Clinical trial NCT03150056
Conditions: Solid Tumours
Keywords: Abiraterone Castrate-resistant prostate cancer Androgen receptor targeted therapy RP2D Enzalutamide GSK525762
Sponsor: GlaxoSmithKline
Start date: 2017-07-18; Completion date: 2021-06-22
Enrollment: 73 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to evaluate the combination of GSK525762 with other agents that have been shown to be effective in the treatment of CRPC or metastatic (m)CRPC. This study is designed to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles of GSK525762 in combination with either abiraterone (Arm A) or enzalutamide (Arm B).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: GSK525762 intervention 2: Abiraterone intervention 3: Enzalutamide intervention 4: Prednisone
Intervention descriptions: intervention 1: GSK525762 will be administered. intervention 2: Abiraterone will be administered. intervention 3: Enzalutamide will be administered. intervention 4: Prednisone will be administered as a concomitant medication in combination with abiraterone

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase IB open-label, dose escalation and expansion study to
investigate the safety, pharmacokinetics, pharmacodynamics and
clinical activity of GSK525762 in combination with androgen
deprivation therapy and other agents in subjects with castrate
resistant prostate cancer (CRPC)
Compound Number:
GSK525762
Development Phase:
Ib
Effective Date:
06-MAY-2020
Protocol Amendment Number:  4
Author (s):
 
 
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N238310_00
2016-OCT-13
Original
2015N238310_01
2017-FEB-01
Amendment No. 1
Amendment 1 applies to all global sites. The following changes were based on review 
and comments from the FDA during review: 

Clarifications to Exclusion #6 which clarified that subjects with recent clinical 
significant hemorrhage would be excluded from the trial

Addition to Exclusion criteria for exclusionary medications

Addition of Table to Section 6.3 to clarify what the dose reductions of GSK525762 
should be as instructed by the study or investigator staff

Addition of medications to both the prohibited and cautionary lists in Section 6.11.2.1 
and Section 6.11.2.3

Adjustments to Dose Adjustment/Stopping Safety Criteria in Appendix 12.2 
regarding Grade 3 and Grade 4 Thrombocytopenia. 
In addition to the requests of the FDA, additional changes which were included were: 

Added new information regarding monotherapy CRPC study

Clarification to Inclusion #12 for time of use

Update and revision to GSK525762 dose wording in Section 4.6.2

Clarifications in when formulations of GSK525762 listed in Section 6.1 will be 
utilized during the trial

Clarification to planned dose adjustment Section 6.3 to clarify impact on combination 
dosing during dose interruption of GSK525762

Revision of male subject lifestyle changes, addition of Pregnancy wording with 
Section 7.3.7 and addition of Appendix 12 to clarify allowed contraception

Update of the cautionary and prohibited medication tables. 

Clarification to the Time and Events table to clarify the possible lead-in dosing of 
either abiraterone acetate or enzalutamide, adjustment to Echocardiogram schedule
and addition of EORTC-QLQ-PR25 to Dose Expansion due to erroneous absence in 
prior protocol 

Adjustment of Time and Events table to clarify timing of assessments post week 49 
and clarification of required laboratory testing

Addition of limited laboratory assessments every 2 week visit at Week 7 and 11  

Removal of CTC-ARV at screening, movement of the assessment of CTC-
enumeration and exploratory whole blood analysis to occur in conjunction with scan 
assessments

Removal of the allowance for disease assessments every 16 weeks post Week 52

Addition of Factor VII monitoring in both dose escalation and dose expansion (at 
Screening, W3D1, Week 5, Week 9 and every 4 weeks thereafter and reflex testing if 
PT or INR are ≥1.5XULN, or in case of a bleeding event) and addition of laboratory 
values required prior to performing the post-dose biopsy.

Revision of Tumor Biopsy wording to specify time required on GSK525762 prior to 


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on-treatment biopsy. Added platelet and coagulation requirements prior to biopsy. 
Revised section to also include restrictions on planned surgical procedures

Clarification of analysis populations

Addition of Appendix 13 to provide specifics for Amendment changes.

Other minor clarifications were also added
2015N238310_02
2018-FEB-08
Amendment No. 2
Amendment 2 applies to France only due to requests from their country agency, 
Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) and the 
central Ethics Committee, Comité de Protection des Personnes (CPP) Sud-Est III. The 
changes from Amendment 1 include: 

Revision of Inclusion Criteria #6 in Section 1 and Section 5 to clarify patient 
population

Addition of statement in Section 1 and Section 4.1.1 regarding the targeted number of 
subjects to be enrolled in France. 

Clarification to Section 4.2.2.1 to require regulatory approval if above 120 mg dose of 
GSK525762

Addition of statement to remove allowance of restart and/or rechallenge when liver or 
cardiac stopping criteria is met as per Section 5.4.1.1 and Section 5.4.2. Applicable 
changes also made in referenced Appendix 12.2 and Appendix 12.7. 

Update to toxicity management guidelines for QTcF and liver event monitoring in 
Appendix 2
2015N238310_03
2018-JUL-12
Amendment No. 3
Amendment 3 applies to all global sites. The following changes were based on review 
and comments from global agencies and include additions revisions noted by study team 
from Amendment 1: 

Update to Author list, sponsor signatory, and sponsor contact list

Clarification of L2 line of therapy definition

Addition of disease control rate as secondary endpoint in multiple locations including 
the synopsis and Section 3, Section 4.1, Section 9.1.2., and Section 9.4.4., of the 
protocol

Modification of PSA progression definition in multiple locations including the 
synopsis and Section 3, Section 4.1, Section 7.6.1., and Section 9.4.4. of the protocol

Update to the dose futility utility wording in multiple locations to correct initial 
wording 

Modified wording where necessary to clarify what data would be used to calculate 
whether a cohort would need to be closed

In multiple locations in language for both Arm A and Arm B, added or modified 
language to enhance flexibility for projected dose levels and/or schedules. Updated 
Figures of Arm A and Arm B to reflect these changes. Addition of wording to clarify 
that subjects would not be randomized by prior line of therapy if one dose level 
explored in dose expansion

Clarifications to the Inclusion/Exclusion criteria including: clarification of qualifying 
screening biopsy collection time period; when prior treatment could occur; removal 
of requirement for prior abiraterone or enzalutamide within 30 days prior to initiation 
of study treatment; clarification for prior chemotherapy treatment (global inclusion of 


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Amendment #2 wording); revision of baseline QTcF interval per safety panel; global 
addition of aspirin dose per local standards; clarification of Troponin entry criteria; 
contraception language update; revision of seizure related criteria; and removal of 
prohibited medications with risk of Torsades de pointes with update to QTc language

Revisions to various locations in Section 4.6.3 and Section 4.6.4 to update to current 
language in most recent Investigator’s Brochure

Modifications to QTc stopping and management wording in Section 5.4.2. and 
Section 12.2 to reflect updated recommendations of GSK safety panel

Update to the definition of study completion (Section 5.5)

Modification to description of 20 mg GSK525762 tablet and addition of 500 mg 
tablet of abiraterone acetate due to change in available formulation from sponsor
(Section 6.1)

Addition of language to Section 6.3. to clarify the lowest minimum allowed dose 
reduction in Arm B 

Removal of Section 6.3.1. for consistency with IB

Modified Section 6.11.2.1. to clarify aspirin level and to remove prohibited 
medications with significant risk of Torsades de pointes and moved to cautionary 
section. Removed Table 7 and Table 8 and refer all readers to internet link for most 
current list

Revisions to Section 7.1 including: revision of triplicate ECGs to only during 
Screening or abnormal findings and single ECG or other timepoints; removal of 
ECHO/MUGA at Week 1 Day 1; extended window for on-treatment tumor biopsy; 
removal of CTC-ARV testing from Week 5, 9 and End of Treatment; addition of 
language to footnote sections including modification of PK language (also added to 
Section 7.2.2.) and addition of dosing requirements for on-treatment biopsy; and 
addition of Week 6 sample collection per GSK safety panel recommendations

Increase of Screening window from 14 days to 28 days, with limitation that screening 
laboratory results must be within 72 hours of first study treatment

Revision to Section 7.3.4.1. regarding ECGs to ensure consistency with changes in 
Section 7.1 and per GSK safety panel

Minor clarifications to Clinical Laboratory Test table

Revision to Section 7.5.1. to ensure consistency with changes in Section 7.1 for on 
treatment tumor biopsy

Removal of language in Section 7.7.3. related to planned CTC analyses

Modification to Section 9.3.1. Analysis Populations

For Appendix 8, Section 12.8.2, removed bullet h. as no current protocol specific 
SAEs for GSK525762 per IB 

Update to Appendix 12, Section 12.12.1 due to updates to the standard GSK text for 
contraceptive guidance and pregnancy information collection

Other minor clarifications/revisions were included
2015N238310_04
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Amendment No. 4
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.


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Changes to the protocol include:

Enrolment into the study is now closed

Removes the requirement for specific protocol assessments and survival follow-
up (Section 7.1 – Time and Events Tables)

Update to the GSK authors, GSK signatory and GSK medical monitor


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary 
Medical 
Monitor 
 
 MD
GSK R&D, Gunnels 
Wood, Stevenage, Herts, 
SG1 2NY 
Secondary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
UP4410
Collegeville, PA 19426, 
USA
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.  
Regulatory Agency Identifying Number(s): Investigational New Drug (IND) number 
IND132433, EudraCT number 2016-003416-13
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204697
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204697......................................................14
2.
INTRODUCTION....................................................................................................30
2.1.
Study Rationale ..........................................................................................30
2.2.
Brief Background ........................................................................................30
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................33
4.
STUDY DESIGN ....................................................................................................34
4.1.
Overall Design ............................................................................................34
4.1.1.
Type and Number of Subjects......................................................39
4.2.
Dose Escalation..........................................................................................39
4.2.1.
Treatments Arms and Duration....................................................39
4.2.2.
Dose Escalation...........................................................................40
4.2.2.1.
Planned Dose Levels..................................................40
4.2.2.2.
Dose-Limiting Toxicity ................................................41
4.2.2.3.
Non-Limiting Toxicities ...............................................42
4.2.2.4.
Maximum Dose Increment..........................................43
4.2.2.5.
Dose Escalation Decisions .........................................43
4.2.2.6.
Alternative Dosing Schedules.....................................44
4.3.
Decision to Proceed to Expansion phase....................................................45
4.4.
Expansion Cohorts .....................................................................................45
4.4.1.
Type and Number of Subjects......................................................45
4.4.2.
Dose Selection ............................................................................46
4.4.3.
Statistical Design .........................................................................46
4.5.
Design Justification.....................................................................................46
4.6.
Dose Justification........................................................................................47
4.6.1.
Drug-Drug Interactions.................................................................47
4.6.2.
Starting Doses .............................................................................48
4.6.3.
Overlapping Toxicities..................................................................49
4.6.3.1.
Predicted Overlapping Toxicities ................................50
4.6.3.1.1.
Gastrointestinal Safety Findings .............50
4.6.3.1.2.
Hepatic Safety Findings..........................50
4.6.3.1.3.
Hematopoietic Safety Findings ...............51
4.6.3.1.4.
General Toxicity Findings .......................52
4.6.4.
Predicted Single-Agent Toxicities ................................................52
4.6.4.1.
Cardiovascular Safety Findings ..................................52
4.6.4.2.
General toxicities........................................................53
4.6.4.3.
Seizure.......................................................................53
4.6.4.4.
Posterior Reversible Encephalopathy 
Syndrome (PRES)......................................................53
4.6.5.
Risk Assessment .........................................................................54
4.6.6.
Benefit Assessment.....................................................................54
4.6.7.
Overall Benefit: Risk Conclusion..................................................54
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............55
5.1.
Inclusion Criteria.........................................................................................55
5.2.
Exclusion Criteria........................................................................................58


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5.3.
Screening/Baseline/Run-in Failures............................................................60
5.4.
Withdrawal/Stopping Criteria.......................................................................61
5.4.1.
Liver Chemistry Stopping Criteria ................................................62
5.4.1.1.
Study Treatment Restart or Rechallenge....................64
5.4.2.
QTc Stopping Criteria ..................................................................65
5.4.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria..........65
5.4.4.
Other Stopping Criteria ................................................................65
5.5.
Subject and Study Completion....................................................................66
6.
STUDY TREATMENT ............................................................................................66
6.1.
Investigational Product and Other Study Treatment....................................66
6.2.
Treatment Assignment................................................................................67
6.3.
Planned Dose Adjustments.........................................................................68
6.4.
Blinding.......................................................................................................69
6.5.
Packaging and Labeling..............................................................................69
6.6.
Preparation/Handling/Storage/Accountability..............................................69
6.7.
Compliance with Study Treatment Administration.......................................70
6.8.
Treatment of Study Treatment Overdose....................................................70
6.9.
Treatment after the End of the Study ..........................................................71
6.10.
Lifestyle and/or Dietary Restrictions............................................................71
6.10.1.
Dietary Restrictions......................................................................71
6.11.
Concomitant Medications and Non-Drug Therapies....................................72
6.11.1.
Permitted Medications and Non-Drug Therapies..........................72
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................72
6.11.2.1.
Prohibited Medications ...............................................72
6.11.2.2.
Prohibited Non-Drug Therapies ..................................73
6.11.2.3.
Cautionary Medications ..............................................73
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................74
7.1.
Time and Events Table...............................................................................76
7.2.
Screening and Critical Baseline Assessments ............................................84
7.2.1.
Critical Baseline Assessments.....................................................85
7.2.2.
Visit Windows ..............................................................................85
7.3.
Safety .........................................................................................................86
7.3.1.
Physical Exams ...........................................................................86
7.3.2.
ECOG Performance Status..........................................................87
7.3.3.
Vital Signs....................................................................................87
7.3.4.
Cardiac Safety .............................................................................87
7.3.4.1.
Electrocardiograms.....................................................87
7.3.4.2.
Echocardiogram or Multigated Acquisition 
Scan...........................................................................87
7.3.5.
Clinical Safety Laboratory Assessments ......................................88
7.3.6.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........89
7.3.6.1.
Time period and Frequency for collecting AE 
and SAE information...................................................90
7.3.6.2.
Method of Detecting AEs and SAEs ...........................90
7.3.6.3.
Follow-up of AEs and SAEs........................................90
7.3.6.4.
Cardiovascular and Death Events ..............................91
7.3.6.5.
Other sentinel events..................................................91
7.3.6.6.
Regulatory Reporting Requirements for SAEs............91
7.3.7.
Pregnancy ...................................................................................92
7.4.
Pharmacokinetics .......................................................................................92


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7.5.
Pharmacodynamics ....................................................................................92
7.5.1.
Tumor Biopsy Collection/Surgical Procedures .............................93
7.6.
Evaluation of Anti-Cancer Activity ...............................................................93
7.6.1.
Disease Progression Endpoint.....................................................94
7.6.2.
PSA Response per PCWG3 Criteria............................................94
7.6.3.
Radiographic Response per PCWG3 Criteria ..............................95
7.6.4.
Circulating Tumor Cells (CTC) per PCWG3 Criteria.....................95
7.7.
Translational Research...............................................................................95
7.7.1.
Tumor Biomarker Analysis...........................................................96
7.7.2.
Tumor Tissue...............................................................................96
7.7.3.
Circulating Tumor Cells................................................................97
7.7.3.1.
CTC Conversion Rate ................................................97
7.7.4.
Circulating-Free Tumor DNA/RNA and Soluble Markers..............97
7.8.
Genetics .....................................................................................................98
7.9.
Value Evidence and Outcomes...................................................................98
7.9.1.
PRO-CTCAE ...............................................................................98
7.9.2.
EORTC-QLQ-C30, EORTC-QLQ-PR25 & Brief Pain 
Inventory – Short Form (BPI-SF) .................................................98
8.
DATA MANAGEMENT ...........................................................................................98
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................99
9.1.
Hypotheses.................................................................................................99
9.1.1.
Dose escalation ...........................................................................99
9.1.2.
Dose expansion cohorts ..............................................................99
9.2.
Sample Size Considerations.....................................................................101
9.2.1.
Sample Size Assumptions .........................................................101
9.2.2.
Sample Size Sensitivity..............................................................101
9.2.3.
Sample Size Re-estimation or Adjustment.................................101
9.3.
Data Analysis Considerations ...................................................................101
9.3.1.
Analysis Populations..................................................................101
9.3.2.
Interim Analysis .........................................................................102
9.3.2.1.
Dose Escalation and Safety Analyses ......................102
9.3.2.2.
Dose expansion Cohorts ..........................................103
9.3.2.2.1.
Efficacy Analyses .................................103
9.3.3.
Final Analysis ............................................................................103
9.4.
Key Elements of Analysis Plan .................................................................103
9.4.1.
Safety Analyses.........................................................................103
9.4.1.1.
Extent of Exposure ...................................................104
9.4.1.2.
Adverse Events ........................................................104
9.4.1.3.
Clinical Laboratory Evaluations ................................104
9.4.1.4.
Other Safety Measures.............................................104
9.4.2.
Pharmacokinetic Analyses.........................................................104
9.4.2.1.
Pharmacokinetic Parameters....................................104
9.4.2.2.
Statistical Analysis of Pharmacokinetic Data ............105
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses...........................105
9.4.4.
Efficacy Analyses.......................................................................106
9.4.5.
Other Analyses ..........................................................................108
9.4.5.1.
Translational Research Analyses .............................108
9.4.5.2.
Novel Biomarker(s) Analyses ...................................108
9.4.5.3.
Pharmacogenetic Analyses ......................................108
9.4.6.
Simulations and Design Operating Characteristics ....................108


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9.4.6.1.
Simulation Description..............................................108
9.4.6.2.
Software Details .......................................................109
9.4.6.3.
Trial Sample Size and Simulation Scenarios ............109
9.4.6.4.
Operation Characteristics .........................................110
9.4.6.5.
Stopping Early..........................................................111
9.4.6.6.
Mean Proportion of advancing to Phase 2................111
10. STUDY GOVERNANCE CONSIDERATIONS......................................................111
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........111
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................111
10.3.
Quality Control (Study Monitoring) ............................................................112
10.4.
Quality Assurance.....................................................................................113
10.5.
Study and Site Closure .............................................................................113
10.6.
Records Retention....................................................................................113
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................114
11. REFERENCES.....................................................................................................115
12. APPENDICES......................................................................................................117
12.1.
Appendix 1: Abbreviations and Trademarks..............................................117
12.2.
Appendix 2: Management of Suspected Toxicity.......................................122
12.3.
Appendix 3: ECOG Performance Status ...................................................128
12.4.
Appendix 4: Cockcroft and Gault Method for Calculated Creatinine 
Clearance .................................................................................................129
12.5.
Appendix 5: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – modified and adapted from 
PCWG3 guidelines [Scher, 2016] and RECIST 1.1 [Eisenhauer, 
2009] ........................................................................................................130
12.5.1.
Baseline Documentation of Target and Non-Target 
Lesions ......................................................................................130
12.5.2.
Assessment Guidelines .............................................................131
12.5.3.
Guidelines for Evaluation of Disease .........................................132
12.5.4.
Response Criteria......................................................................133
12.6.
Appendix 6: Liver Safety Required Actions and Follow up 
Assessments ............................................................................................137
12.7.
Appendix 7: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................141
12.8.
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................144
12.8.1.
Definition of Adverse Events......................................................144
12.8.2.
Definition of Serious Adverse Events.........................................145
12.8.3.
Definition of Cardiovascular Events ...........................................147
12.8.4.
Recording of AEs and SAEs ......................................................147
12.8.5.
Evaluating AEs and SAEs..........................................................148
12.8.6.
Reporting of SAEs to GSK.........................................................149
12.9.
Appendix 9: Genetic Research .................................................................150
12.10. Appendix 10: Country Specific Requirements...........................................153
12.11. Appendix 11: Child-Pugh score [Pugh, 1973]............................................154
12.12. Appendix 12:  Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................155


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12.12.1. Contraception Guidance: ...........................................................155
12.12.2. Collection of Pregnancy Information ..........................................156
12.12.3. References ................................................................................156
12.13. Appendix 13: Protocol Amendment Changes............................................158


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1.
PROTOCOL SYNOPSIS FOR STUDY 204697
Rationale
Prostate cancer is the most frequently diagnosed cancer among men and the second-
leading cause of cancer-related death in men. As the growth of prostate cancer is 
dependent on androgens (mediated through androgen receptor), the primary target of 
treatment has been focused on depleting or blocking androgen activity. While many cases 
of prostate cancer can be treated definitively with a multi-modal approach of surgery, 
radiation, and/or hormonal manipulation, metastatic prostate cancer remains an incurable 
disease. The next generation hormonal agents (e.g., abiraterone and enzalutamide), 
immunotherapy (e.g., sipuleucel-T), and novel chemotherapeutics (e.g., cabazitaxel) have 
increased the overall survival (OS) of patients with this disease. However, for individuals 
whose tumors no longer respond to hormonal manipulation (also known as metastatic 
castration-resistant prostate cancer [mCRPC]), current approaches are palliative. 
The androgen receptor (AR) is a constitutively-expressed transcription factor in cells of 
the prostate, and upregulates gene expression to control cell growth, proliferation, and 
differentiation. The AR is activated by binding to androgens, a class of steroidal 
molecules that includes testosterone. Androgen-deprivation therapy (ADT) remains the 
cornerstone of prostate cancer therapy, even upon the emergence of resistance to primary 
androgen deprivation achieved by super stimulation with a gonadotrophin releasing 
hormone (GnRH) agonist like goserelin. In this context, direct antagonism of AR (e.g., by 
enzalutamide) and/or inhibition of steroid hormone synthesis (e.g., by abiraterone) has 
been demonstrated to provide clinical benefit upon the failure of primary ADT. Despite 
the success of the next-generation AR-targeted therapies, inherent or acquired resistance 
remains a major clinical challenge in mCRPC. Importantly, genomic analysis identified 
high frequency of AR pathway alterations in advanced mCRPC patients [Robinson, 
2015], implicating strong dependency on AR signalling, and the continued need for 
alternate forms of AR inhibition.
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as bromodomain and extraterminal domains (BET). Studies have 
demonstrated that BET inhibition can lead to growth arrest and cell death in a variety of 
preclinical models, including models of CRPC. The first-in-human (FIH) study from 
GlaxoSmithKline (GSK), BET115521, evaluated the safety and preliminary efficacy of 
single-agent GSK525762, a potent inhibitor of BET proteins, in a number of tumor types 
including mCRPC. Preliminary data from the futility analysis of the CRPC arm indicated 
there were no partial or complete responses. This data will be further examined as the 
data continues to mature.
The study (204697) proposes to evaluate the combination of GSK525762 with other 
agents that have been shown to be effective in the treatment of CRPC or metastatic 
CRPC (mCRPC), including approved agents (e.g. abiraterone, enzalutamide etc) as well 
as investigational agents for mCRPC that have proven to show efficacy and can be 
combined based on complimentary mechanism of action (immunotherapy like anti-
PD1/anti-PD-L1, poly-ADP ribose polymerase (PARP)  inhibitors like 
oleparib/talazoparib or Phosphoinositide 3 kinase (PI3K)/Protein kinase B (AkT) 


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pathway inhibitors). As a first step, this study will evaluate the combination of 
GSK525762 with new generation ADT agents, combining with either abiraterone or 
enzalutamide, based on the hypothesis that GSK525762, by inhibiting transcription 
overdrive, can overcome resistance to secondary ADT. This study will evaluate the safety 
and clinical activity in subjects who have progressed after treatment with abiraterone or 
enzalutamide, either as first line treatment (subjects treated in this study will be 
considered mCRPC Line 2 [L2, having failed first line treatment with or without one 
prior line of chemotherapy]) or on re-treatment after failure of multiple lines of therapy 
including prior ADT/prior chemotherapy/prior radiation therapy (subjects treated in this 
study will be considered mCRPC Line X [Lx]). Both populations will be included in both 
dose escalation and dose expansion; however, assignment during dose expansion will use 
forced randomization. 
Objective(s)/Endpoint(s)
Objectives
Endpoints
Co-Primary (Both Arms)

To determine the safety and tolerability of 
GSK525762, when given in combination with 
either abiraterone (Arm A) or enzalutamide 
(Arm B) in men with CRPC 

To determine clinical activity and recommended 
Phase 2 dose (RP2D) of GSK525762, when 
given in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in men with 
mCRPC

For both arms, adverse events (AEs), serious 
adverse events (SAEs), dose reductions or 
delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory 
parameters, vital signs, electrocardiogram 
[ECG], cardiotoxicity, gastrointestinal, etc.)

For both arms, primary response rate is defined 
as the percent of subjects achieving PSA50 at 
12 weeks or thereafter (PSA50 is ≥50% 
decrease in Prostate Specific Antigen (PSA) 
from baseline) 
Secondary (Both Arms)

To characterize the pharmacokinetics (PK) or 
exposure of GSK525762 and selected 
metabolites, when given in combination with 
abiraterone or enzalutamide, in men with 
mCRPC

To characterize the pharmacokinetics (PK) or 
exposure of abiraterone or enzalutamide, when 
given in combination with GSK525762, in men 
with mCRPC

PK parameter or concentration values for 
GSK525762 and selected metabolites following 
repeat-dose oral administration in combination 
with abiraterone or enzalutamide

PK parameter or concentration values for 
abiraterone or enzalutamide following repeat-
dose oral administration in combination with 
GSK525762 

To evaluate additional measures of clinical 
activity in subjects with CRPC 

For both arms, clinical activity evaluated by 
disease control rate (DCR) through 24 weeks. 

Composite Response Rate (CRR) based on any 
of the following – a) Response based on 
PCWG3-modified RECIST1.1, b) PSA decrease 
of ≥50% at Week 12 and thereafter, or c) CTC 
count conversion as defined above

Objective Response Rate (ORR) defined as 
complete response (CR) rate plus partial 
response (PR) rate per Prostate Cancer 


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Objectives
Endpoints

To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on patient-related 
outcomes 
Working Group (PCWG3)-modified Response 
Evaluation Criteria In Solid Tumors (RECIST) 
1.1 

Circulating Tumor Cells (CTC) response rate 
defined as percent of subjects having favorable 
(CTC<5/7.5 mL) at nadir, if baseline is 
unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA after 4 weeks of study treatment

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1, or progression in bone or PSA 
progression with accompanying progression by 
RECIST 1.1 or bone scan or clinical 
progression)

Radiological progression free survival (rPFS) 
per PCWG3-modified RECIST1.1

Performance status, pain scores, quality of life
Exploratory (Both Arms)

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamics [PK/PD]) 
relationship between GSK525762 and 
abiraterone or enzalutamide and safety and 
efficacy parameters 

To characterize the pharmacodynamics of 
GSK525762 and abiraterone or enzalutamide, 
when given in combination

Exploratory analysis between exposure 
parameters, change from baseline levels in PD 
markers and safety and/or efficacy parameters.

Transcriptomic and/or protein changes in 
molecular markers of BET inhibition and AR 
signaling in tumor tissue

To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on other measures 
of efficacy

To identify potential indicators of sensitivity or
response to GSK525762 and abiraterone or 
enzalutamide, when given in combination

To describe the kinetics of tumor growth in the 
presence of GSK525762 for each treatment and 
investigate the relationship between tumor 
growth kinetics and clinical activity

Overall survival (OS) over duration of study; 
Number of subjects with reduction in CTC of at 
least 30%

Correlate baseline tumor genomic 
deoxyribonucleic acid (DNA), protein and/or 
transcription ribonucleic acid (RNA) profiles with 
response. Correlate circulating biomarkers (e.g. 
AR-V7) with response

Tumor size or PSA levels over time, tumor 
growth rate constants, and time to tumor growth 
(TTG) predicted with the model parameters and 
relationship with clinical activity parameters


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Overall Design
This study is a two-arm, open-label Phase Ib dose escalation and dose expansion cohort 
study with oral administration of GSK525762 in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in subjects with mCRPC in whom at least one line of 
treatment with abiraterone or enzalutamide has failed. 
This study is designed to determine the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetic, and 
efficacy profiles. Arm A is designed to determine the MTD and RP2D of GSK525762 
when given in combination with abiraterone, based upon safety and clinical response 
profiles. Arm B is designed to determine the MTD and RP2D of GSK525762 when given 
in combination with enzalutamide, based upon safety and clinical response profiles. 
During dose escalation, both treatment arms will follow a modified Toxicity Probability 
Interval (mTPI) design. The design assumes (i) approximately 3 to 6 subjects per dose 
cohort will complete the dose-limiting toxicity (DLT) evaluation period and (ii) the true 
underlying toxicity rate for GSK525762 in combination with either abiraterone or 
enzalutamide falls within the range from 25% to 35% and centered at 30%. Subjects 
included in the study must have progressed, despite previous treatment with abiraterone 
and/or enzalutamide (L2 or Lx). Subjects will be enrolled based upon their more recent 
prior treatment (e.g. subjects who were most recently treated with abiraterone will be 
enrolled into Arm A, and subjects most recently treated with enzalutamide will be 
enrolled into Arm B). 
Because of the concern for potential drug-drug interactions (DDI) between GSK525762 
and both abiraterone and enzalutamide, there will be extensive PK sampling, to 
specifically address the DDI effects with these drugs. Specifically, enzalutamide is a 
known cytochrome P450 (CYP) 3A4 inducer, and DDI could potentially lower the 
exposure of GSK525762 levels. Also, GSK525762 is a moderate CYP3A inducer and 
could potentially lower the exposure of abiraterone, which is a substrate of CYP3A. 
Therefore, emerging PK data will be used to assist with dose escalation decisions, the 
decision for MTD and RP2D. 
A comparison of primary endpoint will be performed between the investigational arms if 
data warrant. Efficacy data will be collected from all subjects. All evaluable subjects 
treated during dose escalation and in the dose expansion cohorts will be incorporated into 
the final analysis. The totality of data, including safety/tolerability, PK, PD, and efficacy, 
will be used to determine RP2D.
During dose expansion, the study will employ a Bayesian predictive adaptive design that 
allows the trial to be monitored more frequently at multiple stages. Bayesian statistics 
will be employed to calculate the expected utility of the dose (dU) is greater than the 
clinically significant minimum utility (CSMU) at interim analysis for each dose. The 
interim analysis will be conducted for each individual dose and it may be conducted 
when at least 10 evaluable subjects are available for a given dose. After the first interim 
analysis, the interim analysis can be conducted after every 10 additional subjects become 
evaluable.


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For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the posterior probability that the utility 
(dU) ≥CSMU (25) is small (e.g., less than a 4% chance for the utility to be larger than the 
CSMU). Decisions made to stop enrolment in any cohort will be based on the totality of 
the data, including safety/tolerability and efficacy.
Arm A
In Arm A, eligible subjects with mCRPC will be enrolled into two dosing level cohorts to 
determine the MTDs (and RP2D) of GSK525762 when administered in combination with 
abiraterone. Eligible subjects include those that are abiraterone-refractory or resistant 
(including L2 and Lx), but the most recent treatment before enrolment into Arm A must 
be abiraterone (Figure 1). 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The approved dose of 
abiraterone (1000 mg) will be used for all GSK525762 dose level exploration. The initial 
GSK525762 dose level will be dose level 60 mg (DL60), which is one dose level lower 
than the single-agent RP2D. If DL60 does not exceed the MTD, DL80 (GSK525762 
given 80 mg QD) will be opened (Figure 1). If any dose level cohort is opened, but 
exceeds the maximum permitted toxicity rate, then additional subjects will not be 
enrolled at that dose level. 
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL60 exceeds the maximum permitted toxicity rate, then
intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose level (DL-
1, 40 mg) may be evaluated. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated and randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each may be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 1). If only one dose level is tolerable for 
dose expansion, subjects will be enrolled and not randomized.


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Figure 1
Study Schematic
Arm B
In Arm B, eligible subjects with mCRPC will be enrolled into dosing level cohorts to 
determine the MTDs (and RP2D) of GSK525762 when administered in combination with 
enzalutamide. Eligible subjects include those that are enzalutamide-refractory or resistant 
from second line as well as third line and above (including L2 or Lx), but the most recent 
treatment before enrolment into Arm B must be enzalutamide (Figure 2). 
Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved dose of enzalutamide (160 mg). As enzalutamide is a known CYP3A4 
inducer, DDI could potentially lower the exposure of GSK525762 active moiety levels by 
20%. Therefore, subjects will be enrolled at DL80 as the starting dose. 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The initial GSK525762 
dose level will be dose level 80 mg (DL80), which is equivalent to one dose level lower 
than the single-agent RP2D due to expected DDI. If DL80 does not exceed the MTD, 
DL100 (GSK525762 given 100 mg QD) will be opened (Figure 2). If any dose level 
cohort is opened, but exceeds the maximum permitted toxicity rate, then additional 
subjects will not be enrolled at that dose level. 
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 


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schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL80 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily dose level (DL-
1, 60 mg) may be evaluated.
Based on PK analysis from DL80 and DL100 dose escalation cohorts, if the exposure to 
GSK525762 active moiety is 40% lower than its single agent exposure (determined from 
GSK525762 80 mg cohort in BET115521 study), DL120 may be opened. The study team 
will carefully review PK and safety data from the DL80 and DL100 levels to determine if 
it is acceptable to open the DL120 dose level. If DL120 is opened, subjects in DL120 will 
begin dosing with GSK525762 at 120 mg and the approved dose of enzalutamide. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated and randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each may be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 2). If only one dose level is tolerable for 
dose expansion, subjects will be enrolled and not randomized. 
Figure 2
Study Schematic
Treatment Arms and Duration
All subjects will receive GSK525762 in combination with either abiraterone or 
enzalutamide. Subjects will begin combination therapy and continue until unacceptable 
toxicity, progression of disease, withdrawal of consent, death, or completion of study. 


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The total duration of study will depend on recruitment rates, withdrawals due to toxicity 
or progression or death, and, with an approximate duration of 2-3 years.
For subjects receiving GSK525762 in combination with abiraterone, daily administration 
of combination therapy (GSK525762 plus abiraterone) will commence immediately 
(Day 1) for abiraterone-failed subjects who are still on abiraterone (i.e., not stopped 
abiraterone dosing at progression and during screening). However, if these subjects are 
off abiraterone treatment for more than 3 days at the time of assignment to a cohort, there 
would be a lead in period for at least 7 days of abiraterone (Day -7 to Day 0) before the 
start of combination treatment (GSK525762 plus abiraterone on Day 1). The lead-in 
dosing will ensure that abiraterone is at steady state upon initiation of GSK525762
treatment. 
For subjects receiving GSK525762 in combination with enzalutamide, daily 
administration of combination therapy (GSK525762 plus enzalutamide) will commence 
immediately (Day 1) for enzalutamide-failed subjects who are still on enzalutamide (i.e. 
not stopped enzalutamide dosing at progression and during screening). However, if these 
subjects are off enzalutamide treatment for more than 7 days at the time of assignment to 
a cohort, there would be a lead in period for at least 28 days of enzalutamide (Day -28 to 
Day 0) before the start of combination treatment (GSK525762 and enzalutamide). There 
will be a 14 day lead in period if enzalutamide (Day -14 to Day 0) interruption was less 
than or equal to 7 days prior to start of combination treatment (Day 1). The lead-in dosing 
will ensure that enzalutamide is at steady state upon initiation of GSK525762 treatment. 
Based upon emerging data, additional subjects may be enrolled above, at, or below the 
combination doses mentioned previously, in order to collect additional safety and PK 
data. 
Initial dosing will maintain a fixed dose of abiraterone (1000 mg daily) or enzalutamide 
(160 mg daily). GSK525762 as a single agent was investigated at the highest dose of 
80 mg (amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Phase 2 
Dose, RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). Doses beyond the single-agent RP2D may be explored if the drug is 
tolerated and PK analysis demonstrates reduced GSK525762 exposure (Area under 
concentration-time curve [AUC] and/or maximum observed concentration [Cmax]) when 
administered in combination with enzalutamide. Dose reductions for individual subjects 
may be required, based on toxicity observed during the study, and the frequency and 
duration of dose reductions will be reported. If enzalutamide is discontinued for more 
than or equal to 7 days, then the maximum dose of GSK525762 should be the single 
agent RP2D of 80 mg. If enzalutamide is re-started, GSK525762 should remain at 80 mg 
until after at least 14 days until the dose is escalated, if applicable. Subjects who require 
permanent discontinuation of either abiraterone or enzalutamide in the combination may 
continue GSK525762 as a single agent if there is evidence of continuing benefit on 
treatment. If GSK525762 is continued as a single agent, the maximum dose would be 
80 mg. Intra-subject dose escalations from the planned starting dose during dose 
escalation will not be permitted. Intra-subject dose escalation may be permitted during 
dose expansion if for the lower dose level only if that dose is determined to be futile. 


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Based on emerging information collected from PK, PD and safety/tolerability data, other 
dosing regimens (such as intermittent dosing for GSK525762 or staggered dosing of the 
two drugs) may be explored during the study. 
The decision of which dose combination to identify as the RP2D from either arm will be 
based on the totality of data, including safety/tolerability, PK, and any preliminary 
efficacy data generated from the study. 
The study will be considered completed for purposes of a final analysis when 70% of all 
the subjects enrolled have progressed or died. Survival follow-up will continue until this 
70% event is met. The investigator is responsible for ensuring that consideration has been 
given for the post-study care of the subject’s medical condition.
Type and Number of Subjects
Approximately 130 subjects worldwide may be enrolled in the study as a whole. In 
France, approximately 28 subjects are to be enrolled. 
During dose escalation, subjects with a histologically-confirmed diagnosis of mCRPC 
will be treated in escalating dose level cohorts until the DL MTD(s) is/are established. 
The total number of subjects required will depend upon the number of escalation steps 
required to identify the MTD(s). Once safe DL(s) are identified, the dose expansion 
phase will open and subjects with a histologically-confirmed diagnosis of CRPC will be 
randomized based on prior lines of therapy (L2 or Lx). For both Arms, each dose level 
cohort may enroll or randomize up to 30 subjects. Subjects from both dose escalation and 
dose expansion may be combined to reach 30 subjects. 
Inclusion/Exclusion Criteria
Inclusion Criteria: 
1. Written informed consent provided
2. Males 18 years of age (at the time written consent is obtained for screening)
3. Histologically confirmed adenocarcinoma of the prostate: 
a.
Screening and on-treatment biopsy is mandatory. If adequate number of paired 
biopsy samples are collected (≥ 20 paired samples for each dose level in each 
Arm, unless an Arm is closed early), then further biopsy sampling will be 
considered based on available data. 
b. Screening biopsy can be waived if patient had a recent biopsy after failure of the 
most recent therapy (within 30 days) and the biopsy sample is secured to be sent 
as screening biopsy for this study. 
4. Surgically or medically castrated, with testosterone levels of 50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior 
to Week 1 Day 1 and must be continued throughout the study.
5. Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 


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a.
Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide in any prior line 
b. Lead-in dosing period for enzalutamide only will be required under the following 
circumstance: 
i. If the subject has enzalutamide discontinuation for >7 days prior to dosing 
start with GSK525762 plus enzalutamide on trial, then an enzalutamide only 
lead-in dosing of 28 days is required
ii. If the subject has enzalutamide discontinuation for ≤7 days prior to dosing 
start with GSK525762 plus enzalutamide on trial, then an enzalutamide only 
lead-in dosing of 14 days is required
iii.
If the subject is on continuous dosing with enzalutamide prior to dosing 
start with GSK525762 plus enzalutamide on trial, then subject can start on 
combined dosing at end of screening period.
c.
Lead-in dosing period for abiraterone only will be required under the following 
circumstance: 
i. If the subject has abiraterone discontinuation for more than 3 days prior to 
dosing start with GSK525762 plus abiraterone on trial, then an abiraterone 
only lead-in dosing of 7 days is required
6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy. 
7. Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.
PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be 
≥5 ug/L (5 ng/mL) if PSA is the only indication of progression; subjects on 
systemic glucocorticoids for control of symptoms must have documented PSA 
progression by PCWG3 while on systemic glucocorticoids prior to commencing 
Week 1 Day 1 treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
criteria or bone metastasis with 2 or more documented new bone lesions on a 
bone scan/ CT scan with or without PSA progression
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Life expectancy >12 weeks
10. Able to swallow and retain orally administered medication
11. Adequate organ function as defined in Table 1.


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Table 1
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
White blood cells
Absolute neutrophil count (ANC)
>3 X 109/L
1.5 X 109/L
Hemoglobin
9 g/dL (subjects that required transfusion or growth 
factor need to demonstrate stable hemoglobin for 7 
days of 9 g/dL)
Platelets
100 X 109/L
Prothrombin Time (PT)/International normalized 
ratio (INR) and Partial thromboplastin time (PTT)
≤ 1.5 X upper limit of normal (ULN)
Hepatic
Albumin
≥2.5 g/dL
Total bilirubin
Aspartate transaminase (AST)
≤1.5 x ULNa
2.5 ULN
Alanine transaminase (ALT) 
2.5 ULN OR <5x ULN is acceptable for subjects 
with documented liver metastases/tumor infiltration
Renal
Creatinine
OR
Creatinine clearance [either directly measured or 
calculated by Cockcroft-Gault formulab]
≤1.5 X ULN the institutional upper limit of normal 
≥ 50 mL/min
Cardiac
Ejection fraction
≥ lower limit of normal (LLN) by echocardiogram or 
multigated acquisition scan (MUGA) and minimum of 
50% LVEF
Troponin (I or T)
≤ULN
Other 
Testosterone
≤50 ng/dL
a.
Isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% or 
subject has a diagnosis of Gilbert’s syndrome
b.
Refer to Cockcroft-Gault formula
NOTE: Laboratory results obtained during Screening should be used to determine 
eligibility criteria. In situations where laboratory results are outside the permitted 
range, the investigator may opt to retest the subject and the subsequent within range 
screening result may be used to confirm eligibility. 
12. Male Participants: Contraceptive use by men or female partner should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. 
Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 16 weeks after the last dose of study treatment:

Refrain from donating sperm
            PLUS either:


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
Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent.
OR

Must agree to use contraception/barrier as detailed below:
Agree to use a male condom and female partner to use an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in Appendix 
12 when having sexual intercourse with a woman of childbearing potential who is 
not currently pregnant.   If partner becomes pregnant, agree to use/continue use of 
condoms until 16 weeks after the last dose of study medication.
Exclusion Criteria:
1. Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of Week 1 Day 1. 
2. Subjects with neuroendocrine and/or small cell CRPC
3. Recent prior therapy, defined as:
a.
Any investigational or approved non-biologic anti-cancer drug (see exception 
below) within 14 days prior to the first dose of GSK525762 and 
abiraterone/enzalutamide
Exception: For allowed androgen deprivation therapy (hormonal, abiraterone, 
enzalutamide), refer to inclusion criteria. Concomitant prednisone (or equivalent) 
allowed in combination with abiraterone dosing.  
b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of 
GSK525762 and abiraterone/enzalutamide
c.
Any anti-cancer biologic agents within five half-lives prior to the first dose of 
GSK525762 and abiraterone/enzalutamide
d. If the subject received radiotherapy < 90 days prior to study treatment, the 
irradiated lesion cannot be the only lesion used for evaluating response.
Exception: Any radiotherapy within 14 days prior to the first dose of GSK525762 
and abiraterone/enzalutamide must be limited to a single fraction of radiotherapy 
for the purpose of palliation (confined to one field).
e.
Any major surgery within 28 days prior to the first dose of GSK525762 and 
abiraterone/enzalutamide
4. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, in 
the opinion of the Investigator.
a.
Systolic blood pressure higher than 150 mmHg or diastolic blood pressure higher 
than 90 mmHg found on 2 separate occasions separated by 1 week, despite 
adequate therapy, will be defined as uncontrolled hypertension. 


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b. Uncontrolled diabetes mellitus (despite therapeutic; compliance to intervention) 
as defined by a hemoglobin A1c (HbA1c) level more than 8% and/or occurrence 
of more than 2 episodes of ketoacidosis in the 12 months prior to the first dose of 
study drug. 
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
interval ≥480 msec 
b. Clinically significant conduction abnormalities or arrhythmias, such as subjects 
with second degree (Type II) or third degree atrio-ventricular block
c.
History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).
d. History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects 
with a history of stent placement requiring ongoing anti-coagulant therapy (e.g., 
clopidogrel, prasugrel) will not be permitted to enroll.
NOTE: Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.
e.
Known cardiac metastasis
6. Subjects with history of known bleeding disorder(s) or history of clinically significant 
hemorrhage (e.g., GI, neurologic), within the past 6 months.
7. Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin 
[LMWH], or novel oral anticoagulants) must be discontinued and coagulation 
parameters must be normalized prior to the first dose of GSK525762 and 
abiraterone/enzalutamide. Prophylactic anticoagulation, with low doses (per standard 
practice) of agents such as low molecular weight heparin (LMWH), direct thrombin 
inhibitors, or factor Xa inhibitors is permitted.
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed, or 
100 mg, as per country standards) and non-steroidal anti-inflammatory drugs 
(NSAIDS), except for where NSAIDs provide documented benefit over other 
analgesics and then to be used with caution including concomitant use of proton 
pump inhibitors
9. Any acute toxicities due to prior chemotherapy and / or radiotherapy that have not 
resolved to a National Cancer Institute-Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) v4 grade ≤1 with the exception of chemotherapy induced 
alopecia and grade 2 peripheral neuropathy. 
10. The patient has an active second malignancy other than curatively resected basal cell 
or squamous cell carcinoma of the skin, in situ carcinoma of the bladder, or other 
cancers for which they are treated with curative intent with no active disease in the 3 
years prior to enrollment. 
11. Subjects with known symptomatic brain metastasis are not suitable for enrolment. 
Subjects with asymptomatic, stable, treated brain metastases are eligible for study 
entry. 


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12. History of seizure within 6 months of first dose of study treatment or any condition 
that may predispose subject to seizure (e.g., prior cortical stroke or significant brain 
trauma) or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
13. History of loss of consciousness or transient ischemic attack within 12 months prior 
to enrollment
14. Subjects with symptomatic or impending cord compression unless appropriately 
treated beforehand and clinically stable and asymptomatic. 
15. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications that are potent inducers or inhibitors of CYP3A4 enzymes or strong 
inhibitors of CYP2C8.
16. Subjects with gastrointestinal disorders likely to interfere with absorption of the study 
medication.
17. Subjects with known bleeding diathesis will be excluded from the study.
18. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator assessment).
19. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to Week 1 Day 1. Subjects on a stable bisphosphonate or denosumab 
therapy are eligible and may continue. 
20. Any serious known immediate or delayed hypersensitivity reaction to GSK525762 or 
idiosyncrasy to drugs chemically related to the investigational drugs. Additionally, 
any known hypersensitivity to either enzalutamide, abiraterone or any excipients 
would be excluded.
21. Known history of human immunodeficiency virus (HIV)
22. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening.
NOTE: Subjects with positive hepatitis C antibody due to prior resolved disease can be 
enrolled only if a confirmatory negative hepatitis C RNA PCR is obtained.
Analysis
The dose escalation will follow a mTPI design to identify the MTD(s) of GSK525762 in 
combination with either abiraterone or enzalutamide. A Bayesian adaptive design will be 
employed which allows the trial to be frequently monitored with the constraint of both 
Type I and Type II error rates. An initial interim analysis in each cohort may be 
performed when at least 10 evaluable subjects have been enrolled in that cohort, inclusive 
of subjects in both dose escalation and dose expansion. Enrolment to an individual cohort 
may be stopped early for toxicity or meeting futility criteria, but cohorts will not be 
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analyses. Decisions to stop enrolment within a cohort will be based on the totality of the 
data including safety/tolerability and efficacy.
The clinical activity primary response rate will be defined as the rate of subjects 
achieving PSA reduction from baseline ≥50% at 12 weeks or thereafter 
In assessing clinical activity which demonstrates an initial clinically meaningful response 
rate, this is defined as follows:

A response rate of 30% at 12 weeks or later, relative to a 10% response rate 
suggesting no activity. This will be conducted by testing the null hypothesis that 
P0<=0.1 versus the alternative that P1 ≥ 0.3, assuming the maximum response rate 
for an ineffective drug is 10% and the minimum response rate for an effective drug 
is 30%. 
These hypotheses are based on observations from a meta-analysis study in subjects who 
had received prior ADT both in chemo-naïve and prior chemotherapy setting. Chemo-
naïve subjects treated with a second ADT (L2 subjects) had rates of ≥50% PSA decline 
ranging from 25.5% to 36%. Subjects treated with both prior ADT and chemotherapy (Lx 
subjects) had variable responses of ≥50% PSA decrease which ranged from 4% to 26% in 
studies with larger subject populations (>30 subjects per study). Based on these findings, 
and considering a mixed population (L2 plus Lx) in both arms of the study, it is 
hypothesized that a response rate ≤10% would indicate no benefit for the combination of 
ADT failure, while a response rate of ≥30% in patients who just progressed on prior ADT 
will indicate there is a benefit that can be further explored. 
In addition to the primary endpoint, the efficacy of each combination cohort will be 
evaluated based on the totality of all efficacy endpoints (primary and secondary). The 
following secondary efficacy endpoints will also be considered for drawing conclusions 
on the clinical activity of the combination(s): 

Disease control rate (DCR) at 24 weeks 

CRR based on the following – a) response based on PCWG3-modified RECIST 1.1, 
b) PSA decrease of ≥50% at week 12 or thereafter, or c) CTC count conversion 

ORR defined as CR and PR rate per PCWG3-modified RECIST 1.1

CTC response rate defined as percent of subjects having favorable CTC <5/7.5mL at 
nadir if baseline is or conversion of unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent of subjects achieving ≥30% decrease 
from baseline PSA at 4 weeks 

Time to disease progression according to PCWG3 criteria (either by PCWG3-
modified RECIST 1.1 or progression in bone or PSA progression with accompanying 
progression by RECIST 1.1 or bone scan or clinical progression)

Radiological PFS per PCWG3-modified RECIST 1.1
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. The study will conclude 


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when the last subject has completed/discontinued study treatment and completed the end 
of treatment visit.


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2.
INTRODUCTION
GSK525762 is a novel inhibitor of bromodomain and extraterminal (BET) proteins 
currently under investigation to treat a number of human malignancies. Enzalutamide and 
abiraterone are next generation androgen receptor (AR) signalling targeted therapies that 
have been demonstrated to provide clinical benefit upon the failure of androgen-
deprivation therapy (ADT). Pre-clinically, combined inhibition of BET and AR results in 
improved effects on tumor cell growth compared to single agent therapy in a subset of 
prostate cancer models. The current protocol (study 204697) aims to test the safety, 
tolerability, PK, PD, and preliminary efficacy of this combination when administered 
concomitantly to human subjects with castrate-resistant prostate cancer (CRPC).
2.1.
Study Rationale
In the United States, prostate cancer is the most common malignancy in men, affecting an 
estimated one out of every seven males during their lifetime [SEER, 2015]. While many 
cases of prostate cancer can be treated definitively with a multi-modal approach of 
surgery, radiation, and/or hormonal manipulation, metastatic prostate cancer remains 
incurable as patients with this disease become resistant to ADT as well as next generation 
AR-targeted therapies. Importantly, AR reactivation is one of the top resistance 
mechanisms in majority of these mCRPC patients, indicating the continued dependency 
on AR signalling. Recent studies have shown an alternate mode of AR inhibition by 
targeting a new class of proteins known as BET. These proteins bind to chromatin and 
regulate gene expression, and preclinical data suggest that combination with next 
generation AR-therapies may provide therapeutic benefit. The current protocol (204697) 
proposes to evaluate the combination of the BET inhibitor GSK525762 with second-
generation AR-targeted agents such as enzalutamide or abiraterone in men with 
metastatic or advanced CRPC who have progressed on at least one line of prior AR-
targeted therapy.
2.2.
Brief Background
Prostate cancer is the most frequently diagnosed cancer among men and the second-
leading cause of cancer-related death in men [American Cancer Society, 2013]. Over the 
past decades, the primary target of treatment has been focused on depleting or blocking 
androgen activity as the growth of prostate cancer is dependent on androgens. Hormonal 
therapy includes surgical castration, use of gonadotropin-releasing hormone (GnRH) 
analogues, AR antagonists, ketoconazole and estrogenic compounds. Despite early 
sensitivity to hormonally directed therapies and while maintaining castrate levels of 
serum testosterone, these tumors often eventually progress as CRPC. Once metastatic 
CPRC (mCRPC) develops, the mean survival time in these patients is approximately 16 
to 18 months, indicating the need for novel therapeutic agents [Karantanos, 2013].
The AR is a constitutively-expressed transcription factor in cells of the prostate, and 
upregulates gene expression to control cell growth, proliferation, and differentiation 
[Ferraldeschi, 2015; Watson, 2015]. The AR is activated by binding to androgens, a class 
of steroidal molecules that includes testosterone. Untreated prostate cancer is dependent 
upon androgen at least initially for its continued growth. Most androgen production 


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occurs in the testes (90-95%), but the adrenal glands also produce a small fraction of 
circulating androgens. Thus, over the past decades, ADT remains the cornerstone of 
prostate cancer therapy, even upon the emergence of castration resistance to primary 
androgen deprivation achieved by super stimulation with a GnRH agonist like goserelin. 
Importantly, AR signaling axis frequently remains active despite castration therapy in 
CRPC, as is clinically evident by the rise in prostate-specific antigen (PSA) and 
hypersensitivity to even low levels of residual androgens, suggesting that continued 
treatment directed at the AR signaling axis may provide benefit. In this context, direct 
antagonism of AR (e.g., by enzalutamide) and/or inhibition of steroid hormone synthesis 
(e.g., by abiraterone) has been demonstrated to provide clinical benefit upon the failure of 
primary ADT. 
Enzalutamide (Xtandi) is an orally bioavailable, AR signalling inhibitor approved in the 
United States (US) and the European Union for the treatment of patients with mCRPC 
who have previously received treatment with docetaxel, and pre-chemotherapy in the US 
with mCRPC [Xtandi, 2015]. Enzalutamide acts on several steps in the AR signaling 
pathway, including competitive inhibition of androgen binding to ARs and inhibition of 
AR nuclear translocation and its interaction with deoxyribonucleic acid (DNA). 
Abiraterone (Zytiga) is an inhibitor of cytochrome P450 (CYP) 17A1 that acts by 
blocking production of multiple steroid hormones, including alternative androgens that 
are produced in various tissues and are responsible for ADT resistance [Zytiga, 2015]. Its 
mechanism of action (MoA) is indirect, and does not interact directly with AR, but 
reduces levels of circulating androgen. This indirect MoA means that it cannot be studied 
in a cell culture model, but the effects in humans on androgen production results in the 
same effects as enzalutamide; down-regulation of AR signaling and clinical response in 
this AR-driven tumor type. 
Despite the success of these next-generation AR-targeted therapies, inherent or acquired 
resistance remains a major clinical challenge in mCRPC. Importantly, integrative 
genomic analysis identified a potentially actionable somatic or germline event in 90% of 
mCRPC affected individuals, including 63% with aberrations in AR [Robinson, 2015]. 
The high frequency of AR pathway alterations in these advanced mCRPC patients imply 
the strong dependency on AR signaling, and the continued need for alternate forms of AR 
inhibition. In addition to AR, alterations were observed in important pathways including 
PI3K (49%), wingless-type MMTV integration site family member (Wnt) (18%), cell 
cycle (21%) and DNA repair (13%) [Robinson, 2015], suggesting the importance of 
combinational strategies to suppress various resistance mechanisms in mCRPC, 
simultaneously. There are no large clinical trials assessing the efficacy of abiraterone in 
patients who have previously been treated with enzalutamide and vice versa. 
Retrospective analyses suggest that although abiraterone has some activity in this setting, 
it is limited compared with patients who have not been treated with enzalutamide [Loriot, 
2013; Noonan, 2013]. Conversely, enzalutamide appears to retain some activity in 
patients who have been previously treated with abiraterone. 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as BET [Wyce, 2013]. The BET family, comprised of bromodomain 2 
(BRD), BRD3, BRD4 and BRDT, recognize acetyl groups on the tails of histones and are 
critical for recruiting transcriptional machinery necessary for gene expression. BRD4 has 


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been shown to interact with AR, and BET inhibition abrogated BRD4 localization to a 
subset of AR target loci and reduced AR-mediated gene transcription, causing 
suppression of AR signaling [Assangani, 2014]. Studies have demonstrated that BET 
inhibition can lead to growth arrest and cell death in a variety of preclinical models, 
including models of CRPC [Wyce, 2013]. The first-in-human (FIH) study from 
GlaxoSmithKline (GSK), BET115521, evaluated the safety and preliminary efficacy of 
single-agent GSK525762, a potent inhibitor of BET proteins, in a number of tumor types 
including mCRPC. Preliminary data from the futility analysis of the CRPC arm indicated 
there were no partial or complete responses. This data will be further examined as the 
data continues to mature. Preliminary safety and efficacy data is summarized in the 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 2011N113741_07, 
2018]. 
This study (204697) proposes to evaluate the combination of GSK525762 with other 
agents that have been shown to be effective in the treatment of CRPC or mCRPC), 
including approved agents (e.g. abiraterone, enzalutamide) as well as investigational 
agents for mCRPC that have proven to show efficacy and can be combined based on 
complimentary mechanism of action (immunotherapy like anti-PD1/anti-PD-L1, PARP 
(poly-ADP ribose polymerase) inhibitors like oleparib/talazoparib or PIK3/AkT pathway 
inhibitors). As a first step, this study will evaluate the combination of GSK525762 with 
the new generation ADT agents, combining with either abiraterone or enzalutamide, 
based on the hypothesis that GSK525762, by inhibiting transcription overdrive, can 
overcome resistance to secondary ADT. 
As described above, preclinical data suggest that BET proteins act in complex with AR at 
transcriptional level to mediate androgen signalling. Co-treatment with anti-androgens 
and BET inhibitors results in significantly improved tumor growth inhibition compared to 
single agent therapy in a subset of CRPC models tested (VCAP xenograft model, 
[Assangani, 2016]. One of the major resistance mechanisms against second generation 
AR-targeted therapies is the development of AR alterations including mutations and 
splice variants (e.g.AR-Vs). Importantly, AR-V levels were also down-regulated by 
another small molecule BET inhibitor JQ1 alone or in combination with enzalutamide 
[Chan, 2015; Assangani, 2016]. Therefore, combining BET with either abiraterone or 
enzalutamide gives an opportunity for vertical AR inhibition at the receptor as well as 
transcriptional level, offering a mechanism by which resistance may be overcome. 
This study will evaluate the safety and clinical activity in subjects who have progressed 
after treatment with abiraterone or enzalutamide, either as first line treatment (subjects 
treated in this study will be considered mCRPC Line 2 (L2, having failed first line
treatment with or without one prior line of chemotherapy) or on re-treatment after failure 
of multiple lines of therapy including prior ADT/prior chemotherapy/prior radiation 
therapy (subjects treated in this study will be considered mCRPC Line X (Lx)). Both 
populations will be included in both dose escalation and dose expansion; however, 
assignment during dose expansion will use forced randomization. 


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Co-primary (Both Arms)

To determine the safety and tolerability of 
GSK525762, when given in combination with 
either abiraterone (Arm A) or enzalutamide 
(Arm B) in men with castration-resistant 
prostate cancer (CRPC)

To determine clinical activity and recommended 
Phase 2 dose (RP2D) of GSK525762, when 
given in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in men with 
castration-resistant prostate cancer (CRPC)

For both arms, adverse events (AEs), serious 
adverse events (SAEs), dose reductions or 
delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory 
parameters, vital signs, electrocardiogram 
(ECG), cardiotoxicity, gastrointestinal, etc.)

For both arms, primary response rate (RR)is 
defined as the percent of subjects achieving 
PSA50 at 12 weeks or thereafter (PSA50 is 
≥50% decrease in PSA from baseline)
Secondary (Both Arms)

To characterize the pharmacokinetics (PK) or 
exposure of GSK525762 and selected 
metabolites, when given in combination with 
abiraterone or enzalutamide, in men with 
mCRPC

To characterize the pharmacokinetics (PK) or 
exposure of abiraterone or enzalutamide, when 
given in combination with GSK525762, in men 
with mCRPC

PK parameter or concentration values for 
GSK525762 and selected metabolites following 
repeat-dose oral administration in combination 
with abiraterone or enzalutamide

PK parameter or concentration values for 
abiraterone or enzalutamide following repeat-
dose oral administration in combination with 
GSK525762 

To evaluate other measures of clinical activity in 
subjects with CRPC 

For both arms, clinical activity evaluated by 
DCR through 24 weeks

CRR based on any of the following – a) 
Response based on PCWG3-modified 
RECIST1.1, b) PSA decrease of ≥50% at Week 
12 and thereafter, or c) CTC count conversion 
as defined above

ORR defined as CR and PR rate per Prostate 
Cancer Working Group (PCWG3)-modified 
Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1

CTC response rate as defined as percent of 
subjects having favorable (CTC<5/7.5mL) at 
nadir, if baseline is unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA after 4 weeks of study treatment

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1 or progression in bone or PSA 
progression with accompanying progression by 
RECIST 1.1 or bone scan or clinical 


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Objectives
Endpoints

To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on patient-related 
outcomes
progression)

rPFS per PCWG3-modified RECIST 1.1

Performance status, pain scores, quality of life
Exploratory (Both Arms)

To evaluate the exposure response 
(pharmacokinetic/pharmacodynamics [PK/PD]) 
relationship between GSK525762 and 
abiraterone or enzalutamide and safety and 
efficacy parameters 

To characterize the pharmacodynamics of 
GSK525762 and abiraterone or enzalutamide, 
when given in combination

Exploratory analysis between exposure 
parameters, change from baseline levels in PD 
markers and safety and/or efficacy parameters.

Transcriptomic and/or protein changes in 
molecular markers of BET inhibition and AR 
signaling in tumor tissue

To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on other measures 
of efficacy

To identify potential indicators of sensitivity or 
response to GSK525762 and abiraterone or 
enzalutamide, when given in combination

To describe the kinetics of tumor growth in the 
presence of GSK525762 for each treatment and 
investigate the relationship between tumor 
growth kinetics and clinical activity

Overall survival (OS) over duration of study; 
Number of subjects with reduction in CTC of at 
least 30%.

Correlate baseline tumor genomic (DNA), 
protein and/or transcription (RNA) profiles with 
response. Correlate circulating biomarkers (e.g. 
AR-V7) with response

Tumor size or PSA levels over time, tumor 
growth rate constants, and time to tumor growth 
(TTG) predicted with the model parameters and 
relationship with clinical activity parameters
4.
STUDY DESIGN
4.1.
Overall Design
This study is a two-arm, open-label Phase Ib dose escalation and dose expansion cohort 
study with oral administration of GSK525762 in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in male subjects with mCRPC in whom at least one 
line of treatment with abiraterone or enzalutamide has failed. 
This study is designed to determine the maximum tolerated dose (MTD) and RP2D based 
on safety, tolerability, pharmacokinetic, and efficacy profiles. Arm A is designed to 
determine the MTD and RP2D of GSK525762 when given in combination with 
abiraterone, based upon safety and clinical response profiles. Arm B is designed to 
determine the MTD and RP2D of GSK525762 when given in combination with 
enzalutamide, based upon safety and clinical response profiles. During dose escalation, 
both treatment arms will follow a modified Toxicity Probability Interval (mTPI) design 
[Ji, 2013]. The design assumes (i) approximately 3 to 6 subjects per dose cohort will 
complete the dose-limiting toxicity (DLT) evaluation period and (ii) the true underlying 


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toxicity rate for GSK525762 in combination with either abiraterone or enzalutamide falls 
within the range from 25% to 35% and centered at 30%. Subjects included in the study 
must have progressed, despite previous treatment with abiraterone and/or enzalutamide 
(L2 or Lx). Subjects will be enrolled based upon their most recent prior treatment (e.g. 
subjects who were most recently treated with abiraterone will be enrolled into Arm A, 
and subjects most recently treated with enzalutamide will be enrolled into Arm B). 
Because of the concern for potential drug-drug interactions (DDI) between GSK525762 
and both abiraterone and enzalutamide, there will be extensive PK sampling as noted in 
Section 7.1, to specifically address the DDI effects with these drugs. Specifically, 
enzalutamide is a known CYP3A4 inducer, and DDI could potentially lower the exposure 
to GSK525762. Also, GSK525762 is a moderate CYP3A inducer and could potentially 
lower the exposure of abiraterone, which is a substrate of CYP3A. Therefore, emerging 
PK data will be used to assist with dose decisions for MTD and RP2D. 
The co-primary endpoints will evaluate both safety and clinical activity of each treatment 
combination. The primary clinical activity outcome will be defined by the rate of ≥50% 
reduction in PSA (PSA50) at 12 weeks or thereafter. Secondary endpoints include: 1) 
DCR through 24 weeks; 2) CRR based on the following – a) response based on PCWG3-
modified RECIST 1.1, b) PSA decrease of ≥50%, or c) CTC count conversion; 3) ORR 
defined as CR and PR rate per PCWG3-modified RECIST 1.1; 4) CTC response rate 
defined as percent of subjects having favorable CTC <5/7.5mL at nadir if baseline is 
unfavorable CTC≥5/7.5mL; 5) PSA week 4 response rate defined as percent of subjects 
achieving ≥30% decrease from baseline PSA after 4 weeks of study treatment; 6) time to 
disease progression according to PCWG3 criteria (either by PCWG3-modified RECIST 
1.1 or progression in bone or PSA progression with accompanying progression by 
RECIST 1.1 or bone scan or clinical progression); 7) rPFS per PCWG3-modified 
RECIST 1.1. Other endpoints include OS, number of subjects with reduction in CTC of 
at least 30%, and PK will be evaluated. Safety will be evaluated by Adverse Events (AE), 
withdrawals due to toxicities, and changes in safety parameters from baseline (e.g., 
laboratory parameters, vitals, ECG). 
During dose expansion, the study will employ a Bayesian predictive adaptive design that 
allows the trial to be monitored more frequently at multiple stages based on the utility 
score of the dose. Bayesian statistics will be employed to calculate the posterior 
probability that the utility of the dose (dU) is greater than the clinically significant 
minimum utility (CSMU) at interim analysis for each dose. The interim analysis will be 
conducted for each individual dose and it may be conducted when at least 10 evaluable 
subjects are available for a given dose. After the first interim analysis, the interim 
analysis can be conducted after every 10 additional subjects become evaluable.
For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the posterior probability that the utility 
(dU) ≥CSMU (25) is small (e.g., less than a 4% chance for the utility to be larger than the 
CSMU). Decisions to stop enrolment for a cohort will be based on the totality of the data, 
including safety/tolerability and efficacy (primary and secondary parameters).


