
3.
Screening ECGs within 35 days of first dose.  ECGs prior to dosing.  If QTcF increase >30msec, ECGs performed 
 
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daily through W2.
4.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
5.
Subjects with MM or AML will have bone marrow aspirates collected on W1 D3 approximately 2-4 hours after the 
dose.  Subjects with NHL will have a lymph node biopsy collected on W1D3 approximately 3-5 hours after the 
dose. Timing of tissue collection will be based on tumor type and may be modified based on emerging data.  For 
operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection 
remain as described. A PK sample will need to be obtained within 1 hour of the tissue sampling.  Details 
described in the SPM see Table 8 disease specific assessments for details).  
6.
The collection of tumor samples for translational research are requested at end of treatment for subjects with 
progressive disease.
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; 
ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; PD=Pharmacodynamics; 
PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 
weeks; SCR=Screening; Wk=week
Revised Text:
Deleted below table:
Table 13
Disease Specific Assessments: Part 2
Section 6.1.2. Visit Windows
Rationale for Change: The changes were minor corrections made for clarity.
Revised Text:
Second paragraph onwards:
Part 1 only - Visits during Week 1: Based on subject and clinic schedule, Week 1 Day 
5 assessments can be 1 day.
Part 1 only - Visits between Week 2 through to Week 34: Based on subject and clinic 
schedule, assessments can be +3 days.
Part 1 and Part 2 – Visits between Week 4 through to Week 9: Clinic visits can be 
scheduled 3 days.
Part 1 and Part 2 - Monthly vVisits after Week 10 9 until Week 52: After the first 
disease assessment has been completed then the month clinic visits can be scheduled 5 
days.
Part 1 and Part 2 - Monthly visits after Week 52: clinic visits can may be scheduled 
7 days.
 
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Section 6.2. Baseline Assessment
Rationale for Change: The changes were minor corrections made for clarity.
Revised Text:
Subjects diagnosed with refractory hematological malignancy for (MM, lymphoma 
and/or acute leukemias), will be assessed at baseline for general disease characteristics as 
noted in Section 6.2.1 and tumor type specific measures as noted in Section 6.2.2, Section 
6.2.3 and Section 6.2.4, respectively.
Baseline is defined as the assessment closest to first dose, (i.e., Week[W]1Day[D]W1D1
assessment) or screening if SCR sample collected within 72h of first dose.
Section 6.2.3. Baseline assessment for Subjects with lymphoma
Rationale for Change: The additions include description for diagnosis of double- and 
triple-hit lymphoma.
Revised Text:
Below point added:

FISH, cytogenetics/molecular analysis, and/or IHC for MYC, BCL2, and/or 
BCL6 (only required to enrol in double- and triple-hit lymphoma sub-cohort).
Section 6.3.5. Electrocardiograms
Rationale for Change:  The changes include updated QTc management guidelines.
Revised Text:
Fourth paragraph: 
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.

QTc interval ≥ 500 msec OR interval increase from baseline 60 msec: IP 
will be discontinued unless the benefits of therapy outweigh the risk of 
rechallenge in the opinion of the Investigator, the GSK Medical Monitor, as 
well as the GSK medical governance. In this situation, rechallenge may be 
permitted (see Section 7.7 for rechallenge guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
 
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The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
Baseline results are defined by the nearest timepoint prior to first dose. For this trial the 
Baseline QTcF value is determined by the mean of the triplicate W1D1 predose QTcF 
results. If these results are not available, then the mean QTcF of the screening triplicate 
ECG results would be used.
All ECGs must include QTcF measurements.  Those values greater than 480 msec as 
calculated by the machine must be confirmed manually using Fridericia’s formula given 
below:

The Fridericia’s formula is: QTcF=QT x (1/[RR*/1000])1/3

If there are any clinically significant abnormalities including but not limited to a 
QTcF >480 msec, confirm with two additional ECGs taken at least 5 minutes apart.
*RR=Time interval from the onset of one QRS complex to the onset of the next QRS 
complex.
Table 14
QT Withdrawal Criteria
If QTcF > 480 msec, or uncorrected QT > 600 msec (Grade 3 or 4), or any change from baseline* 
of ≥60 msec even if not exceeding 480 msec, (all measurements based on an averaged manual 
overread of three ECGs over at least 15 minutes) discontinue study medications and notify the 
GSK Medical Monitor. Subject may restart if QTcF <480 after discussion with medical monitor
Baseline QTcF value
Discontinuation QTcF
<450 msec
>480 msec or ≥60 msec over baseline
* Baseline results are defined by the nearest time point prior to first dose. For this trial the Baseline QTcF value is 
determined by the mean of the triplicate W1D1 predose QTcF results. If these results are not available, then the mean 
QTcF of the screening triplicate ECG results would be used.
Section 6.3.6. Holter Monitoring
Rationale for Change: Minor reference and clarification added.
Revised Text:
Second paragraph last sentence:
Meals should be administered according to the guidelines provided in Section 7.3, and in 
the SPM as meal and snack times will need to be adjusted accordingly on dosing and 
ECG sampling days.
 
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Section 6.3.7. Telemetry
Rationale for Change: Correction was added to clarify that Holter review was not 
required for dosing.
Revised Text:
First paragraph last sentence:
Day 3 dosing should proceed only after review of Holter data by an appropriate 
physician.
Section 6.3.8. Clinical Laboratory Assessments
Rationale for Change: Clarification added to further define AEs.
Revised Text:
Fourth paragraph:
Abnormal laboratory results that are considered by the investigator to be clinically 
significant should be recorded on the eCRF as AEs.  Laboratory results or other safety 
assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay, must be recorded as an 
associated AE or SAE.   In addition, these clinically significant abnormal laboratory 
results should be followed until the abnormality resolves or is determined to be stable.
Section 6.4.1. Disease Assessment
Rationale for Change: Minor reference and clarification added.
Revised Text:
Response will be assessed as outlined in the Section 5 Time and Events Table 78 by the 
investigator using the appropriate criteria for MM, lymphoma and/or leukemias, as noted 
in Appendix 6, Appendix 7 and Appendix 8, respectively.  See the SPM for additional 
instructions.
Section 6.5.3. Urine Collection
Rationale for Change: Clarification added for sample collection during BID.
Revised Text:
For QD cohorts, Uurine samples for quantitative analysis of GSK525762 will be 
collected over a dosing interval (12 or 24 hours) in two samples (first sample collected 0-
2hr and second sample collected 2-24hr) immediately following dosing on Week 1 Day 1 
and Week 2 Day 7.  For the BID cohort, the first sample will be collected over 0-2h and 
the second over 2-12h, also immediately following dosing on Week 1 Day 1 and Week 2 
 
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Day 7. Urine samples will be collected from at least 6 subjects in Part 1 at the MTD.  
Additional sampling may be instituted based on emerging data.
Section 6.6. Translational Research
Rationale for Change: The rationale and overall schedule for collection of biological 
samples was added as a reference.
Revised Text:
Blood and or tumor tissue specimens will be collected at various times throughout the 
study in order to support research aimed at understanding the biological effect of 
GSK525762 and BET inhibition as well as identifying indicators of sensitivity or 
resistance to GSK525762.
Toward that end the successful collection of quality tumor specimens will be critical to 
furthering our understanding of BET biology and indentifying the best way to treat 
patients with a BET inhibitor. Specifically, the evaluation of responders, responders at 
relapse, and non-responders for gene mutation status and/or pathway activation may lead 
to the discovery of potential new diagnostic markers or novel combinations. Similarly, 
pre- and post-dose tumor specimens will be evaluated for markers of target engagement, 
tumor response, and/or evaluated for changes in gene expression; thus supporting 
identification of a biologically effective dose and furthering our mechanistic 
understanding of BET inhibition in these settings. 
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology. Biopsies may also be assessed for DNA, RNA or 
proteins which may be potential predictors of sensitivity or resistance to BET inhibition 
based on emerging data.
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies are 
mandatory. For subjects in Part 1 and 2, if tumor tissue is not accessible, discussion with 
the GSK medical monitor is required.
Section 6.6.1. Tumor Specific Tissue Collection
Rationale for Change: The schedule for the collection of biological samples was 
clarified or changed for each disease type due to emerging pre-clinical data.
Revised Text:
6.6.1. Tumor Specific Tissue and Blood Collection from All Subjects
The tissue collection and PD tests for Part 1 are disease specific and outlined below: 
 
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
For subjects with leukemias, changes in specific protein markers and/or mRNA 
expression signatures will be assessed in bone marrow and/or tumor cell-
enriched PBMCs isolated from whole blood.

For subjects with lymphomas, lymph node biopsies (or bone marrow, if 
appropriate) will be required before and after treatment to evaluate changes in 
tumor-specific protein markers and/or gene expression signatures.

For subjects with MM, bone marrow will be evaluated for changes in tumor-
specific protein markers and/or gene expression signatures (for example, c-
Myc).
The tissue collection to support translational and mechanistic research for Part 2 is also 
disease specific and is similar to that described above.
Specific timing of post-treatment sample collection is defined in the T&E table. See 
Study Procedures Manual (SPM) and central lab manual for additional details.
All subjects in Part 1 and 2 will be asked to submit the following:

An archival (most recent) tumor specimen in order to conduct retrospective tests 
for the identification of potential markers of sensitivity or resistance.  This 
exploratory work may include protein measurements, mRNA measurements as 
well as DNA (mutation, DNA copy number, translocation) and epigenetic (DNA 
methylation, microRNA) measurements.  Results of previous cytogenetic work 
performed on the subject will also be collected.

A biopsy at progression or end of treatment, when feasible to collect.

Blood samples collected at various times:

At screening, disease assessment and disease progression for plasma isolation 
and studying circulating biomarkers (eg, cfDNA).

At pre and post dose for treatment related changes in RNA.

At pre and post dose for treatment related changes in plasma cytokines.
A change in frequency of blood biomarker sampling times may be implemented based on 
emerging data.  This would be determined during dose escalation decision meetings and 
communicated to the sites in the meeting minutes for implementation.
Section 6.6.2. Blood Sample Collection for Surrogate PD Biomarkers
Rationale for Change: The rationale for the collection of biological samples was 
added for clarity.
Revised Text:
6.6.2. Tumor TissueBlood Sample Collection for Surrogate PD CohortBiomarkers
Blood samples collected at time points described below and in the Time and Events 
tables for PK and PD testing will be required for all subjects.
 
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
Part 1 &2: At screening, disease assessment and disease progression for 
plasma isolation and studying circulating biomarkers (eg, cfDNA).

Part 1 Only: At pre and post dose for treatment related changes in RNA.

Part 1 Only: At pre and post dose for treatment related changes in plasma 
cytokines.
6.6.2.1.
Plasma for Changes in Cytokines, Chemokines, and Acute Phase 
Proteins
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, MCP-1, MIP1-α, IL-8) will also be measured in plasma samples taken during 
PK sampling and at the time of any Grade 2 fever or symptoms of a cytokine storm. This 
will assess systemic inflammatory response in the subject using biomarkers such as pro-
inflammatory cytokines and acute phase proteins and correlate the systemic response to 
drug with that in stimulated and unstimulated blood. These biomarkers are expected to 
change over days rather than hours, based on the plasma half lives and pre-clinical data, 
such that sampling will also be performed after repeat dosing.
6.6.2.2.
Whole Blood for Changes in mRNA
GSK525762 has been shown to modulate the expression of a number of different genes in 
unstimulated whole blood between 1 h and 6 h. The mRNA levels of 31 such genes form 
a ‘signature’ panel which will also be used as a biomarker of engagement of 
pharmacology and will be measured using mRNA isolated from whole blood. The 
modulation of a number of these genes will also be measured as changes in systemic 
proteins as well as in the analysis of the ex vivo assay blood samples (e.g. CCL2 and IL-
8) thus relating mRNA and protein expression with drug concentration.  Other 
translational research studies, such as transcriptomics profiling, may also be performed 
using whole blood mRNA from selected patients.Subjects who consent to tumor PD 
assessments will also be required to provide pre- and post-treatment tumor specimens as 
appropriate in order to assess tumor PD response.    The PD tests and tissue required are 
disease specific as outlined below.

For subjects with leukemias, changes in specific protein markers and/or 
mRNA expression signatures will be assessed in bone marrow and/or tumor 
cell-enriched PBMCs isolated from whole blood.

For subjects with lymphomas, lymph node biopsies (or bone marrow, if 
appropriate) will be required before and after treatment to evaluate changes 
in tumor-specific protein markers and/or gene expression signatures.

For subjects with MM, bone marrow will be evaluated for changes in 
tumor-specific protein markers and/or gene expression signatures (for 
example, c-Myc).
Section 6.9. Pharmacogenetics
Rationale for Change: An additional assessment was added to evaluate potential 
excretion mechanisms.
 
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Revised Text:
Second paragraph:
Subjects who provide consent will have a blood sample taken for analysis.  The 
presence/absence of genetic variations in selected candidate genes in DNA from blood 
saliva will be analysed to determine their relationship with response (safety, tolerability, 
PK, and efficacy) to treatment with GSK525762.
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for Change: The deletion of the 100 mg dose strength reflects a change in 
manufacturing.
Revised Text:
Table 1417
Investigational Product Dosage/ Administration
Investigational Product
Product name:
GSK525762 Tablets
Unit dose strength(s)/Dosage level(s):
1mg
10mg
30mg
100mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
GSK
Physical description:
white to off-white, round, 
biconvex tablets with no 
markings
white to off-white, 
capsule shaped, 
biconvex tablets 
with no markings
Section 7.7.1. Dose and Safety Management Guidelines
Rationale for Change: The change in thrombocytopenia management guidelines were 
introduced to ensure consistent management of thrombocytopenia in a disease-specific 
manner. The QTc management guidelines were updated to ensure consistency with new 
QTc management guidelines.
Revised Text:
Table 1518
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Grade 3 (platelets 
<50,000, 
≥25,000/mm3)
After discussion with medical monitor and using sound 
clinical judgement, continue at same dose or dose reduce 
to previously cleared dose level. adjust dose (e.g. consider 
reduced daily dosing or dosing on alternate days). Monitor 
CBC at least twice a week, or more frequently if necessary 
clinically indicated.
Grade 4 (platelets 
<25,000/mm3) 
and/or any grade 
accompanied by 
severe bleeding 
related to 
thrombocytopenia
For Lymphoma and Multiple Myeloma:
Temporarily iInterrupt study medication and monitor CBC 
every 2-3 days. 
1. If platelet counts recover to Grade 2 and are steady for 
at least 2 CBC measurements at least 3 days apart, or 
rising, discuss with the medical monitor. Based on 
clinical  judgement, resume resuming treatment at the 
same or adjusted previously cleared lower dose based 
on sound medical judgement. 
2. Platelet transfusion is allowed based on institutional 
guidelines. In case of If platelet transfusions are 
required, hold drug for at least 7 days from day of 
transfusion, and if until platelet counts recover to 
Grade 2, and are steady for at least 2 CBC 
measurements at least 3 days apart, or rising. Using 
clinical judgement and after consultation with the 
medical monitor, consider initiating resuming treatment 
at a same or  the previously cleared lower dose using 
sound clinical judgement and after consulting with the 
GSK medical monitor. 
3. Discontinue treatment if drug has to be held for >14 
days or greater than 2 dose reductions required.
For Acute Myeloid Leukemia - if platelet count <25,000 but 
10,000mm3: Use clinical judgement to institute more 
frequent monitoring as necessary.
For Acute Myeloid Leukemia - if platelet count 
<10,000/mm3:
1. Continue treatment and start platelet transfusion as 
per institutional guidelines. After platelet transfusion, 
assess platelet level within a couple of hours of 
transfusion. Institute more frequent monitoring as 
clinically indicated.
2. If repeat platelet transfusions are not able to rescue 
platelet count to 10,000/mm3(or to 20,000/mm3in 
case of accompanying fever, sepsis, or minor 
bleeding) in 2 days, then interrupt treatment. If 
subsequent transfusions are able to increase the 
platelet count within 14 days of interruption, consider 
restarting therapy at the same or  previously cleared 
dose after discussing with the medical monitor and 
approval by GSK medical governance.  If  transfusions 
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
are unable to increase the platelet count within 14 
days of interruption, therapy will be discontinued.
3. Use of adjunctive therapies is permitted.
4. Use of hydroxyurea is permitted in the setting of 
increased blast counts in conjunction with decreased 
platelet counts.
QTcF
If >30msec and < 60 
msec change from 
baseline  AND manual 
QTcF <500 (average of 
three ECGs over at 
least 15 minutes)

Continue current dose of GSK525762

Supplement electrolytes, particularly potassium 
and magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels >0.85 
mmol/L

Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider 24 hour or longer telemetry monitoring if clinically 
indicated.
If 60 msec change 
from baseline occurs
OR
QTcF 500 
(average of three ECGs 
over at least 15 
minutes)

Discontinue GSK525762 and notify the GSK Medical 
Monitor. 
(1) Supplement electrolytes to recommended levels:
a.
Maintain serum potassium > 4mol/L
b.
Maintain serum magnesium levels >0.85 
mmol/L
(2) Rule out other potential etiologies for prolonged 
QTcF such as cardiac ischemia
(3) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(4) Consider telemetry monitoring if clinically indicated.

This subject may consider restarting study treatment 
at a previous dose level if the following criteria for QTcF 
rechallenge are met:

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless under 
the following conditions: 
(1) QTcF event reduced to <480 msec,
(2) potassium and magnesium levels are within 
institutional normal range,
(3) a favorable risk/benefit profile (in the medical 
judgement of the Investigator and the GSK Medical 
Monitor),
(4) approval within GSK medical governance:
a.
agreement with SERM MD and PPL,
b.
review with Chair or co-Chair of the GSK 
QT panel,
c.
SERM VP and Clinical VP approval
d.
Head Unit Physician approval
(5) Institutional IRB (or equivalent) approval, and
(6) The subject is re-consented regarding the possible 
increased risk of QTc prolongation. 
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines

If approval for re-challenge is granted, the subject 
must be re-consented (with a separate informed 
consent specific to QTc prolongation)

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the subject 
should complete the following activities post-dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be monitored 
weekly for two weeks, and then next assessment at 4 
weeks post-dose.
(3) If QTcF results have not resolved to baseline by 4 
weeks post-dose, then continue every 4-5 weeks until 
resolution
QTcF
QT monitoring:
If >30msec and ≤60 
msec change from
baseline* occurs.
Management Guidelines for QTcF: 
Continue dosing and follow activities.

Manually calculate QTcF to reconfirm clinically 
significant prolongation.

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
(1) Maintain serum potassium > 4 mmol/L
(2) Maintain serum magnesium levels 0.85 mmol/L

Consider 24 hour or longer telemetry monitoring if 
clinically indicated.
QTcF
If a >60msec change 
from baseline*  and 
QTcF<480 msec 
(Averaged manual 
overread of three 
ECGs over at least 
15 minutes).
Grade 1 or 2 Temporarily interrupt study medication and 
review the following activities:

Manual calculate QTcF to reconfirm clinically 
significant prolongation.

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
(1) Maintain serum potassium > 4 mmol/L
(2) Maintain serum magnesium levels 0.85 mmol/L

Rule out other potential etiologies for prolonged QTcF 
such as cardiac ischemia

Discontinue any concomitant medications with 
potential for QTcF prolongation.

Consider telemetry monitoring if clinically indicated.

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
GSK Medical Monitor.
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
QTcF>480 msec 
(averaged manual 
overread of three 
ECGs over at least 
15 minutes)
If QTcF > 60 msec over 
baseline* value AND 
QTcF>480 msec 
(Averaged manual 
overread of three 
ECGs over at least 
15 minutes)
Permanently discontinue study medications and notify the 
GSK Medical Monitor.

If the subject QTcF variable around 480 msec 
assessments may be repeated.  This subject may 
consider restarting study treatment at a reduced dose 
or dose level pre-event based on discussions with 
GSK Medical Monitor, Investigator and cardiologist.

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless under the 
following conditions: 

(1)
QTcF event reduced to Grade ≤1,

(2)
potassium and magnesium levels are within 
institutional normal range,

(3)
a favorable risk/benefit profile,

(4)
approval by the internal GSK Medical Monitor,

(5)
IRB/ EC approval, and
(6)
the subject is re-consented regarding the 
possible increase risk of QTcF prolongation.  If 
approval for re-treatment is granted, the subject must 
be re-consented (with a separate informed consent 
specific to QTcF prolongation).

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, 
the subject should complete the following 
activities post-dose:

(1)
Evaluation by cardiologist.

(2)
Weekly assessments for QTcF should be 
monitored weekly for two weeks, and then next 
assessment at 4 weeks post-dose.  If QTcF results 
have not resolved to baseline then continue every 4-
5 weeks until resolution.  Consider also doing 
telemetry if needed.
Section 8.2.1. Cautionary Medications
Rationale for Change: The data source was updated for the table in this section.
 
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Revised Text:
Table 1720
Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution
Generic Name
Brand Name
Astemizole
Hismanal
Amiodarone
Cordarone, Pacerone, Nexterone
Citalopram
Celexa, Cipramil
Chlorpromazine
Thorazine
Clarithromycin
Biaxin
Escitalopram
Lexapro
Haloperidol
Haldol
Moxifloxacin
Avelox, Avalox, Avelon, Moxeza, and Vigamox
1.
NOTE: There may be situations when the subject is on study that Advanced Cardiac Life Support (ACLS) 
requires the use of amiodarone, which should be used as per local clinical guidelines.
2.
Data Source: CredibleMeds, 20145 (www.crediblemeds.org)
After starting cautionary medications such as in Co-administration of medications that 
are known to prolong the QT interval and have a risk of causing Torsades de Pointes are 
to be used with EXTREME CAUTION beginning 14 days prior to the first dose of 
study drug until discontinuation from the study.  These medications include (but are not 
limited to) those listed in Table 1720 it is recommended that ECGs are implemented daily 
until the steady state is reached.  If there are abnormalities, implement additional 
cardiotoxicity monitoring.
Section 8.3. Prohibited Medications
Rationale for Change: The data source was updated in this section.
Revised Text:
Table 1922
Drugs with a Risk of Torsades de Pointes that are Prohibited
In footnote:
Data Source: CredibleMeds, 20145 (www.crediblemeds.org)
Fourth paragraph:
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (up to a maximum dose of 0.25 mg 
daily) and ondansetron (up toat a maximum dose of 8 mg TID) are the only allowed 
drugs in this class.
Section 10. DATA MANAGEMENT
Rationale for Change: The data management guidelines for screen failures were 
clarified in this section.
 
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Revised Text:
Fifth Paragraph:
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled.  Data for screen failures will be collected in source 
documentation at the site but will not be transmitted to GSK.
Section 11.1.1. Part I, Dose Escalation
Rationale for Change: The statistical design for Part 1 was clarified in this section.
Revised Text:
The sample size in Part 1 is not driven by statistical considerations.  The total number of 
subjects will depend on the number of dose escalations needed.  However, the maximum 
anticipated number of subjects will be approximately 60-70.
Doses to be studied in Part 1 will be guided by calculating the posterior probability that  
the DLT rate falls within an acceptable range for each subsequent dose after each dose 
cohort observation period.  The N-CRM method will be used to calculate posterior 
probabilities utilizing a pre-specified prior distribution.
Section 11.1.2. Part 2, Expansion Cohort
Rationale for Change: MM and NHL cohorts were added to Part 2 and the statistical 
design for Part 2 was clarified in this section.
Revised Text:
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with AML, 
MM, and NHL. 

For AML, efficacy is defined as detect a clinically meaningful response rate (defined 
as the percentage of subjects that have achieved a CR, CRp, PR or a morphologic 
leukemia-free state ) of 30% in AML relative to a 10% response rate suggesting no 
activity.

For MM, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, VGPR, or PR) of 20% relative to a 
5% response rate suggesting no activity.

For NHL, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, or PR) of 30% relative to a 10% 
response rate suggesting no activity.  For this cohort, double/triple-hit lymphoma 
subjects will be excluded from initial efficacy analysis and will be evaluated 
separately.
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
 
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in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 
weak prior Beta distribution with a mean response rate equal to the target response rate is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution (e.g. Beta (0.03, 0.07)) and the observed data x, the 
posterior distribution of the response rate follows a beta distribution, i.e.
In the following case, 30% is the target response rate.
p Beta (0.03 + x, 0.07 + n-x) with posterior mean (0.03+ x)/(0.07 + n).
Futility analysis for each disease cohort will begin when response data is available for at 
least 10 subjects. Each disease cohort may be stopped early for futility if the predictive 
probability of success (response rate ≥  historical response rate) is less than 1%.  Futility 
stopping rules are defined for each cohort in Section 3.2.4.
For the AML and NHL disease cohorts,>Symbolically, the null hypothesis is:
H0: RR≤10%
The alternative hypothesis is:
HA:RR≥30%
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate ≥30% at interim and final analysis using a weak/non-informative prior. A 
Bayesian analysis expresses uncertainty about a parameter in terms of probability.  A 
prior is defined to characterize the level of knowledge about a parameter before the data 
are collected.  Once the data are collected, a posterior distribution is formed using the 
prior and the likelihood (i.e., the data).  A very weak prior Beta (0.03, 0.07) with a mean 
response rate of 30% is assumed.  Thus, the posterior distribution for the response rate 
will be primarily driven by the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior and the likelihood of the observed data x, the posterior distribution of 
the response rate follows a beta distribution, i.e.,
p Beta (0.03 + x, 0.07 + n-x) with the posterior mean (0.03+ x)/(0. 1 + n).
Sstarting with a cohort of 10 subjects and allowing for a maximum sample size of 32 
subjects at the RP2D with stopping guidelines as described in Section 4.2.3.23.2.4, this 
design will have a Type I Error () of 0.034404 and 87% power. Futility analysis will be 
based on subjects who have at least one post-baseline disease assessment. The trial will 
 
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be stopped early for futility if the predictive probability of success (that the response rate 
≥30% historical response rate) is less than 1%. If the true response rate is 10%, the 
average sample size is 20 and the probability of early termination (PET) for futility is 
93%. If the true response rate is 30%, the average sample size is 31 subjects and the PET 
is 9%.
For the MM disease cohort, starting with a cohort of 13 subjects and allowing for a 
maximum sample size of 37 subjects at the RP2D with stopping guidelines as described 
in Section 3.2.4, this design will have a Type I Error () of 0.032 and 85% power. 
Futility analysis will be based on subjects who have at least one post-baseline disease 
assessment. The trial will be stopped early for futility if the predictive probability of 
success (that the response rate ≥historical response rate) is less than 1%. If the true 
response rate is 5%, the average sample size is 22 and the probability of early termination 
(PET) for futility is 91%. If the true response rate is 20%, the average sample size is 36 
subjects and the PET is 10%.
Section 11.4. Interim Analysis
Rationale for Change: MM and NHL cohorts were added to Part 2 and the statistical 
design for Part 2 was clarified in this section.
Revised Text:
Second and third paragraphs:
For each disease type in Part 2, after the initial 10 subjects in the AML and NHL cohorts 
and initial 13 subjects in the MM cohort have enrolled at the selected dose regimen for 
the Expansion Cohort, data will be reviewed for clinical benefit on an ongoing basis and 
the number of subjects with observed clinical benefit will be compared with the stopping 
guidelines provided in Section 3.2.4.
The study will not only stop due to lack of efficacy.  The trial will may continue to enrol 
the maximum planned sample size to provide a better an estimate on the distribution of 
the response rate in the target patient populations.
Section 11.6.1. Primary Analysis
Rationale for Change: MM and NHL cohorts were added to Part 2 and the statistical 
design for Part 2 was clarified in this section.
Revised Text:
Second paragraph onwards:
The primary aim of Part 2 is to detect demonstrate a possibly a clinically meaningful 
response rate of 30% relative to a 10%  response rate suggesting no activity in each of the 
disease cohorts separately. Each disease subtype (AML, MM, and NHL) will be 
evaluated separately.
 
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Overall Response rate is defined as 

AML: Tthe percentage of subjects who achieved CR, CRp, PR and a morphologic 
leukemia-free state. A waterfall plot of percent change from baseline in bone marrow 
blasts and peripheral blasts will be provided. Response rates of subjects with AML 
M3 will be summarised separately.

MM: The percentage of subjects who achieved CR, VGPR, or PR.

NHL: The percentage of subjects who achieved CR or PR.  Response rates of 
subjects with double/triple-hit lymphoma will be summarised separately.
among All subjects who received at least one dose of treatment in the target population
will be included in the evaluation for response.  Response rates and the associated 2-sided 
95% exact confidence limits will be provided.  A waterfall plot of percent change from 
baseline in bone marrow blasts and peripheral blasts will be provided. Response rates of 
subjects with AML M3 will be summarised separately.
Section 11.6.2. Secondary Analysis
Rationale for Change: The statistical design for the secondary endpoints in Part 2 was 
clarified in this section.
Revised Text:
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, PR, or SD) prior to the initiation of therapy. 
Otherwise, if the subject does not have a documented date of events, PFS will be 
censored at the date of the last adequate assessment. For the analysis of overall survival 
(OS), the last date of known contact will be used for those subjects who have not died at 
the time of analysis; such subjects will be considered censored. Further details on rules 
for censoring will be provided in the RAP. Sensitivity analyses of PFS and further details 
on censoring rules will be provided in the RAP.  Progression free survival (PFS) and 
overall survival (OS) will be summarized using Kaplan-Meier method.
The duration of response is defined for the subject or subjects with a confirmed CR or PR 
for NHL, CR, CRp, PR or morphologically leukemia free for AML, and CR, VGPR, or 
PR for MM as the time from the first documented evidence response until the first 
documented disease progression or death due to any cause. Censoring rules for duration 
of response will be outlined in detail in the RAP.
Time to Response is defined, for subjects with a confirmed response as the time from first 
dose to the first documented evidence of response.
If sample size permits, duration of response and time to response will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Only the subset of subjects who 
show a confirmed response will be included. Censoring rules for duration of response 
will follow the rules for PFS outlined in detail in the RAP.
 
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OS along with 95% confidence intervals for MM, lymphoma and/or leukemias subjects 
treated at RP2Din Part 1 and Part 2, will be estimated using the Kaplan Meier method.  
OS analysis for AML will exclude subjects with AML subtype M3. NHL will be 
separately reported based on double/triple hit status.  All cause mortality will be used and 
censoring will be performed using the date of last known contact for those who are alive 
or lost to follow-up at the time of analysis.
Section 11.7.3. Clinical Laboratory Evaluations
Rationale for Change: Minor correction was made.
Revised Text:
Second sentence:
Laboratory test results outside the reference ranges that do not have an associated NCI-
CTCAE criteria will be summarized using proportions.
Section 12.6. Study and Site Closure
Rationale for Change: The terms for site closure were clarified.
Revised Text:
Third paragraph:
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  GSK may also close sites which fail to recruit.  When feasible, GSK 
will provide advance notice to the investigator or head of the medical institution of the 
impending action.
Fifth paragraph:
GSK may also close sites which fail to recruit within a predefined timeframe, as defined 
within the SPM.
Section 14. REFERENCES
Rationale for Change: The data source was updated.
Revised Text:
Seventh reference:
CredibleMeds. List of drugs with a risk of Torsades de Pointes. Available at: http://www.
crediblemeds.org   Accessed 18-Aug-2014 02 March 2015
 
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Section 15.3. Appendix 3: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Rationale for Change: Minor corrections were made due to changes in figures.
Revised Text:
Liver Chemistry Follow-up Procedures
First sentence:
Refer to the diagram in Figure 7 Figure 5 for a visual presentation of the procedures listed 
below.
Liver Chemistry Monitoring Criteria
Second paragraph:
Refer to Figure 7 Figure 5 for the algorithm of liver chemistry monitoring, stopping and 
follow up criteria.
Liver Safety Drug Restart Guidelines
Drug Restart/Rechallenge Process (also see Figure 8 Figure 6)
Second paragraph:
GSK Medical Monitor & Clinical Safety Physician to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 2023)
Section 15.4. Appendix 4: Dose Adjustment/Stopping Criteria/Supportive 
Care
Rationale for Change: Minor correction.
Revised Text:
Fever
First paragraph:
Safety monitoring cytokine blood samples may be collected (based on Section 7.7.1 of 
the protocol).  These samples include (but not limited to) assessments for TNF-alpha, IL-
1, IL-6, and IL-10 as outlined in the SPM.
Section 15.5. Appendix 5: Pharmacogenetic Research
Rationale for Change:  An additional assessment and clarifications were added based 
on emerging data.
 
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Revised Text:
PGx Associations with Safety Events
Third paragraph:
Collection of whole bloodsaliva samples, may enable PGx analysis to be conducted if at 
any time it appears that there is a potential unexpected or unexplained variation in 
handling or response to GSK525762.
Study Assessments and Procedures
In addition to any blood samples taken for the clinical study, a whole bloodA saliva
sample (~10mL) will be collected for the PGx research using an Oragene DNA self 
collection tube containing ethylenediaminetetraacetic acid (EDTA).  It is recommended 
that the blood saliva sample be taken at the first opportunity after a subject has been 
randomized and provided informed consent for PGx researchday 1, but may be taken at 
any time while the subject is participating in the clinical study after the subjects provided 
informed consent for the PGx research.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff.  Coded samples do not carry 
personal identifiers (such as name or social security number).  The blood saliva sample is 
taken on a single occasion unless a duplicate sample is required due to inability to utilize 
the original sample.
The DNA extracted from the blood saliva sample may be subjected to sample quality 
control analysis.  This analysis will involve the genotyping of several genetic markers to 
confirm the integrity of individual samples.  If inconsistencies are noted in the analysis, 
then those samples may be destroyed.
Following subsection deleted:
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator must complete the appropriate documentation to request sample destruction 
within the timeframe specified by GSK and maintain the documentation in the site study 
records.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood sample being 
taken for PGx research.
 
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15.18.
Appendix 18: Protocol Changes for Amendment 5 (08-JUL-
2015) from the Protocol Amendment 4 (06-APR-2015)
Where the Amendment Applies
Amendment 5 applies to all study centres. 
General Protocol Changes
Amendment 5:  Updated inclusion criteria and guidance on contraception use based on 
emerging data from preclinical studies of embryo-fetal development.  Minor 
clarifications were made regarding the Echo and Holter monitoring requirements and the 
list of medications with risk for Torsades de Pointes and prohibited medications were 
updated. The AML response criteria were updated with modified Cheson 2003 
guidelines. Futhermore, the dosing schedule was updated to a continuous daily dosing 
schedule. Finally, after an internal QTc analysis and evaluation of cardiac safety data 
collected from all subjects in the BET115521 study up to and including the 100mg QD 
cohort available by 15 May 2015, the 48-hour telemetry requirement has been removed 
for all parts of the study and the frequency of Holter Monitoring was decreased in Part 1.  
Minor clarifications, reformatting of tables and typographical errors were also addressed 
in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
18.14.1
List of Changes
Sponsor/medical monitor Information Page
Medical Monitor and Sponsor Contact Information:
Rationale for Change: Updated to include back up medical monitor’s cell phone 
number.
Revised Text:
After-hours Phone/Cell/Pager Number 
for secondary medical monitor 
has been added.
ABBREVIATIONS
Rationale for Change: Abbreviations deleted as part of the protocol amendment
Deleted Text: 
HI
Hematologic Improvement
IVCD
Intraventricular conduction delays
RBC
Red blood cell
 
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PROTOCOL SYNOPSIS

STUDY DESIGN AND DURATION:  
Rationale for Change: Minor correction
Revised Text:
Second sentence:
Eligible subjects with relapsed refractory hematological malignancies will be enrolled in 
once daily (OD) and/or twice daily (BID) dosing cohorts until a maximum tolerated dose 
(MTD) is established.

OBJECTIVES AND ENDPOINTS:
Rationale for Change: Minor correction
Revised Text:
Part 1 Objectives
Part 1 Endpoints
Secondary

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration following 
QD and/or BID dosing schedules.

GSK525762 PK parameters following 
single- (Day 1) and repeat-dose 
(Day 15) administration of 
GSK525762, including Area under 
concentration-time curve(AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.

INCLUSION/EXCLUSION CRITERIA:
Inclusion Criteria
Rationale for Change: Based on emerging data from pre-clinical fetal and embryo 
toxicity studies, the inclusion criteria specifying contraception requirements were updated 
to extend the length of time for contraception use for subjects. A summary of the findings 
from these preclinical studies may be found in the body of the protocol under 
Reproductive Risks in Section 1.5.
Revised Text:
Inclusion criteria 8: A female subject is eligible to participate if she is of:
 
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
Second bullet point: Child-bearing potential and agrees to use one of the 
contraception methods (described in Section 9.1) for an appropriate period of 
time (as determined by the product label or investigator) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy at that point.  Female 
subjects must agree to use contraception until at least 4 weeks 7 months after the 
last dose of study medication.
Inclusion criteria 9: Male subjects must agree to use one of the methods of contraception 
specified.  This method must be used from the time of the first dose of study medication 
until least 16 weeks after the last dose of study medication.  In addition, male subjects 
whose partners are or become pregnant while on study medication must continue to use 
condoms for 7 days after stopping study medications.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN: 
Rationale for Change: The original dosing schedule (1,3,5,7) was designed to include 
a dosing break over the course of the first week to monitor for any potential immediate 
toxicities before moving into continuous daily dosing in the second week. As included in 
the rationale for removal of 48-hour telemetry and reduction of holter monitoring 
frequency, after an internal QTc analysis and evaluation of cardiac safety data 
collected from all subjects up to the 100 mg QD cohort available by May 15 2015, 
evidence of a slight delayed QT prolonging effect was noted, however this did not lead to 
any marked prolongation and there were no individual subjects with delta >60ms or QTc 
>500ms. 
In an effort to achieve an optimal dosing schedule and further explore alternate dosing 
schedules (i.e.; two weeks of dosing, followed by one week off study drug), the 
intermittent dosing was modified to allow subjects to begin continuous daily dosing on 
Day 1. 
Revised Text:

Starting dose will be 5 mg, orally (tablets), once a day.  Dose escalations will be 
performed in Part 1 and dose adjustments are allowed to address tolerability and 
safety issues.  BID dosing will be explored in a parallel cohort. Alternate dosing 
schedules e.g. intermittent dosing) may be required to manage toxicities and 
may be considered based on investigator assessment and after consultation with 
GSK; and may be implemented if the safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) data suggest that a sufficient therapeutic exposure 
cannot be achieved using the protocol schedule and after without requiring a 
protocol amendment.

SAFETY MEASUREMENTS:  
Rationale for Change: After an internal QTc analysis and evaluation of cardiac safety 
data collected from all subjects up to the 100 mg QD cohort available by May 15 2015, 
the 48-hour telemetry requirement was removed for all parts of the study and the 
frequency of Holter Monitoring was decreased in Part 1. There was no GSK525762 
related QTc prolongation observed within the first 48 hours of treatment.Therefore the 
inpatient telemetry on W1D1 and W1D2 was discontinued. Although the presence of a 
 
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slight delayed QT prolonging effect was noted, this did not lead to any marked 
prolongation (no individual subjects with delta >60ms or QTc >500ms). The frequency of 
Holter monitoring in Part 1 was also reduced from 6 timepoints to 4 timepoints, as the 
ECG time-points currently included in the required assessments provide adequate cardiac 
safety assessments of any potential QT-prolonging effect (including potential delayed 
effects). All Holter monitoring will continue to be reviewed at a central lab for 
arrhythmia assessment. The overnight stays previously mandated as part of the 48-hour 
in-patient telemetry will only be required on serial ECG/PK days at sites that are unable 
to collect after-hours PK timepoints as outpatient.
Revised Text:

Routine physical examinations, vital sign measurements, echocardiograms, and 
monitoring of adverse events will be performed.  Stringent Cardiac safety 
monitoring will be required, consisting of at least 48 hours of telemetry 
following the first dose (overnight stays in research facility necessary), 24 hours 
of Holter monitoring at Screening, Week 1, and Week 4, and triplicate 12-lead 
ECGs prior to dosing on selected days and prior to drawing PK samples on 
serial PK sampling days (overnight stays in research facility may be necessary in 
Part 1).  Laboratory testing includes, in addition to standard hematology, clinical 
chemistry, pancreatic, coagulation, and liver chemistry panels, testing for 
troponin, N-terminal prohormone B-type Natriuretic Peptide (NT pro-BNP), c-
peptide, 1,5-Anhydroglucitol (1, 5 AG), Hemoglobin A1c (HbA1c), and thyroid 
monitoring.  Additional safety assessments may be necessary based on emerging 
data.
Section 1.3.1.1.2. Human Pharmacokinetics and Equivalent Exposure for 
NOEL for QTc prolongation
Rationale for Change: Minor correction
Revised Text:
Last Paragraph:
Updated PK information obtained after first subject first dose is presented in Section 
15.10. Appendix 13 (Section 15.13)
Section 1.3.2.2. Clinical Rationale for BID
Rationale for Change: Minor correction
Revised Text:
First paragraph:
Pharmacokinetics of GSK525762 has been evaluated in subjects in studies BET115521 
and BET116183 following single and repeated daily administration of GSK525762 
(Section 15.13) Section 15.10.
 
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Section 1.5.1. Risk Assessment
Rationale for Change: Minor correction
Revised Text:
First paragraph, second sentence:
Toxicology studies performed in dogs, rats and mice suggest that the primary toxicities of 
GSK525762 are gastrointestinal, cardiovascular, pancreatic, hematologic and 
reproductive (see the GSK525762 IB [GlaxoSmithKline Document Number 
2011N113741_03], Section 4.4).]).  
Rationale for Change: The Telemetry was removed from the Risk Assessment section 
after an internal QTc analysis and evaluation of cardiac safety data collected from all 
subjects up to the 100 mg QD cohort available by May 15 2015, the 48-hour telemetry 
requirement was removed for all parts of the study and the frequency of Holter 
Monitoring was decreased in Part 1. There was no GSK525762 related QTc prolongation 
observed within the first 48 hours of treatment. Therefore the inpatient telemetry on 
W1D1 and W1D2 was discontinued. Although the presence of a slight delayed QT 
prolonging effect was noted, this did not lead to any marked prolongation (no individual 
subjects with delta >60ms or QTc >500ms). The frequency of Holter monitoring in Part 
1 was also reduced from 6 timepoints to 4 timepoints, as the ECG time-points currently 
included in the required assessments provide adequate cardiac safety assessments of any 
potential QT-prolonging effect (including potential delayed effects). All Holter 
monitoring will continue to be reviewed at a central lab for arrhythmia assessment. 
The Reproductive Risk section was also updated after new findings related to 
GSK525762 in a rat female fertility study in which adverse reproductive findings in 
pregnant rats (maternal and embryo-fetal) were observed. This section was updated with 
a summary of those findings.
Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human 
ICF includes the risk of (fatal) 
arrhythmias
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring and cardiac 
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose (no 
effects were observed in the 28 day 
toxicology studies); increase in mean BP up to 
11 mmHg; decrease in mean BP up to 13 
mmHg.
QA interval (indirect measure of cardiac 
contractility).
Increased QA interval at single non-tolerated 
doses; up to 10msec. No effects were 
observed in the 28 day toxicology studies).
ejection fraction) during the study, 
and dose stopping/modifications 
criteria for the management 
cardiac events.
Drugs with a risk of Torsades de 
Pointes are prohibited, (refer to 
Section 8.3).
All subjects will receive their first 
doses of study medication (Week 
1 Day 1 and Week 1 Day 2) in the 
hospital with telemetry monitoring 
for the first 48 hours of dosing.
Given the risks of long QTc 
associated arrhythmias, and of 
compound associated 
cardiomyopathy, subjects will be 
monitored closely for changes in 
QTc with triplicate 12-lead ECG, 
Holter monitoring, and for 
elevations in plasma Troponin.  
Inpatient 48-hour telemetry was 
originally required for all subjects 
following the first dose of study 
drug, as part of the cardiac 
monitoring. Evaluation of cardiac 
safety data from subjects treated 
up to and including the 100 mg QD 
cohort by the cut-off date of May 
15, 2015 demonstrated no 
significant QTc prolongation after 
single and repeat dose 
administration. Therefore, the 48-
hour telemetry requirement was 
removed and the frequency of 
Holter monitoring was reduced 
with Protocol Amendment 5.
Specific stopping criteria and 
management guidelines are 
provided for cardiac toxicities.
Electrolytes, including potassium 
and magnesium will be checked at 
baseline and at regular intervals or 
when clinically indicated. 
Appropriate medical management 
will be instituted to assure that 
electrolytes are kept within the 
 
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normal range.
Reproductive
GSK525762 has shown adverse and 
potentially irreversible effects on testes in rats, 
rabbits and dogs, with no no observed 
adverse effect level (NOAEL) in rabbits. An 
effect on spermatogenesis is anticipated.
In definitive four-week oral toxicology studies, 
sperm retention and degenerative effects 
occurred in male dogs and rats. Degenerative 
changes were also observed in rabbits dosed 
dermally for 14 days.
In a dose range rat embryofetal development 
study, GSK525762 has been shown to impact 
fetal development at doses ≥1 mg/kg/day, 
including embryo-fetal toxicity, leading to a 
complete loss of litters at 30 mg/kg/day and 
developmental toxicity including fetal 
malformations at doses ≥1 mg/kg/day. These 
adverse reproductive effects occur in rats at 
systemic exposures approximately 3-fold 
below the exposure observed in patients 
given 2 mg/day on the ongoing dose 
escalation Phase 1 clinical trial BET115521.
The findings from the dose-range reproductive 
toxicity study in rats with GSK525762 are 
consistent with literature reports that BRD2, 
BRD3, BRD4 and BRDT have crucial roles in 
reproductive function and embryofetal 
development (see the GSK 525762 IB 
[GlaxoSmithKline Document Number 
2011N113741_03] for references). Based on 
the findings in this reproductive toxicity study 
in rats with GSK525762, there is a 
substantiated risk for adverse effects on 
embryofetal development. There is a 
theoretical risk that GSK525762 may also 
impact female reproductive organs (ovaries). 
A rat female fertility study is ongoing to 
evaluate this risk.
No ovarian histologic changes were observed 
in the 4 week toxicology studies, however 
female fertility (disrupted estrous cyclicity, 
delays to mating and/or reduced fertility index) 
was affected in rats given 30 mg/kg/day 
GSK525762 for 15 days prior to mating and 
15 days prior to mating through to Day 6 post 
ICF includes the risk of damage to 
reproductive organs such as testes 
or ovaries.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects and collecting 
testosterone (free and complete) 
for male subjects.
ICF includes the potential risk of 
reproductive effects.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects.
 