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Arm A
In Arm A, eligible subjects with mCRPC will be enrolled into two dosing level cohorts to 
determine the MTDs (and RP2D) of GSK525762 when administered in combination with 
abiraterone. Eligible subjects include those that are abiraterone-refractory or resistant 
from second line as well as third line and above (including L2 or Lx) chemo-naive or 
chemo-treated), but the most recent treatment before enrolment into Arm A must be 
abiraterone (Figure 3). 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The approved dose of 
abiraterone (1000 mg) will be used for all GSK525762 dose level exploration. The initial 
GSK525762 dose level will be dose level 60 mg (DL60), which is one dose level lower 
than the single-agent RP2D. If DL60 does not exceed the MTD, DL80 (GSK525762 
given 80 mg QD) will be opened (Figure 3). If any dose level cohort is opened, but 
exceeds the maximum permitted toxicity rate, then additional subjects will not be 
enrolled at that dose level. 
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
level, either at a dose level where daily treatment may be intolerable or at a lower dose. 
For example, if DL60 exceeds the maximum permitted toxicity rate, then an 
alternate/intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose 
level (DL-1, 40 mg) may be evaluated.
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated and randomized by prior lines of therapy (L2 and Lx). A total of 
30 subjects each may be enrolled into both cohorts, and approximately10 enrolled 
subjects will be L2 and 20 subjects will be Lx (Figure 3). If only one dose level is 
tolerable for dose expansion, subjects will be enrolled and not randomized. Refer to 
Section 4.6 for further dose information. 


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Figure 3
Study Schematic
Arm B
In Arm B, eligible subjects with mCRPC will be enrolled into dosing level cohorts to 
determine the MTDs (and RP2D) of GSK525762 when administered in combination with 
enzalutamide. Eligible subjects include those that are enzalutamide-refractory or resistant 
from second line as well as third line and above (including L2 or Lx), but the most recent 
treatment before enrolment into Arm B must be enzalutamide (Figure 4). 
Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved dose of enzalutamide (160 mg). As enzalutamide is a known CYP3A4 
inducer, DDI could potentially lower the exposure of GSK525762 active moiety levels by 
20%. Therefore, subjects will be enrolled at DL80 as the starting dose. 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The initial GSK525762 
dose level will be dose level 80 mg (DL80), which is equivalent to one dose level lower 
than the single-agent RP2D due to expected DDI. If DL80 does not exceed the MTD, 
DL100 (GSK525762 given 100 mg QD) will be opened (Figure 4). If any dose level 
cohort is opened, but exceeds the maximum permitted toxicity rate, then additional 
subjects will not be enrolled at that dose level. 
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 


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level, either at a dose level where daily treatment may be intolerable or at a lower dose. 
For example, if DL80 exceeds the maximum permitted toxicity rate, then an 
alternate/intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily dose 
level (DL-1, 60 mg) may be evaluated.
Based on PK analysis from DL80 and DL100 dose escalation cohorts, if the exposure to 
GSK525762 active moiety is 40% lower than its single agent exposure (determined from 
GSK525762 80 mg cohort in BET115521 study), DL120 may be opened. The study team 
will carefully review PK and safety data from the DL80 and DL100 dose levels to 
determine if it is acceptable to open the DL120 dose level. If DL120 is opened, subjects 
in DL120 will begin dosing with GSK525762 at 120 mg and the approved dose of 
enzalutamide. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated and randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each may be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 4). If only one dose level is tolerable for 
dose expansion, subjects will be enrolled and not randomized. Refer to Section 4.6 for 
further dose information.
Figure 4
Study Schematic


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4.1.1.
Type and Number of Subjects
Approximately 130 subjects worldwide will be enrolled in the study as a whole. In 
France, approximately 28 subjects are to be enrolled. 
During dose escalation, subjects with a histologically-confirmed diagnosis of mCRPC 
will be treated in escalating dose level cohorts until the DL MTD(s) is/are established. 
The total number of subjects required will depend upon the number of escalation steps 
required to identify the MTD(s). Once safe DL(s) are identified, the dose expansion 
phase will open and subjects with a histologically-confirmed diagnosis of CRPC will be 
randomized based on prior lines of therapy (L2 or Lx). For both Arms, each dose level 
cohort may enroll or randomize up to 30 subjects. Subjects from both dose escalation and 
dose expansion may be combined to reach 30 subjects.
4.2.
Dose Escalation
4.2.1.
Treatments Arms and Duration
All subjects will receive GSK525762 in combination with either abiraterone or 
enzalutamide. Subjects will begin combination therapy and continue until unacceptable 
toxicity, progression of disease, withdrawal of consent, death, or completion of the study. 
The total duration of study will depend on recruitment rates, withdrawals due to toxicity 
or progression or death, and, with an approximate duration of 2 to 3years.
This study will consist of dose escalation and dose expansion cohorts. A mTPI design 
will be followed during dose escalation to establish safe DLs to move to dose expansion. 
During dose expansion, subjects who have failed prior abiraterone/enzalutamide-
treatment both as L2 as well as Lx will be enrolled to either of the following arms:

Forced randomization of subjects that are abiraterone-refractory or resistant 
from L2 and Lx to the two most tolerable dose level cohorts with 1/3 of the 
subjects from L2 and 2/3 of the subjects from Lx: - GSK525762 + 
abiraterone/prednisone (Arm A).

Forced randomization of subjects that are enzalutamide-refractory or resistant 
from L2 and Lx to the two most tolerable dose level cohorts with 1/3 of the 
subjects from L2 and 2/3 of the subjects from Lx:- GSK525762 at RP2D+ 
enzalutamide (Arm B) 
For subjects receiving GSK525762 in combination with abiraterone, daily administration 
of combination therapy (GSK525762 and abiraterone) will commence immediately (Day 
1) for abiraterone-failed subjects who are still on abiraterone (i.e, not stopped abiraterone 
dosing at progression and during screening). However, if these subjects are off 
abiraterone treatment for more than 3 days at time of assignment to a cohort, there would 
be a lead in period for at least 7 days of abiraterone (Day -7 to Day 0) before the start of 
combination treatment (GSK525762 and abiraterone). The lead-in dosing will ensure that 
abiraterone is at steady state upon initiation of GSK525762 treatment (Table 2). Based on 
emerging information collected from PK, PD and safety/tolerability data, other dosing 
regimens (such as BID dosing for both drugs or intermittent dosing for GSK525762 or 
staggered dosing of the two drugs) may be explored during the study.


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Table 2
Prior Abiraterone Treatment Guidance
Situation: 
Action: 
Subject has continued prior abiraterone dosing 
at time of assignment 
Subject may start combination treatment once 
assigned to cohort. 
Subject has stopped abiraterone for more than 
3 days at time of assignment 
Subject must initiate lead-in single agent 
abiraterone dosing for at least 7 days prior to 
initiation of combination treatment with 
GSK525762
For subjects receiving GSK525762 in combination with enzalutamide, daily 
administration of combination therapy (GSK525762 plus enzalutamide) will commence 
immediately (Day 1) for enzalutamide-failed subjects who are still on enzalutamide (i.e. 
not stopped enzalutamide dosing at progression and during screening). However, if these 
subjects are off enzalutamide treatment for more than 7 days at the time of assignment to 
a cohort, there would be a lead in period for at least 28 days of enzalutamide (Day -28 to 
Day 0) before the start of combination treatment (GSK525762 and enzalutamide). There 
will be a 14 day lead in period (Day -14 to Day 0) if enzalutamide interruption was less 
than or equal to 7 days prior to start of combination treatment (Day 1). The lead-in dosing 
will ensure that enzalutamide is at steady state upon initiation of GSK525762 treatment 
(Table 3). Based upon emerging data, additional subjects may be enrolled above, at, or 
below the combination doses, in order to collect additional safety and PK data. 
Table 3
Prior Enzalutamide Treatment Guidance
Situation: 
Action: 
Subject has continued prior enzalutamide 
dosing at time of assignment 
Subject may start combination treatment once 
assigned to cohort. 
Subject has stopped enzalutamide for more 
than 7 days at time of assignment 
Subject must initiate lead-in single agent 
enzalutamide dosing for at least 28 days prior to 
initiation of combination treatment with 
GSK525762
Subject has stopped enzalutamide for 7 or less 
days at time of assignment 
Subject must initiate lead-in single agent 
enzalutamide dosing for at least 14 days prior to 
initiation of combination treatment with 
GSK525762
4.2.2.
Dose Escalation
4.2.2.1.
Planned Dose Levels
GSK525762 as a single agent was investigated at the highest dose of 80 mg (amorphous 
tablet)/ 75 mg (besylate tablet) once daily (Recommended Phase 2 Dose, RP2D) in the 
expansion cohorts of the first time in human solid tumor study (BET115521). All doses 
of GSK525762 refer to the besylate tablet formulation. For Arm A, projected dose levels 


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of GSK525762 are 60 mg and 80 mg administered once daily. Due to emerging data 
(safety/tolerability/efficacy), additional dose levels may be explored. These dose levels 
may either be a lower daily dose level or an intermittent dose level, either at a dose level 
where daily treatment may be intolerable or at a lower dose. For example, if DL60 
exceeds the maximum permitted toxicity rate, then an alternate/intermittent dosing at 60 
mg dose level (DL60 ALT) and/or a lower daily dose level (DL-1, 40 mg) may be 
evaluated. 
For Arm B, projected dose levels of GSK525762 are 80 mg, and 100 mg administered 
once daily. A dose of 120 mg may be evaluated in combination with enzalutamide based 
on emerging PK and safety data. Due to emerging data (safety/tolerability/efficacy), 
additional dose levels may be explored. These dose levels may either be a lower daily 
dose level or an intermittent dose level, either at a dose level where daily treatment may 
be intolerable or at a lower dose. For example, if DL80 exceeds the maximum permitted 
toxicity rate, then an alternate/intermittent dosing at 80 mg dose level (DL80 ALT) 
and/or a lower daily dose level (DL-1, 60 mg) may be evaluated.
Projected dose levels of abiraterone and enzalutamide are 1000 mg and 160 mg 
respectively, administered once daily. No doses will be explored beyond 1000 mg 
abiraterone or 160 mg enzalutamide, these doses that are considered to be the Maximum 
Feasible Dose (MFD), unless emerging PK data demonstrate reduced exposure of either 
drug in combination compared to single agent. As determined from pre-clinical studies, 
the maximum clinical dose of GSK525762 will not exceed 200 mg. Any GSK525762 
dose above 120 mg would require regulatory authority review and approval. 
4.2.2.2.
Dose-Limiting Toxicity
An event will be considered a DLT if it occurs within the first 28 days of combination 
treatment (Day 1 to Day 28) and meets one of the criteria listed in Table 4, unless it can 
be clearly established that the event is unrelated to treatment.


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Table 4
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 3 or greater neutropenia for 5 days

Febrile neutropenia

Grade 4 anemia of any duration

Grade 4 thrombocytopenia of any duration or Grade 3 
thrombocytopenia with bleeding
Non-hematologic

ALT >3x upper limit of normal (ULN) + bilirubin 2xULN (>35% direct) 
or ALT between 3-5 X ULN with bilirubin < 2xULN but with hepatitis 
symptoms or rash (See Section 5.4.1 for Liver Stopping Criteria)

Grade 3 nausea, vomiting or diarrhea that does not improve within 72h 
despite appropriate supportive treatment(s)

Grade 4 nausea, vomiting, or diarrhea

Grade 3 hypertensiona (uncontrolled despite addition of up to 
2 antihypertensive medications)

Grade 4 hypertension

Grade 3 or greater clinically significant non-hematologic toxicity 
(including QT duration corrected for heart rate by Fridericia’s formula 
(QTcF) except toxicities listed in Section 4.2.2.3.

Ejection fraction < lower limit of normal (LLN) with an absolute 
decrease of >10%from baseline 
Other

Inability to receive at least 75% of scheduled doses in the DLT 
observation period due to drug-related toxicity, or any toxicity which 
requires permanent discontinuation of investigational agent(s) during 
the DLT observation periodb

Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and Medical Monitor is considered to be a 
DLT
Toxicity Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4 [NCI-CTCAE, 2009]
a.
Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not considered to be a DLT.
b.
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.
Refer to Appendix 2 for management of selected toxicities.
4.2.2.3.
Non-Limiting Toxicities
The following toxicities have been deemed to be non-serious for the purposes of this 
study. These toxicities will not be taken into account for dose escalation decisions unless, 
in the opinion of the investigator and the Medical Monitor, they represent a dose-limiting 
toxicity. For all other toxicities and their management, see Appendix 2.

Grade 2 or less:
o
Fatigue
o
Rash
o
Alopecia


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
Grade 3 or less nausea, vomiting, or diarrhea that improves to ≤Grade 1 within 
24h (refer to Section 6.11.2.3 for discussion of permitted anti-emetic regimens)

Electrolyte imbalance or other laboratory abnormalities that improves to ≤ Grade 
1, without clinical sequelae, within 24h
4.2.2.4.
Maximum Dose Increment
The pre-planned dose levels are described in Section 4.2. Only GSK525762 will be dose-
escalated at each dose escalation step.
4.2.2.5.
Dose Escalation Decisions
A data review team, consisting (at a minimum) of the investigator(s), medical monitor(s), 
safety physician, pharmacokineticist, clinical representatives, and statistician, will be 
responsible for determining whether dose escalation should continue as planned 
according to the mTPI design rules (Figure 5) [Ji, 2013].  Prior to the dose escalation 
decision, the data review team will review available relevant data on all adverse events 
including non-DLT toxicities, laboratory assessments and other safety evaluations, as 
well as PK data. The dose decision and rationale for each cohort will be documented in 
writing with copies maintained at each study site and in the master study files at 
GlaxoSmithKline (GSK).
Dose escalation will follow mTPI dose-escalation procedure. The design assumes (i) 
approximately 3 to 6 subjects per dose cohort will complete the dose-limiting toxicity 
(DLT) evaluation period and (ii) the true underlying toxicity rate for GSK525762 in 
combination with enzalutamide falls within the range from 25% to 35% and centered at 
30%. Dose limiting toxicities (DLTs) are based on any observed toxicity in the first 28 
days of treatment (please see Section 4.2.2.2). At DL60, 3 subjects will be enrolled. If no 
DLT is observed, proceed to next dose level. If one of the three evaluable subject 
experiences a DLT, then 3 additional subjects will be enrolled at that dose level. 
Evaluation of available safety data from at least 6 subjects who have completed a 
minimum of 28 days (1 cycle) at the current highest safe dose level is required prior to 
expanding a cohort.
A modified Toxicity Probability Interval (mTPI) design will be implemented (Figure 5) 
[Ji, 2013]. The mTPI decision rule will be followed for monitoring safety until up to 10 
subjects have been assigned at the same dose. 
The design assumes (i) Approximately 3-6 subjects will complete the DLT evaluation 
period and (ii) the true underlying toxicity rate for GSK525762 in combination with 
abiraterone or enzalutamide falls within the range from 25% to 35% and centered at 30%. 
The monitoring rules guiding dose escalation are provided in Figure 5. Columns provide 
the numbers of subjects treated at the current dose level, and rows provide the 
corresponding numbers of subjects experiencing toxicity. The entries of the table are 
dose-finding decisions (i.e., E, S, and D) representing escalating the dose, staying at the 
same dose, and de-escalating the dose. If the current dose is at the highest dose level and 
the decision is E, it indicates that the highest dose level is below MTD and the next 
subject(s) will be treated at the same dose level. In addition, decision U means that the 


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current dose level is unacceptable because of high toxicity and should be excluded from 
the trial. For example, when one of three subjects experiences toxicity, the decision can 
be located at row 1 and column 3, which is S – to stay at the current dose level. 
Consequently the next cohort of subjects will be treated at the same dose level currently 
being used. If zero of three subjects experiences toxicity, the decision is at row 0 and 
column 3, which is E – to escalate if there is higher available dose otherwise stop dose 
escalation if there are 6 evaluable subjects on the current dose. Thus, the next cohort of 
subjects will be treated at the next-higher dose level. If three of three subjects experiences 
toxicity, the decision is DU – to de-escalate to the next-lower dose level and exclude the 
current dose from the trial, because the high toxicity level is unacceptable.
Figure 5
Dose-finding spreadsheet of the modified toxicity probability interval 
(mTPI) method
   
The spreadsheet was generated based on a beta/binomial model and precalculated before trial initiation. The 
letters in different colors are computed based on the decision rules under the mTPI method and represent 
different dose-finding actions. In addition to actions de-escalate the dose (D), stay at the same dose (S), and 
escalate the dose (E), the table includes action unacceptable toxicity (U), which is defined as the execution of the 
dose-exclusion rule in mTPI.
The cohort may be expanded up to 10 subjects to further evaluate safety, 
pharmacokinetics and tolerability before dose escalation or reduction decision is 
determined. 
4.2.2.6.
Alternative Dosing Schedules
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK, PD, 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 no higher than the maximum tolerated or 
completed dose level with the initial schedule. Escalation can then proceed as described 
in Section 4.2.2.


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The dosing schedule may also be adjusted to expand a prior dose cohort to further 
evaluate safety, pharmacokinetic and/or pharmacodynamic findings at a given dose level, 
or to add cohorts to evaluate additional dose levels. The study procedures for these 
additional subject(s) or cohort(s) will be the same as that described for other study 
subjects.
Any changes to the dosing schedule may be made only after review of all available data 
and clearance by the medical monitor(s). Any planned changes will apply to a cohort of 
subjects and not an individual subject. Changes will be communicated to the site in 
writing along with justification and data supporting the change. A modified Study 
Reference Manual (SRM), including updated Time & Events Table, will be provided to 
the sites prior to initiation of the alternative regimen.
4.3.
Decision to Proceed to Expansion phase
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Dose escalation will be considered complete when a MTD have been determined, any 
remaining subjects have completed the 28-day DLT observation period and have 
undergone all necessary sample collection procedures scheduled for the first four weeks 
on therapy (e.g., the on-dose tumor biopsy and any associated blood draws). At that time, 
all available data (including data from subjects who prematurely discontinue therapy) 
will be compiled and summarized. The totality of the data, including safety/tolerability, 
PK, PD, and efficacy will be used to determine expansion cohort dose for GSK525762 to 
be administered in combination. Clinical activity data from evaluable subjects treated at 
or above the dose combination selected as the RP2D will be considered in the analysis of 
efficacy described in Section 9.4.4.
At the completion of dose escalation, any subjects still receiving therapy with 
GSK525762 and/or abiraterone/enzalutamide may continue receiving drug(s) until 
progression, death, withdrawal of consent, unacceptable toxicity, or completion of study 
as described in Section 5.4. Clinic visits and efficacy analysis should continue as 
described in the Time and Events Table.
4.4.
Expansion Cohorts
4.4.1.
Type and Number of Subjects
All subjects with a histologically-confirmed diagnosis of CRPC will be enrolled. Subjects 
will be enrolled based upon their most recent prior treatment (e.g. subjects who were 
most recently treated with abiraterone will be enrolled into Arm A, and subjects most 
recently treated with enzalutamide will be enrolled into Arm B). The total number of 
subjects required will depend upon the number of escalation steps required to identify the 
MTD(s). Once safe DL(s) are identified, the dose expansion phase will open and subjects 


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with a histologically-confirmed diagnosis of CRPC will be randomized based on prior 
lines of therapy (L2 or Lx). For both Arms, each dose level cohort may enroll or 
randomize up to 30 subjects. Subjects from both dose escalation and dose expansion may 
be combined to reach 30 subjects. If only one DL is opened for dose expansion, subjects 
will continue to be enrolled and their prior line of therapy (L2 or Lx) will be collected, 
but subjects will not be randomized. 
Refer to Section 9.1.1 for the statistical rationale for the number of subjects to be 
enrolled.
During dose expansion, subjects will not be replaced if they prematurely discontinue 
therapy.
4.4.2.
Dose Selection
For both Arms, it is anticipated that the two most tolerable dose level combinations per 
arm will be carried forward into expansion cohorts. If data warrants, only one dose level 
combination may be carried into dose expansion. 
4.4.3.
Statistical Design
During dose expansion, each combination cohort will employ a Bayesian adaptive design 
that allows the trial to be frequently monitored with the constraint of both Type I and 
Type II error rates. This design allows the enrollment to be halted due to futility. For 
details of the design and decision rules, refer to Section 9.1.2. 
Inference stemming from the Bayesian probabilities of efficacy and tolerability in 
subjects harboring mCRPC are intended to inform decision making. Actual decisions will 
depend on the totality of the efficacy and safety data. The decision to terminate a cohort 
will not depend solely on the results of the statistical model but will take all factors into 
account, including the results of the model, additional efficacy parameters, safety, 
tolerability, PK, and PD data. In some cases, the enrolment for a cohort won’t stop even 
if the model suggests a low likelihood of clinically meaningful utility score in that 
combination.
4.5.
Design Justification
Dose escalation will establish whether the combination of GSK525762 and 
abiraterone/enzalutamide are safe in targeted dose levels for abiraterone or targeted dose 
levels for enzalutamide. For each arm, up to 2 dose levels will be taken forward, with a 
lower and higher GSK525762 dose, either as a continuous or intermittent dose 
administration. Further evaluation will be conducted by the study team to determine if 
only 1 dose level will be required per either Arm during dose expansion.
By taking forward up to two doses per arm into dose expansion, the study may be able to 
determine the ideal dose level in combination with abiraterone/enzalutamide that can be 
defined as the RP2D for each combination. To further establish a potential signal in 


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advanced disease, both L2 and Lx subjects will be enrolled. Stratification will be utilized 
to target a total of 1/3 L2 and 2/3 Lx in each dose expansion cohort in both arms. 
4.6.
Dose Justification
4.6.1.
Drug-Drug Interactions
The risk of a pharmacokinetic drug-drug interaction between GSK525762 and
abiraterone is low; however, the risk of a drug-drug interaction between GSK525762 and 
enzalutamide is high with an anticipated significant decrease in GSK525762 exposure. 
Drugs as victim: GSK525762 appears to be primarily metabolized by cytochrome P450
(CYP) 3A4 and does not appear to be metabolized by CYP2C8, CYP2C9, or CYP2C19. 
Abiraterone acetate is hydrolyzed to active metabolite abiraterone, and the conversion is 
probably through esterase activity, and is not CYP mediated. Abiraterone is a substrate of 
CYP3A4. Drug-drug interaction studies using a strong CYP3A4 inducer (rifampin) 
reduced abiraterone exposure by 55%, suggesting avoidance of CYP3A4 inducers during 
abiraterone treatment. If a strong CYP3A4 inducer is warranted clinically, the dose of
abiraterone should be increased to 1000 mg twice daily; once the other drug is removed, 
the dose of abiraterone can decrease to the labelled 1000 mg daily indication. However, 
co-administration of a strong CYP3A4 inhibitor (ketoconazole) didn’t cause any 
meaningful clinical effects on the PK of abiraterone. 
Enzalutamide is metabolized by CYP3A4 and CYP2C8 to an active metabolite 
N-desmethyl enzalutamide and primarily eliminated by hepatic metabolism. Drug-drug 
interaction studies using a strong CYP3A4 inducer (rifampin) reduced enzalutamide 
exposure by 37%, suggesting avoidance of CYP3A4 inducers during enzalutamide 
treatment. If a strong CYP3A4 inducer must be used, the dose of enzalutamide may be 
increased to 240 mg daily; if the CYP3A4 inducer is ultimately discontinued, then the 
dose can return to 160 mg daily. 
Drugs as perpetrator: The potential for GSK525762 to inhibit the clearance of possible 
co-medications metabolized by major CYP enzymes was considered to be low. An in 
vitro study in human liver microsomes with clinically-relevant substrates of CYPs 2B6, 
2C8 and 3A4 revealed that GSK525762 did not directly inhibit these enzymes (IC50 
>100 M), nor was there any metabolism-dependent inhibition. Based on in vitro and in 
vivo data showing reduction of exposure to GSK525762 following repeated 
administration, there is a potential for GSK525762 to be a moderate inducer of CYP3A 
enzymes.
Abiraterone is an inhibitor of CYP2D6 and CYP2C8, and in a drug-drug interaction trial, 
maximum observed concentration Cmax and Area under concentration-time curve (AUC) 
of dextromethorphan (a CYP2D6 substrate) were increased. These studies suggest 
avoidance of CYP2D6 substrates along with abiraterone; and if alternative treatment 
cannot be used, consider a dose reduction of the respective CYP2D6 substrate drug. 


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Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 
inducer in humans. Co-administration of enzalutamide with substrates for CYP3A4 
(midazolam), CYP2C9 (warfarin) and CYP2C19 (omeprazole) reduced the plasma 
concentration of these respective substrates. Dose adjustments for concomitant strong 
CYP2C8 inhibitors and CYP3A4 inducers are noted. Thus, avoid concomitant use if 
possible of a strong CYP2C8 inhibitor; if clinically needed, consider lowering the dose to 
80 mg once daily. If that drug is subsequently discontinued, then the dose of 
enzalutamide can go back to 160 mg daily. 
4.6.2.
Starting Doses
GSK525762
A Phase I/II study (BET115521) with GSK525762 (as a single agent) was conducted in 
subjects with advanced solid tumors, including CRPC. Doses of 2 to 100 mg once daily
and doses of 20 mg, 30 mg and 40 mg BID were evaluated. The RP2D was determined to 
be 80 mg QD for GSK525762. Please see Section 5.3 of the GSK525762 Investigator’s 
Brochure [GlaxoSmithKline Document Number 2011N113741_07, 2018], which details 
the clinical experience to date with GSK525762 and clinical safety data in the solid tumor 
population up to 100 mg once daily and in the hematologic malignancy population up to 
120 mg once daily.
The initial dose of GSK525762 in dose escalation administered in combination with 
abiraterone will be reduced to 60 mg besylate salt tablets, which represents an 
approximate 20% dose reduction from the single-agent RP2D. 
At clinically relevant doses, enzalutamide has been shown to be an inducer of CYP3A4, 
with an 86% decrease in midazolam exposure. Enzalutamide also has the potential to be a 
clinical inducer and inhibitor of the transport protein P-glycoprotein. The initial dose of 
GSK525762 in dose escalation administered in combination with enzalutamide will be 
80 mg besylate salt tablets. It is anticipated that enzalutamide will reduce the steady-state 
exposure (AUC) to GSK525762 by 60% and to GSK525762 active moiety (GSK525762 
+ active metabolites) by around 20% (extrapolation of the net effect in GSK525762 
exposure due to CYP3A4/ P-gp Induction and P-gp Inhibition). Therefore, the initial dose 
of GSK525762 in both arms should be approximately equivalent. 
Enzalutamide:
For enzalutamide (Xtandi), doses ranging from 30 to 600 mg have been administered to 
subjects with CRPC [Scher, 2010]. A dose of 160 mg has been studied extensively in 
Phase 3 studies and has shown superior clinical activity [Xtandi, 2015]. The currently 
approved dose of enzalutamide is 160 mg orally once daily. It can be given with or 
without food and should be taken at the same time each day. Capsules cannot be chewed, 
dissolved externally or opened.  
As it is not anticipated that GSK525762 will impact the pharmacokinetics of 
enzalutamide, for the purpose of initial dosing, enzalutamide will be started at the 
approved dose of 160 mg once daily orally. 


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This same dose will also be used during the lead in period for subjects who have 
discontinued enzalutamide prior to coming onto this study.
Abiraterone:
For Abiraterone (Zytiga), doses ranging from 250 to 2000 mg have been administered to 
subjects with CRPC [Attard, 2008]. A dose of 1000 mg has been studied extensively in 
Phase 3 studies and has shown superior clinical activity [Zytiga, 2015]. The currently 
approved dose of abiraterone is 1000 mg orally once daily. Additionally, as per 
abiraterone label, 5 mg twice daily prednisone must be administered. Administration of 
Abiraterone orally is done in a fasted state with the prescribing information suggesting no 
food 2 hours prior to and for at least 1 hour after abiraterone dosing. Tablets must be 
swallowed with water and cannot be crushed or chewed.
As it is not anticipated that GSK525762 will have a major impact on the 
pharmacokinetics of abiraterone, for the purpose of initial dosing in the Phase 1 portion, 
abiraterone will be started at the approved dose of 1000 mg once daily orally in fasted 
conditions with co-administration of prednisone. 
4.6.3.
Overlapping Toxicities
As monotherapy, GSK525762 and enzalutamide/abiraterone have overlapping toxicity 
profiles, including effects on the hepatic, hematopoietic, gastrointestinal, and 
reproductive systems. The potential for additive severity and incidence of these adverse 
events exists. 
Due to the anticipated reductive effect that enzalutamide is expected to have on 
GSK525762, the starting dose will remain at 80 mg once daily in combination with 
enzalutamide. The likelihood that GSK525762 or abiraterone will have an effect on the 
PK of the other is low. The AE profiles of both agents, however, contain some common 
toxicities. To reduce the risk of toxicity and assess the safety and tolerability of the 
combination, the starting dose of GSK525762 will be reduced to 60 mg once daily in 
combination with the approved dose of abiraterone. Lower exposures (either via lower 
dose or intermittent dosing) may be evaluated if the starting doses of either proves to 
yield unacceptable toxicity. 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK525762 can be found in the Investigator Brochure. GSK525762 data provided in 
Section 4.6.3 reflects study treatment related AEs across all dose levels administered in 
the single-agent BET115521 solid tumor study as described in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2011N113741_07, 2018]. The data cut-
off date was 29 Jan 2018. Summaries of findings from both clinical and non-clinical 
studies conducted with enzalutamide/abiraterone can be found in the Food and Drug 
Administration (FDA) package insert. The following section outlines the risk assessment 
and mitigation strategy for this protocol. 


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4.6.3.1.
Predicted Overlapping Toxicities
4.6.3.1.1.
Gastrointestinal Safety Findings
Enzalutamide: As described in the enzalutamide FDA package insert (Section 6.1) 
[Xtandi, 2015], in two randomized clinical trials with CRPC subjects, some of the most 
commonly reported adverse effects per treatment arm were gastrointestinal, including 
constipation and diarrhea. Gastrointestinal toxicity was almost predominantly Grades 1 
and 2; Grade 3 and 4 level gastrointestinal toxicity was observed in<1% subjects.
Abiraterone: As described in the abiraterone FDA package insert (Section 6.1) [Zytiga, 
2015], in two randomized clinical trials with CRPC subjects, some of the most commonly 
reported adverse effects per treatment arm were gastrointestinal, including constipation, 
dyspepsia, vomiting and diarrhoea . Gastrointestinal toxicity was almost predominantly 
Grades 1 and 2; Grade 3 and 4 level gastrointestinal toxicity were observed in<1% 
subjects.
GSK525762: Gastrointestinal effects were frequently the dose-limiting toxicities in non-
clinical animal studies of GSK525762. Dogs, rats and mice treated with repeated doses of 
GSK525762 experienced reduced body weight, ulceration/inflammation of the 
gastrointestinal (GI) tract, and abnormal feces. In study BET115521, drug-related GI 
events were reported, as well. Drug-related nausea was reported in 41%, decreased 
appetite was reported in 36%, diarrhea was reported in 32%, dysgeusia was reported in 
30%, and vomiting was reported in 27% of subjects. Gastrointestinal toxicity was 
predominantly Grades 1 and 2; 5% of subjects reported Grade 3 nausea, 4% reported 
Grade 3 decreased appetite, 3% reported Grade 3 vomiting, and 2% of subjects reported 
Grade 3 diarrhea. No Grade 4 GI effects were observed.
Monitoring and Management: During clinical studies, medical history, physical 
examination (including weight) and clinical laboratory assessments will be used to 
identify and assess toxicity in the GI tract. Management guidelines are included in the 
protocol for gastrointestinal toxicity. In the event of clinically significant toxicity, 
treatment will be withheld, and supportive therapy provided according to standard 
medical practice.
4.6.3.1.2.
Hepatic Safety Findings
Abiraterone: As described in the FDA package insert (Section 6.1), in the two 
randomized clinical trials, Grade 3 or 4 ALT/AST increases were observed in 4% of 
subjects that received abiraterone. In 1% of subjects, treatment was discontinued due to 
increase in liver enzymes. Subjects with elevated baseline ALT/AST experienced liver 
test elevation than those subjects with normal values. 
GSK525762: In non-clinical animal studies, non-adverse liver changes were observed in 
rats, mice and dogs including increases in bilirubin levels in rats, increased bile acids in 
rats and mice and transient, reversible increased in AST and/or ALT in rats and dogs. 
Hepatocellular necrosis was observed in a single rat at a non-tolerated dose. In the 
BET115521 clinical trial, liver effects have been noted. Cases of liver events meeting the 
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≥2X ULN) have been reported in study BET115521. Additional complicating factors 
were reported for these cases (e.g. liver metastasis and sepsis) with liver enzymes 
trending towards normal levels upon stopping GSK525762. Drug related elevated blood 
bilirubin was reported in 24%, aspartate aminotransferase (AST) elevation was reported 
in 11%, and alanine aminotransferase (ALT) elevation was reported in 8% of subjects. 
These drug related hepatic toxicities were predominantly Grades 1 and 2; 7% reported 
Grade 3 and <1% reported Grade 4 blood bilirubin increased and 2% of subjects reported 
Grade 3 AST increase. There were no Grade 4 ALT increases noted.  
Monitoring and Management: Inclusion/exclusion criteria will include hepatic 
eligibility criteria. All subjects will be monitored for hepatic dysfunction. Management 
and stopping criteria are included in the protocol as described in Appendix 2 and Section 
5.4.1.
4.6.3.1.3.
Hematopoietic Safety Findings
Abiraterone: As described in the FDA package insert (Section 6.1), abiraterone was 
associated with anemia in >2% of subjects.
GSK525762: In non-clinical studies of GSK525762, lymphoid / hematologic toxicity 
was observed in rats, mice 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 (rat); decreased white cell /lymphocyte/platelet count and variable and 
inconsistent changes in multiple red blood cells parameters and reticulocyte counts.
Effects were generally reversible but minimal bone marrow cellularity was still evident in 
rats following an off-dose period.
In the BET115521 clinical trial, thrombocytopenia has been observed in subjects with 
solid tumors mainly at doses of 60 mg and above. Thrombocytopenia was only noted 
after more than a week of continuous dosing, and platelet counts recovered after cessation 
of the drug. Drug related thrombocytopenia was reported in 59%, anemia was reported in 
29%, international normalized ratio increased was reported in 14%, prothrombin time 
prolonged in 12% and coagulation factor VII level decreased in 10% of subjects. These 
AEs were mainly Grade 1 or 2; with Grade 3 thrombocytopenia reported in 22%, Grade 3 
anemia reported in 12% and Grade 3 factor VII decrease in 4% of subjects. Grade 4 
thromobocytopenia was reported in 16%, anaemia in 1% and factor VII decrease in 4% 
of subjects. 
Mild to severe hemorrhagic events have been observed during the use of GSK525762, 
primarily during occurrences of moderate to severe thrombocytopenia. Most events have 
been associated with confounding factors beyond thrombocytopenia such as disease 
under study, and/or with metastases to affected areas, low molecular weight heparin use 
and previous radiation. There have been SAEs noted of decrease in Coagulation Factor 
VII. Refer to IB for additional details [GlaxoSmithKline Document Number 
2011N113741_07, 2018].
Monitoring and Management: Inclusion/exclusion criteria will require appropriate 
baseline hematologic and coagulation values prior to enrolment. Subjects will undergo 


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frequent complete blood count (CBC) measurements, and management guidelines 
(Appendix 2) are included in the protocol to guide dose interruption/reduction decisions.
4.6.3.1.4.
General Toxicity Findings
Enzalutamide: As described in the enzalutamide FDA package insert (Section 6.1), in 
two randomized clinical trials with CRPC subjects, asthenia/fatigue were reported as a 
more common adverse reaction in both studies. In study 1, subjects with mCRPC 
following chemotherapy, all grades of asthenia/fatigue occurred more commonly (≥2% 
over placebo; 50.6% vs. 44.4%). In this study, the occurrence of Grade 3-4 AEs was 
similar in both the enzalutamide and placebo arms. In study 2, subjects with 
chemotherapy-naive mCRPC, all grades of asthenia/fatigue occurred more commonly 
(≥2% over placebo; 46.9% vs. 33.0%). In this study, the occurrence of Grade 3-4 was 
similar in both the enzalutamide and placebo arms. It was noted that this was the most 
common AE leading to treatment discontinuation which occurred in 1% of subjects in 
both arms. 
Abiraterone: As described in the FDA package insert (Section 6.1), abiraterone was 
associated with fatigue in >2% of subjects. 
GSK525762: In the BET115521 study, 25% of subjects reported fatigue and 24% 
reported asthenia. Most of these AEs were Grade 1 or 2; with Grade 3 asthenia reported 
in 9% and Grade 3 fatigue in 3% of subjects. No Grade 4 asthenia/fatigue AEs were 
reported. 
Monitoring and Management: Medical and previous therapy history will be used to 
identify and assess whether these effects have been previously experienced by subjects, 
the severity and if withholding ADT was required. These affects are generally managed 
by rest and withholding treatment if fatigue is intolerable. 
4.6.4.
Predicted Single-Agent Toxicities
4.6.4.1.
Cardiovascular Safety Findings
GSK525762: Reversible changes in the corrected QT (QTc) interval were noted in dogs 
in single- and repeated-dose studies. In addition, reversible increases in biomarkers of 
cardiac damage (cardiac troponin T, myosin light chain and/or cardiac troponin I) were 
also seen in the rat and dog. Despite these QTc and cardiac biomarker changes, there was 
no evidence of compound-related myocardial necrosis or other histopathological changes 
in cardiac tissue of either species. 
An internal safety review of categorical analysis of QTc increase (and decrease) from 
baseline of 271 subjects dosed up to 100 mg in the BET115521 and up to 120 mg in the 
BET116183 clinical trials demonstrated a clinically negligible effect on QTc. Based on 
this analysis, the entry and stopping criteria have been modified. 
Monitoring and Management: Subjects will be monitored closely for changes in QTc 
with 12-lead ECG and for elevations in plasma troponin. Safety ECGs will be performed 
at the time points specified in Time and Events tables (Section 7.1) using a standard 12-
lead ECG machine that automatically calculates the heart rate (HR) and measures PR, 
QRS, QT and QTcF intervals. As clinically indicated, the mean from triplicate ECGs will 


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be evaluated. Safety ECGs will be reviewed by the investigator on an ongoing basis for 
safety purposes. Dosing should not begin until the safety ECG has been reviewed and no 
significant abnormalities have been detected. 
To monitor for cardiomyopathy, echocardiograms will be performed at the time points 
specified in the Time and Events tables (Section 7.1). Management guidelines (Appendix 
2) and stopping criteria (Section 5.4.2 and Section 5.4.3) are incorporated in the protocol.
Laboratory evaluations for cardiac troponins and electrolytes (including potassium and 
magnesium) will be performed at baseline and at regular intervals (as specified in the 
Time and Events tables), and when clinically warranted during the study treatment. 
Troponin I or T (based on availability) levels will be tested by a local laboratory. 
Appropriate medical therapy will be provided by the investigator for any clinically 
significant increase in troponins including withholding or discontinuing the study 
medication. Appropriate medical management will be instituted to assure that electrolytes 
are kept within the normal range.
4.6.4.2.
General toxicities
Enzalutamide: As described in the enzalutamide FDA package insert, any enzalutamide 
related toxicities, as determined by the Investigator, will require at least a one week hold 
of enzalutamide until a return to ≤Grade 2 toxicity. 
Monitoring and Management: Subjects will be monitored according to the management 
guidelines (Appendix 2).
4.6.4.3.
Seizure
Enzalutamide: As described in the enzalutamide FDA package insert (Section 6.1), in 
two randomized clinical trials with CRPC subjects, 7 of 800 (0.9%; study 1) and 1 of 871 
(0.1%; study 2) subjects experienced seizure. 
Monitoring and Management: Exclusion criteria include history of seizure or any 
condition that may predispose subject to seizure (e.g., prior cortical stroke or significant 
brain trauma), and subjects will be monitored. Enzalutamide should be permanently 
discontinued in subjects who develop a seizure during treatment. 
4.6.4.4.
Posterior Reversible Encephalopathy Syndrome (PRES)
Enzalutamide: As described in the enzalutamide FDA package insert (Section 6.1), there 
have been reports of PRES in subjects receiving enzalutamide. 
Monitoring and Management: Subjects will be monitored according to the management 
guidelines and brain magnetic resonance imaging (MRI) is mandated if clinically 
required. Enzalutamide should be permanently discontinued in subjects who develop a 
seizure during treatment.


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4.6.5.
Risk Assessment
The toxicities listed below are a summary of those most likely to be observed in clinical 
practice, or are of special interest. For a full list of predicted and observed toxicities, refer 
to the GSK525762 IB and the FDA package insert for enzalutamide/abiraterone.
4.6.6.
Benefit Assessment
Study 204697 is a Phase I dose-escalation and expansion study, and the first comparative 
study of a BET inhibitor in combination with the next generation AR-targeting agents 
abiraterone or enzalutamide in men with metastatic or advanced CRPC who have 
progressed on abiraterone or enzalutamide. 
Both GSK525762 and abiraterone/enzalutamide have been administered as single agents 
to men with mCRPC. Abiraterone and enzalutamide are currently approved as single 
agent to treat mCRPC. Data from the first in human study with GSK525762 used as a 
single agent to treat late stage mCRPC subjects is preliminary, but indicates at least 
minimal activity as evidenced by fluorodeoxyglucose (FDG)-positron emission 
tomography (PET) response and decrease in bone pain. Additional data is being collected 
at the single agent RP2D. 
Study 204697 is based on the hypothesis that adding the BET inhibitor GSK525762 to 
androgen deprivation therapy (ADT) will overcome resistance to ADT. If successful, the 
main benefits are two-fold – i) provides a new treatment regimen for mCRPC that will be 
an added option for treatment of subjects who fail single agent ADT and may prolong 
survival; ii) for mCRPC patient who fail first line ADT, the scope to delay chemotherapy.
4.6.7.
Overall Benefit: Risk Conclusion
The adverse event profile for abiraterone and enzalutamide are well known and guidance 
is available on the label for dose modification in the event of defined AEs. The adverse 
event profile of GSK525762 is evolving, but data is available from more than 150 
subjects treated and management algorithms are available for the most common as well 
as serious AEs. Totality of the data indicates that overlapping toxicity in combination will 
most likely be hepatotoxicity, for which monitoring and stopping rules are built into the 
study. Extensive PK sampling and adverse event profile will be used to determine dosing 
levels and RP2D. If any one of the combinations is found to be tolerable and meeting 
efficacy targets set out in the study, then a randomized controlled Phase 2 study will be 
designed to establish the benefits outlined the Section above. This may provide additional 
lines of treatment for subjects with mCRPC who progress on current regimens based on 
ADT.
Taking into account the measures taken to minimise the risk to subjects participating in 
Phase I clinical trials, and potentially enriching for CRPC subjects who may respond to 
the combination of a BET inhibitor and an AR antagonist, the potential risks identified in 
association with GSK525762 and abiraterone/enzalutamide are justified by the 
anticipated benefits that may be afforded to subjects with advanced or metastatic CRPC, 
who have failed prior therapies.


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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s) for 
GSK525762 and the enzalutamide/abiraterone product label.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Written informed consent provided
2. Males 18 years of age (at the time written consent is obtained for screening)
3. Histologically confirmed adenocarcinoma of the prostate: 
a.
Screening and on-treatment biopsy is mandatory. If adequate number of paired 
biopsy samples are collected (≥ 20 paired samples for each dose level in each 
Arm, unless an Arm is closed early), then further biopsy sampling will be 
considered based on available data. 
b. Screening biopsy can be waived if patient had a recent biopsy after failure of the 
most recent therapy (within 30 days) and the biopsy sample is secured to be sent 
as screening biopsy for this study.
4. Surgically or medically castrated, with testosterone levels of 50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior 
to Week 1 Day 1 and must be continued throughout the study.
5. Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 
a.
Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide in any prior line
b. Lead-in dosing period for enzalutamide only will be required under the following 
circumstance: 
i. If the subject has enzalutamide discontinuation for >7 days prior to dosing 
start with GSK525762 plus enzalutamide on trial, then an enzalutamide only 
lead-in dosing of 28 days is required
ii. If the subject has enzalutamide discontinuation for ≤7 days prior to dosing 
start with GSK525762 plus enzalutamide on trial, then an enzalutamide only 
lead-in dosing of 14 days is required


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iii.
If the subject is on continuous dosing with enzalutamide prior to dosing 
start with GSK525762 plus enzalutamide on trial, then subject can start on 
combined dosing at end of screening period.
c.
Lead-in dosing period for abiraterone only will be required under the following 
circumstance: 
i. If the subject has abiraterone discontinuation for more than 3 days prior to 
dosing start with GSK525762 plus abiraterone on trial, then an abiraterone 
only lead-in dosing of 7 days is required
6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy.
7. Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.
PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be 
≥5 ug/L (5 ng/mL) if PSA is the only indication of progression; subjects on 
systemic glucocorticoids for control of symptoms must have documented PSA 
progression by PCWG3 while on systemic glucocorticoids prior to commencing 
Week 1 Day 1 treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
(Appendix 5) criteria or bone metastasis with 2 or more documented new bone 
lesions on a bone scan/ CT scan with or without PSA progression
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Life expectancy > 12 weeks
10. Able to swallow and retain orally administered medication
11. Adequate organ function as defined in Table 5.


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Table 5
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
White blood cells
Absolute neutrophil count (ANC)
>3 X 109/L
1.5 X 109/L
Hemoglobin
9 g/dL (subjects that required transfusion or growth 
factor need to demonstrate stable hemoglobin for 7 
days of 9 g/dL)
Platelets
100 X 109/L
Prothrombin time (PT)/International normalized 
ration (INR) and Partial thromboplastin time (PTT)
≤ 1.5 X upper limit of normal (ULN)
Hepatic
Albumin
≥2.5 g/dL
Total bilirubin
Aspartate transaminase (AST)
≤1.5 x ULNa
2.5 ULN
Alanine transaminase (ALT) 
2.5 ULN OR <5x ULN is acceptable for subjects 
with documented liver metastases/tumor infiltration
Renal
Creatinine
OR
Creatinine clearance [either directly measured or 
calculated by Cockcroft-Gault formulab]
≤1.5 X ULN the institutional upper limit of normal 
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by echocardiogram or MUGA and minimum of 
50% LVEF
Troponin (I or T)
≤ ULN
Other 
Testosterone
≤50 ng/dL
a.
Isolated bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin <35% or 
subject has a diagnosis of Gilbert’s syndrome
b.
Refer to Appendix 4 for Cockcroft-Gault formula
NOTE: Laboratory results obtained during Screening should be used to determine 
eligibility criteria. In situations where laboratory results are outside the permitted 
range, the investigator may opt to retest the subject and the subsequent within range 
screening result may be used to confirm eligibility. 
12. Male Participants: Contraceptive use by men or female partner should be consistent 
with local regulations regarding the methods of contraception for those participating 
in clinical studies. 
Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 16 weeks after the last dose of study treatment:

Refrain from donating sperm
PLUS either:


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
Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent.
OR

Must agree to use contraception/barrier as detailed below:
Agree to use a male condom and female partner to use an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in Appendix 
12 when having sexual intercourse with a woman of childbearing potential who is 
not currently pregnant.   If partner becomes pregnant, agree to use/continue use of 
condoms until 16 weeks after the last dose of study medication.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of Week 1 Day 1. 
2. Subjects with neuroendocrine and/or small cell CRPC
3. Recent prior therapy, defined as:
a.
Any investigational or approved non-biologic anti-cancer drug (see exception 
below) within 14 days prior to the first dose of GSK525762 and 
abiraterone/enzalutamide
Exception: For allowed androgen deprivation therapy (hormonal, abiraterone, 
enzalutamide), refer to inclusion criteria. Concomitant prednisone (or equivalent) 
allowed in combination with abiraterone dosing.  
b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of 
GSK525762 and abiraterone/enzalutamide
c.
Any anti-cancer biologic agents within five half-lives prior to the first dose of 
GSK525762 and abiraterone/enzalutamide
d. If the subject received radiotherapy < 90 days prior to study treatment, the 
irradiated lesion cannot be the only lesion used for evaluating response.
Exception: Any radiotherapy within 14 days prior to the first dose of GSK525762 
and abiraterone/enzalutamide must be limited to a single fraction of radiotherapy 
for the purpose of palliation (confined to one field) is permitted.
e.
Any major surgery within 28 days prior to the first dose of GSK525762 and 
abiraterone/enzalutamide
4. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, in 
the opinion of the Investigator.


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a.
Systolic blood pressure higher than 150 mmHg or diastolic blood pressure higher 
than 90 mmHg found on 2 separate occasions separated by 1 week, despite 
adequate therapy, will be defined as uncontrolled hypertension. 
b. Uncontrolled diabetes mellitus (despite therapeutic, compliance intervention) as 
defined by a hemoglobin A1c (HbA1c) level more than 8% and/or occurrence of 
more than 2 episodes of ketoacidosis in the 12 months prior to the first dose of 
study drug. 
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QTcF interval ≥480 msec 
b. Clinically significant conduction abnormalities or arrhythmias, such as subjects 
with second degree (Type II) or third degree atrio-ventricular block
c.
History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).
d. History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects 
with a history of stent placement requiring ongoing anti-coagulant therapy (e.g., 
clopidogrel, prasugrel) will not be permitted to enroll.
NOTE: Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.
e.
Known cardiac metastasis
6. Subjects with history of known bleeding disorder(s) or history of clinically significant 
hemorrhage (e.g., GI, neurologic), within the past 6 months
7. Therapeutic-dose anticoagulation (e.g., warfarin, low-molecular weight heparin 
[LMWH], or novel oral anticoagulants) must be discontinued and coagulation 
parameters must be normalized prior to the first dose of GSK525762 and 
abiraterone/enzalutamide. Prophylactic anticoagulation, with low doses (per standard 
practice) of agents such as low molecular weight heparin (LMWH), direct thrombin 
inhibitors, or factor Xa inhibitors is permitted. 
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed or 100 
mg, as per country standards) and non-steroidal anti-inflammatory drugs (NSAIDS), 
except for where NSAIDs provide documented benefit over other analgesics, and then 
to be used with caution including concomitant use of proton pump inhibitors.
9. Any acute toxicities due to prior chemotherapy and / or radiotherapy that have not 
resolved to a NCI-CTCAE v4 [NCI-CTCAE, 2009] grade 1 with the exception of 
chemotherapy induced alopecia and grade 2 peripheral neuropathy. 
10. The patient has an active second malignancy other than curatively resected basal cell 
or squamous cell carcinoma of the skin, in situ carcinoma of the bladder, or other 
cancers for which they are treated with curative intent with no active disease in the 3 
years prior to enrollment. 
11. Subjects with known symptomatic brain metastasis are not suitable for enrolment. 
Subjects with asymptomatic, stable, treated brain metastases are eligible for study 
entry. 


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12. History of seizure within 6 months of study treatment initiation or any condition that 
may predispose subject to seizure (e.g., prior cortical stroke or significant brain 
trauma) or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital (see Section 6.11.1). 
13. History of loss of consciousness or transient ischemic attack within 12 months prior 
to enrollment
14. Subjects with symptomatic or impending cord compression unless appropriately 
treated beforehand and clinically stable and asymptomatic. 
15. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications that are potent inducers or inhibitors of CYP3A4 enzymes or strong 
inhibitors of CYP2C8 (see Section 6.11.2 for the list of prohibited medications).
16. Subjects with gastrointestinal disorders likely to interfere with absorption of the study 
medication 
17. Subjects with known bleeding diathesis will be excluded from the study.
18. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease 
per investigator assessment).
19. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to Week 1 Day 1. Subjects on a stable bisphosphonate or denosumab 
therapy are eligible and may continue. 
20. Any serious known immediate or delayed hypersensitivity reaction to GSK525762 or 
idiosyncrasy to drugs chemically related to the investigational drugs. Additionally, 
any known hypersensitivity to either enzalutamide, abiraterone or any excipients 
would be excluded.
21. Known history of human immunodeficiency virus (HIV)
22. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening.
NOTE: Subjects with positive hepatitis C antibody due to prior resolved disease can 
be enrolled only if a confirmatory negative hepatitis C RNA PCR is obtained. 
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (Appendix 8). Run-in failures are 
defined as subjects who start the run-in of either abiraterone or enzalutamide and 
withdraw from this run-in and do not proceed to dose with GSK525762.


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5.4.
Withdrawal/Stopping Criteria
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry, hematologic/non-
hematologic toxicity, QTc prolongation, or left ventricular ejection fraction 
(LVEF)/valvular dysfunction as defined in Section 5.4.1 through Section 5.4.3. Subjects 
may be permitted to continue on therapy in the setting of equivocal progression (e.g., 
rising tumor markers early in therapy in the absence of confirmed radiographic 
progression, or equivocal radiographic imaging as described in Appendix 5) provided that 
the subject is not experiencing significant toxicity, the investigator believes (and the 
medical monitor concurs) that the subject may continue to receive benefit, and the subject 
has no other reasonable option for therapy that will provide long-term control of disease.
In addition, study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the subject or proxy (withdrawal of consent by subject or proxy)

investigator’s discretion

subject is lost to follow-up 

study is closed or terminated

a dose delay of >14 days unless the investigator and Medical Monitor agree that 
further treatment may benefit the subject

A subject may withdraw from study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioural or administrative reasons. All subjects who discontinue from study 
treatment will have safety assessments at the time of discontinuation and during 
post-study treatment follow-up as specified in Time and Events Table (Section 
7.1).

If a subject withdraws consent from the study, no further assessments will be 
completed, he/she may request destruction of any samples taken, and the 
investigator must document this in the site study records. 
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s 
last known mailing address or local equivalent methods). These contact 
attempts should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost 
to Follow-up”. 


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The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF). 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event 
(AE)’ will be recorded as the primary reason for permanently discontinuation on the 
eCRF.  
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated. 
During dose escalation, specific dosing regimen(s) may be terminated if they are unable 
to be tolerated in an acceptable proportion of subjects. These regimen(s) will not be 
carried forward into expansion phase. Any subject receiving a terminated regimen may 
continue to receive that regimen, so long as that subject does not experience unacceptable 
toxicity, or else be switched to a previously cleared dose at the discretion of the 
investigator after discussion with the medical monitor.
During dose expansion, unless a dose level is closed early, survival follow-up will 
continue in each cohort until approximately 70% of the total number of subjects have 
progressed or died. At such time, all cohorts will be closed and any further follow-up on 
subjects enrolled in each cohort will cease. 
Subjects who require permanent discontinuation of either abiraterone or enzalutamide the 
given combination may continue GSK525762 as a single agent if there is evidence of 
continuing benefit on treatment until disease progression, withdrawal of consent, 
unacceptable toxicity, or closure of the study.
At the time of study completion, subjects with radiologically confirmed lack of disease 
progression (dose escalation and expansion phase) who are still receiving GSK525762 
and/or abiraterone/enzalutamide may continue treatment through a separate mechanism 
(e.g., roll-over protocol) to be determined at that time. 
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
See Figure 6 and Figure 7 for liver stopping criteria for subjects without and with liver 
metastases, respectively. The algorithms are best read from left to right.


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Figure 6
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6


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Figure 7
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria 
ALT>2.5xULN but ≤5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
5.4.1.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 7 for full guidance. 
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.


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5.4.2.
QTc Stopping Criteria
For the purposes of this study, the corrected QT (QTc) is the QT interval corrected for 
heart rate according to Fridericia’s formula (QTcF; defined as [QT/(RR1/3)]). QTcF will 
be used for all subjects for purposes of eligibility, data analysis, and withdrawal. The 
QTcF should be based on averaged QTcF values of triplicate electrocardiograms obtained 
over a brief (e.g., 5-10 minute) recording period. 
Study treatments will be withheld if either of the following occurs:

QTcF interval ≥500 msec AND 60 msec change from baseline 

QTcF interval ≥530 msec AND <60 msec change from baseline
In either case, both GSK525762 and abiraterone/enzalutamide will be discontinued 
unless the benefits of therapy outweigh the risk of rechallenge in the opinion of the 
investigator, the Medical Monitor, as well as GSK medical governance. In this situation, 
rechallenge may be permitted (see Appendix 2 for rechallenge guidelines).
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.
5.4.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
Echocardiography (ECHO) or MUGA scan must be performed at Screening and 
periodically throughout the study as outlined in the Time and Events Table (Section 7.1). 
Please refer to the LVEF management guidelines in Appendix 2 of the protocol for 
further detail.
Copies of all scans and cardiology consultations performed on subjects who experience a 
>10% decrease in LVEF from baseline and whose cardiac ejection fraction is 
<institution’s LLN will be required by GSK, or designee, for review. Instructions for 
submitting qualifying scans are provided in the SRM.
5.4.4.
Other Stopping Criteria
To monitor for hematologic toxicity, CBCs will be drawn twice during the first week 
(includes screening), weekly for the next four weeks of study, and then every four weeks, 
as described in the Time and Events table. Subjects who develop Grade 3 or greater 
anemia or thrombocytopenia may be monitored more frequently, as clinically indicated. 
Please see Appendix 2 for suggested management of hematologic toxicity.
Safety will be reviewed on an ongoing basis by the Safety Review Team (SRT) which 
will be compromised of, at a minimum, a medical monitor, GSK Global Safety 
representative, and clinical study representative (including a representative from 
Biostatistics). All events of potential causality, including deaths, SAEs, and Grade 3/4 
adverse events, will be carefully evaluated.
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.


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5.5.
Subject and Study Completion
A subject will be considered to have completed the study if they are followed until death.
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study. The End of Study eCRF should only be completed when a 
subject is no longer being followed. The study will be considered completed for purposes 
of a final analysis when 70% of evaluable subjects enrolled have progressed or died. If 
available, subjects continuing on GSK525762 at the time of final analysis may be offered 
the option to continue it through another mechanism (eg, in a rollover trial).
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.


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Investigational Product
Product 
name:
GSK525762 Besylate Tablets
Abiraterone acetate
Enzalutamide
Unit dose 
strength(s)/Do
sage level(s):
5 mga
25 mga
20 mga
250 mg
500 mgb
40 mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Janssen
Janssen
Astellas
Physical 
description:
White to slightly 
colored, round, 
biconvex tablets 
with no markings, 
film-coated tablet
Yellowis
h-pink, 
round, 
biconvex 
tablets 
with no 
markings
, film-
coated
White to 
off-white, 
oval tablets 
debossed 
with AA250 
on one side
Film-
coated, 
purple oval 
tablets 
debossed 
with AA on 
one side 
and 500 on 
the other 
side
White to off-white oblong soft 
gelatin capsules imprinted in 
black ink with ENZ
Route/
Administratio
n/ Duration:
Oral; see Time and Event 
Tables for schedule and 
administration timings
Oral; see Time and Event 
Tables for schedule and 
administration timings
Oral; see Time and Event 
Tables for schedule and 
administration timings
Dosing 
instructions:
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
Dose with 240 mL water 
and should be taken on an 
empty stomach, and no 
food should be consumed 
from 2hrs before the dose 
until 1hr after the dose. 
Dose 5 mg prednisone 
orally twice daily as per 
prescribing information. 
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
NOTE: These formulation details are current at the time of protocol finalization and may be updated in other 
documents (e.g., SRM and/or informed consent form) without requiring protocol amendment
a.
The 20 mg tablet formulation is in development and will be utilized during the planned duration of the study. 
The 5 mg and 25 mg tablet formulation may be discontinued when the 20 mg tablet formulation is available. 
The use of 20 mg tablets will require regulatory authority approvals.  
b.
The 500 mg tablet may be supplied dependent on the availability by Janssen. The use of 250 mg tablet 
formulation may be discontinued when 500 mg tablet is available
6.2.
Treatment Assignment
Subjects will be assigned to receive GSK525762 and abiraterone/enzalutamide in an 
open-label fashion. Subjects will be identified by a unique subject number that will 
remain consistent for the duration of the study.
For Arm A, during the initial evaluation of DL60, approximately 3 to 10 subjects will be 
enrolled until it is determined that DL60 does not exceed the MTD. Due to emerging data 
(safety/tolerability/efficacy), additional dose levels may be explored. These dose levels 
may either be a lower daily dose level or an intermittent dose schedule, either at a dose 
level where daily treatment may be intolerable or at a lower dose. For example, if DL60 
exceeds the maximum permitted toxicity rate, then intermittent dosing at 60 mg dose 


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level (DL60 ALT) and/or a lower daily dose level (DL-1, 40 mg) may be evaluated). If 
DL60 has been cleared in dose escalation, approximately 6 to 10 subjects will be enrolled 
in the DL80 cohort for evaluation of dose escalation. If any dose level cohort is opened, 
but exceeds the maximum permitted toxicity rate, then additional subjects will not be 
enrolled at that dose level. Subjects enrolled during dose escalation will continue 
treatment and will not roll into dose expansion.
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be randomized into 2 expansion cohorts and will be based on prior lines of 
therapy (L2 or Lx). A maximum of up to 30 subjects each (in addition to those enrolled in 
dose escalation) will be enrolled into each dose level cohort.
If either dose level cohort is filled or terminated, then all subjects will be enrolled in the 
remaining prior treatment-specific cohort until it is filled or terminated. 
For Arm B, as enzalutamide is a known CYP3A4 inhibitor, and DDI could potentially 
lower the exposure of GSK525762 levels, the planned dose levels are expected to provide 
equivalent doses similar to those being examined in Arm A. 
During the initial evaluation of DL80, approximately 3 to 10 subjects will be enrolled 
until it is determined that DL80 does not exceed the MTD. Due to emerging data 
(safety/tolerability/efficacy), additional dose levels may be explored. These dose levels 
may either be a lower daily dose level or an intermittent dose schedule, either at a dose 
level where daily treatment may be intolerable or at a lower dose. For example, if DL80
exceeds the maximum permitted toxicity rate, then intermittent dosing at 80 mg dose 
level (DL80 ALT) and/or a lower daily dose level (DL-1, 60 mg) may be evaluated. If 
DL80 has been cleared in dose escalation, approximately 3 to 10 subjects will be enrolled 
in the DL100 cohort until it is determined that DL100 does not exceed the MTD. If any 
dose level cohort is opened, but exceeds the maximum permitted toxicity rate, then 
additional subjects will not be enrolled at that dose level. 
An additional dose level, DL120, may be initiated after careful review of the PK and 
safety data from the DL80 and DL100 dose levels. If the DL120 cohort is opened, it will 
enrol approximately 3 to 10 subjects until it is determined whether DL120 does not 
exceed the MTD. Subjects enrolled during dose escalation will continue treatment and 
will not roll into dose expansion. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated and eligible subjects may be randomized by prior lines of therapy 
(L2 or Lx). A maximum up to 30 subjects each (in addition to those enrolled in dose 
escalation) will be enrolled into each dose level cohort. If only one dose level is tolerable 
for dose expansion, subjects will be enrolled and not randomized.
6.3.
Planned Dose Adjustments
There are no pre-planned dose adjustments per protocol. Dose reductions for individual 
subjects may be required, based on toxicity observed during the study (please refer to 
Appendix 2), and the frequency and duration of dose reductions will be reported. Table 6
clarifies the dose reductions for GSK525762 at any planned study dose. 


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Table 6
GSK525762 Dose Reductions
Current GSK525762 Dose: 
If subject requires dose level reduction: 
40 mg
No further dose reduction allowed
60 mg
40 mg
80 mg
60 mg
100 mg
80 mg
120 mg
100 mg
If enzalutamide is discontinued for more than or equal to 7 days, then the dose of 
GSK525762 should be reduced one dose level and the maximum dose of GSK525762 
should be the single agent RP2D of 80 mg. If enzalutamide is re-started, GSK525762 
should remain at the reduced dose level or the maximum single agent RP2D of 80 mg 
until after at least 14 days until the dose is escalated, if applicable. Subjects who require 
permanent discontinuation of either abiraterone or enzalutamide in the combination may 
continue GSK525762 as a single agent if there is evidence of continuing benefit on 
treatment. If GSK525762 is continued as a single agent, the maximum dose would be 
80 mg. Intra-subject dose escalations from the planned starting dose during dose 
escalation will not be permitted. Intra-subject dose escalation may be permitted during 
dose expansion for the lower dose level only if that dose is determined to be futile.
Based on dose table (Table 6) and effect of enzalutamide on GSK525762, no dose 
level/schedule of less than 40 mg QD will be allowed for Arm B. If a subject is on an 
alternate dosing schedule and requires a de-escalation to 40 mg, then the subject must 
move to 40 mg QD.
During any dose interruption of GSK525762, abiraterone or enzalutamide may be 
continued at the protocol dose unless dose interruption of these combination products is 
also required. If GSK525762 is permanently discontinued, subject must be discontinued 
from the abiraterone or enzalutamide treatment and withdrawn from the study. 
6.4.
Blinding
This is an open-label study which does not require blinding. 
6.5.
Packaging and Labeling
GSK525762 and abiraterone/enzalutamide will be provided to the sites by GSK. 
Prednisone will not be supplied by GSK. The contents of the labels will be in accordance 
with all applicable regulatory requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.


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
Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure environmentally controlled and 
monitored (manual or automated) area in accordance with the labelled storage 
conditions with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, 
and record maintenance (i.e. receipt, reconciliation and final disposition 
records). 

Further guidance and information for final disposition of unused study 
treatment are provided in the SRM. 
Limited exposure and precautionary action (e.g., wearing gloves, washing hands post 
exposure, etc.) should be taken by site staff dispensing GSK525762. A Material Safety 
Data Sheet (MSDS)/equivalent document describing occupational hazards and 
recommended handling precautions either will be provided to the investigator, where this 
is required by local laws, or is available upon request from GSK.
6.7.
Compliance with Study Treatment Administration
At each visit, an evaluation of subject compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant subjects into 
compliance. 
When subjects are dosed with GSK525762 or abiraterone/enzalutamide at the site, they 
will receive study treatment directly from the investigator or designee, under medical 
supervision. The date and time of each dose administered in the clinic will be recorded in 
the source documents. The dose of study treatment and study subject identification will 
be confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study treatment. 
Compliance of study treatment administration will be assessed through querying the 
subject during the site visits, review of subject dosing diaries and documented in the 
source documents and eCRF. 
A record of the number of GSK525762 and abiraterone/enzalutamide 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.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK525762 or abiraterone/enzalutamide greater than the 
protocol-specified dose within a 24 hour time period (± 4 hours) will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose. 
In the event of an overdose the investigator (or treating physician) should:


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
Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK525762 and/or abiraterone/enzalutamide can no longer be detected systemically 
(at least 28 days)

Obtain a plasma sample for PK analysis within 3 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis)

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 Medical Monitor based on the clinical evaluation of the subject.
6.9.
Treatment after the End of the Study
Post study treatment will not be provided as part of the protocol. Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) therapy at 
the discretion of the treating physician. New anti-cancer therapy should be documented 
on the eCRF. Every effort should be made to complete the required withdrawal and 
follow up evaluations prior to initiating further therapy or dosing of an investigational 
agent (see Section 7.1 for follow-up assessments and procedures). 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Dietary Restrictions
Abiraterone will be administered with no food for 2 h before and 1 h after each dose, 
whereas Enzalutamide can be taken under fasting or fed conditions. GSK525762 can be 
taken under fasting or fed conditions, except on serial PK sampling days (Week [W] 1 
Day [D] 1 and W3D1) for at least 12 subjects at each dose level, as described below.
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug.
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.
On serial PK sampling days (W1D1 and W3D1 for at least 12 subjects at each dose 
level), subjects should fast overnight (i.e., at least 8 hours) and should continue fasting 
until at least 2 hours after administration of GSK525762. Fasting will consist of avoiding 
the oral ingestion of calorie-containing products; however, ingestion of water is 
permitted. 


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6.11.
Concomitant Medications and Non-Drug Therapies
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the eCRF. The minimum 
requirement is that drug name, dose and the dates of administration are to be recorded. 
Additionally, a complete list of all prior anti-cancer therapies will be recorded in the 
eCRF.
Questions regarding concomitant medications should be directed to the Medical Monitor 
for clarification.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter.
6.11.1.
Permitted Medications and Non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. The only caveat is that subjects should not receive those 
medications listed as prohibited in Section 6.11.2.1.
Bisphosphonates and denosumab will be allowed if subjects have been on a stable dose 
for at least three months prior to receiving the first doses of GSK525762 and 
abiraterone/enzalutamide.
6.11.2.
Prohibited Medications and Non-Drug Therapies
6.11.2.1.
Prohibited Medications
Subjects should not receive other anti-cancer therapy [including chemotherapy, 
immunotherapy, biologic therapy, investigational therapy, or hormonal therapy (other 
than leuprolide or other luteinizing hormone-releasing hormone (LHRH) 
agonists/antagonists)] while on treatment in this study. Requirement for additional 
systemic anti-cancer therapy will necessitate permanent discontinuation of study drugs. 
Subjects may continue to use Aspirin, but doses are not allowed to be greater than 81 mg 
per day (or 100 mg, as per country standards). The use of non-steroidal anti-inflammatory 
drugs (NSAIDs) will be excluded, except for when NSAIDs will provide benefit over 
other analgesics and then to be used with caution including concomitant use of proton 
pump inhibitors. 
Subjects taking enzyme-inducing antiepileptic agents or other potent inhibitors or 
inducers of CYP3A4 enzymes should be transitioned to another agent at least 14 days (or 
5 half-lives, whichever is longer) prior to the first dose of study agents.


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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 End of Treatment visit. Low dose (prophylactic) anticoagulants are permitted 
provided that the subject’s PT/PTT values meet entry criteria.
As described in Section 4.6, enzalutamide is an inducer of CYP3A, CYP2C9 and 
CYP2C19 at therapeutic concentrations. Medications that have a narrow therapeutic 
index and that are substrates of CYP3A or CYP2C9 or CYP2C19 should be avoided, as 
their metabolism may be affected by co-administration with enzalutamide and result in 
decreased exposure. 
6.11.2.2.
Prohibited Non-Drug Therapies
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the post-study 
follow-up visit. 
NOTE: Subjects may receive focal palliative (e.g., for management of pain or other 
local symptom) radiation treatment and/or surgical intervention during this study. 
Target lesions used for response assessment may not receive focal palliative 
therapy. Any proposed focal therapy must be approved by the investigator and the 
Medical Monitor prior to intervention.
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit. Herbal products include, but are not limited to: St. John’s Wort, 
kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, ginseng, and marijuana.
6.11.2.3.
Cautionary Medications
Subjects should minimize the use of medications which contain acetaminophen. 
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (administered per the prescribing 
information) and oral ondansetron (up to a maximum oral dose of 8 mg TID) are the only 
allowed drugs in this class (dolasetron and granisetron are not permitted). Drugs with a 
low risk of causing QTc prolongation (e.g., aprepitant) may be used without restriction.
Co-administration of GSK525762 and medications which may have an increased risk of 
Torsades de Pointes requires extreme caution beginning 14 days prior to the first dose of 
study drug until discontinuation from the study. Please reference current list of 
medications at crediblemeds.org. 
After starting cautionary medications such as any listed in the referenced internet link, it 
is recommended that ECGs are implemented daily until the steady state of the new 
medication is reached. If there are ECG abnormalities, implement additional 
cardiotoxicity monitoring as addressed Appendix 2.
As described in Section 4.6, abiraterone is an inhibitor of CYP2C8 and CYP2D6 at 
therapeutic concentrations. Medications that have a narrow therapeutic index and that are 


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substrates of CYP2C8 or CYP2D6 should be administered with caution, as their 
metabolism may be affected by co-administration with abiraterone and result in increased 
exposure. These include thiazolidinediones (e.g., rosiglitazone, pioglitazone) and 
repaglinide and thioridazine.
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.
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.
Questions regarding concomitant medications should be directed to the Medical Monitor 
for clarification.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment. The
exact timing of each assessment is listed in the Time and Events Table Section 7.1. 
The following points must be noted: 

If assessments are scheduled for the same nominal time, the assessments should 
occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments may be altered during the 
course of the study based on newly available data to ensure appropriate 
monitoring. 


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
The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. All such 
changes will be incorporated in the protocol at the next earliest amendment.

The IRB/Independent Ethics Committee (IEC) will be informed of any safety 
issues that require alteration of the safety monitoring scheme or amendment of 
the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Table
Table 7
Dose Escalation Time and Events
Procedure
SCR
Lead-In 
Dosing (if 
required)
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q12w
EOT1, 
22
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49 
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register/ Randomize4 Subject
X
Safety
Physical Exam5
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
12-lead ECGs 6
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments7
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA8
X
X
Weeks 
13, 25 
and 37
X
X
PRO-CTCAE9
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication review
Continuous from signing of informed consent
Study Treatment
Administer GSK52576210
Daily
Administer Combination 
product10,11
Daily (if 
required)
Daily
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples12


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Procedure
SCR
Lead-In 
Dosing (if 
required)
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q12w
EOT1, 
22
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49 
W49 and 
thereafter
Tumor biopsy13
X
Whole blood for exploratory 
analyses14
X
PGx blood sample15
X
Biomarker Assessments
CTC-ENU16
X
CTC – ARV17
Efficacy
Computerized Tomography 
(CT) chest/abdomen/pelvis18
X
MRI Brain19
X
Bone Scan20
X
EORTC-QLQ-C30, EORTC-
QLQ-PR25 & BPI-SF21
X
1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. With the implementation of amendment 04, following the EOT 
visit, subjects will be no longer be contacted approximately every 3 months (± 14 days) to collect survival data.
2.
Screening echocardiogram or MUGA scans should be completed within 35 days prior to the first dose of study drugs. All other assessments should be within 28 days prior to first 
dose of any study drugs. Clinical labs used for screening must be within 72 hours of first does of study drugs.
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
Subjects will register based on most recent ADT only. 
5.
Complete physical examination required at screening, Week (W)1 Day (D)1 (W1D1), and end of the treatment (EOT) visits. Limited examinations permitted at all other visits, as 
noted. Definition of complete and limited examinations may be found in Section 7.3.1.
6.
Triplicate ECG should be performed at Screening. All other timepoints may be single ECG prior to dosing and evaluated for abnormality prior to administration of dose. Triplicate 
ECGs would be performed as clinically indicated due to abnormal finding. 
7.
Refer to Table 8 for details of clinical safety labs and timing of collection
8.
Scanning modality used at screening should be maintained for all subsequent scans.
9.
With the implementation of amendment 04, the PRO-CTCAE will no longer be collected.
10. Drugs should be administered as described in Section 6.1. On PK collection days in Week 1 and Week 3, subjects should abstain from food from 8h prior until 2h after dose as 
described in Section 6.10.1. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks thereafter. Review of treatment compliance 
should occur during each study visit using a combination of staff review of subject compliance diaries and returned product packaging. 


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11. Lead-in administration of combination product will be dependent on treatment with applicable product prior to inclusion in the study. Abiraterone lead-in should be 7 days (Days -7 
to Day 0); Enzalutamide lead-in will either be 28 days (Days -28 to Day 0) or 14 days (Days -14 to Day 0). Assigned combination product should be administered as described in 
Section 6.1. Please refer to combination product label for dose adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks 
thereafter. Review of treatment compliance should occur during each study visit using a combination of staff review of subject compliance diaries and returned product 
packaging.
12. With the implementation of amendment 04, PK samples will no longer be collected.
13. With the implementation of amendment 04, on treatment and EOT tumor biopsies will no longer be collected.
14. With the implementation of amendment 04, whole blood for exploratory analyses will no longer be collected.
15. With the implementation of amendment 04, if a PGx sample has not yet been collected, collection will no longer be required
16. With the implementation of amendment 04, CTC-ENU whole blood samples will no longer be collected.
17. With the implementation of amendment 04, CTC-ARV whole blood samples will no longer be collected.
18. With the implementation of amendment 04, contrast-enhanced tomography (CT) scan data will no longer be required. Disease assessment should be managed 
according to local standard of care. 
19. With the implementation of amendment 04, MRI scan data will no longer be required. Disease assessment should be managed according to local standard of care.
20. With the implementation of amendment 04, bone scan data will no longer be required. Disease assessment should be managed according to local standard of care.
21. With the implementation of amendment 04, quality of life questionnaires will no longer be collected.
22. For subjects with progression on the basis of PSA alone may continue to receive treatment until it is determined that there is no longer clinical benefit or the subject’s 
experiences progression by RECIST 1.1 or bone scan determination.


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Table 8
Dose Escalation Time and Events, Laboratory Assessments
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
Week 6
q2w
q4w
q4w
q12w
EOT
D1
D4
D1
D4
D1
D4
D1
D1
D1
W7 and 
11
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Troponin, N-terminal 
pro–B-Type natriuretic 
peptide (NT- proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Factor VII Assay1
X
X
X
HbA1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
Thyroid stimulating 
hormone (TSH), free 
triiodothyronine (T3), free 
thyroxine (T4))3
X
X
X
X
X
Pancreatic Markers
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B surface 
antigen (HBsAg), 
Hepatitis C Virus (HCV) 
Antibody
X
PSA2
X
Testosterone
X
X
1.
In addition to scheduled timepoints, perform if PT or INR or aPTT are ≥1.5XULN, or in case of a bleeding event.
2.
With the implementation of amendment 04, samples for PSA will no longer be collected. Disease assessment should be managed according to local 
standard of care.
3.
TSH testing is mandatory. T4 testing is only required if TSH is abnormal. T3 testing is required when clinically applicable (if both TSH and T4 are abnormal).


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Table 9
Dose Expansion Time and Events
Procedure
SCR
Lead-In 
Dosing (if 
required)
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q12w
EOT1, 22
D1
D1
D1
D1
D1
W9 to 
W49
W9 to W49
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register/ Randomize4
Subject
X
Safety
Physical Exam5
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
12-lead ECGs 6
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments7
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA8
X
X
Weeks 
13, 25 
and 37
X
X
PRO-CTCAE9
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication 
review
Continuous from signing of informed consent
Study Treatment
Administer GSK52576210
Daily
Administer Combination 
product10,11
Daily (if 
required)
Daily
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples12


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Procedure
SCR
Lead-In 
Dosing (if 
required)
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q12w
EOT1, 22
D1
D1
D1
D1
D1
W9 to 
W49
W9 to W49
W49 and 
thereafter
Tumor biopsy13
X
Whole blood for exploratory 
analyses14
X
PGx blood sample15
X
Biomarker Assessments
CTC-ENU16
X
CTC – ARV17
Efficacy
CT chest/abdomen/pelvis18
X
MRI Brain19
X
Bone Scan20
X
EORTC-QLQ-C30, EORTC-
QLQ-PR25 & BPI21
X
1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. With the implementation of amendment 04, following the EOT 
visit, subjects will be no longer be contacted approximately every 3 months (± 14 days) to collect survival data.
2.
Screening echocardiograms should be completed within 35 days prior to the first dose of study drugs. All other assessments should be within 28 days prior to first dose of any 
study drugs. Clinical labs used for screening must be within 72 hours of first does of study drugs.
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
Subjects will be force randomized into 1 of 2 dose cohorts in addition to the most recent ADT. 
5.
Complete physical examination required at screening, Week (W)1 Day (D)1 (W1D1), and end of the treatment (EOT) visits. Limited examinations permitted at all other visits, as 
noted. Definition of complete and limited examinations may be found in Section 7.3.1.
6.
Triplicate ECG should be performed at Screening. All other timepoints may be single ECG prior to dosing and evaluated for abnormality prior to administration of dose. Triplicate 
ECGs should be performed as clinically indicated due to abnormal finding. 
7.
Refer to Table 10 for details of clinical safety labs and timing of collection
8.
Scanning modality used at screening should be maintained for all subsequent scans.
9.
With the implementation of amendment 04, the PRO-CTCAE will no longer be collected.
10. Drugs should be administered as described in Section 6.1. On PK collection days in Week 1 and Week 3, subjects should abstain from food from 8h prior until 2h after dose as 
described in Section 6.10.1. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks thereafter. Review of treatment compliance 
should occur during each study visit using a combination of staff review of subject compliance diaries and returned product packaging. 
11. Lead-in administration of combination product will be dependent on treatment with applicable product prior to inclusion in the study. Abiraterone lead-in should be 7 days (Days -7 
to Day 0); Enzalutamide lead-in will either be 28 days (Days -28 to Day 0) or 14 days (Days -14 to Day 0). Assigned combination product should be administered as described in 


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Section 6.1. Please refer to combination product label for dose adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks 
thereafter. Review of treatment compliance should occur during each study visit using a combination of staff review of subject compliance diaries and returned product 
packaging.
12. With the implementation of amendment 04, PK sample will no longer be collected.
13. With the implementation of amendment 04, on treatment and EOT tumor biopsies will no longer be collected.
14. With the implementation of amendment 04, whole blood for exploratory analyses will no longer be collected.
15. With the implementation of amendment 04, if a PGx sample has not yet been collected, collection will no longer be required
16. With the implementation of amendment 04, CTC-ENU whole blood samples will no longer be collected.
17. With the implementation of amendment 04, CTC-ARV whole blood samples will no longer be collected.
18. With the implementation of amendment 04, contrast-enhanced tomography (CT) scan data will no longer be required. Disease assessment should be managed 
according to local standard of care.
19. With the implementation of amendment 04, MRI scan data will no longer be required. Disease assessment should be managed according to local standard of care.
20. With the implementation of amendment 04, bone scan data will no longer be required. Disease assessment should be managed according to local standard of care.
21. With the implementation of amendment 04, quality of life questionnaires will no longer be collected.
22. For subjects with progression on the basis of PSA alone may continue to receive treatment until it is determined that there is no longer clinical benefit or the subject’s 
experiences progression by RECIST 1.1 or bone scan determination.


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Table 10
Dose Expansion Time and Events, Laboratory Assessments
SCR
Week 
1
Week 
2
Week 
3
Week 4
Week 
5
Week 6
q2w
q4w
q4w
q12w
EOT
D1
D1
D1
D1
D1
D1
W7 and 11
W9 to 
W49
W49 and 
thereafte
r
W49 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X2
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X2
X2
X
X2
X
X
Liver chemistry
X
X
X
X
X
X
X2
X2
X
X2
X
X
Troponin, N-terminal pro–B-
Type natriuretic peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X2
X2
X
X2
X
X
Factor VII Assay1
X
X
X
HbA1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
Thyroid (Thyroid stimulating 
hormone (TSH), free 
triiodothyronine (T3), free 
thyroxine (T4))3
X
X
X
X
X
Pancreatic Markers
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B surface antigen
(HBsAg), Hepatitis C Virus
(HCV) Antibody
X
PSA2
X
Testosterone
X
X
1.
In addition to scheduled timepoints, perform if PT or INR or aPTT are ≥1.5XULN, or in case of a bleeding event.
2.
With the implementation of amendment 04, samples for PSA will no longer be collected. Disease assessment should be managed according to local 
standard of care
3.
TSH testing is mandatory. T4 testing is only required if TSH is abnormal. T3 testing is required when clinically applicable (if both TSH and T4 are abnormal).


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7.2.
Screening and Critical Baseline Assessments
All subjects must sign written Informed Consent prior to the commencement of any study 
specific screening procedures. Consent may be obtained up to 28 days prior to Week 1 
Day 1. Subjects will have a screening period of up to 28 days prior to Week 1 Day 1. 
Evaluations obtained as part of routine medical care and performed during the screening 
period may be used in place of protocol-specific evaluations. In addition, disease specific 
assessments performed within a specified time frame prior to informed consent may be 
used for the study-such as biopsy specimens, prior scans (if done within 28 days) and 
ECHO (if done within 35 days). Subjects will acknowledge and agree to the possible use 
of this information for the study by giving informed consent.
A patient who is screened but not enrolled, e.g. because entry criteria were not met or 
enrollment did not occur within the specified time, may be considered for screening again 
if, for example there is a change in the patient’s medical background or a modification of 
study entry criteria 
The following procedures will be performed at the screening visit:

Obtain written informed consent before any other study-related procedures are 
performed.

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening.

Demographic parameters will be captured: year of birth, sex, race and ethnicity.

Medical/medication/family history will be assessed as related to the 
inclusion/exclusion criteria listed in Section 5. Medical, surgical, and treatment 
history including date of first diagnosis, start and stop dates of treatment/therapy, 
best response to prior systemic therapy, histology, disease progression details 
(radiological and/or biological) as defined per PCWG3 criteria, and current sites 
of disease will be taken as part of the medical history and disease status. Details 
concerning concomitant medication will be recorded starting from screening 
through post-study follow-up. At a minimum, the drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates 
should be recorded.
An unscheduled visit may be performed at any time during the study at the request of the 
patient or as deemed necessary by the investigator. The date and reason for the 
unscheduled visit will be recorded on the eCRF as well as any other data obtained 
(adverse events, concomitant medications and treatments, and results from procedures or 
tests). 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging studies, etc.) and obtained prior to signing of informed consent may be 
utilized for Screening or baseline purposes provided the procedure meets the protocol-
defined criteria and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 


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local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
7.2.1.
Critical Baseline Assessments
Baseline imaging is required for all subjects at screening, as follows:

All subjects should have a contrast-enhanced (oral and IV) CT scan of the chest, 
abdomen, and pelvis performed. Baseline characterization of target- and non-
target lesions should be performed as described in Appendix 5. For subjects with 
a contraindication to contrast-enhanced CT (e.g., documented allergy to iodinated 
contrast), then other modalities, such as non-enhanced CT of the chest and 
gadolinium-enhanced MRI of the abdomen and pelvis, may be used after 
discussion with the medical monitor. At each post-baseline assessment, re-
evaluation of the site(s) of disease identified by these scans, using the same 
imaging modality, is required.

An MRI of the brain will be required at baseline, and subjects with untreated 
central nervous system (CNS) disease will be excluded as described in 
Section 5.2.
A baseline tumor biopsy sample is required for all subjects, as follows: Archival tissue is 
permitted; however, if no archival tissue is available then a fresh biopsy specimen should 
be provided.
7.2.2.
Visit Windows
With the implementation of amendment 04, specific assessments and collection of 
survival follow-up data will no longer be required. Please see Section 7.1 for further 
details. 
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to first dose of study drugs. All other assessments should 
be completed within 28 days prior to first dose of study drugs. Screening labs collected 
outside of the 72-hour window prior to the first dose of study treatment must be repeated 
before confirming eligibility and completing first dose. Clinical labs performed during 
screening within 72 hours of first dose do not need to be repeated on Day 1.
Week 1: Visits for Week 1 Day 1 must be performed on the day indicated. During dose 
escalation, Week 1 Day 4 assessment may be ± 1 day based on subject and clinic 
schedule.
Week 2: Based on subject and clinic schedule, assessments can be ± 2 days. 
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days. During dose 
escalation, assessments on Week 3 Day 4 may be scheduled ± 2 days.
Note: The Week 3 Day 1 PK collection is timed to permit evaluation of GSK525762 PK 
at steady-state dosing (at least 7 consecutive days dosing prior to collection). If a subject 
is not receiving GSK525762 on Week 3 Day 1 as a consequence of a planned drug 
holiday, then serial PK collection should occur between Week 2 Day 4 and Week 2 Day 


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7 prior to their planned drug interruption. If subject is not receiving GSK525762 on 
Week 3 Day 1 due to toxicity, then serial PK collection should be rescheduled for a later 
time point when the subject is again being dosed for at least 7 consecutive days, and the 
alternate collection date noted in the eCRF. However, in this case a single pre-dose 
sample should still be collected to evaluate for abiraterone/enzalutamide trough 
concentration. 
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 2 days. The first disease assessment 
may be scheduled ± 7 days.
Every 4-week and 8-week visits after Week 9 until Week 49: After the first disease 
assessment has been completed, then the clinic visits can be scheduled 7 days. During 
visits with planned PK sample collection, for subjects in the alternate dosing schedule or 
who have interrupted dosing, the collection should be postponed until the subject has 
received at least 7 consecutive doses of GSK525762.   
Every 12 week visits after Week 49: Visit assessments, with the exceptions to limited 
laboratory sampling as referenced in Section 7.1, will adjust to every 12-weeks, based on 
clinical judgment. Every 12-week clinic visits can be scheduled 7 days. 
End of Treatment (EOT) visit: should be within 30 days from last dose of study drugs. 
If a subject is unable to return to the clinic due to hospitalization, site staffs are 
encouraged to telephone the subject for assessment of adverse events.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Additional time points for safety tests may be added during the course of 
the study based on newly available data to ensure appropriate safety monitoring. Safety 
data will be collected and reported from all subjects enrolled in the study (both dose 
escalation and expansion cohort).
7.3.1.
Physical Exams
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 once, at screening.
A complete physical examination will include measurement of vital signs (see
Section 7.3.3) and assessments of the head, eyes, ears, nose, throat, skin, thyroid, 
neurological system, lungs, cardiovascular system, abdomen (liver and spleen), lymph 
nodes and extremities. 
A brief physical examination will include measurement of vital signs and assessments of 
the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight will also 
be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses, as well as to any prior toxicity or other event while on study. Any visible or 
palpable disease should be noted for response or progression as described in Appendix 5.


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7.3.2.
ECOG Performance Status
The performance status will be assessed using the ECOG scale (Appendix 3) as specified 
in the Time and Events Table (Section 7.1).
7.3.3.
Vital Signs

Vital signs to be measured in semi-supine position after 5 minutes rest will include 
temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate. 

In case of an abnormal first reading, three readings of blood pressure and pulse 
rate should be taken and averaged to give the measurement to be recorded in the 
eCRF. 

Vital signs will be measured more frequently if warranted by clinical condition of the 
subject. On days where vital signs are measured multiple times, temperature does not 
need to be repeated unless clinically indicated. 
Refer to the SRM for details regarding measurement of vital signs.
7.3.4.
Cardiac Safety
7.3.4.1.
Electrocardiograms
Triplicate 12-lead ECGs will be obtained at Screening. On treatment single ECGs will be 
completed, prior to dosing, on days specified in the Time and Events Tables during the 
study using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals. Details will be provided in the SRM. Any values 
>480 msec as calculated by the machine must be confirmed manually according to 
Fridericia’s formula. Refer to Section 5.4.2 for QTcF calculations and QTc withdrawal 
criteria, and to Appendix 2 for management strategies for QTcF prolongation. Triplicate 
ECGs should be performed as clinically indicated due to abnormal findings.
The baseline QTcF value is determined by the mean of the triplicate Screening ECG 
results. 
ECGs should be evaluated manually on-site prior to final decision making.
ECG data will be transferred to a central facility for collection. Any central data may be 
reviewed by an independent central reviewer for retrospective analysis. With the 
implementation of amendment 04, transfer of ECG data to a central facility is no longer 
required.
7.3.4.2.
Echocardiogram or Multigated Acquisition Scan
For all subjects, ECHO or MUGA scans will be performed at screening and at assessment 
times as outlined in Section 7.1. Scans should be evaluated and compared to baseline by 
the same reader. Copies of all scans performed on subjects who experience an absolute 
decrease >10% in LVEF compared to baseline concurrent with LVEF < LLN will be 
required by GSK for review. 


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Scan data may be transferred and reviewed by an independent cardiologist. Instructions 
for submission of qualifying scans are provided in the SRM. With the implementation of 
amendment 04, transfer of scan data for independent cardiologist review is no longer 
required.
Refer to Section 5.4.3 for LVEF stopping criteria. For management of other changes 
identified by ECHO or MUGA, see Appendix 2.
7.3.5.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 11, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Some laboratory assessments can vary throughout the day. It is recommended but not 
mandated that laboratory assessments are collected at approximately the same time on 
each clinic day.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
From the first dose of GSK525762 and abiraterone/enzalutamide until 14 days after the 
last dose of study treatment, all laboratory tests with abnormal values that are considered 
clinically significant should be repeated as clinically indicated until the values return to 
normal (per institutional guidelines) or back to the pre-study baseline. If such values do 
not return to normal within a period judged reasonable by the investigator, the etiology
should be identified and the sponsor notified.


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Table 11
Clinical Laboratory Tests
Clinical Chemistry
Sodium
Fasting Glucose
Potassium
Magnesium 
Chloride
Calcium (total and ionized)
Total Carbon Dioxide
Total Protein
Blood Urea Nitrogena
Albumin
Creatinine
Lactate dehydrogenase
Hematology
White blood cell count
Automated White Blood Cell Differential: 
Hemoglobin
Neutrophils
Platelet count
Lymphocytes
Monocytes
Eosinophils
Basophils
Liver Function
Bilirubin (Total and Direct)b
Aspartate Aminotransferase
Alanine Aminotransferase
Alkaline Phosphatase
Routine Urinalysis
Specific gravity, pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if urinalysis is abnormal, if available at participating site)
Cardiac Studies
Troponin (I or T at local laboratory, may be collected at central laboratory if local draw is not possible)
NT-proBNP
Fasting Lipid panel (Total Cholesterol, LDL, HDL, triglycerides)
Other Studies
Coagulation Studies:
Endocrine Studies:
Safety Screening Studies:
Prothrombin Time/INR
TSH
HIV, HbSag, HCV antibody
Partial Thromboplastin Time
Free Thyroxine 3 (Free T3)
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Factor VII Assay
Hemoglobin A1c
Amylase
PSA
Lipase
Testosterone
a.
Direct and/or calculated BUN values are acceptable. 
b.
Direct bilirubin is only required if total bilirubin values are abnormal
NT-ProBNP = N-terminal pro b-type natriuretic peptide; LDL = Low-density lipoprotein; HDL = High-density lipoprotein; 
INR = International normalized ratio; TSH = Thyroid-stimulating hormone; PSA = Prostate-specific antigen; HIV = 
Human immunodeficiency virus; HbSag = Hepatitis B surface antigen; HCV = Hepatitis C virus  
Note: Not all studies are performed at each visit; please refer to Section 7.1, Table 8 and Table 10 for timing of 
required studies
7.3.6.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 8. The severity of adverse 
events will be graded utilizing the NCI-CTCAE v4 [NCI-CTCAE, 2009]. Additional 
details regarding management of specific AEs or SAEs are described in Section 5.4, 
Appendix 2, and Appendix 8.


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AEs will also be assessed using select items from the Patient-Reported Outcomes Version 
of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library 
(Version 1.0) for select subjects, based on the availability of translated versions.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.6.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the signing of informed consent until 
the end of study visit (see Section 7.3.6.3), at the time points specified in the 
Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

All SAEs will be recorded and reported to GSK or designee within 24 hours, 
as indicated in Appendix 8.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at 
any time after a subject has been discharged from the study, and he/she 
considers the event reasonably related to the study treatment or study 
participation, the investigator must promptly notify GSK or designee.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 8.
7.3.6.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?”
7.3.6.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest 
(as defined in Appendix 8 will be followed until resolution, until the condition stabilizes, 


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until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.4). Further information on follow-up procedures is given in Appendix 8.
7.3.6.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 8 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will 
be required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the eCRF within one week of receipt of 
a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.3.6.5.
Other sentinel events
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, that are 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.
7.3.6.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.


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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.7.
Pregnancy
Details of all pregnancies in female partners of male subjects will be collected after the 
start of dosing and until at least 16 weeks post-last dose.
If a pregnancy is reported then the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 12. 
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 reported 
as an AE or SAE.
7.4.
Pharmacokinetics
With the implementation of amendment 04, PK samples will no longer be collected.
Blood samples for pharmacokinetic (PK) analysis of abiraterone/enzalutamide and 
GSK525762 (including relevant metabolite(s)) will be collected at the time points 
indicated in Table 7, Table 8, Table 9, and Table 10. The actual date and time of each 
blood sample collection will be recorded. Subjects should be instructed to withhold their 
dose of orally administered study drugs, including GSK525762 and 
abiraterone/enzalutamide, until after the pre-dose pharmacokinetic blood sample is 
collected.
The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring. Blood samples for 
pharmacokinetic analysis should be collected at the time of a SAE whenever possible.
Plasma analysis will be performed under the supervision of GlaxoSmithKline by an 
external vendor, the details of which will be included in the SRM. Concentrations of 
GSK525762 (plus any relevant metabolite(s)) and abiraterone/enzalutamide will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site (detailed in the SRM).
Details of PK blood sample collection, processing, storage and shipping procedures are 
provided in the SRM.
7.5.
Pharmacodynamics
With the implementation of amendment 04, tumor samples will no longer be collected.
Tumor samples will be collected pre-dose and on-treatment in order to evaluate changes 
in molecular markers of BET inhibition (e.g., expression of RNA/proteins regulated by 
BET) and AR signalling.


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7.5.1.
Tumor Biopsy Collection/Surgical Procedures
In the dose escalation and expansion cohort(s), paired fresh biopsies must be provided 
pre- (within 28 days of the first dose) and on-treatment at the time points indicated from 
all the subjects. Any fresh on-treatment biopsy should be accompanied by a whole blood 
sample collected as close as possible to the time of biopsy (preferably within 1h). 
Subjects providing an on-treatment fresh tumor biopsy must have received at least 4 
consecutive days of GSK525762 prior to the collection of the sample. Further details 
regarding sample type and processing will be provided in the SRM. If a potential subject 
does not have disease amenable to biopsy, participation may occur only upon discussion 
with and approval of the medical monitor; in this situation, an archival tumor sample 
retrieved after completion of most recent ADT will be required. 
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
WNL within 48 hours prior to the post-dose biopsy or any other planned surgical 
procedure. If the on therapy biopsy is not performed during the defined timeline due to 
lab abnormalities or subject status, it should be performed after subject recovery and the 
next visit as agreed upon with the medical monitor. Further details regarding sample type 
and processing will be provided in the SRM.
7.6.
Evaluation of Anti-Cancer Activity
With the implementation of amendment 04, CT, MRI, and Bone scan data will no 
longer be required for disease assessment, and samples for PSA ad CTC-ENU will 
no longer be collected. See the Time and Events Table (Section 7.1) for the updated 
schedule of assessments. Disease assessment should be managed according to local 
standard of care.
The baseline disease assessment will be completed prior to the first dose of GSK525762 
and abiraterone/enzalutamide (or first dose of lead in abiraterone/enzalutamide). All 
imaging to support anti-cancer activity will occur every 8 weeks start of therapy for the 
first 6 months of treatment and then every 12 weeks thereafter until completion of study 
treatment. Assessment of PSA will occur every 4 weeks until completion of treatment. 
Evaluation of CTC will occur at Week 5 and then at Week 9 and every 8 weeks 
thereafter. All evaluations will occur at the final study visit. See the Time and Events 
Table (Section 7.1) for the schedule of assessments of anti-cancer activity. 

Assessments must be performed on a calendar schedule and should not be affected 
by dose interruptions/delays. 

For post-baseline assessments, a window of 5-7 days is permitted to allow for 
flexible scheduling (see Section 7.2.2). If the last radiographic assessment was more 
than 14 days prior to the subject’s withdrawal from study and progressive disease has 
not been documented, a disease assessment should be obtained at the time of 
withdrawal from study.

Subjects enrolled with measurable disease by PCWG3-modified RECISIT 1.1 
(Appendix 5) and whose disease responds (either CR or PR) should have a 
confirmatory disease assessment performed no less than 4 weeks after the date of 
assessment during which the response was demonstrated. The next assessment 


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following a confirmatory disease assessment should follow the regular schedule, 
occurring approximately 4 weeks after the confirmatory assessment.

To ensure comparability between the baseline and subsequent assessments, the same 
method of assessment and the same technique will be used when assessing response.
7.6.1.
Disease Progression Endpoint
The disease progression endpoint is defined by 1 or more of the following criteria:

Radiographic progression in by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG3 criteria (Section 7.6.3).

PSA progression according to the PCWG3 criteria (Section 7.6.2) accompanied 
by any of the following: investigator-defined clinical progression or either of the 
above RECIST 1.1 or bone progression.
Subjects are not required to discontinue treatment on the basis of meeting PSA 
progression alone. 
In assessing clinical activity which demonstrates a clinically meaningful primary 
response rate, this is defined as follows:

A response rate of 30% at 12 weeks or later, relative to a 10% response rate 
suggesting no activity. This will be conducted by testing the null hypothesis that 
P0<=0.1 versus the alternative that P1 ≥0.3, assuming the maximum response rate 
for an ineffective drug is 10% and the minimum response rate for an effective drug is 
30%.
These hypotheses are based on observations from a meta-analysis study in subjects who 
had received prior ADT both in chemo-naïve and prior chemotherapy setting. Chemo-
naïve subjects treated with a second ADT (L2 subjects) had rates of ≥50% PSA decline 
ranging from 25.5% to 36%. Subjects treated with both prior ADT and chemotherapy (Lx 
subjects) had variable responses of ≥50% PSA which ranged from 4% to 26% in studies 
with larger subject populations (>30 subjects per study). Based on these findings, and 
considering a mixed population (L2 plus Lx) in both arms of the study, it is hypothesized 
that a response rate ≤10% would indicate no benefit for the combination of ADT failure, 
while a response rate of ≥30% in patients who just progressed on prior ADT will indicate 
there is a benefit that can be further explored [Chi, 2015].
7.6.2.
PSA Response per PCWG3 Criteria
Only subjects who have a baseline PSA value and at least one post-baseline assessment 
will be included in the analysis of PSA response.
PSA Response Rate is defined as proportion of subjects with a decrease of 50% in the 
PSA concentration from the baseline PSA value determined at least 12 weeks after start 
of treatment and confirmed after ≥4 weeks by an additional PSA evaluation.
PSA progression [Scher, 2016] is defined as:


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
If there has been a decline from baseline: time from start of therapy to first PSA 
increase that is 25% and 2 ng/mL in absolute value from the nadir, and which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend) at 
least 12 weeks after the start of treatment

If there has NOT been a decline from baseline: time from start of therapy to first 
PSA increase that is 25% and 2 ng/mL in absolute value from the baseline value, 
determined at least 12 weeks after start of treatment
7.6.3.
Radiographic Response per PCWG3 Criteria
Lesion assessment method and timing, evaluation of disease, disease progression and 
response will be conducted according to PCWG3-modified Response Evaluation Criteria 
in Solid Tumors (RECIST 1.1) [Scher, 2016; Eisenhauer, 2009] as outlined below and in 
Appendix 5 of this protocol. Disease assessment modalities may include imaging (CT 
scan, MRI, bone scan, plain radiography) and physical examination (as indicated for 
palpable/superficial lesions). Contrast-enhanced CT of the chest, abdomen, and pelvis at 
each disease assessment timepoint is the preferred imaging modality. The same medical 
imaging modality with the same contrast media should be used for each time point. 
However, subjects with contraindication to CT may have other modalities performed as 
clinically indicated.
GSK requires sites to provide electronic copies (upload digital images or images on CD) 
of scans for all subjects for central storage which may be transferred to a central 
independent imaging center. This includes baseline scans and all scans performed during 
the course of the study. Evaluation of response and rPFS will be made by the 
Investigator/site radiologist. GSK may request an independent review of scans. See the 
SRM for additional details. With the implementation of amendment 04, transfer of scans 
to a central facility is no longer required.
Bone progression will be determined as the appearance of 2 new lesions on bone scan 
and at least an additional 2 bone lesions at the next scan (every 8 weeks). The date of 
progression is the date of the first scan that indicates the change. Subjects should not be 
discontinued from study treatment(s) due to the occurrence of bone scan changes in the 
first 12 weeks that do not meet PCWG3 guidelines for progression.
7.6.4.
Circulating Tumor Cells (CTC) per PCWG3 Criteria
Baseline CTC enumeration will be assessed. Unfavorable will be defined as ≥5/7.5mL of 
blood compared to favorable <5/7.5mL of blood. The number of conversations from 
unfavorable CTC to favorable CTC will be assessed. Absolute percent change of CTC 
from baseline will also be assessed. 
7.7.
Translational Research
After completion of the clinical trial and/or of any Interim Analysis, investigations may 
be performed on samples collected during the course of the trial to detect factors or 
profiles that correlate with response to treatment with the combination of GSK525762 
and abiraterone/enzalutamide or with tumor progression status. The results gained may 
also be applied to medically related conditions.


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Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to GSK525762 and abiraterone/enzalutamide in combination is observed.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK525762 and abiraterone/enzalutamide in combination or provide new insights 
into tumor progression and medically related conditions. Comparative examination of 
post-dosing profiles in conjunction with pre-dosing profiles may yield known and novel 
candidate biomarkers/profiles and new insights which relate to the action of GSK525762 
and abiraterone/enzalutamide in combination.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with tumor progression or medically related conditions and/or the 
action of GSK525762 and abiraterone/enzalutamide in combination may be identified by 
application of:

DNA/gene, RNA and/or protein analysis of tumor tissue or circulating tumor cells 
(CTCs).

Circulating cell free-DNA/RNA analysis of blood/plasma.

Protein analysis of plasma and/or tumor tissue samples.
7.7.1.
Tumor Biomarker Analysis
To further characterize the subject population, DNA, RNA and/or protein measurements 
may be utilized to identify predictors of sensitivity or resistance to GSK525762 and 
abiraterone/enzalutamide in combination utilizing baseline tissue (archival tissue or a 
recent biopsy) and tissue obtained at disease progression. Amplification of AR and 
expression of AR-variants (AR-Vs) will be retrospectively analyzed to evaluate 
correlation with clinical response. 
7.7.2.
Tumor Tissue
With the implementation of amendment 04, tumor samples will no longer be collected.
If consent is provided by the subject, an optional progression biopsy (fresh tumor tissue) 
for subjects who initially responded to combination therapy and then progressed is 
requested in order to better understand the mechanism of resistance. It is preferable to 
obtain the progression biopsy from a new lesion or a lesion which had previously 
responded and then progressed. Biopsy samples from other lesions will be accepted as 
well. Both soft tissue and bone biopsies will be accepted. Details on sample collection, 
processing, storage and shipping procedures for all samples are provided in the SRM.
Samples will be analyzed using appropriate technologies including, but not limited to, 
RNAseq, exome or targeted DNA sequencing, Immunohistochemistry (IHC), and/or 
quantitative reverse transcription polymerase chain reaction (qRT-PCR).


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Samples will be analyzed at GSK or a laboratory associated with GSK and retained for a 
maximum of 15 years after the last subject completes the trial. 
7.7.3.
Circulating Tumor Cells
With the implementation of amendment 04, blood samples for CTC enumeration will no 
longer be collected.
Blood samples will be collected and analyzed to enumerate CTCs in circulation at the 
time points indicated in the Time and Events Tables (Section 7.1). The CTCs may also be 
utilized for additional analysis like alterations in AR genes and may include additional 
genes implicated in the prostate cancer or related to AR signaling pathway. 
If subject withdraws consent for further treatment and data collection, all samples 
collected for the biomarker analysis at the time of withdrawal will still proceed for 
analysis to meet the intended objectives defined in this protocol.
Details on sample collection, processing, storage and shipping procedures for all blood 
and tissue samples are provided in the SRM.
7.7.3.1.
CTC Conversion Rate
CTC enumeration will be performed at a central laboratory using the analytically valid 
CellSearch system. For subjects with baseline CTC counts of 5 cells per 7.5 mL of
blood, a conversion is defined as a decline in the CTC count to <5 cells per 7.5 mL of 
blood. Genetic analysis of CTCs may also be performed by other laboratories.
7.7.4.
Circulating-Free Tumor DNA/RNA and Soluble Markers
With the implementation of amendment 04, blood samples for cfDNA and soluble 
markers will no longer be collected.
Tumor-specific cfDNA levels detected in plasma or serum have been found to correlate 
with increasing tumor burden and decline following therapy. Furthermore, cfDNA in 
cancer subjects can harbor many genetic alterations (mutations, microsatellite alterations, 
aberrant methylation), which are generally consistent with the tumor. Thus, tumor-
specific circulating cfDNA has the potential to be a useful biomarker of therapeutic 
response as well as offering a less invasive blood based technique for identifying 
predictive biomarkers. Additionally exosomes, released from tumors cells into 
circulation, contain both DNA and RNA; therefore, exosomes may serve as an additional 
source of predictive biomarkers or facilitate enrichment thereof.
Plasma samples for analysis of cfDNA/RNA and soluble markers will be collected at the 
time points provided in the Time and Events Tables in Section 7.1.
If subject withdraws consent for further treatment and data collection, all samples 
collected for the biomarker analysis at the time of withdrawal will still proceed for 
analysis to meet the intended objectives defined in this protocol.
Details on sample collection, processing, storage and shipping procedures for all plasma 
samples are provided in the SRM.


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7.8.
Genetics
With the implementation of amendment 04, if a subject has consented for PGx research 
but the sample has yet to be collected, this will no longer be required.
An important objective of the clinical study is PGx research. Participation in PGx is 
optional but all subjects who are eligible for the clinical study will be given the 
opportunity to participate. Subjects may decline participation without effect on their 
medical care or care during the clinical study. A separate consent signature is required for 
PGx research.
Subjects who provide consent will have a blood sample taken for analysis. The 
presence/absence of genetic variations in host DNA from blood will be analyzed to 
determine their relationship with response (safety, tolerability, pharmacokinetics, and 
efficacy) to treatment with GSK525762 and abiraterone/enzalutamide.
7.9.
Value Evidence and Outcomes
7.9.1.
PRO-CTCAE
With the implementation of amendment 04, the PRO-CTCAE will no longer be 
completed.
Select items of the Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events (PRO-CTCAE) Item Library (version 1.0) will be 
administered to select subjects based on the availability of translated versions.
7.9.2.
EORTC-QLQ-C30, EORTC-QLQ-PR25 & Brief Pain Inventory –
Short Form (BPI-SF)
With the implementation of amendment 04, the quality of life questionnaires will no 
longer be completed.
The effect of GSK525762 and abiraterone/enzalutamide, when given in combination, on 
symptoms and quality of life will be assessed using the European Organisation for 
Research and Treatment of Cancer (EORTC) Quality of Life questionnaire, the EORTC-
QLQ-PR25, for evaluating prostate cancer, and the Brief Pain Inventory-Short Form 
(BPI-SF). These quality of life tools will be assessed as scheduled in Section 7.1. 
8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events and concomitant medications terms 
will be coded using MedDRA (Medical Dictionary for Regulatory Activities) and an 
internal validated medication dictionary, GSKDrug. 


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Electronic CRFs (eCRF) (including queries and audit trails) will be retained by GSK, and 
copies will be sent to the investigator to maintain as the investigator copy. Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Any changes to the planned analyses outlined below will be covered in the Reporting and 
Analysis Plan (RAP).
9.1.
Hypotheses
9.1.1.
Dose escalation
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, based upon the safety, PK and efficacy profiles of GSK525762 plus 
abiraterone or enzalutamide in subjects with CRPC.
9.1.2.
Dose expansion cohorts
The goal of the trial is to characterize the dose-response curve for both efficacy and 
safety and to identify whether there is a dose of GSK525762 with an acceptable 
combination of efficacy and safety.
The primary efficacy endpoint is defined as the clinically meaningful response rate (% of 
subjects achieving PSA reduction from baseline ≥50%) at 12 weeks and/or thereafter for 
the subjects treated at each dose level. The critical safety endpoint for evaluation in this 
trial is the percentage of subjects at dose level d who had dose modification due to drug 
related AEs. The dose modification rate R is a weighted average of the rate of different 
types of dose modifications: R=0.6R1+ 0.2R2+0.2R3, where R1 is the rate that subjects 
who withdrew from study treatment due to drug-related adverse events, R2 is the rate that 
subjects who had dose reductions due to drug-related adverse events, R3 is the rate that 
subjects who had dose interruptions due to drug-related adverse events. If a subject had 
more than one type of dose modifications, it will only be counted once in calculation of R 
and will be counted in the most severe modification category (withdrawal > reduction > 
interruption). A response rate of 30% or greater is desired while 10% represents a 
response rate that is clinically unacceptable. With respect to dose modification rate R, a 
dose modification rate of 12% or greater represents a dose with unacceptable tolerability. 


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If R is lower than 12%, a withdrawal rate higher than 10% also represents a dose with 
unacceptable tolerability.
The response rate and dose modification rate will be jointly assessed using a utility 
function. For each dose expansion cohort the utility (dU) will be calculated and used for 
decision making at each interim analysis and final analysis. At the end of each arm, the 
dose with the highest probability of having clinically significant utility score may be 
picked as the RP2D. The totality of the data will be used to assess which dose will be 
picked as the RP2D. Further details of the calculation of utility function will be provided 
in RAP.
The dose expansion cohort stage of the study will employ a Bayesian predictive adaptive 
design that allows the trial to be monitored more frequently at multiple stages. Bayesian 
statistics will be employed to calculate the expected utility of the dose (dU) is greater 
than the clinically significant minimum utility (CSMU) at interim for each dose. 
The interim analysis will be conducted for each individual dose and it may be conducted 
when at least 10 evaluable subjects are available for a given dose. After the first interim 
analysis, the interim analysis can be conducted after every 10 additional subjects become 
evaluable. The evaluable subjects are defined as the subjects who have had the week 12 
or later PSA results or have progressed (per PSA result) or died or permanently 
discontinued from the study treatment.
For the separate interim looks in each combination in expansion cohort, the enrolment for 
that cohort may be stopped due to futility if the posterior probability that the utility (dU) 
>CSMU (25) is small (e.g., less than a 4% chance for the utility to be larger than the 
CSMU). The totality of the data including safety/tolerability and primary and secondary 
efficacy endpoints will be used to decide whether to stop enrolment within a cohort at an 
interim analysis. At the final analysis for each dose combination, the dose will be claimed 
positive if the posterior probability that the utility (dU) >CSMU (25) is at least 20%.  
However, determination of whether to pursue future development of GSK525762 plus 
abiraterone or enzalutamide will be based on the totality of the data including 
safety/tolerability, PK, PD and all efficacy endpoints.
No formal hypotheses are set up to compare the activity between the two dose levels. The 
difference of PSA response rate, composite response rate and DCR through 24 weeks
between two dose levels within the same combination will be reported. 
The maximum utility dose which is defined as the dose with the highest probability of 
having clinically significant utility in the same arm will be recommended as RP2D for 
each combination, respectively. The details of the utility function calculations will be 
discussed in RAP. This calculation is for guidance only, the final decision of RP2D will 
be based on totality of data. 


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
Up to 60 subjects will be enrolled/randomized into each combination arms (based on 
prior therapy) with up to 30 at each DL to collect safety/tolerability, PK, PD, and clinical 
activity data. Additional subjects may be enrolled at, or below the combination doses, in 
order to collect additional safety and PK data. 
To determine the maximum sample size for each dose level in dose expansion cohort,
Bayesian predictive adaptive design will be used for testing hypotheses and sample size 
determination:
H0: RR≤10%
HA: RR≥30%
Enrollment into specific cohorts may be halted early based on results from interim 
analyses incorporating emerging response data. Response data from a minimum of 10 
evaluable subjects will be required in a cohort before it may discontinue enrollment for 
futility. Data from evaluable subjects treated in the dose escalation cohorts will be 
analyzed together with expansion cohort subjects treated at the same dose in the same 
combination for futility analysis. 
Simulation studies were conducted to evaluate the performance of the Bayesian design 
using utility function defined in Section 9.1.2 under various assumptions for the 
distribution of true RR and DLT rates across the cohorts. Operating characteristics 
including power, type I error, estimation of the RR, and the probability of halting 
enrollment at interim analyses were assessed.
When the treatment effect is positive, the design maintains at least 80% power and type I 
error rate ≤0.10 on individual cohort. If both dose level are positive, the chance of 
advancing to phase 2 is as high as 90%. For more details, please see Section 9.4.6. 
9.2.2.
Sample Size Sensitivity
Sample size sensitivity assessments are described in the simulations presented in 
Section 9.4.6.
9.2.3.
Sample Size Re-estimation or Adjustment
Sample size re-estimation is not planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK525762 or abiraterone or enzalutamide. Safety and anti-cancer activity will be 
evaluated based on this analysis population.


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The Modified All Treated Population is defined as all subjects who receive at least one 
dose of GSK525762 plus abiraterone/enzalutamide. Safety and anti-cancer activity will 
be evaluated based on this analysis population if different from the All Treated 
Population.
All Evaluable Subjects will be defined as the study population used for decision-making 
at the interim futility analysis. Subjects who have had Week 12 or later visit disease 
assessment results or have progressed according to the guidelines described in Section 
7.6.1 or died or permanently withdrew from the study treatment will be included in this 
population. 
The PK Population will consist of all subjects from the All Treated Safety Population 
for whom a PK sample is obtained and analyzed.
Additional analysis populations may be defined in the Reporting and Analysis Plan 
(RAP) 
9.3.2.
Interim Analysis
9.3.2.1.
Dose Escalation and Safety Analyses
Once 3 to6 subjects have been enrolled at each dose level, an interim analysis will be 
performed to determine if dose-escalation and/or dose expansion is appropriate. The 
primary driver for the dose escalation decisions will be safety and tolerability of each 
dose level cohort.


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9.3.2.2.
Dose expansion Cohorts
9.3.2.2.1.
Efficacy Analyses
Interim analyses during dose expansion cohorts
Interim analysis will be conducted for each DL separately. Interim data will be evaluated 
to monitor efficacy and safety, and a planned interim analysis may be performed when at 
least 10 evaluable subjects are available at any DL. Enrollment may be stopped early in 
any of the expansion cohorts for toxicity or lack of efficacy, should various criteria occur 
based on accrued data. The decision to stop enrolment within a cohort for futility will be 
based on the totality of the data including safety/tolerability and evaluation of primary 
and secondary efficacy endpoints.
9.3.3.
Final Analysis
The final analyses will be conducted when the study is completed. Data from the dose 
escalation and expansion cohort will be combined as appropriate.
9.4.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the 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.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently there will be no 
imputation for missing data. 
For the PFS endpoint, subjects who are alive and have not progressed at the time of 
analysis will be censored at the date associated with the last visit with adequate 
assessment.
Demographic and baseline characteristics will be summarized.
9.4.1.
Safety Analyses
Safety data for this study be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
The All Treated Safety Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP.


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9.4.1.1.
Extent of Exposure
Extent of exposure of GSK525762 and abiraterone or enzalutamide will depend on 
tolerability of the subjects to the doses administered and the course of their disease. The 
number of subjects exposed to the combination of GSK525762 and abiraterone or 
enzalutamide will be summarized for each dose level administered.
9.4.1.2.
Adverse Events
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class. Adverse events (AEs) will be graded by the investigator according to the 
NCI-CTCAE v4 [NCI-CTCAE, 2009].
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, serious adverse events (SAEs) and AEs leading to discontinuation of study 
treatment and dose modification. Adverse events (AEs), if listed in the NCI-CTCAE v4, 
will be summarized by the maximum grade. 
Dose-limiting toxicities (DLTs) will be listed for dose escalation subjects and 
summarized by dose cohort. 
Any AEs of special interest will be summarized as detailed in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
9.4.1.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4. Laboratory test results outside the reference 
ranges that do not have an associated NCI-CTCAE criterion will be summarized using 
proportions. Summaries by visit 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 ‘worse case 
post baseline’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study treatment.  Further details will be provided 
in the RAP.
9.4.1.4.
Other Safety Measures
Data for vital signs, ECGs, and ECHOs and/or MUGA scans will be summarized based 
on predetermined criteria identified to be of potential clinical concern. Further details will 
be provided in the RAP.
9.4.2.
Pharmacokinetic Analyses
9.4.2.1.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK.


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Pharmacokinetic (PK) analysis of GSK525762 (and its metabolite[s]), and abiraterone 
concentration-time data will be conducted by non-compartmental methods under the 
direction of CPMS, Quantitative Sciences, GSK. Calculations will be based on the actual 
sampling times recorded during the study. The following PK parameters will be 
determined if data permit: 

maximum observed plasma concentration (Cmax) 

time to Cmax (tmax)

area under the curve over a dosing interval (AUC(0-τ))

trough concentration (Cτ)
Sparse plasma concentration-time data for GSK525762 and its metabolite(s) may be 
combined with data from other studies and analyzed using a population approach. A 
nonlinear mixed effects model will be used to determine population pharmacokinetic 
parameters and identify important covariates (e.g., age, weight, or disease related 
covariates).
9.4.2.2.
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the PK parameters data will be the responsibility of Clinical 
Statistics, GSK.
GSK525762 and abiraterone or enzalutamide concentration-time data will be listed for 
each subject and summarized by descriptive statistics at each time point by cohort. 
Individual subject parameter values as well as a descriptive summary (mean, standard 
deviation, median, minimum, maximum, and the standard deviation and geometric mean 
of log-transformed parameters) by dose cohort will be reported.
Data from this study for GSK525762 may be combined with data from others studies for 
further evaluation of the population PK of GSK525762. Detail of the analysis may be 
provided in the separate data analysis plan (DAP). 
9.4.3.
Pharmacokinetic/Pharmacodynamic Analyses
Observed or predicted concentrations will be combined with safety, efficacy, and other 
pharmacodynamic measures of interest to examine potential exposure response 
relationships.
Other quantitative safety parameters and biomarkers of interest will be plotted 
graphically against summary exposure measures (e.g., Cmax, Cτ, and Cav). Where 
evidence of a signal is seen, linear and non-linear mixed effect models will be fitted to 
the data to estimate PKPD parameters of interest; slope, baseline (E0), concentration for 
50% of maximum effect (EC50) and maximum effect (Emax).
Overall efficacy data, as assessed by PCWG3 criteria may be described using ordered 
categorical model and/or continuous models with summary exposure parameters (e.g.; 
Cmax, Ctrough, and Cav) as covariates derived from the population PK analysis. Further 
model details will be provided in the RAP.


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9.4.4.
Efficacy Analyses
The clinical activity primary response rate (RR) will be defined as the rate of achieving 
the following responses
PSA reduction from baseline ≥50% at 12 weeks and/or thereafter 
RR
RR is defined as the response rate that a PSA reduction from baseline ≥50% is observed 
at 12th weeks and later (must be confirmed by a second value). RR will be reported for 
each cohort along with the exact 95% confidence interval. Waterfall plots will be 
presented (as per PCWG3 recommendations) that show the maximum percentage of 
change in PSA from baseline. 
The following secondary responses will also be considered for drawing conclusions on 
the clinical activity of the combination(s): 
Disease Control Rate at 24 weeks 
Disease control rate (DCR) is defined as the percentage of subjects with SD, PR or CR at 
≥24 weeks. Subjects with unknown or missing response will be treated as non-
responders (i.e. these subjects will be included in the denominator when calculating the 
percentage).
Duration of PSA response 
Duration of PSA response is calculated from the time the PSA value first declines by at 
least 50% of the Week 1 Day 1 (baseline) value (must be confirmed by a second value) 
until the time there is an increase of 25% of PSA nadir, provided the absolute increase is 
at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement 
that is at least 25% above the nadir. If the PSA never shows a 25% increase over the 
nadir value, then the patient will be censored at the last PSA measurement. Duration of 
PSA response will be summarised by the median and presented along its 95% confidence 
interval.
ORR
The objective response (ORR) rate is defined as the percentage of subjects with a 
confirmed complete response (CR) or a partial response (PR) at any time as per PCWG3-
modified RECIST 1.1 (Appendix 5). Subjects with unknown or missing response will be 
treated as non-responders, i.e. these subjects will be included in the denominator when 
calculating the percentage. The number and types of responses, as outlined in PCWG3-
modified RECIST 1.1, will be listed and summarized separately, as appropriate. The 
analysis of ORR will only be performed for subjects with measurable disease only. The 
observed ORR, observed confirmed and unconfirmed ORR will be reported at the interim 
and final analysis for each cohort specified in treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided.


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CTC Response 
CTC response rate is defined as the proportion of subjects with a CTC conversion to 
<5/7.5 mL blood at nadir (confirmed by a second consecutive value obtained four or 
more weeks later) will be presented along an exact two-sided 95% confidence interval. 
Subjects with CTC<5/7.5 mL at baseline will be excluded from this analysis. Waterfall 
plots of maximum CTC falls will also be presented that show the percentage change in 
CTC counts from baseline. The CTC response need to be confirmed by a second 
consecutive value obtained four or more weeks later.
Composite Response Rate 
CRR is a composite endpoint based on the following – a) response based on PCWG3-
modified RECIST 1.1, b) PSA decrease of ≥50% at Week 12 or thereafter, or c) CTC 
count conversion. The responders for each endpoint are the same as defined in PSA 
responses, CTC response and CR or PR per PCWG3-modified RECIST 1.1. Subjects 
with unconfirmed response per PCWG3-modified RECIST 1.1will be classified as non-
responders. 
The PR and ORR differences of the same Arm between two doses will be provided along 
with corresponding 95% CI. A chi-square test will be used to test for differences between 
doses at the final analysis.
Time to disease progression
Time to disease progression is defined as time from first dose date of study treatment to 
disease progression defined as one or more of the following criteria:

Radiographic progression by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG3 criteria (Section 7.6.3).

PSA progression according to the PCWG3 criteria (Section 7.6.2) accompanied 
by any of the following: investigator-defined clinical progression or either of the 
above RECIST 1.1 or bone progression.
Subjects without disease progression at the time of analysis will be censored at the earlier 
date of last PSA assessment and last radiological assessment.
PSA Week 4 response rate 
PSA Week 4 response rate (Week 4 RR) is defined as the response rate that a PSA 
reduction from baseline ≥30% is observed at 4 weeks [Rescigno, 2016]. Week4 RR will 
be reported for each cohort along with the exact 95% confidence interval. The percentage 
of subjects have PSA >=25% increase from baseline at 4 weeks will also be reported for 
each cohort.
Radiographic Progression-free survival (rPFS) will be defined as the time from study 
treatment start until the first date of either disease progression or death due to any cause. 
The date of disease progression will be defined as the earliest date of disease progression 
as assessed by the investigator using PCWG3-modified RECIST, version 1.1 or 


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progression on bone scan. For subjects who have not progressed or died at the time of the 
rPFS analysis, censoring will be performed using the date of the last adequate disease 
assessment. In addition, subjects with an extended loss to follow-up or who start a new 
anti-cancer therapy prior to a rPFS event will be censored at the date of the last adequate 
disease assessment (e.g. assessment where visit level response is CR, PR, or stable 
disease [SD]) prior to the extended loss to follow-up or start of new anti-cancer therapy, 
respectively. Further details on rules for censoring will be provided in the RAP. rPFS will 
be summarized by dose level specified in expansion cohort using Kaplan-Meier quantile 
estimates along with 2-sided 95% CIs at the time of interim and end of Phase I interim 
analysis, if data warrant.
For the analysis of overall survival (OS), the last date of known contact will be used for 
those subjects who have not died at the time of analysis; such subjects will be considered 
censored. Further details on rules for censoring will be provided in the RAP. If data 
warrant, OS will be summarized by arm and dose level using Kaplan-Meier quantile 
estimates along with 2-sided 95% CIs.
9.4.5.
Other Analyses
9.4.5.1.
Translational Research Analyses
The results of translational research investigations will be reported separately from the 
main clinical study report (CSR). 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.
9.4.5.2.
Novel Biomarker(s) Analyses
The results of these biomarker investigations, including correlation between ESR1 
mutations and clinical response, will be reported separately from the main clinical study 
report. All endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.
9.4.5.3.
Pharmacogenetic Analyses
Further details on pharmacogenetic (PGx) analyses will be addressed in Appendix 9 and 
the PGx RAP.
9.4.6.
Simulations and Design Operating Characteristics
9.4.6.1.
Simulation Description
Extensive simulations have been conducted to develop and understand the performance 
of the seamless design, interim monitoring, and decision criteria. The simulations are 
conducted for one combination arm. Same operating characteristics are expected in the 
other combination arm. 