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coitus (pc). Systemic exposure in rats was 
approximately 2-fold higher than current 
exposure in late stage cancer patients (at 60 
mg/day). No fertility effects were observed 
when 30 mg/kg/day was given for 6 weeks 
followed by 6 weeks off-dose prior to mating.
Reproductive and developmental toxicity 
(decreased fetal body weight, fetal 
malformations or variations and / or pre- and 
post-implantation loss) occurred in rats given 
GSK525762 ≥1mg/kg/day from conception 
through gestation day 17 (of 21 days) and 
when dosed at ≥10 mg/kg/day for 14 days 
and dosing stopped prior to mating or 
continued until Day 6 pc. Systemic exposure 
in rats was approximately 80-fold lower than 
current exposure in late stage cancer patients 
(at 60 mg/day). These results are consistent 
with observations that BRD2, BRD3, 
BRD4 and BRDT have crucial roles in 
reproduction and development [see the GSK 
525762 IB [GlaxoSmithKline Document 
Number 2011N113741_03] for references.
Based on the findings in these reproductive 
and developmental toxicity studies in rats with 
GSK525762, there is a substantiated risk for 
adverse effects on embryofetal development 
and impacts on female fertility.
Section 3.2.1.1. Dose Escalation and Schedule
Rationale for Change:  The original dosing schedule was designed to include a dosing 
break during the first week to monitor for any potential immediate toxicities before 
moving into continuous daily dosing in the second week. As included in the rationale for 
removal of 48-hour telemetry and reduction of holter monitoring frequency, after an 
internal QTc analysis and evaluation of cardiac safety data collected from all subjects up 
to the 100 mg QD cohort available by May 15 2015, evidence of a slight delayed QT 
prolonging effect was noted, however this did not lead to any marked prolongation and 
there were no individual subjects with delta >60ms or QTc >500ms. 
In an effort to achieve an optimal dosing schedule and further explore alternate dosing 
schedules (i.e.; two weeks of dosing, followed by one week off study drug), the 
intermittent dosing was modified to allow subjects to begin continuous daily dosing on 
Day 1. 
 
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Revised Text:
A staggered dosing schedule will be implemented to monitor for safety including any 
delayed toxicity.  This approach allows repeat dosing in a step-wise fashion to detect 
changes in safety, such as cardiotoxicity.  Based on a low risk of drug accumulation and 
the aggressive nature of relapsed and/or refractory hematologic malignancies, a three 
week period will be used for DLT monitoring and dose escalation decision making.  
Alternative dosing regimens and/or schedule may be implemented based on emerging PK 
and safety data and after without requiring a protocol amendment.
In Part 1, subjects will follow the dose schedule outlined below in Table 1.  Alternative 
dosings regimens and/or schedule may be implemented based on emerging PK and safety 
data.  Specifically, in Week 1 subjects will receive study drug on Day 1 through Day 5, 
and rest Day 6 and Day 7.  From Week 2 the subject will start daily dosing which will 
continue until study completion (Section 4.2.3).
Extensive monitoring for cardiac safety signals will be performed including in-subject 
telemetry during the first 48 hours after initial study treatment as well as triplicate 12-lead 
ECG and 24-hour Holter monitoring on the days indicated in Table 1.
Table 1
Three Week DLT monitoring: Dosing Schedule and Cardiac Monitoring 
(QD and BID)
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
Dose
offDose
offDose
ECG, Holter
48h Telemetry*
ECG,
ECG,
Holter
ECG
Week 2
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
ECG
ECG, 
Holter
Week 3
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
* 48h Telemetry: start predose d1, remove on d3
Please refer to Time and Events Tables Section 5 for more details 
Section 3.2.1.4. Alteration of Schedule
Rationale for Change: This section was updated to include a statement that PK 
sampling and other assessments may be modified if alternate dosing schedules are 
explored to reflect the new dosing schedule. This was to allow PK and/or other safety 
assessments to be collected during dosing days, and also to exempt subjects from having 
these assessments if they fell on a non-dosing day under a revised altered schedule.
Revised Text:
Added text at the end of second paragraph:
If alternative dosing schedules are explored, PK sampling times and other safety 
assessments may be modified to reflect the new dosing schedule.
 
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Section 3.2.1.5. BID dosing
Rationale for Change: Minor correction
Revised Text:
First paragraph:
Twice daily (BID) dosing, may also be explored, initially in subjects with acute leukemia, 
as described in Section 1.3.2. The initial dose level for BID will be a maximum of 20 mg 
(ie 2x 20mg 12 hours apart, total daily dose of 40mg) or a dose level lower than 20 mg 
depending on emerging safety, PK and PD data and dosing will be separated by 
approximately 12 hours.  Escalation can then proceed as described using the 3 + 3 dose 
escalation.
3.2.4. Part 2: Disease Specific Expansion Cohorts
Rationale for Change: This section was updated to clarify that during the futility 
assessment for individual cohorts in Part 2, if stopping criteria were met, further 
enrolment into that specific cohort would cease, but would not require stopping 
enrolment in other cohorts.
Revised Text:
Footnotes of Figure 5 and Figure 6:
The shaded regions are the specific regions for stopping the studyenrollment for futility.  
For instance, if there is no response in 10 subjects, then the predictive probability for 
success will be 1% or less (the futility criterion) and the study further enrollment in these 
cohorts may be stopped.
Section 4.2.1. Inclusion Criteria
Rationale for Change: Based on emerging data from pre-clinical fetal and embryo 
toxicity studies, the inclusion criteria specifying contraception requirements were updated 
to extend the length of time for contraception use for subjects. A summary of the findings
from these preclinical studies may be found in the body of the protocol under 
Reproductive Risks in Section 1.5.
Revised Text:
Inclusion criteria 8: A female subject is eligible to participate if she is of:

Second bullet point: Child-bearing potential and agrees to use one of the 
contraception methods (described in Section 9.1) for an appropriate period of 
time (as determined by the product label or investigator) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy at that point.  Female 
subjects must agree to use contraception until at least 4 weeks 7 months after the 
last dose of study medication.
 
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Inclusion criteria 9: Male subjects must agree to use one of the methods of contraception 
specified.  This method must be used from the time of the first dose of study medication 
until least 16 weeks after the last dose of study medication.  In addition, male subjects 
whose partners are or become pregnant while on study medication must continue to use 
condoms for 7 days after stopping study medications.
Section 4.2.3.1. Permanent Discontinuation from Study Treatment
Rationale for Change: Updates were made to this section to further clarify the follow 
up phase requirements
Revised Text: 
Last Paragraph:
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in the 
Section 5 Time and Events Tables.
All subjects who permanently discontinue study treatment without disease progression 
will be followed for progression according the the protocol schedule until:

progression

death, or

subject has been followed for 2 years after stopping treatment
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy every 6 months until death or until the subject has been 
followed for 2 years.  Reporting of any pregnancies in female subjects and/or female 
partners of male subjects will also be collected until 7 months after the last dose of study 
drug.  Upon discontinuation, any samples previously collected for PD and/or translational 
research will be retained and tested as defined in the protocol, unless consent is 
specifically withdrawn.
 
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Section 5. TIME AND EVENTS TABLES
Rationale for Change: The time and events tables were modified to ensure 
consistency of timings, correct previous errors, provide additional clarifications and to 
include new updates based on removal of telemetry and revised holter monitoring 
schedule.
Revised Text:
Table 5
Time and Events: Part 1
q3w
and 
q6w 
Initiat
ed 
from 
Wk 
10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
6
W
7
W
1
0
q
3
W
q
6
W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
TREATMENT PHASE
Study Drug: For QD or BID details see Table 8 and Table 9
Administer study drug 
(Administer about same time of 
day. No food or antacids 1h 
before and 2h after.)
X X X X X X X X X X X X X X
Daily
Safety
Height and weight (Height at 
SCR only)
X X
X
X
X
X
X
X X X
X
Cardiac Monitoring
Holter monitoring
(At least 24 h, on dosing days 
start predose)
X X
X
X
X
X
Telemetry (Starting predose d1 
for min 48 h, remove on d3)
X 
Table 6
Time and Events: Part 1 Laboratory Assessments
Table column heading text q3w and q6w Initiated from Wk 10 has been added above the 
columns of q3WD1 and q6WD1.
Troponin, NT pro-BNP Assessment Notes:
Troponin: W1D1 &, W1D2: troponin local lab sample collect 3X/24hper day; central 
troponin lab sample 1X/24hper day. All other timepoints and uUnscheduled troponin, 
collect 2 samples: 1 for local, 1 for central lab.
 
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Table 7
Disease Specific Assessments: Part 1 and 2
Table column heading text q3w and q6w Initiated from Wk 10 has been added above the 
columns of q3WD1 and q6WD1 under Multiple Myeloma (MM) and Leukaemia 
Assessments.
Table column heading text q3w and q6w Initiated from Wk 10 has been added above the 
columns of q6WD1 and q12WD1 under Lymphoma Assessments.
Table 9
Time and Events: Part 1 (BID Cohorts) Serial Electrocardiograms,
Pharmacokinetics and Biomarker Sampling
12-lead ECG measurement added at 12 hours and  15 minutes time point at W1D1
The event name cytokine/APP changed to plasma cytokines samples
Table 10
Time and Events: Part 2 Expansion Cohort
Revised table column heading text “Further Cycles (q3w and q6w Initiated from Wk 10)” 
above the columns of q3WD1 and q6WD1.
Deleted a Part 2 Procedure “Telemetry (Starting predose d1,  for min 48 h, remove on d3) 
see Section 6.3.7” from the table.
Table 11
Time and Events: Part 2 Laboratory Assessments
Revised table column heading text “Further Cycles (q3w and q6w Initiated from Wk 10)” 
above the columns of q3WD1 and q6WD1.
The event name Cytokines changed to Safety Cytokines and the timing changed as 
follows: as clinically appropriate following fever
Section 6.3.4. Echocardiogram (ECHO)
Rationale for Change: This section was updated to clarify that GSK is receiving all
ECHOs, not just those with a >10% LVEF decrease from baseline. 
Revised Text:
For all subjects, ECHOs will be performed at screening and at assessment times as 
outlined in Section 5.  ECHOs should be evaluated and compared to baseline by the same 
reader.  Copies of all ECHO scans performed on subjects who experience an absolute 
decrease >10% in Left ventricular ejection fraction (LVEF) compared to baseline 
concurrent with LVEF < LLN will be required by GSK for review.
All ECHO data may will be transferred and reviewed by an independent cardiologist.
Section 6.3.6. Holter Monitoring
Rationale for Change: This section was updated to reflect the actual analysis of the 
Holter Monitoring at the central cardiac monitoring lab and clarify that ECGs are not 
 
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being extracted from the 24-hour holter; however arrhythmia assessments will continue at 
the central cardiac monitoring lab for the holter monitoring.
Revised Text:
Third paragraph onwards:
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory.  Around each of the designated time points, 3 ECGs will be 
selected approximately 2 minutes apart.  In order to increase consistency of ECG 
interpretation, a limited number of central ECG over-readers will be used throughout the 
study.  All ECGs for a given subject will be over-read by the same reader from the central 
validated ECG laboratory.  The central reader will be blinded to subject identifiers (e.g., 
subject number, age, and sex), treatment assignment, and study day when Holter data
ECGs were collected.  The final intervals and morphology analyses entered into the 
database will be those generated by the central ECG laboratory.
Baseline QT/QTcF values will be determined on Study Day -1 using time matched ECGs 
obtained from the Holter monitor at approximately the same time points as described in 
the Section 5 Time and Events.  The mean from triplicate ECGs will be evaluated at each 
time point.  For a given time point, the mean QTcF from 3 separate beats should be 
analyzed on each ECG.  Analysis of Lead II will be conducted with V5 as back-up and 
one of the remaining precordial leads as an alternative when T waves are not well defined 
in Leads II or V5.  QTcF for an individual beat will be calculated from the preceding RR 
interval since using the average heart rate (RR) intervals from the ECG could result in 
inaccurate QTcF calculations due to beat to beat variations in the RR intervals.
QT values should not be reported when the rhythm is other than sinus rhythm (sinus 
rhythm with normal respiratory variation is acceptable), and in intraventricular 
conduction delays (IVCD, QRS >120 msec).  The other ECG information (including the 
rhythm and presence of IVCD) should be reported.  The choice of the 3 consecutive beats 
to be measured should avoid ectopic beats and the first beat after an ectopic beat.  If 
IVCD occur, these should be reported.
Section 6.3.7. Telemetry 
Rationale for Change: The rationale for removing the 48-hour telemetry is explained 
above and all sections containing language around the original telemetry requirements 
were updated throughout the protocol.
Revised Text:
Whole section deleted:
6.3.7. Telemetry
To complement real-time ECG assessments, monitoring for potential adverse arrhythmias 
will be conducted utilizing continuous telemetry for at least 48 hours from the start of 
 
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dosing.  If clinically indicated, telemetry may be extended past 48 hours.  Participating 
sites will have trained staff capable of monitoring and responding in real time to any
potential cardiac adverse event detected by telemetry.  In addition, emergency 
resuscitation equipment including appropriate pharmacological agents will also be 
immediately accessible.  At the end of Part 1, an analysis of data collected on the QT 
interval up to, and including, the MTD expansion will be carried out. If the analysis by 
the GSK Cardiac Safety Panel of internal and external experts indicates that telemetry is 
no longer required for monitoring the QT interval, then the study can progress to the next 
stage without telemetry. 
Removal of the telemetry requirement will be conveyed to the sites in the first instance 
through a separate document (or “note to file”) that will note - i) a summary of the 
analysis, and ii) the decision to proceed without telemetry monitoring in the next stage of 
this study. This will allow the sites to submit the necessary documentation to the 
IECs/IRBs for approval and to start the next stage of this study without telemetry. 
However, this process will be permitted only if there are no other cardiac monitoring 
changes to be implemented. If additional cardiac monitoring changes are required, a 
protocol amendment will be necessary before the next stage of the study can start.
Section 6.5.2. Plasma Sample Analysis
Rationale for Change: A statement was added to further clarify planned analysis for 
plasma samples from subjects.
Revised Text:
First Paragraph:
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline.  Concentrations of 
GSK525762 will be determined in plasma samples using the currently approved 
analytical methodology.  In addition, selected metabolites of GSK525762 may also be 
quantified using approved analytical methodology. Raw data will be stored in the GLP 
Archives, GlaxoSmithKline.
Section 6.5.3. Urine Collection
Second Paragraph:
Selected urine samples may be analyzed qualitatively and/or quantitatively for 
GSK525762 metabolites and the results will be reported under a separate DMPK 
protocol.
Section 6.6. Translational Research
Rationale for Change: A statement was added in this section to further clarify 
analysis of samples from the leukemia population.
 
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Revised Text:
End of second paragraph:
In certain settings such as leukemia specimens, samples may be used to evaluate changes 
in leukemic stem cell populations or to generate PDX models.
Section 6.8.1. Time period for collecting pregnancy information
Rationale for Change: The length of time for collecting information on any possible 
pregnancies after stopping study drug was extended to 7 months based on emerging data 
from the preclinical female fertility studies in rats. The summary of findings from these 
studies may be found in the Reproductive Risks section under Risk Assessment Section 
1.5 of the protocol.
Revised Text:
Reporting of any pregnanciesAll pregnancies in female subjects and/or female partners of 
male subjects will be collected after the start of dosing and until 16 weeks 7 months after 
the last dose of study drug.
Section 8.2.1. Cautionary Medications
Rationale for Change: This table was updated with the most recent list of drugs with a 
Risk of Torsades de Pointes which are permitted with extreme caution during the study.
Revised Text:
Table 17
Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution
Generic Name
Brand Name
Clarithromycin
Biaxin
Haloperidol
Haldol
Section 8.2.2. Drugs Potentially Affecting GSK525762 Pharmacokinetics
Rationale for Change: This section was updated with emerging metabolite data from 
the ongoing clinical studies with GSK525762.
Revised Text:
The precise in vivo metabolic liability for GSK525762 has yet to be assessed.  In vitro 
data suggests that GSK525762 has a low potential to inhibit the major human CYP 
isoforms (IC50’s ≥ 33 µM) with no evidence for time dependent inhibition of CYP2D6 
or CYP3A4.  These results suggest a low risk for therapeutic drug interactions although 
inducers and inhibitors of both CYP2D6 and CYP3A4 should be avoided as they may 
increase or decrease exposure to GSK525762.  Table 18 provides a list of possible 
 
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medication including but not limited to those drug substances that may alter GSK525762 
exposure.
In vitro data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of inducers and inhibitors of CYP3A4 should be avoided during the 
course of the study where possible as they may respectively decrease or increase 
exposure to GSK525762. GSK525762 has low potential to inhibit the major human CYP 
isoforms (IC50’s ≥ 33 µM) or major transporters. There is no evidence for time 
dependent inhibition of CYP2D6 or CYP3A4. Potential interactions with other 
Cytochrome P450 metabolized drugs have not been assessed.
Table 18
Drugs Potentially Affecting GSK525762 Pharmacokinetics Resulting in 
Increased or Decreased GSK525762 Exposure
Drug Class 
Agent 
Drugs that may increase exposure to GSK525762 (CYP3A4 or CYP2D6 Inhibitors)
Antifungals 
Fluconazole (>150 mg daily), itraconazole, ketoconazole, terbinafine, 
posaconazole, voriconazole 
Antidepressants 
Bupropion, duloxetine, fluoxetine, fluvoxamine, nefazodone paroxetine,  
Cinacalcet, diphenydramine, perhexiline
Section 8.3. Prohibited Medications
Rationale for Change:
Revised Text: This section was updated to include additional drugs that may impact the 
exposure of GSK525762 based on emerging metabolite data from the ongoing clinical 
studies with GSK525762
Table 19
Drugs with a Risk of Torsades de Pointes that are Prohibited
Generic Name
Brand Name
Clarithromycin
Biaxin, Prevpac
Section 9.1.1. Female Subjects
Rationale for Change: Based on emerging data from pre-clinical fetal and embryo 
toxicity studies, the inclusion criteria specifying contraception requirements were updated 
to extend the length of time for contraception use for subjects. A summary of the findings 
from these preclinical studies may be found in the body of the protocol under 
Reproductive Risks in Section 1.5. Double Barrier method was also removed from 
Contraceptive Methods with a Failure Rate of 1% to align with the Clinical Trial 
Facilitation Group (CTFG)’s guidance related to contraception use in clinical trials which 
lists a combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) as an acceptable, but not a highly effective, birth 
control method.
 
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Revised Text:
Fourth Paragraph:
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping medications and so must be sexually inactive by abstinence or 
use contraceptive methods with a failure rate of < 1%.
Contraceptive Methods with a Failure Rate of 1%
Third bullet point:

Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository).
Section 9.1.2. Male Subjects
Rationale for Change: The additional guidance for condom use specific to males with 
a pregnant partner were included as there is not yet sufficient evidence to rule out the 
potential of GSK525762 being transferred to a developing embryo or fetus via the semen.
Revised Text:
At the end the following text added:
In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 7 days after stopping study medications.
Section 11.6.1. Primary Analysis
Rationale for Change: This section was updated to be in line with the Response 
Criteria for Leukaemias referenced in Section 15.8
Revised Text:
Third paragraph: Overall Response rate is defined as 
First bullet point:

AML: The percentage of subjects who achieved CR, CRp, CRi, and PR and a 
morphologic leukemia-free state. A waterfall plot of percent change from baseline in 
bone marrow blasts and peripheral blasts will be provided.  Response rates of 
subjects with AML M3 will be summarised separately.
 
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Section 11.6.2. Secondary Analysis
Rationale for Change: Minor correction
Revised Text:
Second paragraph: The duration of response is defined for the subject or subjects with a 
confirmed CR or PR for NHL, CR, CRp, CRi, or PR or morphologically leukemia free
for AML, and CR, VGPR, or PR for MM as the time from the first documented evidence 
response until the first documented disease progression or death due to any cause. 
Censoring rules for duration of response will be outlined in detail in the RAP.
Section 14. REFERENCES
Rationale for Change: This section was updated to be in line with the Response 
Criteria for Leukaemias referenced in Section 15.8
Revised Text:
Following references were deleted:
Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to 
standardize response criteria for myelodysplastic syndromes. Blood. 2000; 96: 3671-4.
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, 
Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003. 21:4642-9. Erratum in: J Clin Oncol. 2004; 22:576.
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood. 2006; 108: 419-25.
Following reference was added:
Cheson BD, Bennett JM, Kopecky KJ, et al..  International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003 Dec 
15;21(24):4642-9.
Section 15.5. Appendix 5: Pharmacogenetic Research
Rationale for Change: Minor Correction
 
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Revised Text:
PGx Associations with Safety Events
Collection of whole saliva samples, may enable PGx analysis to be conducted if at any 
time it appears that there is a potential unexpected or unexplained variation in handling or 
response to GSK525762.
Section 15.8.1. Acute Leukemias, MDS, Chronic Myelogenous Leukemia in 
Blast Phase (CML-BP), Chronic MyeloMonocytic Leukaemia (CMML)
Rationale for Change: This section was updated to reflect the Cheson 2003 response 
criteria.
Revised Text:
[Cheson, 2000; Cheson, 2004; Cheson, 2006 Modified Cheson 2003]
Complete remission (CR):  The subject must achieve a morphologic leukemia-free state 
(≤5% blasts) and have no evidence of extramedullary disease.  The subject must be free 
of all symptoms related to leukemia, and have an absolute neutrophil count 1 x 10
9/L 
and platelet count 100 x 10
9/L, and normal marrow differential (5% blasts) be 
transfusion independent.
CRp: Marrow response as per CR but platelet count <100 x 10
9/L.
CRi: Marrow response as per CR but platelet count <100 x 10
9/L or neutrophil count <1 
x 10
9/L.
Partial remission (PR): Count recovery as per CR, with 6 to 25% abnormal cells in the 
marrow or 50% decrease in bone marrow blasts. (AML only: If all other criteria for CR 
are met, then a value of <5% blasts with Auer rods present or abnormal morphology is 
considered partial remission) A decrease from baseline of at least 50% in the number of 
bone marrow blasts, to between 5% and 25% of the bone marrow aspirate.
No response: Subject does not meet criteria for CR, CRp, CRi, or PR.
Recurrence: Morphologic relapse, defined as the reappearance of peripheral blasts or 
increase in bone marrow blasts ≥ 5% not attributable to any other cause (e.g., infection, 
growth factor support, bone marrow regeneration)
Morphologic leukemia-free state: Normal marrow differential (<5% blasts); neutrophil 
and platelet counts are not considered.  (AML only)
Marrow CR:  Bone marrow: 5% myeloblasts and decrease by 50% over pre-treatment 
(MDS only) 
 
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Hematologic Improvement (HI): Hematologic improvement should be described by the 
number of individual, positively affected cell lines (e.g., HI-E; HI-E + HI-N; HI-E+ HI-P 
+ HI-N).
Erythroid response (HI-E)
Major response: For subjects with pretreatment hemoglobin less than 11 g/dL, 
greater than 2 g/dL increase in hemoglobin; for red blood cell (RBC) transfusion-
dependent subjects, transfusion independence.
Minor response: For subjects with pretreatment hemoglobin less than 11g/dL, 1 to 
2 g/dL increase in hemoglobin; for RBC transfusion-dependent subjects, 
50% decrease in transfusion requirements.
Platelet response (HI-P)
Major response: For subjects with a pretreatment platelet count less than 
100 x 109/L, an absolute increase of 30 x 109/L or more; for platelet transfusion-
dependent subjects, stabilization of platelet transfusion independence.
Minor response: For subjects with a pre-treatment platelet count less than 
100 x 109/L a 50% or more increase in platelet count with a net increase greater than 
10 x 109/L but less than 30 x 109/L.
Neutrophil response (HI-N)
Major response: For absolute neutrophil count (ANC) less than 1.5 x 109/L before 
therapy, at least a 100% increase, or an absolute increase of more than 0.5 x 109/L, 
whichever is greater.
Minor response: For ANC less than 1.5 x 109/L before therapy, ANC increase of at 
least 100%, but absolute increase less than 0.5 x 109/L.
Progression/relapse after HI:  One or more of the following: a 50% or greater 
decrement from maximum response levels in granulocytes or platelets, a reduction in 
hemoglobin concentration by at least 2 g/dL, or transfusion.
 
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15.19.
Appendix 19: Protocol Changes for Amendment 6 (15-MAR-
2016) from the Protocol Amendment 5 (08-JUL-2015)
Where the Amendment Applies
Amendment 6 applies to all study centres. 
General Protocol Changes
Amendment 6:  Updated Section 6.1.2. Visit Windows to provide additional clarification 
on clinical visits. Updated Section 7.1. GSK525762 Investigational Product 
Dosage/Administration to include both amorphous free base and crystalline besylate 
formulations of GSK525762 in the study. Updated Section 7.3. Meals and Dietary 
Restrictions to include the meals and dietary requirements for the new besylate 
formulation included in the study.Minor clarifications, reformatting of tables and 
typographical errors were also addressed in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Changes
Sponsor/medical monitor Information Page
Medical Monitor and Sponsor Contact Information:
Rationale for Change: Change in primary and secondary medical monitors.
Revised Text:
Role
Name
Day 
Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
 
 MD, 
PhD
 
MD, PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
, 
MD, Ph
 
 MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
Section 5 TIME AND EVENTS TABLES
Rationale for Change: Minor change was made to ensure consistency with the body 
text.
 
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Revised Text:
Table 10 Time and Events: Part 2 Expansion Cohort
Part 2 Procedure (Notes): 
TREATMENT PHASE
Study Drug
Dispense study drug (Administer 
about same time of day. No food or 
antacids 1h before and 2h after.)
Continuous daily dosing (unless safety, PK or 
PD data necessitate a different dosing 
schedule), see Section 3.2.4
X
Section 6.1.2. Visit Windows
Rationale for Change: This section was revised to provide additional clarification on 
clinical visits.
Revised Text:
Fifth paragraph onwards:
Every 3-week and 6-week visits Week 10 through Week 48 Clinic visits can be 
scheduled 7 days.
After Week 48: Every 3-week visits are no longer required, based on clinical judgment.  
Every 6-week clinic visits must include safety assessments from the “q3w” column in the 
Time and Events Table and can be scheduled 7 days.  Response assessments may be 
scheduled 7 days.
Visits after Week 10 may be scheduled 7 days.
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for Change: This section was revised to include both amorphous free base 
and crystalline besylate formulations of GSK525762 in the study.
Revised Text:
GSK525762 tablets will be provided to sites by GSK.  The contents of the label will be in 
accordance with all applicable regulatory requirements. An amorphous, free-base 
formulation of GSK525762 (Table 14) and a crystalline, besylate formulation (Table 15) 
will be utilized.  
In the BET115521 study, a sub-study was conducted to evaluate the PK characteristics of 
the new besylate formulation. This sub-study was an open-label, randomized, single dose, 
four period, cross over sub-study performed to investigate the relative bioavailability of 
the besylate tablet compared to the amorphous free-base tablet, the effect of high-fat 
high-calorie meal on the bioavailability of the besylate tablet and the dose proportionality 
of two doses of GSK525762 administered as besylate tablets. 
 
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The sub-study results showed that  the besylate salt coated tablet is bioequivalent to the 
amorphous free-base uncoated tablet. In addition, there is a lack of effect of a high-fat 
high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered as 
besylate coated tablets while administration with food tended to slightly decrease Cmax. 
The fasting requirement is thus no longer necessary in subjects taking the besylate 
formulation in Part 2.  
Either amorphous or besylate tablets may be used in Part 1, based on the bioequivalence 
described above.  During the DLT observation period, subjects will only receive one or 
the other formulation; any individual cohort will only enrol subjects receiving a single 
formulation type.  Upon completion of the DLT observation window, subjects may be 
changed from amorphous to besylate tablets at the equivalent dose.
The besylate tablet will be utilized in Part 2.
When used under the conditions of handling and administration described in Section 7.2, 
investigational product is not expected to pose significant safety risks to site staff.  A 
Material Safety Data Sheet (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request.
Table 14
GSK525762 Amorphous Free Base Investigational Product Dosage/ 
Administration
Investigational Product
Product name:
GSK525762 Amorphous Free Base Tablets
Unit dose strength(s)/Dosage level(s):
1mg
10mg
30mg
Dosage form
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Physical description:
white to off-white, round, biconvex tablets with no markings
Route/
Administration/ Duration:
Oral; see the Section 5 Time and Events Tables for 
schedule and administration timings
Dosing instructions:
Dose with 240 mL water and should be taken within a 
similar time frame each morning.  No food or antacids for at 
least 1h before and 2h after dosing.  (If a subject vomits 
after taking study drug, the subject should be instructed not 
to retake the dose and should take the next scheduled 
dose.)
 
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Table 15 GSK525762 Besylate Investigational Product Dosage/Administration
Investigational Product
Product name:
GSK525762 Besylate Tablets
Unit dose strength(s)/Dosage level(s):
5mg
25mg
50mg
Dosage form
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Physical description:
White to slightly 
colored round, 
biconvex tablets with 
no markings, film-
coated tablet
White to slightly colored , 
oval, biconvex tablets with 
no markings, film-coated 
tablet
Route/
Administration/ Duration:
Oral; see Time and Event Tables for schedule and 
administration timings
Dosing instructions for Part 1:
Dose with 240 mL water and should be taken at the 
same time each day, preferably in the morning. No 
food or antacids for at least 1h before and 2h after 
dosing. (If a subject vomits after taking study drug, 
the subject should be instructed not to retake the 
dose and should take the next scheduled dose.)
Dosing Instructions for Part 2
Dose with 240mL water and should be taken at the 
same time each day, preferably in the morning. (If a 
subject vomits after taking study drug, the subject 
should be instructed not to retake the dose and 
should take the next scheduled dose.)
Section 7.3. Meals and Dietary Restrictions
Rationale for Change: This section was revised to include the meals and dietary 
requirements for the new besylate formulation included in the study.
Revised Text:
Subjects enrolled under Part 1 will fast for at least one hour prior to each dose of study 
drug (amorphous free or besylate). No food or antacid should be taken for 2 hours after 
dosing. Subjects should not eat a heavy meal in the morning prior to the 1 hour washout 
before dosing to minimize potential risk for food interaction.  On serial PK sampling 
days, subjects should fast overnight (i.e., at least 8 hours). After dosing, subjects will be 
asked to fast for an additional two hours.  These fasting requirements have been 
implemented in the protocol and informed consents to minimize PK variability.
 
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If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next scheduled dose.Requirements for fasting before 
and after dosing may be modified based on emerging PK, PD and safety data.  Any 
change in fasting requirements will be communicated to each investigator and site staff in 
a future protocol amendment.  Should a twice daily regimen be required, additional 
consideration will be paid to this requirement once the escalation period is past.
Fasting will consist of avoiding the oral ingestion of calorie-containing products; 
however, ingestion of water is permitted.
Based on the results of the BET115521 sub-study showing a lack of effect of a high-fat 
high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered as 
besylate coated tablets, the fasting requirement is being lifted for subjects in Part 2 only 
except on Serial PK sampling days (Week 1 and Week 4).  On these days, subjects should 
fast overnight (i.e., at least 8 hours). After dosing, subjects will be asked to fast for an 
additional two hours.  These fasting requirements have been implemented in the protocol 
and informed consents to minimize PK variability.
 
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15.20.
Appendix 20: Protocol Changes for Amendment 7 (23-JUN-
2016) from the Protocol Amendment 6 (15-MAR-2016)
Where the Amendment Applies
Amendment 7 applies to all study centres. 
General Protocol Changes
Amendment 7: Study design was amended to include collection of additional safety data 
of GSK525762 BID dosing (exploratory cohort) after determination of maximum 
tolerated dose with QD dose and to evaluate the preliminary efficacy of GSK525762 BID 
dosing. The secondary objectives of Part 1 were updated to include evaluation of clinical 
efficacy of GSK525762 (overall response rate). The endpoints for secondary objective of 
Part 2 (determination of clinical activity of GSK525762) was updated to include TTP, 
DOR, PFS for MM and NHL. Eligibility criteria were clarified specifying hematologic 
malignancies (AML, MM, NHL) for both Part 1 and 2. Risk associated with drug 
interaction was updated. Permanent discontinuation from study treatment section was 
updated. Time and events tables were also updated in line with study design 
modifications. Whole section of urine collection was removed. Tables of cautionary 
medications, prohibited medications and drugs affecting PK of GSK525762 were
updated. Interim analysis was included for part 1. Minor clarifications, formatting and 
typographical errors were also addressed in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
15.17.1        List of Changes 
Title Page, Authors
Rationale for change:  The sponsor information were updated based on internal GSK 
team personnel changes.
Revised Text:
Oncology Stats and Programming, USA
Precision Medicine and Diagnostics, USA
Biology, Epigenetics Management, USA
Global Clinical Operational Sciences, USA
Global Clinical Safety & Pharmacovigilance, USA
RD PCPS Qsci Clinical Statistics, USA
Global Formulation Development, PTS, USA
Biotransformation and Drug Disposition, PTS, UK
Molecular Medicine Unit, USA
Cancer Research Epigenetics Management, USA
Clinical Pharmacology Modeling & Simulation, USA
Global Clinical Operational Sciences, USA
Global Clinical Operational Sciences, USA
               
Precision Medicine and Diagnostics, USA
Clinical Oncology, USA
 
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Global Clinical Operational Sciences, UK
Precision Medicine and Diagnostics, USA
SA Pathology, PTS, UK
EpiNova DPU, UK
Global Clinical Safety & Pharmacovigilance, USA
Biology, Epigenetics Management, USA
Statistics, Oncology TA Group, USA
LIST OF ABBREVIATIONS
Rationale for Change: Abbreviation deleted and added as part of the protocol 
amendment
Deleted/Added Text: 
CV
Coefficient of variance
CTCL
Cutaneous T cell lymphoma
DHL
Double hit lymphoma
DLBCL
Diffuse large B cell lymphoma
DOR
Duration of Response
EOT
End of treatment
FL
Follicular lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
ISS
International Staging System
ORR
Overall Response rate
PFS
Progression Free Survival
TTP
Time to Progression
PROTOCOL SYNOPSIS

STUDY DESIGN AND DURATION:  
Rationale for Change: Twice daily dosing will no longer be completed prior to 
determining the Maximum Tolerated Dose (MTD) if a twice daily dosing is explored this 
will occur after the MTD/R2PD has been determined.
Revised Text:

Eligible subjects with select relapsed refractory hematological malignancies(acute 
myeloid leukemia [AML], non-Hodgkin’s Lymphoma [NHL]and multiple 
myeloma [MM]),  will be enrolled in once daily (QOD) and/or twice daily (BID) 
dosing cohorts until a maximum tolerated dose (MTD) is established. Subjects 
 
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may continue treatment in the study until disease progression, unacceptable 
toxicity, or withdrawal of consent.  Upon determination of the MTD, twice daily 
(BID) dosing cohorts may be opened to collect additional safety data and evaluate 
the preliminary efficacy of GSK525762 administered BID.

STUDY RATIONALE
Rationale for Change: This section was updated to further clarify the disease 
subtypes.  
Revised Test: 
Current data from GSK525762 preclinical development indicate a potential to inhibit the 
BET family of bromodomain (BRD) proteins and that this inhibition may have clinical 
utility in the treatment of various tumors, including hematological malignancies. 
Relapsed and/or refractory hematological malignancies such as Acute Myeloid Leukemia 
(AML), Adult Acute Lymphoblastic Leukemia (ALL), non-Hodgkin’s Lymphoma 
(NHL), and Multiple Myeloma (MM) and high-risk Myelodysplastic Syndromes (MDS)
have an overall poor outlook. This is the first study of this agent to be conducted in 
subjects with these relapsed and/or refractory hematological malignancies for which no 
standard therapies are anticipated to result in a durable remission with few or no 
conventional treatment options that could be expected to provide any lasting benefit. 

OBJECTIVES AND ENDPOINTS:
Rationale for Change: This section was updated to remove twice daily dosing from 
the primary objectives, Overall response rate and safety and tolerability were added as 
secondary endpoints and metabolite and urine excretion endpoints have been removed 
from exploratory research.  
Revised Text:
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) 
administrationand/or twice daily (BID) 
dosing schedules, establishing the 
recommended Phase 2 dose (RP2D) 
of GSK525762 in adult subjects with 
acute myeloid leukemia (AML), 
multiple myeloma (MM), or non-
Hodgkin’s lymphoma (NHL).

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
 
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Part 1 Objectives
Part 1 Endpoints
Secondary

To evaluate clinical efficacy following 
QD administration in subjects with 
AML, MM, and NHL.

Overall response rate (ORR), as 
measured by standard response 
criteria

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration following 
QD and/or twice daily (BID) dosing 
schedules.

GSK525762 PK parameters following 
single- and repeat-dose administration 
of GSK525762, including Area under 
concentration-time curve(AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters following 
QD and/or BID dosing schedules.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC), following 
single and repeat-dose oral 
administration of GSK525762)

To evaluate the relationship between 
GSK525762 dose/exposure and 
pharmacodynamic (PD) response 
following QD and/or BID dosing 
schedules.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess overall response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To evaluate safety, tolerability, and 
efficacy following BID administration 
of GSK525762 in subjects with AML, 
MM, and NHL

AEs, SAEs, DLTs, dose reductions or 
delays, withdrawals due to toxicities, 
changes in safety assessments, and 
ORR (as measured by standard 
response criteria)
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762 
following QD and/or BID dosing 

Pharmacogenomic (PGx) study using 
clinical samples.
 
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Part 1 Objectives
Part 1 Endpoints
schedules.

To investigate the mechanism of 
action and indicators of 
sensitivity and resistance to 
GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response.

To generate samples (data 
reported separately) with which 
to characterize the metabolic 
profile of GSK525762 after single 
and repeat-dosing (In the PK/PD 
expansion cohort only).

Samples to characterize the 
metabolites in plasma and/or urine.

To determine the amount of 
GSK525762 excreted in urine 
after oral single and repeat-
dosing.

Concentration of GSK525762 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over 
time.
Hypothesis

No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in acute 
myeloid leukemia (AML).

For AML: Objective response rate (% of 
subjects achieving Complete Response 
[(CR]), Partial Response (PR), CRp [(as 
per CR but platelet count <100 x 109/L]), 
CRi [as per CR but platelet count <100 x 
10
9/L or neutrophil count <1 x 10
9/L], or 
Partial Response [PR],morphologic 
leukemia-free state) per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in multiple 
myeloma (MM)

For MM: Objective response rate (defined 
as the percentage of subjects that have 
achieved a stringent CR [sCR], CR, very 
good partial response [VGPR], or PR) per 
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in non-
Hodgkin’s Lymphoma (NHL)

For NHL: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, or PR) per response 
criteria.
Secondary

To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL after repeat-dose administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 

PK/PD relationship between 
 
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Part 2 Objectives
Part 2 Endpoints
(i.e., PK/PD) relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL.
GSK525762 exposure markers and 
safety and efficacy parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 3 disease-
specific cohorts of subjects with AML, 
MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.

To evaluate the relationship between 
GSK525762 doseexposure and PD 
response in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL.

Dose related change in molecular 
markers (e.g., gene transcription 
and/or expression of proteins 
regulated by BRD proteins) in tumor 
tissue and/or peripheral blood 
samples.

To determine the clinical activity 
of GSK525762 in 3 disease-
specific cohorts of subjects with 
AML, MM or NHL.

TTP (Time to Progression) , DOR 
(Duration of Response),  PFS 
(Progression Free Survival) for MM 
and NHL 

Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for AML, MM and NHL.
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and
safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To investigate the mechanism of 
action and indicators of 
sensitivity and resistance to 
GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response; Leukemic Stem 
Cell studies; PDX model studies and 
other translational medicine studies.

INCLUSION/EXCLUSION CRITERIA:
Inclusion Criteria
Rationale for Change: This section was updated to clarify and standardize NHL and 
MM eligibility. 
Revised Text:
Inclusion criteria 2: Males and females 18 years old or olderInclusion criteria 3 and 4: In 
Part 1 and, subjects must have relapsed and/or refractory hematologic malignancies (e.g., 
 
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leukemias, myeloproliferative neoplasms, lymphomas, and myelomas) for which no 
standard therapies are available or anticipated to result in remission. 
In Part 2, subjects must have Acute Myeloid Leukemia (AML), Multiple Myeloma 
(MM), or non-Hodgkin’s Lymphoma (NHL).

Subjects with AML (Part 1 and Part 2), are eligible if they
o have relapsed and/or refractory disease, OR
o are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

Subjects with multiple myeloma are eligible if they have progressed despite 
therapy with an alkylating agent, proteasome inhibitor, and immunomodulatory 
agent, either as individual regimens or in combination.

Subjects with NHL are eligible if they have received at least two prior lines of 
systemic therapy, including at least one line of immunochemotherapy with an 
anti-CD20 antibody (if their tumor expresses CD20).
In Part 2, the NHL cohort will separately enrol subjects with double- and 
triple hit lymphoma, so that a minimum of 10 subjects with this subset of 
disease will be enrolled. To be eligible for this sub-cohort, tumor sample 
from the subject must demonstrate rearrangement and/or overexpression 
of MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or 
triple-hit status may be performed via appropriate local testing, and the 
determination of double- or triple-hit diagnosis will be at the discretion of 
the investigator and GSK Medical Monitor.
Inclusion criteria 9: Male subjects must agree to use one of the methods of contraception 
specified.  This method must be used from the time of the first dose of study medication 
until 16 weeks after the last dose of study medication.  In addition, male subjects whose 
partners are or become pregnant while on study medication must continue to use 
condoms for 7 days after stopping study medications.
Definitions for Adequate Organ Function
System
Laboratory Values
Renal
Creatinine3
OR
Calculated creatinine clearance [calculated by Cockcroft 
Gault formula2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN (≤2 X ULN for MM)
≥ 50 mL/min
≥ 50 mL/min
1.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
2.
Refer to Appendix 1 for Cockcroft Gault formula
3.
For MM subjects, adequate renal function is defined as serum creatinine ≤2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥ 30 mL/min
4.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
 
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Exclusion Criteria
Rationale for Change: This section was updated to clarify the allowable timeframe.
Revised Text:
Exclusion criteria 3, second Note, first sentence: 
Note: the following are NOT allowed:
Investigational anti-cancer drug within 2 weeks (or 5 half-lives of the drug, 
whichever is longer) prior to the first dose of GSK525762.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN: 
Rationale for Change: This section was updated to remove exploring twice daily 
dosing in the determination of the MTD.
Revised Text:
Third sentence
BID dosing will be explored in a parallel cohortonce MTD has been identified in once 
daily dosing; the total daily dose administered BID will not exceed the QD MTD.

EFFICACY MEASUREMENTS: 
Rationale for Change: This section was updated to add Overall response rate and 
Overall survival as efficacy measures
Revised Text:

Type ORR and OS in AML, MM, and NHL; time to progression and duration of 
response in AML, MM and NHL.

STASTICAL ANALYSIS: 
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for the flexibility to conduct an interim analysis at some point during the study 
prior to the end of Part 2
Revised Text:
Second sentence
All data will be pooled and descriptive safety analyses summarized and listed by cohort 
at study conclusion of Part 2 expansion cohorts. Additional analyses may occur between 
Part 1 and Part 2; details will be included in the Reporting Analysis Plan (RAP).  
Last sentence
For additional details, please refer to the reporting and analysis plan (RAP).
 
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Section 1.2. Study Population Rationale
Rationale for Change: This section was updated to clarify the indications.
Revised Text:
First paragraph, first sentence
Relapsed and/or refractory hematological malignancies such as AML, ALL, NHL, and
MM and high-risk Myelodysplastic Syndromes (MDS) have an overall poor outlook.  
Figure 1
Hematological cancer cell line sensitivity to GSK525762, 63-day growth-death assay
Cell Line 
Tumor Type
% Sensitive Linesa
Total Lines 
Median gIC50
ALL
100
4
0.29
AML
96
25
0.10
Burkitt 
50
8
1.2
CML
100
4
0.32
CTCL
100
3
0.22
DLBCL
90
29
0.17
Erythroleukemia
100
2
0.38
 
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Cell Line 
Tumor Type
% Sensitive Linesa
Total Lines 
Median gIC50
FL
100
4
0.06
MCL
80
5
0.80
MM
100
12
0.06
a.
Cell lines defined as sensitive to GSK525762 if the gIC50 <1.0 M.  
Abbreviations:  ALL = Acute lymphoblastic leukemia; AML = Acute myeloid leukemia; CML = Chronic myeloid 
leukemia; CTCL = Cutaneous T cell lymphoma; DLBCL = Diffuse large B cell lymphoma; 
FL = Follicular lymphoma; gIC50 = Growth IC50, 6-day assay; MCL = Mantle cell 
lymphoma; MM = Multiple myeloma.
Third paragraph, first two sentences
Ninety-one percent of hematological cancer cell lines tested (94/10487/96) are highly
sensitive to GSK525762, exhibiting growth IC50 (gIC50) values below 1.0M. Some of 
the most sensitive hematological cancer cell types include CML FL (median gIC50= 
4060 nM), MM (median gIC50= 4960 nM), CTCL (median gIC50= 77 nM), and AML 
(median gIC50= 94 100 nM), and DLBCL (median gIC50=  170 nM).
Section 1.3.1.1.2. Human Pharmacokinetics and Equivalent Exposure for 
NOEL for QTc prolongation
Rationale for Change: This section was updated to include reference to the latest 
Investigator Brochure, rather than include a summary of the pharmacokinetic data 
collected to date in this section, as study is ongoing and data is continuously emerging.
Revised Text:
Last sentence
Updated PK information obtained up to January 2016 is available in the Investigator’s 
Brochure Section 5.2after first subject first dose is presented in Section 15.10. 
Section 1.3.2.2. Clinical Rationale for BID
Rationale for Change: This section was updated to include reference to the latest 
Investigator Brochure, and provide brief summary of data analysed to date.  
Revised Text:
Pharmacokinetics of GSK525762 has been evaluated in subjects in studies BET115521 
and BET116183 following single and repeated daily administration of GSK525762 
Section 15.10. 
 
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As described in the GSK525762 IB, Section 5.2, GSK525762 pharmacokinetics 
following once and twice daily administration is characterized by a rapid absorption with 
maximum concentration occurring mostly within two hours the first hour after dosing. 
GSK525762 is eliminated rapidly with an average terminal phase half-life of 3 to 7 hours, 
leading to a lack of accumulation following once daily oral administration. Following 
single oral administration and repeated once daily administration of 2 mg to 60 mg of 
GSK525762, Cmax and AUC tended to increase in a dose proportional fashion.
Based on the pharmacokinetics of GSK525762 observed to date, and evidence of a short 
half-life of about 5 hours, trough concentrations at 100 mg QD are predicted to be below 
the average in vitro IC50 (0.08 uM to 1.3 uM) for the tumor types selected for this study. 
Furthermore, based on the pharmacokinetics to date, it is predicted that even 100 mg QD 
doses would result in the trough concentrations below the average in vitro IC50.  
Dividing the daily dose into two doses administered about 12 hours apart would allow the 
trough concentration to be above the lower in vitro IC50 for doses around 30 mg BID.
Section 1.3.2.3. Starting Dose for BID
Rationale for Change: This section was updated to include reference to the latest 
Investigator Brochure, and provide brief summary of data analysed to date.  
Revised Text:
As detailed in the GSK525762 IB, Section 5.2.2 and Section 5.3.1, doses of 20 mg and 
30 mg BID have been administered to subjects with solid tumors.  The PK and 
safety/tolerability profile for the 30 mg BID dose is comparable to subjects treated with 
an equivalent total daily dose (i.e., 60 mg once daily).  In this study, once the QD MTD 
of GSK525762 has been identified for each disease subtype (AML, MM, and NHL), an 
exploratory cohort will be opened for each disease type to evaluate safety, tolerability, 
and preliminary efficacy of BID dosing.  
For each disease subtype, the total daily dose selected for BID evaluation will be no 
higher than the once-daily MTD, divided approximately equally between two doses  
administered approximately 12 hours apart.  
The maximum starting dose for BID will be 20 mg provided the 40 mg QD dose cohort 
has been cleared. A lower BID starting dose will may be considered depending on 
emerging safety, PK, and PD data.
Section 1.3.3. Dose escalation steps (QD Only)
Rationale for Change: Removed BID as this will no longer be a part of dose 
escalation
Revised Text:
1.3.3.  Dose escalation steps (QD only)(QD and BID)
 
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Section 1.5.1. Risk Assessment
Rationale for Change: This section was updated based on emerging metabolite data.
Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Drug Interactions
There is low potential for GSK525762 to 
induce or inhibit cytochrome P450 (CYP) 
enzymes or to inhibit P-glycoprotein (Pgp) or 
Breast Cancer Resistance Protein (BCRP).
The precise in vivo metabolic liability for 
GSK525762 has yet to be assessed.  In vitro
data suggests that GSK525762 has a 
negligible turnover and low potential to inhibit 
the major human CYP isoforms (IC50s ≥ 33 
μM) with no evidence for time dependent 
inhibition of CYP2D6 or CYP3A4.
GSK525762 is a substrate for CYP3A4 
enzymes, and for P-gp and BCRP 
transporters. 
GSK525762 clearance is virtually solely via 
CYP3A4.  There is evidence of potential auto-
induction after repeat dosing in clinical studies 
since reduction in parent exposures (~25% at 
lower doses to ≥60% at doses ≥60mg, mainly 
in BET115521 study) have been observed.
There is low potential for GSK525762 to 
induce or inhibit cytochrome P450 (CYP) 
enzymes or to inhibit P-glycoprotein (Pgp) or 
Breast Cancer Resistance Protein (BCRP) 
based on in vitro data. GSK525762 was 
shown to be an inhibitor of OATP1B1 and 
OAT3 in vitro.
The potential for drug-drug 
interactions will be monitored in 
clinical trials.
Use of concomitant medications, 
herbal medicines and fruit juices 
that are strong or moderate 
CYP3A4 inhibitors or inducers 
should be avoided during the 
course of the study where possible 
as they may respectively decrease 
or increase exposure to 
GSK525762.
Use of concomitant medications 
that are sensitive substrates of 
OATP1B1 and OAT3 should be 
done with caution.
Section 1.5.2. Benefit Assessment
Rationale for Change: This section was updated to clarify eligibility. 
Revised Text:
First sentence
Study BET116183 is an open-label, dose escalation study and the first study of this agent 
 
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to be conducted in subjects with hematological malignancies for which no standard 
therapies are anticipated to result in a durable remission that have not responded to or 
have relapsed following standard therapy.  
Section 2. OBJECTIVE, ENDPOINTS, HYPOTHESIS
Rationale for Change: This section was updated to remove twice daily dosing from 
the primary objectives.  Overall response rate and safety and tolerability were added as 
secondary endpoints and metabolite and urine excretion endpoints have been removed 
from exploratory research.  
Revised Text:
Part 1
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety, tolerability 
and maximum tolerated dose (MTD) 
following once daily (QD) 
administrationand/or twice daily (BID) 
dosing schedules, establishing the 
recommended Phase 2 dose (RP2D) 
of GSK525762 in adult subjects with 
acute myeloid leukemia (AML), 
multiple myeloma (MM), or non-
Hodgkin’s lymphoma (NHL).

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters).
Secondary

To evaluate clinical efficacy following 
QD administration in subjects with 
AML, MM, and NHL.

Overall response rate (ORR), as 
measured by standard response 
criteria

To characterize the Pharmacokinetic 
(PK) of GSK525762 after single- and 
repeat-dose administration following 
QD and/or twice daily (BID) dosing 
schedules.

GSK525762 PK parameters following 
single- and repeat-dose administration 
of GSK525762, including Area under 
concentration-time curve(AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters following 
QD and/or BID dosing schedules.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC), following 
 
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Part 1 Objectives
Part 1 Endpoints
single and repeat-dose oral 
administration of GSK525762)

To evaluate the relationship between 
GSK525762 dose/exposure and 
pharmacodynamic (PD) response 
following QD and/or BID dosing 
schedules.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess overall response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To evaluate safety, tolerability, and 
efficacy following BID administration 
of GSK525762 in subjects with AML, 
MM, and NHL

AEs, SAEs, DLTs, dose reductions or 
delays, withdrawals due to toxicities, 
changes in safety assessments, and 
ORR (as measured by standard 
response criteria)
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762 
following QD and/or BID dosing 
schedules.

Pharmacogenomic (PGx) study using 
clinical samples.

To investigate the mechanism of 
action and indicators of 
sensitivity and resistance to 
GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response.

To generate samples (data 
reported separately) with which 
to characterize the metabolic 
profile of GSK525762 after single 
and repeat-dosing (In the PK/PD 
expansion cohort only).

Samples to characterize the 
metabolites in plasma and/or urine.

To determine the amount of 
GSK525762 excreted in urine 
after oral single and repeat-
dosing.

Concentration of GSK525762 in urine 
measured with an investigational bio-
analytical method and extrapolated to 
total amount excreted in urine over 
time.
Hypothesis

No formal statistical hypotheses will be tested in Part 1.  Analysis will be descriptive and 
exploratory.
 
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Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in acute 
myeloid leukemia (AML).

For AML: Objective response rate (% of 
subjects achieving Complete Response 
[(CR]), Partial Response (PR), CRp [(as 
per CR but platelet count <100 x 109/L]), 
CRi [as per CR but platelet count <100 x 
10
9/L or neutrophil count <1 x 10
9/L], or 
Partial Response [PR],morphologic 
leukemia-free state) per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in multiple 
myeloma (MM)

For MM: Objective response rate (defined 
as the percentage of subjects that have 
achieved a stringent CR [sCR], CR, very 
good partial response [VGPR], or PR) per 
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in non-
Hodgkin’s Lymphoma (NHL)

For NHL: Objective response rate (defined 
as the percentage of subjects that have 
achieved a CR, or PR) per response 
criteria.
Secondary

To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL after repeat-dose administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 
(i.e., PK/PD) relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL.

PK/PD relationship between 
GSK525762 exposure markers and 
safety and efficacy parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 3 disease-
specific cohorts of subjects with AML, 
MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.

To evaluate the relationship between 
GSK525762 doseexposure and PD 
response in 3 disease-specific 
cohorts of subjects with AML, MM or 
NHL.

Dose related change in molecular 
markers (e.g., gene transcription 
and/or expression of proteins 
regulated by BRD proteins) in tumor 
tissue and/or peripheral blood 
samples.
 
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Part 2 Objectives
Part 2 Endpoints

To determine the clinical activity 
of GSK525762 in 3 disease-
specific cohorts of subjects with 
AML, MM or NHL.

TTP (Time to Progression) , DOR 
(Duration of Response),  PFS 
(Progression Free Survival) for MM 
and NHL 

Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for AML, MM and NHL.
Exploratory

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To investigate the mechanism of 
action and indicators of 
sensitivity and resistance to 
GSK525762.

Transcriptomics and protein studies of 
blood and tumor cells; correlation of 
tumor baseline genetic and genomic 
profiles with response; Leukemic Stem 
Cell studies; PDX model studies and 
other translational medicine studies.
Section 3.1. Study Design/Schematic
Rationale for Change: This section was updated to remove twice daily dosing from 
the escalation phase.  
Revised Text:
Second paragraph
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD in 
subjects with acute myeloid leukemia, and multiple myeloma, and /non-Hodgkin’s 
Lymphoma, and the recommended Phase 2 dose (RP2D) for GSK525762 given once-
daily (QD) orally and twice daily (BID) orally.  Safety, tolerability, PK, and efficacy will 
also be explored in a limited number of subjects treated twice daily (BID). Both 
PartsPart 1 will be conducted in adult subjects with relapsed and/or refractory 
hematological malignancies.  Expansion cohorts (Part 2) are planned to further explore 
clinical activity of GSK525762 in subjects with acute myeloid leukemias, multiple 
myeloma, and non-Hodgkin’s lymphomas (Figure 3).
Revised Figure 3
Figure was modified to remove assessment of BID dosing in parallel with QD. Number 
of subjects were also modified. 
Section 3.2.1. Part 1: Dose Escalation
Rationale for Change: This section was updated to remove twice daily dosing from 
the escalation phase.  
 
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Revised Text:
Second paragraph
Thereafter, subjects will be enrolled in a standard 3+3 design.  Separate dose escalation 
cohorts will be opened for subjects with AML, NHL, and MM, as well as for QD and 
BID dosing.
Fourth paragraph
Dose escalation will continue until an MTD is determined or until a dose of 200 mg per 
day is reached.  After the MTD has been determined for a disease type in Part1, then BID 
cohort(s) (Section 3.2.1.5) and the Part 2 dose expansion cohorts will be opened for that 
disease type. 
Section 3.2.1.2. Accelerated Dose Escalation in Part 1 
Rationale for Change: This section was updated to remove twice daily dosing from 
the escalation phase.  
Revised Text:
Table 2, footnote
NOTE: Route/Administration/Duration: Oral QD or BID (specific dosing instructions will be provided to each subject)
Section 3.2.1.3. 3 + 3 Dose Escalation in Part 1 
Rationale for Change:  This section was updated to clearly define the percentage of 
doses a subject must receive to be evaluable.
Revised Text:
Third paragraph
Subjects unable to receive at least 75% of scheduled doses for reasons other than toxicity 
(e.g., acute illness, disease progression) will not be evaluable for DLT purposes and will 
be replaced in the cohort.
Revised Figure 4
Figure was modified to clarify assessment of BID dosing after MTD is declared with QD 
dosing. 
Section 3.2.1.4. Alteration Schedule 
Rationale for Change: This section was updated to add specifics altering decisions 
based on  toxicities.   Additionally added specific language as to the PK sampling that is 
required when a dose reduction/escalation occurs.  
 
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Revised Text:
Third and fourth paragraph
Subjects may need to undergo dose modification(s) to manage toxicities.  A dose 
adjustment may be made after consultation with the GSK medical monitor. The 
investigator should use clinical judgment to determine whether the dosing scheduling 
may be contributing to any potential toxicity necessitating dose adjustment, and make the 
appropriate change after consultation with the GSK Medical Monitor.
In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling (pre-dose, 0.5, and 3 
hours) at the new dose level, after 4-7 days at the adjusted dose level.
Section 3.2.1.5. BID Dosing 
Rationale for Change: This section was updated to clarify that BID dosing will occur 
after MTD is determined per disease subtype.  
Revised Text:
Once the MTD of QD administration has been identified for a disease subtype, a cohort 
may be opened to explore the safety, tolerability, PK, and efficacy of GSK525762 when 
administered BID.  Initially, only one cohort per disease type is planned, though lower 
doses may be explored based on toxicity observed after the initial few subjects.  The 
selected total daily dose (administered in two approximately equal doses) for BID 
administration will not exceed the QD MTD.  A lower starting dose may be selectedThe 
initial dose level for BID will be a maximum of 20 mg (ie 2x 20mg 12 hours apart, total 
daily dose of 40mg) or a dose level lower than 20 mg depending on emerging safety, PK 
and PD data. and dDosing will be separated by approximately 12 hours.  Escalation can 
then proceed as described using the 3 + 3 dose escalation. The total number of evaluable 
subjects per disease type treated BID will not exceed 10 subjects.
Subjects may need to undergo dose modification(s) to manage toxicities.  A dose 
adjustment (e.g., QD at the same dose level or lower BID dose level) may be made after 
consultation with the GSK medical monitor. The investigator should use clinical 
judgment to determine whether the dosing scheduling may be contributing to any 
potential toxicity necessitating dose adjustment, and make the appropriate change after 
consultation with the GSK Medical Monitor.
Section 3.2.1.6. Intra-Subject Dose Escalation 
Rationale for Change: Minor updates were made to this section to further clarify 
when an intra-subject dose escalation may occur.
 
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Revised Text:
First and second sentence of first paragraph
Intra-subject dose escalations may be considered on a case-by-case basis, provided that a 
higher dose level cohort (accelerated phase or 3+3 phase) has been cleared without a 
DLT, and after review of all safety data and approval by a GSK Medical Monitor and 
discussion with the investigator.  The subject on a lower dose level may be increased up 
to the highest dose level testedcleared.  
Section 3.2.2. Dose Limiting Toxicity (DLT) 
Rationale for Change: This section was updated to clearly define the percentage of 
doses a subject must receive to be evaluable and to further clarify Dose limiting 
toxicities.
Revised Text:
First paragraph
An event will be considered a DLT if it occurs within the first 3 weeks of treatment and 
meets one of the following criteria unless it can be clearly established that the event is 
unrelated to treatment.  As described in Section 3.2.1.3, subjects unable to receive at least 
75% of scheduled doses for reasons other than toxicity (e.g., acute illness, disease 
progression) will not be evaluable for DLT purposes and will be replaced in the cohort.
Third paragraph

Grade 4 thrombocytopenia lasting more than 7 day and do not responding to 
transfusions, or Grade 3 thrombocytopenia associated with bleeding (>10mL) 
Third bullet of third paragraph
Grade 2 Troponin T elevation (central laboratory >Upper Limit of Normal [ULN]), 
measured on two separate occasions within 48 hours in order to confirm elevation and
with other clinical signs, symptoms, and/or laboratory tests consistent with cardiac
toxicity.  In the event a troponin T [central laboratory assessment] is not performed or a 
laboratory error occurs, considerations for a DLT criterion will involve review of two 
separate local troponin (I or T) assays done within 48 hours at a local investigator site.  
Troponin I or T elevations greater than the upper limit of normal, and > 10% coefficient 
of variance (CV) for that assay will be considered as a Grade 2 elevation).
Section 3.2.3. Maximum Tolerated Dose (MTD) and Recommended Phase 2 
Dose (RP2D)
Rationale for Change: Minor update was made to further clarify that a separate RP2D 
will be determined per disease type.
 
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Revised Text:
Second sentence
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects in 
Part 1 for that disease type.  
Section 4.1 Number of Subjects 
Rationale for Change: Added reference for evaluable subjects.
Revised Text:
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study.  To 
complete Part 1, it is estimated 60 to 70 evaluable (as described in Section 11) subjects 
will be enrolled.  Part 2 will enroll up to 111 subjects (three disease-specific cohorts of 32 
to 37 subjects each, depending on disease subtype, and one disease-specific cohort of 10 
subjects)
Section 4.2.1.  Inclusion Criteria 
Rationale for Change: This section was updated to clarify and standardize NHL and 
MM eligibility. 
Revised Text:
Inclusion criteria 3: In Part 1 and, subjects must have relapsed and/or refractory 
hematologic malignancies (e.g., leukemias, myeloproliferative neoplasms, lymphomas, 
and myelomas) for which no standard therapies are available or anticipated to result in 
remission. 
In Part 2, subjects must have Acute Myeloid Leukemia (AML), Multiple Myeloma 
(MM), or non-Hodgkin’s Lymphoma (NHL).

Subjects with AML (Part 1 and Part 2), are eligible if they
o have relapsed and/or refractory disease, OR
o are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

Subjects with multiple myeloma are eligible if they have progressed despite 
therapy with an alkylating agent, proteasome inhibitor, and immunomodulatory 
agent, either as individual regimens or in combination.

Subjects with NHL are eligible if they have received at least two prior lines of 
systemic therapy, including at least one line of immunochemotherapy with an 
anti-CD20 antibody (if their tumor expresses CD20).
 
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In Part 2, the NHL cohort will separately enrol subjects with double- and 
triple hit lymphoma, so that a minimum of 10 subjects with this subset of 
disease will be enrolled. To be eligible for this sub-cohort, tumor sample 
from the subject must demonstrate rearrangement and/or overexpression 
of MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or 
triple-hit status may be performed via appropriate local testing, and the 
determination of double- or triple-hit diagnosis will be at the discretion of 
the investigator and GSK Medical Monitor.
Inclusion criteria 9: Male subjects must agree to use one of the methods of contraception 
specified.  This method must be used from the time of the first dose of study medication 
until 16 weeks after the last dose of study medication.  In addition, male subjects whose 
partners are or become pregnant on study medication must continue to use condoms for 7 
days after stopping study medications.
Table 4   Definitions for Adequate Organ Function
System
Laboratory Values
Renal3
Creatinine3
OR
Calculated creatinine clearance [calculated by Cockcroft 
Gault formula2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN (≤2 X ULN for MM)
≥ 50 mL/min
≥ 50 mL/min
5.
If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
6.
Refer to Appendix 1 for Cockcroft Gault formula
7.
For MM subjects, adequate renal function is defined as serum creatinine ≤ 2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥ 30 mL/min
8.
If TSH is abnormal but free T3 and or Free T4 are normal, then the subject can be enrolled.
Exclusion Criteria
Rationale for Change: This section was updated to clarify the allowable timeframe.
Revised Text:
Exclusion criteria 3, second Note, first sentence: 
Note: the following are NOT allowed:
Investigational anti-cancer drug within 2 weeks (or 5 half-lives of the drug, 
whichever is longer) prior to the first dose of GSK525762.
Section 4.2.3.1. Permanent Discontinuation from Study Treatment 
Rationale for Change: This section was updated to provide clear guidance as to 
requirements if a subject dies.
 
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Revised Text:
Third paragraph
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). If a subject dies 
while on study, the cause of death should be recorded in the eCRF.
Section 4.2.3.2. Subject Completion
Rationale for Change: This section was modified to clearly define in Part 1 and Part 2 
a subject who has completed the study.
Revised Text:
In Part 1, a subject will be considered to have completed the study if:

they complete screening assessments, the 21-day DLT observation period, and the 
end-of-treatment follow-up visit,

they progress or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
In Part 2, a subject will be considered to have completed the study if:

they progressed or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  A subject will be considered to have withdrawn from the 
study if the subject has not died and is lost to follow-up, has withdrawn consent, or at the 
investigator’s discretion is no longer being followed.  The End of Study eCRF should 
only be completed when a subject is no longer being followed.  The study may be 
considered completed for purposes 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.For Part 1 (dose-
escalation phase) subjects who are not treated with the RP2D, a completed subject is one 
who has completed the study 2 years after the last treatment or if the subject dies or is 
still in follow-up at the time the study is closed or terminated, whichever is sooner.  
For subjects treated at the RP2D (subset of Part 1 and all of Part 2), a completed subject 
is one who has discontinued study treatment and was followed to death or has died while 
receiving study treatment.  
Document the cause of death in the CRF.  A subject will be considered to have 
withdrawn from the study if the subject has not died and is lost to follow-up, has 
withdrawn consent, or at the investigator’s discretion is no longer being followed.
 
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Section 5. TIME AND EVENTS TABLES
Rationale for Change: The time and events tables were modified to ensure 
consistency of timings, correct previous errors, provide additional clarifications.
 
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Revised Text:
Table 5 
Time and Events Table: Part 1
Starting from W10k 
10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
6
W
7
W
1
0
q3W
q6W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
Informed consent
(Unless otherwise 
noted, screening 
assessments to be 
completed within 14 
days of first dose.)
X
Demography
X
Medical historya
X
Disease characteristics
X
Cardiology eval.uation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug: For QD or BID details see Table 8 and Table 9
Administer study drug (Administer about same time of 
day. No food or antacids 1h before and 2h after.)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Daily
 
 
 
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Starting from W10k 
10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
6
W
7
W
1
0
q3W
q6W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
Review subject diary 
(Not required when dosed in clinic.)
X
X
X
X
X
X
X
Safety
Pregnancy test/ testosterone ab
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital Signs bc
X
X
X
X
X
X
X
X
X
X
X
Height and weight (Height at Scr only)
X
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test cd
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 6.7.5)
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 6
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO (Within 35 days of first dose)
X
X
X
X
X
X
12-lead ECGs de
X
O
O
O X
X
X
X
O X
X
X
X
X
O
X
X
X
Holter monitoring
(At least 24 h, on dosing days start predose)
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 8 and Table 9
PK Blood samples for GSK525762
X
X
X
gh
f
X
X
X
X
X
X
Xef
PK blood samples for metabolite evaluation (only at MTD 
or RP2D in 6 subjects)
X
X
X
X
PD Blood samples for biomarkers (mRNA)
X
X
X
X
Blood samples for plasma cytokines
X
X
X
X
PK Urine samples
X
X
X
X
 
 
 
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Starting from W10k 
10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
6
W
7
W
1
0
q3W
q6W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
(only at MTD or RP2D in 6 subjects )
PD Tumor Sample 
X
g
Xf
h
Translational Research hi
Pharmacogenomics (PGx) sample
X
Blood samples for Translational Medicine study
X
Additional samples will be collected on the date of disease assessment/bone marrow biopsy and date of 
progression
Tumor biopsy at progression
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have completed the 
study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects 
have died or 5 years after the last subject is enrolled in Phase 2.
a.  Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the 
medical history and disease status.
b. Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter.
c. Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, respiratory rate and temperature
d. Pulmonary tests as appropriate: subjects with severe COPD, history of pneumonitis, alveolar hemorrhage, chest radiation
e. 12-lead ECGs : Screening ECGs within 14 days of first dose.  Triplicate ECGs prior to dosing.  For timing of ECGs on “O” days, see Table 8 for QD and Table 9 for BID. Otherwise, 
triplicate ECGs at approximately same time of day, and prior to dose on dosing days. If QTcF increase >30msec, ECGs performed daily through W2.)
f. For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W. Reduce to q12w after 12 months on study.
g. Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
h. During 3+3 dose escalation, PD tumor sample collection will be mandatory unless infeasible to collect, and approval is obtained by the GSK medical monitor.  Subjects with MM or 
AML will have bone marrow aspirates collected on W1 D3 approximately within 2-43-6 hours after the dose.  Subjects with AML will have bone marrow aspirates or peripheral blood 
collection (provided that there are sufficient leukemic cells in the peripheral circulation) collected on W1 D3 within 3-6 hours after the dose. Subjects with NHL will have a lymph 
nodetissue biopsy (lymph node or other affected organ/region) collected on W1D3 approximately within 3-5 6 hours after the dose. Timing of tissue collection will be based on tumor 
type and may be modified based on emerging data. For operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection remain as 
described. A PK sample will need to be obtained within 1 hour of the tissue sampling.  Details described in the SPM see Table 7 disease specific assessments for details).
i. Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
 
 
 
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Starting from W10k 
10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W4
W
5
W
6
W
7
W
1
0
q3W
q6W
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
i. Refer to Section 6.6 for details on Translational Research and Appendix 5 for details on PGx Research.
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; PGx=Pharmacogenetics; COPD=Chronic obstructive pulmonary disease; SPM=Study Procedures Manual; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; 
q6W=every 6 weeks; SCR=Screening; W=week
 
 
 
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Table 6
Time and Events: Part 1 Laboratory Assessments
q3w and 
q6w Initiated 
from Wk 10
NB: On dosing days, collect blood samples prior to dosing. W1D1 samples not 
needed if SCR sample collected within 72h 24h of first dose.
SCR
W1
W2
W3
W4
W5
W6
W7
W10
q3W
q6W
EOT
Assessment
Notes
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
HBsAg, HepC 
antibody
If hepatitis C antibody positive, perform third generation 
immunoassay (if test is available) on same sample to 
confirm results, or alternatively, use HCV RNA test (either 
quantitative or qualitative).
X
 
 
 
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Table 7
Disease Specific Assessments: Part 1 and 2
Multiple Myeloma (MM) Assessments
q3w and q6w Initiated from 
Wk 10
Procedure
Notes
SCR
Week 1
Week 2
W
3
W4
W7
W10
q3W
q6W
EOT
D
1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
Disease Characteristics 
Including cytogenetics as 
appropriate 
X
Total Protein, CRP, 2 
microglobulin
X
X
X
X
X
SPEP, FLC assay, 
quantitative 
immunoglobulins ( IgG, 
IgA, IgM)
Not required for subjects 
with non-secretory MM; 
X
X
X
X
X
UPEP
Only required if paraprotein 
is present in urine
X
X
X
X
Extramedullary 
Disease Assessment 
Only required for MM with 
extramedullary disease
X
X
X
X
BM aspirate and biopsy 
Required for non-secretory 
MM, or as appropriate for 
other subjects
X
X
Response assessment
Every 6 weeks after wk4; 
Response criteria in 
Appendix 6
X
X
X
 
 
 
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Lymphoma Assessments
q3w and q6w Initiated from 
Wk 10
Procedure
Note
s
SCR
Week 1
Week 2
W4
W7
W10
q3W
q6W
q12W
EOT
D1
D2
D5
D1
D6
D1
D4
D1
D1
D1
D1
D1
Disease characteristics, 
including historya
immunophenotypes, 
cytogenetics  and 
prognostic markers b
X
2-microglobulin
X
X
B Symptoms
X
X
X
X
X
Lymph node and organ 
exam
X
X
X
X
X
Bone marrow/tissue 
biopsy c
X
X
Bone marrow/tissue 
biopsy c
X
X
CT Scan d
X
X
Wk 16, wk 24, then q12wks
PET Scan d, e 
X
X
Response evaluation f
X
Wk 16, wk 24, then q12wks
a.
Including date of first diagnosis, disease stage, and complete history of diagnostic results and therapies.
b.
Examples of prognostic markers may include:  ALC, FLIPI-1, FLIPI-2 (includes ß2-microglobulin), FcR gamma 3A.
c.
A sample will be required at screening only if clinically appropriate for the lymphoma subtype AND an appropriate previous sample is available. A follow-up bone marrow 
biopsy will be performed no later than 8 weeks following CR (as judged by investigator) in accordance with the response guidelines (Appendix 7) if a subject had 
involvement of the BM at the start of the study.
d.
Baseline/Screening Computerized Tomography (CT) and PET scans may be obtained within 35 days of first dose Follow-up CT scans at week 7 wk 16, wk 24 and then 
every 12 weeks.
e.
PET or PET/CT scan if clinically indicated (e.g., confirmation of CR for Diffuse large B-cell lymphoma). 
f.
Evaluation of response for lymphoma at week 7, week 16, week 24 and then every 12 weeks. Assessments are described in Appendix 7 : Response Criteria for 
Lymphoma.
 
 
 
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Leukaemia Assessments
q3w and q6w Initiated 
from Wk 10
Procedure
Notes
SCR
Week 1
Week 2
W3
Wk4
W5
W
7
W10
q3W
q6W
EO
T
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
Disease 
characteristics
, including 
history, 
immuno-
phenotype, 
cytogenetics 
and molecular 
studies as 
appropriate  
and History a
X
Lymph node 
and spleen 
assessment 
Only as 
appropriate 
X
X
X
X
X
X
Response 
Assessmentb
X
X
X
X
X
BM biopsy and 
aspirate
FISH, 
cytogenetics
, FLT3, 
IgVH, Zap-
70 as 
appropriate
Xb
Xc
Xc
X
Transfusion 
History cd
X
X
X
X
X
X
X
X
Bleeding 
History
X
X
X
X
X
X
X
X
Hematology e,f
d,e
X
X
X
X
X
X
X
X
Response 
assessment g
X
X
X
 
 
 
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a.
Including date of diagnosis and complete history of diagnostic results and therapies.
b.
Bone marrow biopsy/aspirate should be obtained for response assessment at the timepoints indicated.  Subjects without marrow involvement may be assessed by other means 
(e.g., medical photography for leukemia cutis) after discussion with the medical monitor, provided that the same method is used for all assessments of that subject.  Response 
criteria are described in Appendix 8.  This bone marrow sample is required for baseline disease assessment, but aA peripheral blood sample can be taken at baseline if the a
bone marrow sample could can not be collected.  See the study procedures manual (SPM) for sample handling. Subjects should be off cytokine support (granulocyte colony-
stimulating factor [GCSF] or granulocyte-macrophage colony-stimulating factor [GMCSF]) for a minimum of 7 days before obtaining bone marrow to document remission.Bone 
marrow biopsy and aspirate obtained for the assessment of response.  Subjects should be off cytokine support (granulocyte colony-stimulating factor [GCSF] or granulocyte-
macrophage colony-stimulating factor [GMCSF]) for a minimum of 7 days before obtaining bone marrow to document remission.
c.
Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly cumulative basis.
d.
Hematology includes complete blood count (CBC) with white blood cell count differential (including neutrophils, eosinophils, basophils, lymphocytes and monocytes) and 
platelets; hemoglobin, hematocrit, red blood cell count.  A CBC with differential and platelets, hemoglobin and hematocrit may be performed daily during in-patient care; once 
subject is discharged, assessments to continue weekly until disease response assessment.  This is collected at baseline/screening; daily during chemotherapy treatment, then 
weekly.  Platelet count achievement of 20,000/mL for 3 days is entered into the eCRF and the date of platelet count achievement of 100,000/mL is entered into the eCRF.
e.
A blood cell smear to measure peripheral blood blasts.
Response assessments for leukemia at wk 4, wk 10 and every 6 weeks thereafter. Assessments are described in Appendix 8: Response Criteria for Leukaemias.
 
 
 
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Table 8
Time and Events: Part 1 (QD cohorts) Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling
Procedure 
/ time after 
dose
W1D1 
W1D2
W1D5
pre 
dos
e
0h
15 
min 
± 5m
30 
mi
n 
±5
m
1h 
±1
0m
2h 
±15
m
4h 
±15
m
8h 
±1h
12h 
±2h
24h 
±1
h
0h
0
h
30 
min 
±10m
3h 
±30
m
Dose
X
X
X
12-lead 
ECG a
X
X
X
X
X
X
X
X
X
X
X
PK sample 
for 
GSK52576
2 b
X
X
X
X
X
X
X
X
X b
X
X
PK sample 
for 
metabolite 
b,c
X
X
X
X
X
X
X
X
X b
Blood 
sample for
biomarkers 
(mRNA)
Xcd
X
X
X
X
X
Plasma 
cytokine 
sample
Xcd
X
X
X
X
X
Urine PK 
sampling  c
X 
0-2 h
2-24h
Urine 
metabolite 
samplingc
X
0-2 h
2-24h
Proce
dure / 
time 
after 
dose
W2
D4
W2
D6
W2D7 (if dose has been altered (including held and 
resumed) serial PK sampling should occur 4 to 7 days 
after dosing resumed)
W3D1
W7D1 ±4 days de
pre
dos
e
pre
dos
e
pre 
dos
e
0
h
15 
mi
n 
± 
5
m
30 
min 
±5m
1h 
±10
m
2h 
±15
m
4h 
±15
m
8
h 
±
1
h
12
h 
±2
h
24
h 
±1
h
0
h
pre 
dos
e
0
h
0.5
-2h
4 
-
8
h
Dose
X
X
X
12-
lead 
ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK 
sampl
e for 
GSK5
25762
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK 
sampl
e for 
metab
X
X
X
X
X
X
X
X
X
 
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olite c 
Blood 
sampl
e 
biomar
kers 
(mRN
A)
X
X
Plasm
a 
cytokin
es 
sampl
es
X
X
X
X
X
X
Urine 
PK 
sampli
ng c
0-2h
2-24h
Urine 
metab
olite 
sampli
ngc
0-2h
2-24h
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 min prior to PK draw. For timepoint with a 
±5 minute it is acceptable for the first ECG to be out of the minus 5-min window to allow scheduling 
in this short time frame, as long as PK sample is collected after the last ECG and at least within +5 
minutes of the window.
b.
Sample to be obtained before dosing on Week 1, Day 2.
Urine PK sample is collected only at MTD or RP2D in 6 subjects
c.
May be collected within 14 days prior to first dose. 
d.
If dose was escalated, the W4D1 visit may be performed +4 to +7 days.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
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Table 9
Time and Events: Part 1 (BID Cohorts) Serial Electrocardiograms,
Pharmacokinetics and Biomarker Sampling
W1D1
W1D2
W1
D3
W1
D4
W1D5
Timepo
int;
Hours 
after 
AM 
dose 
(hours 
after 
PM 
dose)
Pre-Dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
Predose     
12h-15 min
12h (0h)
12 h 15 min±5m
12h 30 min ±5m
13h (1h) ±10m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h prior to dosing
AM & PM
AM & PM
AM & PM
AM
30 min ±5m
3h ±15m
PM
Dose
X
X
X
X
XX
XX
X
X
12-lead 
ECG a
X
X
X
X
X
X
X
X
X
X
X
X
♦ ♦
X
X
X
PK 
GSK52
5762b
X
X
X
X
X
X
X
X
X
X
X
X
♦
♦
X
X
X
Biomar
ker 
sample 
(mRNA) 
c
Xd
X
X
X
X
♦
♦
♦
X
Plasma 
cytokin
es 
sample
s
Xd
X
X
X
X
♦
♦
♦
X
Urine 
PK f
X
0-2
2-12
 
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W2D4 W2D6
W2D7
W3D1
W7D1 ±4 days e
Time 
point; 
Hour
s 
after 
AM 
dose 
(hour
s 
after 
PM 
dose)
pre AM dose
AM & PM
pre AM dose
AM & PM
Pre dose
0h
15 min ± 5m
30 min ±5m
1h ±10m
2h ±15m
4h ±15m
8h  ±1h
Predose
12h -15min
12h (0h)
12h15 min ±5m
12h  30 min ±5m
13h (1h) ±10m
14h (2h) ±15m
16h (4h) ±15m
20h (8h) ±1h
24h (12h)±1h
Prior to dosing
AM & PM
pre dose
0h
0.5-2h
4 - 8h
12h
Dose
X
X
X
X
X
X
XX
X
X
12-
lead 
ECG a
X
X
X
X X
X
X
X
X
X
♦
♦♦♦
♦
♦
X
X
X
X
PK 
GSK5
25762
X
X
X
X X
X
X
X
X
X
♦
♦♦♦
♦
♦
X
X
X
X
Biom
arker 
sampl
e 
(mRN
A) c
X
X
♦
X
Plasm
a 
cytoki
nes 
sampl
es
X
X
X
X
X
Urine 
PK f
0-2
2-12
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 minutes prior to PK draw. For time points 
with a ±5 minute it is acceptable for the first ECG to be out of the minus 5-min window to allow 
scheduling in this short time frame, as long as PK sample is collected after the last ECG and at least 
within +5 minutes of the window.
b.
PK blood sample collected overnight may be kept refrigerated at 4C in the event the laboratory is closed. 
c.
Blood sample for PD biomarker.
d.
May be collected within 14 days prior to first dose
e.
If dose was escalated, the W4D1 visit may be performed +4 to +7 days.
f.
Urine PK sample is collected only at MTD or RP2D in 6 subjects.
APP=acute phase protein; ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose; 
♦=optional assessment where feasible (e.g., for subjects staying overnight only).
 
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Table 10
Time and Events: Part 2 Expansion Cohort
Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
Informed 
consent
(Unless 
otherwis
e noted, 
screenin
g 
assess
ments to 
be 
complet
ed 
within 
14 days 
of first 
dose.)
X
Demogra
phy
X
Medical 
historya
X
Disease 
characte
ristics
X
Cardiolo
gy 
evaluatio
n
X
Prior 
therapy
X
Register 
subject
X
TREATMENT PHASE
Study Drug
Dispense study drug 
(Administer about 
same time of day.)
Continuous daily dosing (unless safety, PK or PD data necessitate a different dosing 
schedule), see Section 3.2.4
X
Review compliance 
(Not required when 
dosed in clinic.)
X
X
X
X
X
X
X
X
Safety
Pregnancy 
test/testosterone ab
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
Vital Signs bc//Pain
Assessment
X
X
X
X
X
X
X
X
X
Weight and height 
(Height at SCR only)
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 6.7.5)
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 11
Tests
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO (Within 35 
days of first dose). 
X
X
X
X
X
X
X
12-lead ECGs cd
X
X
X
X
X
X
X
X
X
Holter monitoring 
(Min 24h, on dosing 
days start predose)
X
X
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
PK and Blood PD
PK 
Blood 
samples
Three 
samples 
to be 
collecte
d  each 
samplin
g dayfor 
each 
type of 
analysis
: During 
the first 
3 weeks 
collect a 
Ppredos
e (within 
60 
minutes 
prior to 
dose), a
single 
draw 
between 
0.5 to 2 
h 
postdos
e,and a  
single 
draw 
between 
4-8h 
X
Xe
Xf
X
X
X
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
postdos
e 
(fasting 
require
ments 
apply).  
Thereaft
er W7 
and 
Q6W 
only a 
predose 
and 0.5 
hour 
post 
dose 
sample 
are 
collecte
dW7 
and 
Q6W 
only 
predose
Translational Research
PGx sample
X
Tumor sample (e.g., 
bone marrow biopsy, 
lymph node biopsy, 
or peripheral blood 
collection [only for 
Xde
X 
e
Xf
Xgf
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
subjects with 
circulating 
disease])(biopsy)
Blood samples for 
Translational 
Medicine study 
exploratory 
translational 
research
X
Xf
Additional samples will be collected on the date of disease assessment/bone marrow biopsy and date of progression or 
when patient is discontinued from study/end of treatment
Blood samples for 
Translational 
Medicine study
X
Additional samples will be collected on the date of disease assessment/bone marrow biopsy and date of progression
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have completed the 
study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects 
have died or 5 years after the last subject is enrolled in Phase 2.
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated from Wk 10)
EOT
W1
W1
W
2
W3
W4
W7
W10
q3W
q6W
D1
D3
D1
D1
D1
D1
D1
D1
D1
a.
Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the 
medical history and disease status
b.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter.
c.
Vital signs include SBP, DBP, heart rate, respiratory rate and temperature
d.
Screening ECGs within 35 days of first dose.  ECGs prior to dosing.  If QTcF increase >30msec, ECGs should be repeated every 2-3 days until the QTcF is within 30 msec of 
baselineperformed daily through W2.
e.
Pretreatment biopsy for tumor sample must be performed within 14 days of first dose.
f.
Subjects with MM or AML willshould have bone marrow aspirates collected on W1 D3 W3D1 within approximately 2-4 3-6 hours after the dose. Subjects with AML should have 
bone marrow aspirates or peripheral blood collection (provided that there are sufficient leukemic cells in the peripheral circulation) collected on W3 D1 within 3-6 hours after the 
dose.  Subjects with NHL will have a lymph node biopsy collected on W1 D3 W3D1 within approximately 3-5 6 hours after the dose. Timing of tissue collection will be based on 
tumor type and may be modified based on emerging data. For operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection 
remain as described. A PK sample will need to be obtained within 1 hour of the tissue sampling.  Details described in the SPM see Table 7 disease specific assessments 
for details).  
g.
The collection of Ttumor samples for translational research are requested at end of treatment for subjects with progressive disease. 
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by 
Fridericia’s formula; PD=Pharmacodynamics; PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 weeks; 
SCR=Screening; Wk=week
 
 
 
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Table 11
Time and Events: Part 2 Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing.  W1D1 
samples not needed if SCR sample 
is within 72h 24h of first dose. 
(Notes)
SCR
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4
Further 
Cycles
q3w and 
q6w 
Initiated 
from Wk 10
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
a. Assess platelet count as clinically appropriate but at minimum twice weekly for weeks 1 and 2; weekly for weeks 3 to 
8.
Abbreviations: NT-proBNP=N-terminal pro–B-type Natriuretic Peptide; 1,5 AG=1,5-Anhydroglucitol; Hb=Hemoglobin; 
TSH=Thyroid Stimulating Hormone; HBsAg = Hepatitis B surface Antigen HepC=Hepatitis C; D=day; EOT=End of 
Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week
 
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Section 6.1.2. Visit Windows
Rationale for Change: The visit windows were updated to clarify timing of the visits.
Revised Text:
Screening (baseline to pre-dose): All assessments should be completed within 14 days 
prior to screening unless otherwise noted in the Section 5 Time and Events Tables.  Note 
for females, pregnancy testing should be performed within 7 days prior to first dose.  
Also, clinical labs performed during screening within 72 24 hours of first dose do not 
need to be repeated on Day 1.
Visits during Week 1: Based on subject and clinic schedule, Week 1 Day 5 assessments 
can be 1 day.
Visits between Week 2 through Week 3 (inclusive): Based on subject and clinic 
schedule, assessments can be +3 days.
Visits between Week 4 through Week 9 (inclusive): Clinic visits can be scheduled 3 
days.
Every 3-week and 6-week visits from Week 10 through Week 48 Clinic visits can be 
scheduled 7 days.
After Week 48: Every 3-week visits are no longer required, based on clinical judgment.  
Every 6-week clinic visits must include safety assessments from the “q3w” column in the 
Time and Events Table and can be scheduled 7 days.  Response assessments may be 
scheduled 7 days.
Discontinuation visit: should be within 14 to 28 days from last dose of study drugs.  If a 
subject is unable to return to the clinic due to hospitalization, site staff are encouraged to 
telephone the subject for assessment of adverse events.
Section 6.2. Baseline Assessment
Rationale for Change: This section was updated to provide consistency throughout 
protocol.
Revised Text:
Subjects diagnosed with refractory hematological malignancy (MM, lymphoma and/or 
acute myeloid leukemias), will be assessed at baseline for general disease characteristics 
as noted in Section 6.2.1 and tumor type specific measures as noted in Section 6.2.2, 
Section 6.2.3 and Section 6.2.4, respectively.
Baseline is defined as the assessment closest to first dose, (i.e., Week[W]1Day[D]1 
assessment) or screening if SCR sample collected within 24h of first dose.
 
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Section 6.2.1.  Baseline assessment for all subjects

Primary tumor  type (immunophenotyping and histology if applicable)

History of other tumor types/medical history

Date of initial diagnosis of primary tumor type

Date of relapse/progression

Details of any metastatic disease
Section 6.2.2.  Baseline assessment for subjects with AML
6.2.2  Baseline assessment for Subjects with leukemiaAML
AML:

WHO classification

FAB classification

Source of AML

Cytogenetics
CLL

Modified Rai staging at initial diagnosis and screening

Binet stage at initial diagnosis and screening

Indication  of active disease: evidence of bone marrow failure, splenomegaly, 
lymphadenopathy, lymphocytosis, B-symptoms

Cytogenetics
Section 6.3.1. Physical Examination
Rationale for Change: The section was updated to clarify the Investigator 
responsibility and the possible need to consult a cardiologist.
Revised Text:
Last sentence
Cardiovascular medical history/risk factors will also be assessed at baseline by the 
Investigator.  Additional assessment by a cardiologist may be required at the discretion of 
the Investigator and/or Medical Monitor [prior to enrolment/first dose] if any 
cardiovascular risk factors or ECG/laboratory abnormalities are identified.a cardiologist.
 
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Section 6.3.6. Holter Monitoring 
Revised Text:
Second and third sentence
Collection of critical ECG data shortly after meals or during sleep should be avoided 
since QT prolongation occurs at these times and a change in the QT-RR relationship 
occurs during sleep.  Meals should be administered according to the guidelines provided 
in Section 7.3, as meal and snack times will need to be adjusted accordingly on dosing 
and ECG sampling days.
Analysis of intervals and morphology from the continuous digital ECG data will may be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory.  .  In order to increase consistency of ECG interpretation, a 
limited number of central ECG over-readers will be used throughout the study.  All ECGs 
for a given subject will be over-read by the same reader from the central validated ECG 
laboratory.  The central reader will be blinded to subject identifiers (e.g., subject number, 
age, and sex), treatment assignment, and study day when Holter data were collected.  The 
final intervals and morphology analyses entered into the database will be those generated
by the central ECG laboratory.
Section 6.4.1. Disease Assessment 
Rationale for Change: This section was updated to reflect the disease types and 
provide consistency throughout the protocol.
Revised Text:
First sentence
Response will be assessed as outlined in the Section 5 Time and Events Table 7 by the 
investigator using the appropriate criteria for MM, lymphoma and/or leukemiasAML, as 
noted in Appendix 6, Appendix 7 and Appendix 8, respectively.  
Section 6.5.3. Urine Collection 
Rationale for Change: This section was removed as metabolite collection and analysis 
will no longer be required as enough data was collected during the BET115521 study.
 