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9.4.6.2.
Software Details
Simulations were conducted by the R code provided by Berry Consultants. For each 
assumed scenario, 1,000 sets of trials were simulated. Posterior distributions were 
estimated via Markov chain Monte Carlo methods using 10,000 iterations for each 
analysis, discarding the first 1,000 iterations for each analysis as burn-in.
9.4.6.3.
Trial Sample Size and Simulation Scenarios
Sample size requirements for halting enrolment at interim analyses for simulations is 
based on the number of subjects enrolled; while in practice, they will be based on the 
number of subjects with available response data. This discrepancy is due to software 
feasibility, but should not have a significant impact on operating characteristics of the 
design. Simulations assumed the first interim analysis occurring once 10 evaluable 
subjects in the same cohort at the same dose level have been enrolled. An average of 5 
subjects per month per cohort is assumed. The time from subject entry until the response 
assessment was performed is assumed to be 12 weeks. For each dose, a maximum 6 
subjects will be assigned to the dose escalation stage and if that dose is safe to expand, a 
maximum of 30 subjects will be assigned to each cohort in total. 
Although actual enrollment may vary, the estimated enrollment rate of 5 subjects per 
month per cohort is incorporated into the simulations. It is also assumed that a dose with 
DLT rate 0.1, 0.3 and 0.4 will have dose modification rate R=0.05, 0.08 and 0.12, 
respectively. The real enrollment rate may vary from the assumed enrollment rate in 
simulation, but should not impact on operating characteristics of the design. Simulation 
scenarios and design characteristics for one cohort on two dose levels DL1 and DL2 are 
listed in Table 12 under 1000 simulations. The DLT rates and RR listed are listed in the 
order of DL1 and DL2. 


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Table 12
Simulation Scenarios and Design Characteristics for One cohort
Scenarios    
(DL1 DL2)
<= MTD (%) 
Declare 
Efficacious 
and 
tolerable if 
≤MTD (%) 
Advance to phase 
2 (%) 
Average N 
Early 
termination 
due to 
futility in 
expansion 
(%) 
DLT rates/ 
RRs 
DL1 
DL2 
DL1 
DL2 
DL1 
DL2 
Any 
dose 
DL1 
DL2 
DL1 
DL2 
0.1, 0.2 
/0.1,0.1 
Safe/Null 
97.4
77.3
9.34
7.89
9.2
6.3
15.2
19.4
16.0
75.1
75.7
0.1, 0.2 
/0.1,0.3  
Safe/ one 
posi
98.1
77.6
8.46
80
8.5
62.8
70
20.5
20.4
76.45
7.35
0.1,0.2 
/0.3,0.3  
Safe/ Posi 
98.3
79.7
85.7
80
84.6
64.7
94.6
25.8
20
5.4
7.5
0.2, 0.4 
/0.1,0.3 One 
safe/ One 
Posi 
89.9
38.4
11.4
78.4
11.7
36.1
44.5
16.9
6.7
64.31
5.08
0.2, 0.4 
/0.3,0.3 One 
safe/ Posi 
90.4
40.9
82.19
71.88
77.1
34.1
87.5
18
6.70
5.2
6.4
0.2, 0.4 
/0.3,0.5 One 
safe/ Posi 
90.5
38.4
83.98
95.31
77.4
44.2
90
19.6
7.0
4.75
0
0.3, 0.4 
/0.3,0.3 
MTD/ Posi 
77.1
23
80.9
74.5
67.4
19.3
83.3
15.3
4.0
3.9
4.4
9.4.6.4.
Operation Characteristics
The probability of declaring a dose is efficacious and tolerable within an individual 
cohort if the dose is declared lower than MTD at end of dose escalation stage (power and 
type I error rate) per dose are examined across scenarios for the distribution of assumed 
true DLT rates and RRs for each dose in the same combination arm. Similar results are 
expected for the other combination arm. The power is the probability declaring a 
tolerable and efficacious dose when the true underlying RR is larger than its 
corresponding historical control 0.1 and dose modification rate ≤0.12. Type 1 error rate is 
the probability of declaring a tolerable and efficacious dose within an individual cohort 
when the true underlying response rate is equal to the historical control.


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The power and type I error rate on individual dose level are calculated if the dose is 
determined to be lower than or equal to MTD at dose escalation stage. In the simulations 
that a particular dose is declared over MTD, it won’t be included in the calculation. When 
the dose is tolerable and efficacious, the design maintains at least 80% power. The type I 
error rate is controlled to <0.12. 
9.4.6.5.
Stopping Early
Table 12 also presents the proportion of trials that halt enrolment early for futility across 
simulation scenarios if expansion cohort starts. Since the study requires at least 10 
evaluable subjects in a particular cohort at the same dose prior to stopping early for 
futility, the ability for a cohort to stop early is largely dependent upon the projected 
maximum sample size and enrollment rate per cohort. 
Non-responsive cohorts stop early for futility between 55% and 61% of the time.
Responsive cohorts generally have lower than 10% chance stop early for futility.
9.4.6.6.
Mean Proportion of advancing to Phase 2
To evaluate the design performance in making the decision of advancing to Phase 2, 
Table 12 listed the probabilities of advancing any or both of the two doses to Phase 2 
after this study. In the scenario where both DLs are safe and positive, there is an 89.3% 
chance that at least one dose will be picked for RP2D. If the trial data indicates both 
doses are safe and positive, the utility function calculation discussed in Section 9.1.2 will 
be used as guidance to pick the best dose to take into Phase 2. When both dose levels are 
safe but not positive, there is 16% chance that at least one dose will be picked as RP2D. 
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.


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The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in 
writing, or both.

Signed informed consent must be obtained for each subject prior to 
participation in the study

The IEC/IRB, and where applicable the regulatory authority, approve the 
clinical protocol and all optional assessments, including genetic research. 

Optional assessments (including those in a separate protocol and/or under 
separate informed consent) and the clinical protocol should be concurrently 
submitted for approval unless regulation requires separate submission. 

Approval of the optional assessments may occur after approval is granted for 
the clinical protocol where required by regulatory authorities. In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK 
procedures, GSK monitors, or designee, will contact the site prior to the start 
of the study to review with the site staff the protocol, study requirements, and 
their responsibilities to satisfy regulatory, ethical, and GSK requirements. 

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.

Source documents provide the evidence for the existence of the participant 
and substantiate the integrity of the data collected. Source documents are filed 
at the investigator’s site. 

Data entered in the eCRFs that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. 
The investigator may need to request previous medical records or transfer 
records, depending on the study; also current medical records must be 
available. 
GSK will monitor the study and site activity to verify that the:


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
Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and 
any other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.
GSK reserves the right to temporarily suspend or prematurely discontinue this study at 
any time for reasons including, but not limited to, safety or ethical issues or severe non-
compliance. For multicenter studies, this can occur at one or more or at all sites. 
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable). 
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action. 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location. 


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The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken. 
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required. Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 
requirements or local laws or regulations, GSK standards/procedures, and/or institutional 
requirements. 
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to, archival at an off-site facility or transfer of ownership of the records in 
the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.


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11.
REFERENCES
American Cancer Society. Cancer Facts and Figures 2013. Atlanta: American Cancer 
Society, 2013.
Assangani IA, Dommeti VL, Wang X, Malik R, Cieslik M, Yang R, et al. Therapeutic 
targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature.
2014;510:278-282.
Assangani IA, Wilder-Romans K, Dommeti VL, Krishnamurthy PM, Apel IJ, Escara-
Wilke J, et al. BET bromodomain inhibitors enhance efficacy and disrupt resistance to 
AR antagonists in the treatment of prostate cancer. Molecular Cancer Research.
2016;14:324-331.
Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical 
trial of selective inhibitor of CYP17, abiraterone acetate, confirms that castration-
resistant prostate cancer commonly remains hormone driven. Journal of Clinical 
Oncology. 2008;26:4563-4571.
Chan SC, Selth LA, Li Y, Nyquist MD, Miao L, Bradner JE, et al. Targeting chromatin 
binding regulation of constitutively active AR variants to overcome prostate cancer 
resistance to endocrine-based therapies. Nucleic Acids Research. 2015; doi: 
10.1093/nar/gkv262.
Chi K, Hotte J, Joshua AM, North S, Wyatt AW, Collins LL, et al. Treatment of mCRPC 
in the AR-axis-targeted therapy-resistant state. Annals of Oncology. 2015; 
doi:10.1093/annonc/mdv267.
Cockcroft DW, Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron 1976; 16: 31-41.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: Revised RECIST guidelines (version 1.1). 
European Journal of Cancer. 2009;45:228-247.
Ferraldeschi R, Welti J, Luo J, Attard G, de Bono JS. Targeting the androgen receptor 
pathway in castration-resistant prostate cancer: progresses and prospects. Oncogene. 
2015;34:1745-1757.
GlaxoSmithKline Document Number 2011N113741_07. GSK525762 Investigator's 
Brochure, Version 07. 18 May 2018.
Ji Y, Wang, SJ. Modified toxicity probability interval design: a safer and more reliable 
method than the 3+3 design for practical phase I trials. J Clin Oncol. 2013;31:1785-1791.
Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen 
deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. 
Oncogene. 2013;32:5501-5511.


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Loriot Y, Bianchini D, Ileana E, Sandhu S, Patrikidou A, Pezaro C, et al. Antitumour 
activity of abiraterone acetate against metastatic castration-resistant prostate cancer 
progressing after docetaxel and enzalutamide (MDV3100). Annals of Oncology.
2013;24:1807-1812.
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4, 
DCTD, NCI, NIH, DHHS, May 28, 2009.
Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clinical activity of 
abiraterone acetate in patients with metastatic castration-resistant prostate cancer 
progressing after enzalutamide. Annals of Oncology. 2013;24:1802-1807.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982; 5: 649-655.
Rescigno P, Lorente D, Bianchini D, Ferraldeschi R, Kolinsky MP, Sideris S, et al. 
Prostate-specific antigen decline after 4 weeks of treatment with Abiraterone acetate and 
overall survival in patients with metastatic castration-resistant prostate cancer. Eur Urol.
2016; doi: 10.1016/j.eururo.2016.02.055
Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. 
Integrative clinical genomics of advance prostate cancer. Cell. 2015;161:1215-1228.
Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumor 
activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet.
2010;375:1437:1446.
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
objectives for castration-resistant prostate cancer: updated recommendations from the 
Prostate Cancer Clinical Trials Working Group 3. Journal of Clinical Oncology. 2016; 
doi: 10.1200/JCO.2015.64.2702.
SEER Cancer Statistics Factsheets: Prostate cancer. National Cancer Institute. Bethesda, 
MD, http://seer.cancer.gov/statfacts/html/prost.html. 2015.
Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen 
receptor inhibitors in prostate cancer. Nature Reviews Cancer. 2015;15:701-711.
Wyce A, Degenhardt Y, Bai Y, Le B, Korenchuk S, Crouthame MC, et al. Inhibition of 
BET bromodomain proteins as a therapeutic approach in prostate cancer. Oncotarget.
2013;4:2419-2429.
Xtandi (enzalutamide) Product Package Insert. Astellas Pharma US, Inc, Northbrook, IL 
and Medivation Inc., San Francisco, CA. October 2015.
Zytiga (abiraterone acetate) Product Package Insert. Janssen Biotech, Inc, Horsham, PA. 
May 2015.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACLS
Advance Cardiac Life Support
ADT
Androgen-deprivation therapy
AE
Adverse event
AkT
Protein kinase B
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time 
AR
Androgen receptor
AR-V
Androgen receptor splice variants
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-τ)
Area under the curve over a dosing interval
BAL
Brochoalveolar lavage
BCRP
Breast Cancer Resistance Protein
BET
Bromodomain and extraterminal domains
BID
Bis in die - Twice daily
BPI- SF
Brief Pain Inventory-Short Form
BRD
Bromodomain
Cav
Average observed concentration
CBC
Complete blood count
cfDNA
Cell free deoxyribonucleic acid
CI
Confidence interval
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modeling and Simulation
CR
Complete response
CRR
Composite response rate
CRPC
Castrate-resistant prostate cancer
CSMU
Clinically significant minimum utility
CSR
Clinical study report
CT
Computerized Tomography
CTC
Circulating tumor cells
CTC – ARV
CTC measuring AR-Vs
CTC – ENU
CTC enumeration
CV
Cardiovascular or Coefficient of variance
CYP
Cytochrome P450 
Cτ
Pre-dose (trough) concentration at the end of a dosing 
interval


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dL
Deciliter
D
Day
DAP
Data Analysis Plan
DCR
Disease Control Rate
DDI
Drug-drug interactions
DHEA
Dehydroepiandrosterone
DILI
Drug induced liver injury
DL
Dose level
DL60
Dose level 60
DL80
Dose level 80
DL100
Dose level 100
DL120
Dose level 120
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
dU
Utility of a given dose
E0
Baseline effect
EC50
Concentration for 50% of maximum effect
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
Emax
Maximum Effect
EORTC – QLQ-C30
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core-30
EOT
End of treatment
FDA
Food and Drug Administartion
FDG
Fluorodeoxyglucose
FIH
First-in-human
g
Gram
GCP
Good Clinical Practice
GI
Gastrointestinal
GnRH
Gonadotropin-releasing hormone
GSK
GlaxoSmithKline
h, hr
hour
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HDL
High-density lipoprotein
HIV
Human immunodeficiency virus
HPLC
High pressure liquid chromatography
HR
Heart rate
IA
Interim analysis
IB
Investigator’s Brochure


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ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
L
Liter
L2
Line 2, having failed first line treatment
Lx
Failure to multiple lines of therapy including prior 
ADT/prior chemotherapy/prior radiation therapy
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LHRH
Luteinizing hormone-releasing hormone
LLN
Lower limit of normal 
LMWH
Low molecular weight heparin
LVEF
Left ventricular ejection fraction
µM
Micromolar
mg
Milligrams
mL
Milliliter
mm
Millimeter
mmHg
Millimeter of Mercury
mmol
Millimole
msec
Milliseconds
mCRPC
Metastatic castrate-resistant prostate cancer
MedDRA
Medical Dictionary for Regulatory Activities
MFD
Maximum feasible dose
m, min
Minute
MoA
Mechanism of action
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval 
MUGA
Multigated acquisition scan
N, n
Number
ng
Nanograms
nM
Nanomolar
NA
Not applicable
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria 
for Adverse Events


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NE
Not evaluable
NSAIDs
Non-steroidal anti-inflammatory drugs
NT-proBNP
N-terminal pro–B-Type natriuretic peptide
NYHA
New York Heart Association
OAT
Organic anion transporter
ORR
Objective response rate
OS
Overall survival
PARP
Poly ADP ribose polymerase
PCR
Polymerase chain reaction
PCWG3
Prostate cancer working group 3
PD
Pharmacodynamic or Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PGx
Pharmacogenetics 
Pgp
P-glycoprotein
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PR
Partial response
PRES
Posterior Reversible Encephalopathy Syndrome
PRO-CTCAE
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events
PSA
Prostate-specific antigen
PSA50
Prostate-specific antigen from baseline ≥50%
PT
Prothrombin time/ Preferred (coded) term
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time
QD
quaque die - Once daily
qRT-PCR
Quantitative reverse transcription polymerase chain reaction
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria In Solid Tumors
RP2D
Recommended Phase II dose
rPFS
Radiological progression free survival
RNA
Ribonucleic acid
RR
Response rate
SAE
Serious adverse event
SCR
Screening visit
SD
Stable disease
SRM
Study Reference Manual 
SRT
Safety review team 
TID
ter in die – three times daily
Tmax
Time to maximum concentration
TSH
Thyroid stimulating hormone
TTG
Time to tumor growth
T3
Free triiodothyronine


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T4
Free thyroxine
ULN
Upper limit of normal
US 
United States
W
Week
Wnt
Wingless-type MMTV integration site family member
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
CellSearch
MedDRA
Xtandi
Zytiga


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12.2.
Appendix 2: Management of Suspected Toxicity
The following dose modification criteria in Table 13 should be used to provide guidance, 
but not act as a replacement for sound clinical judgment. If a given toxicity is considered 
by the investigator to be related to a single investigational drug and not both, then dose 
modification may only occur with the drug associated with a specific toxicity or event of 
clinical concern.
Table 13
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 (platelets <LLN 
to ≥75,000/mm3) & 
Grade 2 (platelets 
<75,000 to 
≥50,000/mm3)
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary.
Grade 3 (platelets 
<50,000, ≥25,000/mm3)
Withhold GSK525762 and check activated partial 
thromboplastin time (aPTT), PT, and INR. Monitor CBC 
and coagulation studies at least twice a week, or more 
frequently if clinically indicated. 
Hold GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at a dose level lower, after 
discussion with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued or restarted at another dose 
level lower, after discussion with medical monitor. If safety 
lab abnormalities recur to the same level following a 
second rechallange, drug will be discontinued.
Grade 4 (platelets 
<25,000/mm3),or any 
moderate to severe 
bleeding accompanied 
by drug related
thrombocytopenia
Withhold GSK525762 and check aPTT, PT, and INR. 
Monitor CBC and coagulation studies every 2-3 days. Hold 
GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at a lower dose level, after 
discussion with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued until platelet count recovers to 
Grade 2 (≥50,000/mm3). 
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3 (Grade 
2) within 14 days, GSK525762 should be permanently 
discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) within 
14 days, GSK525762 may be continued at the 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
current/reduced dose after discussion with the medical 
monitor. 
If platelet count does not recover to ≥25,000/mm3 (Grade 
3) within 7 days, GSK525762 should be permanently 
discontinued.
QTcF
If 60 msec change 
from baseline occurs
AND QTcF 500 msec
OR 
QTcF≥530 msec AND 
<60 msec change from 
baseline 
(average of three ECGs 
over at least 15 
minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Evaluation by cardiologist

Supplement electrolytes to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.

24-hour telemetry monitoring if clinically indicated.
This subject may consider restarting study treatment at 
one dose level reduced if all of the following criteria for 
QTcF re-challenge are met. 
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged.
If approval for re-challenge is granted, the subject must be 
re-consented (with a separate informed consent specific to 
QTc prolongation)
(1)
QTcF 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 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 
required by IRB (or equivalent), and
(6)
The subject is re-consented regarding the 
possible increased risk of 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 until ≤30 msec 
change from baseline reached, and then next 
assessment at 4 weeks post-dose.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
(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 as soon as 
possible (ideally within 24-48 hours).
For asymptomatic subjects with repeat troponin values 
>ULN, hold study medication(s), refer to a cardiologist and 
contact the 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 permanently 
discontinued and the subject will be referred immediately 
to a cardiologist for appropriate medical care.
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 medical monitor, the subject may be 
restarted on investigational drug(s) at a reduced dose. 
Monitoring to be performed at 2 and 4 weeks after 
restarting investigational drug(s) and then per protocol 
specifications.

If LVEF does not recover within 4 weeks, permanently 
discontinue investigational drug(s). Evaluation by a 
cardiologist will be conducted. Ejection fraction should 
continue to be monitored at 2 weeks, 4 weeks and 
every 4 weeks until 16 weeks or resolution, whichever 
is longer.

Grade 3 or 4

Permanently discontinue 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, 
whichever is longer.
Liver 

ALT ≥5X ULN, OR

ALT ≥3X ULN plus 
either bilirubin ≥2X 
ULN (>35% direct 
bilirubin, bilirubin 
fractionation 
required) or INR 
Refer to Section 5.4.1 for liver chemistry stopping criteria 
and treatment algorithms, and to Appendix 7 for reporting 
and follow-up of suspected liver events.
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged. 
For subjects who develop hepatotoxicity during treatment, 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
>1.5 without 
evidence of biliary 
obstruction or 
progressive disease, 
OR

ALT ≥3X ULN plus 
symptoms of liver 
injury or 
hypersensitivitya
hold abiraterone until recovery. Retreatment may be 
initiated at a reduced dose of 750 mg QD following return 
of liver function tests to baseline. If hepatotoxicity recurs at 
dose of 750 mg QD, reduce dose to 500 mg QD following 
return of liver function tests to baseline. If hepatotoxicity 
recurs at 500 mg, discontinue treatment with abiraterone. 

Elevated bilirubin, 
hypoalbuminemia, 
prolonged PT, 
ascites, and/or 
encephalopathy
Refer to Appendix 11 for definition of Child-Pugh score

Child-Pugh Class A: No change to abiraterone dose 
required

Child-Pugh Class B: Reduce dose of abiraterone to 
250 mg, administered as per the standard schedule. 

Child-Pugh Class C: Do not use. 
In addition, please refer to “other non-hematologic 
toxicity”, below, for management of GSK525762

Elevated bilirubin 
without other 
evidence of liver 
injury
Refer to “other non-hematologic toxicity”, below 
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for eCRF 
reporting use 
NCI-CTCAE v4.0 
[NCI-CTCAE, 
2009] grading 
system) 

Fasting blood 
glucose >150 mg/dL 
to 250 mg/dL (Mild 
hyperglycemia)

Monitor fasting and preprandial glucose.

If persistent over 2 repeats over 3-4 weeks, consult 
Diabetologist, consider starting metformin

Fasting blood 
glucose any blood 
glucose >250 mg/dL 
(Moderate to Severe 
hyperglycemia)

Hold investigational product(s) and instruct subject to 
notify investigator immediately.

Monitor for ketoacidosis as clinically indicated.

If subject has evidence of ketoacidosis, initiate prompt 
therapy. Antihyperglycemic therapy with insulin is 
preferred. Consult Diabetologist/Endocrinologist 
.Careful monitoring should be performed to control for 
rebound hypoglycemia as effect of investigational 
product(s) resolve

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
Medical monitor.

Fasting blood 
glucose <70 mg/dL 
(Moderate to 
Severe 
hypoglycemia)

Hold investigational product(s)

Provide sugar containing liquids and monitor blood 
sugar closely. Check for insulin and c-peptide levels. 
After blood sugar normalizes 

Restart study treatment one dose level lower if the 
hypoglycemia cannot be attributed to any other cause, 
and fasting blood sugar will be monitored on a daily 
basis until the blood glucose level is stabilized.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Diarrhea

Grade 1

Initiate supportive care including loperamide.

Grade 2

Initiate supportive care including loperamide. Consider 
temporary discontinuation of study medications and 
discuss with Medical Monitor.

Grade 3 or 4

Above plus consider IV hydration, hospital admission 
and prophylactic antibiotics as appropriate. Withhold 
study drug until diarrhea has resolved to ≤Grade 1, 
continue diarrheal prophylaxis. 

Restart study treatment one dose level lower.
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.

For mucositis >Grade 3, hold GSK525762 until 
mucositis is <Grade 1 and resume the same dose of 
GSK525762. If mucositis >Grade 3 recurs, hold 
GSK525762 until mucositis is <Grade 1, then reduce 
GSK525762 one dose level. If mucositis >Grade 3 
recurs a third time at reduced dose, hold GSK525762 
until mucositis resolved to <Grade 1, then reduce 
GSK525762 one dose level (if possible) or discontinue 
permanently
Pneumonitis
Grade 1

(For all Grades) Obtain high resolution chest CT.

Consider evaluation by pulmonologist. Consider room 
air O2 saturation at rest via weekly room air pulse 
oximetry reading (X 2, 5 mins apart). 

If any decline is observed in O2 saturation, hold study 
drug, repeat chest x-ray to determine if progression of 
pneumonitis has occurred and consult pulmonologist. 
Grade 2

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. 

Must be evaluated by a pulmonologist. Perform 
pulmonary function tests including: spirometry, 
Diffusing Capacity of the Lung for Carbon Monoxide 
(DLCO), and weekly room air O2 saturation at rest via 
pulse oximetry reading (X 2, 5 mins apart). Repeat 
evaluations every 4 weeks until pneumonitis has 
resolved.  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.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Grade 3 and 4

Discontinue investigational drug(s)

Evaluation by pulmonologist required. 

Required pulmonary function tests including: 
spirometry, DLCO, and weekly 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 treatment with corticosteroids in the 
appropriate clinical setting and in consultation with the 
pulmonologist (1-2 mg/kg of prednisone [or equivalent] 
IV once daily) if infectious origin is ruled out. Taper 
over 4-6 weeks.
Other non-
hematologic 
toxicity (except 
those listed in 
Section 4.2.2.3)

Grade 1

No change in dose

Grade 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)

Grade 3

Hold dose until toxicity is ≤Grade 1, then restart with 
no change for 1st episode. Reduce by one dose level 
with 2nd episode if recovery to ≤Grade 1 within 21 
days. If no recovery to ≤Grade 1 after a 21 day delay 
in the 2nd episode, subject should be permanently 
discontinued. 

Grade 4

In patients with objective evidence of clinical benefit, 
hold therapy until toxicity is ≤Grade 1, then restart 
with one dose level lower. If the same Grade 4 non-
hematological toxicity recurs, study drug will be 
permanently discontinued. 
Enzalutamide 
General Toxicity 

Enzalutamide 
related Grade 3 or 4

Withhold dosing for one week or until symptoms 
improve to ≤ Grade 2, then resume at the same or 
reduced dose (120 mg or 80 mg), if warranted.
a.
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)
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


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12.3.
Appendix 3: ECOG Performance Status
The performance status assessment is based on the ECOG scale [Oken, 1982]
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.


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12.4.
Appendix 4: Cockcroft and Gault Method for Calculated 
Creatinine Clearance
Calculated creatinine
clearance (mL/min) =
(140 age [yrs] ) weight (kg)
72 serum creatinine (mg/100mL)
Female subjects: multiply by 0.85
[Cockcroft, 1976]


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12.5.
Appendix 5: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – modified and adapted 
from PCWG3 guidelines [Scher, 2016] and RECIST 1.1 
[Eisenhauer, 2009]
12.5.1.
Baseline Documentation of Target and Non-Target Lesions

All baseline lesion assessments must be performed within 28 days of randomization. 

Lesions 10mm in the longest dimension are considered measurable.

Lymph nodes that have a short axis of <10mm are considered non-pathological and 
should not be recorded or followed.

Lymph nodes with <15mm and but 10mm short axis are considered pathologic 
according to clinical discretion, and nontarget

Pathological lymph nodes with 15mm short axis are considered measurable and can 
be selected as target lesions.

Per PCWG3 guidelines, documentation of prior progression should be defined as 
growth of pre-existing lesions, development of new lesions, or both. Documentation 
of site of progression either in a single organ or disease site versus multiple sites 
should occur. Bone scan lesions should be identified and tracked independently.

Per PCWG3 guidelines, documentation of nodal disease should be considered either 
loco-regional (pelvic) versus extrapelvic (e.g., retroperitoneal, mediastinal, thoracic, 
other). Visceral disease (e.g., lung/liver/CNS) should be documented separately from 
nodal disease. Up to 5 measurable lesions can be documented per site of spread (e.g., 
nodes, lung, liver as separate sites). Each of these lesions should be identified, 
recorded and measured at baseline. These lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 

Documentation of progression at entry into trial should be recording as PSA alone, 
bone with or without nodes by location, nodes by location only or viscera (or other 
sites). 
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation should not be considered as target lesions. 

Bone scans are standard for PCWG3 guidelines, with documentation of absence or 
metastasis recorded at baseline. 

All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be group by organ. 
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 


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
The following are required at baseline: CT for Chest/Abdomen/Pelvis or MRI for 
Abdomen/ Pelvis. At each post baseline assessment, evaluations of the sites of 
disease identified by these scans are required. 
Confirmation of CR and PR are required per protocol. Confirmation assessments must be 
performed no less than 4 weeks after the criteria for response have initially been met and 
may be performed at the next protocol scheduled assessment. If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required (e.g. evaluations must occur at each protocol 
scheduled timepoint regardless of unscheduled assessments).
A baseline brain scan is required for all subjects. For subjects without CNS disease at 
baseline, subsequent brain scans should only be performed as clinically indicated (e.g. 
symptoms suggestive of CNS progression).
12.5.2.
Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion.  Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.

All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers.

Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose (FDG)- Positron emission tomography (PET) is generally not 
suitable for ongoing assessments of disease. However FDG-PET can be useful in 
confirming new sites of disease where a positive FDG-PET scans correlates with the 
new site of disease present on CT/MRI or when a baseline FDG-PET was previously 
negative for the site of the new lesion. FDG-PET may also be used in lieu of a 
standard bone scan providing coverage allows interrogation of all likely sites of bone 
disease and FDG-PET is performed at all assessments.

If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 
anatomical coverage and prescribed use of contrast. The method of assessment 
should be noted as CT on the eCRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required [Eisenhauer, 2009].
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimised for 


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the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible the same 
scanner should be used [Eisenhauer, 2009].
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.
12.5.3.
Guidelines for Evaluation of Disease
Measurable and Non-measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5mm. If 
the slice thickness is greater than 5mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest x-ray.
Additionally lymph nodes can be considered pathologically enlarged and measurable if

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm). At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009].
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques (Eisenhauer, 2009).
Measurable disease: Measureable lesions are not required at study entry if subject meets 
PSA requirements for progression (rising PSA values at a minimum of 1-week intervals 
or PSA doubling time with at least 3 values available ≥4 weeks apart). . Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 


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12.5.4.
Response Criteria
Evaluation of target lesions
Each site of disease should be evaluated independently. Definitions for assessment of 
response for target lesion(s) are as follows:

Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes must be <10mm in the short axis. 

Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions). When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments. However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented. If an assessment of 
PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm). If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured. The response at the time when the lesion reappears will depend upon 
the status of the other lesions. For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance. However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 


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remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.

Bone lesions with change in intensity of uptake alone do not constitute progression 
or regression. Pseudoprogression in the absence of symptoms or other signs of 
progression will be excluded. 

Bone lesion progression will require at least 2 new bone lesions on first post-
treatment scan, with at least 2 additional bone lesions on the next scan. In this 
instance, the date of the first scan will represent the date of bone progression. 
Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response (CR): The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. <10 
mm short axis).

Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥ 10 mm short axis.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 

Not Applicable (NA): No non-target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

In the presence of non-measurable only disease consideration should be given to 
whether or not the increase in overall disease burden is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease.

Sites of non-target lesions, which are not assessed at a particular timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable"). 
New lesions
New malignancies denoting disease progression must be unequivocal. Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions. Nodes that have progress to ≥10 mm to <15 mm are pathologic, subject to 
clinical discretion, and non-measurable. Previously normal lymph nodes must have 
grown by ≥5 mm in the short axis to be considered to have progressed. 


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Any equivocal new lesions should continue to be followed. Treatment can continue at the 
discretion of the investigator until the next scheduled assessment. If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
Evaluation of overall response
Table 14 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 14
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the CR.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point. 

To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after first dose at a minimum interval of 49 days.

If the minimum time for SD is not met, best response will depend on the subsequent 
assessments. For example if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement the best response will be PD. 


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Alternatively, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
Confirmation Criteria:

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.


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12.6.
Appendix 6: Liver Safety Required Actions and Follow up 
Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
Subject with entry criteria ALT≤ 2.5 x ULN
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Liver Chemistry Stopping Criteria – Liver Stopping Event
Including subjects with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN
ALT-absolute
Both ALT 5xULN and 2x baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
Both ALT 3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity


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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 7)

If restart/rechallenge is not granted, 
permanently discontinue study treatment and 
may continue subject in the study for any 
protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) analysis, 
obtained approximately within 48h after last 
dose5

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications

Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins).

Serum acetaminophen adduct high pressure liquid 
chromatography (HPLC) assay (quantifies 
potential acetaminophen contribution to liver injury 
in subjects with definite or likely acetaminophen 
use in the preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 


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bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the 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 SRM.
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Subject with entry criteria ALT≤2.5x ULN
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks
Subject with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
For subjects with documented liver 
metastases/tumor infiltration at baseline AND entry 
criteria ALT>2.5 x ULN but ≤5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
<1.5x baseline value, and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries 
normalize or return to within baseline


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1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior 
to first dose of study treatment
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.7.
Appendix 7: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009] 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.
Approval by GSK for rechallenge with study treatment can be considered where:


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
Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available. 

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.  

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death. 

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart. 

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Appendix 8.
2. Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded


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


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12.8.
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.8.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 


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condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.8.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These should also be 
considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if 
unavailable, measure urinary bilirubin via dipstick. If fractionation is unavailable and 
ALT 3xULN and total bilirubin 2xULN, then the event is still to be reported as an 
SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form.

Refer to Appendix 6 for the required liver chemistry follow-up instructions


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12.8.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.8.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 


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the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.8.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe: An event that prevents normal everyday activities. - an AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 


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information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.8.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the
Sponsor/Medical Monitor Contact Information page.


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12.9.
Appendix 9: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including GSK525762 and/or abiraterone or 
enzalutamide, or any concomitant medicines;

mCRPC susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study. Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above. Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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


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


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12.10.
Appendix 10: Country Specific Requirements
No country-specific requirements exist.


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12.11.
Appendix 11: Child-Pugh score [Pugh, 1973]
Measure
1 point
2 points
3 points
Points
Class
References:
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-649.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data 
collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.12.
Appendix 12: Contraceptive Guidance and Collection of 
Pregnancy Information
12.12.1.
Contraception Guidance:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)


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12.12.2.
Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 24 hours of learning of the partner’s pregnancy 

Female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
12.12.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006.
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50. 
Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)


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International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998] WHO, 
2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants and 
Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9. 
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.13.
Appendix 13: Protocol Amendment Changes
Protocol changes for Amendment (01-Feb-2017) from Original Protocol (13-
Oct-2016)
Protocol Amendment 1 applies to all global site(s) participating in the conduct of the 
study
Amendment 1 Summary
Amendment 1 includes the following changes which were based on review and 
comments from the FDA during review: clarifications to Exclusion #6 and addition of 
new Exclusion Criterion; addition of dose reduction table; additional wording on 
prohibited and cautionary medications; and adjustments to the Dose Adjustment/Stopping 
Safety Criteria. In addition to the FDA requests, additional changes which were included 
were: new information added regarding monotherapy CRPC study; revision to Inclusion 
#12; clarifications to GSK525762 formulation wording; clarification to planned dose 
adjustment section; revision to male lifestyle changes with additions of pregnancy section 
and contraceptive appendix; update of prohibited and cautionary medication tables; 
various clarifications to Table and Events table; removal of screening CTC-ARV sample; 
adjustment to timing of CTC-enumeration and exploratory whole blood analysis; 
adjustment to the visit window wording; clarifications to the laboratory testing section; 
revision to tumor biopsy section and clarification to analysis population section. 
List of Specific Changes
Section 1 - Protocol Synopsis Rationale 
Rationale for Change: 
Additional wording to clarify results of recently completed analysis for BET115521 
monotherapy study – CRPC arm. 
Previous text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as bromodomain and extraterminal domains (BET) [Wyce, 2013]. 
Studies have demonstrated that BET inhibition can lead to growth arrest and cell death in 
a variety of preclinical models, including models of CRPC [Wyce, 2013]. An ongoing 
first-in-human (FIH) study from GlaxoSmithKline (GSK), BET115521, is currently 
evaluating the safety and preliminary efficacy of single-agent GSK525762, a potent 
inhibitor of BET proteins, in a number of tumor types including mCRPC. 
Revised Text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as bromodomain and extraterminal domains (BET) [Wyce, 2013]. 
Studies have demonstrated that BET inhibition can lead to growth arrest and cell death in 


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a variety of preclinical models, including models of CRPC [Wyce, 2013]. An ongoing 
first-in-human (FIH) study from GlaxoSmithKline (GSK), BET115521, is currently 
evaluating the safety and preliminary efficacy of single-agent GSK525762, a potent 
inhibitor of BET proteins, in a number of tumor types including mCRPC. Preliminary 
data from the futility analysis of the CRPC arm indicated there were no partial or 
complete responses. This data will be further examined as the data continues to 
mature.
Section 1 - Protocol Synopsis Overall design
Rationale for Change: 
Arm B: Revision of section due to missed wording which is present in the body of the 
text 
Previous text: 
However, based on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 level to 
determine if it is acceptable to open the DL120 dose level. If DL120 is opened, subjects 
in DL120 will begin dosing with GSK525762 at 120 mg and the approved dose of 
enzalutamide. 
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at these selected doses will be initiated 
and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 subjects each 
will be enrolled into both cohorts, and approximately10 enrolled subjects will be L2 and 
20 subjects will be Lx (Figure 2). 
Revised text:
However, based on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 and 
DL100 levels to determine if it is acceptable to open the DL120 dose level. If DL120 is 
opened, subjects in DL120 will begin dosing with GSK525762 at 120 mg and the 
approved dose of enzalutamide. 
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at these selected higher and lower
doses will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A 
total of 30 subjects each will be enrolled into both cohorts, and approximately10 enrolled 
subjects will be L2 and 20 subjects will be Lx (Figure 2). 


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Section 1 - Synopsis Inclusion Criteria
Rationale for Change: 
Clarification of Inclusion Criteria #12 with required time frame of contraception use
Previous text: 
12.    Male subject with a female partner of childbearing potential or pregnant must agree 
to use two acceptable methods of contraception from time of Screening until 3 months 
after the last dose of study treatments. 
Revised text:
12.    Male subject with a female partner of childbearing potential or pregnant must agree 
to use two acceptable methods of contraception from time of first dose of study 
treatment Screening until 4 3 months after the last dose of study treatments. 
Section 1 - Synopsis Exclusion Criteria
Rationale for Change: 
Due to FDA feedback, the wording related to bleeding was to include clinically 
significant haemorrhage within a defined time period in addition to known bleeding 
disorder(s)
Previous text: 
6.   Subjects with history of known bleeding disorder(s)
Revised text:
6.   Subjects with history of known bleeding disorder(s) including clinically significant 
hemorrhage (e.g., GI, neurologic), within the past 6 months.
Section 1 - Synopsis Exclusion Criteria
Rationale for Change: 
Based on FDA review and emerging safety data from the BET115521 monotherapy 
study, it was suggested that the study limit the use of certain medications. This required a 
new Exclusion Criteria #8 and caused a re-numbering of criteria after the addition of this 
new Exclusion Criteria. 
New text: 
8.   Concurrent use of high dose aspirin (doses up to 81mg oral dose daily allowed) and 
non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide 
documented benefit over other analgesics and then to be used with caution including 
concomitant use of proton pump inhibitors.


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Section 1 - Synopsis Exclusion Criteria
Rationale for Change: 
Due to change in Exclusion #6, removed wording to Exclusion #17 to prevent 
duplication.
Previous text: 
17.  Subjects with gastrointestinal disorders likely to interfere with absorption of the 
study medication; History of major gastrointestinal bleeding within the last 6 months.
Revised text: 
17.  Subjects with gastrointestinal disorders likely to interfere with absorption of the 
study medication.; History of major gastrointestinal bleeding within the last 6 months.
Section 2.2 - Brief Background
Rationale for Change: 
Additional wording to clarify results of recently completed analysis for BET115521 
monotherapy study – CRPC arm. 
Previous text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as BET [Wyce, 2013]. The BET family, comprised of bromodomain 2 
(BRD), BRD3, BRD4 and BRDT, recognize acetyl groups on the tails of histones and are 
critical for recruiting transcriptional machinery necessary for gene expression. BRD4 has 
been shown to interact with AR, and BET inhibition abrogated BRD4 localization to a 
subset of AR target loci and reduced AR-mediated gene transcription, causing 
suppression of AR signaling [Assangani, 2014]. Studies have demonstrated that BET 
inhibition can lead to growth arrest and cell death in a variety of preclinical models, 
including models of CRPC [Wyce, 2013]. An ongoing first-in-human (FIH) study from 
GlaxoSmithKline (GSK), BET115521, is currently evaluating the safety and preliminary 
efficacy of single-agent GSK525762, a potent inhibitor of BET proteins, in a number of 
tumor types including mCRPC. Preliminary safety and efficacy data is summarized in the 
Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 2011N113741_05, 
2016]. 
Revised text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as BET [Wyce, 2013]. The BET family, comprised of bromodomain 2 
(BRD), BRD3, BRD4 and BRDT, recognize acetyl groups on the tails of histones and are 
critical for recruiting transcriptional machinery necessary for gene expression. BRD4 has 
been shown to interact with AR, and BET inhibition abrogated BRD4 localization to a 


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subset of AR target loci and reduced AR-mediated gene transcription, causing 
suppression of AR signaling [Assangani, 2014]. Studies have demonstrated that BET 
inhibition can lead to growth arrest and cell death in a variety of preclinical models, 
including models of CRPC [Wyce, 2013]. An ongoing first-in-human (FIH) study from 
GlaxoSmithKline (GSK), BET115521, is currently evaluating the safety and preliminary 
efficacy of single-agent GSK525762, a potent inhibitor of BET proteins, in a number of 
tumor types including mCRPC. Preliminary data from the futility analysis of the 
CRPC arm indicated there were no partial or complete responses. This data will be 
further examined as the data continues to mature. Preliminary safety and efficacy 
data is summarized in the Investigator’s Brochure (IB) [GlaxoSmithKline Document 
Number 2011N113741_05, 2016].
Section 4.1 – Overall Design
Rationale for Change: 
Clarification of wording to clarify selected doses. 
Previous text:
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at the selected doses will be initiated 
and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 subjects each 
will be enrolled into both cohorts, and approximately10 enrolled subjects will be L2 and 
20 subjects will be Lx (Figure 4). Refer to Section 4.6 for further dose information.
Revised text: 
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at the selected higher and lower doses 
will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each will be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 4). Refer to Section 4.6 for further dose 
information.
Section 4.2.2.2 - Dose-Limiting Toxicity
Rationale for Change: 
Addition of inadvertently missed superscript footnote letter and update of language of 
footnote to match DLT in Table 4. 


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Previous text: 
Other

Inability to receive at least 75% of scheduled doses in the DLT 
observation period due to drug-related toxicity, or any toxicity which 
requires permanent discontinuation of investigational agent(s) during 
the DLT observation period

Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and Medical Monitor is considered to be a 
DLT
Toxicity Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4 [NCI-CTCAE, 2009]
a.     Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not considered to be a DLT.
b.     Subjects unable to receive at least 80% 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 Text: 
Other

Inability to receive at least 75% of scheduled doses in the DLT 
observation period due to drug-related toxicity, or any toxicity which 
requires permanent discontinuation of investigational agent(s) during 
the DLT observation periodb

Grade 2 or higher toxicity that occurs beyond 28 days which in the 
judgment of the investigator and Medical Monitor is considered to be a 
DLT
Toxicity Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v4 [NCI-CTCAE, 2009]
a.     Grade 3 hypertension adequately controlled by antihypertensive medication(s) is not considered to be a DLT.
b.     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.
Section 4.6.2 – Starting Doses
Rationale for Change: 
Emerging data from clinical pharmacology to provide updated wording on potential 
effect of Enzalutamide on the starting dose of GSK525762 in combination
Previous text: 
The initial dose of GSK525762 in dose escalation administered in combination with 
enzalutamide will be 80 mg besylate salt tablets. It is anticipated that enzalutamide will 
reduce the steady-state exposure (AUC) to GSK525762 by 60% and to GSK525762 
active moiety (GSK525762 + active metabolites) by around 20%, as predicted by a 
mechanistic physiologically based pharmacokinetic (PBPK) model, as part of the 


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SimCYP population-based PBPK simulator incorporating the effects observed on 
GSK525762 and active metabolites exposures following co-administration with 
itraconazole. Therefore, the initial dose of GSK525762 in both arms should be 
approximately equivalent. 
Revised text: 
At clinically relevant doses, enzalutamide has been shown to be an inducer of 
CYP3A4, with an 86% decrease in midazolam exposure. Enzalutamide also has the 
potential to be a clinical inducer and inhibitor of the transport protein P-
glycoprotein. The initial dose of GSK525762 in dose escalation administered in 
combination with enzalutamide will be 80 mg besylate salt tablets. It is anticipated that 
enzalutamide will reduce the steady-state exposure (AUC) to GSK525762 by 60% and to 
GSK525762 active moiety (GSK525762 + active metabolites) by around 20% 
(extrapolation of the net effect in GSK525762 exposure due to CYP3A4/ P-gp 
Induction and P-gp Inhibition). , as predicted by a mechanistic physiologically based 
pharmacokinetic (PBPK) model, as part of the SimCYP population-based PBPK 
simulator incorporating the effects observed on GSK525762 and active metabolites 
exposures following co-administration with itraconazole Therefore, the initial dose of 
GSK525762 in both arms should be approximately equivalent. 
Section 4.6.4.1 – Cardiovascular Safety Findings
Rationale for Change: 
Removed wording which should have been removed in original protocol. 
Previous wording: 
To monitor for cardiomyopathy and valvular toxicity, echocardiograms will be performed 
at the time points specified in the Time and Events tables (Section 7.1). Management 
guidelines (Appendix 2) and stopping criteria (Section 5.4.2 and Section 5.4.3) are 
incorporated in the protocol.
Revised wording: 
To monitor for cardiomyopathyand valvular toxicity, echocardiograms will be performed 
at the time points specified in the Time and Events tables (Section 7.1). Management 
guidelines (Appendix 2) and stopping criteria (Section 5.4.2 and Section 5.4.3) are 
incorporated in the protocol.
Section 5.1 - Inclusion Criteria
Rationale for Change: 
Clarification of Inclusion Criteria #12 with required time frame of contraception use


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Previous text: 
12.    Male subject with a female partner of childbearing potential or pregnant must agree 
to use two acceptable methods of contraception from time of Screening until 3 months 
after the last dose of study treatments (Section 6.10.2). 
Revised text:
12.    Male subject with a female partner of childbearing potential or pregnant must agree 
to use two acceptable methods of contraception from time of first dose of study 
treatment Screening until 4 3 months after the last dose of study treatments (Section 
6.10.2). 
Section 5.2 - Exclusion Criteria
Rationale for Change: 
Due to FDA feedback, the wording related to bleeding was to include clinically 
significant haemorrhage within a defined time period in addition to known bleeding 
disorder(s)
Previous text: 
6.   Subjects with history of known bleeding disorder(s)
Revised text:
6.   Subjects with history of known bleeding disorder(s) including clinically significant 
hemorrhage (e.g., GI, neurologic), within the past 6 months.
Section 5.2 - Exclusion Criteria
Rationale for Change: 
Based on FDA review and emerging safety data from the BET115521 monotherapy 
study, it was suggested that the study limit the use of certain medications. This required a 
new Exclusion Criteria #8 and caused a re-numbering of criteria after the addition of this 
new Exclusion Criteria. 
New text: 
8.   Concurrent use of high dose aspirin (doses up to 81mg oral dose daily allowed) and 
non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide 
documented benefit over other analgesics and then to be used with caution including 
concomitant use of proton pump inhibitors.


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Section 5.2 - Exclusion Criteria
Rationale for Change: 
Due to change in Exclusion #6, removed wording to Exclusion #17 to prevent 
duplication.
Previous text: 
17.  Subjects with gastrointestinal disorders likely to interfere with absorption of the 
study medication; History of major gastrointestinal bleeding within the last 6 months.
Revised text: 
17.  Subjects with gastrointestinal disorders likely to interfere with absorption of the 
study medication.; History of major gastrointestinal bleeding within the last 6 months.
Section 5.3 – Screening/Baseline/Run-in Failures 
Rationale for Change: 
Wording added to further clarify how subjects would be classified if withdrawn during 
the combination run-in. 
Previous text: 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (Appendix 8). 
Revised text: 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (Appendix 8). Run-in failures 
are defined as subjects who start the run-in of either abiraterone or enzalutamide 
and withdraw from this run-in and do not proceed to dose with GSK525762.
Section 6.1 – Investigational Product and Other Study Treatment 
Rationale for Change: 
Clarification of the GSK525762 dosages. 


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Previous text: 
Investigational Product
Product 
name:
GSK525762 Besylate Tablets
Abiraterone acetate
Enzalutamide
Unit dose 
strength(s)/Do
sage level(s):
5 mg
20 mg
25 mg
250 mg
40 mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Janssen
Astellas
Physical 
description:
White to slightly colored, 
round, biconvex tablets with 
no markings, film-coated 
tablet
White to off-white, oval 
tablets debossed with 
AA250 on one side
White to off-white oblong soft 
gelatin capsules imprinted in 
black ink with ENZ
Route/
Administratio
n/ Duration:
Oral; see Time and Event 
Tables for schedule and 
administration timings
Oral; see Time and Event 
Tables for schedule and 
administration timings
Oral; see Time and Event 
Tables for schedule and 
administration timings
Dosing 
instructions:
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
Dose with 240 mL water 
and should be taken on an 
empty stomach, and no 
food should be consumed 
from 2hrs before the dose 
until 1hr after the dose. 
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
NOTE: These formulation details are current at the time of protocol finalization and may be updated in other 
documents (e.g., SRM and/or informed consent form) without requiring protocol amendment 


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Revised text:  
Investigational Product
Product 
name:
GSK525762 Besylate Tablets
Abiraterone acetate
Enzalutamide
Unit dose 
strength(s)/Do
sage level(s):
5 mg a
250 mg
a
205 mg
a
250 mg
40 mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Janssen
Astellas
Physical 
description:
White to slightly 
colored, round, 
biconvex tablets 
with no markings, 
film-coated tablet
Beige, 
round, 
biconv
ex 
tablets 
with no 
markin
gs, 
film-
coated
White to off-white, oval 
tablets debossed with 
AA250 on one side
White to off-white oblong soft 
gelatin capsules imprinted in 
black ink with ENZ
Route/
Administratio
n/ Duration:
Oral; see Time and Event 
Tables for schedule and 
administration timings
Oral; see Time and Event 
Tables for schedule and
administration timings
Oral; see Time and Event 
Tables for schedule and 
administration timings
Dosing 
instructions:
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
Dose with 240 mL water 
and should be taken on an 
empty stomach, and no 
food should be consumed 
from 2hrs before the dose 
until 1hr after the dose. 
Dose 5 mg prednisone 
orally twice daily as per 
prescribing information.
Dose with 240 mL water and 
should be taken around the 
same time every day without 
regards to timing of meal (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.)
NOTE: These formulation details are current at the time of protocol finalization and may be updated in other 
documents (e.g., SRM and/or informed consent form) without requiring protocol amendment
a.    The 20 mg tablet formulation is in development and will be utilized during the planned duration of the 
        study.  The 5 mg and 25 mg tablet formulation may be discontinued when the 20 mg tablet formulation
        is available.  The use of 20 mg tablets will require regulatory authority approvals.   
Section 6.3 – Planned Dose Adjustments 
Rationale for Change: 
Per FDA response, GSK525762 dose level reductions discussed in the protocol were not 
well defined. Addition of a dose level reduction table to clarify the possible dose 
reductions. Additional clarifications were added beyond the FDA response to further 
clarify dosing of combination product during any GSK525762 dose interruption. 


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Previous text: 
There are no pre-planned dose adjustments per protocol. Dose reductions for individual 
subjects may be required, based on toxicity observed during the study (please refer to 
Appendix 2), and the frequency and duration of dose reductions will be reported.
If enzalutamide is discontinued for more than or equal to 7 days, then the maximum dose 
of GSK525762 should be the single agent RP2D of 80 mg. If enzalutamide is re-started, 
GSK525762 should remain at 80 mg until after at least 14 days until the dose is escalated, 
if applicable. Subjects who require permanent discontinuation of either abiraterone or 
enzalutamide in the combination may continue GSK525762 as a single agent if there is 
evidence of continuing benefit on treatment. If GSK525762 is continued as a single 
agent, the maximum dose would be 80 mg. Intra-subject dose escalations from the 
planned starting dose during dose escalation will not be permitted. Intra-subject dose 
escalation may be permitted during dose expansion for the lower dose level only if that 
dose is determined to be futile. 
Revised text: 
There are no pre-planned dose adjustments per protocol. Dose reductions for individual 
subjects may be required, based on toxicity observed during the study (please refer to 
Appendix 2), and the frequency and duration of dose reductions will be reported. Table 6
clarifies the dose reductions for GSK525762 at any planned study dose. 
Table 6 
GSK525762 Dose Reductions
Current GSK525762 Dose: 
If subject requires dose level reduction: 
40mg
No further dose reduction allowed
60mg
40mg
80mg
60mg
100mg
80mg
120mg
100mg
If enzalutamide is discontinued for more than or equal to 7 days, then the dose of 
GSK525762 should be reduced one dose level and the maximum dose of GSK525762 
should be the single agent RP2D of 80 mg. If enzalutamide is re-started, GSK525762 
should remain at the reduced dose level or the maximum single agent RP2D of 80 mg 
until after at least 14 days until the dose is escalated, if applicable. Subjects who require 
permanent discontinuation of either abiraterone or enzalutamide in the combination may 
continue GSK525762 as a single agent if there is evidence of continuing benefit on 
treatment. If GSK525762 is continued as a single agent, the maximum dose would be 80 
mg. Intra-subject dose escalations from the planned starting dose during dose escalation 
will not be permitted. Intra-subject dose escalation may be permitted during dose 
expansion for the lower dose level only if that dose is determined to be futile.
During any dose interruption of GSK525762, abiraterone or enzalutamide may be 
continued at the protocol dose unless dose interruption of these combination 


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products is also required. If GSK525762 is permanently discontinued, subject must 
be discontinued from the treatment and withdrawn from the study.
Section 6.5 – Packaging and Labeling 
Rationale for Change: 
Added clarification on sourcing of prednisone which is required for abiraterone dosing 
per the prescribing information. 
Previous text: 
GSK525762 and abiraterone/enzalutamide will be provided to the sites by GSK. The 
contents of the labels will be in accordance with all applicable regulatory requirements.
Revised text: 
GSK525762 and abiraterone/enzalutamide will be provided to the sites by GSK. 
Prednisone will not be supplied by GSK. The contents of the labels will be in 
accordance with all applicable regulatory requirements.
Section 6.10.2 – Male Subjects 
Rationale for Change: 
Protocol template revised allowed contraception for subjects and also moved these 
choices to an Appendix. Language updated to reflect template update. Additional 
clarification added to section to confirm non-allowed contraception and restrictions if 
female partner was to become pregnant during the trial.
Previous text: 
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 (note that these requirements do not apply if female partners are 
not of child-bearing potential):

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), OR

Condom PLUS

history of surgical sterilization (i.e., vasectomy) with subsequent documentation of 
azoospermia, OR
partner use of a highly effective contraceptive (i.e., a failure rate ≤1%) such as hormonal 
contraception, intrauterine device, or occlusive cap (diaphragm or cervical/vault cap) plus 
spermicidal agent (foam/gel/film/cream/suppository).


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Revised text: 
Subjects with female partners of child-bearing potential must use acceptable, highly 
effective forms of contraceptive methods (i.e., a failure rate of ≤1%) defined in 
Appendix 12 one of the following contraceptive methodsafter the first dose of study 
treatment and until 16 weeks 4 months after the last dose of study drug (note that 
these requirements do not apply if female partners are not of child-bearing 
potential). 

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), OR

Condom PLUS

history of surgical sterilization (i.e., vasectomy) with subsequent documentation of 
azoospermia, OR
Female partner use of hormonal means of birth control such as oral contraceptives 
are NOT acceptable forms of birth control given that their efficacy has not been 
evaluated when given in combination with the investigational drugs.
In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 4 months after stopping study 
medications.
Section 6.11.2.1 – Prohibited Medications 
Rationale for Change: 
Based on FDA review and emerging safety data from the BET115521 monotherapy 
study, it was suggested that the study limit the use of certain medications. Revision of 
Table 7 to provide updated list of Prohibited Medication from May 2016 and addition of 
footnote to Table. 
New text: 
Subjects may continue to use Aspirin, but doses are not allowed to be greater than 
81mg per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be 
excluded, except for when NSAIDs will provide benefit over other analgesics and 
then to be used with caution including concomitant use of proton pump inhibitors. 
Previous text: 
Drugs with a Risk of Torsades de Pointes that are Prohibited


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Amiodarone
Donepezil
Methadone
Anagrelide
Dronedarone
Moxifloxacin
Astemizole
Droperidol
Papaverine
Azithromycin
Erythromycin
Pentamidine
Bepridil
Escitalopram
Pimozide
Chloroquine
Flecainide
Probucol
Chlorpromazine
Fluconazole
Procainamide
Cilostazol
Gatifloxacin
Propofol
Ciprofloxacin
Grepafloxacin
Quinidine
Cisapride
Halofantrine
Sevoflurane
Citalopram
Haloperidol
Sotalol
Clarithromycin
Ibutilide
Sparfloxacin
Cocaine
Levofloxacin
Sulpiride
Disopyramide
Levomepromazine
Terfenadine
Dofetilide
Levomethadyl
Thioridazine
Domperidone
Mesoridazine
Data Source: crediblemeds.org revision date 17 Dec 2015.
Revised text: 
Drugs with a Risk of Torsades de Pointes that are Prohibited
Amiodarone
Dronedarone
Moxifloxacin
Anagrelide
Droperidol
Papaverine
Azithromycin
Erythromycin
Pentamidine 
Chloroquine
Escitalopram
Pimozide
Chlorpromazine
Flecainide
Procainamide
Cilostazol
Fluconazole
Propofol
Ciprofloxacin
Halofantrine
Quinidine
Citalopram
Haloperidol
Roxithromycin
Clarithromycin
Ibogaine
Sevoflurane
Cocaine
Ibutilide
Sotalol
Disopyramide
Levofloxacin
Sulpiride
Dofetilide
Levomepromazine
Sultopride
Domperidone
Levosulpiride
Terlipressin
Donepezil
Methadone
Thioridazine
Data Source: crediblemeds.org revision date 09 January 2017.
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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Section 6.11.2.3 – Cautionary Medications 
Rationale for Change: 
Based on FDA review and emerging safety data from the BET115521 monotherapy 
study, it was suggested that the study limit the use of certain medications. Revision of 
Table 8 to provide updated list of Prohibited Medication from May 2016 and addition of 
footnote to Table. 
Previous text: 
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 oral dose of 8 mg TID) are the only allowed 
drugs in this class (dolasetron and granisetron are not permitted). Drugs with a low risk of 
causing QTc prolongation (e.g., aprepitant) may be used without restriction.
Co-administration of GSK525762 and the following medications requires extreme 
caution beginning 14 days prior to the first dose of study drug until discontinuation from 
the study, due to an increased risk of Torsades de Pointes. These medications include (but 
are not limited to):
Drugs with a Risk of Torsades de Pointes which are permitted for co-administration 
with Extreme Caution
Alfuzosin
Iloperidone
Ranolazine
Apomorphine
Imipramine
Rilpivirine
Aripiprazole
Isradipine
Risperidone
Artenimole+piperaquine
Roxithromycin
Asenapine
Mifepristone
Saquinavir
Atazanavir
Lithium
Sertindole
Atomoxetine
Mifepristone
Tacrolimus
Bedaquiline
Mirabegron
Telavancin
Clomipramine
Mirtazapine
Telithromycin
Clozapine
Moexipril/ hydrochlorothiazide
Tetrabenazine
Delamanid
Nortriptyline
Tizanidine
Desipramine
Ofloxacin
Tolterodine
Dexmedetomidine
Olanzapine
Toremifene
Famotidine
Oxytocin
Trimipramine
Felbamate
Paliperidone
Tropisetron
Fingolimod
Pasireotide
Vardenafil
Foscarnet
Perflutren lipid microspheres
Venlafaxine
Gemifloxacin
Pipamperone
Hydrocodone ER
Promethazine
Data Source: crediblemeds.org revision date 17 Dec 2015


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Revised text: 
Subjects should minimize the use of medications which contain acetaminophen. 
Subjects should be informed of alternative medications. 
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (administered per the prescribing 
informationup to a maximum dose of 0.25 mg daily) and oral ondansetron (up to a 
maximum oral dose of 8 mg TID) are the only allowed drugs in this class (dolasetron and 
granisetron are not permitted). Drugs with a low risk of causing QTc prolongation (e.g., 
aprepitant) may be used without restriction.
Co-administration of GSK525762 and the following medications requires extreme 
caution beginning 14 days prior to the first dose of study drug until discontinuation from 
the study, due to an increased risk of Torsades de Pointes. These medications include (but 
are not limited to):
Drugs with a Risk of Torsades de Pointes which are permitted for co-administration 
with Extreme Caution
Alfuzosin
Foscarnet
Perphenazine
Apomorphine
Gemifloxacin
Pipamperone
Aripiprazole
Hydrocodone ER
Promethazine
Artenimole+piperaquine
Iloperidone
Rilpivirine
Asenapine
Imipramine
Risperidone
Atomoxetine
Isradipine
Saquinavir
Bedaquiline
Leuprolide
Sertindole
Buprenorphine
Lithium
Solifenacin
Clomipramine
Melperone
Tacrolimus
Clozapine
Mifepristone
Telavancin
Cyamemazine
Mirabegron
Telithromycin
Degarelix
Mirtazapine
Tetrabenazine
Delamanid
Moexipril/ hydrochlorothiazide
Tiapride
Desipramine
Nicardipine
Tizanidine
Dexmedetomidine
Norfloxacin
Tolterodine
Efavirenz
Nortriptyline
Trimipramine
Ezogabine
Ofloxacin
Tropisetron
Famotidine
Oxytocin
Vardenafil
Felbamate
Paliperidone
Venlafaxine
Fingolimod
Pasireotide
Zotepine
Flupentixol
Perflutren lipid microspheres
Data Source: crediblemeds.org revision date 09 January 2017
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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Section 7.1 – Time and Events Tables  
Rationale for Change: 
Revision to the Dose Escalation and Dose Expansion table of events and associated 
laboratory tables. For study assessment tables, these were modified to include a column 
for possible lead-in abiraterone or enzalutamide dosing, clarification for weeks for every 
4 weeks and every 8 weeks and addition of column for revised every 12 weeks 
scheduling post Week 49. Adjustment to footnotes 11, 13, 16, and 17. For the laboratory 
tables, these were adjusted to add in a clarification of visits for every 4 weeks, addition of 
column for revised every 12 weeks scheduling post Week 49, additional row to clarify 
testing of Factor VII assay. Addition of footnotes 1 and 2. 
Previous text:
Table 9 
Dose Escalation Time and Events
Procedure
SC
R
Week 1
Week 2
Week 3
Wee
k 4
Wee
k 5
q4w
q8w
EOT
1, 22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 and 
thereaft
er
W9 and 
thereaft
er
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusio
n Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register/ 
Randomize4
Subject
X
Safety
Physical Exam5
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments7
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
or MUGA8
X
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Study Treatment
Administer 
GSK52576210
Daily
Administer 
Combination 
product10,11
Daily


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Procedure
SC
R
Week 1
Week 2
Week 3
Wee
k 4
Wee
k 5
q4w
q8w
EOT
1, 22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 and 
thereaft
er
W9 and 
thereaft
er
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood 
samples12
PK
PK
O
X
Tumor biopsy13
X
One sample, 
collected 3-
6h post-
GSK525762 
dose, 
between 
W3D1 and 
W4D1
X14
Whole blood for 
exploratory 
analyses 
X
X
X15
Week 9 
only
Week 
13, 
q8w 
after
X
PGx blood sample
X
Biomarker Assessments
CTC-ENU16
X
X
X
X
X
CTC – ARV17
X
X
X
Week 9 
only
X
Efficacy
Computerized 
Tomography (CT) 
chest/abdomen/pe
lvis18
X
Q8wks 
up to 
six 
months
, then 
Q12wk
s
X
MRI Brain19
X
Bone Scan20
X
Q8wks 
up to 
six 
months
, then 
Q12wk
s
EORTC-QLQ-
C30, EORTC-
QLQ-PR25 & BPI-
SF21
X
X
X
X
X
X
X
X
11. Assigned combination product should be administered as described in Section 6.1. Please refer to combination 
product label for dose adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, 
Week 5 and every 4 weeks thereafter. Review of treatment compliance should occur during each study visit 
using a combination of staff review of subject compliance diaries and returned product packaging.
13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 1h).
Refer to the SRM for further details.


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16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1, W5D1
of the combination treatment period; thereafter, pre-dose every 8 weeks during treatment; and EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on Screening, W1D1, W5D1, 
and W9D1 of the combination treatment period; and EOT. 
Table 10
Dose Escalation Time and Events, Laboratory Assessments
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
EOT
D1
D4
D1
D4
D1
D4
D1
D1
W9 and 
thereafter
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X1
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
Troponin, N-
terminal pro–B-
Type 
natriuretic 
peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
Fasting lipids
X
X
X
X
Thyroid 
stimulating 
hormone
(TSH), free 
triiodothyronine 
(T3), free 
thyroxine (T4))
X
X
X
X
Pancreatic 
Markers
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
HIV, Hepatitis 
B surface 
antigen
(HBsAg), 
Hepatitis C 
Virus (HCV) 
Antibody
X
PSA
X
X
X
X
X
Testosterone
X
X
Table 11
Dose Expansion Time and Events
Procedure
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
q8w
EOT1, 
22
D1
D1
D1
D1
D1
W9 and 
thereafter
W9 and 
thereafter
Screening2
Informed Consent
X
Demography
X


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Procedure
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
q8w
EOT1, 
22
D1
D1
D1
D1
D1
W9 and 
thereafter
W9 and 
thereafter
Medical History
X
Inclusion/Exclusion 
Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register/ Randomize4
Subject
X
Safety
Physical Exam5
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments7
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA8
X
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Study Treatment
Administer 
GSK52576210
Daily
Administer 
Combination 
product10,11
Daily
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples12
PK
PK
O
X
Tumor biopsy13
X
One sample, 
collected 3-6h 
post-GSK525762 
dose, between 
W3D1 and W4D1
X14
Whole blood for 
exploratory analyses 
X
X
X15
Week 9 
only
Week 13, 
q8w after
X
PGx blood sample
X
Biomarker Assessments
CTC-ENU16
X
X
X
X
X
CTC – ARV17
X
X
X
Week 9 
only
X
Efficacy
Computerized 
Tomography (CT) 
chest/abdomen/pelvis18
X
Q8wks 
up to six 
months, 
then 
Q12wks
X
MRI Brain19
X


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Procedure
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
q8w
EOT1, 
22
D1
D1
D1
D1
D1
W9 and 
thereafter
W9 and 
thereafter
Bone Scan20
X
Q8wks 
up to six 
months, 
then 
Q12wks
EORTC-QLQ-C30, 
EORTC-QLQ-PR25 & 
BPI-SF21
X
X
X
X
X
X
X
X
11. Assigned combination product should be administered as described in Section 6.1. Please refer to combination 
product label for dose adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, 
Week 5 and every 4 weeks thereafter. Review of treatment compliance should occur during each study visit 
using a combination of staff review of subject compliance diaries and returned product packaging.
13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 1h). .
Refer to the SRM for further details.
16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1, W5D1 
of the combination treatment period; thereafter, pre-dose every 8 weeks during treatment; and EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on Screening, W1D1, W5D1, 
and W9D1 of the combination treatment period; and EOT. 
Table 12
Dose Expansion Time and Events, Laboratory Assessments 
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
EOT
D1
D1
D1
D1
D1
W9 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X1
X
Liver chemistry
X
X
X
X
X
X
X
X
Troponin, N-terminal 
pro–B-Type natriuretic 
peptide (NT- proBNP)
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
Fasting lipids
X
X
X
X
Thyroid (Thyroid 
stimulating hormone
(TSH), free 
triiodothyronine (T3), 
free thyroxine (T4))
X
X
X
X
Pancreatic Markers
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
HIV, Hepatitis B surface 
antigen (HBsAg), 
Hepatitis C Virus (HCV) 
Antibody
X
PSA
X
X
X
X
X
Testosterone
X
X


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Revised text: 
Table 9
Dose Escalation Time and Events
Procedure
SC
R
Lead-
In 
Dosin
g (if 
requir
ed)
Week 1
Week 2
Week 3
We
ek 
4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
therea
fter
Screening2
Informed 
Consent
X
Demography
X
Medical History
X
Inclusion/Exclu
sion Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register/ 
Randomize4
Subject
X
Safety
Physical 
Exam5
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
X
Clinical 
Laboratory 
Assessments7
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogra
m or MUGA8
X
X
X
Wee
ks 
13, 
25 
and 
37
X
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication 
review
Continuous from signing of informed consent
Study Treatment
Administer 
GSK52576210
Daily
Administer 
Combination 
product10,11
Daily 
(if 
requir
ed)
Daily


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Procedure
SC
R
Lead-
In 
Dosin
g (if 
requir
ed)
Week 1
Week 2
Week 3
We
ek 
4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
therea
fter
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood 
samples12
P
K
PK
O
X
Tumor biopsy13
X
One 
sample, 
collected 
3-6h post-
GSK5257
62 dose, 
between 
W3D1 and 
W4D1
X14
Whole blood 
for exploratory 
analyses 
X
X
X15
Q8w
ks 
up to 
six 
mont
hs, 
then 
Q12
wks
X
X
PGx blood 
sample
X
Biomarker Assessments
CTC-ENU16
X
X
X
Q8wk
s up 
to six 
mont
hs, 
then 
Q12w
ks
X
X
CTC – ARV17
X
X
Wee
k 9 
only
X
Efficacy
Computerized 
Tomography 
(CT) 
chest/abdomen
/pelvis18
X
Q8wk
s up 
to six 
mont
hs, 
then 
Q12
wks
X
X
MRI Brain19
X


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Procedure
SC
R
Lead-
In 
Dosin
g (if 
requir
ed)
Week 1
Week 2
Week 3
We
ek 
4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
therea
fter
Bone Scan20
X
Q8wk
s up 
to six 
mont
hs, 
then 
Q12
wks
X
EORTC-QLQ-
C30, EORTC-
QLQ-PR25 & 
BPI-SF21
X
X
X
X
X
X
X
X
X
11. Lead-in administration of combination product will be dependent on treatment with applicable product 
prior to inclusion in the study. Abiraterone lead-in should be 7 days (Days -7 to Day 0); Enzalutamide 
lead-in will either be 28 days (Days -28 to Day 0) or 14 days (Days -14 to Day 0). Assigned combination 
product should be administered as described in Section 6.1. Please refer to combination product label for dose 
adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks 
thereafter. Review of treatment compliance should occur during each study visit using a combination of staff 
review of subject compliance diaries and returned product packaging.
13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 
hours prior to the post-dose biopsy. Refer to the SRM for further details.
16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1 of the 
combination treatment period, W5D1, W9D1 and every 8 weeks for the first 6 months and thereafter 
every 12 weeks; of the combination treatment period; thereafter, pre-dose every 8 weeks during treatment; and 
EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on Screening, W1D1, W5D1, 
and W9D1 of the combination treatment period; and EOT. Based on emerging data, GSK may decide to 
discontinue the collection of these samples.


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Table 10
Dose Escalation Time and Events, Laboratory Assessments
SC
R
Week 
1
Week 
2
Week 3
Wee
k 4
Week 
5
q2w
q4w
q4W
q12w
EO
T
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D1
W7 
and 
11
W9 
to 
W49
W49 
and 
therea
fter
W49 
and 
therea
fter
Clinical 
chemistry
X
X
X
X
X
X
X
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X
X
X
X2
X1
X2
X
X
Liver 
chemistry
X
X
X
X
X
X
X
X
X
X2
X
X2
X
X
Troponin, N-
terminal pro–
B-Type 
natriuretic 
peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X2
X
X2
X
X
Factor VII 
Assay1
X
X
X
HbA1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
Thyroid 
stimulating 
hormone
(TSH), free 
triiodothyronin
e (T3), free 
thyroxine 
(T4))
X
X
X
X
X
Pancreatic 
Markers
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
HIV, Hepatitis 
B surface 
antigen
(HBsAg), 
Hepatitis C 
Virus (HCV) 
Antibody
X
PSA
X
X
X
X
X2
X
X
Testosterone
X
X
1.
In addition to scheduled timepoints, perform if PT or INR or aPTT are ≥1.5XULN, or in case of a bleeding 
event.
2.
Local labs can be used to collect this information.


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Table 11
Dose Expansion Time and Events
Procedure
SC
R
Lead-In 
Dosing 
(if 
require
d)
Wee
k 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
q4w
q8w
q12w
EOT
1, 22
D1
D
1
D
1
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
thereaft
er
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion 
Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register/ 
Randomize4
Subject
X
Safety
Physical Exam5
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments7
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA8
X
X
X
Week
s 13, 
25 
and 
37
X
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Study Treatment
Administer 
GSK52576210
Daily
Administer 
Combination 
product10,11
Daily (if 
require
d)
Daily
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples12
PK
PK
O
X
Tumor biopsy13
X
One sample, 
collected 3-
6h post-
GSK525762 
dose, 
between 
W3D1 and 
W4D1
X14


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Procedure
SC
R
Lead-In 
Dosing 
(if 
require
d)
Wee
k 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
q4w
q8w
q12w
EOT
1, 22
D1
D
1
D
1
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
thereaft
er
Whole blood for 
exploratory 
analyses 
X
X
X15
Q8wks 
up to 
six 
month
s, then 
Q12wk
s
X
X
PGx blood sample
X
Biomarker Assessments
CTC-ENU16
X
X
X
Q8wks 
up to 
six 
month
s, then 
Q12wk
s
X
X
CTC – ARV17
X
X
Week 
9 only
X
Efficacy
CT 
chest/abdomen/pel
vis18
X
Q8wks 
up to 
six 
months
, then 
Q12wk
s
X
X
MRI Brain19
X
Bone Scan20
X
Q8wks 
up to 
six 
months
, then 
Q12wk
s
X
EORTC-QLQ-C30, 
EORTC-QLQ-PR25
& BPI21
X
X
X
X
X
X
X
X
X
11. Lead-in administration of combination product will be dependent on treatment with applicable product 
prior to inclusion in the study. Abiraterone lead-in should be 7 days (Days -7 to Day 0); Enzalutamide 
lead-in will either be 28 days (Days -28 to Day 0) or 14 days (Days -14 to Day 0). Assigned combination 
product should be administered as described in Section 6.1. Please refer to combination product label for dose 
adjustments. Dispensation of product package should occur at Day 1 visit of Week 1, Week 5 and every 4 weeks 
thereafter. Review of treatment compliance should occur during each study visit using a combination of staff 
review of subject compliance diaries and returned product packaging.


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13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 
hours prior to the post-dose biopsy. Refer to the SRM for further details.
16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1 of the 
combination treatment period, W5D1, W9D1 and every 8 weeks for the first 6 months and thereafter 
every 12 weeks; of the combination treatment period; thereafter, pre-dose every 8 weeks during treatment; and 
EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on Screening, W1D1, W5D1, 
and W9D1 of the combination treatment period; and EOT. Based on emerging data, GSK may decide to 
discontinue the collection of these samples.


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Table 12
Dose Expansion Time and Events, Laboratory Assessments
SC
R
Week 
1
Week 
2
Week 3
Wee
k 4
Week 
5
q2w
q4w
q4W
q12w
EO
T
D1
D1
D1
D
1
D1
W7 
and 
11
W9 
to 
W49
W49 
and 
therea
fter
W49 
and 
therea
fter
Clinical 
chemistry
X
X
X
X
X
X
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X2
X1
X2
X
X
Liver 
chemistry
X
X
X
X
X
X
X2
X
X2
X
X
Troponin, N-
terminal pro–
B-Type 
natriuretic 
peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X2
X
X2
X
X
Factor VII 
Assay1
X
X
X
HbA1c
X
X
X
X
X
Fasting lipids
X
X
X
X
X
Thyroid 
stimulating 
hormone
(TSH), free 
triiodothyronin
e (T3), free 
thyroxine 
(T4))
X
X
X
X
X
Pancreatic 
Markers
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
HIV, Hepatitis 
B surface 
antigen
(HBsAg), 
Hepatitis C 
Virus (HCV) 
Antibody
X
PSA
X
X
X
X
X2
X
X
Testosterone
X
X
1.
In addition to scheduled timepoints, perform if PT or INR or aPTT are ≥1.5XULN, or in case of a bleeding 
event.
2.
Local labs can be used to collect this information.
Section 7.2.2 – Visit Windows 
Rationale for Change:  
Clarification to this section to reflect change of timing when visits shift to less frequent 
visit; clarified the timeframe and additional assessments and updated wording to section. 


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Previous text: 
Every 4-week and 8-week visits after Week 9 until Week 52: After the first disease 
assessment has been completed, then the clinic visits can be scheduled 5 days.
Every 4-week and 8-week visits after Week 52: Every 4 week visits (and their 
associated laboratory studies) are no longer required, based on clinical judgment. Every 
8-week clinic visits can be scheduled 7 days. Disease assessments will only be required 
every 16 weeks and can be scheduled 7 days.
Revised text: 
Every 4-week and 8-week visits after Week 9 until Week 4952: After the first disease 
assessment has been completed, then the clinic visits can be scheduled 5 days.
Every 124 week and 8 week visits after Week 4952: Visit assessments, with the 
exceptions to limited laboratory sampling as referenced in Section 7.1, will adjust to 
every 12-weeks, based on clinical judgment. Every 4 week visits (and their associated 
laboratory studies) are no longer required, based on clinical judgment. Every 812-week 
clinic visits can be scheduled 7 days. Disease assessments will only be required every 
16 weeks and can be scheduled 7 days.
Section 7.3.5 – Clinical Safety Laboratory Assessments 
Rationale for Change: 
Clarification that Factor VII assay should be completed under the Other Stuides section 
of the Laboratory Assessments, highlighted in Table 13. 


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Previous text: 
Other Studies
Coagulation Studies:
Endocrine Studies:
Safety Screening Studies:
Prothrombin Time/INR
TSH
HIV, HbSag, HCV antibody
Partial Thromboplastin Time
Free Thyroxine 3 (Free T3)
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Hemoglobin A1c
Amylase
PSA
Lipase
Testosterone
Revised text: 
Other Studies
Coagulation Studies:
Endocrine Studies:
Safety Screening Studies:
Prothrombin Time/INR
TSH
HIV, HbSag, HCV antibody
Partial Thromboplastin Time
Free Thyroxine 3 (Free T3)
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Hemoglobin A1c
Amylase
Factor VII Assay
PSA
Lipase
Testosterone
Section 7.3.7 – Pregnancy 
Rationale for Change: 
Based on safety team review, added Pregnancy information that is needed in this male 
only study.
New text: 
Details of all pregnancies in female partners of male subjects will be collected after the 
start of dosing and until at least 4 months post-last dose.
If a pregnancy is reported then the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 12. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
Section 7.4 – Pharmacokinetics 
Rationale for Change: 
Removal of wording to prevent confusion on what PK samples are being analysed. All 
abiraterone PK samples will be analysed. 
Previous text: 
Blood samples for pharmacokinetic (PK) analysis of abiraterone/enzalutamide and 
GSK525762 (including relevant metabolite(s)) will be collected at the time points 


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indicated in Table 9, Table 10, Table 11, and Table 12. While GSK525762 PK samples 
will be collected at all time points starting on Week 1 Day 1, only the pre dose samples 
will be analysed for abiraterone/enzalutamide. The actual date and time of each blood 
sample collection will be recorded. Subjects should be instructed to withhold their dose 
of orally administered study drugs, including GSK525762 and abiraterone/enzalutamide, 
until after the pre-dose pharmacokinetic blood sample is collected.
Revised text: 
Blood samples for pharmacokinetic (PK) analysis of abiraterone/enzalutamide and 
GSK525762 (including relevant metabolite(s)) will be collected at the time points 
indicated in Table 9, Table 10, Table 11, and Table 12. While GSK525762 PK samples 
will be collected at all time points starting on Week 1 Day 1, only the pre dose samples 
will be analysed for abiraterone/enzalutamide. The actual date and time of each blood 
sample collection will be recorded. Subjects should be instructed to withhold their dose 
of orally administered study drugs, including GSK525762 and abiraterone/enzalutamide, 
until after the pre-dose pharmacokinetic blood sample is collected.
Section 7.5.1 – Tumor Biopsy Collection 
Rationale for Change: 
Updated title to include Surgical Procedures. Added additional requirements based on 
emerging safety data. 
Previous text:
In the dose escalation and expansion cohort(s), paired fresh biopsies must be provided 
pre- (within 14 days of the first dose) and on-treatment at the time points indicated from 
all the subjects. Any fresh on-treatment biopsy should be accompanied by a whole blood 
sample collected as close as possible to the time of biopsy (preferably within 1h). Further 
details regarding sample type and processing will be provided in the SRM. If a potential 
subject does not have disease amenable to biopsy, participation may occur only upon 
discussion with and approval of the medical monitor; in this situation, an archival tumor 
sample retrieved after completion of most recent ADT will be required. 
Further details regarding sample type and processing will be provided in the SRM.
Revised text: 
In the dose escalation and expansion cohort(s), paired fresh biopsies must be provided 
pre- (within 14 days of the first dose) and on-treatment at the time points indicated from 
all the subjects. Any fresh on-treatment biopsy should be accompanied by a whole blood 
sample collected as close as possible to the time of biopsy (preferably within 1h). 
Subjects providing an on-treatment fresh tumor biopsy must have received at least 4 
consecutive days of GSK525762 prior to the collection of the sample. Further details 
regarding sample type and processing will be provided in the SRM. If a potential subject 
does not have disease amenable to biopsy, participation may occur only upon discussion 


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with and approval of the medical monitor; in this situation, an archival tumor sample 
retrieved after completion of most recent ADT will be required. 
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that 
are WNL within 48 hours prior to the post-dose biopsy or any other planned 
surgical procedure.  Further details regarding sample type and processing will be 
provided in the SRM.
Section 7.7.3 – Circulating Tumor Cells 
Rationale for Change: 
Added language that would allow flexibility on collection of CTC-ARV samples. 
Previous text:
Additional blood samples will be collected at the time points indicated in the Time and 
Events Tables (Section 7.1) to isolate CTCs. The isolated CTCs will be analyzed for AR 
variants or other protein markers and potential genomic alterations (e.g. AR 
amplifications, phosphatase and tensin homolog (PTEN) allele loss etc.). 
Revised text: 
Additional blood samples will be collected at the time points indicated in the Time and 
Events Tables (Section 7.1) to isolate CTCs. The isolated CTCs will be analyzed for AR 
variants or other protein markers and potential genomic alterations (e.g. AR 
amplifications, phosphatase and tensin homolog (PTEN) allele loss etc.). Based on 
emerging data, GSK may decide to discontinue the collection of these samples.
Section 9.3.1 – Analysis Populations 
Rationale for Change: 
Added another population group to clarify how to handle data from subjects who may 
withdraw during the run-in period. 
Previous text: 
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK525762 plus abiraterone/enzalutamide. Safety and anti-cancer activity will be 
evaluated based on this analysis population.
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.
Revised text: 
The All Treated Safety Population is defined as all subjects who receive at least one 
dose of GSK525762 or abiraterone or enzalutamide. Safety and anti-cancer activity 
will be evaluated based on this analysis population.


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The All Clinical Activity Treated Population is defined as all subjects who receive at 
least one dose of GSK525762 plus abiraterone/enzalutamide. Safety and anti-cancer 
activity will be evaluated based on this analysis population.
The PK Population will consist of all subjects from the All Treated Safety Population 
for whom a PK sample is obtained and analyzed.
Section 9.4.1 – Safety Analyses  
Rationale for Change: 
Clarification of population to use for analyses due to update to population section. 
Previous text:
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP.
Revised text: 
The All Treated Safety Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, electrocardiogram [ECGs]) 
will be summarized according to the scheduled, nominal visit at which they were 
collected and across all on-treatment time points using a “worst-case” analysis. Complete 
details of the safety analyses will be provided in the RAP.
Appendix 2 – Management of Suspected Toxicity  
Rationale for Change: 
Revisions to the Thrombocytopenia section of the Dose Adjustment/Stopping Safety 
Criteria table based on agreement with the FDA. 


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Previous text:
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)
Withhold GSK525762 and check activated partial 
thromboplastin time (aPTT), PT, and INR. Monitor CBC 
and coagulation studies at least twice a week, or more 
frequently if clinically indicated. 
Hold GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at lower dose level, after discussion 
with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued or restarted at a lower dose 
level, after discussion with medical monitor. 
Grade 4 (platelets 
<25,000/mm3),or any 
moderate to severe 
bleeding accompanied 
by drug related 
thrombocytopenia
Withhold GSK525762 and check aPTT, PT, and INR. 
Monitor CBC and coagulation studies every 2-3 days. Hold 
GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at a lower dose level, after 
discussion with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued until platelet count recovers to 
Grade 2 (≥50,000/mm3). 
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3 (Grade 
2) within 14 days, GSK525762 should be permanently 
discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) within 
14 days, GSK525762 may be continued at the 
current/reduced dose after discussion with the medical 
monitor. 


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Revised text: 
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 1 (platelets 
<LLN to ≥75,000/mm3) 
& Grade 2 (platelets 
<75,000 to 
≥50,000/mm3)
Continue dosing at same dose level with weekly or more 
frequent monitoring as necessary.
Grade 3 (platelets 
<50,000, ≥25,000/mm3)
Withhold GSK525762 and check activated partial 
thromboplastin time (aPTT), PT, and INR. Monitor CBC 
and coagulation studies at least twice a week, or more 
frequently if clinically indicated. 
Hold GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at the same dose or at a lower dose 
level lower, after discussion with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued or restarted at another dose
level lowerdose level, after discussion with medical 
monitor. If safety lab abnormalities recur to the same 
level following a second rechallange, drug will be 
discontinued.
Grade 4 (platelets 
<25,000/mm3),or any 
moderate to severe 
bleeding accompanied 
by drug related 
thrombocytopenia
Withhold GSK525762 and check aPTT, PT, and INR. 
Monitor CBC and coagulation studies every 2-3 days. Hold 
GSK525762 until thrombocytopenia has resolved to 
≤Grade 2 AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at a lower dose level, after 
discussion with medical monitor.
If safety lab abnormalities recur following rechallenge, 
drug may be discontinued until platelet count recovers to 
Grade 2 (≥50,000/mm3). 
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3 (Grade 
2) within 14 days, GSK525762 should be permanently 
discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) within 
14 days, GSK525762 may be continued at the 
current/reduced dose after discussion with the medical 
monitor. 
If platelet count does not recover to ≥25,000/mm3
(Grade 3) within 7 days, GSK525762 should be 
permanently discontinued.


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Appendix 12 - Contraception and Pregnancy Information
Rationale for change: 
Section was not included in original protocol as this is a male only study and 
contraception language was in Section 6.10.2. After additional safety review, decision 
was made to add Appendix per protocol template and to give further information for male 
subjects and female partners of reproductive potential. References added also in this
section but not captured in this section.  
New text: 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)
The list does not apply to male subjects with partners of FRP who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable)
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study 
medication until 4 month after the last dose of study medication.
1. 
Sterilization with documentation of azoospermia. The documentation on 
male sterility can come from the site personnel’s: review of subject’s medical 
records, medical examination and/or semen analysis, or medical history 
interview.
2. 
Male condom plus partner use of intrauterine device or intrauterine system.
Note: Hormonal methods of contraception for female partners of FRP are not 
permitted since the efficacy of these methods in combination with GSK525762 has 
not been assessed. Hormone-releasing IUDs are a permitted form of contraception. 
LHRH-acting agents alone are not considered an adequate form of contraception.   
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female 
partner of a male study subject who becomes pregnant while participating in 


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this study. This applies only to subjects who are randomized to receive study 
medication. 

After obtaining the necessary signed informed consent from the female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 weeks of learning of the 
partner’s pregnancy 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure. 
Other changes to provide additional clarifications or to correct inadvertent 
errors in previous versions of the protocol:
Title Page: 
Updated author list to include new authors: 
, and 
 and remove
. 
Table of Contents: 
Revision to Table of Contents to reflect changes protocol addressed earlier in this 
Appendix. 
Protocol Synopsis: 
Throughout the synopsis, revised by removing references and links as per internal 
requirements. 
List of Abbreviations: 
Addition of new abbreviations to table: ORR – Objective Response Rate, PSA50 –
Prostate-specific antigen decrease from baseline ≥50%, rPFS – Radiological progression 
free survival, and RR – Response rate
PPD
PPD
PPD


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Protocol changes for Amendment 2 (08-Feb-2018) from Amendment 1 (01 –
Feb-2017)
Protocol Amendment 2 applies only to France due to requests from their country agency, 
Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) and the 
central Ethics Committee, Comité de Protection des Personnes (CPP) Sud-Est III. 
Original text is displayed as strikethrough indicates replaced or removed text. New text is
displayed as underline. If applicable, revisions within the tables will be displayed as text
or if same revision affects multiple tables, the changes will be summarized; revisions to
figures will be displayed first by the old figure, and then followed by the new figure.
List of Specific Changes
Section 1 – Type and Number of Subjects
Rationale for Change: 
Per committee request, addition of statement regarding potential number of subjects to be 
enrolled in France. 
Previous text: 
Approximately 130 subjects worldwide may be enrolled in the study as a whole.
Revised text: 
Approximately 130 subjects worldwide may be enrolled in the study as a whole. In 
France, approximately 28 subjects are to be enrolled. 
Section 1 - Protocol Synopsis Inclusion Criteria
Rationale for Change: 
Added wording at the request of the France agency ANSM to clarify patient population. 
Previous text: 
6.   One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Revised text: 
6.   One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy.


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Section 4.1.1.: Type and Number of Subjects
Rationale for Change: 
Per committee request, addition of statement regarding potential number of subjects to be 
enrolled in France. 
Previous text: 
Approximately 130 subjects worldwide may be enrolled in the study as a whole.
Revised text: 
Approximately 130 subjects worldwide may be enrolled in the study as a whole. In 
France, approximately 28 subjects are to be enrolled. 
Section 4.2.2.1: Planned Dose Levels
Rationale for Change: 
Added wording at the request of the France agency ANSM to clarify allowed top dose of 
GSK525762. 
Previous text: 
GSK525762 as a single agent is being investigated at the highest dose of 80 mg 
(amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Part 2 Dose, 
RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). All doses of GSK525762 refer to the besylate tablet formulation. For Arm 
A, projected dose levels of GSK525762 are 60 mg and 80 mg administered once daily. 
For Arm B, projected dose levels of GSK525762 are 80 mg, and 100 mg administered 
once daily. A dose of 120 mg may be evaluated in combination with enzalutamide based 
on emerging PK and safety data. Projected dose levels of abiraterone and enzalutamide 
are 1000 mg and 160 mg respectively, administered once daily. Additional doses and 
schedules may be explored based on emerging safety, PK, and PD data. No doses will be 
explored beyond 1000 mg abiraterone or 160 mg enzalutamide, these doses that are 
considered to be the Maximum Feasible Dose (MFD), unless emerging PK data 
demonstrate reduced exposure of either drug in combination compared to single agent.
As determined from pre-clinical studies, the maximum clinical dose of GSK525762 will 
not exceed 200 mg.
Revised text: 
GSK525762 as a single agent is being investigated at the highest dose of 80 mg 
(amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Part 2 Dose, 
RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). All doses of GSK525762 refer to the besylate tablet formulation. For Arm 
A, projected dose levels of GSK525762 are 60 mg and 80 mg administered once daily. 
For Arm B, projected dose levels of GSK525762 are 80 mg, and 100 mg administered 


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once daily. A dose of 120 mg may be evaluated in combination with enzalutamide based 
on emerging PK and safety data. Projected dose levels of abiraterone and enzalutamide 
are 1000 mg and 160 mg respectively, administered once daily. Additional doses and 
schedules may be explored based on emerging safety, PK, and PD data. No doses will be 
explored beyond 1000 mg abiraterone or 160 mg enzalutamide, these doses that are 
considered to be the Maximum Feasible Dose (MFD), unless emerging PK data 
demonstrate reduced exposure of either drug in combination compared to single agent.
As determined from pre-clinical studies, the maximum clinical dose of GSK525762 will 
not exceed 200 mg. Any GSK525762 dose above 120 mg would require regulatory 
authority review and approval.
Section 5.1: Inclusion Criteria 
Rationale for Change: 
Added wording at the request of the France agency ANSM to clarify patient population. 
Previous text: 
6.   One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Revised text: 
6.   One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen.
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy.
Section 5.4.1.1: Study Treatment Restart or Rechallenge 
Rationale for Change: 
Added wording at the request of the France central Ethics Committee, Comité de 
Protection des Personnes (CPP) Sud-Est III, to clarify restriction for restart and 
rechallenge in French subjects.  
Previous text: 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 7 for full guidance. 


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Revised text: 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 7 for full guidance. 
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.
Section 5.4.2: QTc Stopping Criteria 
Rationale for Change: 
Added wording at the request of the France central Ethics Committee, Comité de 
Protection des Personnes (CPP) Sud-Est III, to clarify restriction for restart and 
rechallenge in French subjects.  
Previous text: 
For the purposes of this study, the corrected QT (QTc) is the QT interval corrected for 
heart rate according to Fridericia’s formula (QTcF; defined as [QT/(RR1/3)]). QTcF will 
be used for all subjects for purposes of eligibility, data analysis, and withdrawal. The 
QTcF should be based on averaged QTcF values of triplicate electrocardiograms obtained 
over a brief (e.g., 5-10 minute) recording period. 
Study treatments will be withheld if either of the following occurs:

QTcF interval ≥500 msec 

QTcF interval increase from baseline 60 msec 
In either case, both GSK525762 and abiraterone/enzalutamide will be discontinued 
unless the benefits of therapy outweigh the risk of rechallenge in the opinion of the 
investigator, the Medical Monitor, as well as GSK medical governance. In this situation, 
rechallenge may be permitted (see Appendix 2 for rechallenge guidelines).
Revised text: 
For the purposes of this study, the corrected QT (QTc) is the QT interval corrected for 
heart rate according to Fridericia’s formula (QTcF; defined as [QT/(RR1/3)]). QTcF will 
be used for all subjects for purposes of eligibility, data analysis, and withdrawal. The 
QTcF should be based on averaged QTcF values of triplicate electrocardiograms obtained 
over a brief (e.g., 5-10 minute) recording period. 
Study treatments will be withheld if either of the following occurs:


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
QTcF interval ≥500 msec 

QTcF interval increase from baseline 60 msec 
In either case, both GSK525762 and abiraterone/enzalutamide will be discontinued 
unless the benefits of therapy outweigh the risk of rechallenge in the opinion of the 
investigator, the Medical Monitor, as well as GSK medical governance. In this situation, 
rechallenge may be permitted (see Appendix 2 for rechallenge guidelines).
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.
Appendix 2 – Management of Suspected Toxicity  
Rationale for Change: 
Revisions to the QTcF and Liver Chemistry stopping criteria  section of the Dose 
Adjustment/Stopping Safety Criteria table based on agreement with the French agency, 
ANSM and the France central Ethics Committee, Comité de Protection des Personnes 
(CPP) Sud-Est III, to clarify restriction for restart and rechallenge in French subjects.  
Previous text: 
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
If >30msec and < 60 
msec change from 
baseline AND manual 
QTcF <500 (average of 
three ECGs over at 
least 15 minutes)
Continue current dose of GSK525762

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.


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If 60 msec change 
from baseline occurs
OR
QTcF 500 
(average of three ECGs 
over at least 15 
minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Supplement electrolytes to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.
This subject may consider restarting study treatment at 
one dose level reduced if all of the following criteria for 
QTcF re-challenge are met. If approval for re-challenge is 
granted, the subject must be re-consented (with a 
separate informed consent specific to QTc prolongation)
(1) QTcF reduced to <450 msec,
(2)
Potassium and magnesium levels are within 
institutional normal range,
(3)
A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the 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. 
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 
performed 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


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Liver

ALT ≥5X ULN, OR

ALT ≥3X ULN plus 
either bilirubin ≥2X 
ULN (>35% direct 
bilirubin, bilirubin 
fractionation 
required) or INR 
>1.5 without 
evidence of biliary 
obstruction or 
progressive disease, 
OR
ALT ≥3X ULN plus 
symptoms of liver injury 
or hypersensitivitya
Refer to Section 5.4.1 for liver chemistry stopping criteria 
and treatment algorithms, and to Appendix 7 for reporting
and follow-up of suspected liver events.
For subjects who develop hepatotoxicity during treatment, 
hold abiraterone until recovery. Retreatment may be 
initiated at a reduced dose of 750 mg QD following return 
of liver function tests to baseline. If hepatotoxicity recurs at 
dose of 750 mg QD, reduce dose to 500 mg QD following 
return of liver function tests to baseline. If hepatotoxicity 
recurs at 500 mg, discontinue treatment with abiraterone. 
Revised text: 
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
If >30msec and < 60 
msec change from 
baseline AND manual 
QTcF <500 (average of 
three ECGs over at 
least 15 minutes)
Continue current dose of GSK525762

Evaluation by cardiologist

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.


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If 60 msec change 
from baseline occurs
OR
QTcF 500 
(average of three ECGs 
over at least 15 
minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Evaluation by cardiologist

Supplement electrolytes to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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 24-hour telemetry monitoring if clinically 
indicated.
This subject may consider restarting study treatment at 
one dose level reduced if all of the following criteria for 
QTcF re-challenge are met. 
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged. 
If approval for re-challenge is granted, the subject must be 
re-consented (with a separate informed consent specific to 
QTc prolongation)
(1)
QTcF reduced to <450 msec,
(2)
Potassium and magnesium levels are within 
institutional normal range,
(3)
A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the 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 if 
required by IRB (or equivalent), and
(6)
The subject is re-consented regarding the 
possible increased risk of 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 until ≤30 msec 
change from baseline reached should be 
performed 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


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Liver

ALT ≥5X ULN, OR

ALT ≥3X ULN plus 
either bilirubin ≥2X 
ULN (>35% direct 
bilirubin, bilirubin 
fractionation 
required) or INR 
>1.5 without 
evidence of biliary 
obstruction or 
progressive disease, 
OR
ALT ≥3X ULN plus 
symptoms of liver injury 
or hypersensitivitya
Refer to Section 5.4.1 for liver chemistry stopping criteria 
and treatment algorithms, and to Appendix 7 for reporting 
and follow-up of suspected liver events.
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged. 
For subjects who develop hepatotoxicity during treatment, 
hold abiraterone until recovery. Retreatment may be 
initiated at a reduced dose of 750 mg QD following return 
of liver function tests to baseline. If hepatotoxicity recurs at 
dose of 750 mg QD, reduce dose to 500 mg QD following 
return of liver function tests to baseline. If hepatotoxicity 
recurs at 500 mg, discontinue treatment with abiraterone. 
Appendix 7 – Management of Suspected Toxicity  
Rationale for Change: 
Added wording at the request of the France central Ethics Committee, Comité de 
Protection des Personnes (CPP) Sud-Est III, to clarify restriction for restart and 
rechallenge in French subjects.  
Previous text: 
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
Revised text: 
In France, if stopping criteria is met, subjects will not be allowed to restart or be 
rechallenged.
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject


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If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments


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Protocol changes for Amendment 3 (12-Jul-2018) from Amendment 1 (01-
Feb-2017) and France specific Amendment (08-Feb-2018)
Protocol Amendment 3 applies to all global site(s) participating in the conduct of the 
study
Amendment 3 Summary
Amendment 3 includes the following changes which incorporate revisions based on 
internal and external feedback and a change in the abiraterone formulation: updates to 
sponsor information; further clarification of L2 line of therapy; addition of new 
secondary endpoint; clarification of PSA progression definition for endpoint analysis; 
update to dose utility wording and other statistical analysis updates; enhanced flexibility 
of dose level/schedule; modifications to inclusion/exclusion criteria; updated safety 
language based on current Investigator’s Brochure; revision to QTc wording due to GSK 
safety panel recommendations and associated prohibited medication language; inclusion 
of 500 mg abiraterone to replace 250 mg abiraterone; clarification to dose reduction 
language; revisions to Time and Events including removal of Week 1 ECHO/MUGA, 
AR-V sampling post screening, adjustment to screening and tumor biopsy windows; 
addition of Week 6 lab sample per safety panel recommendation; modifications to 
Appendix 2 to reflect QTc changes; and Appendix 8 to remove protocol specific SAE 
wording. Additions are underlined and deletions have been struck through. 
Original text is displayed as strikethrough indicates replaced or removed text. New text is 
displayed as underline. If applicable, revisions within the tables will be displayed as text 
or if same revision affects multiple tables, the changes will be summarized; revisions to 
figures will be displayed first by the old figure, and then followed by the new figure. 
Administrative changes, such as minor wording changes that do not affect the intent of a 
statement, will not be displayed in the summary of changes. 
List of Specific Changes
Section 1 - Protocol Synopsis Rationale 
Rationale for Change: 
Revision of language regarding BET115521 which has closed. 
Previous text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as bromodomain and extraterminal domains (BET). Studies have 
demonstrated that BET inhibition can lead to growth arrest and cell death in a variety of 
preclinical models, including models of CRPC. An ongoing first-in-human (FIH) study 
from GlaxoSmithKline (GSK), BET115521, is currently evaluating the safety and 
preliminary efficacy of single-agent GSK525762, a potent inhibitor of BET proteins, in a 
number of tumor types including mCRPC. Preliminary data from the futility analysis of 
the CRPC arm indicated there were no partial or complete responses. This data will be 
further examined as the data continues to mature.


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Revised text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as bromodomain and extraterminal domains (BET). Studies have 
demonstrated that BET inhibition can lead to growth arrest and cell death in a variety of 
preclinical models, including models of CRPC. TheAn ongoing first-in-human (FIH) 
study from GlaxoSmithKline (GSK), BET115521, evaluatedis currently evaluating the 
safety and preliminary efficacy of single-agent GSK525762, a potent inhibitor of BET 
proteins, in a number of tumor types including mCRPC. Preliminary data from the futility 
analysis of the CRPC arm indicated there were no partial or complete responses. This 
data will be further examined as the data continues to mature.
Section 1 - Protocol Synopsis Rationale 
Rationale for Change: 
Update of L2 definition to clarify allowance of 1 prior line of chemotherapy.
Previous text: 
This study will evaluate the safety and clinical activity in subjects who have progressed 
after treatment with abiraterone or enzalutamide, either as first line treatment (subjects 
treated in this study will be considered mCRPC Line 2 [L2, having failed first line 
treatment]) or on re-treatment after failure of multiple lines of therapy including prior 
ADT/prior chemotherapy/prior radiation therapy (subjects treated in this study will be 
considered mCRPC Line X [Lx]).
Revised text: 
… This study will evaluate the safety and clinical activity in subjects who have 
progressed after treatment with abiraterone or enzalutamide, either as first line treatment 
(subjects treated in this study will be considered mCRPC Line 2 [L2, having failed first 
line treatment with or without one prior line of chemotherapy]) or on re-treatment after 
failure of multiple lines of therapy including prior ADT/prior chemotherapy/prior 
radiation therapy (subjects treated in this study will be considered mCRPC Line X 
[Lx])…
Section 1 - Protocol Synopsis Objective(s)/Endpoint(s)
Rationale for Change: 
Addition of new secondary endpoint and clarifications/reorder of other secondary 
endpoints.
Previous text: 
Secondary (Both Arms)

To characterize the pharmacokinetics (PK) or 
exposure of GSK525762 and selected 
metabolites, when given in combination with 
abiraterone or enzalutamide, in men with 
mCRPC

To characterize the pharmacokinetics (PK) or 
exposure of abiraterone or enzalutamide, when 
given in combination with GSK525762, in men 

PK parameter or concentration values for 
GSK525762 and selected metabolites following 
repeat-dose oral administration in combination 
with abiraterone or enzalutamide

PK parameter or concentration values for 
abiraterone or enzalutamide following repeat-
dose oral administration in combination with 


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with mCRPC
GSK525762 

To evaluate additional measures of clinical 
activity in subjects with CRPC 

To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on patient-related 
outcomes 

Objective Response Rate (ORR) defined as 
complete response (CR) rate plus partial 
response (PR) rate per Prostate Cancer 
Working Group (PCWG3)-modified Response 
Evaluation Criteria In Solid Tumors (RECIST) 
1.1 

Circulating Tumor Cells (CTC) response rate 
defined as percent of subjects having favorable 
(CTC<5/7.5 mL) at nadir, if baseline is 
unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA at 4 weeks 

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1, PSA progression, and/or 
progression in bone)

Radiological progression free survival (rPFS) 
per PCWG3-modified RECIST1.1

Composite Response Rate (CRR) based on any 
of the following – a) Response based on 
PCWG3-modified RECIST1.1, b) PSA decrease 
of ≥50% at Week 12 and thereafter, or c) CTC 
count conversion as defined above

Performance status, pain scores, quality of life
Revised text: 
Secondary (Both Arms)

To characterize the pharmacokinetics (PK) or 
exposure of GSK525762 and selected 
metabolites, when given in combination with 
abiraterone or enzalutamide, in men with 
mCRPC

To characterize the pharmacokinetics (PK) or 
exposure of abiraterone or enzalutamide, when 
given in combination with GSK525762, in men 
with mCRPC

PK parameter or concentration values for 
GSK525762 and selected metabolites following 
repeat-dose oral administration in combination 
with abiraterone or enzalutamide

PK parameter or concentration values for 
abiraterone or enzalutamide following repeat-
dose oral administration in combination with 
GSK525762 

To evaluate additional measures of clinical 
activity in subjects with CRPC 

For both arms, clinical activity evaluated by 
disease control rate (DCR) through 24 weeks. 

Composite Response Rate (CRR) based on any 
of the following – a) Response based on 
PCWG3-modified RECIST1.1, b) PSA decrease 


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
To evaluate the effect of treatment with 
GSK525762 and abiraterone or enzalutamide, 
when given in combination, on patient-related 
outcomes 
of ≥50% at Week 12 and thereafter, or c) CTC 
count conversion as defined above

Objective Response Rate (ORR) defined as 
complete response (CR) rate plus partial 
response (PR) rate per Prostate Cancer 
Working Group (PCWG3)-modified Response 
Evaluation Criteria In Solid Tumors (RECIST) 
1.1 

Circulating Tumor Cells (CTC) response rate 
defined as percent of subjects having favorable 
(CTC<5/7.5 mL) at nadir, if baseline is 
unfavorable CTC≥5/7.5mL

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA after at 4 weeks of study 
treatment.

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1, PSA progression, and/or 
progression in bone or PSA progression with 
accompanying progression by RECIST 1.1 or 
bone scan or clinical progression)

Radiological progression free survival (rPFS) 
per PCWG3-modified RECIST1.1

Composite Response Rate (CRR) based on any 
of the following – a) Response based on 
PCWG3-modified RECIST1.1, b) PSA decrease 
of ≥50% at Week 12 and thereafter, or c) CTC 
count conversion as defined above

Performance status, pain scores, quality of life
Section 1 - Protocol Synopsis Overall Design
Rationale for Change: 
Revision of futility dose utility wording based on input from Berry Consulting and 
updates necessary to clarify intent of analyses.
Previous text: 
… For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the predictive probability that the 
expected utility (dU) ≥CSMU (30) is small (e.g., less than a 20% chance for the expected 
utility to be larger than the CSMU).


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Revised text: 
… For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the posteriorpredictive probability that 
theexpected utility (dU) ≥CSMU (2530) is small (e.g., less than a 420% chance for 
theexpected utility to be larger than the CSMU). Decisions made to stop enrolment in any 
cohort will be based on the totality of the data, including safety/tolerability and efficacy.
Section 1 - Protocol Synopsis Overall Design
Rationale for Change: 
Revisions to Arm A to clarify previous language and add flexible language. 
Previous text: 
… During dose escalation, eligible subjects in dose level 60 (DL60) will begin dosing 
with GSK525762 at 60 mg (one dose level lower than the single-agent RP2D), and the 
approved dose of abiraterone. If DL60 does not exceed the MTD, DL80 (GSK525762 
given 80 mg QD) will be opened (Figure 1). Subjects in DL80 will begin dosing with 
GSK525762 at 80 mg (equivalent to single-agent RP2D), and the approved dose of 
abiraterone. If DL60 exceeds the maximum permitted toxicity rate, then a lower dose 
level (DL-1, 40 mg) will be evaluated. If DL80 cohort is opened, but exceeds the 
maximum permitted toxicity rate, then additional subjects will not be enrolled at DL80. 
If DL80 does not exceed MTD, the dose expansion cohorts at both DL60 and DL80 will 
be initiated and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each will be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 1).
Figure 1
Revised text: 
… During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The approved dose of 
abiraterone (1000 mg) will be used for all GSK525762 dose level exploration. The 
initialin GSK525762 dose level will be 60 (dose level 60 mg (DL60), which is one dose 
level lower than the single-agent RP2D.  will begin dosing with GSK525762 at 60 mg 
(one dose level lower than the single-agent RP2D), and the approved dose of abiraterone.


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If DL60 does not exceed the MTD, DL80 (GSK525762 given 80 mg QD) will be opened 
(Figure 1). Subjects in DL80 will begin dosing with GSK525762 at 80 mg (equivalent to 
single-agent RP2D), and the approved dose of abiraterone. If DL60 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 40 mg) will be 
evaluated. If any dose level cohortDL80 cohort is opened, but exceeds the maximum 
permitted toxicity rate, then additional subjects will not be enrolled at that dose level. 
DL80.
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL60 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose level (DL-
1, 40 mg) may be evaluated.  
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels If DL80 does not exceed MTD, the dose expansion cohorts at both DL60 and 
DL80may will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A 
total of 30 subjects each may will be enrolled into both cohorts, and approximately10 
enrolled subjects will be L2 and 20 subjects will be Lx (Figure 1). If only one dose level 
is tolerable for dose expansion, subjects will be enrolled and not randomized.
Figure 1 
Section 1 - Protocol Synopsis Overall Design
Rationale for Change: 
Revisions to Arm B to clarify previous language and add flexible language.  
Previous text: 
… Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved doses of enzalutamide. As enzalutamide is a known CYP3A4 inducer, 
DDI could potentially lower the exposure of GSK525762 active moiety levels by 20%. 
Therefore, subjects will be enrolled at DL80 as the starting dose. 


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During dose escalation, eligible subjects in dose level 80 (DL80) will begin dosing with 
GSK525762 at 80 mg (equivalent of single-agent RP2D), and the approved dose of 
enzalutamide. If DL80 does not exceed the MTD, DL100 (GSK525762 given 100 mg 
once daily will be opened (Figure 2). Subjects in DL100 will begin dosing with 
GSK525762 at 100 mg and the approved dose of enzalutamide. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. If DL100 cohort is opened, but exceeds the maximum permitted toxicity rate, 
then additional subjects will not be enrolled at DL100. 
However, based on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 and 
DL100 levels to determine if it is acceptable to open the DL120 dose level. If DL120 is 
opened, subjects in DL120 will begin dosing with GSK525762 at 120 mg and the 
approved dose of enzalutamide. 
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at the selected higher and lower doses 
will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each will be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 2). 
Figure 2
Revised text: 
… Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved doses of enzalutamide (160 mg). As enzalutamide is a known CYP3A4 
inducer, DDI could potentially lower the exposure of GSK525762 active moiety levels by 
20%. Therefore, subjects will be enrolled at DL80 as the starting dose. 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The initialin
GSK525762 dose level will be 80 (dose level 80 mg (DL80), which is equivalent to one 
dose level lower than the single-agent RP2D due to expected DDI.  will begin dosing 
with GSK525762 at 80 mg (equivalent of single-agent RP2D), and the approved dose of 


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enzalutamide. If DL80 does not exceed the MTD, DL100 (GSK525762 given 100 mg 
QD) once daily will be opened (Figure 2). Subjects in DL100 will begin dosing with 
GSK525762 at 100 mg and the approved dose of enzalutamide. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. If any dose level cohortDL100 cohort is opened, but exceeds the maximum 
permitted toxicity rate, then additional subjects will not be enrolled at that dose level. 
DL100.
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL80 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily dose level (DL-
1, 60 mg) may be evaluated.  
However, bBased on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 and 
DL100 levels to determine if it is acceptable to open the DL120 dose level. If DL120 is 
opened, subjects in DL120 will begin dosing with GSK525762 at 120 mg and the 
approved dose of enzalutamide. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels Once a higher dose (either DL100 or DL120) and a lower dose (DL80) are 
determined to not exceed MTD, the dose expansion cohorts at the selected higher and 
lower doses may will be initiated and will be randomized by prior lines of therapy (L2 or 
Lx). A total of 30 subjects each may will be enrolled into both cohorts, and 
approximately10 enrolled subjects will be L2 and 20 subjects will be Lx (Figure 2). If 
only one dose level is tolerable for dose expansion, subjects will be enrolled and not 
randomized.
Figure 2


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Section 1 - Protocol Synopsis Treatment Arms and Duration
Rationale for Change: 
Clarification of term change from BET to product number, adjustment of other language 
in section. 
Previous text: 
… For subjects receiving GSK525762 in combination with abiraterone, daily 
administration of combination therapy (GSK525762 plus abiraterone) will commence 
immediately (Day 1) for abiraterone-failed subjects who are still on abiraterone (i.e., not 
stopped abiraterone dosing at progression and during screening). However, if these 
subjects are off abiraterone treatment for more than 3 days at the time of assignment to a 
cohort, there would be a lead in period for at least 7 days of abiraterone (Day7 to Day 0) 
before the start of combination treatment (GSK525762 plus abiraterone on Day 1). The 
lead-in dosing will ensure that abiraterone is at steady state upon initiation of BET 
treatment. Based on emerging information collected from PK, PD and safety/tolerability 
data, other dosing regimens (such as BID dosing for both drugs or intermittent dosing for 
GSK525762 or staggered dosing of the two drugs) may be explored during the study.
For subjects receiving GSK525762 in combination with enzalutamide, daily 
administration of combination therapy (GSK525762 plus enzalutamide) will commence 
immediately (Day 1) for enzalutamide-failed subjects who are still on enzalutamide (i.e. 
not stopped enzalutamide dosing at progression and during screening). However, if these 
subjects are off enzalutamide treatment for more than 7 days at the time of assignment to 
a cohort, there would be a lead in period for at least 28 days of enzalutamide (Day 28 to 
Day 0) before the start of combination treatment (GSK525762 and enzalutamde). There 
will be a 14 day lead in period if enzalutamide (Day -14 to Day 0) interruption was less 
than or equal to 7 days prior to start of combination treatment (Day 1). The lead-in dosing 
will ensure that enzalutamide is at steady state upon initiation of BET treatment. Based 
upon emerging data, additional subjects may be enrolled above, at, or below the 
combination doses mentioned previously, in order to collect additional safety and PK 
data. 
Initial dosing will maintain a fixed dose of abiraterone (1000 mg daily) or enzalutamide 
(160 mg daily). GSK525762 as a single agent is being investigated at the highest dose of 
80 mg (amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Phase 2 
Dose, RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). Doses beyond the single-agent RP2D may be explored if the drug is 
tolerated and PK analysis demonstrates reduced GSK525762 exposure (Area under 
concentration-time curve [AUC] and/or maximum observed concentration [Cmax]) when 
administered in combination with enzalutamide. Dose reductions for individual subjects 
may be required, based on toxicity observed during the study, and the frequency and 
duration of dose reductions will be reported. If enzalutamide is discontinued for more 
than or equal to 7 days, then the maximum dose of GSK525762 should be the single 
agent RP2D of 80 mg. If enzalutamide is re-started, GSK525762 should remain at 80 mg 
until after at least 14 days until the dose is escalated, if applicable. Subjects who require 
permanent discontinuation of either abiraterone or enzalutamide in the combination may 
continue GSK525762 as a single agent if there is evidence of continuing benefit on 


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treatment. If GSK525762 is continued as a single agent, the maximum dose would be 
80 mg. Intra-subject dose escalations from the planned starting dose during dose 
escalation will not be permitted. Intra-subject dose escalation may be permitted during 
dose expansion if for the lower dose level only if that dose is determined to be futile. 
Revised text: 
… For subjects receiving GSK525762 in combination with abiraterone, daily 
administration of combination therapy (GSK525762 plus abiraterone) will commence 
immediately (Day 1) for abiraterone-failed subjects who are still on abiraterone (i.e., not 
stopped abiraterone dosing at progression and during screening). However, if these 
subjects are off abiraterone treatment for more than 3 days at the time of assignment to a 
cohort, there would be a lead in period for at least 7 days of abiraterone (Day -7 to Day 0) 
before the start of combination treatment (GSK525762 plus abiraterone on Day 1). The 
lead-in dosing will ensure that abiraterone is at steady state upon initiation of BET
GSK525762 treatment. Based on emerging information collected from PK, PD and 
safety/tolerability data, other dosing regimens (such as BID dosing for both drugs or 
intermittent dosing for GSK525762 or staggered dosing of the two drugs) may be 
explored during the study.
For subjects receiving GSK525762 in combination with enzalutamide, daily 
administration of combination therapy (GSK525762 plus enzalutamide) will commence 
immediately (Day 1) for enzalutamide-failed subjects who are still on enzalutamide (i.e. 
not stopped enzalutamide dosing at progression and during screening). However, if these 
subjects are off enzalutamide treatment for more than 7 days at the time of assignment to 
a cohort, there would be a lead in period for at least 28 days of enzalutamide (Day -28 to 
Day 0) before the start of combination treatment (GSK525762 and 
enzalutamdeenzalutamide). There will be a 14 day lead in period if enzalutamide (Day -
14 to Day 0) interruption was less than or equal to 7 days prior to start of combination 
treatment (Day 1). The lead-in dosing will ensure that enzalutamide is at steady state 
upon initiation of GSK525762BET treatment. Based upon emerging data, additional 
subjects may be enrolled above, at, or below the combination doses mentioned 
previously, in order to collect additional safety and PK data. 
Initial dosing will maintain a fixed dose of abiraterone (1000 mg daily) or enzalutamide 
(160 mg daily). GSK525762 as a single agent was is being investigated at the highest 
dose of 80 mg (amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended 
Phase 2 Dose, RP2D) in the expansion cohorts of the first time in human solid tumor 
study (BET115521). Doses beyond the single-agent RP2D may be explored if the drug is 
tolerated and PK analysis demonstrates reduced GSK525762 exposure (Area under 
concentration-time curve [AUC] and/or maximum observed concentration [Cmax]) when 
administered in combination with enzalutamide. Dose reductions for individual subjects 
may be required, based on toxicity observed during the study, and the frequency and 
duration of dose reductions will be reported. If enzalutamide is discontinued for more 
than or equal to 7 days, then the maximum dose of GSK525762 should be the single 
agent RP2D of 80 mg. If enzalutamide is re-started, GSK525762 should remain at 80 mg 
until after at least 14 days until the dose is escalated, if applicable. Subjects who require 
permanent discontinuation of either abiraterone or enzalutamide in the combination may 
continue GSK525762 as a single agent if there is evidence of continuing benefit on 


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treatment. If GSK525762 is continued as a single agent, the maximum dose would be 
80 mg. Intra-subject dose escalations from the planned starting dose during dose 
escalation will not be permitted. Intra-subject dose escalation may be permitted during 
dose expansion if for the lower dose level only if that dose is determined to be futile. 
Based on emerging information collected from PK, PD and safety/tolerability data, other 
dosing regimens (such as intermittent dosing for GSK525762 or staggered dosing of the 
two drugs) may be explored during the study. 
Section 1 - Protocol Synopsis Inclusion Criteria
Rationale for Change: 
Revisions to wording of specific criteria to correct or clarify original wording and revise 
based on investigator feedback/internal decisions. Only the criteria which has been 
affected will be listed in both Previous and Revised sections. 
Previous text: 
3.  Histologically confirmed adenocarcinoma of the prostate: 
b.  Screening biopsy can be waived if patient had a recent biopsy after failure of ADT 
therapy (within 30 days) and the biopsy sample is secured to be sent as screening 
biopsy for this study. 
4.  Surgically or medically castrated, with testosterone levels of ≤ 50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to 
Cycle 1 Day 1 and must be continued throughout the study.
5.  Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 
a.  Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide 
b.  Has not been without abiraterone or enzalutamide treatment for >30 days prior to 
initiation of study treatment
6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen. 
7.  Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.  PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be ≥5 ug/L 
(5 ng/mL) if PSA is the only indication of progression; subjects on systemic 
glucocorticoids for control of symptoms must have documented PSA progression 
by PCWG3 while on systemic glucocorticoids prior to commencing Cycle 1 Day 1 
treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
criteria or bone metastasis with 2 or more documented new bone lesions on a bone 
scan with or without PSA progression


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11. Adequate organ function as defined in Table 1: 
System
Laboratory Values
Cardiac
Ejection fraction
≥ lower limit of normal (LLN) by echocardiogram or 
multigated acquisition scan (MUGA) and minimum of 
50% LVEF
12. Male subject with a female partner of childbearing potential or pregnant must agree to
use two acceptable methods of contraception from time of first dose of study treatment 
until 4 months after the last dose of study treatments.
Revised text: 
3.  Histologically confirmed adenocarcinoma of the prostate: 
b.  Screening biopsy can be waived if patient had a recent biopsy after failure of ADT 
therapy the most recent therapy (within 30 days) and the biopsy sample is secured to 
be sent as screening biopsy for this study. 
4.  Surgically or medically castrated, with testosterone levels of ≤50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to 
Week 1 Cycle 1 Day 1 and must be continued throughout the study.
5.  Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 
a.  Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide in any prior line
b.  Has not been without abiraterone or enzalutamide treatment for >30 days prior to 
initiation of study treatment
6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen. 
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy.
7.  Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.  PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be ≥5 ug/L 
(5 ng/mL) if PSA is the only indication of progression; subjects on systemic 
glucocorticoids for control of symptoms must have documented PSA progression 
by PCWG3 while on systemic glucocorticoids prior to commencing WeekCycle 1 
Day 1 treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
criteria or bone metastasis with 2 or more documented new bone lesions on a bone 
scan/ CT scan with or without PSA progression
11. Adequate organ function as defined in Table 1: 


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System
Laboratory Values
Cardiac
Ejection fraction
≥ lower limit of normal (LLN) by echocardiogram or 
multigated acquisition scan (MUGA) and minimum of 
50% LVEF
Troponin (I or T)
≤ ULN
12. Male subject with a female partner of childbearing potential or pregnant must agree to 
use two acceptable methods of contraception from time of first dose of study treatment 
until 4 months after the last dose of study treatments. Male Participants: Contraceptive 
use by men or female partner should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 16 weeks after the last dose of study treatment:
•
Refrain from donating sperm
                   PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
•
Must agree to use contraception/barrier as detailed below:
Agree to use a male condom and female partner to use an additional highly
effective contraceptive method with a failure rate of <1% per year as described in 
Appendix 12 when having sexual intercourse with a woman of childbearing potential 
who is not currently pregnant.   If partner becomes pregnant, agree to use/continue use 
of condoms until 16 weeks after the last dose of study medication.
Section 1 - Protocol Synopsis Exclusion Criteria
Rationale for Change: 
Revisions to wording of specific criteria to correct or clarify original wording and revise 
based on investigator feedback/internal decisions. Only the criteria which has been 
affected will be listed in both Previous and Revised sections.  
Previous text: 
1.  Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of Cycle 1 Day 1.
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
interval ≥450 msec
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed) and 
non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide 
documented benefit over other analgesics and then to be used with caution including 
concomitant use of proton pump inhibitors
12.  History of seizure or any condition that may predispose subject to seizure (e.g., prior 
cortical stroke or significant brain trauma).


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15. Subjects who have experienced a seizure or seizures within 6 months of study 
treatment or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
16. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications with significant risk of Torsades de pointes as well as those that are 
potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.
20. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to Cycle 1 Day 1. Subjects on a stable bisphosphonate or denosumab 
therapy are eligible and may continue.
Revised text: 
1.  Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of WeekCycle 1 Day 1.
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
interval ≥4850 msec
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed, or 100 
mg, as per country standards) and non-steroidal anti-inflammatory drugs (NSAIDS), 
except for where NSAIDs provide documented benefit over other analgesics and then 
to be used with caution including concomitant use of proton pump inhibitors
12.  History of seizure within 6 months of first dose of study treatment or any condition 
that may predispose subject to seizure (e.g., prior cortical stroke or significant brain 
trauma) or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
15. Subjects who have experienced a seizure or seizures within 6 months of study 
treatment or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
15. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications with significant risk of Torsades de pointes as well as those that are 
potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.
19. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to WeekCycle 1 Day 1. Subjects on a stable bisphosphonate or 
denosumab therapy are eligible and may continue.


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Section 1 - Protocol Synopsis Analysis 
Rationale for Change: 
Revision of wording to clarify intent of analyses, add and modify secondary endpoints, 
and add minor language changes.
Previous text: 
The dose escalation will follow a mTPI design to identify the MTD(s) of GSK525762 in 
combination with either abiraterone or enzalutamide. A Bayesian adaptive design will be 
employed which allows the trial to be frequently monitored with the constraint of both 
Type I and Type II error rates. An initial interim analysis in each cohort will be 
performed once 10 evaluable subjects have enrolled in that cohort, inclusive of subjects 
in both dose escalation and dose expansion. Enrolment to an individual cohort may be 
stopped early for toxicity or meeting futility criteria, but cohorts will not be stopped early 
if the response rate meets or exceeds the alternate hypothesis at the interim analyses….
… These hypotheses are based on observations from a meta-analysis study in subjects 
who had received prior ADT both in chemo-naïve and prior chemotherapy setting. 
Chemo-naïve subjects treated with a second ADT (L2 subjects) had rates of ≥50% PSA 
decline ranging from 25.5% to 36%. Subjects treated with both prior ADT and 
chemotherapy (Lx subjects) had variable responses of ≥50% PSA which ranged from 4% 
to 26% in studies with larger subject populations (>30 subjects per study).  Based on 
these findings, and considering a mixed population (L2 plus Lx) in both arms of the 
study, it is hypothesized that a response rate ≤10% would indicate no benefit for the 
combination of ADT failure, while a response rate of ≥30% in patients who just 
progressed on prior ADT will indicate there is a benefit that can be further explored. 
The following secondary responses will also be considered for drawing conclusions on 
the clinical activity of the combination(s):

Time to disease progression according to PCWG3 criteria (either by PCWG3-
modified RECIST 1.1, PSA progression, and/or progression in bone)
Revised text: 
The dose escalation will follow a mTPI design to identify the MTD(s) of GSK525762 in 
combination with either abiraterone or enzalutamide. A Bayesian adaptive design will be 
employed which allows the trial to be frequently monitored with the constraint of both 
Type I and Type II error rates. An initial interim analysis in each cohort maywill be 
performed when at leastonce 10 evaluable subjects have been enrolled in that cohort, 
inclusive of subjects in both dose escalation and dose expansion. Enrolment to an 
individual cohort may be stopped early for toxicity or meeting futility criteria, but cohorts 
will not be stopped early if the response rate meets or exceeds the alternate hypothesis at 
the interim analyses. Decisions to stop enrolment within a cohort will be based on the
totality of the data including safety/tolerability and efficacy….
… These hypotheses are based on observations from a meta-analysis study in subjects 
who had received prior ADT both in chemo-naïve and prior chemotherapy setting. 
Chemo-naïve subjects treated with a second ADT (L2 subjects) had rates of ≥50% PSA 
decline ranging from 25.5% to 36%. Subjects treated with both prior ADT and 
chemotherapy (Lx subjects) had variable responses of ≥50% PSA decrease which ranged 


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from 4% to 26% in studies with larger subject populations (>30 subjects per study).  
Based on these findings, and considering a mixed population (L2 plus Lx) in both arms of 
the study, it is hypothesized that a response rate ≤10% would indicate no benefit for the 
combination of ADT failure, while a response rate of ≥30% in patients who just 
progressed on prior ADT will indicate there is a benefit that can be further explored. 
In addition to the primary endpoint, the efficacy of each combination cohort will be 
evaluated based on the totality of all efficacy endpoints (primary and secondary).
The following secondary efficacy endpointsresponses will also be considered for drawing 
conclusions on the clinical activity of the combination(s):

Disease control rate (DCR) at 24 weeks 

Time to disease progression according to PCWG3 criteria (either by PCWG3-
modified RECIST 1.1 or progression in bone or, PSA progression with 
accompanying progression by RECIST 1.1 or bone scan or clinical progression, 
and/or progression in bone))
Section 2.2 – Brief Background 
Rationale for Change: 
Revisions of wording to clarify closure of FTIH study and clarification of L2 definition. 
Previous text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as BET [Wyce, 2013]. The BET family, comprised of bromodomain 2 
(BRD), BRD3, BRD4 and BRDT, recognize acetyl groups on the tails of histones and are 
critical for recruiting transcriptional machinery necessary for gene expression. BRD4 has 
been shown to interact with AR, and BET inhibition abrogated BRD4 localization to a 
subset of AR target loci and reduced AR-mediated gene transcription, causing 
suppression of AR signaling [Assangani, 2014]. Studies have demonstrated that BET 
inhibition can lead to growth arrest and cell death in a variety of preclinical models, 
including models of CRPC [Wyce, 2013]. An ongoing first-in-human (FIH) study from 
GlaxoSmithKline (GSK), BET115521, is currently evaluating the safety and preliminary 
efficacy of single-agent GSK525762, a potent inhibitor of BET proteins, in a number of 
tumor types including mCRPC. Preliminary data from the futility analysis of the CRPC 
arm indicated there were no partial or complete responses. This data will be further 
examined as the data continues to mature. Preliminary safety and efficacy data is 
summarized in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number 
2011N113741_07, 2016]….
….This study will evaluate the safety and clinical activity in subjects who have 
progressed after treatment with abiraterone or enzalutamide, either as first line treatment 
(subjects treated in this study will be considered mCRPC Line 2 (L2, having failed first 
line treatment) or on re-treatment after failure of multiple lines of therapy including prior 
ADT/prior chemotherapy/prior radiation therapy (subjects treated in this study will be 
considered mCRPC Line X (Lx)). Both populations will be included in both dose 
escalation and dose expansion; however, assignment during dose expansion will use 
forced randomization.