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Revised Text:
Whole section deleted
6.5.3. Urine Collection 
For QD cohorts, urine samples for quantitative analysis of GSK525762 will be collected 
over a dosing interval (12 or 24 hours) in two samples (first sample collected 0-2hr and 
second sample collected 2-24hr) immediately following dosing on Week 1 Day 1 and 
Week 2 Day 7.  For the BID cohort, the first sample will be collected over 0-2h and the 
second over 2-12h, also immediately following dosing on Week 1 Day 1 and Week 2 Day 
7. Urine samples will be collected from at least 6 subjects in Part 1 at the MTD.  
Additional sampling may be instituted based on emerging data.
Selected urine samples may be analyzed qualitatively and/or quantitatively for 
GSK525762 metabolites and the results will be reported under a separate DMPK 
protocol.
Details of urine sample collection, processing, storage and shipping procedures are 
provided in the SPM.
Section 6.6.1. Tumor Specific Tissue Collection
Rationale for Change: This section was updated to provide consistency throughout 
the protocol.
Revised Text:

Second and third sentence

For subjects with leukemias AML, changes in specific protein markers and/or 
mRNA expression signatures will be assessed in bone marrow and/or tumor 
cell-enriched PBMCs isolated from whole blood.

For subjects with lymphomas, lymph node tissue biopsies (or bone marrow, if 
appropriate) will be required before and after treatment to evaluate changes in 
tumor-specific protein markers and/or gene expression signatures.
Section 6.6.2. Blood sample collection for Exploratory Translational 
Research
Rationale for Change: This section was updated to clarify the translational research 
which will be performed.
 
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Revised Text: 

Section heading and first bullet
6.6.2.  Blood sample collection for Surrogate PD Biomarkers Exploratory 
Translational Research

Part 1 &2: At screening, date of bone marrow biopsy (Part 2 only), disease 
assessment and disease progression for isolating plasma for circulating 
biomarkers (eg, cfDNA), isolation PBMCs and neutrophils and studying 
Section 6.9. Pharmacogenetics
Rationale for Change:  Minor correction made for consistency.
Revised Text:

Second paragraph, first sentence

Subjects who provide consent will have a blood saliva sample taken for analysis.  
Section 7.2. Handling and Storage of Study Treatment
Rationale for Change: Updated storage requirements were included in this section 
for the besylate tablets.
Revised Text:

Storage, last two sentences
GSK525762 Amorphous free-base tablets are to be stored at up to 30°C (86°F) and 
protected from light and moisture.
GSK525762 Besylate Tablets are to be stored at up to 30°C (86°F) and protected from 
moisture.
Section 7.7.1. Dose and Safety Management Guidelines
Rationale for Change: The 10% coefficient of variability was removed as this is not 
standardized.   
 
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
Table 16
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Troponin
Troponin level >ULN
and >10% CV level.

Contact the subject immediately for evaluation of 
symptoms and to obtain ECG.  Repeat troponin within 
24-48 hours or as soon as possible.

For asymptomatic subjects with repeat troponin values 
>ULN and >10% CV, hold study medication(s), refer to 
a cardiologist and contact the GSK Medical Monitor.  If 
the repeat value is within the normal range, the subject 
may continue study medication with close follow-up for 
symptoms, ECG monitoring and further troponin 
measurements as clinically indicated.

If the subject is symptomatic or the troponin level 
approaches the threshold for MI according to local lab 
parameters, the study medication must be withdrawn 
and the subject will be referred immediately to a 
cardiologist for appropriate medical care.

May consider restarting study treatment at a reduced 
dose based on discussion with GSK Medical Monitor.
Pneumonitis
Grade 1

(For all Grades) Obtain high resolution chest CT if 
possible.

Consider evaluation by pulmonologist.  Consider 
room air O2 saturation at rest via pulse oximetry 
reading (X 2, 5 mins apart).  Repeat evaluations every 
8-12 weeks until return to within normal limits (wnl).  
Continue investigational drug(s) at current dose(s).
Grade 2

Consider evaluation by pulmonologist.  Consider 
pulmonary function tests including: spirometry, 
Diffusing Capacity of the Lung for Carbon Monoxide 
(DLCO), and room air O2 saturation at rest via pulse 
oximetry reading (X 2, 5 mins apart).  Repeat 
evaluations every 8-12 weeks until return to wnl.  
Consider a bronchoscopy with biopsy and/or 
bronchoalveolar lavage.  (BAL).

Treat only if symptomatic.  Consider corticosteroids 
if symptoms are troublesome and infectious origin is 
ruled out.  Taper as medically indicated.

Hold investigational drug(s) until recovery to <Grade 
1, then reduce dose by at least 25%.  Discontinue 
investigational drug(s) if no recovery to <Grade 1 
within 4 weeks.  May consider escalation to pre-event 
dose after discussion with GSK Medical Monitor.
Grade 3 and 4

Permanently discontinue investigational drug

Evaluation by pulmonologist.  Required pulmonary 
function tests including: spirometry, DLCO, and room 
air O2 saturation at rest via pulse oximetry reading (X 
 
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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
2, 5 mins apart).  Repeat evaluations at least every 8 
weeks until return to normal.  Bronchoscopy with 
biopsy and/or BAL is recommended.

Consider corticosteroids if infectious origin is ruled out. 
Taper as medically indicated.

(Grade 3) Discontinue investigational drug(s) (Grade 
4) Discontinue investigational drug(s)

Grade 3-4

Temporary discontinuation of study medication and 
monitor for change in severity

Assess or inquire if the subject is experiencing in 
combination with fever: swelling, redness, extreme 
fatigue or nausea.

Collect “Cytokine blood samples” (which include blood 
sample for TNF-alpha, IL-1,IL-6, IL-10).  Collect blood 
culture and investigate viral infections as applicable.

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
GSK Medical Monitor.
a.
These guidelines are for suspected drug associated fever; please perform any additional tests as clinically 
appropriate for other causes of fever such as infection.
*Baseline results are defined by the nearest time point prior to first dose. If W1D1 results are available, these are 
considered the baseline results. If screening occurred within 72h of fit dose, W1D1 samples are not needed and 
screening data are considered as baseline.
Abbreviations:  GSK=GlaxoSmithKline; QTcF= QT duration corrected for heart rate by Fridericia’s formula; 
ECG=Electrocardiogram; IRB=Institutional review board; EC=Ethics committee; ULN=Upper limit of normal; 
LLN=Lower limit of normal; CV= Coefficient of variance; LVEF= Left ventricular ejection fraction; ALT=Alanine 
Transferase; BAL=Bronchoalveolar lavage; DLCO=Diffusing Capacity of the Lung for Carbon Monoxide; IL=Interleukin
Section 8.2.1. Cautionary Medications
Rationale for Change: This section was updated to reflect the most recent listing of 
medications per CredibleMeds, 15 May 2016.
Revised Text:

Table 18 Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution
 
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Generic Name
Brand Name
Astemizole
Hismanal
Amiodarone
Cordarone, Pacerone, Nexterone
Citalopram
Celexa, Cipramil
Chlorpromazine
Thorazine
Escitalopram
Lexapro
Moxifloxacin
Avelox, Avalox, Avelon, Moxeza, and Vigamox
Alfuzosin
Lithium
Apomorphine
Mifepristone
Aripiprazole
Mirabegron
Artenimol + piperaquine
Mirtazapine
Asenapine
Moexipril/HCTZ
Atomoxetine
Nicardipine
Bedaquiline
Norfloxacin
Buprenorphine
Nortriptyline
Clomipramine
Ofloxacin
Clozapine
Olanzapine
Cyamemazine
Oxytocin
Degarelix
Paliperidone
Delamanid
Pasireotide
Desipramine
Perflutren lipid microspheres
Dexmedetomidine
Pipamperone
Dolasetron
Promethazine
Ezogabine
Rilpivirine
Famotidine
Risperidone
Felbamate
Roxithromycin
Fingolimod
Saquinavir
Fluconazole
Sertindole
Foscarnet
Telavancin
Gemifloxacin
Telithromycin
Granisetron
Tetrabenazine
Hydrocodone – ER
Tizanidine
Iloperidone
Tolterodine
Imipramine
Trimipramine
Isradipine
Tropisetron
Leuprolide
Vardenafil
Levofloxacin
Venlafaxine
NOTE: There may be situations when the subject is on study that Advanced Cardiac Life Support (ACLS) requires 
the use of amiodarone, which should be used as per local clinical guidelines.
Data Source: CredibleMeds, 15 May 20165 (www.crediblemeds.org).
Section 8.2.2. Drugs Potentially Affecting GSK525762 Pharmacokinetics
Rationale for Change: This DDI section was updated based on emerging metabolite 
data.
 
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Revised Text:
In vitro data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of inducers and inhibitors of CYP3A4 should be avoided during the 
course of the study where possible as they may respectively decrease or increase 
exposure to GSK525762. GSK525762 is considered to have a low risk of causing 
clinically relevant perpetrator drug interactions with CYP3A4, CYP2B6 and CYP2C8 
enzymes and/or PgP, BCRP, OATP1B3, OAT1, OCT2, MATE1, MATE2-K, BSEP or 
MRP2 transporters either via direct or metabolism-dependent inhibition. Potential 
interactions with other Cytochrome P450 metabolized drugs have not been assessed.
GSK525762 was shown to be an inhibitor of OATP1B1 and OAT3 in vitro, however, the 
clinical impact of this inhibition is only deemed a concern for sensitive substrates of 
OATP1B1 or OAT3 (e.g. methotrexate).
GSK525762 has low potential to inhibit the major human CYP isoforms (IC50’s ≥ 33 
µM) or major transporters. There is no evidence for time dependent inhibition of 
CYP2D6 or CYP3A4. Potential interactions with other Cytochrome P450 metabolized 
drugs have not been assessed.

Table 19 Drugs Potentially Affecting GSK525762 Pharmacokinetics Resulting 
in Increased or Decreased GSK525762 Exposure
Drug Class 
Agent 
Drugs that may decrease exposure to GSK525762 (CYP and/or Pgp Inducers)
Antibiotics 
Nafcillin, all rifamycin class agents (e.g., rifampicin, rifabutin, rifapentine) 
Anticonvulsants 
Phenytoin, carbamezepine, barbiturates (e.g., phenobarbital) 
Antiretrovirals 
Efavirenz, etravirine, nevirapine, tipranivir, 
Glucocorticoids (oral) 
Cortisone (>50 mg), hydrocortisone (>40 mg), prednisone or prednisolone 
(>10 mg), methylprednisolone or triamcinolone (>8 mg), betamethasone or 
dexamethasone (>1.5 mg) 
Other 
Bosentan, St. John’s Wort, modafinil 
Drugs that may increase exposure to GSK525762 (CYP3A4 Inhibitors)
Antibiotics 
Clarithromycin, flucloxacillin, telithromycin, troleandomycin,
Antifungals 
Fluconazole (>150 mg daily), itraconazole, ketoconazole, terbinafine,
posaconazole,voriconazole 
Antiretrovirals, Protease 
Inhibitors
Amprenavir, atazanaivir, boceprevir, delaviridine, fosamprenavir, indinavir, 
lopinivir,nelfinavir, ritonavir, saquinavir, telaprevir
Calcium channel blockers 
Diltiazem, verapamil
Antidepressants, anxiolytics
, fluvoxamine, nefazodone, tofisopam   
GI Agents 
Cimetidine 
Other 
Seville oranges, grapefruit or grapefruit juice and/or kumquats, pomegranate 
or pomegranate juice, pomelos, exotic citrus fruit (i.e., star fruit, bitter 
melon), grapefruit hybrids or fruit juices, or other foods and juices known to 
inhibit CYP3A4 
NOTE:  Topical or inhaled steroids are permitted.
 
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Section 8.3. Prohibited Medications
Rationale for Change: This section was updated to reflect the most recent listing of 
prohibited  medications per CredibleMeds, 15 May 2016.

Revised Text:

Second paragraph, first sentence

Co-administration of medications that are known to prolong the QT interval and 
have a risk of causing Torsades de Pointes are PROHIBITED for 5 half-lives of 
the drug, or 14 days, whichever is longer, prior to the first dose of study drug 
until discontinuation from the study drug with the exception of amiodarone
which is prohibited beginning 6 months prior to Screening through 
discontinuation from the study.  

Table 20 Drugs with a Risk of Torsades de Pointes that are Prohibited
 
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Generic Name
Brand Name
Arsenic trioxide
Trisenox
Bepridil
Vascor
Chloroquine
Aralen
Cisapride
Propulsid
Clarithromycin
Biaxin, Prevpac
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S.
Haloperidol
Haldol
Halofantrine
Halfan
Ibutilide
Corvert
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Quinaglute, Cardioquin
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Amiodarone
Grepafloxacin
Anagrelide
Halofantrine
Azithromycin
Haloperidol
Chloroquine
Ibutilide
Chlorpromazine
Levomepromazine
Cilostazol
Methadone
Ciprofloxacin
Moxifloxacin
Citalopram
Papaverine
Clarithromycin
Pentamidine (IV)
Cocaine
Pimozide
Disopyramide
Procainamide
Dofetilide
Propofol
Domperidone
Quinidine
Donepezil
Sevoflurane
Dronedarone
Sotalol
Droperidol
Sulpiride
Escitalopram
Thioridazine
Flecainide
NOTE: There may be situations when the subject is on study that Advanced Cardiac Life Support (ACLS) requires the 
use of amiodarone, which should be used as per local clinical guidelines.
Data Source: CredibleMeds, 15 May 20165 (www.crediblemeds.org).
The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of the 
subject.
 
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
Third paragraph

At time of screening, if a subject is currently receiving any of the listed 
prohibited medications/substances, the medication or substance must be 
discontinued for a period of at least 5 half-lives of the drug or 14 days 
whichever is longer, prior to the administration of the first dose of study drug in 
order for the subject to meet study eligibility.
Section 8.4. Non-Drug Therapies
Rationale for Change: This section was updated to clarify the requirements in Part 1 
of the study.

Revised Text:
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the transition screening visit through the post-
study follow-up visit.
NOTE: Subjects may receive palliative radiation treatment during this study.
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit. Subjects enrolled in Part 1 of the study should abstain from 
coffee and tea from 24 hours prior to an extensive PK collection day (i.e. W1D1 and 
W2D7)  until the end of PK collection on that day 
Section 9.1.1. Female Subjects
Rationale for Change:  This section was updated to further clarify hormonal forms of 
birth control.

Revised Text:

Last sentence
HAll hormonal means of birth control such as oral, injectable, dermal, subdermal or 
topical contraceptives are NOT acceptable forms of birth control given that their efficacy 
has not been evaluated when given in combination with the investigational drugs.
Section 9.1.2. Male Subjects
Rationale for Change: This section was updated to further clarify the contraception 
requirements for male subjects with a female partner of child bearing potential.  
 
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
Revised Text:
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug(s):

Vasectomy, or

Condom use PLUS partner use of highly effective contraceptive such as occlusive 
cap (diaphragm or cervical/vault cap) plus spermicidal agent 
(foam/gel/film/cream/suppository), or intrauterine device. (<1% rate of failure per 
year) such as intrauterine device or system, or hormonal birth control such as 
contraceptive subdermal implant, combined estrogen and progestogen oral 
contraceptive, injectable progestogen, contraceptive vaginal ring, or percutaneous 
contraceptive patches, or

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception
Male subjects whose partners are or become pregnant must use condoms while on study 
and for 7 days after stopping study medication(s).
Male subjects should be advised not to donate sperm while on study and for 16 weeks 
after the last dose of study drug(s).
In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 7 days after stopping study 
medications.
Section 9.2. Caffeine, Alcohol, and Tobacco 
Rationale for Change: This section was updated to clarify that subjects must abstain 
during Part 1.

Revised Text:
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or PD sample during each extensive PK
session in Part 1.
Section 11.1.1. Part I, Dose Escalation 
Rationale for Change: This section was included to allow for subjects from Part 1 to 
be included in the efficacy analysis.
 
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
Revised Text:

Last sentence 
Subjects in Part 1 treated at the RP2D may be included in the efficacy analysis as 
described in Section 11.6.1.
Section 11.1.1. Part 2, Expansion Cohort 
Rationale for Change: This section was included to allow for subjects from Part 1 to 
be included in the efficacy analysis

Revised Text: 

First paragraph, first and second bullet

For AML, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, CRp, CRi, or PR or a morphologic 
leukemia-free state) of 30% relative to a 10% response rate suggesting no activity.

For MM, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a sCR, CR, VGPR, or PR) of 20% relative 
to a 5% response rate suggesting no activity.

Fourth paragraph
Futility analysis for each disease cohort will begin when response data is available for at 
least 10 subjects treated at the RP2D in Part 1 and Part 2. Each disease cohort may be 
stopped early for futility if the predictive probability of success (response rate  > 
historical response rate) is less than 1%.  Futility stopping rules are defined for each 
cohort in Section 3.2.4.
Section 11.2. Analysis Population 
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for flexibility to conduct an interim analysis during the study, prior to the end of 
Part 2.  This section was included to note that full details of the analysis populations will 
be included in the reporting and analysis plan (RAP).

Revised Text:
Last sentence
More details of the analysis populations will be specified in RAP.
 
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Section 11.4. Interim Analysis 
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for flexibility to conduct an interim analysis during the study, prior to the end of 
Part 2.  

Revised Text:
No formal interim analysis will be performed for Part 1 of the study.  Safety, PK, and PD 
marker data will be examined ongoing while the study is being conducted.
Interim analysis on Part 1 may be conducted when 

Part1 is completed or 

All subjects enrolled in any or all of AML, MM, and NHL cohorts in Part 1 have 
had at least one post-baseline disease assessment or progressed or died or 
withdrawn from the study
For each disease type in Part 2, after the initial 10 evaluable subjects in the AML and 
NHL cohorts and initial 13 evaluable subjects in the MM cohort have enrolled at the 
selected dose regimen for the Expansion Cohort, data will be reviewed for clinical benefit 
on an ongoing basis and the number of subjects with observed clinical benefit will be 
compared with the stopping guidelines provided in Section 3.2.4. Subjects in Part 1 
treated at the RP2D may be included in this analysis of efficacy.
The study will not only stop due to lack of efficacy.  The trial will may continue to enrol 
the maximum planned sample size to provide a better an estimate on the distribution of 
the response rate in the target patient populations.
Section 11.5. Final Analysis 
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for flexibility to conduct an interim analysis during the study, prior to the end of 
Part 2.  

Revised Text:
Final primary analysis will occur when at least 70% of subjects are dead, have withdrawn 
consent, or are lost to follow-up, or all subjects still in follow-up have had at least 5 years 
follow-up, whichever is earlier.
The 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 GSK525762.  Data from Part 1 and Part 2 may be 
combined for some analyses at the end of the trial, as appropriate.  More detail on the 
data displays will be provided in the RAP.
 
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Final OS analysis will occur when at least 70% of subjects are dead, have withdrawn 
consent, or are lost to follow-up, or all subjects still in follow-up have had at least 5 years 
follow-up, whichever is earlier. Final OS analysis may be conducted when all subjects 
have completed the study. 
Section 11.6.1. Primary Analysis 
Rationale for Change:  The analyses sections were updated throughout the protocol to 
allow for flexibility to conduct an interim analysis during the study, prior to the end of 
Part 2.  This section was included to allow for subjects from Part 1 to be included in the 
efficacy analysis. 

Revised Text:
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria described in the Section 5 Time and Events Table 7 for MM, lymphoma and/or 
leukemias, as noted in Appendix 6, Appendix 7 and Appendix 8, respectively.  If the data 
warrant, the response data will be summarized by dose level. In addition, any subject in 
Part 1 treated at the RP2D may be included in the analysis of efficacy described below.
The primary aim of Part 2 is to detect demonstrate a possibly clinically meaningful 
response rate in each of the disease cohorts separately. Each disease subtype (AML, MM,
and NHL) will be evaluated separately.
Overall Response rate is defined as 

AML: The percentage of subjects who achieved CR, CRp, CRi, and PR. A waterfall 
plot of percent change from baseline in bone marrow blasts and peripheral blasts will 
be provided.  Response rates of subjects with AML M3 will be summarised 
separately.

MM: The percentage of subjects who achieved sCR, CR, VGPR, or PR.

NHL: The percentage of subjects who achieved CR or PR. Response rates of 
subjects with double/triple-hit lymphoma will be summarised separately.
All subjects who received at least one dose of treatment will be included in the evaluation 
for response.  Response rates and the associated 2-sided 95% exact confidence limits will 
be provided.   
Section 11.6.2. Secondary Analysis 
Rationale for Change:This section was updated to align with the primary and 
secondary endpoints.

Revised Text:
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, PR, or SDNot Evaluable) prior to the 
 
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initiation of therapy. Otherwise, if the subject does not have a documented date of events, 
PFS will be censored at the date of the last adequate assessment. 
For the analysis of overall survival (OS), the last date of known contact will be used for 
those subjects who have not died at the time of analysis; such subjects will be considered 
censored. Further details on rules for censoring will be provided in the RAP. Sensitivity 
analyses of PFS and further details on censoring rules will be provided in the RAP.  
Progression free survival (PFS) and overall survival (OS) will be summarized using 
Kaplan-Meier method if data warrant.
The duration of response is defined for the subject or subjects with a confirmed CR or PR 
for NHL, CR, CRp, CRi, or PR for AML, and sCR, CR, VGPR, or PR for MM as the 
time from the first documented evidence response until the first documented disease 
progression or death due to any cause. Censoring rules for duration of response will be 
outlined in detail in the RAP.
Time to Response Progression is calculated from the start of treatment defined, until the 
first documented disease progression or death due to any cause. Censoring rules for 
duration of response will be outlined in detail in the RAP.
for subjects with a confirmed response as the time from first dose to the first documented 
evidence of response.
If sample size permits, duration of response and time to responseprogression will be 
summarized descriptively using Kaplan-Meier medians and quartiles. Only the subset of 
subjects who show a confirmed response will be included. Censoring rules for duration of 
response will follow the rules for PFS outlined in detail in the RAP
OS along with 95% confidence intervals for MM, lymphoma and leukemia subjects 
treated in Part 1 and Part 2, will be estimated using the Kaplan Meier method if data 
warrant.  OS analysis for AML will exclude subjects with AML subtype M3. NHL will 
be separately reported based on double/triple hit status. All cause mortality will be used 
and censoring will be performed using the date of last known contact for those who are 
alive or lost to follow-up at the time of analysis.  
Section 11.8. Pharmacokinetic Analysis 
Rationale for Change:  This section was updated to clarify that parent and metabolite 
data would both be analyzed as part of PK analysis.  

Revised Text:
PK analyses will be the responsibility of GSK CPMS.  Plasma GSK525762 and relevant 
metabolite(s), as appropriate, concentration-time data from dose escalation (Part 1) will 
be analyzed by non-compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacology parameters will be 
determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
 
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Week1 Day1 only) and apparent terminal phase half-life (t½).  Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state.  
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from the ratio of AUC(0-) in Week 2 Day 7 / AUC(0-) in 
Week 1 Day 1.  The ratio of AUC(0-) on Week 2 Day 7 / Week 1 Day 1 AUC(0-∞) will 
be calculated to assess time invariance.  GSK525762 concentrations will be determined 
in urine samples to determine urinary recovery of unchanged drug and renal clearance.
Plasma concentration-time data will be listed by dose, dosing regimen, and summarized 
using descriptive statistics (n, mean, standard deviation [SD], median, minimum and 
maximum) by planned relative assessment time.  Mean and/ or median values will be 
plotted over time.  Individual plasma and urinary (if available) PK parameters values as 
well as a descriptive summary (mean, standard deviation, median, minimum, maximum, 
geometric mean, and the standard deviation, CV% and 95% confidence interval of log-
transformed parameters [if applicable]) by day, dose and dose regimen cohort will be 
reported.
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) will be plotted as a 
function of the dose administered and dosing regimen.  If more than 2 dose cohorts are 
evaluated, dose proportionality of AUC and Cmax for GSK525762 will be assessed using 
the power model (details will be provided in the RAP).
Plasma concentration-time data from Parts 1 and 2 will be combined and may be 
combined with data from other studies and further analyzed using a population approach.  
A nonlinear mixed effects model will be used to determine population PK parameters 
(absorption rate, Ka, apparent clearance, CL/F and volume of distribution, V/F) and 
summary exposure measures (Cmax, AUC and Average observed concentration 
(Cav) = AUC/) and identify important covariates (e.g., age, weight, or disease related 
covariates). This analysis may be reported separately.
Section 11.9. Pharmacokinetic/Pharmacodynamic Analysis 
Rationale for Change: Minor update 

Revised Text:
Last paragraph
Overall efficacy data and overall tumor burden may be described using ordered 
categorical/ model and continuous models with summary exposure parameters (e.g., 
Cmax, C, and Cav) as covariates derived from the population PK analysis.  Further 
model details will be provided in the RAP.
 
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Section 12.2. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Rationale for Change: Removed the reference of subjects less than 18 years of age as 
a subject must be 18 or older to be eligible. 
Last paragraph
Written informed consent must be obtained from each subject, or from a guardian if the 
subject is less than 18 years of age, prior to participation in the study.
Section 15.8.1. Acute Leukemias, MDS, Chronic Myelogenous Leukemia in 
Blast Phase (CML-BP), Chronic MyeloMonocytic Leukaemia (CMML)
Rationale for Change: This section was updated to align the leukemia  population as 
was done throughout the protocol as all leukemia subjects enrolled to date have been 
acute myeloid leukemia.

Revised Text:
Section 15.8.1. Acute Myeloid Leukemias, MDS, Chronic Myelogenous 
Leukemia in Blast Phase (CML-BP), Chronic MyeloMonocytic Leukaemia 
(CMML)
Last sentence
Marrow CR:  Bone marrow: 5% myeloblasts and decrease by 50% over pre-treatment 
(MDS only) 
Section 15.8.2. CLL
Rationale for Change: This section was removed as the leukemia population was 
updated to only include acute myeloid leukemia.

Revised Text:
Section 15.8.2. CLL
[Hallek, 2008]
Complete Response:
Peripheral blood: Absolute lymphocyte count (ALC) <4 x 10
9/L with Hb >11 g/dL, 
ANC 1.5 x 10
9/L and platelet count >100 x 10
9/L (without need for growths factors 
or transfusions).
Tumor: disappearance of all palpable lymph nodes, spleen, and liver without the 
appearance of new lesions. Absence of constitutional symptoms.
Bone Marrow: <30% lymphocytes in normocellular marrow; if lymphoid nodules are 
seen, response is deemed as nodular (nPR). If all CR criteria are fulfilled but subject 
 
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has drug-related cytopenia, consider CR with incomplete bone marrow recovery 
(CRi).
Partial Response:
Peripheral blood: ALC reduced by 50% from pre-treatment baseline value, Hb >11 
g/dL or 50% improvement over baseline without transfusions, ANC 1.5 x 10
9/L or 
50% improvement over baseline, and platelet count >100 x 10
9/L or 50% 
improvement over baseline.
Tumor: When compared with pre-treatment measurements, a reduction 50% in 
measurable lesions without the appearance of new lesions.
Progressive Disease or Relapse of Disease
Peripheral blood: A 50% increase in ALC over baseline in first course, or lowest 
prior thereafter, with a sustained level >5 x 10
9/L.
Tumor: An increase in the product of two perpendicular diameters of a measured 
lesion by 50% over the size present at entry on study or for subjects who respond, 
the size at the time of maximum regression and/or the appearance of new areas of 
malignant disease.  Transformation to a more aggressive histology (e.g., Richter’s 
syndrome).  Deterioration in performance status or increasing symptoms do not 
constitute progression; however, their appearance should initiate a new evaluation 
for extent of disease.
Section 15.8.3. Agnogenic Myeloid Metaplasia (AMM)
Rationale for Change: This section was removed as the leukemia population was 
updated to only include acute myeloid leukemia.

Revised Text:
Section 15.8.3. Agnogenic Myeloid Metaplasia (AMM)
[Tefferi, 2001]
Complete Response: Absence of signs or symptoms of the disease.  White blood cells 
(WBC) between 1 to 10 x 10
9/L with no peripheral blasts, promyelocytes, or myelocytes 
and with normalization of bone marrow (<5% blasts in normocellular or hypercellular 
marrow).
Resolution of pretreatment cytopenias:
ANC  1.0 x 109/L without G-CSF or GM-CSF.
Hgb  12.0 gm/dL (11.0 gm/dL for females) without erythropoietin or transfusion 
support.
PLT  100 x 109/L without growth factor or transfusion support.
 
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Resolution of pretreatment leukocytosis and/or thrombocytosis:
WBC 10 x 109/L without peripheral blasts, promyelocytes, or myelocytes.
PLT  100 x 109/L but less than 450 x 109/L.
Partial Response:
Improvement of two or more of the following:
ANC: Increase by 100% and to above 109/L for neutropenia.
WBC: between 1 - 10 x 109/L with persistence of immature cells (blasts, myelocytes, 
metamyelocytes) for pretreatment leukocytosis.
Hemoglobin: Increase by 2 gm/dL if it was below 10 gm/dL or decrease in 
transfusion requirements by at least 50% (decrease in frequency and/or volume).
Platelet Count: below that level prior to therapy or persistent thrombocytosis 
>450 x 109/L but < 50% of pre-treatment.
Marrow Blasts: Reduction of marrow blasts to 5% or less if it was above 10% in 
normocellular or hypercellular marrow.
Organomegaly: Reduction in splenomegaly and/or hepatomegaly by 50% of 
pre-treatment dimensions (measured as length below the left costal margin on 
palpation) confirmed by imaging in difficult cases.
Section 14. Reference
Rationale for Change: Reference updated as per latest version available.

Revised Text:
CredibleMeds. List of drugs with a risk of Torsades de Pointes. Available at: http://www.
crediblemeds.org   Accessed 02 March 20156
Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of 
chronic lymphocytic leukemia: a report from the International Workshop on Chronic 
Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood. 2008; 11: 5446–56
Tefferi A. Chronic myeloid disorders: Classification and treatment overview. Semin 
Hematol. 2001; 38(1 Suppl 2): 1–4
 
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15.21.
Appendix 21: Protocol Changes for Amendment 8 (14-FEB-
2017) from the Protocol Amendment 7 (23-JUN-2016)
Where the Amendment Applies
Amendment 8 applies to all study centres. 
General Protocol Changes
Amendment 8: 
The study population for the AML cohort in Part 2 was amended from a population of 
subjects with AML to a population of subjects with relapsed or refractory 
myelodysplastic syndrome (MDS) or hypoproliferative AML that has arisen from an 
antecedent MDS. The Part 2 primary and secondary objectives along with the eligibility 
criteria were updated to include this new population.   The safety assessments were 
updated to be in line with the Investigator Brochure. The dose limiting toxicity criteria 
were modified to remove the specific criteria for leukemia. The time and events tables 
were updated to reduce the cardiac monitoring (ecg, holter and troponin), remove mRNA 
and cytokine collection, add a Pain Assessment, addition of an exploratory translational 
research blood draw and to add Factor VII assay collection. The disease related 
events/outcomes section was removed and the pregnancy reporting timeframe was 
reduced to 24 hours. Fever was removed from the dose adjusting/stopping safety 
criteria. Aspirin and non-steroidal-anti-inflammatory drugs (NSAIDs) were added to the 
Cautionary medications. Response Criteria for MDS was added as an Appendix.
GlaxoSmithKline Document Number 2011N113741_03 Version 3 changed to 
GlaxoSmithKline Document Number 2011N113741_05 Version 5 throughout the 
document.
Table numbers are updated (Figure no.1 becomes Table no. 1 Three Week DLT 
monitoring: Dosing Schedule and Cardiac Monitoring (QD and BID) and Table No.1  
Accelerated Dose Escalation Procedures in Part 1is deleted, all other Table numbers are 
same). Figure numbers are updated throughout the document (Figure no. 2 now becomes 
Figure no. 1, Figure no. 3 becomes Figure no. 2 and so on). Minor clarifications, 
formatting and typographical errors were also addressed in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
PROTOCOL SYNOPSIS

STUDY DESIGN AND DURATION:  
Rationale for Change: After an evaluation of data from the Part 1 AML cohort, the 
following observations prompted changes to the Part 2 cohort: clinical responses were 
observed at doses of 60 mg and above, these responses occurred in subjects whose 
disease harbored complex karyotype and recurrent mutations in TP53 and in proteins that 
regulate gene expression, suggesting that these subjects had an antecedent MDS that 
transformed to AML. Furthermore, most subjects with AML discontinued GSK525762 
 
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early in the course of their treatment as a consequence of their underlying AML or 
disease complications. Responses tended to be delayed (at the four week mark or later, 
with many requiring more than 10 weeks to manifest). Thus, most subjects were not 
remaining on study for long enough to achieve benefit. In order to maximize time on-
study, Part 2 was updated to enroll subjects with a more slowly-progressing disease that 
maintained many of the clinical characteristics of the AML responses that were observed 
in Part 1.
Revised Text:
Part 2 will explore clinical activity at the MTD or RP2D; separate expansion cohorts will 
be planned for myeloid malignancies (high-risk myelodysplastic syndrome [MDS] or
acute myeloid leukemia [AML] that has evolved from an antecedent MDS, hereafter 
referred as the “myeloid cohort”), non-Hodgkin’s Lymphoma (NHL, including an 
exploratory sub-cohort of subjects with myc and B-Cell Leukemia (BCL)2 and/or BCL6 
rearrangements/overexpression [double- and triple-hit lymphoma]), and multiple 
myeloma (MM).
STUDY RATIONALE:
Rationale for Change: This section was updated to include the MDS Population.
Revised Text:
Relapsed and/or refractory hematological malignancies such as MDS, Acute Myeloid 
Leukemia (AML), non-Hodgkin’s Lymphoma(NHL), and Multiple Myeloma (MM) have 
an overall poor outlook. This is the first study of this agent to be conducted in subjects 
with these relapsed and/or refractory hematological malignancies with few or no 
conventional treatment options that could be expected to provide any lasting benefit. 

OBJECTIVES AND ENDPOINTS:
Rationale for Change: This section was updated to include the MDS population and 
remove the BID administration objective to remove obligation of this cohort and 
make it optional. 
Revised Text:
Part 1
Part 1 Objectives
Part 1 Endpoints
Secondary

To evaluate clinical efficacy following 
QD administration in subjects with 
AML, MM, and NHL.

Objective Overall response rate 
(ORR), as measured by standard 
response criteria

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess objective overall response rate 
(ORR) according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
 
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Part 1 Objectives
Part 1 Endpoints
lymphoma, as a function of dose and 
exposure markers.

To evaluate safety, tolerability, 
and efficacy following BID 
administration of GSK525762 in 
subjects with AML, MM, and 
NHL

AEs, SAEs, DLTs, dose reductions or 
delays, withdrawals due to toxicities, 
changes in safety assessments, and 
ORR (as measured by standard 
response criteria)
Exploratory

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
following QD and/or BID dosing 
schedules.

Pharmacogenomic (PGx) study using 
clinical samples.
Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in high-
risk myelodysplastic syndrome (MDS) 
or acute myeloid leukemia (AML) that 
has evolved from an antecedent MDS 
(“myeloid cohort”).

For AMLMDS cohort: Objective response 
rate (% of subjects achieving Complete 
Response [CR], marrow CR, CRp [as per 
CR but platelet count <100 x 109/L], CRi 
[as per CR but platelet count <100 x 10
9/L 
or neutrophil count <1 x 10
9/L], or Partial 
Response [PR],) per response criteria.
Secondary

To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL after 
repeat-dose administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 
(i.e., PK)/PD) relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL.

PK/PD relationship between GSK525762 
exposure markers and safety and efficacy 
parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 3 disease-
specific cohorts of subjects with 
AMLMDS/AML, MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.

To evaluate the relationship between 
GSK525762 dose and PD response
in 3 disease-specific cohorts of 
subjects with AML, MM or NHL.

Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.
 
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Part 2 Objectives
Part 2 Endpoints

To determine the clinical activity of 
GSK525762 in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL.

TTP (Time to Progression) , DOR (Duration 
of Response),  PFS (Progression Free 
Survival) for MDS/AML, MM and NHL 

Overall survival (OS, the time from the 
treatment start date until death from any 
cause) for AMLMDS/AML, MM and NHL.
Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Acute myeloid leukemiaMyelodysplastic syndrome and transformed MDS: A response 
rate of 30% relative to a 10% response rate suggesting no activity in subjects with acute 
leukemiaMDS/AML.  

INCLUSION/EXCLUSION CRITERIA:
Rationale for Change: This section was updated to include criteria specific for the 
MDS population and also update contraception language based on GSK guidances.
Revised Text:  
Inclusion Criteria
9.
Males subjects with a female partner of childbearing potential or who is pregnant
must agree to use one of the methods of contraception specified in Section 9.1.  This 
method must be used from the time of the first dose of study medication until 16 
weeks after the last dose of study medication. In addition, male subjects whose 
partners are or become pregnant must use/continue to use condoms until 16 weeks 
after last dose of study medication.
3. In Part 1 and Part 2 sSubjects must have a diagnosis of relapsed or refractory 
Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), Multiple 
Myeloma (MM), or non-Hodgkin’s Lymphoma (NHL).

(Part 1 only): Subjects with AML, are eligible if they 
o have relapsed and/or refractory disease, OR

(Part 2 only): Subjects with MDS/AML (myeloid cohort) are eligible if they:
o Have high-risk (defined as intermediate [INT]-2 or higher by International 
Prognostic Scoring System [IPSS] criteria [Greenberg], or high/very high 
by IPSS-Revised [IPSS-R] criteria [Greenberg]) MDS that has relapsed 
after or been refractory to prior therapy with hypomethylating agent, OR
o Have AML that has arisen from an antecedent MDS (irrespective of 
IPSS/IPSS-R score)
 
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
Subjects must have progressed despite, or failed to respond to, prior 
therapy with hypomethylating agent, AND

At least one bone marrow biopsy obtained within 28 days of first 
dose of GSK525762 must demonstrate a marrow blast percentage of 
no more than 30%

Note: If marrow blasts exceed 30% on any biopsy within 28 days of 
first dose of GSK525762, enrolment will only be permitted after 
discussion with the medical monitor

(Part 1 and Part 2): Subjects with multiple myeloma are eligible if they have 
progressed despite therapy with an alkylating agent, 

(Part 1 and Part 2): Subjects with NHL are eligible if they have received at 
least two prior lines of systemic therapy, 
Definitions for Adequate Organ Function
Rationale for Change: Inclusion criteria were made more restrictive in order to reduce 
the risk of bleeding events.
Revised Text:
System
Laboratory Values
Hematologic
Coagulation assays (prothrombin time/ international 
normalized ratio [PT/INR] and activated partial 
thromboplastin time [aPTT] 1
1.52 X upper limit of normal (ULN)
Exclusion Criteria
Rationale for Change:Minor correction
Revised Text: 
4. Evidence of severe of or uncontrolled infection.

DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN: 
Rationale for Change: Minor correction  
Revised Text:
BID dosing will may be explored once MTD has been identified in once daily 
dosing; the total daily dose administered BID may not exceed the QD MTD.
PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: 
Rationale for Change: This section was updated to clarify that blood sampling for PD 
measurements will not be completed for all subjects.  
 
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Revised Text:
There will be serial blood sampling for PK and PD (in some subjects) measurements 
in Part 1 of this study and more limited PK sampling in Part 2 of this study.  
EFFICACY MEASUREMENTS:  
Rationale for Change: Addition of PFS and the MDS patient population to align with 
the newly revised objectives and endpoints.
Revised Text:
ORR, PFS and OS in AML, MDS, MM, and NHL; time to progression and duration 
of response in MM and NHL
SAFETY MEASUREMENTS: 
Rationale for Change: After an internal QTc analysis and evaluation of cardiac safety 
data collected from all subjects up to the 120 mg QD cohort available by 10Jun2016, the 
Holter Monitoring was removed, as the ECG time-points currently included in the 
required assessments provide adequate cardiac safety assessments of any potential QT-
prolonging effect (including potential delayed effects).
Revised Text:
Cardiac safety monitoring will be required, consisting of 24 hours of Holter 
monitoring at Screening, Week 1, and Week 4, and triplicate 12-lead ECGs prior to 
dosing on selected days and prior to drawing PK samples on serial PK sampling days 
(overnight stays in research facility may be necessary in Part 1).
STATISICAL ANALYSIS: 
Rationale for Change: This section was updated for Part 2 of the study to include 
population change from AML to MDS.
Revised Text:
The assessments are based on the predictive probability of success (response rate > 
historical response rate) with a maximum of 32 subjects treated per cohort (for 
AMLMDS and non- double hit NHL cohorts) or 37 subjects treated (MM cohort) 
and assessed for response.  
Section 1.2. Study Population Rationale
Rationale for Change:  After an evaluation of data from the Part 1 AML cohort, the 
following observations prompted changes to the Part 2 cohort: clinical responses were 
observed at doses of 60 mg and above, these responses occurred in subjects whose 
disease harbored complex karyotype and recurrent mutations in TP53 and in proteins that 
regulate gene expression, suggesting that these subjects had an antecedent MDS that 
transformed to AML. Furthermore, most subjects with AML discontinued GSK525762 
early in the course of their treatment as a consequence of their underlying AML or 
disease complications. Responses tended to be delayed (at the four week mark or later, 
 
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with many requiring more than 10 weeks to manifest). Thus, most subjects were not 
remaining on study for long enough to achieve benefit. In order to maximize time on-
study, Part 2 was updated to enroll subjects with a more slowly-progressing disease that 
maintained many of the clinical characteristics of the AML responses that were observed 
in Part 1.
Revised Text:
MDS and AML are related neoplasms of myeloid cells characterized by an excess of 
immature myeloblasts in the bone marrow, as well as ineffective hematopoiesis leading 
to peripheral cytopenias.  MDS and AML exist along a spectrum defined by the 
percentage of marrow blasts, with > 20% delineating the boundary between the two 
diseases.  While AML may arise de novo, it may also evolve from an antecedent 
myelodysplasia or myeloproliferative syndrome.  Both AML and MDS are increasingly 
defined by genetic characteristics, with cytogenetic abnormalities and mutations in genes 
involved in RNA splicing and epigenetic regulation frequently observed in MDS as well 
as AML that transformed from MDS.  The only approved therapies for MDS are the 
hypomethylating agents 5-azacitidine and decitabine; these agents are frequently used in 
patients with AML who are not suitable candidates for aggressive induction 
chemotherapy (e.g., as a consequence of advanced age or other comorbidity).  To date, 
there are no second-line agents for subjects who did not respond to or who have 
progressed despite hypomethylating agent therapy, and overall survival for patients who 
have failed prior therapy is typically measured in months (Prebet, 2011; Sekeres, 2013; 
Jabbour, 2010).
Non-Hodkin’s lymphomas are a family of more than sixty malignancies arising from 
abnormal lymphoid, histiocytoid, or dendritic cell development (Swerdlow, 2016).  They 
constitute a spectrum of diseases that may be focal or systemic, indolent or aggressive, 
based on the underlying cell of origin and other biological factors.  Therapy is 
customized for each patient based on the disease subtype and location and typically 
involves radiation, systemic therapy, or both.  Recently, targeted systemic therapies have 
emerged and have been approved based on promising response data.  However, NHL is 
an incurable disease for most patients and thus new approaches are necessary in the face 
of inexorable progression and relapse.
Multiple myeloma is a neoplastic proliferation of plasma cells.  In almost all cases, 
myeloma is incurable; though novel therapies have emerged in the past decade and a half, 
most patients with multiple myeloma will die from their disease.  Thus, new therapies are 
necessary.
Relapsed and/or refractory hematological malignancies such as AML, MDS, NHL, and 
MM have an overall poor outlook.  
Section 1.3.2.3 Starting Dose for BID
Rationale for Change: This section was updated to add flexibility to the BID dosing 
regimen.  
 