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Revised text: 
Recent studies have shown an alternate mode of AR inhibition by targeting a new class of 
proteins known as BET [Wyce, 2013]. The BET family, comprised of bromodomain 2 
(BRD), BRD3, BRD4 and BRDT, recognize acetyl groups on the tails of histones and are 
critical for recruiting transcriptional machinery necessary for gene expression. BRD4 has 
been shown to interact with AR, and BET inhibition abrogated BRD4 localization to a 
subset of AR target loci and reduced AR-mediated gene transcription, causing
suppression of AR signaling [Assangani, 2014]. Studies have demonstrated that BET 
inhibition can lead to growth arrest and cell death in a variety of preclinical models, 
including models of CRPC [Wyce, 2013]. TheAn ongoing first-in-human (FIH) study 
from GlaxoSmithKline (GSK), BET115521, evaluatedis currently evaluating the safety 
and preliminary efficacy of single-agent GSK525762, a potent inhibitor of BET proteins, 
in a number of tumor types including mCRPC. Preliminary data from the futility analysis 
of the CRPC arm indicated there were no partial or complete responses. This data will be 
further examined as the data continues to mature. Preliminary safety and efficacy data is 
summarized in the Investigator’s Brochure (IB) [GlaxoSmithKline Document Number
2011N113741_07, 20168]….
….This study will evaluate the safety and clinical activity in subjects who have 
progressed after treatment with abiraterone or enzalutamide, either as first line treatment 
(subjects treated in this study will be considered mCRPC Line 2 (L2, having failed first 
line treatment with or without one prior line of chemotherapy) or on re-treatment after 
failure of multiple lines of therapy including prior ADT/prior chemotherapy/prior 
radiation therapy (subjects treated in this study will be considered mCRPC Line X (Lx)). 
Both populations will be included in both dose escalation and dose expansion; however, 
assignment during dose expansion will use forced randomization.
Section 3. – Objective(s) and Endpoint(s) 
Rationale for Change: 
Addition of new Secondary Endpoint and revision of wording of other secondary 
endpoints. 


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Previous text: 
Objectives
Endpoints
Secondary (Both Arms)

To evaluate other measures of clinical activity in 
subjects with CRPC 

ORR defined as CR and PR rate per Prostate 
Cancer Working Group (PCWG3)-modified 
Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1

CTC response rate as defined as percent of 
subjects having favorable (CTC<5/7.5mL) at 
nadir, if baseline is unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA at 4 weeks

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1, PSA progression, and/or 
progression in bone)

rPFS per PCWG3-modified RECIST 1.1

CRR based on any of the following – a) 
Response based on PCWG3-modified 
RECIST1.1, b) PSA decrease of ≥ 50% at 
Week 12 and thereafter, or c) CTC count 
conversion as defined above


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Revised text: 
Objectives
Endpoints
Secondary (Both Arms)

To evaluate other measures of clinical activity in 
subjects with CRPC 

For both arms, clinical activity evaluated by 
DCR through 24 weeks

CRR based on any of the following – a) 
Response based on PCWG3-modified 
RECIST1.1, b) PSA decrease of ≥ 50% at 
Week 12 and thereafter, or c) CTC count 
conversion as defined above

ORR defined as CR and PR rate per Prostate 
Cancer Working Group (PCWG3)-modified 
Response Evaluation Criteria In Solid Tumors 
(RECIST) 1.1

CTC response rate as defined as percent of 
subjects having favorable (CTC<5/7.5mL) at 
nadir, if baseline is unfavorable CTC≥5/7.5mL 

PSA week 4 response rate defined as percent 
of subjects achieving ≥30% decrease from 
baseline PSA afterat 4 weeks of study treatment

Time to disease progression according to 
PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1 , PSA progression, and/or 
progression in bone or PSA progression with 
accompanying progression by RECIST 1.1 or 
bone scan or clinical progression)

rPFS per PCWG3-modified RECIST 1.1

CRR based on any of the following – a) 
Response based on PCWG3-modified 
RECIST1.1, b) PSA decrease of ≥ 50% at 
Week 12 and thereafter, or c) CTC count 
conversion as defined above
Section 4.1. – Overall Design 
Rationale for Change: 
Revision to language in section to include new secondary endpoint and to modify other 
secondary endpoint language. Revision of futility dose utility wording based on input 
from Berry Consulting and updates necessary to clarify intent of analyses.
Previous text: 
The co-primary endpoints will evaluate both safety and clinical activity of each treatment 
combination. The primary clinical activity outcome will be defined by the rate of ≥50% 
reduction in PSA (PSA50) at 12 weeks or thereafter. Secondary endpoints include: 1) 
ORR defined as CR and PR rate per PCWG3-modified RECIST 1.1; 2) CTC response 
rate defined as percent of subjects having favorable CTC <5/7.5mL at nadir if baseline is 
unfavorable CTC≥5/7.5mL; 3) PSA week 4 response rate defined as percent of subjects 
achieving ≥30% decrease from baseline PSA at 4 weeks; 4) time to disease progression 


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according to PCWG3 criteria (either by PCWG3-modified RECIST 1.1, PSA 
progression, and/or progression in bone); 5) rPFS per PCWG3-modified RECIST 1.1; 6) 
CRR based on the following – a) response based on PCWG3-modified RECIST 1.1, b) 
PSA decrease of ≥50%, or c) CTC count conversion. Other endpoints include OS, 
number of subjects with reduction in CTC of at least 30%, and PK will be evaluated. 
Safety will be evaluated by Adverse Events (AE), withdrawals due to toxicities, and 
changes in safety parameters from baseline (e.g., laboratory parameters, vitals, ECG). 
During dose expansion, the study will employ a Bayesian predictive adaptive design 
[Lee, 2008] that allows the trial to be monitored more frequently at multiple stages.
Bayesian statistics will be employed to calculate the expected utility of the dose (dU) is 
greater than the clinically significant minimum utility (CSMU) at interim analysis for 
each dose. The interim analysis will be conducted for each individual dose and it may be 
conducted when at least 10 evaluable subjects are available for a given dose. After the 
first interim analysis, the interim analysis can be conducted after every 10 additional 
subjects become evaluable.
For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the predictive probability that the 
expected utility (dU) ≥CSMU (30) is small (e.g., less than a 20% chance for the expected
utility to be larger than the CSMU). 
Revised text: 
The co-primary endpoints will evaluate both safety and clinical activity of each treatment 
combination. The primary clinical activity outcome will be defined by the rate of ≥50% 
reduction in PSA (PSA50) at 12 weeks or thereafter. Secondary endpoints include: 1) 
DCR through 24 weeks; 2) CRR based on the following – a) response based on PCWG3-
modified RECIST 1.1, b) PSA decrease of ≥50%, or c) CTC count conversion; 3) ORR 
defined as CR and PR rate per PCWG3-modified RECIST 1.1; 432) CTC response rate 
defined as percent of subjects having favorable CTC <5/7.5mL at nadir if baseline is 
unfavorable CTC≥5/7.5mL; 354) PSA week 4 response rate defined as percent of 
subjects achieving ≥30% decrease from baseline PSA afterat 4 weeks of study treatment; 
654) time to disease progression according to PCWG3 criteria (either by PCWG3-
modified RECIST 1.1 or, PSA progression, and/or progression in bone or PSA 
progression with accompanying progression by RECIST 1.1 or bone scan or clinical 
progression); 765) rPFS per PCWG3-modified RECIST 1.1; 76) CRR based on the 
following – a) response based on PCWG3-modified RECIST 1.1, b) PSA decrease of 
≥50%, or c) CTC count conversion. Other endpoints include OS, number of subjects with 
reduction in CTC of at least 30%, and PK will be evaluated. Safety will be evaluated by 
Adverse Events (AE), withdrawals due to toxicities, and changes in safety parameters 
from baseline (e.g., laboratory parameters, vitals, ECG). 
During dose expansion, the study will employ a Bayesian predictive adaptive design 
[Lee, 2008] that allows the trial to be monitored more frequently at multiple stages based 
on the utility score of the dose. Bayesian statistics will be employed to calculate the 
expected posterior probability that the utility of the dose (dU) is greater than the clinically 
significant minimum utility (CSMU) at interim analysis for each dose. The interim 
analysis will be conducted for each individual dose and it may be conducted when at least 
10 evaluable subjects are available for a given dose. After the first interim analysis, the 
interim analysis can be conducted after every 10 additional subjects become evaluable.


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For the separate interim looks in each combination in expansion cohort, the enrollment 
for that cohort may be stopped due to futility if the predictiveposterior probability that the 
expected utility (dU) ≥CSMU (2530) is small (e.g., less than a 420% chance for the 
expectedutility to be larger than the CSMU). Decisions to stop enrolment for a cohort 
will be based on the totality of the data, including safety/tolerability and efficacy 
(primary and secondary parameters).
Section 4.1 – Overall Design
Rationale for Change: 
Revisions to Arm A to clarify previous language and add flexible language.  
Previous text: 
… During dose escalation, eligible subjects in dose level 60 (DL60) will begin dosing 
with GSK525762 at 60 mg (one dose level lower than the single-agent RP2D), and the 
approved dose of abiraterone. If DL60 does not exceed the MTD, DL80 (GSK525762 
given 80 mg QD) will be opened (Figure 3). Subjects in DL80 will begin dosing with 
GSK525762 at 80 mg (equivalent to single-agent RP2D), and the approved dose of 
abiraterone. If DL60 exceeds the maximum permitted toxicity rate, then a lower dose 
level (DL-1, 40 mg) will be evaluated. If DL80 cohort is opened, but exceeds the 
maximum permitted toxicity rate, then additional subjects will not be enrolled at DL80. 
If DL80 does not exceed MTD, the dose expansion cohorts at both DL60 and DL80 will 
be initiated and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each will be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 3).
Figure 3
Revised text: 
… During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The approved dose of 
abiraterone (1000 mg) will be used for all GSK525762 dose level exploration. The 
initialin GSK525762 dose level will be 60 (dose level 60 mg (DL60), which is one dose 
level lower than the single-agent RP2D.  will begin dosing with GSK525762 at 60 mg 
(one dose level lower than the single-agent RP2D), and the approved dose of abiraterone.


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If DL60 does not exceed the MTD, DL80 (GSK525762 given 80 mg QD) will be opened 
(Figure 3). Subjects in DL80 will begin dosing with GSK525762 at 80 mg (equivalent to 
single-agent RP2D), and the approved dose of abiraterone. If DL60 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 40 mg) will be 
evaluated. If any dose level cohortDL80 cohort is opened, but exceeds the maximum 
permitted toxicity rate, then additional subjects will not be enrolled at that dose level. 
DL80.
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL60 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose level (DL-
1, 40 mg) may be evaluated.  
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels If DL80 does not exceed MTD, the dose expansion cohorts at both DL60 and 
DL80may will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A 
total of 30 subjects each may will be enrolled into both cohorts, and approximately10 
enrolled subjects will be L2 and 20 subjects will be Lx (Figure 3). If only one dose level 
is tolerable for dose expansion, subjects will be enrolled and not randomized.
Figure 3
Section 4.1 - Overall Design
Rationale for Change: 
Revisions to Arm B to clarify previous language and add flexible language.  
Previous text: 
… Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved doses of enzalutamide. As enzalutamide is a known CYP3A4 inducer, 
DDI could potentially lower the exposure of GSK525762 active moiety levels by 20%. 
Therefore, subjects will be enrolled at DL80 as the starting dose. 


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During dose escalation, eligible subjects in dose level 80 (DL80) will begin dosing with 
GSK525762 at 80 mg (equivalent of single-agent RP2D), and the approved dose of 
enzalutamide. If DL80 does not exceed the MTD, DL100 (GSK525762 given 100 mg 
once daily will be opened (Figure 4). Subjects in DL100 will begin dosing with 
GSK525762 at 100 mg and the approved dose of enzalutamide. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. If DL100 cohort is opened, but exceeds the maximum permitted toxicity rate, 
then additional subjects will not be enrolled at DL100. 
However, based on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 and 
DL100 levels to determine if it is acceptable to open the DL120 dose level. If DL120 is 
opened, subjects in DL120 will begin dosing with GSK525762 at 120 mg and the 
approved dose of enzalutamide. 
Once a higher dose (either DL100 or DL120) and lower dose (DL80) are determined to 
not exceed the MTD, the dose expansion cohorts at the selected higher and lower doses 
will be initiated and will be randomized by prior lines of therapy (L2 or Lx). A total of 30 
subjects each will be enrolled into both cohorts, and approximately10 enrolled subjects 
will be L2 and 20 subjects will be Lx (Figure 4). 
Figure 4
Revised text: 
… Eligible subjects will be administered escalating doses of GSK525762 in combination 
with the approved doses of enzalutamide (160 mg). As enzalutamide is a known CYP3A4 
inducer, DDI could potentially lower the exposure of GSK525762 active moiety levels by 
20%. Therefore, subjects will be enrolled at DL80 as the starting dose. 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The initialin
GSK525762 dose level will be 80 (dose level 80 mg (DL80), which is equivalent to one 
dose level lower than the single-agent RP2D due to expected DDI.  will begin dosing 
with GSK525762 at 80 mg (equivalent of single-agent RP2D), and the approved dose of 


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enzalutamide. If DL80 does not exceed the MTD, DL100 (GSK525762 given 100 mg 
QD) once daily will be opened (Figure 2). Subjects in DL100 will begin dosing with 
GSK525762 at 100 mg and the approved dose of enzalutamide. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. If any dose level cohortDL100 cohort is opened, but exceeds the maximum 
permitted toxicity rate, then additional subjects will not be enrolled at that dose level. 
DL100.
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
schedule, either at a dose level where daily treatment may be intolerable or at a lower 
dose. For example, if DL80 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily dose level (DL-
1, 60 mg) may be evaluated.  
However, bBased on PK analysis from DL80 and DL100 dose escalation cohorts, if the 
exposure to GSK525762 active moiety is 40% lower than its single agent exposure 
(determined from GSK525762 80 mg cohort in BET115521 study), DL120 may be 
opened. The study team will carefully review PK and safety data from the DL80 and 
DL100 levels to determine if it is acceptable to open the DL120 dose level. If DL120 is 
opened, subjects in DL120 will begin dosing with GSK525762 at 120 mg and the 
approved dose of enzalutamide. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels Once a higher dose (either DL100 or DL120) and a lower dose (DL80) are 
determined to not exceed MTD, the dose expansion cohorts at the selected higher and 
lower doses may will be initiated and will be randomized by prior lines of therapy (L2 or 
Lx). A total of 30 subjects each may will be enrolled into both cohorts, and 
approximately10 enrolled subjects will be L2 and 20 subjects will be Lx (Figure 4). If 
only one dose level is tolerable for dose expansion, subjects will be enrolled and not 
randomized. Refer to Section 4.6 for further dose information. 
Figure 4


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Section 4.2.1 – Treatments Arms and Duration
Rationale for Change: 
Revisions to clarify previous language and add flexible language.  Replacement of word 
‘BET’ in this section with ‘GSK525762’. 
Previous text: 
This study will consist of dose escalation and dose expansion cohorts. A mTPI design 
will be followed during dose escalation to establish safe DLs to move to dose escalation. 
Subjects who have failed prior abiraterone/enzalutamide-treatment both as L2 as well as 
Lx will be enrolled to either of the following arms:
•
Forced randomization of subjects that are abiraterone-refractory or resistant from 
L2 and Lx to DL60 and DL80 with 1/3 of the subjects from L2 and 2/3 of the 
subjects from Lx: - GSK525762 + abiraterone/prednisone (Arm A).
•
Forced randomization of subjects that are enzalutamide-refractory or resistant 
from L2 and Lx to low and high dose expansion cohorts with 1/3 of the subjects 
from L2 and 2/3 of the subjects from Lx:- GSK525762 at RP2D+ enzalutamide 
(Arm B)
Revised text: 
… This study will consist of dose escalation and dose expansion cohorts. A mTPI design 
will be followed during dose escalation to establish safe DLs to move to dose 
expansionescalation. During dose expansion, sSubjects who have failed prior 
abiraterone/enzalutamide-treatment both as L2 as well as Lx will be enrolled to either of 
the following arms:
•
Forced randomization of subjects that are abiraterone-refractory or resistant from 
L2 and Lx to the two most tolerable dose level cohorts DL60 and DL80 with 1/3 
of the subjects from L2 and 2/3 of the subjects from Lx: - GSK525762 + 
abiraterone/prednisone (Arm A).
•
Forced randomization of subjects that are enzalutamide-refractory or resistant 
from L2 and Lx to the two most tolerable low and high dose expansiondose level
cohorts with 1/3 of the subjects from L2 and 2/3 of the subjects from Lx:-
GSK525762 at RP2D+ enzalutamide (Arm B)
Section 4.2.2.1 – Planned Dose Levels
Rationale for Change: 
Revisions to clarify previous language and add flexible language.  
Previous text: 
GSK525762 as a single agent is being investigated at the highest dose of 80 mg 
(amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Part 2 Dose, 
RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). All doses of GSK525762 refer to the besylate tablet formulation. For Arm 
A, projected dose levels of GSK525762 are 60 mg and 80 mg administered once daily.  


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For Arm B, projected dose levels of GSK525762 are 80 mg, and 100 mg administered 
once daily. A dose of 120 mg may be evaluated in combination with enzalutamide based 
on emerging PK and safety data. 
Projected dose levels of abiraterone and enzalutamide are 1000 mg and 160 mg 
respectively, administered once daily. Additional doses and schedules may be explored 
based on emerging safety, PK, and PD data. No doses will be explored beyond 1000 mg 
abiraterone or 160 mg enzalutamide, these doses that are considered to be the Maximum 
Feasible Dose (MFD), unless emerging PK data demonstrate reduced exposure of either 
drug in combination compared to single agent. As determined from pre-clinical studies, 
the maximum clinical dose of GSK525762 will not exceed 200 mg. Any GSK525762 
dose above 120 mg would require regulatory authority review and approval.
Revised text: 
GSK525762 as a single agent wasis being investigated at the highest dose of 80 mg 
(amorphous tablet)/ 75 mg (besylate tablet) once daily (Recommended Phaseart  2 Dose, 
RP2D) in the expansion cohorts of the first time in human solid tumor study 
(BET115521). All doses of GSK525762 refer to the besylate tablet formulation. For Arm 
A, projected dose levels of GSK525762 are 60 mg and 80 mg administered once daily.  
Due to emerging data (safety/tolerability/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an intermittent dose 
level, either at a dose level where daily treatment may be intolerable or at a lower dose. 
For example, if DL60 exceeds the maximum permitted toxicity rate, then an 
alternate/intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose 
level (DL-1, 40 mg) may be evaluated.
For Arm B, projected dose levels of GSK525762 are 80 mg, and 100 mg administered 
once daily. A dose of 120 mg may be evaluated in combination with enzalutamide based 
on emerging PK and safety data. Due to emerging data (safety/tolerability/efficacy), 
additional dose levels may be explored. These dose levels may either be a lower daily 
dose level or an intermittent dose level, either at a dose level where daily treatment may 
be intolerable or at a lower dose. For example, if DL80 exceeds the maximum permitted 
toxicity rate, then an alternate/intermittent dosing at 80 mg dose level (DL80 ALT) 
and/or a lower daily dose level (DL-1, 60 mg) may be evaluated.
Projected dose levels of abiraterone and enzalutamide are 1000 mg and 160 mg 
respectively, administered once daily. Additional doses and schedules may be explored 
based on emerging safety, PK, and PD data. No doses will be explored beyond 1000 mg 
abiraterone or 160 mg enzalutamide, these doses that are considered to be the Maximum 
Feasible Dose (MFD), unless emerging PK data demonstrate reduced exposure of either 
drug in combination compared to single agent. As determined from pre-clinical studies, 
the maximum clinical dose of GSK525762 will not exceed 200 mg. Any GSK525762 
dose above 120 mg would require regulatory authority review and approval.
Section 4.2.2.6 – Alternative Dosing Schedules
Rationale for Change: 
Revisions to clarify previous language. 


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Previous text: 
…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 with the initial schedule. Escalation can then proceed as described in Section 
4.2.2….
Revised text: 
…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 no the higherst than the 
maximum tolerated or completed dose level with the initial schedule. Escalation can then 
proceed as described in Section 4.2.2….
Section 4.4.1 – Type and Number of Subjects 
Rationale for Change: 
Addition of statement to clarify enrolment only would be used if 1 dose level cohort 
opened in dose expansion. 
Previous text:
All subjects with a histologically-confirmed diagnosis of CRPC will be enrolled. Subjects 
will be enrolled based upon their most recent prior treatment (e.g. subjects who were 
most recently treated with abiraterone will be enrolled into Arm A, and subjects most 
recently treated with enzalutamide will be enrolled into Arm B). The total number of 
subjects required will depend upon the number of escalation steps required to identify the 
MTD(s). Once safe DL(s) are identified, the dose expansion phase will open and subjects 
with a histologically-confirmed diagnosis of CRPC will be randomized based on prior 
lines of therapy (L2 or Lx). For both Arms, each dose level cohort may enroll or 
randomize up to 30 subjects. Subjects from both dose escalation and dose expansion may 
be combined to reach 30 subjects. 
Revised text: 
All subjects with a histologically-confirmed diagnosis of CRPC will be enrolled. Subjects 
will be enrolled based upon their most recent prior treatment (e.g. subjects who were 
most recently treated with abiraterone will be enrolled into Arm A, and subjects most 
recently treated with enzalutamide will be enrolled into Arm B). The total number of 
subjects required will depend upon the number of escalation steps required to identify the 
MTD(s). Once safe DL(s) are identified, the dose expansion phase will open and subjects 
with a histologically-confirmed diagnosis of CRPC will be randomized based on prior 
lines of therapy (L2 or Lx). For both Arms, each dose level cohort may enroll or 
randomize up to 30 subjects. Subjects from both dose escalation and dose expansion may 
be combined to reach 30 subjects. If only one DL is opened for dose expansion, subjects 
will continue to be enrolled and their prior line of therapy (L2 or Lx) will be collected, 
but subjects will not be randomized.


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Section 4.4.2 – Dose Selection 
Rationale for Change: 
Revisions to clarify previous language and add flexible language.  
Previous text: 
For Arm A, two dose combinations (DL60 and DL80) will be carried forward into 
expansion cohorts. However, for Arm B, the specific doses chosen will be based upon 
data from dose escalation. Two safe dose combinations will be carried forward into dose 
expansion cohorts.
Revised text: 
For both ArmsA, it is anticipated that the two most tolerable dose level dose 
combinations per arm(DL60 and DL80) will be carried forward into expansion cohorts. If 
data warrants, only one dose level combination may be carried into dose expansion.  
However, for Arm B, the specific doses chosen will be based upon data from dose 
escalation. Two safe dose combinations will be carried forward into dose expansion 
cohorts.
Section 4.4.3 – Statistical Design 
Rationale for Change: 
Revisions to add and clarify language regarding statistical analysis.   
Previous text:
... Inference stemming from the Bayesian probabilities of efficacy in subjects harboring 
mCRPC are intended to inform decision making. Actual decisions will depend on the 
totality of the efficacy and safety data. The decision to terminate a cohort will not depend 
solely on the results of the statistical model but will take all factors into account, 
including the results of the model, safety, tolerability, PK, and PD data. In some cases, 
the enrolment for a cohort won’t stop even if the model suggests a low likelihood of 
clinical activity in that combination.
Revised text: 
... Inference stemming from the Bayesian probabilities of efficacy and tolerability in 
subjects harboring mCRPC are intended to inform decision making. Actual decisions will 
depend on the totality of the efficacy and safety data. The decision to terminate a cohort 
will not depend solely on the results of the statistical model but will take all factors into 
account, including the results of the model, additional efficacy parameters, safety, 
tolerability, PK, and PD data. In some cases, the enrolment for a cohort won’t stop even 
if the model suggests a low likelihood of clinical activity clinically meaningful utility
score in that combination.
Section 4.5 – Design Justification 
Rationale for Change: 
Revisions to clarify previous language and add flexible language.  


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Previous text: 
Dose escalation will establish whether the combination of GSK525762 and 
abiraterone/enzalutamide are safe in two targeted dose levels for abiraterone or up to 3
targeted dose levels for enzalutamide. For dose expansion with enzalutamide, only 2 dose 
levels will be taken forward, with the 80 mg the targeted ‘low’ dose combination. The 
targeted ‘high’ dose combination will either be the 100 mg or 120 mg dose level based on 
the emerging data from the dose escalation part. If any dose level requires de-escalation 
to DL-1, further evaluation will be conducted by the study team to determine if 2 dose 
levels will be required per Arm during dose expansion. 
By taking forward two doses into dose expansion, the study may be able to determine the 
ideal dose level in combination with abiraterone/enzalutamide that can be defined as the 
RP2D for each combination. To further establish a potential signal in advanced disease, 
both L2 and Lx subjects will be enrolled. Stratification will be utilized to target a total of 
1/3 L2 and 2/3 Lx in each dose expansion cohort in both arms.
Revised text: 
Dose escalation will establish whether the combination of GSK525762 and 
abiraterone/enzalutamide are safe in two targeted dose levels for abiraterone or up to 3 
targeted dose levels for enzalutamide. For each arm, up to dose expansion with 
enzalutamide, only 2 dose levels will be taken forward, with a lower and higher 
GSK525762 dose, either as a continuous or intermittent dose administration. , with the 80 
mg the targeted ‘low’ dose combination. The targeted ‘high’ dose combination will either 
be the 100 mg or 120 mg dose level based on the emerging data from the dose escalation 
part. If any dose level requires de-escalation to DL-1, Ffurther evaluation will be 
conducted by the study team to determine if only 1 2 dose levels will be required per 
either Arm during dose expansion. 
By taking forward up to two doses per arm into dose expansion, the study may be able to 
determine the ideal dose level in combination with abiraterone/enzalutamide that can be 
defined as the RP2D for each combination. To further establish a potential signal in 
advanced disease, both L2 and Lx subjects will be enrolled. Stratification will be utilized 
to target a total of 1/3 L2 and 2/3 Lx in each dose expansion cohort in both arms.
Section 4.6.2. – Starting Doses GSK525762
Rationale for Change: 
Update to language due to updated data.  
Previous text: 
A Phase I/II study (BET115521) with GSK525762 (as a single agent) is currently 
underway in subjects with advanced solid tumors, including CRPC. Doses of 2 to 100 mg 
once daily and doses of 20 mg, and 30 mg BID have been evaluated. The RP2D was 
determined to be 80 mg QD for GSK525762. Please see Section 5.3 of the GSK525762 
Investigator’s Brochure [GlaxoSmithKline Document Number 2011N113741_05, 2016], 
which details the clinical experience to date with GSK525762 and clinical safety data in 
the solid tumor population up to 100 mg once daily and in the hematologic malignancy 
population up to 120 mg once daily.


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Revised text: 
A Phase I/II study (BET115521) with GSK525762 (as a single agent) was conductedis 
currently underway in subjects with advanced solid tumors, including CRPC. Doses of 2 
to 100 mg once daily and doses of 20 mg, and 30 mg and 40 mg BID werehave been
evaluated. The RP2D was determined to be 80 mg QD for GSK525762. Please see 
Section 5.3 of the GSK525762 Investigator’s Brochure [GlaxoSmithKline Document 
Number 2011N113741_07, 20186], which details the clinical experience to date with 
GSK525762 and clinical safety data in the solid tumor population up to 100 mg once 
daily and in the hematologic malignancy population up to 120 mg once daily.
Section 4.6.3. – Overlapping Toxicities
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK525762 can be found in the Investigator Brochure. GSK525762 data provided in 
Section 4.6.3 reflects study treatment related AEs across all dose levels administered in 
the single-agent BET115521 solid tumor study as described in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2011N113741_05]. The data cut-off date 
was 27 Jan 2016. Summaries of findings from both clinical and non-clinical studies 
conducted with enzalutamide/abiraterone can be found in the Food and Drug 
Administration (FDA) package insert. The following section outlines the risk assessment 
and mitigation strategy for this protocol
Revised text: 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK525762 can be found in the Investigator Brochure. GSK525762 data provided in 
Section 4.6.3 reflects study treatment related AEs across all dose levels administered in 
the single-agent BET115521 solid tumor study as described in the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2011N113741_075, 2018]. The data cut-
off date was 29 Jan 201827 Jan 2016. Summaries of findings from both clinical and non-
clinical studies conducted with enzalutamide/abiraterone can be found in the Food and 
Drug Administration (FDA) package insert. The following section outlines the risk 
assessment and mitigation strategy for this protocol
Section 4.6.3.1.1. – Gastrointestinal Safety Findings
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
GSK525762: Gastrointestinal effects were frequently the dose-limiting toxicities in non-
clinical animal studies of GSK525762. Dogs and rats treated with repeated doses of 
GSK525762 experienced reduced body weight, ulceration/inflammation of the 
gastrointestinal (GI) tract, and abnormal feces. In study BET115521, drug-related 
gastrointestinal events were reported, as well. Drug-related nausea was reported in 29% 
of subjects, dysgeusia was reported in 19%, decreased appetite was described in 17%, 


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and diarrhea was reported in 16% of subjects. Gastrointestinal toxicity was 
predominantly Grades 1 and 2; 3% of subjects reported Grade 3 nausea and 1% of 
subjects reported Grade 3 diarrhea. No Grade 4 gastrointestinal effects were observed.
Revised text: 
GSK525762: Gastrointestinal effects were frequently the dose-limiting toxicities in non-
clinical animal studies of GSK525762. Dogs,and rats and mice treated with repeated 
doses of GSK525762 experienced reduced body weight, ulceration/inflammation of the 
gastrointestinal (GI) tract, and abnormal feces. In study BET115521, drug-related GI
gastrointestinal events were reported, as well. Drug-related nausea was reported in 
4129% of subjects, decreased appetite was reported in 36%, diarrhea was reported in 
32%, dysgeusia was reported in 3019%, decreased appetite was described in 17%, and 
diarrhea was reported in 16% and vomiting was reported in 27% of subjects. 
Gastrointestinal toxicity was predominantly Grades 1 and 2; 53% of subjects reported 
Grade 3 nausea, 4% reported Grade 3 decreased appetite, 3% reported Grade 3 vomiting, 
and 2% of subjects reported Grade 3 diarrhea.  and 1% of subjects reported Grade 3 
diarrhea. No Grade 4 GIgastrointestinal effects were observed.
Section 4.6.3.1.2. – Hepatic Safety Findings
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
GSK525762: In non-clinical animal studies, non-adverse liver changes were observed in 
rats and dogs. Increased gall bladder vacuolation and; decreased cytoplasmic rarefaction 
in the liver was evident in dogs dosed at ≥1 mg/kg/day for 28 days. Necrosis was 
observed in one rat at 30 mg/kg/day in the 4 week study. In the BET115521 clinical trial, 
liver effects have been noted. Importantly, these effects appear isolated to the higher 
doses, and none have resulted in a pre-designated “liver event”. At doses of 30 mg and 
below, no liver toxicity has been identified; one subject experienced Grade 3 
hyperbilirubinemia but this was attributed by the investigator to the presence of extensive 
hepatic metastases and consequent liver dysfunction. Hyperbilirubinemia has been 
observed at 40 mg total daily dose and above in the solid tumor and hematologic 
malignancy studies. Drug related elevated blood bilirubin was reported in 13%, aspartate 
aminotransferase (AST) elevation was reported in 4%, alanine aminotransferase (ALT) 
elevation was reported in 4% of subjects. All drug related hepatic toxicities were 
predominantly Grades 1 and 2; 4% of subjects reported Grade 3 blood bilirubin increased 
and 1% of subjects reported Grade 3 AST increase. There were no Grade 3 ALT 
increases noted and no Grade 4 drug related hepatic effects were observed.  
Revised text: 
GSK525762: In non-clinical animal studies, non-adverse liver changes were observed in 
rats, mice and dogs including increases in bilirubin levels in rats, increased bile acids in 
rats and mice and transient, reversible increased in AST and/or ALT in rats and dogs. 
Hepatocellular necrosis was observed in a single rat at a non-tolerated dose. Increased 
gall bladder vacuolation and; decreased cytoplasmic rarefaction in the liver was evident 
in dogs dosed at ≥1 mg/kg/day for 28 days. Necrosis was observed in one rat at 30 
mg/kg/day in the 4 week study.  In the BET115521 clinical trial, liver effects have been 


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noted. Cases of liver events meeting the definition of severe liver injury based on liver 
chemistries (ALT ≥3X ULN and Bilirubin ≥2X ULN) have been reported in study 
BET115521. Additional complicating factors were reported for these cases (e.g. liver 
metastasis and sepsis) with liver enzymes trending towards normal levels upon stopping 
GSK525762. Importantly, these effects appear isolated to the higher doses, and none 
have resulted in a pre-designated “liver event”. At doses of 30 mg and below, no liver 
toxicity has been identified; one subject experienced Grade 3 hyperbilirubinemia but this 
was attributed by the investigator to the presence of extensive hepatic metastases and 
consequent liver dysfunction. Hyperbilirubinemia has been observed at 40 mg total daily 
dose and above in the solid tumor and hematologic malignancy studies. Drug related 
elevated blood bilirubin was reported in 2413%, aspartate aminotransferase (AST) 
elevation was reported in 411%, and alanine aminotransferase (ALT) elevation was 
reported in 84% of subjects. TheseAll drug related hepatic toxicities were predominantly 
Grades 1 and 2; 74% of subjects reported Grade 3 and <1% reported Grade 4 blood 
bilirubin increased and 2% and 1% of subjects reported Grade 3 AST increase. There 
were no Grade 43 ALT increases noted and no Grade 4 drug related hepatic effects were 
observed.  
Section 4.6.3.1.3. – Hematopoietic Safety Findings
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
GSK525762: In non-clinical studies of GSK525762, 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 multiple red blood cells parameters and reticulocyte counts.
In the BET115521 clinical trial, thrombocytopenia has been observed in subjects with 
solid tumors mainly at doses of 60 mg and above. Forty one percent (41%) of subjects 
reported thrombocytopenia of any grade, and 24% of subjects reported Grade 3-4 
thrombocytopenia. Thrombocytopenia was only noted after more than a week of 
continuous dosing, and platelet counts recovered after cessation of the drug. Anemia was 
reported in 11% of subjects, and 1% of subjects reported Grade 3 anemia.  
Revised text: 
GSK525762: In non-clinical studies of GSK525762, lymphoid / hematologic toxicity 
was observed in rats, mice 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 (rat); decreased white cell /lymphocyte/platelet count and variable and 
inconsistent changes in multiple red blood cells parameters and reticulocyte counts.
Effects were generally reversible but minimal bone marrow cellularity was still evident in 
rats following an off dose period.
In the BET115521 clinical trial, thrombocytopenia has been observed in subjects with 
solid tumors mainly at doses of 60 mg and above. Forty one percent (41%) of subjects 


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reported thrombocytopenia of any grade, and 24% of subjects reported Grade 3-4 
thrombocytopenia. Thrombocytopenia was only noted after more than a week of 
continuous dosing, and platelet counts recovered after cessation of the drug. Drug related 
thrombocytopenia was reported in 59%, anemia was reported in 29%, international 
normalized ratio increased was reported in 14%, prothrombin time prolonged in 12% and 
coagulation factor VII level decreased in 10% of subjects. These AEs were mainly Grade 
1 or 2; with Grade 3 thrombocytopenia reported in 22%, Grade 3 anemia reported in 12% 
and Grade 3 factor VII decrease in 4% of subjects. Grade 4 thromobocytopenia was 
reported in 16%, anaemia in 1% and factor VII decrease in 4% of subjects. Anemia was 
reported in 11% of subjects, and 1% of subjects reported Grade 3 anemia.  
Mild to severe hemorrhagic events have been observed during the use of GSK525762, 
primarily during occurrences of moderate to severe thrombocytopenia. Most events have 
been associated with confounding factors beyond thrombocytopenia such as disease 
under study, and/or with metastases to affected areas, low molecular weight heparin use 
and previous radiation. There have been SAEs noted of decrease in Coagulation Factor 
VII. Refer to IB for additional details [GlaxoSmithKline Document Number 
2011N113741_07, 2018].
Section 4.6.3.1.4. – General Toxicity Findings
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
GSK525762: In the BET115521 study, 16% of subjects reported fatigue and 9% reported 
asthenia. These effects were all Grade 1 or 2.
Revised text: 
GSK525762: In the BET115521 study, 2516% of subjects reported fatigue and 249% 
reported asthenia. Most of these AEs were Grade 1 or 2; with Grade 3 asthenia reported 
in 9% and Grade 3 fatigue in 3% of subjects. No Grade 4 asthenia/fatigue AEs were 
reported. These effects were all Grade 1 or 2.
Section 4.6.4.1. – Cardiovascular Safety Findings
Rationale for Change: 
Update to language due to additional data.  
Previous text: 
GSK525762:
…In the BET115521 and BET116183 clinical trials, evaluation of cardiac safety data 
from subjects treated up to the 100 mg once daily cohort by the cut-off date of May 15, 
2015 demonstrated no significant QTc prolongation after single and repeat dose 
administration. Full analysis of cardiac safety data will be performed at the end of dose 
escalation in the BET115521 study.
Monitoring and Management: Subjects will be monitored closely for changes in QTc 
with triplicate 12-lead ECG and for elevations in plasma troponin. Safety ECGs will be 
performed at the time points specified in Time and Events tables (Section 7.1) using a 


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standard 12-lead ECG machine that automatically calculates the heart rate (HR) and 
measures PR, QRS, QT and QTcF intervals. The mean from triplicate ECGs will be 
evaluated at each time point. Safety ECGs will be reviewed by the investigator on an 
ongoing basis for safety purposes. Dosing should not begin until the safety ECG has been 
reviewed and no significant abnormalities have been detected.
Revised text: 
GSK525762:
…An internal safety review of categorical analysis of QTc increase (and decrease) from 
baseline of 271 subjects dosed up to 100 mg in In the BET115521 and up to 120 mg in 
the BET116183 clinical trials demonstrated a clinically negligible effect on QTc. Based 
on this analysis, the entry and stopping criteria have been modified., evaluation of cardiac 
safety data from subjects treated up to the 100 mg once daily cohort by the cut-off date of 
May 15, 2015 demonstrated no significant QTc prolongation after single and repeat dose 
administration. Full analysis of cardiac safety data will be performed at the end of dose 
escalation in the BET115521 study.
Monitoring and Management: Subjects will be monitored closely for changes in QTc 
with triplicate 12-lead ECG and for elevations in plasma troponin. Safety ECGs will be 
performed at the time points specified in Time and Events tables (Section 7.1) using a 
standard 12-lead ECG machine that automatically calculates the heart rate (HR) and 
measures PR, QRS, QT and QTcF intervals. As clinically indicated, Tthe mean from 
triplicate ECGs will be evaluated. at each time point. Safety ECGs will be reviewed by 
the investigator on an ongoing basis for safety purposes. Dosing should not begin until 
the safety ECG has been reviewed and no significant abnormalities have been detected.
Section 5.1 – Inclusion Criteria 
Rationale for Change: 
Revisions to wording of specific criteria to correct or clarify original wording and revise 
based on investigator feedback/internal decisions. Only the criteria which has been 
affected will be listed in both Previous and Revised sections.  
Previous text: 
3.  Histologically confirmed adenocarcinoma of the prostate: 
b.  Screening biopsy can be waived if patient had a recent biopsy after failure of ADT 
therapy (within 30 days) and the biopsy sample is secured to be sent as screening 
biopsy for this study. 
4.  Surgically or medically castrated, with testosterone levels of ≤ 50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to 
Cycle 1 Day 1 and must be continued throughout the study.
5.  Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 
a.  Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide 


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b.  Has not been without abiraterone or enzalutamide treatment for >30 days prior to 
initiation of study treatment
6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen. 
7.  Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.  PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be ≥5 ug/L 
(5 ng/mL) if PSA is the only indication of progression; subjects on systemic 
glucocorticoids for control of symptoms must have documented PSA progression 
by PCWG3 while on systemic glucocorticoids prior to commencing Cycle 1 Day 1 
treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
criteria or bone metastasis with 2 or more documented new bone lesions on a bone 
scan with or without PSA progression
11. Adequate organ function as defined in Table 1: 
System
Laboratory Values
Cardiac
Ejection fraction
≥ lower limit of normal (LLN) by echocardiogram or 
multigated acquisition scan (MUGA) and minimum of 
50% LVEF
12. Male subject with a female partner of childbearing potential or pregnant must agree to
use two acceptable methods of contraception from time of first dose of study treatment 
until 4 months after the last dose of study treatments.
Revised text: 
3.  Histologically confirmed adenocarcinoma of the prostate: 
b.  Screening biopsy can be waived if patient had a recent biopsy after failure of ADT 
therapy the most recent therapy (within 30 days) and the biopsy sample is secured to 
be sent as screening biopsy for this study. 
4.  Surgically or medically castrated, with testosterone levels of ≤50 ng/dL (<2.0 nM). If 
the patient is being treated with LHRH agonists/antagonists (patient who have not 
undergone orchiectomy) this therapy must have been initiated at least 4 weeks prior to 
Week 1 Cycle 1 Day 1 and must be continued throughout the study.
5.  Subjects must have failed prior therapy with abiraterone, enzalutamide, or both 
a.  Has completed at least 12 weeks of prior continuous therapy with abiraterone or 
enzalutamide in any prior line
b.  Has not been without abiraterone or enzalutamide treatment for >30 days prior to 
initiation of study treatment


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6. One to two line(s) of prior taxane-based chemotherapy allowed. If docetaxel 
chemotherapy is used more than once, this will be considered as one regimen. 
Subjects who have not received prior chemotherapy in any setting will qualify for 
study if they are ineligible for or refuse chemotherapy.
7.  Documented prostate cancer progression as assessed by the investigator with one of 
the following:
a.  PSA progression defined by a minimum of 3 rising PSA levels with an interval of 
≥1 week between each determination. The PSA value at screening must be ≥5 ug/L 
(5 ng/mL) if PSA is the only indication of progression; subjects on systemic 
glucocorticoids for control of symptoms must have documented PSA progression 
by PCWG3 while on systemic glucocorticoids prior to commencing WeekCycle 1 
Day 1 treatment.
b. Radiographic progression of soft tissue disease by PCWG3-modified RECIST 1.1 
criteria or bone metastasis with 2 or more documented new bone lesions on a bone 
scan/ CT scan with or without PSA progression
11. Adequate organ function as defined in Table 1: 
System
Laboratory Values
Cardiac
Ejection fraction
≥ lower limit of normal (LLN) by echocardiogram or 
multigated acquisition scan (MUGA) and minimum of 
50% LVEF
Troponin (I or T)
≤ ULN
12. Male subject with a female partner of childbearing potential or pregnant must agree to 
use two acceptable methods of contraception from time of first dose of study treatment 
until 4 months after the last dose of study treatments (Section 6.10.2). Male 
Participants: Contraceptive use by men or female partner should be consistent with
local regulations regarding the methods of contraception for those participating in
clinical studies.
Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 16 weeks after the last dose of study treatment:
•
Refrain from donating sperm
                   PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
OR
•
Must agree to use contraception/barrier as detailed below:
Agree to use a male condom and female partner to use an additional highly
effective contraceptive method with a failure rate of <1% per year as described in 
Appendix 12 when having sexual intercourse with a woman of childbearing potential
who is not currently pregnant.   If partner becomes pregnant, agree to use/continue use 
of condoms until 16 weeks after the last dose of study medication.


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Section 5.2 - Exclusion Criteria
Rationale for Change: 
Revisions to wording of specific criteria to correct or clarify original wording and revise 
based on investigator feedback/internal decisions. Only the criteria which has been 
affected will be listed in both Previous and Revised sections.  
Previous text: 
1.  Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of Cycle 1 Day 1.
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
interval ≥450 msec
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed) and 
non-steroidal anti-inflammatory drugs (NSAIDS), except for where NSAIDs provide 
documented benefit over other analgesics and then to be used with caution including 
concomitant use of proton pump inhibitors
12.  History of seizure or any condition that may predispose subject to seizure (e.g., prior 
cortical stroke or significant brain trauma).
15. Subjects who have experienced a seizure or seizures within 6 months of study 
treatment or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
16. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications with significant risk of Torsades de pointes as well as those that are 
potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.
20. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to Cycle 1 Day 1. Subjects on a stable bisphosphonate or denosumab 
therapy are eligible and may continue.
Revised text: 
1.  Surgery or local prostatic intervention (excluding a prostatic biopsy) less than 28 days 
of WeekCycle 1 Day 1.
5. Cardiac abnormalities as evidenced by any of the following:
a.
Baseline QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
interval ≥4850 msec
8. Concurrent use of high dose aspirin (doses up to 81 mg oral dose daily allowed, or 100 
mg, as per country standards) and non-steroidal anti-inflammatory drugs (NSAIDS), 
except for where NSAIDs provide documented benefit over other analgesics and then 
to be used with caution including concomitant use of proton pump inhibitors


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12.  History of seizure within 6 months of first dose of study treatment or any condition 
that may predispose subject to seizure (e.g., prior cortical stroke or significant brain 
trauma) or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
15. Subjects who have experienced a seizure or seizures within 6 months of study 
treatment or who are currently being treated with cytochrome P450 enzyme inducing 
anti-epileptic drugs for seizures (use of anti-epileptic drugs to control pain is allowed 
in subjects not suffering from seizures unless drug is excluded due to CYP3A4 
induction - phenytoin, carbamazepine, phenobarbital).
15. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and abiraterone/enzalutamide. This includes 
medications with significant risk of Torsades de pointes as well as those that are 
potent inducers or inhibitors of CYP3A4 enzymes or strong inhibitors of CYP2C8.
19. Initiating bisphosphonate or denosumab therapy or adjusting dose/regimen within 3 
months prior to WeekCycle 1 Day 1. Subjects on a stable bisphosphonate or 
denosumab therapy are eligible and may continue.
Section 5.4.2. – QTc Stopping Criteria
Rationale for Change: 
Updated wording based on revised recommendations by internal safety panel. 
Previous text: 
… Study treatments will be withheld if either of the following occurs:

QTcF interval ≥500 msec 

QTcF interval increase from baseline 60 msec…
Revised text: 
… Study treatments will be withheld if either of the following occurs:

QTcF interval ≥500 msec AND 60 msec change from baseline

QTcF interval ≥530 msec AND increase from baseline 60 msec change 
from baseline…
Section 5.5. – Subject and Study Completion
Rationale for Change: 
Addition of wording to clarify analysis based on evaluable subject population. 
Previous text:
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study. The End of Study eCRF should only be completed when a 
subject is no longer being followed. The study will be considered completed for purposes 
of a final analysis when 70% of subjects enrolled have progressed or died. If available, 


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subjects continuing on GSK525762 at the time of final analysis may be offered the option 
to continue it through another mechanism (eg, in a rollover trial).
Revised text: 
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study. The End of Study eCRF should only be completed when a 
subject is no longer being followed. The study will be considered completed for purposes 
of a final analysis when 70% of evaluable subjects enrolled have progressed or died. If 
available, subjects continuing on GSK525762 at the time of final analysis may be offered 
the option to continue it through another mechanism (eg, in a rollover trial).
Section 6.1. – Investigational Product and Other Study Treatment
Rationale for Change: 
Addition of new formulation of abiraterone acetate and clarification of wording for 
GSK525762 tablets. 
Previous text: 
Investigational Product
Product 
name:
GSK525762 Besylate Tablets
Abiraterone acetate
Enzalutamide
Unit dose 
strength(s)/Do
sage level(s):
5 mga
25 mga
20 mga
250 mg
40 mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Janssen
Astellas
Physical 
description:
White to slightly 
colored, round, 
biconvex tablets 
with no markings, 
film-coated tablet
Beige, 
round, 
biconvex 
tablets 
with no 
markings, 
film-
coated
White to off-white, oval 
tablets debossed with 
AA250 on one side
White to off-white oblong soft 
gelatin capsules imprinted in 
black ink with ENZ


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Revised text: 
Investigational Product
Product 
name:
GSK525762 Besylate Tablets
Abiraterone acetate
Enzalutamide
Unit dose 
strength(s)/Do
sage level(s):
5 mga
25 mga
20 mga
250 mg
500 mgb
40 mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Janssen
Janssen
Astellas
Physical 
description:
White to slightly 
colored, round, 
biconvex tablets 
with no markings, 
film-coated tablet
BeigeYel
lowish-
pink, 
round, 
biconvex 
tablets 
with no 
markings
, film-
coated
White to 
off-white, 
oval tablets 
debossed 
with AA250 
on one side
Film-
coated, 
purple oval 
tablets 
debossed 
with AA on 
one side 
and 500 on 
the other 
side
White to off-white oblong soft 
gelatin capsules imprinted in 
black ink with ENZ
b.
The 500 mg tablet may be supplied dependent on the availability by Janssen. The use of 250 mg tablet 
formulation may be discontinued when 500 mg tablet is available
Section 6.2. – Treatment Assignment 
Rationale for Change: 
Revisions to clarify previous language and add flexible language.
Previous text: 
…For Arm A, during the initial evaluation of DL60, approximately 3 to 10 subjects will 
be enrolled until it is determined that DL60 does not exceed the MTD. If DL60 exceeds 
the maximum permitted toxicity rate, then a lower dose level (DL-1, 40 mg) will be 
evaluated. If DL60 has been cleared in dose escalation, approximately 6 to 10 subjects 
will be enrolled in the DL80 cohort for evaluation of dose escalation. If DL80 cohort is 
opened, but exceeds the maximum permitted toxicity rate, then additional subjects will 
not be enrolled at DL80. Subjects enrolled during dose escalation will continue treatment 
and will not roll into dose expansion.
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be If DL60 and DL80 are cleared for DLT, eligible subjects will be
randomized into DL60 and DL80 expansion cohorts and will be based on prior lines of 
therapy (L2 or Lx). A maximum of up to 30 subjects each (in addition to those enrolled in 
dose escalation) will be enrolled into each dose level cohort…
…During the initial evaluation of DL80, approximately 3 to 10 subjects will be enrolled 
until it is determined that DL80 does not exceed the MTD. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. If DL80 has been cleared in dose escalation, approximately 3 to 10 subjects 
will be enrolled in the DL100 cohort until it is determined that DL100 does not exceed 
the MTD. If DL100 cohort is opened, but exceeds the maximum permitted toxicity rate, 
then additional subjects will not be enrolled at DL100. 


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An additional dose level, DL120, may be initiated after careful review of the PK and 
safety data from the DL80 and DL100 dose levels. If the DL120 cohort is opened, it will 
enrol approximately 3 to 10 subjects until it is determined whether DL120 does not 
exceed the MTD. Either DL100 or DL120 will be established as the ‘high dose’ and 
DL80 will be the ‘low dose’. Regardless of which dose (DL100 or DL120) is selected as 
the ‘high dose’, a minimum of 6 subjects will be enrolled during initial evaluation prior to 
moving to dose expansion. Subjects enrolled during dose escalation will continue 
treatment and will not roll into dose expansion. 
If the dose escalation DLT cohorts are cleared, eligible subjects will be randomized into 
DL80 and DL100 (or DL120), dose expansion cohorts will be based on prior lines of 
therapy (L2 or Lx). A maximum up to 30 subjects each (in addition to those enrolled in 
dose escalation) will be enrolled into each dose level cohort. 
Revised text: 
…For Arm A, during the initial evaluation of DL60, approximately 3 to 10 subjects will 
be enrolled until it is determined that DL60 does not exceed the MTD. If DL60 exceeds 
the maximum permitted toxicity rate, then a lower dose level (DL-1, 40 mg) will be 
evaluated. Due to emerging data (safety/tolerability/efficacy), additional dose levels may 
be explored. These dose levels may either be a lower daily dose level or an intermittent 
dose schedule, either at a dose level where daily treatment may be intolerable or at a 
lower dose. For example, if DL60 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 60 mg dose level (DL60 ALT) and/or a lower daily dose level (DL-
1, 40 mg) may be evaluated). If DL60 has been cleared in dose escalation, approximately 
6 to 10 subjects will be enrolled in the DL80 cohort for evaluation of dose escalation. If 
any dose levelDL80 cohort is opened, but exceeds the maximum permitted toxicity rate, 
then additional subjects will not be enrolled at that dose levelDL80. Subjects enrolled 
during dose escalation will continue treatment and will not roll into dose expansion.
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be If DL60 and DL80 are cleared for DLT, eligible subjects will be
randomized into DL60 and DL802 expansion cohorts and will be based on prior lines of 
therapy (L2 or Lx). A maximum of up to 30 subjects each (in addition to those enrolled in 
dose escalation) will be enrolled into each dose level cohort…
…During the initial evaluation of DL80, approximately 3 to 10 subjects will be enrolled 
until it is determined that DL80 does not exceed the MTD. If DL80 exceeds the 
maximum permitted toxicity rate, then a lower dose level (DL-1, 60 mg) will be 
evaluated. Due to emerging data (safety/tolerability/efficacy), additional dose levels may 
be explored. These dose levels may either be a lower daily dose level or an intermittent 
dose schedule, either at a dose level where daily treatment may be intolerable or at a 
lower dose. For example, if DL80 exceeds the maximum permitted toxicity rate, then 
intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily dose level (DL-
1, 60 mg) may be evaluated. If DL80 has been cleared in dose escalation, approximately 
3 to 10 subjects will be enrolled in the DL100 cohort until it is determined that DL100 
does not exceed the MTD. If any dose level cohort DL100 cohort is opened, but exceeds 
the maximum permitted toxicity rate, then additional subjects will not be enrolled at that 
dose levelDL100. 


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An additional dose level, DL120, may be initiated after careful review of the PK and 
safety data from the DL80 and DL100 dose levels. If the DL120 cohort is opened, it will 
enrol approximately 3 to 10 subjects until it is determined whether DL120 does not 
exceed the MTD. Either DL100 or DL120 will be established as the ‘high dose’ and 
DL80 will be the ‘low dose’. Regardless of which dose (DL100 or DL120) is selected as 
the ‘high dose’, a minimum of 6 subjects will be enrolled during initial evaluation prior to 
moving to dose expansion. Subjects enrolled during dose escalation will continue 
treatment and will not roll into dose expansion. 
To further explore and identify the MTDs (and RP2Ds), the two most tolerable dose 
levels may be initiated If the dose escalation DLT cohorts are cleared, and eligible 
subjects may will be randomized into DL80 and DL100 (or DL120), dose expansion 
cohorts will be based on by prior lines of therapy (L2 or Lx). A maximum up to 30
subjects each (in addition to those enrolled in dose escalation) will be enrolled into each 
dose level cohort. If only one dose level is tolerable for dose expansion, subjects will be 
enrolled and not randomized.
Section 6.3. – Planned Dose Adjustments 
Rationale for Change: 
Additional language added regarding minimum GSK525762 dose.
Previous text: 
….During any dose interruption of GSK525762, abiraterone or enzalutamide may be 
continued at the protocol dose unless dose interruption of these combination products is 
also required. If GSK525762 is permanently discontinued, subject must be discontinued 
from the abiraterone or enzalutamide treatment and withdrawn from the study.
Revised text: 
Based on dose table (Table 6) and effect of enzalutamide on GSK525762, no dose 
level/schedule of less than 40 mg QD will be allowed for Arm B. If a subject is on an 
alternate dosing schedule and requires a de-escalation to 40 mg, then the subject must 
move to 40 mg QD.
….During any dose interruption of GSK525762, abiraterone or enzalutamide may be 
continued at the protocol dose unless dose interruption of these combination products is 
also required. If GSK525762 is permanently discontinued, subject must be discontinued 
from the abiraterone or enzalutamide treatment and withdrawn from the study.
Section 6.3.1. – Guidelines for Events of Special Interest
Rational for Change: 
Removal of Section for consistency with other modifications in protocol and IB. 
Previous text: 
Guidelines for Events of Special Interest
Events of special interest are defined in Appendix 8 and the GSK525762 IB 
[GlaxoSmithKline Document Number 2011N113741_05]. The severity of adverse events 
(AEs) will be graded utilizing the National Cancer Institute- Common Toxicity Criteria 
for Adverse Events [NCI-CTCAE, version 4, 2009]. Guidelines for dose modifications 


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and interruptions for management of common toxicities associated with the study 
treatment(s) are provided in Appendix 2.
Revised text: 
Guidelines for Events of Special Interest
Events of special interest are defined in Appendix 8 and the GSK525762 IB 
[GlaxoSmithKline Document Number 2011N113741_05]. The severity of adverse events 
(AEs) will be graded utilizing the National Cancer Institute- Common Toxicity Criteria 
for Adverse Events [NCI-CTCAE, version 4, 2009]. Guidelines for dose modifications 
and interruptions for management of common toxicities associated with the study 
treatment(s) are provided in Appendix 2.
Section 6.6. – Preparation/Handling/Storage/Accountability 
Rationale for Change: 
Revisions to language due to updated GSK525762 handling language. 
Previous text: 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff. A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required by 
local laws, or is available upon request from GSK.
Revised text: 
Limited exposure and precautionary action (e.g., wearing gloves, washing hands post 
exposure, etc.) should be taken by site staff dispensing GSK525762. Under normal 
conditions of handling and administration, study treatment is not expected to pose 
significant safety risks to site staff. A Material Safety Data Sheet (MSDS)/equivalent 
document describing occupational hazards and recommended handling precautions either 
will be provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
Section 6.10.2. – Male Subjects 
Rationale for Change: 
Revisions to presentation of language. Removal of section as language moved to 
Inclusion Criteria and Appendix. 
Previous text: 
Subjects with female partners of child-bearing potential must use acceptable, highly 
effective forms of contraceptive methods (i.e., a failure rate of ≤1%) defined in Appendix 
12 after the first dose of study treatment and until 4 months after the last dose of study 
drug (note that these requirements do not apply if female partners are not of child-bearing 
potential). 
Female partner use of hormonal means of birth control such as oral contraceptives are 
NOT acceptable forms of birth control given that their efficacy has not been evaluated 
when given in combination with the investigational drugs.


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In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 4 months after stopping study medications.
Revised text: 
Subjects with female partners of child-bearing potential must use acceptable, highly 
effective forms of contraceptive methods (i.e., a failure rate of ≤1%) defined in Appendix 
12 after the first dose of study treatment and until 4 months after the last dose of study 
drug (note that these requirements do not apply if female partners are not of child-bearing 
potential). 
Female partner use of hormonal means of birth control such as oral contraceptives are 
NOT acceptable forms of birth control given that their efficacy has not been evaluated 
when given in combination with the investigational drugs.
In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 4 months after stopping study medications. 
Section 6.11.2.1. – Prohibited Medications 
Rationale for Change: 
Revisions to language based on exclusion criteria revisions. 
Previous text: 
…Subjects may continue to use Aspirin, but doses are not allowed to be greater than 81 
mg per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be 
excluded, except for when NSAIDs will provide benefit over other analgesics and then to 
be used with caution including concomitant use of proton pump inhibitors….
....Co-administration of the medications listed in Table 7 are prohibited for 5 half-lives 
(or at least 14 days, whichever is longer) prior to the first dose of study drug until 
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone, which is prohibited beginning 6 months prior to screening 
through discontinuation from the study. [However, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines]). 
These medications include (but are not limited to):
Table 7: Drugs with a Risk of Torsades de Pointes that are Prohibited 
Revised text: 
…Subjects may continue to use Aspirin, but doses are not allowed to be greater than 81 
mg per day (or 100 mg, as per country standards). The use of non-steroidal anti-
inflammatory drugs (NSAIDs) will be excluded, except for when NSAIDs will provide 
benefit over other analgesics and then to be used with caution including concomitant use 
of proton pump inhibitors….
....Co-administration of the medications listed in Table 7 are prohibited for 5 half-lives 
(or at least 14 days, whichever is longer) prior to the first dose of study drug until 
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone, which is prohibited beginning 6 months prior to screening 
through discontinuation from the study. [However, there may be situations when the 


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subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines]). 
These medications include (but are not limited to):
Table 7: Drugs with a Risk of Torsades de Pointes that are Prohibited 
Removed Table. 
Section 6.11.2.3. – Cautionary Medications 
Rationale for Change: 
Revisions to language based on exclusion criteria revisions and language based on safety 
panel review. 
Previous text: 
Subjects should minimize the use of medications which contain acetaminophen. Subjects 
should be informed of alternative medications. ….
… Co-administration of GSK525762 and the following medications requires extreme 
caution beginning 14 days prior to the first dose of study drug until discontinuation from 
the study due to an increased risk of Torsades de Pointes. These medications include (but 
are not limited to): 
Table 8: Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution 
After starting cautionary medications such as in Table 8, it is recommended that ECGs 
are implemented daily until the steady state of the new medication is reached. If there are 
ECG abnormalities, implement additional cardiotoxicity monitoring as addressed 
Appendix 2.
Revised text: 
Subjects should minimize the use of medications which contain acetaminophen. Subjects 
should be informed of alternative medications. ….
… Co-administration of GSK525762 and medications which may have an increased risk 
of Torsades de Pointes the following medications requires extreme caution beginning 14 
days prior to the first dose of study drug until discontinuation from the study. , due to an 
increased risk of Torsades de Pointes. Please reference current list of medications at 
crediblemeds.org. These medications include (but are not limited to):
Table 8: Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution 
Removed Table. 
After starting cautionary medications such as any listed in the referenced internet linkin 
Table 8, it is recommended that ECGs are implemented daily until the steady state of the 
new medication is reached. If there are ECG abnormalities, implement additional 
cardiotoxicity monitoring as addressed Appendix 2.


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Section 7.1. – Time and Events Table 
Rationale for Change: 
Revisions and update to tables based on changes in other Sections. Addition of Week 6 
Laboratory Tests due to internal safety panel recommendation. Revisions to footnotes 
where applicable due to changes in other Sections. Only Rows and affected footnotes are 
presented. 
Previous text: 
Table 7 Dose Escalation Time and Events
Procedure
SC
R
Lead
-In 
Dosi
ng (if 
requi
red)
Week 
1
Week 
2
Week 
3
Week 4
Week 
5
q4w
q8
w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D1
D
1
W9 to 
W49
W9 
to 
W4
9 
W49 
and 
there
after
Safety
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA8
X
X
X
Weeks 
13, 25 
and 37
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
Tumor biopsy13
X
One sample, 
collected 3-6h 
post-
GSK525762 
dose, between 
W3D1 and 
W4D1
X14
Biomarker Assessments
CTC – ARV17
X
X
Week 9 
only
X
2.
Screening echocardiogram or MUGA scans should be completed within 35 days prior to the first dose of study 
drugs. Baseline imaging should be completed within 28 days prior to first dose of study drugs. All other 
assessments should be within 14 days prior to first dose of any study drugs. 
6.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.  
12. “PK” = serial PK days. Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 
1h ± 10m, 3h ± 30m, 6 to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained 
pre-dose, 0.5-1h post-dose, and an optional sample 4-12h post-dose. “X” = sample collections to be obtained 
pre-dose as well as 0.5-1h post-dose (note that routine PK is no longer required once the subject has been on 
study for 26 weeks). PK samples will be split to obtain PK samples for abiraterone and enzalutamide. 
Abiraterone PK samples will be collected at all PK time points in Week 1 and Week 3 and only at pre-dose at 
remaining PK visits. Enzalutamide PK samples will be collected at pre-dose for all PK visits. Refer to the SRM for 
further details. Once extensive PK sampling in Week 1 and Week 3 have been collected from at least 12 
subjects for each dose and combination cohorts, PK sampling may be reduced for these visits.
13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 


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1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures. Refer to the SRM for further details
16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1 of the 
combination treatment period, W5D1, W9D1 and every 8 weeks for the first 6 months and thereafter every 12 
weeks; and EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1, W5D1, and W9D1 
of the combination treatment period; and EOT. Based on emerging data, GSK may decide to discontinue the 
collection of these samples.
Table 8 Dose Escalation Time and Events, Laboratory Assessments
SC
R
Week 1
Week 2
Week 3
Wee
k 4
Wee
k 5
q2
w
q4
w
q4w
q12w
EO
T
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W7 
an
d 
11
W9 
to 
W4
9
W49 
and 
thereaft
er
W49 
and 
thereaft
er
Clinical 
chemistry
X
X
X
X
X
X
X
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X
X
X
X2
X
X2
X
X
Liver 
chemistry
X
X
X
X
X
X
X
X
X
X2
X
X2
X
X
Coagulation
X
X
X
X
X
X
X
X2
X
X2
X
X
Thyroid 
stimulating 
hormone
(TSH), free 
triiodothyron
ine (T3), 
free 
thyroxine 
(T4))
X
X
X
X
X


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Table 9 Dose Expansion Time and Events
Procedure
S
C
R
Lead-
In 
Dosin
g (if 
requir
ed)
Wee
k 1
Wee
k 2
Wee
k 3
Week 4
Wee
k 5
q4w
q8w
q12
w
EOT1, 22
D1
D
1
D
1
D1
D
1
W9 to 
W49
W9 
to 
W49
W49 
and 
ther
eafte
r
Safety
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
Echocardiogram 
or MUGA8
X
X
X
Weeks 
13, 25 
and 37
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
Tumor biopsy13
X
One sample, 
collected 3-6h 
post-
GSK525762 
dose, between
W3D1 and 
W4D1
X14
Biomarker Assessments
CTC – ARV17
X
X
Week 
9 only
X
2.
Screening echocardiogram or MUGA scans should be completed within 35 days prior to the first dose of study 
drugs. Baseline imaging should be completed within 28 days prior to first dose of study drugs. All other 
assessments should be within 14 days prior to first dose of any study drugs. 
6.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.  
12. “PK” = serial PK days. Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 
1h ± 10m, 3h ± 30m, 6 to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained 
pre-dose, 0.5-1h post-dose, and an optional sample 4-12h post-dose. “X” = sample collections to be obtained 
pre-dose as well as 0.5-1h post-dose (note that routine PK is no longer required once the subject has been on 
study for 26 weeks). PK samples will be split to obtain PK samples for abiraterone and enzalutamide. 
Abiraterone PK samples will be collected at all PK time points in Week 1 and Week 3 and only at pre-dose at 
remaining PK visits. Enzalutamide PK samples will be collected at pre-dose for all PK visits. Refer to the SRM for 
further details. Once extensive PK sampling in Week 1 and Week 3 have been collected from at least 12 
subjects for each dose and combination cohorts, PK sampling may be reduced for these visits.
13. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures. Refer to the SRM for further details
16. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening; pre-dose on W1D1 of the 
combination treatment period, W5D1, W9D1 and every 8 weeks for the first 6 months and thereafter every 12 
weeks; and EOT.
17. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1, W5D1, and W9D1 
of the combination treatment period; and EOT. Based on emerging data, GSK may decide to discontinue the 
collection of these samples.


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Table 10 Dose Expansion Time and Events, Laboratory Assessments
S
C
R
We
ek 
1
We
ek 2
We
ek 3
Week 
4
We
ek 5
q2w
q4w
q4w
q12w
EOT
D
1
D
1
D
1
D1
D
1
W7 
and 
11
W9 to 
W49
W49 
and 
there
after
W49 
and 
thereaf
ter
Clinical chemistry
X
X
X
X
X
X
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X2
X
X2
X
X
Liver chemistry
X
X
X
X
X
X
X2
X
X2
X
X
Coagulation
X
X
X
X
X
X
X2
X
X2
X
X
Thyroid (Thyroid 
stimulating hormone
(TSH), free 
triiodothyronine (T3), 
free thyroxine (T4))
X
X
X
X
X
Revised text: 
Table 7 Dose Escalation Time and Events
Procedure
SC
R
Lead
-In 
Dosi
ng (if 
requi
red)
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
q4w
q8
w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D1
D1
W9 to 
W49
W9 
to 
W4
9 
W49 
and 
there
after
Safety
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA8
X
X
X
Weeks 
13, 25 
and 37
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
Tumor biopsy13
X
One sample, collected 
3-6h post-GSK525762 
dose, between W3D1 
and W4 5D1
X14
Biomarker Assessments
CTC – ARV17
X
X
Week 9 
only
X
3.
Screening echocardiogram or MUGA scans should be completed within 35 days prior to the first dose of study 
drugs. Baseline imaging should be completed within 28 days prior to first dose of study drugs. All other 
assessments should be within 2814 days prior to first dose of any study drugs. Clinical labs used for screening 
must be within 72 hours of first does of study drugs.
7.
Triplicate ECGs should be performed at Screening. All other timepoints may be single ECG prior to dosing and 
evaluated for abnormality prior to administration of dose. Triplicate ECGs would be performed as clinically 
indicated due to abnormal finding.  
14. “PK” = serial PK days. Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 
1h ± 10m, 3h ± 30m, 6 to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained 
pre-dose, 0.5-1h post-dose, and an optional sample 4-12h post-dose. “X” = sample collections to be obtained 


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pre-dose as well as 0.5-1h post-dose (note that routine PK is no longer required once the subject has been on 
study for 26 weeks). PK samples will be split to obtain PK samples for abiraterone and enzalutamide. 
Abiraterone PK samples will be collected at all PK time points in Week 1 and Week 3 and only at pre-dose at 
remaining PK visits. Enzalutamide PK samples will be collected at pre-dose for all PK visits. Refer to the SRM for 
further details. For subjects in alternate dosing schedule, the Week 3 Day 1 extensive PK will need to occur 
between W2 Day 4 and W2 Day 7 prior to their scheduled dose interruption. For any PK timepoint, subjects 
should have received GS525762 for at least 7 days prior to their scheduled PK draws. This may require the 
subject to return earlier than any planned interruption of dosing. Once extensive PK sampling in Week 1 and 
Week 3 have been collected from at least 12 subjects for each dose and combination cohorts, PK sampling may 
be reduced for these visits.
15. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures and must have received at least 4 consecutive doses of GSK525762 
prior to the collection of the tissue. If the on-therapy biopsy is not performed during the defined timeline due to 
lab abnormalities or subject status, it should be performed after subject recovery and the next visit as agreed 
upon with the medical monitor. Refer to the SRM for further details
18. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening (collected within 7 days 
prior to treatment), Screening; pre-dose on W1D1 of the combination treatment period, W5D1, W9D1 and every 
8 weeks for the first 6 months and thereafter every 12 weeks; and EOT.
19. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1, W5D1, and W9D1 
of the combination treatment period; and EOT. Based on emerging data, GSK may decide to discontinue the 
collection of these samples.
Table 8 Dose Escalation Time and Events, Laboratory Assessments
S
C
R
Week 
1
Week 
2
Week 
3
Week 
4
Week 
5
Week 
6
q2w
q4w
q4w
q12w
E
OT
D
1
D
4
D
1
D
4
D
1
D
4
D1
D1
D1
W7 
and 
11
W9 
to 
W4
9
W49 
and 
therea
fter
W49 
and 
therea
fter
Clinical 
chemistry
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Hematolog
y
X
X
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Liver 
chemistry
X
X
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Coagulatio
n
X
X
X
X
X
X
X
X2
X2
X
X2
X
X
Thyroid 
stimulating 
hormone
(TSH), 
free 
triiodothyr
onine (T3), 
free 
thyroxine 
(T4))3
X
X
X
X
X
3.
TSH testing is mandatory. T4 testing is only required if TSH is abnormal. T3 testing is required when clinically 
applicable (if both TSH and T4 are abnormal).


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Table 9 Dose Expansion Time and Events
Procedure
S
C
R
Lead-
In 
Dosin
g (if 
requir
ed)
Wee
k 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
q4w
q8w
q12w
EOT1, 22
D1
D
1
D
1
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
thereaft
er
Safety
12-lead ECGs 
(Triplicate)6
X
X
X
X
X
X
X
X
X
Echocardiogram 
or MUGA8
X
X
X
Wee
ks 
13, 
25 
and 
37
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
Tumor biopsy13
X
One sample, 
collected 3-6h 
post-GSK525762 
dose, between 
W3D1 and W45D1
X14
Biomarker Assessments
CTC – ARV17
X
X
Wee
k 9 
only
X
3.
Screening echocardiogram or MUGA scans should be completed within 35 days prior to the first dose of study 
drugs. Baseline imaging should be completed within 28 days prior to first dose of study drugs. All other 
assessments should be within 2814 days prior to first dose of any study drugs. Clinical labs used for screening 
must be within 72 hours of first does of study drugs.
7.
Triplicate ECGs should be performed at Screening. All other timepoints may be single ECG prior to dosing and 
evaluated for abnormality prior to administration of dose. Triplicate ECGs would be performed as clinically 
indicated due to abnormal finding.  
14. “PK” = serial PK days. Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 
1h ± 10m, 3h ± 30m, 6 to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained 
pre-dose, 0.5-1h post-dose, and an optional sample 4-12h post-dose. “X” = sample collections to be obtained 
pre-dose as well as 0.5-1h post-dose (note that routine PK is no longer required once the subject has been on 
study for 26 weeks). PK samples will be split to obtain PK samples for abiraterone and enzalutamide. 
Abiraterone PK samples will be collected at all PK time points in Week 1 and Week 3 and only at pre-dose at 
remaining PK visits. Enzalutamide PK samples will be collected at pre-dose for all PK visits. Refer to the SRM for 
further details. For subjects in alternate dosing schedule, the Week 3 Day 1 extensive PK will need to occur 
between W2 Day 4 and W2 Day 7 prior to their scheduled dose interruption. For any PK timepoint, subjects 
should have received GS525762 for at least 7 days prior to their scheduled PK draws. This may require the 
subject to return earlier than any planned interruption of dosing. Once extensive PK sampling in Week 1 and 
Week 3 have been collected from at least 12 subjects for each dose and combination cohorts, PK sampling may 
be reduced for these visits.
15. Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible to obtain 
a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and whole 
blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures and must have received at least 4 consecutive doses of GSK525762 
prior to the collection of the tissue. If the on-therapy biopsy is not performed during the defined timeline due to 


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lab abnormalities or subject status, it should be performed after subject recovery and the next visit as agreed 
upon with the medical monitor. Refer to the SRM for further details
18. CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening (collected within 7 days 
prior to treatment), Screening; pre-dose on W1D1 of the combination treatment period, W5D1, W9D1 and every 
8 weeks for the first 6 months and thereafter every 12 weeks; and EOT.
19. CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1, W5D1, and W9D1 
of the combination treatment period; and EOT. Based on emerging data, GSK may decide to discontinue the 
collection of these samples.
Table 10 Dose Expansion Time and Events, Laboratory Assessments
S
C
R
We
ek 
1
We
ek 
2
We
ek 
3
Wee
k 4
We
ek 
5
Week 
6
q2w
q4w
q4w
q12w
EOT
D
1
D
1
D
1
D
1
D
1
D1
W7 
and 
11
W9 to 
W49
W49 
and 
ther
eafte
r
W49 
and 
therea
fter
Clinical chemistry
X
X
X
X
X
X
X2
X2
X
X2
X
X
Hematology
X
X
X
X
X
X
X2
X2
X
X2
X
X
Liver chemistry
X
X
X
X
X
X
X2
X2
X
X2
X
X
Coagulation
X
X
X
X
X
X
X2
X2
X
X2
X
X
Thyroid (Thyroid 
stimulating 
hormone (TSH), 
free triiodothyronine 
(T3), free thyroxine 
(T4))3
X
X
X
X
X
3.
TSH testing is mandatory. T4 testing is only required if TSH is abnormal. T3 testing is required when clinically 
applicable (if both TSH and T4 are abnormal).
Section 7.2. – Screening and Critical Baseline Assessments
Rationale for Change: 
Updated Screening window period. 
Previous text:
All subjects must sign written Informed Consent prior to the commencement of any study 
specific screening procedures. Consent may be obtained up to 14 days prior to Cycle 1 
Day 1. Subjects will have a screening period of up to 14 days prior to Cycle 1 Day 1. 
Evaluations obtained as part of routine medical care and performed during the screening 
period may be used in place of protocol-specific evaluations. In addition, disease specific 
assessments performed within a specified time frame prior to informed consent may be 
used for the study-such as biopsy specimens, prior scans (if done within 28 days) and 
ECHO (if done within 35 days). Subjects will acknowledge and agree to the possible use 
of this information for the study by giving informed consent.
Revised text: 
All subjects must sign written Informed Consent prior to the commencement of any study 
specific screening procedures. Consent may be obtained up to 2814 days prior to 
WeekCycle 1 Day 1. Subjects will have a screening period of up to 2814 days prior to 
WeekCycle 1 Day 1. Evaluations obtained as part of routine medical care and performed 
during the screening period may be used in place of protocol-specific evaluations. In 


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addition, disease specific assessments performed within a specified time frame prior to 
informed consent may be used for the study-such as biopsy specimens, prior scans (if 
done within 28 days) and ECHO (if done within 35 days). Subjects will acknowledge and 
agree to the possible use of this information for the study by giving informed consent.
Section 7.2.2. – Visit Windows
Rationale for Change: 
Revisions to section wording to reflect changes to Screening period, assessments to be 
completed during Screening and clarification to PK language when alternate dose 
schedule may be utilized. 
Previous text: 
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days and baseline imaging within 28 days prior to the first dose of 
study drugs. All other assessments should be completed within 14 days prior to first dose 
of study drugs. Clinical labs performed during screening within 72 hours of first dose do 
not need to be repeated on Day 1.
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days. During dose 
escalation, assessments on Week 3 Day 4 may be scheduled ± 2 days.
Note: The Week 3 Day 1 PK collection is timed to permit evaluation of GSK525762 PK 
at steady-state dosing. If a subject is not receiving GSK525762 on Week 3 Day 1 (either 
as a consequence of a planned drug holiday or due to toxicity), then serial PK collection 
should be rescheduled for a later time point when the subject is again being dosed steady 
state, and the alternate collection date noted in the eCRF. However, in this case a single 
pre-dose sample should still be collected to evaluate for abiraterone/enzalutamide trough 
concentration.
Every 4-week and 8-week visits after Week 9 until Week 49: After the first disease 
assessment has been completed, then the clinic visits can be scheduled ± 5 days. 
Revised text: 
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to first dose of study drugs., and baseline imaging within 
28 days prior to the first dose of study drugs. All other assessments should be completed 
within 2814 days prior to first dose of study drugs. Screening labs collected outside of the 
72-hour window prior to the first dose of study treatment must be repeated before 
confirming eligibility and completing first dose. Clinical labs performed during screening 
within 72 hours of first dose do not need to be repeated on Day 1.
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days. During dose 
escalation, assessments on Week 3 Day 4 may be scheduled ± 2 days.
Note: The Week 3 Day 1 PK collection is timed to permit evaluation of GSK525762 PK 
at steady-state dosing (at least 7 consecutive days dosing prior to collection). If a subject 
is not receiving GSK525762 on Week 3 Day 1 (either as a consequence of a planned drug 
holiday or due to toxicity), then serial PK collection should occur between Week 2 Day 4 
and Week 2 Day 7 prior to their planned drug interruption. If subject is not receiving 
GSK525762 on Week 3 Day 1 due to toxicity, then serial PK collection should be 
rescheduled for a later time point when the subject is again being dosed for at least 7 


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consecutive daysat steady state, and the alternate collection date noted in the eCRF. 
However, in this case a single pre-dose sample should still be collected to evaluate for 
abiraterone/enzalutamide trough concentration.
Every 4-week and 8-week visits after Week 9 until Week 49: After the first disease 
assessment has been completed, then the clinic visits can be scheduled ± 5 days. During 
visits with planned PK sample collection, for subjects in the alternate dosing schedule or 
who have interrupted dosing, the collection should be postponed until the subject has 
received at least 7 consecutive doses of GSK525762.   
Section 7.3.4.1. – Electrocardiograms
Rationale for Change: 
Revisions to section wording to reflect updated recommendations from internal safety 
group after review of additional treatment data from subjects who have received 
GSK525762. 
Previous text:
Triplicate 12-lead ECGs will be obtained, prior to dosing, on days specified in the Time 
and Events Tables during the study using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTcF intervals. Details will be provided 
in the SRM. Any values >450 msec as calculated by the machine must be confirmed 
manually according to Fridericia’s formula. Refer to Section 5.4.2 for QTcF calculations 
and QTc withdrawal criteria, and to Appendix 2 for management strategies for QTcF 
prolongation. 
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 should be used.
Revised text: 
Triplicate 12-lead ECGs will be obtained at Screening. On treatment single ECGs will be 
completed, prior to dosing, on days specified in the Time and Events Tables during the 
study using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTcF intervals. Details will be provided in the SRM. Any values 
>4580 msec as calculated by the machine must be confirmed manually according to 
Fridericia’s formula. Refer to Section 5.4.2 for QTcF calculations and QTc withdrawal 
criteria, and to Appendix 2 for management strategies for QTcF prolongation. Triplicate 
ECGs should be performed as clinically indicated due to abnormal findings. 
Baseline results are defined by the nearest timepoint prior to first dose. For this trial tThe 
baseline QTcF value is determined by the mean of the triplicate Screening W1D1 predose 
QTcF results. If these results are not available, then the mean QTcF of the screening 
triplicate ECG results.should be used.


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Section 7.3.5. – Clinical Safety Laboratory Assessments
Rationale for Change: 
Clarifications to Table 11. Only relevant changes are reflected in the previous and revised 
text sections.
Previous text:
Table 11 Clinical Laboratory Tests
Clinical Chemistry
Blood Urea Nitrogen
Albumin
Liver Function
Bilirubin (Total and Direct)
Cardiac Studies
Troponin (I or T at local laboratory)
NT-ProBNP = N-terminal pro b-type natriuretic peptide; LDL = Low-density lipoprotein; HDL = High-density lipoprotein; 
INR = International normalized ratio; TSH = Thyroid-stimulating hormone; PSA = Prostate-specific antigen; HIV = 
Human immunodeficiency virus; HbSag = Hepatitis B surface antigen; HCV = Hepatitis C virus  
Note: Not all studies are performed at each visit; please refer to Section 7.1, Table 10 and Table 12 for timing of 
required studies
Revised text: 
Clinical Chemistry
Blood Urea Nitrogena
Albumin
Liver Function
Bilirubin (Total and Direct)b
Cardiac Studies
Troponin (I or T at local laboratory, may be collected at central laboratory if local draw is not possible)
a.
Direct and/or calculated BUN values are acceptable. 
b.
Direct bilirubin is only required if total bilirubin values are abnormal
NT-ProBNP = N-terminal pro b-type natriuretic peptide; LDL = Low-density lipoprotein; HDL = High-density lipoprotein; 
INR = International normalized ratio; TSH = Thyroid-stimulating hormone; PSA = Prostate-specific antigen; HIV = 
Human immunodeficiency virus; HbSag = Hepatitis B surface antigen; HCV = Hepatitis C virus  
Note: Not all studies are performed at each visit; please refer to Section 7.1, Table 810 and Table 1012 for timing of 
required studies
Section 7.3.7. – Pregnancy
Rationale for Change: 
Revision to provide consistency with revised template language. 
Previous text: 
Details of all pregnancies in female partners of male subjects will be collected after the 
start of dosing and until at least 4 months post-last dose.  …
… Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
Revised text:
Details of all pregnancies in female partners of male subjects will be collected after the 
start of dosing and until at least 16 weeks4 months post-last dose. …


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… While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
Section 7.5.1. – Tumor Biopsy Collection/Surgical Procedures
Rationale for Change: 
Revisions to update Screening period and add language to flexibility of timing of on 
therapy sample collection. 
Previous text: 
In the dose escalation and expansion cohort(s), paired fresh biopsies must be provided 
pre- (within 14 days of the first dose) and on-treatment at the time points indicated from 
all the subjects. Any fresh on-treatment biopsy should be accompanied by a whole blood 
sample collected as close as possible to the time of biopsy (preferably within 1h). 
Subjects providing an on-treatment fresh tumor biopsy must have received at least 4 
consecutive days of GSK525762 prior to the collection of the sample. Further details 
regarding sample type and processing will be provided in the SRM. If a potential subject 
does not have disease amenable to biopsy, participation may occur only upon discussion 
with and approval of the medical monitor; in this situation, an archival tumor sample 
retrieved after completion of most recent ADT will be required. 
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
WNL within 48 hours prior to the post-dose biopsy or any other planned surgical 
procedure. Further details regarding sample type and processing will be provided in the 
SRM.
Revised text: 
In the dose escalation and expansion cohort(s), paired fresh biopsies must be provided 
pre- (within 2814 days of the first dose) and on-treatment at the time points indicated 
from all the subjects. Any fresh on-treatment biopsy should be accompanied by a whole 
blood sample collected as close as possible to the time of biopsy (preferably within 1h). 
Subjects providing an on-treatment fresh tumor biopsy must have received at least 4 
consecutive days of GSK525762 prior to the collection of the sample. Further details 
regarding sample type and processing will be provided in the SRM. If a potential subject 
does not have disease amenable to biopsy, participation may occur only upon discussion 
with and approval of the medical monitor; in this situation, an archival tumor sample 
retrieved after completion of most recent ADT will be required. 
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
WNL within 48 hours prior to the post-dose biopsy or any other planned surgical 
procedure.  If the on therapy biopsy is not performed during the defined timeline due to 
lab abnormalities or subject status, it should be performed after subject recovery and the 
next visit as agreed upon with the medical monitor. Further details regarding sample type 
and processing will be provided in the SRM.
Section 7.6.1. – Disease Progression Endpoint


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Rationale for Change: 
Revisions to definition of PSA progression. 
Previous text: 
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG3 criteria (Section 7.6.2)

Radiographic progression in by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG3 criteria (Section 7.6.3)
Revised text: 
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG3 criteria (Section 7.6.2)

Radiographic progression in by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG3 criteria (Section 7.6.3)

PSA progression according to the PCWG3 criteria (Section 7.6.2) accompanied by 
any of the following: investigator-defined clinical progression or either of the above 
RECIST 1.1 or bone progression
Section 7.7.3. – Circulating Tumor Cells
Rationale for Change: 
Revisions to reflect changes in collection time points for CTC-ARV sampling and 
clarification to CTC enumeration language. 
Previous text: 
Blood samples will be collected and analyzed to enumerate CTCs in circulation at the 
time points indicated in the Time and Events Tables (Section 7.1). The CTCs may also be 
utilized for additional analysis like alterations in AR genes and may include additional 
genes implicated in the prostate cancer or related to AR signaling pathway. If baselines 
CTCs are not observed in a subject, GSK may ask to terminate the further sampling for 
CTC enumeration in those subjects.
Additional blood samples will be collected at the time points indicated in the Time and 
Events Tables (Section 7.1) to isolate CTCs. The isolated CTCs will be analyzed for AR 
variants or other protein markers and potential genomic alterations (e.g. AR 
amplifications, phosphatase and tensin homolog (PTEN) allele loss etc.). Based on 
emerging data, GSK may decide to discontinue the collection of these samples.
Revised text: 
Blood samples will be collected and analyzed to enumerate CTCs in circulation at the 
time points indicated in the Time and Events Tables (Section 7.1). The CTCs may also be 
utilized for additional analysis like alterations in AR genes and may include additional 
genes implicated in the prostate cancer or related to AR signaling pathway. If baselines 
CTCs are not observed in a subject, GSK may ask to terminate the further sampling for 
CTC enumeration in those subjects.


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Additional blood samples will be collected at the time points indicated in the Time and 
Events Tables (Section 7.1) to isolate CTCs. The isolated CTCs will be analyzed for AR 
variants or other protein markers and potential genomic alterations (e.g. AR 
amplifications, phosphatase and tensin homolog (PTEN) allele loss etc.). Based on 
emerging data, GSK may decide to discontinue the collection of these samples.


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Section 9.1 – Hypotheses 
Rationale for Change: 
Revisions to correct language in error from previous version and to clarify conduct of 
analyses. Update language based provided by Berry Consulting.  language reflect 
changes in collection time points for CTC-ARV sampling and clarification to CTC 
enumeration language. 
Previous text: 
Dose escalation
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, based upon the safety, PK and efficacy profiles of GSK2879552 plus 
azacitidine in subjects with advanced cancer.
Dose expansion cohorts
The goal of the trial is to characterize the dose-response curve for both efficacy and 
safety and to identify whether there is a dose of GSK525762 with an acceptable 
combination of response rate and safety.
The efficacy endpoint is defined as the clinically meaningful response rate (% of subjects 
achieving PSA reduction from baseline ≥50%) at 12 weeks and/or thereafter for the 
subjects treated at each dose level….
… The response rate and dose modification rate will be jointly assessed using a utility 
function. For each dose expansion cohort the utility (dU) will be calculated and used for 
decision making at each interim analysis and final analysis. At the end of each arm, the 
dose with the highest probability of having the largest utility relative to other doses may 
be picked as the RP2D. Further details of the calculation of utility function will be 
provided in RAP….
The interim analysis will be conducted for each individual dose and it may be conducted 
when at least 10 evaluable subjects are available for a given dose. After the first interim 
analysis, the interim analysis can be conducted after every 10 additional subjects become 
evaluable. The evaluable subjects are defined as the subjects who have had the week 12 
PSA results or have progressed or died or permanently withdraw from the study.
For the separate interim looks in each combination in expansion cohort, the enrolment for 
that cohort may be stopped due to futility if the predictive probability that the expected 
utility (dU) >CSMU (20) is small (e.g., less than a 4% chance for the expected utility to 
be larger than the CSMU). At the final analysis for each dose combination, the dose will 
be claimed positive if the posterior probability that the expected utility (dU) >CSMU (20)
is at least 20%.  
No formal hypotheses are set up to compare the activity between the two dose levels. The 
difference of response rate and R between two dose levels within the same combination 
will be reported. 
The maximum utility dose which is defined as the dose with the highest probability of 
having the largest utility relative to other doses in the same arm will be recommended as 


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RP2D for each combination, respectively. The details of the utility function calculations 
will be discussed in RAP. This calculation is for guidance only, the final decision of 
RP2D will be based on totally of data.
Revised text: 
Dose escalation
With respect to the primary objectives and endpoints, no specific statistical hypotheses 
are being tested. The primary focus will be on determining the recommended dose for 
further exploration, based upon the safety, PK and efficacy profiles of GSK2879552
GSK525762 plus abiraterone or enzalutamide azacitidine in subjects with 
CRPCadvanced cancer.
Dose expansion cohorts
The goal of the trial is to characterize the dose-response curve for both efficacy and 
safety and to identify whether there is a dose of GSK525762 with an acceptable 
combination of response rateefficacy and safety.
The primary efficacy endpoint is defined as the clinically meaningful response rate (% of 
subjects achieving PSA reduction from baseline ≥50%) at 12 weeks and/or thereafter for 
the subjects treated at each dose level….
… The response rate and dose modification rate will be jointly assessed using a utility 
function. For each dose expansion cohort the utility (dU) will be calculated and used for 
decision making at each interim analysis and final analysis. At the end of each arm, the 
dose with the highest probability of having the largest utility relative to other doses 
clinically significant utility score may be picked as the RP2D. The totality of the data will 
be used to assess which dose will be picked as the RP2D. Further details of the 
calculation of utility function will be provided in RAP….
The interim analysis will be conducted for each individual dose and it may be conducted 
when at least 10 evaluable subjects are available for a given dose. After the first interim 
analysis, the interim analysis can be conducted after every 10 additional subjects become 
evaluable. The evaluable subjects are defined as the subjects who have had the week 12 
or later PSA results or have progressed (per PSA result) or died or permanently 
discontinuedwithdraw from the study treatment.
For the separate interim looks in each combination in expansion cohort, the enrolment for 
that cohort may be stopped due to futility if the predictiveposterior probability that the 
expected utility (dU) >CSMU (2025) is small (e.g., less than a 4% chance for the 
expected utility to be larger than the CSMU). The totality of the data including 
safety/tolerability and primary and secondary efficacy endpoints will be used to decide 
whether to stop enrolment within a cohort at an interim analysis. At the final analysis for 
each dose combination, the dose will be claimed positive if the posterior probability that 
the expected utility (dU) >CSMU (2520) is at least 20%.  However, determination of 
whether to pursue future development of GSK525762 plus abiraterone or enzalutamide 
will be based on the totality of the data including safety/tolerability, PK, PD and all 
efficacy endpoints.


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No formal hypotheses are set up to compare the activity between the two dose levels. The 
difference of PSA response rate, composite response rate and DCR through 24 weeks and 
R between two dose levels within the same combination will be reported. 
The maximum utility dose which is defined as the dose with the highest probability of 
having the largest utility relative to other dosesclinically significant utility in the same 
arm will be recommended as RP2D for each combination, respectively. The details of the 
utility function calculations will be discussed in RAP. This calculation is for guidance 
only, the final decision of RP2D will be based on totallytotality of data.
Section 9.3.1. – Analysis Populations 
Rationale for Change: 
Clarifications of the analysis populations. 
Previous text: 
The All Treated Safety Population is defined as all subjects who receive at least one 
dose of GSK525762 or abiraterone or enzalutamide. Safety and anti-cancer activity will 
be evaluated based on this analysis population.
The All Clinical Activity Treated Population is defined as all subjects who receive at 
least one dose of GSK525762 plus abiraterone/enzalutamide. Safety and anti-cancer 
activity will be evaluated based on this analysis population. 
All Evaluable Subjects will be defined as the study population used for decision-making 
at the interim futility analysis. Subjects who have at least two post-baseline radiological 
disease assessments or have had Week 12 visit PSA test results or have progressed or 
died or permanently withdrew from the study will be included in this population.
Revised text: 
The All Treated Safety Population is defined as all subjects who receive at least one
dose of GSK525762 or abiraterone or enzalutamide. Safety and anti-cancer activity will 
be evaluated based on this analysis population.
The Modified All Clinical Activity Treated Population is defined as all subjects who 
receive at least one dose of GSK525762 plus abiraterone/enzalutamide. Safety and anti-
cancer activity will be evaluated based on this analysis population if different from the 
All Treated Population.
All Evaluable Subjects will be defined as the study population used for decision-making 
at the interim futility analysis. Subjects who have at least two post-baseline radiological 
disease assessments or have had Week 12 or later visit PSA testdisease assessment results 
or have progressed according to the guidelines described in Section 7.6.1 or died or 
permanently withdrew from the study treatment will be included in this population.
Section 9.3.2.2.1. – Efficacy Anayses 
Rationale for Change: 
Revision to language for consistency with remainder of protocol and clarifications on 
decision criteria for Interim Analyses.


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Previous text: 
Interim analysis will be conducted for each DL separately. Interim data will be evaluated 
to monitor efficacy and safety, and a planned interim analysis will  be performed when 10 
evaluable subjects are available at any DL. Enrollment may be stopped early in any of the 
expansion cohorts for toxicity or lack of efficacy, should various criteria occur based on 
accrued data. The decision criteria for early stop for futility based on Bayesian 
probability are described in Section 9.1.2.
Revised text: 
Interim analysis will be conducted for each DL separately. Interim data will be evaluated 
to monitor efficacy and safety, and a planned interim analysis will may be performed 
when at least 10 evaluable subjects are available at any DL. Enrollment may be stopped 
early in any of the expansion cohorts for toxicity or lack of efficacy, should various 
criteria occur based on accrued data. The decision criteria for earlyto stop enrolment 
within a cohort for futility based on Bayesian probability are described in Section 
9.1.2.will be based on the totality of the data including safety/tolerability and evaluation 
of primary and secondary efficacy endpoints.
Section 9.4.1.2. – Adverse Events 
Rationale for Change: 
Clarification to language.
Previous text: 
… Dose-limiting toxicities (DLTs) will be listed for Phase I subjects and summarized by 
dose cohort according to International Data Standards Library (IDSL) standards. …. 
Revised text: 
… Dose-limiting toxicities (DLTs) will be listed for Phase Idose escalation subjects and 
summarized by dose cohort. according to International Data Standards Library (IDSL) 
standards…. 
Section 9.4.4. – Efficacy Analyses 
Rationale for Change: 
Addition of Secondary Efficacy Endpoint and clarifications to other definitions. Only 
definitions updated are presented. 
Previous text: 
The following secondary responses will also be considered for drawing conclusions on 
the clinical activity of the combination(s): 
Duration of PSA response 
Duration of PSA response is calculated from the time the PSA value first declines by at 
least 50% of the Cycle 1 Day 1 (baseline) value (must be confirmed by a second value) 
until the time there is an increase of 25% of PSA nadir, provided the absolute increase is 
at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement 
that is at least 25% above the nadir. If the PSA never shows a 25% increase over the 
nadir value, then the patient will be assessed at the last PSA measurement. Duration of 


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PSA response will be summarised by the median and presented along its 95% confidence 
interval.
ORR
The overall response (ORR) rate is defined as the percentage of subjects with a confirmed 
complete response (CR) or a partial response (PR) at any time as per PCWG3-modified 
RECIST 1.1 (Appendix 5). Subjects with unknown or missing response will be treated as 
non-responders, i.e. these subjects will be included in the denominator when calculating 
the percentage. The number and types of responses, as outlined in PCWG3-modified 
RECIST 1.1, will be listed and summarized separately, as appropriate. The observed 
ORR, observed confirmed and unconfirmed ORR will be reported at the interim and final 
analysis for each cohort specified in treated dose, if data warrant. The estimates along 
with 95% exact confidence interval (CI) will be provided.
CTC Response 
CTC response rate is defined as the proportion of subjects with a CTC conversion to 
<5/7.5 mL blood at nadir (confirmed by a second consecutive value obtained four or 
more weeks later) will be presented along an exact two-sided 95% confidence interval. 
Waterfall plots of maximum CTC falls will also be presented that show the percentage 
change in CTC counts from baseline. The CTC response need to be confirmed by a 
second consecutive value obtained four or more weeks later.
Time to disease progression is according to PCWG3 criteria (either by PCWG3-modified 
RECIST 1.1, PSA progression, and/or progression in bone).
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. If data 
warrant, OS will be summarized by cohort and dose level specified in Phase I using 
Kaplan-Meier quantile estimates along with 2-sided 95% CIs at the time of end of Phase 
1 interim analysis.
Revised text: 
The following secondary responses will also be considered for drawing conclusions on 
the clinical activity of the combination(s): 
Disease Control Rate at 24 weeks 
Disease control rate (DCR) is defined as the percentage of subjects with SD, PR or CR at 
≥ 24 weeks. Subjects with unknown or missing response will be treated as non-
responders (i.e. these subjects will be included in the denominator when calculating the 
percentage).
Duration of PSA response 
Duration of PSA response is calculated from the time the PSA value first declines by at 
least 50% of the WeekCycle 1 Day 1 (baseline) value (must be confirmed by a second 
value) until the time there is an increase of 25% of PSA nadir, provided the absolute 
increase is at least 2 ng/mL. The increase must be confirmed by a second consecutive 
measurement that is at least 25% above the nadir. If the PSA never shows a 25% increase 


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over the nadir value, then the patient will be assessedcensored at the last PSA 
measurement. Duration of PSA response will be summarised by the median and 
presented along its 95% confidence interval.
ORR
The overall objective response (ORR) rate is defined as the percentage of subjects with a 
confirmed complete response (CR) or a partial response (PR) at any time as per PCWG3-
modified RECIST 1.1 (Appendix 5). Subjects with unknown or missing response will be 
treated as non-responders, i.e. these subjects will be included in the denominator when 
calculating the percentage. The number and types of responses, as outlined in PCWG3-
modified RECIST 1.1, will be listed and summarized separately, as appropriate. The 
analysis of ORR will only be performed for subjects with measurable disease only. The 
observed ORR, observed confirmed and unconfirmed ORR will be reported at the interim 
and final analysis for each cohort specified in treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided.
CTC Response 
CTC response rate is defined as the proportion of subjects with a CTC conversion to 
<5/7.5 mL blood at nadir (confirmed by a second consecutive value obtained four or 
more weeks later) will be presented along an exact two-sided 95% confidence interval. 
Subjects with CTC<5/7.5 mL at baseline will be excluded from this analysis. Waterfall 
plots of maximum CTC falls will also be presented that show the percentage change in 
CTC counts from baseline. The CTC response need to be confirmed by a second 
consecutive value obtained four or more weeks later.
Time to disease progression
Time to disease progression is defined as time from first dose date of study treatment to 
disease progression according to defined as one or more of the following criteria:

Radiographic progression by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG3 criteria (Section 7.6.3).

PSA progression according to the PCWG3 criteria (Section 7.6.2) accompanied 
by any of the following: investigator-defined clinical progression or either of the 
above RECIST 1.1 or bone progression.
PCWG3 criteria (either by PCWG3-modified RECIST 1.1, PSA progression, and/or 
progression in bone). Subjects without disease progression at the time of analysis will be 
censored at the earlier date of last PSA assessment and last radiological 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. If data 
warrant, OS will be summarized by armcohort and dose level specified in Phase I using 
Kaplan-Meier quantile estimates along with 2-sided 95% CIs at the time of end of Phase 
1 interim analysis.


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Appendix 2: – Management of Suspected Toxicity 
Rationale for Change: 
Removal and revision of QTc language per updated guidance by internal safety review 
panel.
Previous text: 
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
If >30msec and < 60 
msec change from 
baseline AND manual 
QTcF <500 (average of 
three ECGs over at 
least 15 minutes)
Continue current dose of GSK525762

Evaluation by cardiologist

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.


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If 60 msec change 
from baseline occurs
OR
QTcF 500 
(average of three ECGs 
over at least 15 
minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Supplement electrolytes to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.
This subject may consider restarting study treatment at 
one dose level reduced if all of the following criteria for 
QTcF re-challenge are met. 
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged.
If approval for re-challenge is granted, the subject must be 
re-consented (with a separate informed consent specific to 
QTc prolongation)
(1) QTcF reduced to <4850 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 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 
required by IRB (or equivalent), and
(6)
The subject is re-consented regarding the 
possible increased risk of 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 until ≤30 msec 
change from baseline reached, 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


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Revised text: 
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
If >30msec and < 60 
msec change from 
baseline AND manual 
QTcF <500 (average of 
three ECGs over at 
least 15 minutes)
Continue current dose of GSK525762

Evaluation by cardiologist

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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.


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If 60 msec change 
from baseline occurs
ANDOR QTcF 500 
msec
OR 
QTcF≥530 msec AND 
<60 msec change from 
baseline occurs
(average of three ECGs 
over at least 15 
minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Evaluation by cardiologist

Supplement electrolytes to recommended levels:
a. Maintain serum potassium > 4mol/L
b. 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 24-hour telemetry monitoring if clinically 
indicated.
This subject may consider restarting study treatment at 
one dose level reduced if all of the following criteria for 
QTcF re-challenge are met. 
In France, if stopping criteria is met, subjects will not be 
allowed to restart or be rechallenged.
If approval for re-challenge is granted, the subject must be 
re-consented (with a separate informed consent specific to 
QTc prolongation)
(1) QTcF reduced to <4850 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 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 
required by IRB (or equivalent), and
(6)
The subject is re-consented regarding the 
possible increased risk of 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 until ≤30 msec 
change from baseline reached, 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


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Appendix 8: – Definition of and Procedures for Recording, Evaluating, Follow-Up 
and Reporting of Adverse Events 
Rationale for Change: 
Removal of language regarding protocol specific SAEs to clarify all SAEs are followed 
until resolution. 
Previous text: 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
h.
Protocol-specific SAEs (events of special interest):
LVEF decreases (Section 5.4.3) meeting stopping criteria
Liver chemistry abnormalities meeting stopping criteria (Section 5.4.1)
QTcF prolongation meeting stopping criteria (Section 5.4.2)
New primary cancers
Revised text:  
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
i.
Protocol-specific SAEs (events of special interest):
LVEF decreases (Section 5.4.3) meeting stopping criteria
Liver chemistry abnormalities meeting stopping criteria (Section 5.4.1)
QTcF prolongation meeting stopping criteria (Section 5.4.2)
New primary cancers
Appendix 12: Modified List of Highly Effective Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information Contraception 
Guidance and Collection of Pregnancy Information
Rationale for Change: 
Revision to language based on update of GSK template language. 
Previous text: 
12.12.1. Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
The list does not apply to male subjects with partners of FRP who are and will continue 
to be abstinent from penile-vaginal intercourse on a long term and persistent basis, when 
this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, ovulation, 


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symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable)
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 4 month after the last dose of study medication.
1. 
Sterilization with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s: review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
2. 
Male condom plus partner use of intrauterine device or intrauterine system. 
Note: Hormonal methods of contraception for female partners of FRP are not permitted 
since the efficacy of these methods in combination with GSK525762 has not been 
assessed. Hormone-releasing IUDs are a permitted form of contraception. LHRH-acting 
agents alone are not considered an adequate form of contraception.   
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.12.2.  Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 24 weeks of learning of the partner’s pregnancy 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
Revised text: 
12.12.1. Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
The list does not apply to male subjects with partners of FRP who are and will continue 
to be abstinent from penile-vaginal intercourse on a long term and persistent basis, when 
this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception.


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Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable)
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until 4 month after the last dose of study medication.
1. 
Sterilization with documentation of azoospermia. The documentation on male 
sterility can come from the site personnel’s: review of subject’s medical records, 
medical examination and/or semen analysis, or medical history interview.
2. 
Male condom plus partner use of intrauterine device or intrauterine system. 
Note: Hormonal methods of contraception for female partners of FRP are not permitted 
since the efficacy of these methods in combination with GSK525762 has not been 
assessed. Hormone-releasing IUDs are a permitted form of contraception. LHRH-acting 
agents alone are not considered an adequate form of contraception.   
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.12.1.  Contraception Guidance
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:

Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationc

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)c

Bilateral tubal occlusion

Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence 
of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days.

Highly Effective Methodsb That Are User Dependent

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc
oral
intravaginal
transdermal
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable

Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as 


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refraining from heterosexual intercourse during the entire period of risk associated with 
the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when 
used consistently and correctly.
c.
Male condoms must be used in addition to hormonal contraception If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this 
study. Male condom and female condom should not be used together (due to risk of failure with friction)
12.12.2.  Collection of Pregnancy Information

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 24 hours weeks of learning of the partner’s pregnancy 

Female pPartner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
Other changes to provide additional clarifications or to correct inadvertent 
errors in previous versions of the protocol:
Title Page: 
Updated author list to include new authors: 
, 
and remove 
 and 
 
Sponsor Signatory: 
Replacement of Li Yan with Michael Streit as signatory. Revision of Table of Contents to 
reflect changes protocol addressed earlier in this Appendix. 
Sponsor contact information: 
Addition of 
 as primary medical monitor and movement of 
 
to secondary medical monitor; removal of 
. 
References: 
Updated reference of the GSK525762 Investigator’s Brochure to current version.
Reference to Lee, 2008 removed.
List of Abbreviations: 
Addition of new abbreviations to table: DCR – Disease Control Rate
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Protocol changes for Amendment 4 (06-May-2020) from Amendment 3 (12-
Jul-2018) 
Protocol Amendment 04 applies to all global site(s) participating in the conduct of 
the study
Amendment 04 summary:
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Changes to the protocol include:

Enrolment into the study is now closed

Removes the requirement for specific protocol assessments and survival follow-
up (Section 7.1 – Time and Events Tables)

Update to the GSK authors, GSK signatory and GSK medical monitor
List of Specific Changes
Title Page
Rationale for Change: Update to protocol author list
Revised text:
Author (s):
SPONSOR SIGNATORY
Rationale for Change: Update to sponsor signatory
Revised text:
Hesham A. Abdullah, MD, MSc, RAC 
Michael Streit, MD
SVP, Head of Clinical Development, OncologyClinical Development Lead, Oncology
PPD
PPD


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Rationale for Change: Update to Medical Monitor information
Revised text:
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time 
Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Site Address
Primary 
Medical 
Monitor 
 
 MD
GSK R&D, Gunnels Wood, 
Stevenage, Herts, SG1 2NY 
 GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
Section 1. PROTOCOL SYNOPSIS FOR STUDY 204697
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden.
Revised text:
Analysis
Last Paragraph
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. The study will conclude 
when the last subject has completed/discontinued study treatment and completed the end 
of treatment visit.
Section 4.3. Decision to Proceed to Expansion phase
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
PPD
PPD
PPD
PPD
PPD
PPD


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assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden.
Revised text:
First Paragraph
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Section 5.5. Subject and Study Completion
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden.
Revised text:
Last Paragraph
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Section 7.1. Time and Events Table
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden.
Revised text:
Table 7
Dose Escalation Time and Events
Procedure
SC
R
Lead
-In 
Dosi
ng (if 
requi
red)
Week 
1
Week 2
Week 3
Wee
k 4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 
to 
W49 
W49 
and 
there
after
Safety


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Procedure
SC
R
Lead
-In 
Dosi
ng (if 
requi
red)
Week 
1
Week 2
Week 3
Wee
k 4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 
to 
W49 
W49 
and 
there
after
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples12
P
K
PK
O
X
Tumor biopsy13
X
One sample, collected 3-
6h post-GSK525762 
dose, between W3D1 
and W5D1
X14
Whole blood for 
exploratory 
analyses14
X
X
X15
Q8w
ks 
up to 
six 
mont
hs, 
then 
Q12
wks
X
X
PGx blood sample15
X
Biomarker Assessments
CTC-ENU16
X
X
X
Q8w
ks 
up to 
six 
mont
hs, 
then 
Q12
wks
X
X
CTC – ARV17
X
Efficacy
Computerized 
Tomography (CT) 
chest/abdomen/pel
vis18
X
Q8w
ks 
up to
six 
mont
hs, 
then 
Q12
wks
X
X
MRI Brain19
X


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Procedure
SC
R
Lead
-In 
Dosi
ng (if 
requi
red)
Week 
1
Week 2
Week 3
Wee
k 4
We
ek 
5
q4w
q8w
q12w
EO
T1, 
22
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
W9 
to 
W49
W9 
to 
W49 
W49 
and 
there
after
Bone Scan20
X
Q8w
ks 
up to 
six 
mont
hs, 
then 
Q12
wks
X
EORTC-QLQ-C30, 
EORTC-QLQ-PR25 
& BPI-SF21
X
X
X
X
X
X
X
X
X
1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 
With the implementation of amendment 04, following the EOT visit, subjects will be no longer be 
contacted approximately every 3 months (± 14 days) to collect survival data. Following this visit, subjects 
will be contacted approximately every 3 months (14 days) to collect: survival status as of last date of contact 
and initiation of new anti-cancer therapy. Contact may be completed via a clinic visit, a telephone contact or an 
email.
9.   With the implementation of amendment 04, the PRO-CTCAE will no longer be collected.Patient Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 
1.0)
12. With the implementation of amendment 04, PK samples will no longer be collected. “PK” = serial PK days. 
Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 1h ± 10m, 3h ± 30m, 6 
to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose,
and an optional sample 4-12h post-dose. “X” = sample collections to be obtained pre-dose as well as 0.5-1h post-
dose (note that routine PK is no longer required once the subject has been on study for 26 weeks). PK samples 
will be split to obtain PK samples for abiraterone and enzalutamide. Abiraterone PK samples will be collected at 
all PK time points in Week 1 and Week 3 and only at pre-dose at remaining PK visits. Enzalutamide PK samples 
will be collected at pre-dose for all PK visits. Refer to the SRM for further details. For subjects in alternate dosing 
schedule, the Week 3 Day 1 extensive PK will need to occur between W2 Day 4 and W2 Day 7 prior to their 
scheduled dose interruption. For any PK timepoint, subjects should have received GS525762 for at least 7 days 
prior to their scheduled PK draws. This may require the subject to return earlier than any planned interruption of 
dosing. Once extensive PK sampling in Week 1 and Week 3 have been collected from at least 12 subjects for 
each dose and combination cohorts, PK sampling may be reduced for these visits.
13. With the implementation of amendment 04, on treatment and EOT tumor biopsies will no longer be 
collected.Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible 
to obtain a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and 
whole blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures and must have received at least 4 consecutive doses of GSK525762 
prior to the collection of the tissue. If the on-therapy biopsy is not performed during the defined timeline due to lab 
abnormalities or subject status, it should be performed after subject recovery and the next visit as agreed upon 
with the medical monitor. Refer to the SRM for further details.
14. With the implementation of amendment 04, whole blood for exploratory analyses will no longer be 
collected.A tumor biopsy at the end of treatment is optional.


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15. With the implementation of amendment 04, if a PGx sample has not yet been collected, collection will no 
longer be required Whole blood for exploratory analysis at this time point should be collected as close to tumor 
biopsy collection.
16. With the implementation of amendment 04, CTC-ENU whole blood samples will no longer be collected.
CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening (collected within 7 days prior 
to treatment), pre-dose on W1D1 of the combination treatment period, W5D1, W9D1 and every 8 weeks for the 
first 6 months and thereafter every 12 weeks; and EOT.
17. With the implementation of amendment 04, CTC-ARV whole blood samples will no longer be collected.
CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1.Based on emerging 
data, GSK may decide to discontinue the collection of these samples.
18. With the implementation of amendment 04, contrast-enhanced tomography (CT) scan data will no longer 
be required. Disease assessment should be managed according to local standard of care. CT should be 
performed with oral and intravenous (IV) contrast. CT required at screening. Any potential CR or PR should be 
confirmed as described in Appendix 5. Assessments will occur every 8 weeks (7 days) for the first 6 months and 
thereafter every 12 weeks (7 days) in the Treatment Continuation Period, or as clinically indicated, and at the 
time of disease progression. EOT disease assessment is not required if reason for discontinuing therapy was 
progressive disease and prior radiographic assessment was within 14 days of EOT visit. Subjects with 
contraindication to contrast-enhanced CT may have other imaging performed as described in Section 7.2.1.
19. With the implementation of amendment 04, MRI scan data will no longer be required. Disease assessment 
should be managed according to local standard of care.Magnetic resonance imaging (MRI) of the brain 
required at screening and then as clinically indicated thereafter.
20. With the implementation of amendment 04, bone scan data will no longer be required. Disease 
assessment should be managed according to local standard of care.Bone Scan: A bone scan is required for 
all subjects at Screening. For subjects without bone disease at baseline, subsequent bone scans should be 
performed as clinically indicated. Subjects with bone metastases at baseline should have a bone scan performed 
at Week 9, then every 8 weeks (7 days) for the first 6 months and thereafter every 12 weeks (7 days) in the 
Treatment Continuation Period, or as clinically indicated, and at the time of disease progression. If a subject 
discontinues treatment for reasons other than disease progression, bone scans should continue every 3 months 
until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
21. With the implementation of amendment 04, quality of life questionnaires will no longer be 
collected.European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
(QLQ) Core-30, EORTC-QLQ-PR25, for evaluating prostate cancer, and Brief Pain Inventory- Short Form (BPI-
SF).
Table 8
Dose Escalation Time and Events, Laboratory Assessments
SC
R
Week 1
Week 2
Week 3
We
ek 4
We
ek 5
We
ek 6
q2
w
q4
w
q4w
q12w
EO
T
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
D
1
W
7 
an
d 
11
W9 
to 
W4
9
W49 
and 
thereaf
ter
W49 
and 
thereaf
ter
PSA
2
X
X
X
X
X2
X
X
2.
With the implementation of amendment 04, samples for PSA will no longer be collected. Disease 
assessment should be managed according to local standard of care.Local labs can be used to collect 
this information.


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Table 9
Dose Expansion Time and Events
Procedure
S
C
R
Lead-
In 
Dosin
g (if 
requir
ed)
Wee
k 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
q4w
q8w
q12w
EOT1, 22
D1
D
1
D
1
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
thereaft
er
Safety
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood 
samples12
PK
PK
O
X
Tumor biopsy13
X
One sample, 
collected 3-6h post-
GSK525762 dose, 
between W3D1 and 
W5D1
X14
Whole blood for 
exploratory 
analyses14
X
X
X15
Q8wk
s up 
to six 
month
s, 
then 
Q12w
ks
X
X
PGx blood 
sample15
X
Biomarker Assessments
CTC-ENU16
X
X
X
Q8wk
s up 
to six 
month
s, 
then 
Q12w
ks
X
X
CTC – ARV17
X
Efficacy
CT 
chest/abdomen/p
elvis18
X
Q8wk
s up 
to six 
month
s, 
then 
Q12w
ks
X
X
MRI Brain19
X


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Procedure
S
C
R
Lead-
In 
Dosin
g (if 
requir
ed)
Wee
k 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
q4w
q8w
q12w
EOT1, 22
D1
D
1
D
1
D
1
D
1
W9 
to 
W49
W9 to 
W49
W49 
and 
thereaft
er
Bone Scan20
X
Q8wk
s up 
to six 
month
s, 
then 
Q12w
ks
X
EORTC-QLQ-
C30, EORTC-
QLQ-PR25 & 
BPI21
X
X
X
X
X
X
X
X
X
1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 
With the implementation of amendment 04, following the EOT visit, subjects will be no longer be 
contacted approximately every 3 months (± 14 days) to collect survival data. Following this visit, subjects 
will be contacted approximately every 3 months (14 days) to collect: survival status as of last date of contact 
and initiation of new anti-cancer therapy. Contact may be completed via a clinic visit, a telephone contact or an 
email.
9.    With the implementation of amendment 04, the PRO-CTCAE will no longer be collected.Patient Reported 
Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 
1.0)
12. With the implementation of amendment 04, PK sample will no longer be collected.“PK” = serial PK days. 
Sample collections should be obtained at the following timepoints: Pre-dose, 30m ± 5m, 1h ± 10m, 3h ± 30m, 6 
to 12 hours and 24 h± 2h but prior to dosing. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, 
and an optional sample 4-12h post-dose. “X” = sample collections to be obtained pre-dose as well as 0.5-1h post-
dose (note that routine PK is no longer required once the subject has been on study for 26 weeks). PK samples 
will be split to obtain a PK sample for all time points for Week 1 and Week 3 and only pre-dose for other visits for 
abiraterone and only for the pre-dose sample for enzalutamide and its active major metabolite analysis. Refer to 
the SRM for further details. For subjects in alternate dosing schedule, the Week 3 Day 1 extensive PK will need to 
occur between W2 Day 4 and W2 Day 7 prior to their scheduled dose interruption. For any PK timepoint, subjects 
should have received GS525762 for at least 7 days prior to their scheduled PK draws. This may require the 
subject to return earlier than any planned interruption of dosing. Once extensive PK sampling in Week 1 and 
Week 3 have been collected from at least 12 subjects for each dose and combination cohorts, PK sampling may 
be reduced for these visits.
13. With the implementation of amendment 04, on treatment and EOT tumor biopsies will no longer be 
collected.Paired fresh biopsies must be provided pre- and post-dose at time points indicated. If it is not feasible 
to obtain a fresh biopsy, an archival sample must be provided. Fresh biopsies should be paired with plasma and 
whole blood samples for PK and circulating biomarkers collected as close as possible to biopsy (ideally within 
1h). Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are WNL within 48 hours 
prior to the post-dose biopsy procedures and must have received at least 4 consecutive doses of GSK525762 
prior to the collection of the tissue. If the on-therapy biopsy is not performed during the defined timeline due to lab 
abnormalities or subject status, it should be performed after subject recovery and the next visit as agreed upon 
with the medical monitor. Refer to the SRM for further details.
14. A tumor biopsy at the end of treatment is optional.
1415.
With the implementation of amendment 04, whole blood for exploratory analyses will no longer be 
collected.Whole blood for exploratory analysis at this time point should be collected as close to tumor biopsy 
collection.


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15. With the implementation of amendment 04, if a PGx sample has not yet been collected, collection will no 
longer be required
16. With the implementation of amendment 04, CTC-ENU whole blood samples will no longer be collected.
CTC-ENU: Whole blood samples will be obtained for CTC enumeration at Screening (collected within 7 days prior 
to start of treatment), pre-dose on W1D1of the combination treatment period, W5D1, W9D1 and every 8 weeks for 
the first 6 months and thereafter every 12 weeks; and EOT.
17. With the implementation of amendment 04, CTC-ARV whole blood samples will no longer be collected.
CTC-ARV: Whole blood samples will be obtained for measuring AR-Vs at pre-dose on W1D1. Based on emerging 
data, GSK may decide to discontinue the collection of these samples.
18. With the implementation of amendment 04, contrast-enhanced tomography (CT) scan data will no longer 
be required. Disease assessment should be managed according to local standard of care.CT should be 
performed with oral and intravenous (IV) contrast. CT required at screening. Any potential CR or PR should be 
confirmed as described in Appendix 5. Assessments will occur every 8 weeks (7 days) for the first 6 months and 
thereafter every 12 weeks (7 days) in the Treatment Continuation Period, or as clinically indicated, and at the 
time of disease progression. EOT disease assessment is not required if reason for discontinuing therapy was 
progressive disease and prior radiographic assessment was within 14 days of EOT visit. Subjects with 
contraindication to contrast-enhanced computed tomography (CT) may have other imaging performed as 
described in Section 7.2.1.
19. With the implementation of amendment 04, MRI scan data will no longer be required. Disease assessment 
should be managed according to local standard of care. Magnetic resonance imaging (MRI) of the brain 
required at screening and then as clinically indicated thereafter.
20. With the implementation of amendment 04, bone scan data will no longer be required. Disease 
assessment should be managed according to local standard of care. Bone Scan: A bone scan is required for 
all subjects at Screening. For subjects without bone disease at baseline, subsequent bone scans should be 
performed as clinically indicated. Subjects with bone metastases at baseline should have a bone scan performed 
at Week 9, then every 8 weeks (7 days) for the first 6 months and thereafter every 12 weeks (7 days) in the 
Treatment Continuation Period, or as clinically indicated, and at the time of disease progression. If a subject 
discontinues treatment for reasons other than disease progression, bone scans should continue every 3 months 
until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
21. With the implementation of amendment 04, quality of life questionnaires will no longer be collected.
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) 
Core-30, EORTC-QLQ-PR25, for evaluating prostate cancer, and Brief Pain Inventory-Short Form (BPI-SF).
Table 10
Dose Expansion Time and Events, Laboratory Assessments
S
C
R
We
ek 
1
We
ek 
2
We
ek 
3
Wee
k 4
We
ek 
5
Week 
6
q2w
q4w
q4w
q12w
EOT
D
1
D
1
D
1
D
1
D
1
D1
W7 
and 
11
W9 to 
W49
W49 
and 
ther
eafte
r
W49 
and 
therea
fter
PSA2
X
X
X
X
X2
X
X
1.
With the implementation of amendment 04, samples for PSA will no longer be collected. 
Disease assessment should be managed according to local standard of care Local labs can 
be used to collect this information.
Section 7.2.2. Visit Windows
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden.


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Revised text:
First Paragraph
With the implementation of amendment 04, specific assessments and collection of 
survival follow-up data will no longer be required. Please see Section 7.1 for further 
details. 
Paragraph 8, First Sentence
Every 4-week and 8-week visits after Week 9 until Week 49: After the first disease 
assessment has been completed, then the clinic visits can be scheduled 75 days.
Section 7.3.4.1. Electrocardiograms
Rationale for Change: Specific assessments, for purposes of the study, are being 
removed. Transfer of data to a central reader, for purposes of the study, is no longer 
required.
Revised text:
Last Paragraph, Last Sentence
With the implementation of amendment 04, transfer of ECG data to a central facility is no 
longer required.
Section 7.3.4.2. Echocardiogram or Multigated Acquisition Scan
Rationale for Change: Specific assessments, for purposes of the study, are being 
removed. Transfer of data to a central reader, for purposes of the study, is no longer 
required.
Revised text:
Last Paragraph, Last Sentence
With the implementation of amendment 04, transfer of scan data for independent 
cardiologist review is no longer required.
Section 7.4. Pharmacokinetics
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, PK samples will no longer be collected.


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Section 7.5. Pharmacodynamics
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, tumor samples will no longer be collected.
Section 7.6. Evaluation of Anti-Cancer Activity
Rationale for Change: Specific assessments, for purposes of the study, are being 
removed. Transfer of data to a central reader, for purposes of the study, is no longer 
required.
Revised text:
First Paragraph
With the implementation of amendment 04, CT, MRI, and Bone scan data will no 
longer be required for disease assessment, and samples for PSA ad CTC-ENU will 
no longer be collected. See the Time and Events Table (Section 7.1) for the updated 
schedule of assessments. Disease assessment should be managed according to local 
standard of care.
Section 7.6.3. Radiographic Response per PCWG3 Criteria
Rationale for Change: Specific assessments, for purposes of the study, are being 
removed. Transfer of data to a central reader, for purposes of the study, is no longer 
required.
Revised text:
Paragraph 2
With the implementation of amendment 04, transfer of scans to a central facility is no 
longer required.
Section 7.7.2. Tumor Tissue
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, tumor samples will no longer be collected.


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Section 7.7.3. Circulating Tumor Cells
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, blood samples for CTC enumeration will no 
longer be collected.
Section 7.7.4. Circulating-Free Tumor DNA/RNA and Soluble Markers
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, blood samples for cfDNA and soluble 
markers will no longer be collected.
Section 7.8.
Genetics
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, if a subject has consented for PGx research 
but the sample has yet to be collected, this will no longer be required.
Section 7.9.1. PRO-CTCAE
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.
Revised text:
First Sentence
With the implementation of amendment 04, the PRO-CTCAE will no longer be 
completed.
Section 7.9.2. EORTC-QLQ-C30, EORTC-QLQ-PR25 & Brief Pain Inventory –
Short Form (BPI-SF)
Rationale for Change: Specific assessments that are no longer required, due to the status 
of the study, are being removed to minimize patient burden.


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Revised text:
First Sentence
With the implementation of amendment 04, the quality of life questionnaires will no 
longer be completed.
Section 9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES
Rationale for Change: These changes are based on the decision to close out the study 
and stop all new enrolment as the study met protocol defined interim futility. Specific 
assessments that are no longer required, due to the status of the study, are being removed 
to minimize patient burden. Any changes to the planned analyses for the study will be 
addressed in the Reporting Analysis Plan (RAP).
Revised text:
Amendment 04 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment as the study met protocol defined 
interim futility. With the implementation of amendment 04, specific assessments and 
collection of survival follow-up data will no longer be required. Please see Section 7.1 for 
further details. The study will conclude when the last subject has completed/discontinued 
study treatment and completed the end of treatment visit.
Any changes to the planned analyses outlined below will be covered in the Reporting and 
Analysis Plan (RAP).

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204697 
 
1 
 
Division 
: Worldwide Oncology Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a phase IB open-label, 
dose escalation and expansion study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK525762 in combination with androgen 
deprivation therapy and other agents in subjects with 
castrate-resistant prostate cancer (CRPC). 
Compound Number  : GSK525762 
Effective Date  
: 22-JUNE-2020 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the primary Clinical Study Report for Protocol 204697 
• 
This RAP is intended to describe the planned safety, pharmacokinetics and 
efficacy analyses required for the interim analysis. 
• 
This RAP will be provided to the study team members to convey the content of 
dose escalation, data reviews and interim analyses deliverables as well as the 
Statistical Analysis Complete (SAC) content. 
 