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Revised Text:
First paragraph third sentence:
In this study, once the QD MTD of GSK525762 has been identified for each disease 
subtype (AML/MDS, MM, and NHL), an exploratory cohort will may be opened in one 
or more of the for each some? disease types to evaluate safety, tolerability, and 
preliminary efficacy of BID dosing.  
Section 1.3.3 Dose escalation steps (QD only)
Rationale for Change: This section was updated to include the MDS population.
Revised Text:
Second paragraph first sentence:
The MTD of GSK525762 may be different for AML/MDS, NHL, and MM.  
Section 1.4 Rationale for Study and Endpoints
Rationale for Change: After an evaluation of data from the Part 1 AML cohort, the 
following observations prompted changes to the Part 2 cohort: clinical responses were 
observed at doses of 60 mg and above, these responses occurred in subjects whose 
disease harbored complex karyotype and recurrent mutations in TP53 and in proteins that 
regulate gene expression, suggesting that these subjects had an antecedent MDS that 
transformed to AML. Furthermore, most subjects with AML discontinued GSK525762 
early in the course of their treatment as a consequence of their underlying AML or 
disease complications. Responses tended to be delayed (at the four week mark or later, 
with many requiring more than 10 weeks to manifest). Thus, most subjects were not 
remaining on study for long enough to achieve benefit. In order to maximize time on-
study, Part 2 was updated to enroll subjects with a more slowly-progressing disease that 
maintained many of the clinical characteristics of the AML responses that were observed 
in Part 1.
Revised Text:
Second paragraph third sentence onwards:
Part 2 is a cohort expansion, which will study the RP2D of GSK525762 to determine 
preliminary efficacy, safety and tolerability in three separate cohorts of subjects with 
acute myeloid leukemiasmyeloid neoplasms (myelodysplastic syndrome [MDS] or MDS 
that has transformed to AML), multiple myeloma and non-Hodgkin’s lymphoma.
Originally, Part 2 of the study was designed to evaluate preliminary clinical efficacy in 
relapsed or refractory AML, MM, and NHL.  However, after an evaluation of data from 
the Part 1 AML cohort, the following observations prompted changes to the Part 2 
cohort;   clinical responses were observed at doses of 60 mg and above,these responses 
occurred in subjects whose disease harbored complex karyotype and recurrent mutations 
 
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in TP53 and in proteins that regulate gene expression, suggesting that these subjects had 
an antecedent MDS that transformed to AML.  Furthermore, most subjects with AML 
discontinued GSK525762 early in the course of their treatment as a consequence of their 
underlying AML or disease complications.  Responses tended to be delayed (at the four 
week mark or later, with many requiring more than 10 weeks to manifest).  Thus, most 
subjects were not remaining on study for long enough to achieve benefit.  In order to 
maximize time on-study, Part 2 was updated to enroll subjects with a more slowly-
progressing disease that maintained many of the clinical characteristics of the AML 
responses that were observed in Part 1 (i.e., MDS and MDS that has transformed to AML 
with a low burden of disease).
Section 1.5.1. Risk Assessment
Rationale for Change: This section was updated to reflect the results of ongoing 
toxicology studies.
Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Lymphoid / 
Hematologic
Lymphoid / hematologic toxicity was observed 
in rats and dogs and the effects contributed to 
the definition of severely toxic repeat dose in 
rats (30 mg/kg).
The effects manifested as hypocellularity in 
bone marrow, thymus, spleen and lymph 
nodes; decreased spleen and thymic weight; 
mild hemolysis; decreased white cell 
/lymphocyte count and variable and 
inconsistent changes in white cell /lymphocyte 
count, multiple red blood cells parameters and 
reticulocyte counts. Minimal bone marrow 
hypocellularity was still evident in male rats 
previously given 30/20 mg/kg/day for 13 
weeks following a 17 week off dose period.
Changes relating to coagulation were evident 
in both rats (considered non-adverse) and 
dogs (considered adverse at 3 mg/kg/day).  
These included a reduction in platelet counts 
(54%) and an increase in activated partial 
thromboplastin time (aPTT; 1.38X).
Full recovery of aPTT and a compensatory 
increase in platelet counts in dogs (1.27X) 
was evident following the 3 week off-dose 
period.
ICF includes the risk of lymphoid / 
hematologic toxicity.
Protocol includes laboratory 
assessments (complete blood 
count [CBC] and coagulation 
factors [international normalized 
ratio (INR), prothrombin time (PT), 
partial thromboplastin time (PTT)], 
exclusion criteria  if there is 
evidence of clinically significant 
bleeding episodes, monitoring for 
bruising/infection and dose 
stopping/modifications criteria.
Anticoagulants at therapeutic 
doses (e.g., warfarin, direct 
thrombin inhibitors, etc) are 
PROHIBITED from seven days 
prior to the first dose of study drug 
through completion of the Final 
Study Visit.  Low dose 
(prophylactic) anticoagulants are 
permitted provided that the 
subject’s PT/PTT meet entry 
criteria.
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human 
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose 
(1 mg/kg in dogs and 60 mg/kg in rats); no 
effects were observed in the 728 day 
toxicology repeat dose dog CV studyies; 
increase in mean BP up to 11 mmHg; 
decrease in mean BP up to 13 mmHg.
QA interval (indirect measure of cardiac 
contractility).
Increased Decreased QA interval at single 
non-tolerated doses in dog (no effect seen in 
rats); up to 10 msec. No effects were 
observed in the 7 day repeat dose dog CV 28 
day study; No echocardiography changes in 
the 28 day dog toxicology studyies.
ICF includes the risk of (fatal) 
arrhythmias
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring and cardiac 
ejection fraction) during the study, 
and dose stopping/modifications 
criteria for the management 
cardiac events.
Drugs with a risk of Torsades de 
Pointes are prohibited, (refer to 
Section 8.3).
Given the risks of long QTc 
associated arrhythmias, and of 
compound associated 
cardiomyopathy, subjects will be 
monitored closely for changes in 
QTc with triplicate 12-lead ECG, 
Holter monitoring and for 
elevations in plasma Troponin.  
Inpatient 48-hour telemetry was 
originally required for all subjects 
following the first dose of study 
drug, as part of the cardiac 
monitoring. Evaluation of cardiac 
safety data from subjects treated 
up to and including the 100 mg QD 
cohort by the cut-off date of May 
15, 2015 demonstrated no 
significant QTc prolongation after 
single and repeat dose 
administration. Therefore, the 48-
hour telemetry requirement was 
removed and the frequency of 
Holter monitoring was reduced 
with Protocol Amendment 5 and 
removed in Protocol Amendment 8 
following additional analysis of all 
available data by the cut off of 
 
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Potential Risk of 
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Mitigation Strategy
10-Jun-2016.  Specific stopping 
criteria and management 
guidelines are provided for cardiac 
toxicities.
Electrolytes, including potassium 
and magnesium will be checked at 
baseline and at regular intervals or 
when clinically indicated. 
Appropriate medical management 
will be instituted to assure that 
electrolytes are kept within the 
normal range
Cardiovascular -
Troponin
Elevations in cardiac biomarkers relative to 4 
week Good Laboratory Practice (GLP) 
toxicology study control group in:

Cardiac troponin I (up to 15X in rat 
and 4.7X in dog)

Cardiac troponin T (up to 8.9X in rat) 

Myosin light chain III (up to 4.8X in 
rat)

NT-proANP (up to 1.54X in rat)
Changes were reversible and there was no 
evidence of compound related myocardial 
histopathological changes in either species 
after 28 up to 3 months days of dosing.
ICF includes the risk of myocardial 
infarction.
Protocol includes troponin 
monitoring (local laboratory 
monitoring for troponin I or T 
based on availability and troponin 
T at central laboratory) and dose 
stopping/modifications criteria for 
the management of cardiac 
toxicity.
.
Reproductive
GSK525762 has shown adverse degenerative  
and potentially irreversible effects on testes in 
rats, rabbits and dogs, with no observed 
adverse 
effect 
level 
(NOAEL) 
in 
rabbits. These changes were accompanied in 
rats and dogs by changes in
sperm 
morphology, 
motility 
and 
number 
and 
hormonal changes (decreased testosterone 
and Inhibin B in rats and increased FSH in 
rats and dogs).  Reduced prostate weight and 
secretory content was also evident in the rat.  
An effect on spermatogenesis is anticipated. 
Full or partial reversibility of the testicular 
effects was observed in the 3 month rat and 
dogs studies following a 17 week off dose 
period.
An effect on spermatogenesis is anticipated.
In definitive four-week oral toxicology studies, 
ICF includes the risk of damage to 
reproductive organs such as testes 
or ovaries.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
subjects and collecting 
testosterone (free and complete) 
for male subjects.
ICF includes the potential risk of 
reproductive effects.
Protocol includes specific 
contraceptive guidelines and 
precautions for males and females 
and pregnancy testing for female 
 
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Mitigation Strategy
sperm retention and degenerative effects 
occurred in male dogs and rats. Degenerative 
changes were also observed in rabbits dosed 
dermally for 14 days.
No ovarian histologic changes were observed 
in the 4 week toxicology studies, however 
female fertility (disrupted estrous cyclicity, 
delays to mating and/or reduced fertility index) 
was affected in rats given 30 mg/kg/day 
GSK525762 for 15 days prior to mating and 
15 days prior to mating through to Day 6 post 
coitus (pc). Systemic exposure in rats was 
approximately 2-fold higher than current 
exposure in late stage cancer patients (at 60 
mg/day). No fertility effects were observed 
when 30 mg/kg/day was given for 6 weeks 
followed by 6 weeks off-dose prior to mating.
Reproductive and developmental toxicity ( 
decreased 
fetal 
body 
weight, 
fetal 
malformations or variations and / or pre- and 
post-implantation loss) occurred in rats given 
GSK525762 ≥1mg/kg/day from conception 
through gestation day 17 (of 21 days) and 
when dosed at ≥10 mg/kg/day for 14 days 
and dosing stopped prior to mating or 
continued until Day 6 pc. Systemic exposure 
in rats was approximately 80-fold lower than 
current exposure in late stage cancer patients 
(at 60 mg/day). These results are consistent 
with 
observations 
that 
BRD2, 
BRD3, 
BRD4 and BRDT have crucial roles in 
reproduction and development [see the GSK 
525762 
IB 
[GlaxoSmithKline 
Document 
Number 2011N113741_03] for references.
Based on the findings in these reproductive 
and developmental toxicity studies in rats with 
GSK525762, there is a substantiated risk for 
adverse effects on embryofetal development 
and impacts on female fertility.
GSK525762 has shown effects on female 
fertility (disrupted estrous cyclicity, delays to 
mating and/or reduced fertility index), embryo-
fetal toxicity and embryofetal developmental 
(decreased fetal body weight, fetal 
malformations or variations and / or pre- and 
post-implantation loss). A NOAEL has yet to 
be determined. There is a substantiated risk 
subjects.
 
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Mitigation Strategy
for adverse effects on embryofetal 
development and impacts on female fertility.
Pancreatic
A male rat-specific pancreatic change (islet 
cell fibrosis / fibroplasias and peri-islet 
haemorrhage, pigmented macrophages and 
inflammation) was observed at a dose of 
30 mg/kg/day in the 4 week study only. No 
effects were observed in the 3 month 
toxicology studies.
Following the 3 week off-dose period, these 
changes were decreased in incidence and/or 
severity.
An unrelated pancreatic lesion (acinar cell 
apoptosis, vacuolation and/or degranulation) 
was present in female dogs given 
3 mg/kg/day.
ICF includes the risk of pancreatic 
effects.
Protocol includes laboratory 
assessments (glucose -serum and 
urine, insulin and 1,5-
Anhydroglucitol (1,5-AG), c-petide, 
Hemoglobin A1c (HbA1c), 
amylase, lipase) as appropriate 
and monitoring for signs of gastric 
distress, abdominal pain, and 
clinical signs of malabsorption.
Protocol also includes dose 
stopping/modifications criteria for 
the management of 
hypo/hyperglycemia.
Liver/Gallbladder
Non-adverse liver changes were observed in 
preclinical toxicology studies including 
increases in bilirubin levels and transient 
increases in AST in rats. Hepatocellular 
necrosis was observed in a single rat at a 
non-tolerated dose (30 mg/kg/day).
GSK525762 has been demonstrated to 
undergo bioactivation in vitro which indicates 
potential for idiosyncratic heptotoxicity.  The 
precursor metabolite has been observed in 
clinical plasma samples. Non-adverse 
changes observed in the 28 day toxicology 
studies include:
Dog: increased gall bladder vacuolation and 
decreased cytoplasmic rarefaction in the liver 
was evident in dogs dosed at ≥1 mg/kg/day 
for 28 days.
Rat – Necrosis (single decedent rat killed on 
Day 20) and ground glass cytoplasm and/or 
centrilobular hypertrophy was observed in rats 
dosed at 30 mg/kg/day; decreased 
inflammatory cell infiltrate at ≥3 mg/kg/day
ICF includes the risk of 
hepatic/gallbladder effects.
Protocol includes hepatic eligibility 
criteria, laboratory assessments 
during the study, dose 
stopping/modifications criteria for 
the management hepatic events.
Lung effects
Aggregates of foamy macrophages in 
peribronchiolar areas were evident in rats 
given ≥10 mg/kg/day for 28 days.  Following 
the 3 week off-dose period, these changes 
were decreased in incidence.  This finding is 
ICF includes the risk of lung 
effects.
Protocol includes pulmonary 
function assessments as 
 
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unlikely to affect pulmonary function however 
the effect of dosing beyond 4 weeks is 
unknown. No effects were observed in the 3 
month toxicology studies. For more 
information, see the GSK 525762 IB 
[GlaxoSmithKline Document Number 
2011N113741_03].
appropriate (subjects with severe 
Chronic Obstructive Pulmonary 
Disease [COPD], history of 
pneumonitis, alveolar 
haemorrhage, chest radiation) 
chest x-ray at baseline and dose 
stopping/modifications criteria for 
pneumonitis.
Kidney
Eosinophilic inclusions and/or tubular 
basophilia were observed in the kidneys of 
rats in preclinical toxicology studies up to 3 
months dosing. Eosinophilic inclusions were 
observed in the kidneys of female rats dosed 
with 30 mg/kg/day for 28 days. These 
changes were considered non-adverse in this 
study.
Protocol includes renal monitoring 
including urinalysis (assessment 
for protein) and creatinine.
Effect on Teeth
Effects (disruption of dentin formation) on 
incisors (teeth that continually grow in 
rodents) were evident in male rats given ≥10 
mg/kg/day GSK525762 and both male and 
female rats at 30 mg/kg/day in the 13 week 
study, which resulted in pale and broken teeth 
during the in-life phase of the study from 
Week 8.  These microscopic effects were 
lower in severity and incidence after a 
minimum of 3 week off dose period.  No 
effects were observed in molar teeth (non-
growing).
Unlikely to affect adults.
Cytokines
In vitro incubation of human whole blood with 
GSK525762 for 24 hours resulted in a time 
and concentration-dependent induction of 
Interleukin (IL)-1β.  This effect was not 
observed in whole blood from other species 
(rat and dog) or in preparations of human 
peripheral blood mononuclear cells (PBMCs) 
or neutrophils.
Protocol includes close monitoring 
for fever, obtaining cytokine levels 
(e.g., Tumor Necrosis Factor 
(TNF)-alpha,IL-1,IL-6, IL-10) in the 
case of grade 2-4 fever, and dose 
stopping/modifications criteria for 
fever..
 
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Section 2. OBJECTIVE, ENDPOINTS, HYPOTHESIS
Rationale for Change: This section was updated to include the MDS population.
Revised Text:
Part 1
Part 1 Objectives
Part 1 Endpoints
Secondary

To evaluate clinical efficacy following 
QD administration in subjects with 
AML, MM, and NHL.

Objective Overall response rate 
(ORR), as measured by standard 
response criteria

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess objective overall response rate 
(ORR) according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To evaluate safety, tolerability, 
and efficacy following BID 
administration of GSK525762 in 
subjects with AML, MM, and 
NHL

AEs, SAEs, DLTs, dose reductions or 
delays, withdrawals due to toxicities, 
changes in safety assessments, and 
ORR (as measured by standard 
response criteria)
Exploratory

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762 
following QD and/or BID dosing 
schedules.

Pharmacogenomic (PGx) study using 
clinical samples.
Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in acute 
myeloid high-risk myelodysplastic 
syndrome (MDS) or acute myeloid 
leukemia (AML) that has evolved from 
an antecedent MDS (“myeloid 
cohort”) leukemia (AML).

For AMLMDS cohort: Objective response 
rate (% of subjects achieving Complete 
Response [CR], Marrow CR, CRp [as per 
CR but platelet count <100 x 109/L], CRi 
[as per CR but platelet count <100 x 10
9/L 
or neutrophil count <1 x 10
9/L], or Partial 
Response [PR],) per response criteria.
Secondary

To characterize the PK of 
GSK525762 in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL after 
repeat-dose administration.

Population PK parameters for GSK525762 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 
(i.e., PK/PD) relationship between 

PK/PD relationship between GSK525762 
exposure markers and safety and efficacy 
 
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Part 2 Objectives
Part 2 Endpoints
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL.
parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 3 disease-
specific cohorts of subjects with 
AMLMDS/AML, MM or NHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.

To evaluate the relationship between 
GSK525762 dose and PD response
in 3 disease-specific cohorts of 
subjects with AML, MM or NHL.

Dose related change in molecular markers 
(e.g., gene transcription and/or expression 
of proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To determine the clinical activity of 
GSK525762 in 3 disease-specific 
cohorts of subjects with 
AMLMDS/AML, MM or NHL.

TTP (Time to Progression) , DOR (Duration 
of Response),  PFS (Progression Free 
Survival) for MDS/AML, MM and NHL 

Overall survival (OS, the time from the 
treatment start date until death from any 
cause) for AMLMDS/AML, MM and NHL.
Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Acute myeloid leukemiaMyelodysplastic syndrome and transformed MDS: A response 
rate of 30% relative to a 10% response rate suggesting no activity in subjects with acute 
leukemia MDS/AML.  
Section 3.1. Study Design/Schematic
Rationale for Change: This section was updated to include the AML and MDS 
populations.   Additionally the collection of blood samples intended for the analysis of 
mRNA and cytokines for BET116183 study has ceased. These samples were being 
collected as part of a collaboration with Epinova for biomarker studies to assess target 
engagement after BET inhibitor treatment. Similar analysis was being done in the 
BET115521 study (solid tumor). We were informed that sufficient data from the 
BET115521 study had been generated to make future decisions to support clinical 
expansion with this drug. Therefore, no additional samples from the BET116183 study 
would need to be collected and/or analyzed.
Revised Text:
Second Paragraph onwards
This is an open-label repeat dose, multicenter, 2-part study to determine the MTD in 
subjects with acute myeloid leukemia myeloid malignancies, multiple myeloma, and non-
Hodgkin’s Lymphoma, and the recommended Phase 2 dose (RP2D) for GSK525762 
given once-daily (QD) orally.  Safety, tolerability, PK, and efficacy will may also be 
 
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explored in a limited number of subjects treated twice daily (BID). Both parts will be 
conducted in adult subjects with relapsed and/or refractory acute myeloid leukemia
myeloid malignancies, multiple myeloma, and non-Hodgkin’s lymphomas.
In both Parts 1 and 2, all subjects will be evaluated for systemic BET inhibitory effects in 
blood (whole blood transcriptional). A subset of subjects in Part 1 will also be evaluated 
for plasma cytokine profiling. and plasma cytokine profiling).  In addition, pre-treatment 
and post-treatment bone marrow, whole blood for PBMC isolation or lymph node 
samples will be collected from selected subjects to be evaluated for target engagement 
and effects of GSK525762 on tumor biology.
Section 3.2.1. Part 1: Dose Escalation
Rationale for Change: This section was updated to include the AML and MDS 
populations.
Revised Text:
Fifth Paragraph first sentence
Due to the potentially different MTD in subjects with AML myeloid neoplasms, NHL, 
and MM (Section 1.3.3), each dose escalation step will be evaluated separately for the 
three disease types. 
Section 3.2.1.1
Dose Escalation and Schedule
Rationale for Change: The cardiac safety monitoring was removed to avoid duplication 
as all cardiac assessments can be found in the T&E table.
Revised Text:
Second Paragraph Onwards
In Part 1, subjects will follow the dose schedule outlined in Table 5. Alternative dosing 
regimens and/or schedule may be implemented based on emerging PK and safety data.
Extensive monitoring for cardiac safety signals will be performed including triplicate 12-
lead ECG and 24-hour Holter monitoring on the days indicated in the Time and Events 
Table .Table 5
 
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Table 24
Three Week DLT monitoring: Dosing Schedule and Cardiac 
Monitoring (QD and BID)
Dose
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG, 
ECG,
ECG,
Holter
ECG
Week 2
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
ECG
ECG, 
Week 3
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
Please refer to Time and Events Tables Section 5  for more details
Section 3.2.1.3. 3 + 3 Dose Escalation in Part 1
Rationale for Change: This section was updated to include the AML and MDS 
populations.
Revised Text:
First Paragraph first sentence
Due to the potentially different MTDs in acute leukemia myeloid neoplasms, MM, and 
NHL, dose escalation will be evaluated in three separate cohorts divided by disease 
subtype
Section 3.2.1.5.
BID dosing
Rationale for Change: This section was updated to allow a BID cohort to open 
simultaneously regardless of disease type. 
Revised Text:
First paragraph second sentence 
Initially, only one cohort per disease type is planned, though lower doses may be 
explored based on toxicity observed after the initial few subjects.  
Section 3.2.1.6.
Intra-Subject Dose Escalation
Rationale for Change: Minor clarification.
Revised Text:
Second paragraph first sentence 
 
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Subjects approved for intra-subject dose escalation will may require additional limited 
PK sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by GSK 
Clinical Pharmacology. Additional
Section 3.2.2. Dose Limiting Toxicity (DLT)
Rationale for Change: This section was updated as the DLT window for this study is 3 
weeks, so a 6-week myelosuppression criterion is outside the window for DLT 
observation.
Revised Text:
Events under Prolonged myelosupression for leukemia

For leukemia:

At 6 weeks, bone marrow biopsy that demonstrates no evidence of residual 
leukemia AND EITHER:

Marrow aplasia, defined as <5% cellularity by trephine biopsy, OR

Peripheral cytopenias, defined as absolute neutrophil count (ANC) ≤500/uL 
and/or platelets ≤25,000/uL (if baseline ANC and/or platelets were >500/uL 
and/or 25,000/uL, respectively)
Section 3.2.4. Part 2: Disease Specific Expansion Cohorts
Rationale for Change: This section was updated to include the MDS population.
Revised Text:
Up to 32 subjects (per cohort) with acute myeloid leukemia myelodysplastic syndrome or 
non-Hodgkin’s lymphoma (non-DHL), and up to 37 subjects with multiple myeloma, 
may be enrolled in an expansion cohort at the RP2D.  These will be conducted to gather 
more safety data and to further assess anti-tumor activity.  Subjects in Part 2 will start 
with a continuous daily dosing schedule unless safety, or PK or PD data necessitate a 
different dosing schedule.  The final dose and regimen for Part 2 will be decided upon 
completion of dose escalation in Part 1.
At least 10 subjects with tumor that is positive for rearrangement or overexpression of 
MYC plus BCL-2 and/or BCL-6 genes (double- and triple-hit lymphoma) will be 
enrolled.  These subjects will be evaluated separately for efficacy, but hypotheses will not 
be tested.  See Section 11.1 for description of the plan for analysis of the NHL cohorts.
Plasma samples for PK evaluation will be collected in all subjects.  Plasma samples and 
other clinical samples (e.g. lymph node or bone marrow biopsies) will be collected pre-
and post- study drug treatment as defined in the Time and Events Table in Section 5 for 
the PD evaluation.
The Part 2 portion of the study will employ a Bayesian design that allows the trial to be 
monitored with the constraint of both Type I and Type II error rates.  Clinical response 
 
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will be defined per standard evaluation criteria (see Appendix 6, Appendix 7 and 
Appendix 8).
For each cohort, an interim analysis will be conducted after efficacy data at a dose level 
based on RP2D are available on a minimum of 10 subjects in the AMLMDS and NHL 
(non-DHL) cohorts and a minimum of 13 subjects in the MM cohort. The number of 
subjects may be increased up to a total of 32 for the AMLMDS and NHL (non-DHL) 
cohorts and up to a total of 37 for the MM cohort depending on the results observed; a 
separate decision will be made for each disease cohort.  The decision rules, specifying the 
number of subjects with a clinical response needed for continuing enrolment or, stopping 
for futility, are indicated in Figure 4 and Figure 5.  The methodology is based on the 
predictive probability of success (response rate > historical response rate) if enrolment 
continues to 32 subjects for AMLMDS and NHL (non-DHL) and 37 subjects for MM 
[Lee, 2008].  These rules are intended as a guideline.  Actual decisions will depend on the 
totality of the data.
For AMLMDS and NHL (non-DHL) cohorts: Ten subjects will be enrolled in each 
cohort at the RP2D to examine safety and efficacy.  If zero responses are observed in 
either cohort, then that cohort will be terminated and no further subjects will be enrolled 
due to futility. A single response in a cohort will be adequate to pursue further enrolment. 
The number of observed confirmed responses will guide further enrolment according to 
the rules summarized in Figure 4. A maximum of 32 subjects per cohort will be enrolled 
at the RP2D.  All available data will be considered in making enrolment decisions.
Figure 4
Diagram of Stopping Rules for AMLMDS and NHL (non-DHL) 
Cohort Expansion
Section 4.2.1. Inclusion Criteria
Rationale for Change: This section was updated to include criteria specific for the MDS 
population
Revised Text:
3. In Part 1 and Part 2, sSubjects must have a diagnosis of relapsed or refractory
Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Multiple 
Myeloma (MM), or non-Hodgkin’s Lymphoma (NHL).

(Part 1 only) Subjects with AML, are eligible if they 
o have relapsed and/or refractory disease, OR
o are 65 years of age and not candidates for or have refused standard 
chemotherapy. 

(Part 2 only): Subjects with MDS/AML are eligible if they:
o Have high-risk (defined as intermediate [INT]-2 or higher by International 
Prognostic Scoring System [IPSS] criteria [Greenberg], or high/very high 
by IPSS-Revised [IPSS-R] criteria [Greenberg]) MDS that has relapsed 
after or been refractory to prior therapy with hypomethylating agent, OR
 
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o Have AML that has arisen progressed from an antecedent MDS 
(irrespective of IPSS/IPSS-R score)

Subjects must have progressed despite, or failed to respond to, prior 
therapy with hypomethylating agent, AND

At least one bone marrow biopsy obtained within 28 days of first 
dose of GSK525762 must demonstrate a marrow blast percentage of 
no more than 30%
Note: If marrow blasts exceed 30% on any biopsy within 28 days of 
first dose, enrolment will only be permitted after discussion with the 
medical monitor

(Part 1 and Part 2): Subjects with multiple myeloma are eligible if they have 
progressed despite therapy with an alkylating agent, proteasome inhibitor, 
and immunomodulatory agent, either as individual regimens or in 
combination

(Part 1 and Part 2): Subjects with NHL are eligible if they have received at 
least two prior lines of systemic therapy, including at least one line of 
immunochemotherapy with an anti-CD20 antibody (if their tumor expresses 
CD20)
9. Males subjects with a female partner of childbearing potential or who is 
pregnant must agree to use one of the methods of contraception specified in 
Section 9.1.  This method must be used from the time of the first dose of 
study medication until 16 weeks after the last dose of study medication. In 
addition, male subjects whose partners are or become pregnant must 
use/continue to use condoms until 16 weeks after last dose of study 
medication.
Table 4
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Hemoglobin (only for myeloma and lymphoma)
Coagulation assays (prothrombin time/ international 
normalized ratio [PT/INR] and activated partial 
thromboplastin time [aPTT]1
≥8.0 g/dL
1.25 X upper limit of normal (ULN)
 
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Section 4.2.2. Exclusion Criteria
Rationale for Change:  Minor correction
Revised Text
4. Evidence of severe orf uncontrolled infection.
Section 5 Time and Events Table
Rationale for Change:  The time and events tables were modified to ensure consistency 
of timings, correct previous errors, provide additional 
clarifications and to include new updates based on removal of 
holter monitoring, revised ECG schedule, and removal of blood 
sample collections for cytokines and mRNA.
 
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Revised Text
Table 5 Time and Events: Part 1
Starting 
from W10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W
4
W
5
W
6
W
7
W
10
q3w
q6w
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
D
1
Informed consent
(Unless otherwise 
noted, screening 
assessments to 
be completed 
within 14 days of 
first dose.)
X
Demography
X
Medical historya
X
Disease 
characteristics
X
Cardiology eval.
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug: For QD or BID details see Table 8 and Table 9
Administer study drug (Administer 
about same time of day. No food or 
antacids 1h before and 2h after.)
Daily
Review subject diary 
(Not required when dosed in clinic.)
X
X
X
X
X
X
X
Safety
Pregnancy test/ testosterone b
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital Signs c//Pain Assessment
X
X
X
X
X
X
X
X
X
X
X
Height and weight (Height at Scr only)
X
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test d
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 6.7.4)
Concomitant medications
continuous from signing of informed consent
 
 
 
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Starting 
from W10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W
4
W
5
W
6
W
7
W
10
q3w
q6w
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
D
1
Laboratory assessments: For details please see Table 6
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W
4
W
5
W
6
W
7
W
10
q3W
q6w
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
D
1
Cardiac Monitoring
ECHO (Within 35 days of first dose)
X
X
X
X
X
X
12-lead ECGs e
X
O
O
O
X
X
X
O
X
X
X
X
O
X
X
X
Holter monitoring
(At least 24 h, on dosing days start 
predose)
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see Table 8 and Table 9                                                                                           
PK Blood samples for GSK525762
X
X
k
X
h
X
X
X
X
X
k
X
Xf
PD Blood samples for biomarkers 
(mRNA)
X
X
X
X
Blood samples for plasma cytokines
X
X
X
X
PD Tumor Sample 
X
g
X
h
Translational Research i
Pharmacogenomics (PGx) sample
X
Blood samples for Translational 
Medicine study Blood sample for 
exploratory translational research
X
Additional samples will be collected on the date of disease assessment/bone marrow biopsy and date of progression or when 
patient is discontinued from study/end of treatmentj Additional samples will be collected on the date of disease 
assessment/bone marrow biopsy and date of progression
Tumor biopsy at progression
X
FOLLOW-UP PHASE
 
 
 
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Starting 
from W10
Procedure
(Notes)
S
C
R
Week 1
Week 2
W3
W
4
W
5
W
6
W
7
W
10
q3w
q6w
E
O
T
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
1
D
1
D
1
D
1
D
1
D
1
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death (as described in Table 7).  Individual subjects will be considered to have completed the 
study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects 
have died or 5 years after the last subject is enrolled in Phase 2.
a.
Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the 
medical history and disease status.
a.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter.  Pregnancy 
testing not required for females of non-childbearing potential as defined in Section 4.2.1.
b.
Vital signs include systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, respiratory rate and temperature
c.
Pulmonary tests as appropriate: subjects with severe COPD, history of pneumonitis, alveolar hemorrhage, chest radiation
d.
12-lead ECGs : Screening ECGs within 14 days of first dose.  Triplicate ECGs prior to dosing.  For timing of ECGs on “O” days, see Table 8 for QD and Table 9 for BID. Otherwise, 
triplicate ECGs at approximately same time of day, and prior to dose on dosing daysdosing. If QTcF increase >30msec, ECGs performed daily through W2.
e.
For subjects on study longer than 12 weeks, collect a pre-dose PK sample q6W. Reduce to q12w after 12 months on study.
f.
Pretreatment biopsy for PD tumor sample must be performed within 14 days of first dose.
g.
During 3+3 dose escalation, PD tumor sample collection will be mandatory unless infeasible to collect, and approval is obtained by the GSK medical monitor.  Subjects with MM  
will have bone marrow aspirates collected on W1 D3 within 3-6 hours after the dose.  Subjects with AML will have bone marrow aspirates or peripheral blood collection (provided 
that there are sufficient leukemic cells in the peripheral circulation) collected on W1 D3 within 3-6 hours after the dose. Subjects with NHL will have a tissue biopsy (lymph node or 
other affected organ/region) collected on W1D3 within 3-6 hours after the dose. Timing of tissue collection will be based on tumor type and may be modified based on emerging 
data. For operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection remain as described. A PK sample will need to be obtained 
within 1 hour of the tissue sampling.  Details described in the SPM Ssee Table 7 disease specific assessments for details).
h.
Refer to Section 6.6 for details on Translational Research and Appendix 5 for details on PGx Research.
i.
Refer to Table 7 Disease Specific Assessments for timepoints. 
j.
Assessment only completed for Part 1 QD subjects
Abbreviations: ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by Fridericia’s formula; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; PGx=Pharmacogenetics; COPD=Chronic obstructive pulmonary disease; SPM=Study Procedures Manual; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; 
q6W=every 6 weeks; SCR=Screening; W=week
 
 
 
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Table 6
Time and Events: Part 1 Laboratory Assessments
q3w and q6w 
Initiated from 
Wk 10
NB: On dosing days, Ccollect blood samples prior to dosing.  W1D1 samples not 
needed if SCR sample collected within 24h of first dose.
SCR
W1
W2
W3
W4
W5
W6
W7
W10
q3W
q6W
EOT
Assessment
Notes
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, 
NT pro-BNP
Troponin: W1D1 &W1D2:  local lab sample collect 3X/per 
day; central troponin lab sample 1X/per day. Troponin:
All other timepoints and unscheduled troponin, cCollect 2 
samples: 1 for local, 1 for central lab1 sample for local 
lab [troponin I or T], 1 sample for central lab [troponin T])
X
X
X
X
X
X
X
X
X
X
X
Hematology
Increase frequency as medically indicated 
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
Creatine phosphor-
kinase, CK-MB
CK-MB at predose and 12-18 h post dose take on W1D1, 
and as clinically appropriate.
X
X
X
X
X
X
X
X
X
X
X
CK-MB
CK-MB at predose and 12-18 h post dose take on W1D1, 
and as clinically appropriate.
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
LDH
X
X
X
X
X
X
X
X
Fasting blood 
glucose and insulin
Will be performed at central lab if not available at local 
lab
X
X
X
X
X
X
X
X
X
c-peptide and 1, 5 
AG
Will be performed at central lab if not available at local 
lab; performed at baseline and repeated if necessary 
during the study.
X
HbA1c
Performed at baseline and repeated if necessary during 
the study.
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4. If TSH is abnormal W1D1, monitor 
TSH, free T3 and free T4 going forward
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Pregnancy test, 
Serum pregnancy test within 7 days of first dose; urine or 
X
X
X
X
X
X
 
 
 
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q3w and q6w 
Initiated from 
Wk 10
NB: On dosing days, Ccollect blood samples prior to dosing.  W1D1 samples not 
needed if SCR sample collected within 24h of first dose.
SCR
W1
W2
W3
W4
W5
W6
W7
W10
q3W
q6W
EOT
Assessment
Notes
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
females
serum test thereafter
Testosterone, males
Complete and free testosterone at SCR; free 
testosterone thereafter
X
X
X
X
X
X
Safety Cytokines
X
as clinically appropriate following fever
HBsAg, HepC 
antibody
If hepatitis C antibody positive, perform third generation 
immunoassay (if test is available) on same sample to 
confirm results, or alternatively, use HCV RNA test 
(either quantitative or qualitative).
X
Abbreviations: 1,5 AG=1,5-Anhydroglucitol, NT-pro BNP=N-ternimal prohormone B-type Natriuretic Peptide; C=cycle; CK-MB=Creatine Kinase – MB (isoform); LDH=Lactate 
dehydrogenase; TSH=Thyroid stimulating hormone; HBsAg = Hepatitis B surface Antigen; HepC=Hepatitis C; HCV Hepatitis C Virus; RNA=Ribonucleic acid; D=day; EOT=End of 
Treatment Visit; q3W=every 3 weeks; q6W=every 6 weeks; SCR=Screening; W=week
 
 
 
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Table 7 Disease Specific Assessments: Part 1 and 2
Multiple Myeloma (MM) Assessments
q3w and q6w 
Initiated from 
Wk 10
Procedure
Notes
SCR
Week 1
Week 2
W3
W4
W7
W10
q3W
q6W
EOT
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
Disease Characteristics 
Including cytogenetics as appropriate 
X
Total Protein, CRP, 2 microglobulin
X
X
X
X
X
SPEP, FLC assay, quantitative 
immunoglobulins ( IgG, IgA, IgM)
Not required for subjects with non-
secretory MM; 
X
X
X
X
X
UPEP
Only required if paraprotein is 
present in urine
X
X
X
X
Extramedullary Disease Assessment 
Only required for MM with 
extramedullary disease
X
X
X
X
Blood sample for exploratory 
translational research
A blood sample for exploratory 
translational research should be 
collected at EOT and/or date of 
progression and at timepoints as 
indicated
X
X
X
X
BM aspirate and biopsy
Required for non-secretory MM, or as 
appropriate for other subjects
X
X
Response assessment
Every 6 weeks after wk4; Response 
criteria in Appendix 6 
X
X
X
X
 
 
 
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Lymphoma Assessments
q3w and q6w 
Initiated from 
Wk 10
Procedure
Notes
SCR
Week 1
Week 2
W4
W7
W10
q3W
q6W
q12W
EOT
D1
D2
D5
D1
D6
D1
D4
D1
D1
D1
D1
D1
Disease characteristics, including historya
immunophenotypes, cytogenetics  and 
prognostic markers b
X
2-microglobulin
X
X
B Symptoms
X
X
X
X
X
Lymph node and organ exam
X
X
X
X
X
Bone marrow/tissue biopsy c
X
X
Blood sample for exploratory translational 
research
X
X
Wk 16, wk 24, 
then q12wks
Xg
CT Scan d
X
X
Wk 16, wk 24, 
then q12wks
X
PET Scan d, e 
X
X
Response evaluation f
X
Wk 16, wk 24, 
then q12wks
X
a.
Including date of first diagnosis, disease stage, and complete history of diagnostic results and therapies.
b.
Examples of prognostic markers may include:  ALC, FLIPI-1, FLIPI-2 (includes ß2-microglobulin), FcR gamma 3A.
c.
A sample will be required at screening only if clinically appropriate for the lymphoma subtype AND an appropriate previous sample is available. A follow-up bone marrow biopsy will be 
performed no later than 8 weeks following CR (as judged by investigator) in accordance with the response guidelines ( Appendix 7) if a subject had involvement of the BM at the start of 
the study.
d.
Baseline/Screening Computerized Tomography (CT) and PET scans may be obtained within 35 days of first dose Follow-up CT scans at week 7 wk 16, wk 24 and then every 12 
weeks.
e.
PET or PET/CT scan if clinically indicated (e.g., confirmation of CR for Diffuse large B-cell lymphoma). 
f.
Evaluation of response for lymphoma at week 7, week 16, week 24 and then every 12 weeks. Assessments are described in Appendix 7 : Response Criteria for Lymphoma.
g.
A blood sample for exploratory translational research should be collected at EOT and/or date of progression
 
 
 
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MDS and Leukaemia Assessments
q3w and 
q6w Initiated 
from Wk 10
Procedure
Notes
SCR
Week 1
Week 2
W3
Wk4
W5
W7
W10
q3W
q6W
EO
T
D1
D2
D5
D1
D6
D1
D1
D1
D1
D1
D1
D1
Disease characteristics, 
including history, immuno-
phenotype, cytogenetics and 
molecular studies as 
appropriate  and History a
X
Lymph node and spleen 
assessment 
Only as appropriate 
X
X
X
X
X
X
Response Assessmentb
X
X
X
X
X
Blood sample for exploratory 
translational research
X
X
X
X
Xf
Transfusion History c
X
X
X
X
X
X
X
X
Bleeding History
X
X
X
X
X
X
X
X
Hematology d, e
X
X
X
X
X
X
X
X
A.
Including date of diagnosis and complete history of diagnostic results and therapies.
B.
Bone marrow biopsy/aspirate should be obtained for response assessment at the timepoints indicated.  Subjects without marrow involvement may be assessed by other means 
(e.g., medical photography for leukemia cutis) after discussion with the medical monitor, provided that the same method is used for all assessments of that subject.  Response 
criteria for AML are described in Appendix 8; response criteria for MDS are described in Appendix 9.  For subjects with AML, Aa peripheral blood sample can be taken at baseline 
if a bone marrow sample cannot be collected.  Subjects should be off cytokine support (granulocyte colony-stimulating factor [GCSF] or granulocyte-macrophage colony-
stimulating factor [GMCSF]) for a minimum of 7 days before obtaining bone marrow to document remission.
a.
Platelet and blood transfusions to be assessed at designated visits and summarized per unit on a weekly cumulative basis.
b.
Hematology includes complete blood count (CBC) with white blood cell count differential (including neutrophils, eosinophils, basophils, lymphocytes and monocytes) and platelets; 
hemoglobin, hematocrit, red blood cell count.  A CBC with differential and platelets, hemoglobin and hematocrit may be performed daily during in-patient care; once subject is 
discharged, assessments to continue weekly until disease response assessment.  This is collected at baseline/screening;, daily during chemotherapy treatment then weekly.  
Platelet count achievement of 20,000/mL for 3 days is entered into the eCRF and the date of platelet count achievement of 100,000/mL is entered into the eCRF.
c.
A blood cell smear to measure peripheral blood blasts.
d.
A blood sample for exploratory translational research should be collected at EOT and/or date of progression
 
 
 
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Table 8 Time and Events: Part 1 (QD cohorts) Serial Electrocardiograms, Pharmacokinetics, and Biomarker Sampling
Procedure / time after dose
W1D1 
W1D2
W1D5
pre 
dose
0h
15 min 
± 5m
30 min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h ±2h
24h 
±1h
0h
0h
30 min 
±0
2h 
±15m
3h 
±30m
4h 
±15m
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
PK sample for GSK525762 b
X
X
X
X
X
X
X
X
X b
X
X
Blood sample for biomarkers (mRNA)
Xc
X
X
X
X
X
Plasma cytokine sample
Xc
X
X
X
X
X
Procedure / time after dose
W2D4
W2D6
W2D7 (if dose has been altered (including held and resumed) serial PK sampling 
should occur 4 to 7 days after dosing resumed)
W3D1
W7D1 ±4 days c d
pre
dose
pre
dose
pre 
dose
0h
15 min 
± 5m
30 min 
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
12h 
±2h
24h 
±1h
0h
pre 
dose
0h
0.5-
2h
4 -
8h
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample for GSK525762
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for biomarkers 
(mRNA)
X
Plasma cytokine sample
X
X
X
X
X
X
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 min prior to PK draw. For timepoint with a ±5 minute it is acceptable for the first ECG to be out of the minus 5-
min window to allow scheduling in this short time frame, as long as PK sample is collected after the last ECG and at least within +5 minutes of the window. 
b.
Sample to be obtained before dosing on Week 1, Day 2.
c.
May be collected within 14 days prior to first dose
d c If dose was escalated, the W4D1 visit may be performed +4 to +7 days.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
 
 
 
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Table 9 Time and Events: Part 1 (BID Cohorts) Serial Electrocardiograms, Pharmacokinetics and Biomarker Sampling
W1D1
W1D5
W2D4
W2D6
W2D7
W7D1 ±4 days e
Timepoint; 
Hours after AM dose
Pre-Dose
0h
30 min ±5m
2h 
±15m1h±10m
4h ±15m
8h  ±1h
12h (0h)
AM
30 min ±5m 2h 
±15m
4h ±15m3h 
±15m
PM
pre AM dose
AM & PM
pre AM dose
AM & PM
Pre-Dose
0h
30 min ±5m
1h ±10m 2h 
±15m
4h ±15m
12h (0h)
pre dose
0h
0.5-2h
4 - 8h
12h
Dose
X
X
X
X
XX
XX
X
X
X
X
12-lead ECG a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK GSK525762b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample for biomarkers 
(mRNA)
Xd
X
X
X
X
Plasma cytokine sample
Xd
X
X
X
X
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 minutes prior to PK draw. For time points with a ±5 minute it is acceptable for the first ECG to be out of 
the minus 5-min window to allow scheduling in this short time frame, as long as PK sample is collected after the last ECG and at least within +5 minutes of the window.
b.
PK blood sample collected overnight may be kept refrigerated at 4C in the event the laboratory is closed. 
c.
Blood sample for PD biomarker.
d.
May be collected within 14 days prior to first dose
ec. If dose was escalated, the W4D1 visit may be performed +4 to +7 days.
APP=acute phase protein; ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose; 
 
 
 
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Table 10 Time and Events: Part 2 Expansion Cohort
Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated 
from Wk 10)
E
O
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
(Unless otherwise noted, screening 
assessments to be completed within 14 
days of first dose.)
X
Demography
X
Medical historya
X
Disease characteristics
X
Cardiology evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study drug (Administer about same time of day.)
Continuous daily dosing (unless safety, PK or PD data necessitate a 
different dosing schedule), see Section 3.2.4
X
Review compliance (Not required when dosed in clinic.)
X
X
X
X
X
X
X
X
Pregnancy test/testosterone b
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
Vital Signs c//Pain Assessment
X
X
X
X
X
X
X
X
X
Weight and height (Height at SCR only)
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test
X
Adverse events
AEs & SAEs continuous from first dose; SAEs (If study related) from signing of informed consent (see Section 
6.7.46.7.5)
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 11
Tests
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO (Within 35 days of first dose).  
X
X
X
X
X
X
12-lead ECGs d
X
X
X
X
X
X
X
X
X
Holter monitoring (Min 24h, on dosing days start predose)
X
X
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated 
from Wk 10)
E
O
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
PK and Blood PD
PK Blood 
samples
Three samples to be collected  each sampling day: 
During the first 3 weeks collect a predose (within 
60 minutes prior to dose), a single draw between 
0.5 to 2 h postdose, and a  single draw between 4-
8h postdose (fasting requirements apply).  
Thereafter W7 and Q6W only a predose and 0.5 
hour post dose sample are collected 
X
Xf
X
X
Translational Research
PGx sample
X
Tumor sample (e.g., bone marrow biopsy, lymph node biopsy, or 
peripheral blood collection [only for subjects with circulating 
disease])
X e
Xf
Xg
Blood samples for exploratory translational research 
X
Xf
Additional samples will be collected on the date of disease assessment/bone 
marrow biopsy and date of progression or when patient is discontinued from 
study/end of treatment
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months.  Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death (as described in Table7).  Individual subjects will be considered to have completed the 
study 2 years after their last treatment or upon death, whichever is sooner.  Document the cause of death.  For the study, the Follow-up Phase ends after a minimum of 70% of subjects 
have died or 5 years after the last subject is enrolled in Phase 2.
a.
Medical, surgical, alcohol, tobacco and treatment history, including date (month and year) of first diagnosis, histology, and current sites of disease, will be taken as part of the 
medical history and disease status
b.
Females: serum pregnancy test within 7 days of first dose; urine or serum test thereafter.  Males: complete and free testosterone at SCR; free testosterone thereafter. Pregnancy 
testing not required for females of non-childbearing potential as defined in Section 4.2.1.
c.
Vital signs include SBP, DBP, heart rate, respiratory rate and temperature
d.
Screening ECGs within 35 days of first dose.  ECGs prior to dosing.  If QTcF increase >30msec, ECGs should be repeated every 2-3 days until the QTcF is within 30 msec of 
baseline.
e.
Pretreatment biopsy for tumor sample must be performed within 14 days of first dose.
f.
Subjects with MM or should have bone marrow aspirates collected on W3D1 within3-6 hours after the dose. Subjects with AML should have bone marrow aspirates or peripheral 
blood collection (provided that there are sufficient leukemic cells in the peripheral circulation) collected on W3 D1 within 3-6 hours after the dose.  Subjects with NHL will have a 
 
 
 
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Part 2 Procedure 
(Notes)
SC
R
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
(q3w and q6w Initiated 
from Wk 10)
E
O
T
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
lymph node biopsy collected on W3D1 within 3-6 hours after the dose. Timing of tissue collection will be based on tumor type and may be modified based on emerging data. For 
operational reasons sampling can be delayed by up to 2 days as long as the hours post-dose for collection remain as described. A PK sample will need to be obtained 
within 1 hour of the tissue sampling.  Details described in the SPM Ssee See Table 7 disease specific assessments for details).  
g.
Tumor samples for translational research are requested at end of treatment for subjects with progressive disease. 
Abbreviations: ECOG PS=Eastern Cooperative Oncology Group Performance Status; ECHO=echocardiogram; ECG=electrocardiogram; QTcF=QT duration corrected for heart rate by 
Fridericia’s formula; PD=Pharmacodynamics; PK=Pharmacokinetics; PGx=Pharmacogenetics; D=day; EOT=End-of-Treatment; q3W=every 3 weeks; q6W=every 6 weeks; 
SCR=Screening; Wk=week
Table 11 Time and Events: Part 2 Laboratory Assessments
NB: On dosing days,Ccollect blood samples prior to 
dosing.  W1D1 samples not needed if SCR sample is 
within 24h of first dose. (Notes)
SCR
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further Cycles
q3w and q6w 
Initiated from Wk 10
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Safety Cytokines
X
as clinically appropriate following fever
a. Assess platelet count as clinically appropriate but at minimum twice weekly for weeks 1 and 2; weekly for weeks 3 to 8.
Abbreviations: NT-proBNP=N-terminal pro–B-type Natriuretic Peptide; 1,5 AG=1,5-Anhydroglucitol; Hb=Hemoglobin; TSH=Thyroid Stimulating Hormone; HBsAg = Hepatitis B surface 
Antigen HepC=Hepatitis C; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week
 
 
 
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Section 6.1.2 Visit Windows
Rationale for Change:  This section was updated to be consistent with the T&E table
Revised Text
Visits between Week 4 through Week 9 (inclusive): Clinic visits can be scheduled 3 4 
days.
Section 6.2
Baseline Assessment
Rationale for Change:  This section was updated to include the MDS population
Revised Text
Subjects diagnosed with refractory hematological malignancy (MM, lymphoma, MDS
and/or acute myeloid leukemia AML), will be assessed at baseline for general disease 
characteristics
Section 6.2.2 Baseline assessment for Subjects with MDS/AML 
Rationale for Change:  This section was updated to include the MDS population
Revised Text

WHO classification

FAB classification (AML only)

Cytogenetics

IPSS/IPSS-R classification (MDS only)
Section 6.3.5 Electrocardiograms
Rationale for Change:  After an internal QTc analysis and evaluation of cardiac safety 
data collected from all subjects up to the 120 mg QD cohort available by 10Jun2016, the 
Holter Monitoring was removed, as the ECG time-points currently included in the 
required assessments provide adequate cardiac safety assessments of any potential QT-
prolonging effect (including potential delayed effects).
Revised Text
In addition to the Safety ECGs performed during the study, continuous 12-lead Holter 
ECGs (obtained via a Holter monitor) will be acquired while subjects are at the site.  
Dual snap electrodes will be utilized to enable simultaneous collection of Holter and 
safety ECG data.
 
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Section 6.3.6 Holter Monitoring
Digital Holter ECG data will be obtained from a 12-lead continuous Holter monitoring 
device supplied by the Sponsor.  ECG acquisition via the Holter monitoring device will 
be performed at planned time points indicated in the Section 5 Time and Events Tables 
and should be obtained prior to phlebotomy and vital sign time points.
Analysis of intervals and morphology from the continuous digital ECG data may be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory.   In order to increase consistency of ECG interpretation, a 
limited number of central ECG over-readers will be used throughout the study.  All ECGs 
for a given subject will be over-read by the same reader from the central validated ECG 
laboratory.  The central reader will be blinded to subject identifiers (e.g., subject number, 
age, and sex), treatment assignment, and study day when Holter data were collected. The 
final intervals and morphology analyses entered into the database will be those generated 
by the central ECG laboratory.
Section 6.3.6
Clinical Laboratory Assessments
Rationale for Change:  This section was updated as the processing and handling of all 
samples is found in the central lab manual.
Revised Text
All protocol required safety laboratory assessments, as defined in Section 5, are 
performed at the institution’s local laboratory.  All non-safety assessments (e.g., PK 
samples, biopsy, translational samples) will be assessed by a central laboratory.  Please 
refer to the SPM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
 
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Table 12
Clinical Laboratory Tests
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international 
normalized ratio, and fibrinogen)
Factor VII assay
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, low-density lipoprotein 
cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3), Free Thyroxine 4 (Free T4),
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
HBsAg, HepC antibody
Testosterone for males (free and complete testosterone at prior to first dose, free 
testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
24-hour urine creatinine clearance (if needed)
Cytokine Samples
Section 6.4.1 Disease Assessment
Rationale for Change:  This section was updated to include the MDS population
Revised Text
Response will be assessed as outlined in the Section 5 Time and Events Table 7  Table by 
the investigator using the appropriate criteria for MM, lymphoma and AML, and MDS, 
as noted in Appendix 6, Appendix 7 and Appendix 8, and Appendix XXX9, respectively.
Section 6.5.1 Blood Sample Collection
Rationale for Change:  This section was updated as the processing and handling of all 
samples is found in the central lab manual.
Revised Text
Details of PK sample collection, processing, storage and shipping procedures are 
provided in the SPM..
 
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Section 6.6
Translational Research
Rationale for Change:  This section was updated to include all myeloid malignancies
Revised Text
Toward that end the successful collection of quality tumor specimens will be critical to 
furthering our understanding of BET biology and indentifying the best way to treat 
patients with a BET inhibitor. Specifically, the evaluation of responders, responders at 
relapse, and non-responders for gene mutation status and/or pathway activation may lead 
to the discovery of potential new diagnostic markers or novel combinations. Similarly, 
pre- and post-dose tumor specimens will be evaluated for markers of target engagement, 
tumor response, and/or evaluated for changes in gene expression; thus supporting 
identification of a biologically effective dose and furthering our mechanistic 
understanding of BET inhibition in these settings. In certain settings such as myeloid 
malignancies leukemia specimens, samples may be used to evaluate changes in leukemic 
stem cell populations or to generate PDX models.
Section 6.6.2.
Blood Sample Collection for Exploratory Translational Research
Rationale for Change:  The collection of blood samples intended for the analysis of 
mRNA and cytokines for BET116183 study has ceased. These samples were being 
collected as part of a collaboration with Epinova for biomarker studies to assess target 
engagement after BET inhibitor treatment. Similar analysis was being done in the 
BET115521 study (solid tumor). We were informed that sufficient data from the 
BET115521 study had been generated to make future decisions to support clinical 
expansion with this drug. Therefore, no additional samples from the BET116183 study 
would need to be collected and/or analyzed.
Revised Text
Blood samples collected at time points described below and in the Time and Events 
tables for PK and PD testing may will be required for all subjects.

Part 1 &2: At screening, date of bone marrow biopsy (Part 2 only), disease 
assessment (Table 7) and disease progression for isolating plasma for circulating 
biomarkers (eg, cfDNA) , PBMCs and neutrophils.

Part 1 Only: At pre and post dose for treatment related changes in RNA.

Part 1 Only: At pre and post dose for treatment related changes in plasma cytokines.
Section 6.6.2.1 deleted
Rationale for Change:  This section was deleted as the collection of blood samples 
intended for the analysis of mRNA and cytokines for BET116183 study has ceased.
These samples were being collected as part of a collaboration with Epinova for biomarker 
studies to assess target engagement after BET inhibitor treatment. Similar analysis was 
being done in the BET115521 study (solid tumor). We were informed that sufficient data 
 
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from the BET115521 study had been generated to make future decisions to support 
clinical expansion with this drug. Therefore, no additional samples from the BET116183 
study would need to be collected and/or analyzed.
Section 6.6.2.1
Plasma for Changes in Cytokines, Chemokines, and Acute 
Phase Proteins
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, MCP-1, MIP1-α, IL-8) will also be measured in plasma samples taken during 
PK sampling and at the time of any Grade 2 fever or symptoms of a cytokine storm. This 
will assess systemic inflammatory response in the subject using biomarkers such as pro-
inflammatory cytokines and acute phase proteins and correlate the systemic response to 
drug with that in stimulated and unstimulated blood. These biomarkers are expected to 
change over days rather than hours, based on the plasma half lives and pre-clinical data, 
such that sampling will also be performed after repeat dosing.
Section 6.6.2.2 deleted
Rationale for Change:  This section was deleted as the collection of blood samples 
intended for the analysis of mRNA and cytokines for BET116183 study has ceased.
These samples were being collected as part of a collaboration with Epinova for biomarker 
studies to assess target engagement after BET inhibitor treatment. Similar analysis was 
being done in the BET115521 study (solid tumor). We were informed that sufficient data 
from the BET115521 study had been generated to make future decisions to support 
clinical expansion with this drug. Therefore, no additional samples from the BET116183 
study would need to be collected and/or analyzed
Section 6.6.2.2
Whole Blood for Changes in mRNA
GSK525762 has been shown to modulate the expression of a number of different genes in 
unstimulated whole blood between 1 h and 6 h. The mRNA levels of 31 such genes form 
a ‘signature’ panel which will also be used as a biomarker of engagement of 
pharmacology and will be measured using mRNA isolated from whole blood. The 
modulation of a number of these genes will also be measured as changes in systemic 
proteins as well as in the analysis of the ex vivo assay blood samples (e.g. CCL2 and IL-
8) thus relating mRNA and protein expression with drug concentration.  Other 
translational research studies, such as transcriptomics profiling, may also be performed 
using whole blood mRNA from selected patients.
Section 6.7.4 deleted
Section 6.7.4 Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE.  Death due to disease under study is to be recorded on the Death eCRF form.  
However, if the underlying disease (i.e., progression) is greater than that which would 
 
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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/procedures and the disease progression, then this must be reported as an SAE.
New Section 6.7.4.
Time Period and Frequency of Detecting AEs and SAEs
Rationale for Change:  Updated to be consistent with current guidelines.
Revised Text:
Third paragraph Last Line
All SAEs will be reported to GSK within 24 hours, as indicated in Section 6.7.6 6.7.7.
Table 13
Reporting of SAEs and Other Events to GSK
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE 
data collection 
tool 
Pregnancy
24 hours2 
Weeks
Pregnancy 
Notification 
Form
2 Weeks24 
hours
Pregnancy 
Follow up Form
6.8.1. Time period for collecting pregnancy information
Information from Section 6.8.2 included as part of Section 6.8.1 itself.
Rationale for Change:  Updated to be consistent with current guidelines.
Revised Text
Section 6.8.2 Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to GSK within 24 hours of learning of a subject's pregnancy.
.  The investigator will record pregnancy information on the appropriate form and submit 
it to GSK within 2 weeks of learning of a subject's pregnancy.  The subject will also be 
followed to determine the outcome of the pregnancy.  Information on the status of the 
mother and child will be forwarded to GSK.  Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date.  Any premature termination of the 
pregnancy will be reported.
 
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Fourth Paragraph second sentence
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 6.7.6 6.7.7.
Section 6.8.3 Action to be taken if pregnancy occurs in a female partner of a male 
study subject
Rationale for Change:  Updated to be consistent with current guidelines
Revised Text
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  The 
investigator will record pregnancy information on the appropriate form and submit it to 
GSK within 24 hoursweeks of learning of the partner’s pregnancy.  The 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 premature termination of the 
pregnancy will be reported.
Section 7.6.1 Dose and Safety Management Guidelines
Rationale for Change:  This section was updated to remove fever as originally the fever 
guidelines were included due to the possibility of a cytokine 
storm.  To date there have been no occurrences pre-clinically or 
clinically to warrant a need for guidelines.  
Revised Text
Table 16
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose 
Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 
Continue dosing at same dose level with 
weekly or more frequent monitoring as 
necessary
Grade 3 (platelets 
<50,000, 
≥25,000/mm3)
After discussion with medical monitor and 
using sound clinical judgement, continue at 
same dose or dose reduce to previously cleared 
dose level. Monitor CBC at least twice a week, 
or more frequently if clinically indicated. 
Grade 4 (platelets  
<25,000/mm3)
and/or any grade 
For Lymphoma and Multiple Myeloma:
Interrupt study medication and monitor CBC 
every 2-3 days. 
 
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Toxicity
Dose 
Adjustment/
Stopping Criteria
Management Guidelines
accompanied by 
severe bleeding 
related to 
thrombocytopenia
1. If platelet counts recover to Grade 2 
and are steady for at least 2 CBC 
measurements at least 3 days apart, or 
rising, discuss with the medical 
monitor. Based on clinical judgement, 
resume treatment at the same or
previously cleared lower dose. 
2. Platelet transfusion is allowed based on 
institutional guidelines.  If platelet 
transfusions are required, hold drug until 
platelet counts recover to Grade 2, and are 
steady for at least 2 CBC measurements at 
least 3 days apart, or rising. Using clinical 
judgement and after consultation with the 
medical monitor, consider resuming 
treatment at same or the previously 
cleared lower dose. 
3. Discontinue treatment if drug has to be 
held for >14 days.
For Acute Myeloid Leukemia and
Myelodysplastic Syndrome - if platelet count 
<25,000/mm3 but 10,000/mm3: Use clinical 
judgement to institute more frequent 
monitoring as necessary.
For Acute Myeloid Leukemia and 
Myelodysplastic Syndrome - if platelet count 
<10,000/mm3 :
1.
Continue treatment and start platelet 
transfusion as per institutional 
guidelines. After platelet transfusion, 
assess platelet level within a couple of 
hours of transfusion. Institute more 
frequent monitoring as clinically 
indicated.
2.
If repeat platelet transfusions are not 
able to rescue platelet count to 
10,000/mm3  (or to 20,000/mm3in 
case of accompanying fever, sepsis, or 
minor bleeding) in 2 days, then interrupt 
treatment. If subsequent transfusions are 
able to increase the platelet count within 
14 days of interruption, consider 
 
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Toxicity
Dose 
Adjustment/
Stopping Criteria
Management Guidelines
restarting therapy at the same or 
previously cleared dose after discussing 
with the medical monitor and approval 
by GSK medical governance.  If 
transfusions are unable to increase the 
platelet count within 14 days of 
interruption, therapy will be 
discontinued.
3.
Use of adjunctive therapies is permitted.
4.
Use of hydroxyurea is permitted in the 
setting of increased blast counts in 
conjunction with decreased platelet 
counts.
Fever a

Grade 1
Continue current dose(s) of study 
treatment(s) and monitor for change in 
severity.

Grade 2
Consider temporary discontinuation of 
study medication and monitor for change in 
severity.
Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea. Assess vital signs.
Collect “Cytokine blood samples” (which 
include blood sample for TNF-alpha, 
IL-1,IL-6, IL-10).  Collect blood culture 
and investigate viral infections as 
applicable.
May consider restarting study treatment at a 
reduced dose or dose level pre-event based 
on discussion with GSK Medical monitor

Grade 3-4
Temporary discontinuation of study 
medication and monitor for change in 
severity
Assess or inquire if the subject is 
experiencing in combination with fever: 
swelling, redness, extreme fatigue or 
nausea.
Collect “Cytokine blood samples” (which 
include blood sample for TNF-alpha, 
IL-1,IL-6, IL-10).  Collect blood culture 
and investigate viral infections as 
applicable.
May consider restarting study treatment at a 
 
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Dose 
Adjustment/
Stopping Criteria
Management Guidelines
reduced dose or dose level pre-event based 
on discussion with GSK Medical Monitor.
*Baseline results are defined by the nearest time point prior to first dose. If W1D1 results 
are available, these are considered the baseline results. If screening occurred within 72h 
of fit dose, W1D1 samples are not needed and screening data are considered as baseline.
Section 8.2 
Cautionary Medications
Rationale for Change:  This section was updated to include additional criteria for 
cautionary medications and to clarifyspecific Part 1 requirement.
Revised Text:
Third and fourth paragraph 
Aspirin may not be administered at doses that exceed 81 mg per day.  Non-steroidal anti-
inflammatory agents should avoided except where they provide benefit over other 
analgesics; if administered, they should be used with caution and consideration should be 
given to co-administration with proton pump inhibitors.
During Part 1, Antacids should not be consumed for at least 1h before and 2h after 
administration of GSK525762.
Section 8.2.2 Drugs Potentially Affecting GSK525762 Pharmacokinetics or affected 
by GSK525762 Pharmacokinetics
Rationale for Change: This section updated in response to new pharmacokinetic data.
Revised Text:
In vitro data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of potent inducers and moderate or potent inhibitors of CYP3A4 should 
be avoided during the course of the study where possible as they may respectively 
decrease or increase exposure to GSK525762. 
GSK525762 is a moderate CYP3A4 inducer. Medications that have a narrow therapeutic 
index and that are substrates of CYP3A4 should be administered with caution, as their 
metabolism may be affected by co-administration with GSK525762 and result in 
decreased exposure. These include alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline.
GSK525762 is a substrate for breast cancer resistance protein (BCRP) and P-glycoprotein 
(Pgp) transporters. Therefore, potent inhibitors of these transporters, such as 
cyclosporine, tacrolimus, or ketoconazole, should be avoided.
 
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GSK525762 is an inhibitor of organic anion transporter 1A1 (OAT1) and organic anion 
transporter 3 (OAT3) in vitro. Substrates of these transporters include agents such as 
methotrexate, penicillin G, and indomethacin. While co-administration of these agents 
with GSK525762 is not prohibited, they should be used with caution and additional 
monitoring for adverse effects should be utilized.
GSK525762 is considered to have a low risk of causing clinically relevant perpetrator 
drug interactions with CYP3A4, CYP2B6 and CYP2C8 enzymes and/or PgP, BCRP, 
OATP1B3, OAT1, OCT2, MATE1, MATE2-K, BSEP or MRP2 transporters either via 
direct or metabolism-dependent inhibition. Potential interactions with other Cytochrome 
P450 metabolized drugs have not been assessed.
GSK525762 was shown to be an inhibitor of OATP1B1 and OAT3 in vitro, however, the 
clinical impact of this inhibition is only deemed a concern for sensitive substrates of 
OATP1B1 or OAT3 (e.g. methotrexate).
Footnote of Table 19
The above table is not exhaustive and prohibited drugs are defined by the online version 
at the time of screening of the subject.
Section 8.4
Non-Drug Therapies
Rationale for Change: Minor clarification
Revised Text:
Third paragraph
Herbal products include, but are not limited to:
•
St. John’s Wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng, and marijuana.
•
The investigator should contact a GSK Medical Monitor before initiating 
treatment with any herbal preparation including marijuana.
Section 9.1.2 Males Subjects
Rationale for Change: This section updated to align with the Inclusion criteria
Revised Text:

Vasectomy (documentation of azoospermia)
Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. Male 
 
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subjects whose partners are or become pregnant must use condoms while on study and 
for 16 weeks after stopping study medication(s).
Section 11.1.2 Part 2, Expansion Cohort
Rationale for Change: After an evaluation of data from the Part 1 AML cohort, the 
following observations prompted changes to the Part 2 cohort: clinical responses were 
observed at doses of 60 mg and above, these responses occurred in subjects whose 
disease harbored complex karyotype and recurrent mutations in TP53 and in proteins that 
regulate gene expression, suggesting that these subjects had an antecedent MDS that 
transformed to AML. Furthermore, most subjects with AML discontinued GSK525762 
early in the course of their treatment as a consequence of their underlying AML or 
disease complications. Responses tended to be delayed (at the four week mark or later, 
with many requiring more than 10 weeks to manifest). Thus, most subjects were not 
remaining on study for long enough to achieve benefit. In order to maximize time on-
study, Part 2 was updated to enroll subjects with a more slowly-progressing disease that 
maintained many of the clinical characteristics of the AML responses that were observed 
in Part 1.
Revised Text:
Primary goals and 5th paragraph
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with 
AMLMDS, MM, and NHL. 

For AMLMDS, efficacy is defined as a clinically meaningful response rate (defined 
as the percentage of subjects that have achieved a CR, CRp, CRmarrow CR, or PR) 
of 30% relative to a 10% response rate suggesting no activity.  Historically, 
hypomethylating agent failure has conferred a poor prognosis, with a response rate to 
second-line therapy of 10% or less (Prebet, 2011).  Investigational agents have 
demonstrated a response rate of approximately 30%, though no effects on overall 
survival have been reported (Seetharam, 2010).  Because of the high unmet medical 
need of relapsed/refractory MDS, and because no agent to date has exceeded the 
30% response rate published above, 30% was chosen as a realistic goal for subjects 
with MDS.

For MM, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a sCR, CR, VGPR, or PR) of 20% relative 
to a 5% response rate suggesting no activity.  These values were identified in a 
recent meta-analysis that suggested that a response rate of 20% or greater in the 
relapsed/refractory population was highly predictive of clinical success, whereas 
older agents with limited clinical activity had a negligible response rate (Kortuem, 
Zidich, Schuster, et al, Clinical Lymphoma, Myeloma and Leukemia 2014).

For NHL, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a CR, or PR) of 30% relative to a 10% 
response rate suggesting no activity.  These response rates were consistent with 
 
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multiple ongoing studies of single agent, targeted therapy in Phase I clinical trials for 
subjects with relapsed/refractory NHL. For this cohort, double/triple-hit lymphoma
subjects will be excluded from initial efficacy analysis and will be evaluated 
separately.
5th paragraph
For the AMLMDS and NHL disease cohorts, starting with a cohort of 10 subjects 
and allowing for a maximum sample size of 32 subjects at the RP2D with stopping 
guidelines as described in Section 3.2.4, this design will have a Type I Error () of 
0.034 and 87% power.
Section 11.4 Interim Analysis
Rationale for Change: This section was updated to include the MDS population
Revised Text:
2nd Paragraph
For each disease type in Part 2, after the initial 10 evaluable subjects in the AMLMDS or
and NHL cohorts and initial 13 evaluable subjects in the MM cohort have enrolled at the 
selected dose regimen for the Expansion Cohort, data will be reviewed for clinical benefit 
on an ongoing basis and the number of subjects with observed clinical benefit will be 
compared with the stopping guidelines provided in Section 3.2.4.
Section 11.6.1 Primary Analysis
Rationale for Change: This section was updated to include the MDS population
Revised Text:
Second paragraph
The primary aim of Part 2 is to detect demonstrate a possibly clinically meaningful 
response rate in each of the disease cohorts separately. Each disease subtype (AMLMDS, 
MM, and NHL) will be evaluated separately.
Overall response rate definition
Overall Response rate is defined as 

AMLMDS: The percentage of subjects who achieved CR, CRp, CRmarrow CR, and 
PR. A waterfall plot of percent change from baseline in bone marrow blasts and 
peripheral blasts will be provided. Response rates of subjects with AML M3 will be 
summarized separately.

MM: The percentage of subjects who achieved sCR, CR, VGPR, or PR.

NHL: The percentage of subjects who achieved CR or PR. Response rates of 
subjects with double/triple-hit lymphoma will be summarised separately.
 
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Section 11.6.2
Secondary Analysis
Rationale for Change: This section was updated to include the MDS population 
Revised Text: 
Last paragraph
OS along with 95% confidence intervals for leukemia subjects in Part 1, MDS subjects in 
Part 2, and MM and ,lymphoma and leukemia subjects treated in Part 1 and Part 2, will 
be estimated using the Kaplan Meier method if data warrant.  OS analysis for AML will 
exclude subjects with AML subtype M3. NHL will be separately reported based on 
double/triple hit status. All cause mortality will be used and censoring will be performed 
using the date of last known contact for those who are alive or lost to follow-up at the 
time of analysis.  
Section 13 COUNTRY SPECIFIC
Modifications include an updated protocol synopsis as outlined in Section 15.1215.11. 
The protocol amendment 1 may also apply to other countries if specifically requested.
Section 14
References
Rationale for Change: References were added based on updates made throughout the 
protocol amendment.
Revised Text:
One reference was updated and 8 new references are added
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in 
myelodysplasia. Blood  2006; 8:419-426.
GlaxoSmithKline Document Number 2011N113741_0305 Version 35. GSK525762 
Investigator's Brochure. Report Date 2728-Mar-20142016.
Greenberg P, C Cox, MM LeBeau, P Fenaux, P Morel, et al. Blood 1997;89(6):2079-
2088
Greenberg PL, H Tuechler, J Schanz, G Sanz, G Garcia-Manero, et al. Blood 2012 
120:2454-2465
Jabbour, Garcia-Manero, Batty, Shan, et al.  Outcome of Patients with Myelodysplastic 
Syndrome after Failure of Decitabine Therapy.  Cancer, 2010; 116(16): 3830-4
 
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Kantarjian H, Garcia-Manero G, O'Brien S, et al. Phase I clinical and pharmacokinetic 
study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. 
J Clin Oncol. 2010 Jan 10;28(2):285-91. Epub 2009 Nov 23.
Kortuem KM, Zidich K, Schuster SR, Khan ML, Jimenez-Zepeda VH, Mikhael JR, etal. 
Activity of 129 single-agent drugs in 228 phase I and II clinical trials in multiple 
myeloma. Clinical lymphoma, myeloma & leukemia. 2014;14:284-90 e5.
Prebet T, Gore SD, Esterni B, Gardin C, et al.  Outcome of high-risk myelodysplastic 
syndrome after azacitidine treatment failure. Journal of clinical oncology : official journal 
of the American Society of Clinical Oncology. 2011 Aug 20;29(24):3322–7
Seetharam M, Fan A, Tran M, Xu L, et al.   Treatment of Higher Risk Myelodsplastic 
Syndrome Patients Unresponsive to Hypomethylating Agents with ON 01910.NA 
Leukemia Research. 2012; Jan; 36(1): 98–103.
Sekeres MA and Cutler C. How We Treat Higher-Risk Myelodysplastic Syndromes 
Blood. 2014; Feb 6;123(6):829-36.
Swerdlow, Campo, Pileri, et al.  The 2016 revision of the World Health Organization 
Classification of Lymphoid Neoplasms. Blood 2016; 127(20):2375-2390.
Section 15.4
Appendix 4: Dose Adjustment/Stopping Criteria/Supportive Care 
Rationale for Change: This section was updated to remove fever as originally the fever 
guidelines were included due to the possibility of a cytokine storm.  To date there have 
been no occurrences pre-clinically or clinically to warrant a need for guidelines.  
Additionally in the hematologic malignancy population, fever is routinely associated with 
infection and treated with antimicrobials and supportive care.
Revised Text: 
Fever was deleted
Fever
Safety monitoring cytokine blood samples may be collected (based on Section 7.6.1 of 
the protocol).  These samples include (but not limited to) assessments for TNF-alpha, IL-
1, IL-6, and IL-10.
Assess or inquire if the subject is experiencing in combination with fever: swelling, 
redness, extreme fatigue or nausea.
Section 15.8
Appendix 8: Response Criteria for Acute Myeloid Leukaemia
Rationale for Change: Clarified in title that response criteria is specific to the AML 
population
 
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Revised Text:
Title was updated and title (as subsection) was deleted
Section 15.9
Appendix 9: Response Criteria for Myelodysplastic Syndrome
Rationale for Change: Response Criteria added for Part 2 MDS study population.
Revised Text:
Appendix 9 on response criteria for Myelodysplastic Syndrome newly added
[Cheson, 2006]
Complete remission (CR):  Bone marrow ≤5% myeloblasts with normal maturation of 
all cell lines.  Persistent dysplasia may be noted.  The subject must have a haemoglobin 
concentration of ≥11 g/dL, an absolute neutrophil count 1 x 10
9/L, a platelet count 100 
x 10
9/L, and have 0% blasts in the peripheral blood.
Marrow CR: Bone marrow ≤5% myeloblasts and decrease by ≥50% over pretreatment
Partial remission (PR): Bone marrow blasts decreased by ≥50% over pretreatment but 
still >5%.  Cellularity and morphology not relevant
Stable disease: Failure to achieve at least PR, but no evidence of progression for > 8 
weeks
Disease progression: For patients with:
o
Less than 5% blasts: ≥50% increase in blasts to > 5% blasts
o
5% - 10% blasts: ≥50% increase to >10% blasts
o
10% - 20% blasts: ≥50% increase to >20% blasts
o
20% - 30% blasts: ≥50% increase to >30% blasts
AND
Any of the following: At least 50% decrement from maximum remission/response 
in granulocytes or platelets, reduction in haemoglobin by ≥2 g/dL, transfusion 
dependence
Relapse after CR or PR: At least one of the following: return to pretreatment bone 
marrow blast percentage, decrement of ≥50% from maximum remission/response levels 
in granulocytes or platelets, reduction in haemoglobin concentration by ≥1.5 g/dL or 
transfusion dependence
 
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15.22.
Appendix 22: Protocol Changes for Amendment 9 (15-Mar-
2018) from the Protocol Amendment 8 (14-FEB-2017)
Where the Amendment Applies
Amendment 9 applies to all study centres. 
Summary of the changes with rationale
Amendment 9: 
The study population for the NHL cohort in Part 2 was amended from a population of 
subjects with NHL to a population of subjects with cutaneous T-cell lymphoma (CTCL).  
The Part 2 primary and secondary objectives along with the eligibility criteria were 
updated to include this new CTCL population, and removal of expansion into multiple 
myeloma in Part 2.  Eligibility criteria for all populations were updated (ECOG, cardiac 
safety).  The time and events tables were updated to reduce the cardiac monitoring based 
on updated risk/benefit profile, and BID dosing was removed.  Medications affecting QT 
prolongation were re-categorized from prohibited to cautionary.  Liver chemistry 
monitoring, interruption stopping and follow-up criteria were updated as per latest 
criteria.  Response Criteria for CTCL was added as an Appendix, and a QOL 
questionnaire (SKINDEX-29) was added.  Minor clarifications, formatting and 
typographical errors were also addressed in this amendment.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
Overall change: IB has been updated with latest version 2017 throughout the document.
List of specific changes
Title Page
Rationale for Change: change to study staff
Revised Text:
Author (s):
 Precision Medicine and Diagnostics, USA
 (Biology, Epigenetics Management, USA)
                        
Global Clinical Operational Sciences, USA
 Statistics, Oncology TA Group, USA)
 (Biotransformation and Drug Disposition, PTS, UK)
 (Cancer Research Epigenetics Management, USA)
 (Clinical Pharmacology Modeling & Simulation, USA)
 
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PPD
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 Global Clinical Safety & Pharmacovigilance, USA)
 (Global Clinical Operational Sciences, USA)
 Precision Medicine and Diagnostics, USA)
 Clinical Oncology, USA)
 (Pathology, PTS, UK)
 EpiNova DPU, UK
                           
Global Clinical Safety & Pharmacovigilance, USA
 (Global Clinical Safety & Pharmacovigilance, USA)
 (Global Clinical Operational Sciences, USA)
 (Biology, Epigenetics Management, USA)
 Statistics, Oncology TA Group, USA
PROTOCOL SYNOPSIS
STUDY DESIGN AND DURATION:
Rationale for Change: Part 2 was amended from a population of subjects with NHL 
to a population of subjects with cutaneous T-cell lymphoma (CTCL) given the observed 
response rate in CTCL.  
Revised Text:
This study is divided into 2 parts: Part 1 of the study is a dose escalation phase to select 
the recommended Part 2 dose (RP2D) based on the safety, pharmacokinetic, and 
pharmacodynamic profiles observed after oral administration of GSK525762.  Eligible 
subjects with select relapsed refractory hematological malignancies (acute myeloid 
leukemia [AML], non-Hodgkin’s Lymphoma [NHL] and multiple myeloma [MM]), will 
be enrolled in once daily (QD) cohorts until a maximum tolerated dose (MTD) is 
established. Subjects may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent.  Upon determination of the MTD, twice 
daily (BID) dosing cohorts may be opened to collect additional safety data and evaluate 
the preliminary efficacy of GSK525762 administered BID.  Part 2 will explore clinical 
activity at the MTD or RP2D; separate expansion cohorts will be planned for myeloid 
malignancies (high-risk myelodysplastic syndrome [MDS] or acute myeloid leukemia 
[AML] that has evolved from an antecedent MDS, hereafter referred as the “myeloid 
cohort”), non-Hodgkin’s Lymphoma (NHL, including an exploratory sub-cohort of 
subjects with myc and B-Cell Leukemia (BCL)2 and/or BCL6 
rearrangements/overexpression [double- and triple-hit lymphoma])and cutaneous T-cell 
lymphomas (mycosis fungoides [MF], Sézary syndrome [SS], primary cutaneous 
anaplastic large cell lymphoma [pcALCL], and large cell transformation of underlying 
 
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MF/SS; hereafter referred as the “cutaneous T cell lymphoma [CTCL] cohort”).. , and 
multiple myeloma (MM).
STUDY RATIONALE:
Rationale for Change: Part 2 was amended from a population of subjects with NHL 
to a population of subjects with cutaneous T-cell lymphoma (CTCL) given the observed 
response rate in CTCL.  
Revised Text:
Addition at the end of the paragraph:
Dose escalation initially focused on AML, NHL (without consideration to histologic 
subtype), and MM, based on preclinical data.  Emerging clinical data demonstrated 
delayed response in AML subjects, many of whom had evidence of antecedent MDS.  In 
the NHL cohort, more robust clinical efficacy was observed in subjects with CTCL 
compared to other NHL subtypes.  As a result of these observations, dose expansion (Part 
2) was modified to evaluate MDS and CTCL instead of AML and unselected NHL, 
respectively.
OBJECTIVES AND ENDPOINTS:
Rationale for Change: The Part 2 primary and secondary objectives along with the 
eligibility criteria were updated to include this new CTCL population, and removal of 
expansion into multiple myeloma in Part 2.  BID dosing was also removed.
Revised Text:
Part 1: 
Part 1 Objectives
Part 1 Endpoints
Secondary

To characterize the Pharmacokinetic 
(PK) of GSK525762, and relevant 
metabolites, as applicable, after 
single- and repeat-dose 
administration following QD and/or 
twice daily (BID) dosing schedules.

PK parameters for GSK525762 and 
relevant metabolites, as applicable, PK 
parameters following single- and 
repeat-dose administration of 
GSK525762, including Area under 
concentration-time curve (AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.
 
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Part 1 Objectives
Part 1 Endpoints

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters following 
QD and/or BID dosing schedules.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC, following 
single and repeat-dose oral 
administration of GSK525762)

To evaluate the relationship between 
GSK525762 dose/exposure and 
pharmacodynamic (PD) response 
following QD and/or BID dosing 
schedules.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess objective response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.
Exploratory

To evaluate the relationship between 
GSK525762 exposure and cardiac 
and other safety parameters.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC, following 
single and repeat-dose oral 
administration of GSK525762)

To evaluate the relationship between 
GSK525762 dose/exposure and 
pharmacodynamic response.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by BRD proteins) in 
tumor tissue and/or peripheral blood 
samples.

To evaluate the relationship between 
GSK525762 dose and exposure with 
clinical activity of GSK525762

Assess objective response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762
following QD dosing schedules.

Pharmacogenomic (PGx) study using 
clinical samples.
Part 2:
Part 2 Objectives
Part 2 Endpoints
 
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Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in high-
risk myelodysplastic syndrome (MDS) 
or acute myeloid leukemia (AML) that 
has evolved from an antecedent MDS 
(“myeloid cohort”).

For MDS cohort: Objective response rate 
(ORR (defined as the percentage% of 
subjects achieving Complete Response 
[CR], marrow CR, CRp [as per CR but 
platelet count <100 x 109/L], CRi [as per 
CR but platelet count <100 x 10
9/L or 
neutrophil count <1 x 10
9/L], or Partial 
Response [PR],) per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in multiple 
myeloma (MM)

For MM: Objective response rate (defined 
as the percentage of subjects that have 
achieved a stringent CR [sCR], CR, very 
good partial response [VGPR], or PR) per 
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in non-
Hodgkin’s Lymphoma (NHL)CTCL

For NHLCTCL: Objective response rate 
(ORR4); defined as the percentage % of 
subjects that have achieved a CR, or PR, 
per global response criteria and the
modified severity weighted assessment tool 
(mSWAT), lasting more than 4 months 
according to the modified severity weighted 
assessment tool (mSWAT) defined as the 
percentage of subjects that have achieved 
a CR, or PR) per global response criteria, 
based on the modified severity weighted 
assessment tool (mSWAT).
Secondary

To evaluate the effect of GSK525762 
on disease-related symptoms, as 
reported by subjects (CTCL cohort 
only)

For CTCL: measure the effects of skin 
disease based on quality of life 
questionaireutilizing Skindex-29 Patient 
reported outcomes (DEFINE HERE)

To characterize the PK of 
GSK525762, and relevant 
metabolites, as applicable, in 3 2 
disease-specific cohorts of subjects 
with MDS/AML, MM or NHLor CTCL 
after repeat-dose administration.

Population PK parameters for GSK525762
, and relevant metabolites, as applicable, 
such as apparent clearance following oral 
administration (CL/F) and volume of 
distribution (V/F), and relevant covariates 
which may influence exposure (e.g., age, 
weight, or disease associated covariates).

To evaluate the exposure response 
(i.e., PK/PD) relationship between 
GSK525762 and safety/efficacy 
parameters in 3 disease-specific 
cohorts of subjects with MDS/AML, 
MM or .NHL.

PK/PD rRelationship between GSK525762 
exposure markers and safety and efficacy 
parameters.

To evaluate the safety and tolerability 
of RP2D of GSK525762 in 3 2 
disease-specific cohorts of subjects 
with MDS/AML, MM or CTCL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and changes 
in safety assessments (e.g., laboratory 
parameters, vital signs, and cardiac 
parameters) at RP2D.
 
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Part 2 Objectives
Part 2 Endpoints

To determine the clinical activity of 
GSK525762 in 3 2 disease-specific 
cohorts of subjects with MDS/AML, 
MM or NHLCTCL.

TTP (Time to Progression) , DOR Duration 
of response (Duration of ResponseDOR, 
time from onset of response to earlier date 
of disease progression or death due to any 
cause) for MDS/AML and CTCL,  

PFS Progression free survival (Progression 
Free SurvivalPFS, time from the treatment 
start date to earlier date of disease 
progression or death due to any cause) for 
MDS/AML, MM and NHL CTCL. 

Rate of objective global response with a 
duration of 4 months or more (ORR4) in 
CTCL

Overall survival (OS, the time from the 
treatment start date until death from any 
cause) for MDS/AML, MM, and CTCL.

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.
Exploratory

To investigate the relationship 
between genetic variants in candidate 
genes and the pharmacokinetics (PK) 
and safety profile of GSK525762.

Pharmacogenomic (PGx) study using 
clinical samples.

To evaluate the exposure response 
relationship between GSK525762 and 
safety/efficacy parameters in 
2 disease-specific cohorts of subjects
with MDS/AML, or CTCL.

Relationship between GSK525762 
exposure markers and safety and efficacy 
parameters.
Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Myelodysplastic syndrome and transformed MDS: A response rate of 30% relative to a 
10% response rate suggesting no activity in subjects with MDS/AML.  This will be 
conducted by testing the null hypothesis that P0≤0.10 versus the alternative that 
P1≥0.30, assuming the maximum response rate for an ineffective drug is 0.10 and the 
minimum response rate for an effective drug is 0.30.

Multiple myeloma: A response rate of 20% relative to a 5% response rate suggesting no
activity in subjects with multiple myeloma.  This will be conducted by testing the null 
hypothesis that P0≤0.05 versus the alternative that P1≥0.20, assuming the maximum 
response rate for an ineffective drug is 0.05 and the minimum response rate for an 
effective drug is 0.20.

Non-Hodgkin’s lymphoma (non-double hit lymphoma [DHL]):CTCL: A response rate, 
lasting more than 4 months, of 430% relative to a 210% response rate suggesting no 
activity in subjects with non-Hodgkin’s lymphomaCTCL.  This will be conducted by testing 
the null hypothesis that P0≤0.210 versus the alternative that P1≥0.430, assuming the 
maximum response rate for an ineffective drug is 0.210 and the minimum response rate 
for an effective drug is 0.430. Subjects with DHL will be evaluated separately for efficacy, 
but no hypothesis testing will be conducted on the DHL cohort.
 
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SUBJECT SAMPLE:  
Rationale for Change: Total number of subjects updated to reflect changes in study 
population
Revised Text:
Up to 180 138 subjects worldwide
INCLUSION/EXCLUSION CRITERIA:
Rationale for Change: Eligibility criteria for all populations were updated (ECOG, 
cardiac safety).  The time and events tables were updated to reduce the cardiac 
monitoring based on updated risk/benefit profile, and BID dosing was removed.  
Medications affecting QT prolongation were re-categorized from prohibited to 
cautionary.  
Revised Text:
Inclusion Criteria
Inclusion criterion 3
Subjects must have a diagnosis of one of the following hematologic malignancies, which 
has relapsed or been refractory to treatment as follows :Myelodysplastic Syndrome 
(MDS), Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), or non-Hodgkin’s 
Lymphoma (NHL).
Inclusion criterion 3 Bullet 3 onwards

(Part 1 and Part 2): Subjects with multiple myeloma are eligible if they have 
progressed despite therapy with an alkylating agent, proteasome inhibitor, 
and immunomodulatory agent, either as individual regimens or in 
combination

(Part 1 and Part 2only): Subjects with NHL are eligible if they have received 
at least two prior lines of systemic therapy, including at least one line of 
immunochemotherapy with an anti-CD20 antibody (if their tumor expresses 
CD20)

(Part 2 only): Subjects will be eligible for enrolment into the CTCL cohort if 
they:
o
Have histologically- or cytology-proven diagnosis of CTCL (MF, 
SS, pcALCL, or large cell transformation of underlying MF/SS) 
that has failed to respond to, or progressed despite, at least one 
prior systemic therapy

In Part 2, the NHL cohort will separately enrol subjects with double- and 
triple hit lymphoma, so that a minimum of 10 subjects with this subset of 
disease will be enrolled. To be eligible for this sub-cohort, tumor sample 
from the subject must demonstrate rearrangement and/or overexpression of 
 
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MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or triple-
hit status may be performed via appropriate local testing, and the 
determination of double- or triple-hit diagnosis will be at the discretion of the 
investigator and GSK Medical Monitor.
Inclusion criterion 5
Eastern Cooperative Oncology Group (ECOG) performance status of:

1 for all Part 1 Cohorts (AML, MM, and NHL)

. 2 for theall Part 2 cohorts (MDS/AML and CTCL)
Definitions for Adequate Organ Function
Renal
Creatinine3
OR
Calculated creatinine clearance [calculated by Chronic 
Kidney Disease Epidemiology Collaborative (CKD-Epi) 
method Cockcroft Gault formula2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN 
≥50 mL/min
≥50 mL/min
Footnote 2 deleted
Refer to Appendix 1 for Cockcroft Gault formula
Exclusion Criteria
Exclusion criterion 1
Haematological malignancy associated with human immunodeficiency virus (HIV) 
infection or solid organ transplant or history of knownpositive Hepatitis B Antigen or 
positive Hepatitis C antibody at screening or within 3 months prior to first dose (subjects 
with positive Hepatitis C antibody may be enrolled, provided that the confirmatory test 
[e.g., confirmed by Recombinant ImmunoBlot Assay [RIBA], if available or alternately 
confirmed by Hepatitis C Virus [HCV] Ribonucleic acid [RNA] polymerase chain 
reaction [PCR]] is negative).
Exclusion criterion 3 Note 2
Corticosteroids (topical and/or systemic)
Exclusion criterion 5
Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days prior to 
the first dose of GSK525762.  Low dose (prophylactic) anticoagulants (e.g., low 
molecular weight heparin (LMWH) or oral anticoagulants) is permitted.  In addition, INR 
must be monitored in accordance with local institutional practices, as appropriate.
Exclusion criterion 6
 
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Current use of a prohibited medication or requires any of these medicationsplanned use 
of a prohibited medication during treatment with the investigational drugsGSK525762.  
This includes excluding current medications known or suspected to be associated with 
QT prolongation.  In addition, any subject who is expected to require a QT prolonging 
medication while on trial should not be enrolled.
Exclusion criterion 9
Cardiac abnormalities as evidenced by any of the following:

History or current clinically significant conduction abnormalities, 
uncontrolled arrhythmias or hypertension.

Clinically significant conduction abnormalities or arrhythmias, subjects with 
Bundle Branch Block.

Presence of cardiac pacemaker.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

Recent hHistory (within the past 3 months) of acute coronary syndromes 
(including unstable angina and myocardial infarction), coronary angioplasty, 
or stenting. within the past 3 months.
Exclusion criterion 10 Bullet point 1

Baseline QTcF interval ≥450 480 msec.
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN:
Rationale for Change: BID dosing removed from asset development strategy in heme
Revised Text:
Sentence 3 deleted:
BID dosing may be explored once MTD has been identified in once daily dosing; the 
total daily dose administered BID will not exceed the QD MTD. 
EFFICACY MEASUREMENTS:  
Rationale for Change: new ORR4 criteria added for CTCL cohort
Revised Text:
ORR, PFS and OS in AML, MDS, MM, and NHLCTCL; time to progression (TTP) and 
duration of response in MM and CTCL. Rate of objective response lasting at least 4 
months (ORR4) in CTCL
SAFETY MEASUREMENTS
Rationale for Change: Reduction in the cardiac monitoring based on updated 
risk/benefit profile.
 
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Revised Text:
Sentence 3
Cardiac safety monitoring will be required, consisting of triplicate 12-lead ECGs prior to 
dosing on selected days and prior to drawing PK samples on serial PK sampling days 
(overnight stays in research facility may be necessary in Part 1).  
STATISICAL ANALYSIS:
Rationale for Change: revision of statistics plan to align with revision of subject 
cohorts
Revised Text:
Sentence 6 onwards:
The assessments are based on the predictive probability of success (response rate > 
historical response rate), with aif the enrolment continues to the maximum of 32 subjects
in the MDS cohort and 37 subjects in the CTCL cohort respectively, or 37 subjects 
treated (MM cohort) and assessed for response.  Subjects treatedenrolled in Part 1, at the 
Part 2 dose, for diseases under study in Part 2, willmay be included in Part 2 efficacy 
analysis.Additionally at least 10 DHL subjects will be treated.  No hypothesis testing will 
be conducted for the DHL cohort.  For additional details, please refer to the RAP.
Section 1.2. Study Population Rationale
Rationale for Change: Part 2 was amended from a population of subjects with NHL 
to a population of subjects with cutaneous T-cell lymphoma (CTCL) given the observed 
response rate in CTCL.  
Revised Text:
Paragraph 3:
Cutaneous T-cell lymphomas are a family of NHLs characterized by skin infiltration by 
CD4-positive T-cells.  These diseases are characterized by erythroderma and/or tumor-
phase growths on the skin, as well as intense pruritis as a consequence of upregulation of 
multiple pro-inflammatory cytokines (Ahern, 2012).  Targeted systemic therapies remain 
the cornerstone of treatment for many patients, including those with limited-stage 
disease, both to control the disease itself as well as to reduce the overall symptomatic 
burden (Whittaker, 2016).  Recently, a role for BRD4 in the expression of lymphoma-
associated genes has been demonstrated (Kohnken, Blood 2017), making BET inhibition 
a rational approach for treatment of CTCL.
Section 1.3.2 BID Dose Cohort
Rationale for Change: BID removed from asset development strategy in heme
Revised Text:
1.3.2. BID Dose Cohort 
 
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1.3.2.1. Preclinical Rationale for BID
Recent clinical and pre-clinical pharmacokinetic and pharmacodynamic data suggests a 
potential benefit of a twice daily (BID) dosing regimen compared to QD dosing 
[GSK525762 IB, GlaxoSmithKline Document Number 2011N113741_05]. In mice, 
GSK525762 has a short half-life of about 1.5 hours. Single dose pharmacodynamic 
experiments were performed in three SCLC and one CRC cell line xenograft model. 
Dose-dependent changes in gene expression were observed in all models at early time 
points post-dose; however, expression returned to pre-treatment levels within 8-12 hours. 
Additionally, in a subcutaneous multiple myeloma cell line xenograft study, c-Myc 
protein levels were significantly reduced 2 and 5 hours post-dose, and returned to 
baseline by 8 hours.
QD and BID dosing have been further explored in a number of in vivo xenograft efficacy 
studies. In a subcutaneous, patient-derived model of SCLC, BID dosing at 12.5mg/kg 
resulted in improved tumor growth inhibition compared to 25 mg/kg QD (74% versus 
60%, respectively).  Improved efficacy with BID dosing was also observed in a cell line 
xenograft model of CRC. BID dosing at 12.5mg/kg resulted in 48% tumor growth 
inhibition, whereas 25mg/kg QD dosing resulted in 34% inhibition.  In a third model, a 
cell line xenograft of SCLC, there was no significant difference in tumor growth 
inhibition resulting from 12.5mg/kg BID versus 25mg/kg QD dosing. Thus, we observe 
equivalent or improved efficacy with BID dosing in all xenograft models tested.
1.3.2.2. Clinical Rationale for BID
As described in the GSK525762 IB, Section 5.2, GSK525762 pharmacokinetics 
following once and twice daily administration is characterized by a rapid absorption with 
maximum concentration occurring mostly within two hours after dosing. GSK525762 is 
eliminated rapidly with an average terminal phase half-life of 3 to 7 hours.
Based on the pharmacokinetics of GSK525762 observed to date, and evidence of a short 
half-life of about 5 hours, trough concentrations at 100 mg QD are predicted to be below 
the average in vitro IC50 (0.08 uM to 1.3 uM) for the tumor types selected for this study. 
Dividing the daily dose into two doses administered about 12 hours apart would allow the 
trough concentration to be above the lower in vitro IC50 for doses around 30 mg BID.
1.3.2.3. Starting Dose for BID
As detailed in the GSK525762 IB, Section 5.2.2 and Section 5.3.1, doses of 20 mg and 30 
mg BID have been administered to subjects with solid tumors.  The PK and 
safety/tolerability profile for the 30 mg BID dose is comparable to subjects treated with 
an equivalent total daily dose (i.e., 60 mg once daily).  In this study, once the QD MTD 
of GSK525762 has been identified for each disease subtype (AML/MDS, MM, and 
NHL), an exploratory cohort may be opened in one or more of the  disease types to 
evaluate safety, tolerability, and preliminary efficacy of BID dosing.  
For each disease subtype, the total daily dose selected for BID evaluation will be no 
higher than the once-daily MTD, divided approximately equally between two doses  
administered approximately 12 hours apart.  A lower BID dose may be considered 
depending on emerging safety, PK, and PD data.
 
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Section 1.4. Rationale for Study and Endpoints
Rationale for Change: Part 2 was amended from a population of subjects with NHL 
to a population of subjects with cutaneous T-cell lymphoma (CTCL) given the observed 
response rate in CTCL.  
Revised Text:
Paragraph 2 sentence 3
Part 2 is a cohort expansion, which will study the RP2D of GSK525762 to determine 
preliminary efficacy, safety and tolerability in three separate cohorts of subjects with 
myeloid neoplasms (myelodysplastic syndrome [MDS] or MDS that has transformed to 
AML), multiple myeloma and non-Hodgkin’s lymphoma CTCL.
Paragraph 4
The original study design included a dose expansion in non-Hodgkin’s lymphoma, 
enrolling subjects regardless of histological subtype.  Furthermore, this cohort enrolled 
subjects with double- and triple-hit lymphoma (i.e., B-cell lymphomas with 
rearrangement and/or overexpression of myc and BCL2 and/or BCL6) in an exploratory 
sub-cohort.  However, interim analysis of the Part 1 data demonstrated limited activity in 
both B-cell lymphomas in general as well as double/triple hit lymphomas.  Responses, 
including very deep, durable responses, were achieved in subjects with CTCL and other 
T-cell lymphomas of the skin.  Therefore, Part 2 of the study was amended to restrict 
enrollment to these diseases, for which emerging clinical data suggested a reasonable rate 
of benefit.
Section 1.5.1. Risk Assessment
Rationale for Change: Risk assessment tables revised in accordance with changes to 
benefit/risk profile of the asset.
Revised Text:
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular –
QT prolongation
QTc prolongation (up to 20%; 41 msec in 
dog)
Can occur or persists after drug is cleared 
from plasma; general trend to increase on 
repeat dosing; no potentiation beyond day13 
in 28 day toxicology study in dogs.
Reversible on cessation of dosing; not 
potentiated on subsequent dosing following a 
7 day dosing holiday.
No significant arrhythmias were detected in 
preclinical studies. No clear link to human
ether à go-go-related gene (hERG) binding or 
trafficking.  No evidence of heart accumulation 
ICF includes the risk of (fatal) 
arrhythmias
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, N-terminal pro–B-
Type natriuretic peptide [NT-
proBNP], creatine kinase [CK] and 
creatine kinase-MB [CK-MB]), 
cardiac monitoring 
(electrocardiograms [ECGs], and 
cardiac ejection fraction) during 
the study, and dose 
stopping/modifications criteria for 
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
of GSK525762.  Mechanism & risk for 
Torsades de Pointe is unclear.
A review of all available data as of November 
2017 (representing 271 subjects dosed up to 
100 mg in the BET115521 solid tumor study 
and up to 120 mg in the BET116183 heme 
malignancy study) demonstrated a clinically 
negligible effect on QT in humans.
Blood pressure (BP) Variable changes in 
blood pressure following a single dose 
(1 mg/kg in dogs and 60 mg/kg in rats); no 
effects were observed in the 7 day repeat 
dose dog CV study; increase in mean BP up 
to 11 mmHg; decrease in mean BP up to 13 
mmHg.
QA interval (indirect measure of cardiac 
contractility).
Decreased QA interval at single non-tolerated 
doses in dog (no effect seen in rats); up to 10 
msec. No effects were observed in the 7 day 
repeat dose dog CV study; No 
echocardiography changes in the 28 day dog 
toxicology study.
the management cardiac events.
Drugs with a risk of Torsades de 
PointesQT prolongation must are 
prohibitedbe used with caution, 
(refer to Section 8.3).
Given the risks of long QTc 
associated arrhythmias, and of 
compound associated 
cardiomyopathy, subjects will be 
monitored closely for changes in 
QTc with triplicate 12-lead ECG, 
and for elevations in plasma 
Troponin.  Inpatient 48-hour 
telemetry was originally required 
for all subjects following the first 
dose of study drug, as part of the 
cardiac monitoring. Evaluation of 
cardiac safety data from subjects 
treated up to and including the 100 
mg QD cohort by the cut-off date 
of May 15, 2015 demonstrated no 
significant QTc prolongation after
single and repeat dose 
administration. Therefore, the 48-
hour telemetry requirement was 
removed and the frequency of 
Holter monitoring was reduced 
with Protocol Amendment 5 and 
removed in Protocol Amendment 8 
following additional analysis of all 
available data by the cut off of 10-
Jun-2016.
Specific stopping criteria and 
management guidelines are 
provided for cardiac toxicities.
Electrolytes, including potassium 
and magnesium will be checked at 
baseline and at regular intervals or 
when clinically indicated. 
Appropriate medical management 
will be instituted to assure that 
electrolytes are kept within the 
normal range
Cardiovascular -
Elevations in cardiac biomarkers relative to 4 
ICF includes the risk of myocardial 
 
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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Troponin
week Good Laboratory Practice (GLP) 
toxicology study control group in:

Cardiac troponin I (up to 15X in rat 
and 4.7X in dog)

Cardiac troponin T (up to 8.9X in rat) 

Myosin light chain III (up to 4.8X in 
rat)

NT-proANP (up to 1.54X in rat)
Changes were reversible and there was no 
evidence of compound related myocardial 
histopathological changes in either species 
after up to 3 months of dosing.
infarction.
Protocol includes troponin 
monitoring (local laboratory 
monitoring for troponin I or T 
based on availability and troponin 
T at central laboratory) and dose 
stopping/modifications criteria for 
the management of cardiac 
toxicity.
.
Lung effects
Aggregates of foamy macrophages in 
peribronchiolar areas were evident in rats 
given ≥10 mg/kg/day for 28 days.  Following 
the 3 week off-dose period, these changes 
were decreased in incidence.  This finding is 
unlikely to affect pulmonary function. No 
effects were observed in the 3 month 
toxicology studies. For more information, see 
the GSK 525762 IB [GlaxoSmithKline 
Document Number 
2011N113741_052011N113741_06].
ICF includes the risk of lung 
effects.
Protocol includes pulmonary 
function assessments as 
appropriate (subjects with severe 
Chronic Obstructive Pulmonary 
Disease [COPD], history of 
pneumonitis, alveolar 
haemorrhage, chest radiation) 
chest x-ray at baseline and dose 
stopping/modifications criteria for 
pneumonitis.
Drug Interactions
GSK525762 is a substrate for CYP3A4 
enzymes, and for P-gp and breast cancer 
resistance protein (BCRP) transporters. 
GSK525762 clearance is virtually solely via 
CYP3A4.  There is evidence of potential auto-
induction after repeat dosing in clinical studies 
since reduction in parent exposures (~25% at 
lower doses to ≥60% at doses ≥60mg, mainly 
in BET115521 study) have been observed.
There is low potential for GSK525762 to 
inhibit cytochrome P450 (CYP) enzymes or to 
inhibit P-gp or BCRP based on in vitro data.  
GSK525762 was shown to be an inhibitor of 
organic anion transporting polypeptide 1B1 
(OATP1B1) and organic anion transporter 3 
(OAT3) in vitro.
GSK525762 was shown to be a moderate 
inducer of CYP3A4 in a human hepatocyte 
induction studyThere is low potential for 
Use of concomitant medications, 
herbal medicines and fruit juices 
that are strong or moderate 
CYP3A4 inhibitors or inducers 
should be avoided during the 
course of the study where possible 
as they may respectively decrease 
or increase exposure to 
GSK525762.
Potent inhibitors of BCRP and P-
glycoprotein transporters, such as 
cyclosporine, tacrolimus, or 
ketoconazole, should be avoided.
Use of concomitant medications 
that are sensitive substrates of 
OATP1B1 and OAT3 should be 
done with caution.
Medications that have a narrow 
 
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Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
GSK525762 to induce or inhibit cytochrome 
P450 (CYP) enzymes or to inhibit P-
glycoprotein (Pgp) or Breast Cancer 
Resistance Protein (BCRP) based on in vitro 
data. GSK525762 was shown to be an 
inhibitor of OATP1B1 and OAT3 in vitro.
therapeutic index and that are 
substrates of CYP3A4 should be 
administered with caution, as their 
metabolism may be affected by co-
administration with GSK525762 
and result in decreased exposure. 
These include alfentanil, 
cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus, 
and theophylline.
Section 2. OBJECTIVES, ENDPOINTS, HYPOTHESES
Rationale for Change: The study population for the NHL cohort in Part 2 was 
amended from a population of subjects with NHL to a population of subjects with 
cutaneous T-cell lymphoma (CTCL).  The Part 2 primary and secondary objectives along 
with the eligibility criteria were updated to include this new CTCL population, and 
removal of expansion into multiple myeloma in Part 2, and BID dosing was removed.  
Medications affecting QT prolongation were re-categorized from prohibited to 
cautionary.  Response Criteria for CTCL was added as an Appendix, and a QOL 
questionnaire (SKINDEX-29) was added
Revised Text:
 
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Part 1
Part 1 Objectives
Part 1 Endpoints
Secondary

To characterize the 
Pharmacokinetic (PK) of 
GSK525762 after single- and 
repeat-dose administration
following QD and/or twice daily 
(BID) dosing schedules.

GSK525762 PK parameters following 
single- (Day 1) and repeat-dose 
(Day 15) administration of 
GSK525762, including Area under 
concentration-time curve(AUC), 
Minimum observed concentration 
(Cmin), Pre-dose (trough) 
concentration at the end of a dosing 
interval (C), Maximum observed 
concentration (Cmax), Time of 
maximum concentration (tmax),
Apparent terminal half-life (t1/2) (or t1/2, 
eff), time invariance and accumulation 
ratio.

To evaluate the relationship 
between GSK525762 exposure 
and cardiac and other safety 
parameters following QD and/or 
BID dosing schedules.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC), following 
single and repeat-dose oral 
administration of GSK525762

To evaluate the relationship 
between GSK525762 
dose/exposure and 
pharmacodynamic (PD) 
response following QD and/or 
BID dosing schedules.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.

To evaluate the relationship 
between GSK525762 dose and 
exposure with clinical activity of 
GSK525762

Assess objective response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.
Exploratory

To evaluate the relationship 
between GSK525762 exposure 
and cardiac and other safety 
parameters.

Changes in cardiac QT duration 
corrected for heart rate by Fridericia’s 
formula (QTcF) and other safety 
parameters in relation to GSK525762 
exposure markers (dose, 
concentration, Cmax, AUC), following 
single and repeat-dose oral 
administration of GSK525762

To evaluate the relationship 
between GSK525762 
dose/exposure and 
pharmacodynamic response.

Dose/exposure markers related 
change in molecular markers (e.g., 
gene transcription and/or expression of 
proteins regulated by Bromodomain 
[BRD] proteins) in tumor tissue and/or 
peripheral blood samples.
 
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Part 1 Objectives
Part 1 Endpoints

To evaluate the relationship 
between GSK525762 dose and 
exposure with clinical activity of 
GSK525762

Assess objective response rate (ORR) 
according to disease specific 
assessments for leukemia, multiple 
myeloma, and non-Hodgkin’s 
lymphoma, as a function of dose and 
exposure markers.

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of GSK525762
following QD dosing schedules.

Pharmacogenomic (PGx) study using 
clinical l samples.
 
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Part 2
Part 2 Objectives
Part 2 Endpoints
Primary

To evaluate clinical efficacy after 
treatment with GSK525762 in 
high-risk myelodysplastic 
syndrome (MDS) or acute myeloid 
leukemia (AML) that has evolved 
from an antecedent MDS 
(“myeloid cohort”).

For MDS Cohort: Objective response 
rateORR (defined as the percentage%
of subjects achieving Complete 
Response (CR), Marrow CR, CRp [as 
per CR but platelet count <100 x 
109/L], CRi [as per CR but platelet 
count <100 x 109/L or neutrophil count 
<1 x 109/L], or Partial Response [PR] 
per response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in 
multiple myeloma (MM).

For MM: Objective response rate 
(defined as the percentage of subjects 
that have achieved a stringent CR 
[sCR], CR, VGPR, or PR) per 
response criteria.

To evaluate clinical efficacy after 
treatment with GSK525762 in 
CTCLnon-Hodgkin’s Lymphoma 
(NHL).

For CTCL: ORR4; defined as the
percentage of subjects that have 
achieved a CR or PR, per global 
response criteria and the modified 
severity weighted assessment tool 
(mSWAT), lasting more than 4 
months For NHL: Objective response 
rate (defined as the percentage of 
subjects that have achieved a CR, or 
PR) per response criteria.
Secondary

To evaluate the effect of 
GSK525762 on disease-related 
symptoms, as reported by 
subjects (CTCL cohort only)PRO

For CTCL: measure the effects of skin 
disease based on quality of life 
utilizingquestionaire Skindex-29

To characterize the PK of 
GSK525762 in 3 disease specific 
cohorts of subjects with 
MDS/AML, MM, or CTCLNHL
after repeat-dose administration.

Population PK parameters for 
GSK525762 such as apparent 
clearance following oral administration 
(CL/F) and volume of distribution 
(V/F), and relevant covariates which 
may influence exposure (e.g., age, 
weight, or disease associated 
covariates).

To evaluate the exposure 
response (i.e., PK/PD) 
relationship between GSK525762 
and safety/efficacy parameters in 
3 2 disease-specific cohorts of 
subjects with MDS/AML, MM, or 
or CTCLNHL.

PK/PD relationship between 
GSK525762 exposure markers and 
safety and efficacy parameters.

To evaluate the safety and 
tolerability of RP2D of 
GSK525762 in 3 2 disease-
specific cohorts of subjects with 
MDS/AML, MM, or or CTCLNHL.

AEs, SAEs, dose reductions or delays, 
withdrawals due to toxicities and 
changes in safety assessments (e.g., 
laboratory parameters, vital signs, and 
cardiac parameters) at RP2D.

To determine the clinical activity of 

TTP (Time to Progression) , DOR 
 
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Part 2 Objectives
Part 2 Endpoints
GSK525762 in 32 disease-specific 
cohorts of subjects with 
MDS/AML, MM, or or CTCLNHL.
(Duration of Response),  PFS 
Progression free survival (Progression 
Free SurvivalPFS, time from treatment 
start date to disease progression or 
death due to any cause, whichever is 
earlier) for MDS/AML, MM and
NHCTCL.L
Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for MDS/AML, MM and 
CTCL.NHL

Duration of response (DOR, time from 
onset of response to disease 
progression or death due to any 
cause, whichever is earlier in 
responders) for MDS/AML, and CTCL

Rate of objective global response with 
a duration of 4 months or more 
(ORR4) in CTCL

Overall survival (OS, the time from the 
treatment start date until death from 
any cause) for MDS/AML, and CTCL
Exploratory

To evaluate the exposure 
response relationship between 
GSK525762 and safety/efficacy 
parameters in 2 disease-specific 
cohorts of subjects with 
MDS/AML, or CTCL.

Relationship between GSK525762 
exposure markers and safety and 
efficacy parameters.
Hypothesis
The primary goal of Part 2 is to detect a clinically meaningful response rate, defined as 
follows:

Myelodysplastic syndrome and transformed MDS (myeloid cohort): A response rate of 
30% relative to a 10% response rate suggesting no activity in subjects with MDS/AML.  
This will be conducted by testing the null hypothesis that P0≤0.10 versus the alternative 
that P1≥0.300, assuming the maximum response rate for an ineffective drug is 0.10 and 
the minimum response rate for an effective drug is 0.30.

Multiple myeloma: A response rate of 20% relative to a 5% response rate suggesting no 
activity in subjects with multiple myeloma.  This will be conducted by testing the null 
hypothesis that P0≤0.05 versus the alternative that P1≥0.20, assuming the maximum 
response rate for an ineffective drug is 0.05 and the minimum response rate for an 
effective drug is 0.20.

CTCL: Non-Hodgkin’s lymphoma (non-double hit lymphoma [DHL]): A response rate, 
lasting more than 4 months, of 430% relative to a 210% response rate suggesting no 
activity in subjects with non-Hodgkin’s lymphomaCTCL.  This will be conducted by testing 
the null hypothesis that P0≤0.210 versus the alternative that P1≥0.430, assuming the 
maximum response rate for an ineffective drug is 0.210 and the minimum response rate 
for an effective drug is 0.430. Subjects with DHL will be evaluated separately for efficacy, 
but no hypothesis testing will be conducted on the DHL cohort.
 
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Section 3.1. Study Design/Schematic
Rationale for Change: The study population for the NHL cohort in Part 2 was 
amended from a population of subjects with NHL to a population of subjects with 
cutaneous T-cell lymphoma (CTCL).  The Part 2 primary and secondary objectives along
with the eligibility criteria were updated to include this new CTCL population, and 
removal of expansion into multiple myeloma in Part 2.  
Revised Text:
Paragraph 2 sentence 2 onwards
Safety, tolerability, PK, and efficacy may also be explored in a limited number of 
subjects treated twice daily (BID). Part 1 will Both parts will be conducted in adult 
subjects with relapsed and/or refractory myeloid malignancies, multiple myeloma, and 
non-Hodgkin’s lymphomas.  Part 2 will be conducted in adult subjects with relapsed 
and/or refractory myeloid malignancies and cutaneous T-cell lymphoma (Figure 2).
Figure 2
Study Schema
In Part 2 text box
(MDS/AML, CTCL NHL, MM)
(n=32 for MDS/AML& MM, 367 for CTCLNHL)
In MTD/RP2D text box
BID
MDS/AML, NHL, MMCTCL
Paragraph 3
In both Parts 1 and 2, all subjects will may be evaluated for systemic BET inhibitory 
effects in blood (whole blood transcriptional). A subset of subjects in Part 1 will may also 
be evaluated for plasma cytokine profiling.  In addition, pre-treatment and post-treatment 
bone marrow, skin, whole blood for PBMC isolation or lymph node samples will be 
collected from selected subjects to be evaluated for target engagement and effects of 
GSK525762 on tumor biology.
Section 3.2.1. Part 1: Dose Escalation
Rationale for Change: removed of BID dosing from DE plan
Revised Text:
Paragraph 4
Dose escalation will continue until an MTD is determined or until a dose of 200 mg per 
day is reached.  After the MTD has been determined for a disease type in Part1 for each 
disease type, then BID cohort(s) (Section 1.1.1.13.2.1.5) and the then the Part 2 dose 
expansion cohorts will be opened for that disease type.
 
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Section 3.2.1.1. Dose Escalation and Schedule
Rationale for Change: revision of cardiac monitoring criteria due to changes in 
benefit/risk profile
Revised Text:
Paragraph 2
Extensive monitoring for cardiac safety signals will be performed including triplicate 12-
lead ECG on the days indicated in the Time and Events Table. 
Section 3.2.1.3. 3 + 3 Dose Escalation in Part 1
Rationale for Change: BID dosing removed per changes in asset development 
strategy for heme
Revised Text:
Figure 3 Dose Escalation Schema (Part 1)
BID text box removed
BID (QD MTD, divided approximately equally)
Following abbreviations removed
AML: acute myeloid leukemia
BID: twice daily
MM: multiple myeloma
NHL: non-Hodgkin’s Lymphoma
Table 3
3 + 3 Dose Escalation Design
For 0 out of 3 subjects, “” symbol was added before Grade 2 toxicity for the action “Escalate 
to next dose level with an increase of 50% if, in the first 3 weeks of any cohort”.
Section 3.2.1.4. Alteration of Schedule
Rationale for Change: modification to PK sampling timepoints for subjects 
undergoing dose escalation/de-escalation
Revised Text:
Paragraph 4
In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling (pre-dose, 0.5, and 3 
hours) at the new dose level, after 4-at least 7 days at the adjusted dose level.
 
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Section 3.2.1.5. BID dosing
Rationale for Change: BID dosing removed per changes in asset development 
strategy for heme
Revised Text:
3.2.1.5. BID dosing
Once the MTD of QD administration has been identified for a disease subtype, a cohort 
may be opened to explore the safety, tolerability, PK, and efficacy of GSK525762 when 
administered BID.  .  The selected total daily dose (administered in two approximately 
equal doses) for BID administration will not exceed the QD MTD.  A lower starting dose 
may be selected depending on emerging safety, PK and PD data.  Dosing will be 
separated by approximately 12 hours.  The total number of evaluable subjects per disease 
type treated BID will not exceed 10 subjects.
Section 3.2.1.5. Intra-Subject Dose Escalation
Rationale for Change: modification to PK sampling timepoints for subjects 
undergoing dose escalation/de-escalation
Revised Text:
Paragraph 2 sentence 1:
Subjects approved for intra-subject dose escalation may require additional limited PK 
sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by GSK 
Clinical Pharmacology, after at least 7 days at the adjusted dose level.
Section 3.2.4. Part 2: Disease Specific Expansion Cohorts
Rationale for Change: The study population for the NHL cohort in Part 2 was 
amended from a population of subjects with NHL to a population of subjects with 
cutaneous T-cell lymphoma (CTCL).  The Part 2 primary and secondary objectives along 
with the eligibility criteria were updated to include this new CTCL population, and 
removal of expansion into multiple myeloma in Part 2.  
Revised Text:
Up to 32 subjects (per cohort) with myelodysplastic syndrome or non-Hodgkin’s 
lymphoma (non-DHL), and up to 37 subjects with multiple myeloma, CTCL (as defined in 
Section 4.2.1) may be enrolled in an expansion cohort at the RP2D.  These will be 
conducted to gather more safety data and to further assess anti-tumor activity.  Subjects 
in Part 2 will start with a continuous daily dosing schedule unless safety or PK data 
necessitate a different dosing schedule.  The final dose and regimen for Part 2 will be 
decided upon completion of dose escalation in Part 1.
At least 10 subjects with tumor that is positive for rearrangement or overexpression of 
MYC plus BCL-2 and/or BCL-6 genes (double- and triple-hit lymphoma) will be 
 
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enrolled.  These subjects will be evaluated separately for efficacy, but hypotheses will not 
be tested.  See Section 11.1 for description of the plan for analysis of the NHL cohorts.
Plasma samples for PK evaluation will be collected in all subjects.  The Part 2 portion of 
the study will employ a Bayesian design that allows the trial to be monitored with the 
constraint of both Type I and Type II error rates.  Clinical response will be defined per 
standard evaluation criteria (see Appendix 6, Appendix 7 and Appendix 8).  Patient-
reported outcome questionaire, Skindex 29 (Appendix 11) will be used to gauge the 
effects of treatment with GSK525762 on the quality of life and other subjective measures 
in subjects with CTCL.
For each cohort, the firstan interim analysis will be conducted after efficacy data at a dose 
level based on RP2D are available on a minimum ofat least 10 subjects become evaluable 
(have had at least one-post baseline disease assessment, have progressed or died, or have 
discontinued from study treatment) in the MDS and CTCL NHL (non-DHL) cohorts
respectively. and a minimum of 13 subjects in the MM cohort. The number of subjects 
may be increased up to a total of 32 for the MDS cohort and up to a total of 37 for the 
CTCL cohort, NHL (non-DHL) cohorts and up to a total of 37 for the MM cohort
depending on the results observed; a separate decision will be made for each disease 
cohort.  The decision rules, specifying the number of subjects with a clinical response 
needed for continuing enrolment or, stopping for futility, are indicated in Figure 4 and 
Figure 5.  The methodology is based on the predictive probability of success (response 
rate > historical response rate) if enrolment continues to maximum number of32 subjects 
for MDS and CTCL NHL (non-DHL) and 37 subjects for MM [Lee, 2008].  Subjects 
enrolled in Part 1 with the same type of disease as Part 2, and treated at the RP2D, will be 
included in the Part 2 analysis.  These rules are intended as a guideline.  Actual decisions 
will depend on the totality of the data.
For MDS and CTCL NHL (non-DHL) cohorts: Ten subjects will be enrolled in each 
cohort at the RP2D to examine safety and efficacy.  If zero responses are observed in 
either cohort, then that cohort will be terminated and no further subjects will be enrolled 
due to futility.when 10 subjects are included in the first interim analysis, aA single 
responderse in a cohort will be adequate to pursue further enrolment. The number of 
observed confirmed responses will guide further enrolment according to the rules 
summarized in Figure 4 and Figure 5. A maximum of 32 subjects per cohortwith MDS 
and 37 subjects with CTCL will be enrolled at the RP2D.  All available data will be 
considered in making enrolment decisions.
Paragraph 6
For the MM cohort: Thirteen subjects will be enrolled at the RP2D to examine safety and 
efficacy.  If zero responses are observed in this cohort, then no further MM subjects will 
be enrolled due to futility. A single response will be adequate to pursue further 
enrolment. The number of observed confirmed responses will guide further enrolment 
according to the rules summarized in Figure 5. A maximum of 37 subjects will be 
enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.
 
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Figure 6
Diagram of Stopping Rules for MM CTCL Cohort Expansion
Number of Subjects
0
1
2
3
4
5
6
7
8
9
10
11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if there is no response in 
13 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and further enrollment 
in this cohort may be stopped.
 
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Section 4.1. Number of Subjects
Rationale for Change: total number of subjects updated to reflect changes in study 
population
Revised Text:
Part 2 will enroll up to 111 69 subjects (three two disease-specific cohorts of 32 and 37 
subjects, for the MDS and CTCL cohorts, respectively to 37 subjects each, depending on 
disease subtype, and one disease-specific cohort of 10 subjects). )
Section 4.2.1. Inclusion Criteria
Rationale for Change: The Part 2 primary and secondary objectives along with the 
eligibility criteria were updated to include this new CTCL population, and removal of 
expansion into multiple myeloma in Part 2.  Eligibility criteria for all populations were 
updated (ECOG, cardiac safety).  
Revised Text:
Inclusion criterion 3
Subjects must have a diagnosis of one of the following hematologic malignancies, which 
has relapsed or been refractory to treatment as follows :Myelodysplastic Syndrome 
(MDS), Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), or non-Hodgkin’s 
Lymphoma (NHL).
Inclusion criterion 3 Bullet 3 onwards

(Part 1 and Part 2): Subjects with multiple myeloma are eligible if they have 
progressed despite therapy with an alkylating agent, proteasome inhibitor, 
and immunomodulatory agent, either as individual regimens or in 
combination

(Part 1 and Part 2only): Subjects with NHL are eligible if they have received 
at least two prior lines of systemic therapy, including at least one line of 
immunochemotherapy with an anti-CD20 antibody (if their tumor expresses 
CD20)

(Part 2 only): Subjects will be eligible for enrolment into the CTCL cohort if 
they:
o
Have histologically- or cytology-proven diagnosis of CTCL 
(mycosis fungoides [MF], Sézary syndrome [SS], primary 
cutaneous anaplastic large cell lymphoma [pcALCL], or large cell 
transformation of underlying MF/SS) that has failed to respond to, 
or progressed despite, at least one prior systemic therapy

In Part 2, the NHL cohort will separately enrol subjects with double- and 
triple hit lymphoma, so that a minimum of 10 subjects with this subset of 
disease will be enrolled. To be eligible for this sub-cohort, tumor sample 
from the subject must demonstrate rearrangement and/or overexpression of 
MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or triple-
 
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hit status may be performed via appropriate local testing, and the 
determination of double- or triple-hit diagnosis will be at the discretion of the 
investigator and GSK Medical Monitor.
Inclusion criterion 5
Eastern Cooperative Oncology Group (ECOG) performance status of:

1 for all Part 1 Cohorts (AML, MM, and NHL)

2 for theall Part 2 cohorts (MDS/AML and CTCL)
Definitions for Adequate Organ Function
Renal
Creatinine3
OR
Calculated creatinine clearance [calculated by Chronic 
Kidney Disease Epidemiology Collaborative (CKD-Epi) 
method Cockcroft Gault formula2, 3]
OR
24-hour urine creatinine clearance 3
≤1.5 X ULN 
≥50 mL/min
≥50 mL/min
Footnote 2
Refer to Appendix 1 for Cockcroft GaultCKD-Epi formula
Section 4.2.2. Exclusion Criteria
Rationale for Change: The Part 2 primary and secondary objectives along with the 
eligibility criteria were updated to include this new CTCL population, and removal of 
expansion into multiple myeloma in Part 2.  Eligibility criteria for all populations were 
updated (ECOG, cardiac safety).  
Revised Text:
Exclusion criterion 1
Haematological malignancy associated with human immunodeficiency virus (HIV) 
infection or solid organ transplant or history of knownpositive Hepatitis B Antigen or 
positive Hepatitis C antibody at screening (subjects with positive Hepatitis C antibody 
may be enrolled, provided that the confirmatory test [e.g. Heptatitis C Virus confirmed by 
Recombinant ImmunoBlot Assay [RIBA], if available or alternately confirmed by
Hepatitis C Virus [HCV] Ribonucleic acid [RNA] polymerase chain reaction [PCR] is 
negative).
Exclusion criterion 3 Note 2
Corticosteroids (topical and/or systemic)
 
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Exclusion criterion 5
Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days prior to 
the first dose of GSK525762.  Low dose (prophylactic) anticoagulants (e.g., low 
molecular weight heparin (LMWH) or oral anticoagulants) is permitted.  In addition, INR 
must be monitored in accordance with local institutional practices, as appropriate.
Exclusion criterion 6
Current use of a prohibited medication or requires any of these medicationsplanned use 
of a forbidden medication during treatment with the investigational drugsGSK525762.  
This includes excluding current medications known or suspected to be associated with 
QT prolongation.  In addition, any subject who is expected to require a QT prolonging 
medication while on trial should not be enrolled.
Exclusion criterion 9
Cardiac abnormalities as evidenced by any of the following:

History or current clinically significant conduction abnormalities, 
uncontrolled arrhythmias or hypertension.

Clinically significant conduction abnormalities or arrhythmias, subjects with 
Bundle Branch Block.

Presence of cardiac pacemaker.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA) [Appendix 2].

Recent hHistory (within the past 3 months) of acute coronary syndromes 
(including unstable angina and myocardial infarction), coronary angioplasty, 
or stenting. within the past 3 months.
Exclusion criterion 10 Bullet point 1
Baseline QTcF interval ≥450 480 msec.
Section 4.2.3.1. Permanent Discontinuation from Study Treatment
Rationale for Change: language added for CTCL specific population
Revised Text:
Paragraph 1 sentence 3
For subjects with CTCL, in cases where the definition of progressive disease (PD) or 
relapse is met but the clinical impression is questionable, documentation for a period of at 
least 4 weeks is also recommended to avoid a subject being removed prematurely from 
the study.
 
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Section 4.2.3.2. Subject Completion
Rationale for Change: clarification/simplification of wording
Revised Text:
Paragraph 2
In Part 2, a subject will be considered to have completed the study if the subject is 
followed until death or the end of study.:

they progressed or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
Section 5. TIME AND EVENTS TABLES
Rationale for Change: The time and events tables were updated to reduce the cardiac 
monitoring based on updated risk/benefit profile, and BID dosing was removed.  
Medications affecting QT prolongation were re-categorized from prohibited to 
cautionary.  Response Criteria for CTCL was added as an Appendix, and a QOL 
questionnaire (SKINDEX-29) was added.
Revised Text:
Table 5
Time and Events: Part 1
Heading text within table:
Study Drug: For QD or BID details see Table 8 and Table 9
Safety
Pulmonary function test d removed
Cardiac Monitoring
ECHO or MUGA (Within 35 days of first dose)
Footnote d:
Pulmonary tests as appropriate: subjects with severe COPD, history of pneumonitis, 
alveolar hemorrhage, chest radiation
Footnote e:
12-lead ECGs: Screening ECGs within 14 days of first dose.  Triplicate ECGs prior to 
dosing.  For timing of ECGs on “O” days, see Table 8 for QD and Table 9 for BID. 
Otherwise, triplicate ECGs at approximately same time of day, and prior to dosing. If 
QTcF increase >30msec, ECGs performed daily through W2.
Table 6
Time and Events: Part 1 Laboratory Assessments
CK-MB assessment has been removed for W1 D2, W1 D5, W2 D1, W2 D6, W3 D1, 
W4 D1, W10 D1, q6W, and EOT timepoints.
 
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HBsAg, HepC antibody Notes:
If hepatitis C antibody positive, a confirmatory study (e.g., HCV RNA PCR) should be 
performed as per local standardperform third generation immunoassay (if test is 
available) on same sample to confirm results, or alternatively, use HCV RNA test (either 
quantitative or qualitative).
Footnotes:
PCR=polymerase chain reaction added
Table 7
Disease Specific Assessments: Part 1 and 2
Heading text within table:
Multiple Myeloma (MM) Assessments (Part 1)
Blood sample for exploratory translational research on q6W D1 added
Heading text within table:
Lymphoma NHL Assessments (Part 1)
CTCL Assessments (Part 2)
Procedure
SCR
W3
W7
W10
q3W
W16 and beyond
EOT
D1
D1
D1
D1
Disease characteristics, 
including historya and 
current staging
X
Skin assessment (e.g., 
medical photography)
X
X
Wk 16, wk 24, 
then q12wks
X
Cross-sectional imagingb
X
X
Wk 16, wk 24, 
then q12wks
X
Quantitative evaluation 
of disease in blood (e.g., 
flow cytometry)
X
X
Wk 16, wk 24, 
then q12wks
X
Gobal response scoringc
X
X
Wk 16, wk 24, 
then q12wks
X
Skindex 29 (Quality of 
life/symptom 
assessment)
X
X
X
xX
Wk 16, wk 24, 
then q12wks
X
Tissue biopsyd
X
X
X
Blood sample for 
exploratory translational 
researche
X
X
X
Wk 16, wk 24, 
then q12wks
X
a.
Including date of first diagnosis, disease stage, and history of prior therapies
b.
CT, PET/CT, or MRI may be used, as per standard practice
c.
Global response score (refer to Appendix 10 for full description) takes into account status of disease as measured 
by assessment of skin, lymph nodes, viscera, and blood.  Any response or PR should be confirmed by repeat 
assessment no sooner than 4 weeks after the assessment demonstrating response.
d.
Punch biopsy of affected skin lesion should be performed at times indicated for translational research.  Pre- and 
post-dose biopsies should be collected from the same lesion.  The W3D1 biopsy should be collected within 3-6 
hours after the dose
e.
Blood samples should be collected within 3-6 hours after the dose. 
 
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MDS and Leukaemia Assessments (Part 1 and Part 2)
Response Assessment at Screening removed.
Table 8
Time and Events: Part 1 (QD cohorts) Serial Electrocardiograms, 
Pharmacokinetics, and Biomarker Sampling
Procedure / time 
after dose
W2
D4
W2
D6
W2D7 (if dose has been altered (including held and 
resumed) serial PK sampling should occur 4 to 7 
days after dosing resumed)
W3D
1
W7D1 ±4 days c
pr
e
do
se
pr
e
do
se
pr
e 
do
se
0
h
15 
min 
± 
5m
30 
min 
±5
m
1h 
±1
0m
2h 
±1
5m
4h 
±1
5m
8
h 
±
1
h
1
2
h 
±
2
h
2
4
h 
±
1
h
0
h
pre 
do
se
0
h
0.
5-
2
h
4 
-
8
h
Dose
X
X
X
12-lead ECG a
X
X
X
X
X
X
PK sample for 
GSK525762
X
X
X
X
X
X
X
X
X
X
X
b
X
X
X
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
The ECGs are taken in triplicate, 5 minutes apart andA single ECG should be collected at each timepoint,
within 10 min prior to PK draw. .
b.
Sample to be obtained before dosing on Week 1, Day 2 or Week 3 Day 1.
c.
If dose was escalated, the W7D1 visit may be performed +4 to +7 days.
Abbreviations: ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose.
Table 9
Time and Events: Part 1 (BID Cohorts) Serial Electrocardiograms, 
Pharmacokinetics and Biomarker Sampling
W1D1
W1D5
W2D4
W2D6
W2D7
W7D1 ±4 days c
Timepoint
; 
Hours 
after AM 
dose
Pre-Dose
0h
30 min ±5m
2h ±15m
4h ±15m
8h  ±1h
12h (0h)
AM
2h ±15m
4h ±15m
PM
pre AM dose
AM & PM
pre AM dose
AM & PM
Pre-Dose
0h
2h ±15m
4h ±15m
12h (0h)
pre dose
0h
0.5-2h
4 - 8h
12h
Dose
X
X
X
X
X
X
X
X
X
X
X
X
12-lead 
ECG a
X
X
X
X
X
X
X
X
X
X
X
PK 
GSK5257
62b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
The ECGs are taken in triplicate, 5 minutes apart and within 10 minutes prior to PK draw. 
b.
PK blood sample collected overnight may be kept refrigerated at 4C in the event the laboratory is closed. 
c.
If dose was escalated, the W7D1 visit may be performed +4 to +7 days.
APP=acute phase protein; ECG=electrocardiogram; PK=Pharmacokinetics; MTD Maximum Tolerated Dose; 
Table 10
Time and Events: Part 2 Expansion Cohort
Pulmonary function test at Screening has been removed
Cardiac Monitoring
ECHO or MUGA (Within 35 days of first dose).  
 
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PK and Blood pharmacodynamics notes:
Three samples to be collected  each sampling day: During the first 3 weeks collect a 
predose (within 60 minutes prior to dose), a single draw between 0.5 to 2 h postdose, and 
a single draw between 4-8h postdose (fasting requirements apply).  Thereafter W7 and 
Q6W only a predose and 0.5 hour post dose sample are collected. PK sampling may be 
discontinued after 6 months on study
Part 2 
Procedure 
(Notes)
SCR
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Further 
Cycles
(q3w and 
q6w 
Initiated 
from Wk 10)
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
Translational Research
PGx 
sample
X
Tumor 
sample 
(e.g., bone 
marrow 
biopsy, 
lymph 
nodeskin 
punch
biopsy, or 
peripheral 
blood 
collection 
[only for 
subjects 
with 
circulating 
disease])
X e
X f (CTCL only)f
X f (MDS/AML only) 
Xg
Blood 
samples for 
exploratory 
translational 
research 
X
Xf(CTCL only)
X f (MDS/AML only)
Additional samples will be collected on the 
date of disease assessment/bone marrow 
biopsy and date of progression or when 
patient is discontinued from study/end of 
treatment
Footnote f:
Subjects with MM or should have bone marrow aspirates collected on W3D1 within3-6 
hours after the dose. Subjects with MDS/AML should have bone marrow aspirates or 
peripheral blood collection (provided that there are sufficient leukemic cells in the 
peripheral circulation) collected on W3 W4 D1 within 3-6 hours after the dose.  Subjects 
with NHLCTCL will have a lymph nodepunch biopsy of the skin and blood sample 
collected on W3D1 within 3-6 hours after the dose. Any additional blood samples should 
be collected within 3-6 hours post-dose.  Timing of tissue collection will be based on 
tumor type and may be modified based on emerging data. For operational reasons 
sampling can be delayed by up to 2 days as long as the hours post-dose for collection 
remain as described. A PK sample will need to be obtained within 1 hour of the 
 
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tissue sampling. For CTCL subjects the 4-8 hour PK sample required to be drawn can be 
utilized as the sample that is required after tissue sampling.  See Table 7 disease specific 
assessments for details).  
Table 11
Time and Events: Part 2 Laboratory Assessments
NB: Collect blood samples prior to 
dosing.  W1D1 samples not 
needed if SCR sample is within 
24h of first dose. (Notes)
SCR
Cycle 1
Cycle 
2
Cycle 
3
Cycle 
4
Further 
Cycles
q3w and 
q6w 
Initiated 
from Wk 10
EOT
W1
W2
W3
W4
W7
W10
q3W
q6W
D1
D1
D1
D1
D1
D1
D1
D1
HBsAg, HepC antibody (If hepatitis C 
antibody positive, a confirmatory 
study [e.g., HCV RNA PCR] should 
be performed as per local 
standardperform third generation 
immunoassay on same sample to 
confirm results)
X
Section 6.1.2. Visit Windows
Rationale for Change: clarification needed for study visit window
Revised Text:
At the end following added:
Discontinuation Survival Follow Up Visit: can be scheduled ± 7 days
Section 6.2 Baseline Assessment
Rationale for Change: wording revised to reflect changes in cohorts
Revised Text:
Subjects diagnosed with refractory hematological malignancy (MM, lymphomaNHL 
(excepting CTCL), CTCL, MDS and/or AML), will be assessed at baseline for general 
disease characteristics as noted in Section 6.2.1 and tumor type specific measures as 
noted in Section 6.2.2, Section 6.2.3 and Section 6.2.4, and Section 6.2.5, respectively.
Section 6.2.3. Baseline assessment for Subjects with lymphoma NHL (excepting 
CTCL)
Rationale for Change: clarification of name of cohort/population
Revised Text:
Section heading changed as mentioned above
Section 6.2.4 Baseline assessment for Subjects with CTCL
Rationale for Change: new required baseline assessments for CTCL specific cohort
 
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Revised Text:
6.2.4 Baseline assessment for Subjects with CTCL

Modified International Society for Cutaneous Lymphomas (ISCL)/ European 
Organization of Research and Treatment of Cancer (EORTC) stage at initial 
diagnosis and screening (Appendix 10, Table 22)

Quality of life assessment (Skindex-29 [refer to Appendix 11])
Section 6.3.4. Echocardiogram (ECHO) 6.3.4. Left ventricular ejection fraction 
(LVEF) Evaluation
Rationale for Change: updating study procedures to permit additional imaging 
modalities
Revised Text:
For all subjects, ECHOs evaluation of cardiac output will be performed at screening and 
at assessment times as outlined in Section 5.  While ECHO is the preferred modality of 
imaging, MUGA scans may be accepted as an alternative.  Subjects should have the same 
assessment modality performed at each time point listed in Section 5.  When possible,   
ECHOs/MUGAs should be evaluated and compared to baseline by the same reader. 
All ECHO/MUGA data may be transferred and reviewed by an independent cardiologist.
Section 6.3.5. Electrocardiograms
Rationale for Change: The time and events tables were updated to reduce the cardiac 
monitoring based on updated risk/benefit profile
Revised Text:
Paragraph 1 bullet point 2 and 3:

During Part 1, triplicate 12-lead ECG should be performed at all time points 
indicated in the Section 5 Time and Events Tables.  

During Part 2, single 12-lead ECGs should be performed at the time points 
indicated in the Section 5 Time and Events Tables.
Paragraph 3 bullet point 1:

QTc interval ≥500 530 msec OR interval increase from baseline 60 msec: 
Investigational product (IP) will be discontinued unless the benefits of therapy 
outweigh the risk of rechallenge in the opinion of the Investigator, the GSK 
Medical Monitor, as well as the GSK medical governance. In this situation, 
rechallenge may be permitted (see Section 7.6 for rechallenge guidelines).
Paragraph 6:
Baseline results are defined by the nearest timepoint prior to first dose. For this trial the 
Baseline QTcF value is determined by the mean of the triplicate W1D1 predose QTcF 
results. If these results are not available, then the mean QTcF of the screening triplicate 
ECG results would be used.
Section 6.3.6. Clinical Laboratory Assessments
 
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Rationale for Change: fasting requirements reduced to increase subject compliance
Revised Text:
Paragraph 2:
Subjects should be instructed to fast (no food and only water allowed) for 10 8 hours 
prior to any fasting laboratory assessments (example: fasting glucose, fasting lipid panel, 
etc.).
Section 6.4.1. Disease Assessment
Rationale for Change: wording changed to reflect A9 cohort changes
Revised Text:
Response will be assessed as outlined in the Section 5 Time and Events Table 7 Table by 
the investigator using the appropriate criteria for MM, lymphoma, CTCL, AML, and 
MDS, as noted in Appendix 6, Appendix 7 Appendix 8, and Appendix 9, and Appendix 
10, respectively.  
Section 6.5.1. Blood Sample Collection
Rationale for Change: additional analyses to be performed based on emerging data
Revised Text:
Paragraph 1 sentence 1:
Blood samples to enable quantification of GSK525762, and relevant metabolites, as 
applicable, in plasma will be collected at the time points indicated in the Section 5 Time 
and Events Tables.
Section 6.6.2. Blood Sample Collection for Exploratory Translational Research
Rationale for Change: clarification to required procedures for MDS specific 
population
Revised Text:
Paragraph 1 bullet point 1:

Part 1 &2: At screening, date of bone marrow biopsy (Part 2 MDS cohort only), 
disease assessment (Table 7) and disease progression for isolating plasma for 
circulating biomarkers (eg, cfDNA) , PBMCs and neutrophils.
Section 6.10. Quality of Life/Patient-Reported Outcomes
Rationale for Change: Skindex-29 as part of addition of CTCL cohort
 
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Revised Text:
6.10. Quality of Life/Patient-Reported Outcomes
Patient-reported outcome, Skindex 29 (refer to Appendix 11) will be used to gauge the 
effects of treatment with GSK525762 on the quality of life and other subjective measures 
in subjects with CTCL.
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for Change: modification/clarification to IP handling requirements
Revised Text:
When used under the conditions of handling and administration described in Section 7.2, 
investigational product is not expected to pose significant safety risks to site staff.
Precaution will be taken to avoid direct contact with the study treatment. A Material 
Safety Data Sheet (MSDS) describing the occupational hazards and recommended 
handling precautions will be provided to site staff if required by local laws or will 
otherwise be available from GSK upon request.
Table 15
GSK525762 Besylate Investigational Product Dosage/Administration
Investigational Product
Product name:
GSK525762 Besylate Tablets
Unit dose strength(s)/Dosage level(s):
5mg
20mg
25mg
50mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
GSK
Physical description:
White to 
slightly 
colored, 
round, 
biconvex 
tablet.
Yellowish 
pink, 
round, 
biconvex 
tablet
White to 
slightly 
colored, 
round, 
biconvex 
tablet
White to 
slightly 
colored, oval 
shaped tablet
Section 7.2. Handling and Storage of Study Treatment
Rationale for Change: modification/clarification to IP handling requirements
 
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Revised Text:
Handling
Precaution will be taken to avoid direct contact with the study treatment.
Under normal conditions of handling and administration, IP is not expected to pose 
significant safety risks to site staff.  An MSDS describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request
Section 7.3. Meals and Dietary Restrictions
Rationale for Change: clarification to meals/dietary requirements
Revised Text:
Paragraph 4 sentence 1:
Based on the results of the BET115521 sub-study showing a lack of effect of a high-fat 
high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered as 
besylate coated tablets, the fasting requirement is being lifted for subjects in Part 2 only 
except on Serial PK sampling days (Week 1 and Week 43) or days in which required for 
fasting blood draws.  
Section 7.7.1. Dose and Safety Management Guidelines
Rationale for Change: The time and events tables were updated to reduce the cardiac 
monitoring based on updated risk/benefit profile, and BID dosing was removed.  
Medications affecting QT prolongation were re-categorized from prohibited to 
cautionary.  
Revised Text:
Table 16
Dose Adjustment/Stopping Safety Criteria
Stopping criteria: QTcF <500 530
Management guidelines: QTcF
(1)
QTcF event reduced to <4850 msec,
(5)
Institutional IRB (or equivalent) approval (if required), and
Section 7.7.2. Dose Adjustments for Toxicity
Rationale for Change: correction of study number
Revised Text:
Paragraph 2 sentence 1:
Dose escalation decisions will take into account all available data, including PK data and 
the safety profile of prior cohorts, relevant data from Study BET1161835221, and will 
occur following review of these data by the investigator(s), GSK medical monitor, 
pharmacokineticist, and statistician.  
 
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Section 8.2. Cautionary/Prohibited Medications
Rationale for Change: modifications to criteria based on updated risk/benefit profile
Revised Text:
Paragraph 2:
Subjects must not receive other anti-cancer therapy (including chemotherapy, 
immunotherapy, biologic therapy, or hormonal therapy, whether approved or 
investigational) while on treatment in this study.  Short courses of steroids may be co-
administered with permission from the GSK medical monitor.
Paragraph 4 onwards:
Aspirin may not be administered at doses that exceed 81 100 mg per day.  Non-steroidal 
anti-inflammatory agents should be avoided except where they provide benefit over other 
analgesics; if administered, they should be used with caution and consideration should be 
given to co-administration with proton pump inhibitors.
Co-administration of medications that are associated with prolonged QT interval (please 
refer to crediblemeds.org for a complete list of these medications) is permitted as follows:

If a subject is taking a QT-prolonging medication prior to first dose of 
GSK525762, then the subject may continue to take this medication without 
additional monitoring, so long as the baseline QTcF meets criteria as described in 
Section 4.2.2

If a subject must initiate a QT-prolonging medication while receiving 
GSK525762, then additional ECG monitoring should be implemented, per local 
standard, until the QT-prolonging medication achieves therapeutic concentrations.  
Refer to Table 16 for QT management guidelines.
Section 8.2.1. Cautionary Medications
Rationale for Change: Eligibility criteria for all populations were updated (ECOG, 
cardiac safety).  The time and events tables were updated to reduce the cardiac 
monitoring based on updated risk/benefit profile, and medications affecting QT 
prolongation were re-categorized from prohibited to cautionary.  
Revised Text:
8.2.1. Cautionary Medications
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsades de Pointes are to be used with EXTREME CAUTION
beginning 14 days prior to the first dose of study drug until discontinuation from the 
study.  These medications include (but are not limited to) those listed in Table 18.
 
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Table 18
Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution
Alfuzosin
Lithium
Apomorphine
Mifepristone
Aripiprazole
Mirabegron
Artenimol + piperaquine
Mirtazapine
Asenapine
Moexipril/HCTZ
Atomoxetine
Nicardipine
Bedaquiline
Norfloxacin
Buprenorphine
Nortriptyline
Clomipramine
Ofloxacin
Clozapine
Olanzapine
Cyamemazine
Oxytocin
Degarelix
Paliperidone
Delamanid
Pasireotide
Desipramine
Perflutren lipid microspheres
Dexmedetomidine
Pipamperone
Dolasetron
Promethazine
Ezogabine
Rilpivirine
Famotidine
Risperidone
Felbamate
Roxithromycin
Fingolimod
Saquinavir
Fluconazole
Sertindole
Foscarnet
Telavancin
Gemifloxacin
Telithromycin
Granisetron
Tetrabenazine
Hydrocodone – ER
Tizanidine
Iloperidone
Tolterodine
Imipramine
Trimipramine
Isradipine
Tropisetron
Leuprolide
Vardenafil
Levofloxacin
Venlafaxine
Data Source: CredibleMeds, 15 May 2016 (www.crediblemeds.org).
The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject.
After starting cautionary medications such as in Table 18 it is recommended that ECGs 
are implemented daily until the steady state is reached.  If there are abnormalities, 
implement additional cardiotoxicity monitoring.
 
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Section 8.2.1. Drugs Potentially Affecting GSK525762 Pharmacokinetics or affected 
by GSK525762
Rationale for Change: simplification/clarification to wording
Revised Text:
Paragraph 1:
In vitro data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of potent inducers and moderate or potent inhibitors of CYP3A4 should 
be avoided during the course of the study where possible as they may respectively 
decrease or increase exposure to GSK525762. Note: any medication (including 
antibacterials, antifungals, or antivirals) which are necessary for the health, well-being, 
and standard clinical care of patients with hematologic malignancies are exempt from the 
restrictions below.
Table 19
Drugs Potentially Affecting GSK525762 Pharmacokinetics Resulting 
in Increased or Decreased GSK525762 Exposure
Drug Class 
Agent 
Drugs that may decrease exposure to GSK525762 (CYP and/or Pgp Inducers)
Antibiotics 
Nafcillin, all rifamycin class agents (e.g., rifampicin, rifabutin, rifapentine) 
Anticonvulsants 
Phenytoin, carbamezepine, barbiturates (e.g., phenobarbital) 
Antiretrovirals 
Efavirenz, etravirine, nevirapine, tipranivir, 
Glucocorticoids (oral) 
Cortisone (>50 mg), hydrocortisone (>40 mg), prednisone or prednisolone 
(>10 mg), methylprednisolone or triamcinolone (>8 mg), betamethasone or 
dexamethasone (>1.5 mg) 
Other 
Bosentan, St. John’s Wort, modafinil 
Drugs that may increase exposure to GSK525762 (CYP3A4 Inhibitors)
Antibiotics 
Clarithromycin, telithromycin, troleandomycin
Antifungals 
Fluconazole (>150 mg daily), itraconazole, ketoconazole, , 
posaconazole,voriconazole 
Antivirals 
Amprenavir, atazanavir, boceprevir, delaviridine, fosamprenavir, indinavir, 
lopinivir,nelfinavir, ritonavir, saquinavir, telaprevir
Calcium channel blockers 
Diltiazem, verapamil
Antidepressants, anxiolytics 
nefazodone, tofisopam   
GI Agents 
Cimetidine 
Other 
Seville oranges, grapefruit or grapefruit juice and/or kumquats, pomegranate 
or pomegranate juice, pomelos, exotic citrus fruit (i.e., star fruit, bitter 
melon), grapefruit hybrids or fruit juices, or other foods and juices known to 
inhibit CYP3A4 
NOTE:  Topical or inhaled steroids are permitted.
 
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Section 8.3. Prohibited Medications
Rationale for Change: modifications to criteria based on updated risk/benefit profile
Revised Text:
8.3. Prohibited Medications
Subjects should not receive other anti-cancer therapy [including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormonal therapy 
(other than leuprolide or other GnRH agonists), surgery or tumor embolization] while on 
treatment in this study.  Other anti-cancer therapy should not be administered unless one 
of the following occurs: documented disease progression; unacceptable or unmanageable 
toxicity; subject is withdrawn from the study at the investigator’s discretion or consent is 
withdrawn; or no further clinical benefit is anticipated which requires permanent 
discontinuation of study drug.  Note, palliative radiation and/or surgical intervention may 
be permitted (for example to address pain management) and should be discussed with the 
GSK medical monitor prior to invention to determine appropriate dosing and schedule.
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsades de Pointes are PROHIBITED for 5 half-lives of the drug, or 14 
days, whichever is longer, prior to the first dose of study drug until discontinuation from 
the study drug with the exception of amiodarone which is prohibited beginning 6 
months prior to Screening through discontinuation from the study.  (However, there may
be situations when the subject is on study and Advanced Cardiac Life Support (ACLS) 
requires the use of amiodarone, which should be used as per local clinical guidelines).  
These medications include (but are not limited to) those listed in Table 20.
Table 20
Drugs with a Risk of Torsades de Pointes that are Prohibited
Amiodarone
Grepafloxacin
Anagrelide
Halofantrine
Azithromycin
Haloperidol
Chloroquine
Ibutilide
Chlorpromazine
Levomepromazine
Cilostazol
Methadone
Ciprofloxacin
Moxifloxacin
Citalopram
Papaverine
Clarithromycin
Pentamidine (IV)
Cocaine
Pimozide
Disopyramide
Procainamide
Dofetilide
Propofol
Domperidone
Quinidine
Donepezil
Sevoflurane
Dronedarone
Sotalol
Droperidol
Sulpiride
Escitalopram
Thioridazine
Flecainide
NOTE: There may be situations when the subject is on study that Advanced Cardiac Life Support (ACLS) requires the 
use of amiodarone, which should be used as per local clinical guidelines.
Data Source: CredibleMeds, 15 May 2016 (www.crediblemeds.org).
The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of the 
subject.
 
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At time of screening, if a subject is currently receiving any of the listed prohibited 
medications/substances, the medication or substance must be discontinued for a period of 
at least 5 half-lives of the drug or 14 days whichever is longer, prior to the 
administration of the first dose of study drug in order for the subject to meet study 
eligibility.
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (up to a maximum dose of 0.25 mg 
daily) and ondansetron (up to a maximum dose of 8 mg TID) are the only allowed drugs 
in this class.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
Section 8.3. Non-Drug Therapies
Rationale for Change: clarification of permitted procedures
Revised Text:
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the post-study 
follow-up visit, except as follows:.
NOTE: Palliative radiation and/or surgical intervention may be permitted (for example to 
address pain management) and should be discussed with the GSK medical monitor prior 
to invention to determine appropriate dosing and schedule.  Irradiated/resected lesions 
should not subsequently be utilized as the sole lesion(s) for response assessment 
determination. Subjects may receive palliative radiation treatment during this study.
Section 8.5. Treatment of Study Treatment Overdose
Rationale for Change: urine sample not needed
Revised Text:
Paragraph 1 bullet point 3 sub point 1:
-
This plasma or urine sample should be collected as soon as possible from the 
date of the last dose of on-study dosing.
Section 9.1.1. Female Subjects
Rationale for Change: criteria updated following conversation with GSK reproductive 
panel
Revised Text:
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
 
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ovulation methods) and withdrawal are NOT acceptable methods of contraception.  
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1% failure 
rate as stated in the product label

Note: Hormonal IUDs may only be used if the following criteria are met:

Male condoms are required AND

Subjects are informed of the potential for reduced systemic hormone levels 
from the IUD when taking GSK525762
Section 9.1.2. Male Subjects
Rationale for Change: criteria updated following conversation with GSK reproductive 
panel
Revised Text:
Paragraph 3: 
Male subjects whose partners are pregnant, or whose partnersor become pregnant during 
participation in the study, must use condoms while on studyfrom the first dose of study 
medication and for 16 weeks after stopping study medication(s).
Section 11.1.2. Part 2, Expansion Cohort
Rationale for Change: The study population for the NHL cohort in Part 2 was 
amended from a population of subjects with NHL to a population of subjects with 
cutaneous T-cell lymphoma (CTCL).  The Part 2 primary and secondary objectives along 
with the eligibility criteria were updated to include this new CTCL population, and 
removal of expansion into multiple myeloma in Part 2.  
Revised Text:
Paragraph 1:
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with MDS, 
MM, and CTCL NHL.
Bullet point 2 onwards:

For MM, efficacy is defined as a clinically meaningful response rate (defined as the 
percentage of subjects that have achieved a sCR, CR, VGPR, or PR) of 20% relative 
to a 5% response rate suggesting no activity.  These values were identified in a 
recent meta-analysis that suggested that a response rate of 20% or greater in the 
relapsed/refractory population was highly predictive of clinical success, whereas 
older agents with limited clinical activity had a negligible response rate (Kortuem, 
2014).

For cutaneous lymphomaNHLCTCL, efficacy is defined as a clinically meaningful 
response rate (defined as the percentage of subjects that have achieved a CR, or PR
lasting more than 4 months) of 430% relative to a 210% response rate suggesting no 
 
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activity.  Multiple clinical studies with active and approved agents have 
demonstrated a response rate of 30-40% in a comparable patient population (Duvic, 
2007; Piekarz, 2007; Whittaker, 2010).  Therefore, a target response rate of 40% was 
chosen to represent the response rate of an active agent.  Conversely, an agent with a 
response rate of 20% is unlikely to be developed further; this is approximately the 
response rate of placebo described in the denileukin difitox package insert (ONTAK 
package insert). Therefore, 20% was chosen to represent the activity of a futile agent. 
These response rates were consistent with multiple ongoing studies of single agent, 
targeted therapy in Phase I clinical trials for subjects with relapsed/refractory NHL.  
For this cohort, double/triple-hit lymphoma subjects will be excluded from initial 
efficacy analysis and will be evaluated separately.
Paragraph 6 onwards:
For the MDS and cutaneous lymphomaNHLCTCL disease cohorts, starting with a cohort 
of 10 subjects and allowing for a maximum sample size of 32 subjects at the RP2D with 
stopping guidelines as described in Section 3.2.4, this design will have a Type I Error () 
of 0.034 and 87% power. Futility analysis will be based on subjects who have at least one 
post-baseline disease assessment, have progressed or died, or have permanently 
discontinued from study treatment. The trial will be stopped early for futility if the 
predictive probability of success (that the response rate historical response rate) is less 
than 1%. If the true response rate is 10%, the average sample size is 20 and the 
probability of early termination (PET) for futility is 93%. If the true response rate is 30%, 
the average sample size is 31 subjects and the probability of early termination PET is 9%. 
For the MM diseaseCTCL cohort, starting with a cohort of 1310 subjects and allowing 
for a maximum sample size of 37 subjects at the RP2D with stopping guidelines as 
described in Section 3.2.4, this design will have a Type I Error () of 0.032049 and 
85.2% power. Futility analysis will be based on subjects who have at least one post-
baseline disease assessment, have progressed or died, or have permanently discontinued 
from study treatment. The trial will be stopped early for futility if the predictive 
probability of success (that the response rate historical response rate) is less than 1%. If 
the true response rate is 520%, the average sample size is 2223 and the probability of 
early termination (PET) for futility is 9192%. If the true response rate is 2040%, the 
average sample size is 36 subjects and the probability of early termination PET is 
10%11%.
Section 11.4. Interim Analysis
Rationale for Change: Stats plan revised to align with A9 changes
Revised Text:
Paragraph 2:
For each disease type in Part 2, after the initial 10 evaluableat least 10 subjects in the 
MDS or cutaneous lymphoma NHL cohorts and initial 13 evaluable subjects in the MM 
cohort have enrolledbecome evaluable (have had at least one post baseline disease 
assessment, have progressed or died, or have permanently discontinued from study 
treatment) at the selected dose regimen for the Expansion Cohort, data will be reviewed 
 
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for clinical benefit on an ongoing basis and the number of subjects with observed clinical 
benefit will be compared with the stopping guidelines provided in Section 3.2.4.  For the 
CTCL cohort, Ssubjects with CTCL in Part 1 treated at the RP2D may will be included in 
this analysis of efficacy.
Section 11.6.1. Primary Analysis
Rationale for Change: Stats plan revised to align with A9 changes
Revised Text:
Paragraph 2 onwards:
The primary aim of Part 2 is to detect demonstrate a possibly clinically meaningful 
response rate in each of the disease cohorts separately. Each disease subtype (MDS, MM,
and CTCLNHL) will be evaluated separately.
Overall Response rate is defined as 

MDS: The percentage of subjects who achieved CR, marrow CR, and or PR, as 
defined in Appendix 9. A waterfall plot of percent change from baseline in bone 
marrow blasts and peripheral blasts will be provided.

MM: The percentage of subjects who achieved sCR, CR, VGPR, or PR.

Cutaneous lymphomaNHLCTCL: ORR4 is defined as percentage of subjects who 
achieved a CR or PR lasting at least 4 months.  Responses will be defined as per 
consensus guidelines (Olsen 2011) using mSWAT criteria (Appendix 11).  All 
subjects treated at RP2D with CTCL will be counted as the denominator. The 
estimate for ORR4 along with 95% exact confidence interval will be provided. The 
percentage of subjects who achieved CR or PR. Response rates of subjects with 
double/triple-hit lymphoma will be summarised separately.
For subjects in the CTCL cohort, scans, photographs and raw flow cytometry used for 
response assessments may be requested for independent review. Further details regarding 
collection, storage, and transmission of these will be provided in the SRM
Section 11.6.2. Secondary Analysis
Rationale for Change: Stats plan revised to align with A9 changes
Revised Text:
Paragraph 3 onwards:
The duration of response is defined for the subject or subjects responders (subjects with 
CR, marrow CR, or PR for MDS cohort, or subjects with a CR or PR for cutaneous 
lymphomaNHLCTCL cohort), and sCR, CR, VGPR, or PR for MM as the time from the 
first documented evidence of response until the first documented disease progression or 
death due to any cause. Censoring rules for duration of response will be outlined in detail 
in the RAP.
 
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Time to Progression is calculated from the start of treatment until the first documented 
disease progression or death due to any cause. Censoring rules for duration of response 
will be outlined in detail in the RAP.
If sample size permits, duration of response and time to progression will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Censoring rules for duration of 
response will follow the rules for PFS outlined in detail in the RAP
OS along with 95% confidence intervals for leukemia subjects in Part 1, MDS subjects in 
Part 2, and MM and lymphoma subjects treated in Part 1 and cutaneous lymphoma  
subjects treated in Part 2, will be estimated using the Kaplan Meier method if data 
warrant.  OS analysis for AML will exclude subjects with AML subtype M3. NHL will 
be separately reported based on double/triple hit status. All cause mortality will be used 
and censoring will be performed using the date of last known contact for those who are 
alive or lost to follow-up at the time of analysis.
Section 11.9. Pharmacokinetic/Pharmacodynamic Analyses
Rationale for Change: Stats plan revised to align with A9 changes
Revised Text:
Added sentence at the end:
This analysis may be reported separately.
Section 11.12. Quality of Life Analyses
Rationale for Change: Skindex-29 added as part of A9 CTCL cohort
Revised Text:
11.12. Quality of Life Analyses
Skindex-29 inquires about how often during the previous four weeks the patient 
experienced the effect described in each item. It includes three domains: Emotional, 
Symptoms, and Functioning as well as an additional item about Treatment that is not 
scored. Details about the score derivation and analysis will be provided in the RAP.  See 
Appendix 11 for more details.  
Section 14. REFERENCES
Rationale for Change: additional references added for CTCL cohort
Revised Text:
Following references have been added/updated:
Ahern K, Gilmore ES, Poligone B. Pruritus in cutaneous T-cell lymphoma: a review. J 
Am Acad Dermatol. 2012;67(4):760-768.
 
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Duvic M, Talpur R, Ni X, Zhang C, Hazarika P, Kelly C, et al. Phase 2 trial of oral 
vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell 
lymphoma (CTCL). Blood. 2007 Jan 1;109(1):31-39.
GlaxoSmithKline Document Number 2011N113741_062011N113741_05 Version 65. 
GSK525762 Investigator's Brochure. Report Date 06-Apr-201728-Mar-2016.
Kohnken R, Wen J, Mundy-Bosse B, McConnell K, Keiter A, Grinshpun L, et al. 
Diminished microRNA-29b level is associated with BRD4-mediated activation of 
oncogenes in cutaneous T-cell lymphoma. Blood. 2017;131(7):771-781.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI,, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-612.
Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, et al. Phase IIb 
multicenter trial of vorinostat in patients with persistent, progressive, or treatment 
refractory cutaneousT-cell lymphoma. J Clin Oncol. 2007;25: 3109-3115.
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end 
points and response criteria in mycosis fungoides and Sézary syndrome: a consensus 
statement of the International Society for Cutaneous Lymphomas, the United States 
Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the 
European Organisation for Research and Treatment of Cancer. J Clin Oncol. 
2011;29(18):2598-607.
ONTAK (denileukin diftitox) Product Information. October, 2008.
Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, et al. Phase II 
multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy 
for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009;27(32):5410-5417.
Whittaker S, Hoppe R, Prince HM. How I treat mycosis fungoides and Sézary syndrome. 
Blood. 2016;127(25):3142-3153.
Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, et al. Final results 
from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-
cell lymphoma. J Clin Oncol. 2010;28(29):4485-4491.
Section 15.1. Appendix 1: Cockcroft-GaultCKD-Epi Formula
Rationale for Change: change in alignment with GSK nephrology panel
Revised Text:
The Cockcroft-GaultCKD-Epi method formula is a commonly-used surrogate marker for 
actual creatinine clearance (CrCl) and employs creatinine measurements and a subject's 
weight (kg)age and gender to predict the clearance.
Females, serum creatinine >62 μmol/L: 144 (serum creatinine 0.0113/0.7)−1.209 0.993age
 
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Females, serum creatinine ≤62 μmol/L: 144 (serum creatinine 0.0113/0.7)−0.329 0.993age
Males, serum creatinine >80 μmol/L: 141 (serum creatinine 0.0113/0.9)−1.209 0.993age
Males, serum creatinine ≤80 μmol/L: 141 (serum creatinine 0.0113/0.9)−0.411 0.993age
[Levey, 2009]
If the subject is obese (>30% over ideal body weight), use ideal body weight in 
calculation of estimate CrCl.
If the subject is below ideal body weight, use actual body weight in calculation of 
estimate CrCl.
Cockcroft-Gault Formula for serum creatinine in mmol/L
CrCl (mL/min)=
Q X (140-age [years]) X actual body weight (kg)a
48816 X serum creatinine (mmol/L)
Q=0.85 for females
Q=1.0 for males
OR
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Male subjects:
50.0 kg + (2.3 kg X each inch over 5 feet)
or
50.0 kg + (0.906 kg X each cm over 152.4 cm)
Female subjects:
45.5 kg + (2.3 kg X each inch over 5 feet)
or
45.5 kg + (0.906 kg X each cm over 152.4 cm) 4 cm)
Cockcroft-Gault Formula for serum creatinine in mg/dL
For example:
For a male subject with actual body weight = 90.0 kg and height = 68 inches, the 
calculation would be as follows:
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg
This subject’s actual body weight is >30% over ideal body weight.  In this case, the 
subject’s ideal body weight of 68.4 kg should be used in calculating estimated creatinine 
clearance.
 
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Section 15.3 Appendix 3: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria
Rationale for Change: updated as per latest criteria
Revised Text:
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
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 ANY Liver Stopping Event
Actions
Immediately discontinue study treatment 
Report the event to GSK within 24 hours
Complete the liver event CRF and complete SAE data collection tool if the event also meets the criteria 
for an SAE2
Perform liver event follow up assessments 
Monitor the participant until liver chemistriesresolve, stabilize, or return to within baseline (see 
MONITORING below)
Do not restart/rechallenge participant with study treatment unless allowed per protocol and GSK 
Medical Governance approval is granted
If restart/rechallenge not allowed per protocol or not granted, permanently discontinue study 
treatment and may continue participant in the study for any protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:
 
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Repeat liver chemistries(include ALT, AST, alkaline phosphatase, bilirubin) and perform liver event 
follow up assessments within 24 hrs
Monitor participants twice weekly until liver chemistries resolve, stabilize or return to within baseline
A specialist or hepatology consultation is recommended
For All other criteria:
Repeat liver chemistries(include ALT, AST, alkaline phosphatase, bilirubin) and perform liver event 
follow up assessments within 24-72 hrs 
Monitor participants weekly until liver chemistries resolve, stabilize or return to within baseline
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 
2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if 
INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the 
threshold value stated will not apply to participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal, 2005].
6.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments.)  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM. 
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.
Liver chemistry stopping criteria
Liver chemistry threshold stopping criteria have been designed to assure subject 
safety and to evaluate liver event etiology during administration of study treatment(s) 
and the follow-up period.  Study treatment(s) will be stopped if any of the following 
 
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liver chemistry stopping criteria is/are met.  ALT 3xULN and bilirubin 2xULN 
(>35% direct bilirubin) (or ALT3xULN and INR>1.5, if INR measured)
NOTE:  Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury).

ALT 5xULN.

ALT 3xULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or 
eosinophilia).

ALT 3xULN persists for 4 weeks.

ALT 3xULN and cannot be monitored weekly for 4 weeks.
Subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit 
hepatitis symptoms or rash, can continue study treatment as long as they can be 
monitored weekly for 4 weeks.  See following section for details on weekly follow-up 
procedures for these subjects.
Liver Chemistry Follow-up Procedures
Refer to the diagram in Figure 7 for a visual presentation of the procedures listed below.
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined above:

Immediately and permanently withdraw the subject from study treatment 

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event eCRFs.  If the event also meets the criteria of an SAE (see 
Section 6.7.2 of the protocol), the SAE data collection tool will be completed 
separately with the relevant details

Upon completion of the safety follow-up permanently withdraw the subject from the 
study and do not rechallenge with study treatment(s).
Safety Follow-Up Procedures for subjects with ALT 3 times ULN:

Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase 
[AST], alkaline phosphatase [ALP], and bilirubin) resolve, stabilize or return to 
within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3 times ULN and bilirubin 2 
times ULN (or ALT 3 times ULN and INR >1.5):
 
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
This event is considered an SAE (see Section 6.7.2).  Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, ALP, bilirubin) 
resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3 times ULN, every attempt must be made to 
also obtain the following:

Viral hepatitis serology including:

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.

Blood sample for pharmacokinetic (PK) analysis, obtained within 2 days of last dose.  
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 eCRF.  If the date or time of the 
last dose is unclear, provide the subject’s best approximation.  If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are in the SPM.

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 hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE eCRF.

Record use of concomitant medications such as acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the Concomitant 
Medications eCRF page.

Record alcohol use on the Liver Event CRF page.
 
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The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

Liver Imaging and/or Liver Biopsy CRF pages are also to be completed if these tests 
are performed.  Serum acetaminophen adduct HPLC assay (quantifies potential 
acetaminophen contribution to liver injury in subjects with definite or likely 
acetaminophen use in the preceding week [James, 2009]).

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed, it can be 
replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Subject can continue study treatment if liver chemistries (ALT, AST, ALP, bilirubin) 
can be monitored weekly for up to 4 weeks

If at any point these subjects meet the liver chemistry stopping criteria, immediately 
withdraw study treatment, perform additional testing and continue safety follow-up 
until liver chemistries resolve, stabilize or return to baseline values

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.
Refer to Figure 6 for the algorithm of liver chemistry monitoring, stopping and follow up 
criteria.
 
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Figure 6
Liver Safety Algorithms
Liver Safety Drug Restart Guidelines
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
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 participant
If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then participant must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments
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.  
 
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Risk factors for a fatal drug rechallenge outcome include:

Hypersensitivity (Andrade, 2009) with initial liver injury (e.g. fever, rash, 
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

participant currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges (Papay, 2009; Hunt, 2010)

evidence of drug-related preclinical liability (e.g. reactive metabolites;  
mitochondrial impairment (Hunt, 2010)
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a participant 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 
participant who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available.  

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.   

If the rechallenge is approved by GSK Medical Governance in writing, the 
participant 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 participant 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.

Participants 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, participant meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued. 
 
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
Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 6.7. 
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
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).

Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has an 
identified genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate), the presence of the marker should be excluded. If study 
treatment-related liver injury cannot be excluded, the guidance on rechallenge in 
Section 7.7 will apply.

There is no evidence of alcoholic hepatitis.

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 
participant 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 participant 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.

Participants 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, participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.
 
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
Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the participant’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 6.7.
References:

1Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.

2Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 

3Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or 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 in one 
month of initial injury.  However, some drugs seldom result in recurrent liver injury or 
fatality.  Risk factors for a fatal drug restart/rechallenge outcome include: 
hypersensitivity1 with initial liver injury (e.g., fever, rash, eosinophilia), jaundice or 
bilirubin>2xULN or INR>1.5 suggesting severe liver injury, prior IP-related severe or 
fatal drug restart/rechallenge [Papay, 2009; Hunt, 2010] or evidence of drug-related 
preclinical liability / mitochondrial impairment [Hunt, 2010].
Drug Restart/Rechallenge Process (also see Figure 7)
Principal Investigator (PI) requests consideration of drug restart for a subject receiving 
compelling benefit from a critical or life-saving drug, who exhibits liver chemistry 
elevation meeting subject stopping criteria, with no alternative treatment.
GSK Medical Monitor & Clinical Safety Physician to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 17).
 
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Table 17
Checklist for drug restart/rechallenge for critical medicine
Checklist for drug restart/rechallenge for critical medicine (Following drug-induced liver 
injury, drug rechallenge is associated with 13% mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:

Initial liver injury event included:
1. fever, rash, eosinophilia, or hypersensitivity
2. or bilirubin2xULN (direct bilirubin >35% of total)

Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5

Severe or fatal restart/rechallenge has earlier been observed with IP 
If yes, please provide brief explanation:

IP associated with known preclinical hepatic liability/ injury
If GSK provides written approval for restart/rechallenge following the above review, the 
PI must ensure the following:

The PI is to obtain IRB/ EC of drug reinitiation, as required.

PI must discuss the possible benefits and risks of drug reinitiation with the subject.

The subject must sign informed consent with a clear description of possible benefits 
and risks of drug administration, including recurrent liver injury or death.  Consent 
specifically for the IP restart must be recorded in the study chart.

The drug must be reinitiated at GSK approved dose(s).

Subjects approved by GSK for restart of IP must return to the clinic twice a week for 
liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol.  If protocol defined stopping 
criteria for liver chemistry elevations are met, study drug must be stopped.

The IRB/ EC is to be informed of the subject’s outcome, as required.

GSK is to be notified of any adverse events, as per Section 6.7 of the protocol.
 
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Figure 7
Process for Drug Restart After Possible Drug-induced Liver Injury
Section 15.7. Appendix 7: Response Criteria for Non-Hodgkin’s Lymphoma (Part 1)
Rationale for Change: addition of CTCL specific criteria
Revised Text:
The section heading changed as mentioned above
Section 15.10. Appendix 10: Staging and Response Criteria for CTCL (mSWAT 
method)
Rationale for Change: addition of staging and response criteria for CTCL
Revised Text:
15.10. Appendix 10: Staging and Response Criteria for CTCL (mSWAT method)
[Olsen, 2011]
15.10.1. Staging of Subjects with CTCL
Table 17. Modified ISCL/EORTC Revisions to the tumor-node-metastasis-blood 
(TNMB) Classification of MF/SS
 
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TNMB 
Stages
Description of TNMB
Skin*
T1 Limited patches, papules, and/or plaques covering < 10% of the skin 
surface; may further stratify into T1a (patch only) v T1b (plaque ± patch)
T2 Patches, papules, or plaques covering ≥ 10% of the skin surface; may 
further stratify into T2a (patch only) v T2b (plaque ± patch)
T3 One or more tumors (≥ 1 cm diameter)
T4 Confluence of erythema covering ≥ 80% body surface area
Node†
N0 No clinically abnormal lymph nodes; biopsy not required
N1 Clinically abnormal lymph nodes; histopathology Dutch grade 1 or National 
Cancer Institute (NCI) LN0-2
N1a
Clone negative
N1b
Clone positive
N2 Clinically abnormal lymph nodes; histopathology Dutch Grade 2 or NCI 
LN3
N2a
Clone negative
N2b
Clone positive
N3 Clinically abnormal lymph nodes; histopathology Dutch grade 3-4 or NCI 
LN4; clone positive or negative
Nx Clinically abnormal lymph nodes without histologic confirmation or 
inability to fully characterize the histologic subcategories
Visceral
M0 No visceral organ involvement
 
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TNMB 
Stages
Description of TNMB
M1 Visceral involvement (must have pathology confirmation and organ 
involved should be specified)
Blood
B0 Absence of significant blood involvement: ≤5% of peripheral blood 
lymphocytes are atypical (Sézary) cells
B0a
Clone negative
B0b
Clone positive
B1 Low blood tumor burden: > 5% of peripheral blood lymphocytes are 
atypical (Sézary) cells but does not meet the criteria of B2
B1a
Clone negative
B1b
Clone positive
B2
High blood tumor burden: ≥ 1,000/μL Sézary cells with positive clone‡; 
one of the following can be substituted for Sézary cells: CD4/CD8 ≥ 10, 
CD4+CD7- cells ≥ 40% or CD4+CD26- cells ≥ 30%
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, 
European Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; 
SS, Sézary syndrome; NCI, National Cancer Institute.
*Patch = any size lesion without induration or significant elevation above the surrounding 
uninvolved skin: pokiloderma may be present. Plaque = any size lesion that is elevated or 
indurated: crusting or poikiloderma may be present. Tumor = any solid or nodular lesion 
≥ 1 cm in diameter with evidence of deep infiltration in the skin and/or vertical growth.
†Lymph node classification has been modified from 2007 ISCL/EORTC consensus 
revisions to include central nodes. Lymph nodes are qualified as abnormal if > 1.5 cm in 
diameter.
‡The clone in the blood should match that of the skin. The relevance of an isolated clone 
in the blood or a clone in the blood that does not match the clone in the skin remains to be 
determined.
 
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Table 18. Modified ISCL/EORTC Revisions to the Staging of MF/SS
Stage
T
N
M
B
IA
1
0
0
0, 1
IB
2
0
0
0, 1
IIA
1-2
1, 2, X
0
0, 1
IIB
3
0-2, X
0
0, 1
IIIA
4
0-2, X
0
0
IIIB
4
0-2, X
0
1
IVA1
1-4
0-2, X
0
2
IVA2
1-4
3
0
0-2
IVB
1-4
0-3, X
1
0-2
Abbreviations: ISCL, International Society for Cutaneous Lymphomas; EORTC, 
European Organisation for Research and Treatment of Cancer; MF, mycosis fungoides; 
SS, Sézary syndrome; X, clinically abnormal lymph nodes without histologic 
confirmation or inability to fully characterize histologic subcategories.
15.10.2. Response Assessment of Subjects with CTCL
Refer to Table 20, Table 21, Table 23, Table 24, and Table 25 for definitions of response 
in each category.  All subjects achieving CR or PR should be confirmed by repeat 
assessment no sooner than 4 weeks after the prior assessment demonstrating response.
Table 19
Global Response Score
Global 
Score*
Definition
Skin
Nodes
Blood
Viscera
CR
Complete disappearance of 
all clinical evidence of 
disease
CR
All categories have CR/NI
PR
Regression of measurable 
disease
CR
All categories do not have a CR/NI and no 
category has a PD
PR
No category has a PD and if any category 
involved at baseline, at least one has a CR 
or PR
 
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Global 
Score*
Definition
Skin
Nodes
Blood
Viscera
SD
Failure to attain CR, PR, or 
PD representative of all 
disease
PR
No category has a PD and if any category 
involved at baseline, no CR or PR in any
SD
CR/NI, PR, SD in any category and no 
category has a PD
PD
Progressive disease
PD in any category
Relapse
Recurrence disease in prior 
CR
Relapse in any category
Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, 
progressive disease; SD, stable disease.
Refer to Table 22 for definition of mSWAT
Table 20
Response in Skin
Response
Definition
Complete 
response
100% clearance of skin lesions*
Partial response 50%-99% clearance of skin disease from baseline without new tumors 
(T3) in patients with T1, T2 or T4 only skin disease
Stable disease
< 25% increase to < 50% clearance in skin disease from baseline without 
new tumors (T3) in patients with T1, T2, or T4 only skin disease
Progressive 
disease†
≥ 25% increase in skin disease from baseline or
New tumors (T3) in patients with T1, T2 or T4 only skin disease or
Loss of response: in those with complete or partial response, increase of 
skin score of greater than the sum of nadir plus 50% baseline score
Relapse
Any disease recurrence in those with complete response
NOTE. Based on modified Severity Weighted Assessment Tool score.
*A biopsy of normal appearing skin is unnecessary to assign a complete response. 
However, a skin biopsy should be performed of a representative area of the skin if there 
 
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is any question of residual disease (persistent erythema or pigmentary change) where 
otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of mycosis fungoides/Sézary syndrome (see histologic criteria for early 
mycosis fungoides7), the response should be considered a partial response only.
†Whichever criterion occurs first.
Table 21
Modified Severity Weighted Assessment Tool (mSWAT)
Body Region
% BSA in Body 
Region
Assessment of Involvement in 
Patient's Skin
Patch*
Plaque†
Tumor‡
Head
7
Neck
2
Anterior trunk
13
Arms
8
Forearms
6
Hands
5
Posterior trunk
13
Buttocks
5
Thighs
19
Legs
14
Feet
7
Groin
1
Subtotal of lesion BSA
Weighting factor
×1
×2
×4
Subtotal lesion BSA × 
weighting factor
 
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NOTE. mSWAT score equals summation of each column line.
Abbreviations: BSA, body surface area; mSWAT, modified Severity Weighted 
Assessment Tool.
*Any size lesion without induration or significant elevation above the surrounding 
uninvolved skin; poikiloderma may be present.
†Any size lesion that is elevated or indurated; crusting, ulceration, or poikiloderma may 
be present.
‡Any solid or nodular lesion ≥ 1 cm in diameter with evidence of deep infiltration in the 
skin and/or vertical growth.
Table 22
Response in Lymph Nodes
Response
Definition
CR
All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter by 
method used to assess lymph nodes at baseline or biopsy negative for 
lymphoma; in addition, lymph nodes that were N3 classification and ≤1.5 cm in 
their long axis and > 1 cm in their short axis at baseline, must now be ≤1 cm in 
their short axis or biopsy negative for lymphoma
PR
Cumulative reduction ≥ 50% of the SPD of each abnormal lymph node at 
baseline and no new lymph node > 1.5 cm in the diameter of the long axis or > 
1.0 cm in the diameter of the short axis if the long axis is 1-1.5 cm diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD†
≥ 50% increase in SPD from baseline of lymph nodes or
Any new node > 1.5 cm in the long axis or > 1 cm in the short axis if 1-1.5 cm 
in the long axis that is proven to be N3 histologically or
Loss of response: > 50% increase from nadir in SPD of lymph nodes in those 
with PR
Relapse
Any new lymph node > 1.5 cm in the long axis in those with CR proven to be 
N3 histologically
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum 
linear dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable 
disease; PD, progressive disease.
*Peripheral and central lymph nodes.
 
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†Whichever criterion occurs first.
Table 23
Response in Viscera
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be 
enlarged on physical exam and should be considered normal by imaging; no 
nodules should be present on imaging of liver or spleen; any post treatment 
mass must be determined by biopsy to be negative for lymphoma
PR
≥ 50% regression in any splenic or liver nodules, or in measureable disease 
(SPD) in any organs abnormal at baseline; no increase in size of liver or spleen 
and no new sites of involvement
SD
Fails to attain the criteria for CR, PR, or PD
PD*
> 50% increase in size (SPD) of any organs involved at baseline or
New organ involvement or
Loss of response: > 50% increase from nadir in the size (SPD) of any previous 
organ involvement in those with PR
Relapse
New organ involvement in those with CR
Abbreviations: CR, complete response; PR, partial response; SPD, sum of the maximum 
linear dimension (major axis) × longest perpendicular dimension (minor axis); SD, stable 
disease; PD, progressive disease.
*Whichever criterion occurs first.
Table 24
Response in Blood
Response
Definition
CR†
B0
PR‡
> 50% decrease in quantitative measurements of blood tumor burden from 
baseline in those with high tumor burden at baseline (B2)
SD
Fails to attain criteria for CR, PR, or PD
PD§
B0 to B2 or
> 50% increase from baseline and at least 5,000 neoplastic cells/μL or
 
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Response
Definition
Loss of response: in those with PR who were originally B2 at baseline, > 50% 
increase from nadir and at least 5,000 neoplastic cells/μL
Relapse
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, 
progressive disease.
*As determined by absolute numbers of neoplastic cells/μL.
†If a bone marrow biopsy was performed at baseline and determined to unequivocally be 
indicative of lymphomatous involvement, then to confirm a global CR where blood 
assessment now meets criteria for B0, a repeat bone marrow biopsy must show no 
residual disease or the response should be considered a PR only.
‡There is no PR in those with B1 disease at baseline as the difference within the range of 
neoplastic cells that define B1 is not considered significant and should not affect 
determination of global objective response.
§Whichever occurs first.
Section 15.11 Appendix 11: Patient Reported Outcomes Assessments for CTCL 
(Skindex-29)
15.11.1 US English Skindex-29
Note: please refer to the SPM for additional translations of Skindex-29
 
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