RAP Author(s): 
 
Date 
 
15-JUNE-2020 
Senior Biostatistician, Biostatistics FSP, PAREXEL employee 
on behalf of GlaxoSmithKline  
 
 
 
 
 
 
 
 
 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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RAP Team Reviewers: 
Approver 
Date 
Approval 
Method 
 
15-JUNE-2020 
Mail 
Clinical Scientist, Oncology Clinical 
Development 
 
18-JUNE-2020 
Mail 
Director, Clinical Pharmacology Modelling and 
Simulation, GSK 
 
15-JUNE-2020 
Mail 
Study Delivery Lead, Global Clinical Sciences 
& Delivery, GSK 
 
15-JUNE-2020 
Mail 
Medical Director, Oncology Clinical 
Development 
 
19-JUNE-2020 
Mail 
Principal Programmer, Biostatistics, GSK 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval 
Method 
 
- - 
 
Senior Statistics Director, Biostatistics, GSK 
 
- - 
 
Director, Clinical Programming, Biostatistics, 
GSK 
 
 
 
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TABLE OF CONTENTS 
Page 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design ................................................................................................ 8 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 12 
2.4.1. 
Dose escalation ........................................................................... 12 
2.4.2. 
Dose expansion cohorts .............................................................. 13 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Interim Analyses ......................................................................................... 15 
3.1.1. 
Dose Escalation Phase ................................................................ 15 
3.1.1.1. 
Displays To Be Created For Dose Escalation 
Review ....................................................................... 16 
3.1.2. 
Dose Expansion Phase ................................................................ 17 
3.1.2.1. 
Displays for dose expansion Interim Analyses ............ 18 
3.2. 
Final Analyses ............................................................................................ 19 
4. 
ANALYSIS POPULATIONS ................................................................................... 19 
4.1. 
Protocol Deviations ..................................................................................... 20 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 21 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 21 
5.2. 
Reporting Conventions ............................................................................... 21 
5.3. 
Baseline Definitions .................................................................................... 22 
5.3.1. 
Change from baseline .................................................................. 23 
5.3.2. 
Multiple Assessments .................................................................. 23 
5.4. 
Multicentre Studies ..................................................................................... 24 
5.5. 
Examination of Subgroups .......................................................................... 24 
5.5.1. 
Covariates and Other Strata ........................................................ 24 
5.5.2. 
Examination of Subgroups ........................................................... 24 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 24 
6. 
STUDY POPULATION ANALYSES ....................................................................... 26 
6.1. 
Overview of Planned Study Population Analyses ........................................ 26 
6.2. 
Disposition of Subjects ................................................................................ 26 
6.3. 
Protocol Deviations ..................................................................................... 26 
6.4. 
Demographic and Baseline Characteristics ................................................. 26 
6.5. 
Concomitant Medications ............................................................................ 27 
7. 
EFFICACY ANALYSES .......................................................................................... 28 
7.1. 
Primary Efficacy Analyses .......................................................................... 28 
7.1.1. 
PSA Response Rate (RR) ........................................................... 28 
7.1.2. 
Summary Measures ..................................................................... 28 
7.1.3. 
Population of Interest ................................................................... 28 
7.1.4. 
Statistical Analyses / Methods ..................................................... 28 
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7.2. 
Secondary Efficacy Analyses ...................................................................... 29 
7.2.1. 
Endpoint / Variables ..................................................................... 29 
7.2.1.1. 
Disease Control Rate at 24 weeks (DCR) ................... 29 
7.2.1.2. 
Time to Disease Progression ...................................... 29 
7.2.1.3. 
Objective Response Rate (ORR) ................................ 29 
7.2.1.4. 
Circulating Tumour Cells (CTC) Response ................. 29 
7.2.1.5. 
Composite Response Rate (CRR) .............................. 30 
7.2.1.6. 
PSA Week 4 Response Rate (Week4 RR) ................. 30 
7.2.1.7. 
Radiographic Progression-free survival (rPFS) ........... 30 
7.2.2. 
Summary Measure ...................................................................... 30 
7.2.2.1. 
Disease Control Rate (DCR) ...................................... 30 
7.2.2.2. 
Time to Disease Progression ...................................... 31 
7.2.2.3. 
Objective Response Rate (ORR) ................................ 31 
7.2.2.4. 
Circulating Tumour Cells (CTC) Response ................. 31 
7.2.2.5. 
Composite Response Rate (CRR) .............................. 31 
7.2.2.6. 
PSA Week 4 Response Rate (PSA Week4 RR) ......... 31 
7.2.2.7. 
Radiographic Progression-free survival (rPFS) ........... 32 
7.2.3. 
Population of Interest ................................................................... 36 
7.2.4. 
Statistical Analyses / Methods ..................................................... 36 
8. 
SAFETY ANALYSES ............................................................................................. 37 
8.1. 
Adverse Events (AE) Analyses ................................................................... 37 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 38 
8.3. 
Deaths and Serious Adverse Events ........................................................... 39 
8.4. 
Adverse Events Leading to Discontinuation of Study Treatment and 
Other Significant Adverse Events ............................................................... 40 
8.5. 
Extent of Exposure ..................................................................................... 40 
8.6. 
Clinical Laboratory Analyses ....................................................................... 41 
8.6.1. 
Analyses of Liver Function Tests ................................................. 43 
8.7. 
Other Safety Analyses ................................................................................ 43 
8.7.1. 
Vital Signs .................................................................................... 43 
8.7.2. 
Performance Status ..................................................................... 44 
8.7.3. 
ECG ............................................................................................. 44 
8.7.4. 
LVEF ........................................................................................... 45 
8.7.5. 
Liver Events ................................................................................. 45 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 46 
9.1. 
Pharmacokinetic Analyses .......................................................................... 46 
9.1.1. 
Endpoint / Variables ..................................................................... 46 
9.1.1.1. 
Drug Concentration Measures .................................... 46 
9.1.1.2. 
Derived Pharmacokinetic Parameters......................... 46 
9.1.2. 
Summary Measure ...................................................................... 47 
9.1.3. 
Population of Interest ................................................................... 47 
10. PHARMACODYNAMIC ANALYSIS ........................................................................ 48 
11. OTHER STATISTICAL ANALYSES ....................................................................... 49 
11.1. 
Value Evidence and Outcomes ................................................................... 49 
11.1.1. 
EORTC-QLQ-C30 ........................................................................ 49 
11.1.2. 
EORTC-QLQ-PR25 ..................................................................... 49 
11.1.3. 
BPI-SF ......................................................................................... 50 
11.1.4. 
PRO-CTCAE ............................................................................... 50 
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12. REFERENCES ....................................................................................................... 51 
13. APPENDICES ........................................................................................................ 52 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 52 
13.1.1. 
Exclusions from Per Protocol Population ..................................... 52 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 53 
13.2.1. 
Protocol Defined Schedule of Events ........................................... 53 
13.3. 
Appendix 3: Assessment Windows ............................................................. 54 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 54 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 55 
13.4.1. 
Study Phases .............................................................................. 55 
13.4.2. 
Treatment States ......................................................................... 55 
13.4.2.1. Treatment States for Disease Response Data ............ 55 
13.4.3. 
Treatment Emergent Flag for Adverse Events ............................. 56 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 57 
13.5.1. 
Reporting Process ....................................................................... 57 
13.5.2. 
Reporting Standards .................................................................... 57 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 58 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 59 
13.6.1. 
General ........................................................................................ 59 
13.6.2. 
Study Population .......................................................................... 60 
13.6.3. 
Efficacy ........................................................................................ 60 
13.6.4. 
Safety .......................................................................................... 61 
13.6.5. 
Pharmacokinetic .......................................................................... 62 
13.6.6. 
Value Evidence and Outcomes .................................................... 62 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 67 
13.7.1. 
Premature Withdrawals ................................................................ 67 
13.7.2. 
Handling of Missing Data ............................................................. 67 
13.7.2.1. Handling of Missing and Partial Dates ........................ 67 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 71 
13.8.1. 
Laboratory Values ........................................................................ 71 
13.8.2. 
ECG ............................................................................................. 71 
13.8.3. 
Vital Signs .................................................................................... 72 
13.8.4. 
Left Ventricular Ejection Fraction ................................................. 72 
13.9. 
Appendix 9: Abbreviations & Trade Marks .................................................. 73 
13.9.1. 
Abbreviations ............................................................................... 73 
13.9.2. 
Trademarks ................................................................................. 75 
13.10. Appendix 10: List of Data Displays.............................................................. 76 
13.10.1. Data Display Numbering .............................................................. 76 
13.10.2. Mock Example Shell Referencing ................................................ 76 
13.10.3. Deliverables ................................................................................. 76 
13.10.4. Study Population Tables .............................................................. 77 
13.10.5. Efficacy Tables ............................................................................ 82 
13.10.6. Efficacy Figures ........................................................................... 85 
13.10.7. Safety Tables ............................................................................... 87 
13.10.8. Pharmacokinetic Tables ............................................................... 87 
13.10.9. Pharmacokinetic Figures ............................................................. 87 
13.10.10. ICH Listings ................................................................................. 87 
13.10.11. Non-ICH Listings .......................................................................... 87 
13.11. Appendix 11: Example Mock Shells for Data Displays ................................ 87 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 204697 
Revision Chronology: 
Original 
13-OCT-2016 
2015N238310_00 
Amendment No. 1 
01-FEB-2017 
2015N238310_01 
Amendment No. 2 
08-FEB-2018 
2015N238310_02 
Amendment No. 3 
12-JUL-2018 
2015N238310_03 
Amendment No. 4 
06-MAY-2020 
2015N238310_04 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
There are no changes to the protocol defined statistical analysis as per the latest protocol 
amendment. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives  
Endpoints 
Co-Primary (Both Arms) 
Co-Primary Endpoints 
• 
To determine the safety and 
tolerability of GSK525762, when given 
in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in 
men with castration-resistant prostate 
cancer (CRPC) 
• 
For both arms, adverse events (AEs), serious adverse 
events (SAEs), dose reductions or delays, withdrawals 
due to toxicities and changes in safety assessments 
(e.g., laboratory parameters, vital signs, 
electrocardiogram (ECG), cardiotoxicity, 
gastrointestinal, etc.) 
• 
To determine clinical activity and 
recommend Phase 2 dose (RP2D) of 
GSK525762, when given in 
combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in 
men with CRPC 
• 
For both arms, primary response rate (RR) is defined 
as the percent of subjects achieving PSA50 at 12 
weeks or thereafter (PSA50 is ≥50% decrease in 
prostate-specific antigen [PSA] from baseline) 
Secondary (Both Arms) 
Secondary Endpoints 
• 
To characterize the pharmacokinetics 
(PK) or exposure of GSK525762 and 
selected metabolites, when given in 
combination with abiraterone or 
enzalutamide, in men with (metastatic 
Castration-Resistant Prostate Cancer) 
CRPC 
• 
PK parameter or concentration values for GSK525762 
and selected metabolites following repeat-dose oral 
administration in combination with abiraterone or 
enzalutamide 
• 
To characterize the PK or exposure of 
abiraterone or enzalutamide, when 
given in combination with 
GSK525762, in men with CRPC 
• 
PK parameter or concentration values for abiraterone 
or enzalutamide following repeat-dose oral 
administration in combination with GSK525762 
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Objectives  
Endpoints 
• 
To evaluate additional measures of 
clinical activity in subjects with CRPC 
• 
For both arms, clinical activity evaluated by Disease 
control rate (DCR) through 24 weeks 
• 
Composite response rate (CRR) based on any of the 
following – a) Response based on Prostate Cancer 
Working Group (PCWG3)-modified Response 
Evaluation Criteria In Solid Tumours (RECIST) 1.1, b) 
PSA decrease of ≥50% at week 12 and thereafter, or 
c) circulating tumour cells CTC count conversion 
• 
Objective Response Rate (ORR) defined as complete 
response (CR) and partial response (PR) rate per 
PCWG3-modified (RECIST) 1.1 
• 
Circulating Tumor Cells (CTC) response rate defined 
as percent of subjects having favourable 
(CTC<5/7.5mL) at nadir, if baseline is unfavourable 
CTC≥5/7.5mL  
• 
PSA week 4 response rate defined as percent of 
subjects achieving ≥30% decrease from baseline PSA 
after 4 weeks of study treatment 
• 
Time to disease progression according to PCWG3 
criteria (either by PCWG3-modified RECIST 1.1 or 
progression in bone or PSA progression with 
accompanying progression by RECIST 1.1 or bone 
scan or clinical progression) 
• 
Radiological progression free survival (rPFS) per 
PCWG3-modified RECIST 1.1 
• 
To evaluate the effect of treatment 
with GSK525762 and abiraterone or 
enzalutamide, when given in 
combination, on patient-related 
outcomes 
• 
Performance status, pain scores, quality of life 
Exploratory (Both Arms) 
Exploratory Endpoints 
• 
To evaluate the exposure response 
(pharmacokinetic/pharmacodynamics 
[PK/PD]) relationship between 
GSK525762 and abiraterone or 
enzalutamide and safety and efficacy 
parameters 
• 
Exploratory analysis between exposure parameters, 
change from baseline levels in PD markers and safety 
and/or efficacy parameters 
• 
To characterize the 
pharmacodynamics of GSK525762 
and abiraterone or enzalutamide, 
when given in combination 
• 
Transcriptomic and/or protein changes in molecular 
markers of (Bromodomain and ExtraTerminal) BET 
inhibition and (Androgen Receptor) AR signalling in 
tumour tissue 
• 
To evaluate the effect of treatment 
with GSK525762 and abiraterone or 
enzalutamide, when given in 
combination, on other measures of 
efficacy 
• 
Overall survival (OS) over duration of study; Number of 
subjects with reduction in CTC of at least 30% 
• 
To identify potential indicators of 
sensitivity or response to GSK525762 
and abiraterone or enzalutamide, 
when given in combination 
• 
Correlate baseline tumour genomic deoxyribonucleic 
acid (DNA), protein and/or transcription ribonucleic 
acid (RNA) profiles with response. Correlate circulating 
biomarkers (e.g. AR-V7) with response 
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Objectives  
Endpoints 
• 
To describe the kinetics of tumour 
growth in the presence of GSK525762 
for each treatment and investigate the 
relationship between tumour growth 
kinetics and clinical activity 
• 
Tumour size or PSA levels over time, tumour growth 
rate constants, and time to tumour growth (TTG) 
predicted with the model parameters and relationship 
with clinical activity parameters. 
 
2.3. 
Study Design 
Overview of Study Design and Key Features 
 
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Overview of Study Design and Key Features 
 
Design 
Features 
• 
This study is a two arm open-label Phase IB dose escalation and dose expansion 
study with oral administration of GSK525762 in combination with either abiraterone 
(Arm A) or enzalutamide (Arm B) in male subjects with CRPC in whom at least one 
line of treatment with abiraterone or enzalutamide has failed. 
• 
This study is designed to determine the maximum tolerated dose (MTD) and RP2D 
based on safety, tolerability, pharmacokinetic and efficacy profiles. Arm A is 
designed to determine the MTD and RP2D of GSK525762 when given in 
combination with abiraterone, based upon safety and clinical response profiles. Arm 
B is designed to determine the MTD and RP2D of GSK525762 when given in 
combination with enzalutamide, based upon safety and clinical response profiles. 
• 
During dose escalation, treatment arms will follow a modified toxicity probability 
interval (mTPI) design which assumes (i) approximately 3 to 6 subjects per dose 
cohort will complete the dose limiting toxicity (DLT) evaluation period and (ii) the 
true underlying toxicity rate for GSK525762 in combination with either abiraterone 
or enzalutamide falls within the range from 25% to 35% and centred at 30%. 
Subjects included in the study must have progressed, despite previous treatment 
with abiraterone and/or enzalutamide (L2 or Lx). Subjects will be enrolled based 
upon their more recent prior treatment (e.g. subjects who were most recently 
treated with abiraterone will be enrolled into Arm A, and subjects most recently 
treated with enzalutamide will be enrolled into Arm B). 
• 
During dose expansion, the study will employ a Bayesian predictive adaptive design 
that allows the trial to be monitored more frequently at multiple stages based on the 
utility score of the dose. The first interim analysis will be conducted for each 
individual dose and it may be conducted when at least 10 evaluable subjects are 
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Overview of Study Design and Key Features 
available for a given dose. After the first interim analysis, interim analyses can be 
conducted after every 10 additional subjects become evaluable. 
 
Arm A 
• 
In Arm A, eligible subjects with CRPC will be enrolled into two dosing level cohorts 
to determine the MTDs (and RP2D) of GSK525762 when administered in 
combination with abiraterone. Eligible subjects include those that are abiraterone-
refractory or resistant from second line as well as third line and above (including L2 
or Lx chemo-naïve or chemo-treated), but the most recent treatment before 
enrolment into Arm A must be abiraterone. 
• 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The approved 
dose of abiraterone (1000 mg) will be used for all GSK525762 dose level 
exploration. The initial GSK525762 dose level will be dose level 60 mg (DL60), 
which is one dose level lower than the single-agent RP2D. If DL60 does not exceed 
the MTD, DL80 (GSK525762 given 80 mg QD) will be opened. If any dose level 
cohort is opened but exceeds the maximum permitted toxicity rate, then additional 
subjects will not be enrolled at that dose level. 
• 
Once dose escalation phase and dose selection are complete, a total of 30 subjects 
each may be enrolled into both selected dose expansion cohorts, including dose 
escalation subjects, and approximately 10 enrolled subjects will be L2 and 20 
subjects will be Lx. 
 
Arm B 
• 
In Arm B, eligible subjects with CRPC will be enrolled into dosing level cohorts to 
determine the MTDs (and RP2D) of GSK525762 when administered in combination 
with enzalutamide. Eligible subjects include those that are enzalutamide-refractory 
or resistant from second line as well as third line and above (including L2 or Lx), but 
the most recent treatment before enrolment into Arm B must be enzalutamide. 
• 
During dose escalation, eligible subjects will be dosed in at least two dose levels to 
identify the two dose level cohorts to explore in dose expansion. The initial 
GSK525762 dose level will be dose level 80 mg (DL80), which is equivalent to one 
dose level lower than the single-agent RP2D due to expected Drug Drug Interaction 
(DDI). If DL80 does not exceed the MTD, dose level 100 mg (DL100) (GSK525762 
given 100 mg QD) will be opened. If any dose level cohort is opened but exceeds 
the maximum permitted toxicity rate, then additional subjects will not be enrolled at 
that dose level.  
• 
Once dose escalation phase and dose selection are complete, a total of 30 subjects 
each may be enrolled into both each selected dose expansion cohorts, including the 
dose escalation subjects, and approximately 10 enrolled subjects will be L2 and 20 
subjects will be Lx. 
Dosing 
Dose Escalation: 
• 
For Arm A, projected dose levels of GSK525762 are 60 mg and 80 mg administered 
once daily. Due to emerging data (safety/efficacy), additional dose levels may be 
explored. These dose levels may either be a lower daily dose level or an 
intermittent dose schedule, either at a dose level where daily treatment may be 
intolerable or at a lower dose. For example, if DL60 exceeds the maximum 
permitted toxicity rate, then an alternate/intermittent dosing at 60mg dose level 
(DL60 ALT) and/or a lower daily dose level (DL-1, 40 mg) may be evaluated. 
• 
For Arm A, for subjects receiving GSK525762 in combination with abiraterone, daily 
administration of combination therapy (GSK525762 and abiraterone) will commence 
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Overview of Study Design and Key Features 
immediately (Day 1) for abiraterone-failed subjects who are still on abiraterone (i.e. 
not stopped abiraterone dosing at progression and during screening). However, if 
these subjects are off abiraterone treatment for more than 3 days at time of 
assignment to a cohort, there would be a lead in period for at least 7 days of 
abiraterone. (Day -7 to Day 0) before the start of combination treatment 
(GSK525762 and abiraterone). The lead-in dosing will ensure that abiraterone is at 
steady state upon initiation of GSK525762 treatment. Based on emerging 
information collected from PK, PD and safety/tolerability data, other dosing 
regimens (such as twice daily (BID) dosing for both drugs or intermittent dosing for 
GSK525762 or staggered dosing of the two drugs) may be explored during the 
study. 
• 
For Arm B, projected dose levels of GSK525762 are 80 mg and 100 mg 
administered once daily. A dose of 120 mg may be evaluated in combination with 
enzalutamide based on emerging PK and safety data. Due to emerging data 
(safety/tolerability/efficacy), additional dose levels may be explored. These dose 
levels may either be a lower daily dose level or an intermittent dose level, either at 
dose level where daily treatment may be intolerable or at a lower dose. For 
example, if DL80 exceeds the maximum permitted toxicity rate, then an 
alternate/intermittent dosing at 80 mg dose level (DL80 ALT) and/or a lower daily 
dose level (DL-1, 60 mg) may be evaluated. Based on PK analysis from DL80 and 
DL100 dose escalation cohorts, if the exposure to GSK525762 active moiety is 40% 
lower than its single agent exposure (determined from GSK525762 80 mg cohort in 
BET115521 study), DL120 (120 mg Dose Level) may be opened. The study team 
will carefully review PK and safety data from the DL80 and DL100 dose levels to 
determine if it is acceptable to open the DL120 dose level. If DL120 is opened. 
Subjects in DL120 will begin dosing with GSK525762 at 120 mg and the approved 
dose of enzalutamide. 
• 
For Arm B, for subjects receiving GSK525762 in combination with enzalutamide, 
daily administration of combination therapy (GSK525762 and enzalutamide) will 
commence immediately (Day 1) for enzalutamide -failed subjects who are still on 
enzalutamide (i.e. not stopped enzalutamide dosing at progression and during 
screening). However, if these subjects are off enzalutamide treatment for more than 
7 days at the time of assignment to a cohort, there would be a lead in period for at 
least 28 days of enzalutamide. (Day -28 to Day 0) before the start of combination 
treatment (GSK525762 and enzalutamide). There will be a 14-day lead in period 
(Day -14 to Day 0) if enzalutamide interruption was less than or equal to 7 days 
prior to start of combination treatment (Day 1). The lead-in dosing will ensure that 
enzalutamide is at steady state upon initiation of GSK525762 treatment. Based 
upon emerging data, additional subjects may be enrolled above, at, or below the 
combination doses, in order to collect additional safety and PK data. 
• 
Dose levels of abiraterone and enzalutamide are as approved 1000 mg and 160 mg 
respectively, administered once daily. No doses will be explored beyond 1000 mg 
abiraterone or 160 mg enzalutamide, these doses are considered to be the 
Maximum Feasible Dose (MFD), unless emerging PK data demonstrate reduced 
exposure of either drug in combination compared to single agent. As determined 
from pre-clinical studies, the maximum clinical dose of GSK525762 will not exceed 
200 mg. Any GSK525762 dose above 120 mg would require regulatory authority 
review and approval. 
 
Dose Expansion:  
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Overview of Study Design and Key Features 
• 
For both Arms, it is anticipated that the two most tolerable dose level combinations 
per arm will be carried forward into expansion cohorts. If data warrants, only one 
dose level combination may be carried into dose expansion 
Time & 
Events 
• 
Refer to Section 13.2 (Appendix 2: Schedule of Activities) 
Treatment 
Assignment 
• 
Subjects will be assigned to receive GSK525762 and abiraterone/enzalutamide in 
an open-label fashion. 
• 
This study will consist of dose escalation and dose expansion cohorts. An mTPI 
design will be followed during dose escalation to establish safe DLs to move to 
dose expansion. During dose expansion, subjects who have failed prior 
abiraterone/enzalutamide-treatment both as L2 as well as Lx will be enrolled to 
either of the following arms: 
o Forced randomization of subjects that are abiraterone-refractory or 
resistant from L2 and Lx to the two most tolerable dose level cohorts 
with 1/3 of the subjects from L2 and 2/3 of the subjects from Lx: 
GSK525762+abiraterone/prednisone (Arm A). 
o Forced randomization of subjects that are enzalutamide-refractory or 
resistant from L2 and Lx to the two most tolerable dose level cohorts 
with approximately 1/3 of the subjects from L2 and 2/3 of the subjects 
from Lx: - GSK525762 at RP2D+enzalutamide (Arm B). 
Interim 
Analysis 
Dose escalation data reviews: 
• 
For each dose level, once 3 to 6 subjects have been enrolled at each dose level for 
each arm, an interim data review will be performed to determine if dose-escalation, 
dose de-escalation and/or dose expansion is appropriate. The primary driver for the 
dose escalation decisions will be safety and tolerability of each dose level cohort. 
 
Dose Expansion interim analyses: 
• 
Interim analysis will be conducted for each DL separately. Interim data will be 
evaluated to monitor efficacy and safety, and a planned interim analysis may be 
performed when at least 10 evaluable subjects are available at any DL.  
After the first interim analysis, the interim analysis can be conducted after every 10 
additional subjects become evaluable i.e., have had the week 12 PSA results or 
have progressed or died or permanently withdrawn from the study treatment. 
• 
Enrolment may be stopped early in any of the expansion cohorts for toxicity or lack 
of efficacy. 
Final 
Analysis 
• 
The study will be considered completed for purposes of a final analysis when 70% 
of all the subjects enrolled have progressed or died. Survival follow-up will continue 
until this 70% event is met. 
• 
Data from the dose escalation and expansion cohort will be combined as 
appropriate. 
2.4. 
Statistical Hypotheses / Statistical Analyses 
2.4.1. 
Dose escalation 
For dose escalation, no formal statistical hypotheses will be tested. Decisions on 
determining the recommended dose for further exploration will be based upon safety, PK 
and efficacy profiles of GSK525762 plus abiraterone or enzalutamide in subjects with 
CRPC. 
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2.4.2. 
Dose expansion cohorts 
For dose expansion, the efficacy endpoint is defined as the response rate (% of subjects 
achieving PSA reduction from baseline ≥50%) at 12 weeks and/or thereafter for the 
subjects treated at each dose level. A response rate of 30% or greater is desired while 10% 
represents a response rate that is clinically unacceptable. 
The critical safety endpoint for evaluation in this trial is the percentage of subjects at dose 
level d who had dose modification due to drug related AEs. The dose modification rate R 
is a weighted average of the rate of different types of dose modifications: 
R=0.6R1+0.2R2+0.2R3, where R1 is the rate that subjects who withdrew from study 
treatment due to drug-related adverse events, R2 is the rate that subjects who had dose 
reductions due to drug-related adverse events, R3 is the rate that subjects who had dose 
interruptions due to drug-related adverse events. If a subject had more than one type of 
dose modifications, it will only be counted once in calculation of R and will be counted in 
the most severe modification category (withdrawal>reduction>interruption). With respect 
to dose modification rate R, a dose modification rate of 12% or greater represents a dose 
with unacceptable tolerability. If R is lower than 12%, a withdrawal rate higher than 10% 
also represents a dose with unacceptable tolerability.   
The response rate and dose modification rate will be jointly assessed using a utility 
function. For each dose expansion cohort, the utility (dU) will be calculated and used for 
decision making at each interim analysis and also at the final analysis. At the end of each 
arm, the dose with the highest probability of having clinically significant utility score may 
be picked as the RP2D.  The totality of the data will be used to assess which dose will be 
picked as the RP2D. 
The dose expansion cohort stage of the study will employ a Bayesian predictive adaptive 
design that allows the trial to be monitored more frequently at multiple stages. Bayesian 
statistics will be employed to calculate the expected dU is greater than the clinically 
significant minimum utility (CSMU) at interim for each dose.  
The first interim analysis will be conducted for each cohort and it may be conducted when 
at least 10 evaluable subjects are available for a given cohort. After the first interim 
analysis, the interim analyses may be conducted after every 10 additional subjects become 
evaluable. The evaluable subjects are defined as the subjects who have had the week 12 or 
later PSA results or have progressed (per PSA result) or died or permanently discontinued 
from the study treatment. 
For each interim futility analysis in each expansion cohort, the enrolment for that cohort 
may be stopped due to futility if the posterior probability that the dU > CSMU (25) is small 
(e.g. less than a 4% chance for the utility to be larger than the CSMU). The totality of the 
data including safety/tolerability and primary and secondary efficacy endpoints will be 
used to decide whether to stop enrolment within a cohort at an interim analysis. At the final 
analysis for each dose combination, the dose will be claimed positive if the posterior 
probability that the dU > CSMU (25) is at least 20%. However, determination of whether 
to pursue future development of GSK525762 plus abiraterone or enzalutamide will be 
based on the totality of the data including safety/tolerability, PK, PD and all efficacy 
endpoints. 
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No formal hypotheses are set up to compare the activity between dose levels. The 
difference of PSA RR, composite response rate and DCR through 24 weeks between two 
dose levels within the same combination will be reported. 
The maximum utility dose which is defined as the dose with the highest probability of 
having clinically significant utility in the same arm may be recommended as RP2D for 
each combination, respectively. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
Formal interim futility analyses will be performed based on a Bayesian adaptive design. 
Details are provided in Section 3.1.2 
3.1.1. 
Dose Escalation Phase 
Once 3 to 6 subjects have been enrolled at each dose level, a data review will be performed 
to determine if dose-escalation and/or dose expansion is appropriate. The primary driver 
for the dose escalation decisions will be safety and tolerability of each dose level cohort. 
The analysis will be based on Modified All Treated Population. 
The mTPI design rules together with the predicted dose-limiting toxicity rates at all dose 
levels will lead the decision to determine whether dose escalation and expansion will be 
continued as planned. The design assumes (i) Approximately 3-6 subjects will complete 
the DLT evaluation period and (ii) the true underlying toxicity rate for GSK525762 in 
combination with abiraterone and enzalutamide falls within the rage from 25% or 35% and 
centred at 30%. At DL60, 3 subjects will be enrolled. If no DLT is observed, proceed to 
next dose level. If one of the three evaluable subject experiences a DLT, then 3 additional 
subjects will be enrolled at that dose level. Evaluation of available safety data from at least 
6 subjects who have completed a minimum of 28 days (1 cycle) at the current highest safe 
dose level is required prior to expanding a cohort. 
The monitoring rules guiding dose escalation are provided below. Columns provide the 
numbers of subjects treated at the current dose level and rows provide the corresponding 
numbers of subjects experiencing toxicity. The entries of the table are dose-finding 
decisions (i.e E, S and D) representing escalating the dose (E), staying at the same dose (S) 
and de-escalating the dose (D). If the current dose is at the highest dose level and the 
decision is E, it indicates that the highest dose level is below MTD and the next subject(s) 
will be treated at the same dose level. In addition, decision U means that the current dose 
level is unacceptable because of high toxicity and should be excluded from the trial. For 
example, when one of three subject experiences toxicity, the decision can be located at row 
1 and column 3, which is S – to stay at the current dose level. Consequently, the next cohort 
of subjects will be treated at the same dose level currently being used. If zero of three 
subjects experience toxicity, the decision is at row 0 and column 3, which is E – escalate if 
there is higher available dose otherwise stop dose escalation if there are 6 evaluable 
subjects on the current dose. Thus, the next cohort of subjects will be treated at the next-
higher dose level. If three of three subjects experience toxicity, the decision is DU – to de-
escalate to the next-lower doe level and exclude the current dose from the trial, because the 
high toxicity level is unacceptable. 
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Figure 1 
Modified toxicity probability interval (mTPI) method dose finding 
rules 
 
The cohort may be expanded with up to 10 additional subjects to further evaluate safety, 
pharmacokinetic and tolerability before dose escalation or reduction decision is 
determined. 
3.1.1.1. 
Displays To Be Created For Dose Escalation Review 
Review of preliminary data will be performed after 3-10 subjects complete the DLT 
evaluation period of 28 days for each dosing level. 
For the first dose escalation meeting, spreadsheets containing relevant study data will be 
supplied by the study data manager. For dose escalation meetings after the first cohort, 
SDTM datasets will be uploaded and made available in Spotfire. Both GSK and PAREXEL 
personnel will have access to Spotfire and can view subject-level data in Spotfire. 
The PK samples will be analysed for GSK525762 and metabolite after more than three 
subjects are enrolled and PK samples obtained up to Week 3 Day 1. 
Prior to determining a dose for the next cohort, exploratory analyses may be conducted to 
assess the relationship of dose level with safety, PK, and pharmacodynamic parameters 
using all data from available cohorts. 
The GSK study team, in collaboration with study investigators and the PAREXEL study 
team, will review all relevant data to support: 
• 
whether the current dose had acceptable toxicity, and 
• 
the decision regarding the next dose level based on the totality of the data 
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For 
further 
details 
see 
230779 
Dose 
Escalation 
Plan 
20171102 
V1.0 
(230779_Dose_Escalation_Plan_20171102_V_1.0). 
3.1.2. 
Dose Expansion Phase 
Interim analyses for futility will be conducted for each expansion cohort when at least 10 
evaluable subjects are available for a given cohort. Additional interim futility analyses may 
be conducted after every 10 additional subjects become evaluable (refer to Section 4 for 
definition of evaluable subjects). Enrolment may be stopped early in any of the expansion 
cohorts for toxicity or lack of efficacy, using a utility function that is a combination of 
response rate and the dose modification rate. The decision to stop enrolment within a cohort 
for futility will be based on the totality of the data including safety/tolerability and 
evaluation of primary and secondary efficacy endpoints. 
Data from evaluable subjects treated in the dose escalation cohorts will be analysed 
together with expansion cohort subjects treated at the same dose and schedule in the same 
combination for futility analysis. 
The PSA response rate (RR) (see definition Section 7.1) and dose modification rate will be 
jointly assessed using a utility function. For each expansion cohort the dU will be 
calculated and used for decision making at each futility analysis. For each futility analysis 
in each expansion cohort, the enrolment for that cohort may be stopped due to futility if 
the posterior probability that the dU > CSMU (25) is small (less than a 4% chance for the 
utility to be larger than the CSMU). The totality of the data including safety/tolerability, 
primary and secondary efficacy endpoints will be used to decide whether to stop enrolment 
within a cohort at an interim analysis. The utility function mapping given safety and 
efficacy measures is given below: 
Figure 2 
Utility Function Mapping  
 
 
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Utility function is greater than 25 when RR is greater than 0.3 and safety (dose modification 
rate) is less than or equal to 0.12.  Since it is assumed that DLT rate 0.1, 0.3 and 0.4 will 
have dose modification rate R=0.05, 0.08 and 0.12 respectively the DLT rate can be used 
for safety and instead of using 0.12, we have used 0.4 for the DLT rate. Therefore, 
assuming independence of the safety and efficacy (RR) endpoints, we can calculate the 
posterior probability of the dU > CSMU (25) by: 
 
Posterior probability true DLT rate (𝑝1)  ≤ 0.4 multiplied by posterior probability true RR 
(𝑝2)> 0.3 for each dose level in the dose expansion phase.  
 
Posterior probabilities will be calculated using the following assumptions: 
Observed data: # 𝑜𝑓 𝐷𝐿𝑇𝑠 ~ 𝐵𝑖𝑛 (𝑛, 𝑝1) 
Prior distribution of 𝑝1: 𝑝1 ~ 𝐵𝑒𝑡𝑎 (0.0001, 0.0001) 
Posterior distribution of 𝑝1 given observed data:  
𝑝1|# 𝐷𝐿𝑇 ~ 𝐵𝑒𝑡𝑎(0.0001 + # 𝑜𝑓 𝐷𝐿𝑇𝑠, 0.0001 + 𝑛−# 𝑜𝑓 𝐷𝐿𝑇𝑠 ) 
 
Observed data: # 𝑜𝑓 𝑅𝑅𝑠 ~ 𝐵𝑖𝑛 (𝑛, 𝑝2) 
Prior distribution of 𝑝2: 𝑝2 ~ 𝐵𝑒𝑡𝑎 (0.0001, 0.0001) 
Posterior distribution of 𝑝2 given observed data:  
𝑝2|# 𝑅𝑅 ~ 𝐵𝑒𝑡𝑎(0.0001 + # 𝑜𝑓 𝑅𝑅𝑠, 0.0001 + 𝑛−# 𝑜𝑓 𝑅𝑅𝑠 ) 
 
• Posterior probability true DLT rate (𝑝1)  ≤ 0.4: Area under the 𝐵𝑒𝑡𝑎(0.0001 +
# 𝑜𝑓 𝐷𝐿𝑇𝑠, 0.0001 + 𝑛−# 𝑜𝑓 𝐷𝐿𝑇𝑠 ) curve, to the left of 0.4. 
• Posterior probability true RR (𝑝2) > 0.3: Area under the 𝐵𝑒𝑡𝑎(0.0001 +
# 𝑜𝑓 𝑅𝑅𝑠, 0.0001 + 𝑛−# 𝑜𝑓 𝑅𝑅𝑠 ) curve, to the right of 0.3. 
 
Multiplying these probabilities will give the posterior probability that the true dU > 25.  
 
Posterior probabilities for each endpoint (DLT, RR) will be summarised together with the 
utility by dose. 
3.1.2.1. 
Displays for dose expansion Interim Analyses 
The study population of Modified All Treated subjects will be used for efficacy analyses 
at interim. As subjects enrol at different times, not all subjects will have been on the study 
long enough to have single or multiple disease assessments.  
The Modified All Treated population will be used to produce subject disposition, study 
population, demographics and safety summaries, unless otherwise specified.  
RR is defined as the proportion of participants with a PSA reduction from baseline  50% 
is observed at 12 weeks or later (must be confirmed by a second value). 
Subjects with unknown or missing response will be treated as non-responders, i.e. these 
subjects will be included in the denominator when calculating the percentage. Summaries 
of confirmed response rate will be provided for the study team to compare study data to 
the stopping rules for futility. 
A listing of subject status and PSA response will be provided.  This listing will be sorted 
by date of first dose within a subject and will show whether each subject is ongoing with 
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study treatment, whether the subject is evaluable for the futility analysis, maximum PSA 
decline and PSA response. Another listing on subject best response will be provided that 
will include whether the subject had measurable disease at baseline, best radiological 
response and bone progression. 
PSA RR, DCR (confirmed), CRR (confirmed), ORR (confirmed and unconfirmed), CTC 
response rate, and Week 4 PSA response rate will be summarised along with 95% exact 
confidence interval. 
Safety outputs will be generated for the interim analysis with summaries of exposure to 
GSK525762 and enzalutamide, summaries of adverse events and serious adverse events by 
system organ class and preferred terms as well as. Summaries of any drug-related, 
GSK525762-related and enzalutamide-related adverse events and summary of adverse 
events of special interest will also be presented.  
Data from both dose escalation and the expansion cohorts will be reported by arm and L2 
vs. Lx (cf. definition Section 5.5.1) subgroups when appropriate. A full list of displays can 
be found in Appendix 10. 
3.2. 
Final Analyses 
Final analysis is planned when the last subject enrolled has had the opportunity to be 
followed for 6 months in order to allow for maturity of 24 week DCR endpoint maturity. 
Data from the dose escalation and expansion cohort will be combined as appropriate and 
reported by study dose for each arm and L2 vs. Lx (see definition on Section 5.5.1) 
subgroups when appropriate. 
The final analysis will be performed after all required database cleaning activities have 
been completed and final database release (DBR) and database freeze (DBF) has been 
declared by Data Management. As final analysis will be performed at a time when some 
patients may still be on follow-up and more data may become available at the time of 
study closure an amendement to this RAP will be performed if needed allowing for a re-
run of the analysis described below. 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screened 
Population 
• 
Subjects who consent to participate in the trial 
• 
Screen failures 
All Treated 
Population  
• 
All subjects who receive at least one dose of 
GSK525762 or abiraterone or enzalutamide. 
• 
Safety 
• 
Anti-cancer activity 
• 
Study population 
Modified All 
Treated Population 
• 
All subjects who receive at least one dose of 
GSK525762 plus abiraterone or enzalutamide. 
• 
Efficacy 
• 
Safety (if different 
from the All Treated 
population.) 
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Population 
Definition / Criteria 
Analyses Evaluated 
• 
Anti-cancer activity (if 
different from the All 
Treated population.) 
• 
Value Evidence 
Outcomes 
All Evaluable 
Population 
• 
All subjects who have had Week 12 or later visit 
disease assessment results or have progressed 
or died or permanently withdrew from the study 
treatment will be included in this population. 
• 
Dose escalation 
Phase only 
PK Population 
• 
All subjects from the Modified All Treated Safety 
Population for whom a PK sample is obtained 
and analysed. 
• 
PK analysis 
NOTES: Please refer to Appendix 10: List of Data Displays which details the population to be used for each 
display being generated. 
4.1. 
Protocol Deviations 
Major protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be summarised 
and all protocol deviations will be listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Specifications developed by PAREXEL. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the electronic case report form (eCRF). As there is no Per-Protocol Population 
for this study, protocol deviations will not be used to determine membership in any 
particular study population for this study. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Data will be listed and summarised according to the GSK reporting standards, where 
applicable. Data will be listed and summarised mostly by dose levels and by each study 
part and/or combined (wherever applicable).   
5.1. 
Study Treatment & Sub-group Display Descriptors 
Data will be summarised and listed according to GSK reporting standards, as applicable. 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
Clinical Data Interchange Standards Consortium (CDISC) and GSK Data Display 
Standards terminology. Tables, figures and listings will be displayed by treatment doses. 
Actual study treatment doses will depend on the outcome of the dose escalation phase but 
will follow the same format. Subgroups described in Section 5.5.1 may also be used in 
summaries. 
Treatment Group Descriptions 
IRT System 
Data Displays for Reporting  
Description 
Treatment Label 
Order in TLF  
Arm A 
A DL 1 60mg 
GSK762 60mg + Abi 1000mg 
1 
A DL 1 60mg ALT 
GSK762 60mg Alt + Abi 1000mg 
2 
A DL -1 40mg 
GSK762 40mg + Abi 1000mg 
3 
Arm B 
B DL 1 80mg 
GSK762 80mg + Enza 160mg 
4 
B DL-1 60mg 
GSK762 60mg + Enza 160mg 
5 
B DL-1 60mg ALT 
GSK762 60mg Alt + Enza 160mg 
6 
NOTES: Order represents treatments being presented in TFL, as appropriate. 
5.2. 
Reporting Conventions 
• 
Unless otherwise specified, the denominator in percentage calculation at each 
scheduled visit will be based on the number of subjects with non-missing value at each 
visit. 
• 
All data are reported per the dose/regimen initially received by the subject.  
• 
Unless stated otherwise, descriptive summaries will include n, mean, standard 
deviation, median, minimum and maximum for continuous variables and n and percent 
for categorical variables. Display minimum and maximum in the same precision as 
data was collected, mean and median using 1 additional decimal place, and standard 
deviation using 2 additional decimal places. 
• 
At a minimum, data will be listed by treatment group, centre ID, and subject ID. 
• 
Planned times relative to investigational product dosing will be used in all summary 
tables and figures unless otherwise specified. 
• 
Unscheduled visits will be included in the listing using actual time and will be used in 
deriving the maximum or minimum value over time (e.g. worst-case value post dose).  
However, unscheduled visits will not be included in summaries by planned time. 
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• 
Actual, rather than planned, sampling times will be used in the derivation of PK 
parameters and in the individual concentration-time plots.  Planned times will be used 
in the descriptive summaries and in mean and median plots. Listings of PK 
concentration-time data will be done by actual sampling times relative to dosing time. 
• 
No formal assessment windows will be defined for the purpose of classifying 
measurements obtained outside of scheduled assessment times. 
• 
This is a multicentre study.  Data from all study sites will be integrated and no 
controlling for centre-effect will be considered in the statistical analyses. 
• 
Analyses are to be performed using the SAS System, Version 9.4 or higher.  Programs 
will be imported into HARP and the final output will be produced by running drivers 
in HARP. Some graphics may be produced using the TSCG (Tibco Spotfire Clinical 
Graphics) - comprising of S-Plus (R) 7.0.6 or higher.   
• 
Deviations from the analyses in the RAP will be identified in the final clinical study 
report (CSR). 
5.3. 
Baseline Definitions 
For all endpoints, baseline will be defined as the most recent (latest), non-missing 
assessment time-point prior to the first study treatment dose. 
For enrolled subjects who did not receive study treatment during the study, baseline will 
be defined as the latest non-missing assessment time-point providing analysable data. 
For laboratory data, baseline will be defined as the most recent, non-missing value from a 
central laboratory prior to the first study treatment dose. If there are no central labs 
collected for a subject, the most recent, non-missing value from a local laboratory prior to 
the first dose of study treatment will be defined as the baseline value. 
For ECG analyses, the baseline value will be represented by the mean of the triplicate of 
the most recent (latest) assessment time-point prior to the first study treatment dose if 
available. If Fridericia’s QT Interval Corrected for Heart Rate (QTcF) results are not 
available at baseline, then the mean of the screening triplicate QTcF results will be used.  
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Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
*Average of triplicate assessments to be used if available. 
5.3.1. 
Change from baseline 
For records occurring after baseline change from baseline is calculated as: (visit value) – 
baseline value. 
For records occurring after baseline percent change from baseline is calculated as: ((change 
from baseline) / baseline value) * 100 
If either the baseline or visit value is missing, the change from baseline and/or percent 
change from baseline is set to missing. 
5.3.2. 
Multiple Assessments 
All data will be reported according to the nominal visit date for which it was reported (that 
is, no visit windows will be applied during dataset creation). Unscheduled data will only 
be included in the display sections that report worst- case post-baseline. For summaries 
that collapse data across multiple planned time intervals, select the mean data at each 
collapsed interval.  
With the exceptions of ECG and echocardiogram (ECHO/MUGA) assessments, if multiple 
assessments of the same type were performed on different days but reported for the same 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in Data 
Display 
Screening 
Day 1 (Pre-Dose) 
Efficacy 
PSA 
X 
X 
Latest up to Day 1 
CT  
X 
 
Latest up to Screening 
MRI 
X 
 
Latest up to Screening 
Bone scan 
X 
 
Latest up to Screening 
CTC 
X 
X 
Latest up to Day 1 
Safety 
Laboratory 
X 
X 
Latest up to Day 1 
Performance Status 
X 
X 
Latest up to Day 1 
Vital Signs  
X 
X 
Latest up to Day 1 
ECG* (QTc) 
X 
X 
Latest up to Day 1 
ECHO/MUGA 
(LVEF, 
…) 
X 
 
Latest up to Screening 
Liver Events 
X 
X 
Latest up to Day 1 
PRO-CTCAE 
X 
X 
Latest up to Day 1 
Value Evidence Outcomes 
EORTC-QLQ-C30 
X 
X 
Latest up to Day 1 
EORTC-QLQ-PR25 
X 
X 
Latest up to Day 1 
BPI-SF 
X 
X 
Latest up to Day 1 
PRO-CTCAE 
X 
X 
Latest up to Day 1 
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scheduled assessment, then the worst-case assessment for that scheduled assessment will 
be analysed. 
With the exceptions of laboratory, ECG, and ECHO/MUGA assessments if multiple 
assessments of the same type are reported on the same date for the same scheduled planned 
time, then the mean of multiple measurements reported for the same date will be analysed. 
When data could be reported from both central and local laboratories and if laboratory data 
is reported from both central and local laboratories with the same date, then the central 
laboratory data will be analysed to provide consistency with measurements from other 
subjects. As a general rule for ECG and ECHO/MUGA only the post-baseline assessments 
that used the same method (i.e. Electrocardiogram ECHO or Multiple Grated Acquisition 
MUGA) and the same source (i.e. local or central cardiologist read) as the baseline 
assessments will be used to derive the change from baseline, data from the two sources will 
not be combined. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings.  
5.4. 
Multicentre Studies 
Data from all participating centres will be pooled prior to analysis. It is anticipated that 
subject accrual will be spread thinly across centres and summaries of data by centre would 
be unlikely to be informative and will not, therefore, be provided. 
5.5. 
Examination of Subgroups 
5.5.1. 
Covariates and Other Strata 
No covariate-adjusted or stratified analyses are planned for this study. 
5.5.2. 
Examination of Subgroups 
Subject subgroups to be included in analysis and reporting may be represented by prior line 
of therapy L2 (failed first line treatment with or without one prior line of chemotherapy) 
versus Lx (on re-treatment after failure of multiple lines of therapy including prior 
ADT/prior chemotherapy/prior radiation therapy) for efficacy and safety outputs for both 
arms. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.5 
Appendix 5: Data Display Standards & Handling Conventions 
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Section 
Component 
13.6 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.8 
Appendix 8: Values of Potential Clinical Importance 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Treated population, unless 
otherwise specified. Study population summaries will include descriptive summaries and 
data listings of subject disposition, protocol deviations, demographic and baseline 
characteristics, prior and concomitant medications, prior and concomitant anti-cancer 
therapies based on GSK Core Data Standards. Details of the planned displays are presented 
in Appendix 10: List of Data Displays. 
6.2. 
Disposition of Subjects 
A summary of the number and percentage of subjects in each of the analysis populations 
(described in Section 4) and numbers and percentages of exclusions from each population 
will be provided. A listing of subjects excluded from analysis populations will also be 
provided, and both a summary and a listing of subject screening status and reasons for 
screen failure will be provided. A listing of run-in failures will also be provided. 
A summary of study treatment status will be provided. This display will show the number 
and percentage of subjects who are ongoing or discontinued study treatment and a summary 
of the primary reasons for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF. A listing of 
study treatment discontinuation will be generated. The listing will include last dose date, 
and reasons for study treatment discontinuation 
A summary of subject status and reason for study withdrawal will be provided. This display 
will show the number and percentage of subjects who completed the study and those 
withdrew from the study, including primary reasons for study withdrawal. Reasons for 
study withdrawal will be presented in the order they are displayed in the eCRF. A listing 
of reasons for study withdrawal will also be included.  
6.3. 
Protocol Deviations 
Only major protocol deviations will be summarised, whereas all protocol deviations 
(regardless of the categorisation) will be listed including inclusion/exclusion deviations as 
well as other deviations. Protocol deviations will be classified as ‘major’ and ‘minor’ based 
on Protocol Deviation Specifications. 
6.4. 
Demographic and Baseline Characteristics 
Demographic and other baseline characteristics of subjects (e.g., age, race, ethnicity, sex, 
and body height and weight) will be both summarised and included in a listing. Age, height, 
weight will be summarised as continuous variables using the mean, standard deviation, 
minimum, median and maximum whereas sex, race, and ethnicity will be summarised as 
categorical variables. In addition, age will also be categorized and summarised by the 
EudraCT categories of 18-64, 65-84 and ≥85 years and GSK IDSL categories of <18, 18-
64, and ≥65 years. A separate listing dedicated to categorical age and both a separate 
summary and listing dedicated to race/racial combinations will also be provided.  
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Disease history and characteristics at initial diagnosis and study screening will be 
separately summarised; as appropriate per summary, characteristics may include primary 
tumour type, stage, lesion status, time since initial diagnosis in months, stage at initial 
diagnosis, time since latest disease progression (in weeks), method by which progression 
was determined (Biochemical Progression, Radiological Progression – Bone Lesion or 
Radiological Progression – Viceral Lesion) on prior disease progression, screening, 
visceral status. Separate summaries of disease characteristics at initial diagnosis and 
screening will be provided. A summary of disease burden at baseline including sites of 
metastatic disease will be produced. Information on sites of metastatic disease at screening 
will also be listed. 
Medical conditions present at screening will be separately summarised by past and current 
categories; both past and current conditions will be disclosed in a single listing. Medical 
conditions that are not pre-specified will be incorporated into the listing only. 
Substance use, including history of smoking, tobacco, and alcohol, will be disclosed in a 
listing. 
Prior anti-cancer therapy will be coded using the GSK drug coding dictionary. Separate 
summaries of prior anti-cancer therapy will be dedicated to all therapies (including 
radiotherapies), prior dictionary-coded therapies, and number of therapy regimens. A 
summary of best response to most recent prior anti-cancer therapy will be provided.  
Prior and post-treatment cancer-related surgeries will be included in the same listing.  
The details of the planned displays are provided in Appendix 10. 
6.5. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary, summarised 
and listed. The summary will show the number and percentage of subjects taking 
concomitant medications by ingredient. Multi-ingredient products will be summarised by 
their separate ingredients rather than as a combination of ingredients. Anatomical-
Therapeutic-Chemical (ATC) Level 1 (Body System) classification will be included in the 
created dataset but will not appear in the summary table or listing. 
In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions, 
the subject is counted only once under the ingredient ‘Amoxycillin’. In the summary of 
concomitant medications, the ingredients will be summarised by the base only. A single 
listing, incorporating both blood products and supportive care products, will be provided. 
Note that, in order to be considered a concomitant medication, the concomitant medication 
must have been taken at some point during the on-therapy window. 
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7. 
EFFICACY ANALYSES 
The efficacy analyses will be based on the Modified All Treated population, unless 
otherwise specified. All analyses will be presented by dose level for each arm. A 
subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
7.1. 
Primary Efficacy Analyses 
7.1.1. 
PSA Response Rate (RR) 
The primary efficacy endpoint is PSA RR. It is defined as proportion of subjects with a 
decrease of  50% in the PSA concentration from the baseline PSA value determined at 
least 12 weeks (±5 days) after start of treatment and confirmed  4 weeks later by an 
additional PSA evaluation. 
7.1.2. 
Summary Measures 
Only subjects who have a baseline PSA value will be included in the analysis of PSA 
response. Subjects without any assessment at 12 weeks or after will be included in the 
denominator for the calculation of PSA RR. 
Response rate (confirmed) will be summarised for each dose level for each arm along with 
exact 95% confidence interval. A subgroup analysis for response rate by number of lines 
of prior therapy (L2 vs. Lx) will also be provided. 
Waterfall plots will be provided for maximum reduction in PSA value and maximum 
percentage of change in PSA from baseline. In addition, spider plots with PSA percent 
change from baseline over time will be provided for all subjects. 
Absolute values of PSA and its change from baseline in percentage will be listed. 
7.1.3. 
Population of Interest  
The primary efficacy analysis will be based on the Modified All Treated population.  
7.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (if appropriate), and listed. 
Primary Statistical Analyses 
Endpoint(s) 
RR 
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Primary Statistical Analyses 
Method of Analysis 
Exact 95% CI  
7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
Disease Control Rate at 24 weeks (DCR) 
The DCR is defined as the proportion of subjects with confirmed PR or CR or a SD at  24 
weeks (minimum 163 days to account for visit window).  
Subjects with unknown or missing response will be treated as non-responders (i.e. these 
subjects will be included in the denominator when calculating the percentage). 
7.2.1.2. 
Time to Disease Progression 
Time to disease progression is defined as the time from date of first dose of study treatment 
to date of disease progression defined as one or more of the following criteria: 
• Radiographic progression by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease 
• Bone progression on bone scan according to the PCGW3 criteria 
• PSA progression according to the PCWG3 criteria accompanied by any one of the 
following: investigator-defined clinical progression or either of the above RECIST 
1.1 radiographic progression or bone progression 
Subjects without disease progression at the time of analysis or that died will be censored 
at the date of the latest PSA assessment and latest radiological assessment. If a patient dies 
or starts new anti-cancer therapy, then they will be censored at latest date of last PSA 
assessment and last radiological assessment on or prior to new anti-cancer therapy or date 
of death. 
7.2.1.3. 
Objective Response Rate (ORR) 
The ORR is defined as the percentage of subjects with a confirmed CR or a PR at any time 
as per PCWG3- modified RECIST 1.1.  
Subjects with unknown or missing response will be treated as non-responders, i.e. these 
subjects will be included in the denominator when calculating the percentage.  
7.2.1.4. 
Circulating Tumour Cells (CTC) Response 
CTC response rate is defined as the proportion of subjects with a CTC conversion to <5/7.5 
mL blood at nadir (confirmed by a second consecutive value obtained four or more weeks 
later) for subjects with unfavourable (≥5/7.5mL) CTC at baseline. 
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Subjects with CTC<5/7.5 mL at baseline will be excluded from this analysis. 
7.2.1.5. 
Composite Response Rate (CRR) 
CRR is a composite endpoint based on the following:  
• Response based on PCWG3 modified RECIST 1.1 
• PSA decrease of ≥50% from baseline at Week 12 or thereafter 
• CTC count conversion from unfavourable (>=5/7.5mL) at baseline to favourable 
(<5/7.5mL) confirmed by a second assessment at least 4 weeks later. 
The responders for each endpoint are the same as defined in PSA responses, CTC response 
and CR or PR per PCWG3-modified RECIST 1.1. If a subject meets at least one of the 
above requirements, then that subject will be considered a composite responder.  
Subjects with unconfirmed response per PCWG3-modified RECIST 1.1 will be classified 
as non-responders.  
7.2.1.6. 
PSA Week 4 Response Rate (Week4 RR) 
Week 4 RR is defined as the proportion of participants with a PSA reduction from baseline 
≥ 30% observed at 4 weeks.  
7.2.1.7. 
Radiographic Progression-free survival (rPFS) 
rPFS will be defined as the time from date of first dose of study treatment until the first 
date of either radiographic disease progression or death due to any cause whichever occurs 
first. The date of disease progression will be defined as the earliest date of disease 
progression as assessed by the investigator using PCWG3-modified RECIST 1.1 or 
progression on bone scan. For subjects who have not progressed or died at the time of rPFS 
analysis, censoring will be performed using the date of the last adequate disease 
assessment. In addition, subjects with an extended loss to follow-up or who start a new 
anti-cancer therapy prior to a rPFS event will be censored at the date of the last adequate 
disease assessment where visit level response is CR, PR, or stable disease (SD) prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively. 
7.2.2. 
Summary Measure 
7.2.2.1. 
Disease Control Rate (DCR) 
The number and types of responses (confirmed), as outlined in PCWG3-modified RECIST 
1.1, will be listed and summarised separately, as appropriate. The estimate of DCR along 
with an exact two-sided 95% confidence interval (CI) will be provided for each dose level 
and cohortspecified.  
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
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7.2.2.2. 
Time to Disease Progression 
Time to disease progression will be summarised using Kaplan-Meier methods including 
estimates and 95% CI for medians and quartiles based on a g-transformed confidence 
interval for S(t) where g is linear (Klein and Moeschberger method) for each dose level 
specified.  
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
A summary of the assignments for progression and censoring dates for time to disease 
progression are specified in Table 1 below. 
7.2.2.3. 
Objective Response Rate (ORR) 
The observed ORR (confirmed) will be reported for each dose level. The estimates along 
with 95% exact two-sided confidence interval CI will be provided. All data related to 
response assessment from the Investigator will be listed including target lesion 
measurements, non-target lesion assessment, new lesion and response assessments. 
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
If CR or PR response are present in the data a waterfall plot of the maximum percent change 
in target lesions from baseline will be provided. The plot will be colour coded for best 
overall response with confirmation. In addition, spider plots of percent change from 
baseline in target lesions over time will be provided for each subject. 
7.2.2.4. 
Circulating Tumour Cells (CTC) Response 
CTC response rate will be presented along with an exact two-sided 95% confidence interval 
for each dose level. Percent change from baseline in actual cell counts will be summarised 
and listed by visit. 
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
Waterfall plots of maximum CTC percent change from baseline will also be presented. In 
addition, spider plots with CTC counts percent change from baseline over time will be 
provided for each subject. 
7.2.2.5. 
Composite Response Rate (CRR) 
The CRR (confirmed) will be reported for each dose level along with corresponding exact 
two-sided 95% CI.  
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
7.2.2.6. 
PSA Week 4 Response Rate (PSA Week4 RR) 
Week 4 PSA RR will be reported along with the exact two-sided 95% CI for each dose 
level.  
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A subgroup analysis and a listing by number of lines of prior therapy (L2 vs. Lx) may also 
be provided. 
7.2.2.7. 
Radiographic Progression-free survival (rPFS) 
rPFS will be summarised by dose level using Kaplan-Meier quantile estimates along with 
two-sided 95% CI based on a g-transformed confidence interval for S(t) where g is linear 
(Klein and Moeschberger method) for each dose level, if data warrant.  
Kaplan Meier curve will also be produced, if data warrant. 
A subgroup analysis by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
A summary of the assignments for progression and censoring dates for rPFS are specified 
in Table 1 below. 
 
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Table 1 
Assignments of Progression and Censoring Dates for Time to Disease Progression Analysis 
Scenario 
Date of Event (Progression/Death) or Censored  
Event 
(Progression/Death) 
Or Censored 
No adequate baseline assessments2 and the subject has 
not progressed or died and has no PD (from RS (Response 
Dataset) or DS (Disposition Dataset)) 
First dose 
Censored 
No post-baseline assessments and the subject has not died 
and has no PD (from DS) 
First dose 
Censored 
Progression prior to an anti-cancer therapy (Note this 
includes progression at baseline or without any adequate 
assessments) 
Date of assessment of progression1. 
Event 
With post-baseline assessment but no progression (or 
death) or anti-cancer therapy 
Date of last ‘adequate’ assessment of response2 
Censored 
No adequate post-baseline assessment before start of new 
anti-cancer therapy without PD or prior to PD from DS  
First dose 
Censored 
With adequate post-baseline assessment and new anti-
cancer treatment started (without PD or prior to 
documented disease progression).3 
Date of last ‘adequate’ assessment of response2 (prior to starting anti-
cancer therapy)  
Censored 
Death or progression from RS or DS (prior to anti-cancer 
therapy or no anti-cancer therapy) after two or more missed 
consecutive scheduled assessments 
Date of last ‘adequate’ assessment of response2 (prior to missed 
assessments) or first dose when there is no ‘adequate’ assessment2 of 
response:  
(1) If the previous assessment is less than Day 274 and the difference 
between death/PD and last adequate assessment2 is more than 126 days  
(2) If the previous assessment is between Day 274 and Day 344 and the 
difference between death/PD and last adequate assessment2 is more than 
154 days  
(3) If the previous assessment is greater than Day 344 and the difference 
between death/PD and last adequate assessment2 is more than 182 days 
 
Note: The scheduled assessments are every 8 weeks up to 6 months, 
then every 12 weeks. The scheduled assessments windows are: 7d. 
Censored  
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1 The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or (ii) Date of radiological assessment showing unequivocal progression 
in non-target lesions, or (iii) Date of last radiological assessment of measured lesions (if progression is based on increase in sum of measured lesions) 
2 An adequate assessment is defined as an assessment where the Investigator determined response is CR, PR, or SD. Note it can be scheduled or unscheduled. 
3 If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is progression and the date is the date of the assessment of 
progression) 
 
Table 2 
Assignments of Progression and Censoring Dates for rPFS Analysis 
Scenario 
Date of Event (Progression/Death) or Censored  
Event 
(Progression/Death) 
Or Censored 
No adequate baseline assessments2 and the subject has 
not progressed or died (if the subject has died follow the 
rules for death indicated at the bottom of the table) and has 
no PD (from RS or DS) 
First dose 
Censored 
No post-baseline assessments and the subject has not 
died (if the subject has died follow the rules for death 
indicated at the bottom of the table) and has no PD (from 
DS) 
First dose 
Censored 
Without anti-cancer or prior to an anti-cancer, 
progression/death (Note this includes progression/death at 
baseline or without any adequate assessments) 
Date of assessment of progression1 or date of death, whichever comes 
first. 
Event 
With post-baseline assessment but no progression (or 
death) or anti-cancer 
Date of last ‘adequate’ assessment of response2 
Censored 
No adequate post-baseline assessment before start of new 
anti-cancer therapy without PD or prior to PD from DS  
First dose 
Censored 
With adequate post-baseline assessment and new anti-
cancer treatment started (without PD or prior to 
documented disease progression).3 
Date of last ‘adequate’ assessment of response2 (on or prior to starting 
anti-cancer therapy)  
Censored 
Death or progression from RS or DS (prior to anti-cancer 
therapy or no anti-cancer therapy) after two or more missed 
consecutive scheduled assessments 
Date of last ‘adequate’ assessment of response2 (prior to missed 
assessments) or first dose when there is no ‘adequate’ assessment2 of 
response:  
 
Censored  
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Scenario 
Date of Event (Progression/Death) or Censored  
Event 
(Progression/Death) 
Or Censored 
(1) If the previous assessment is less than Day 274 and the difference 
between death/PD and last adequate assessment2 is more than 126 days 
(2) if the previous assessment is between Day 274 and Day 344 and the 
difference between death/PD and last adequate assessment2 is more 
than 154 days 
(3) If the previous assessment is greater than Day 344 and the difference 
between death/PD and last adequate assessment2 is more than 182 days 
 
Note: The scheduled assessments are every 8 weeks up to 6 months, 
then every 12 weeks 
The scheduled assessments windows are: 7d;  
1 The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or (ii) Date of radiological assessment showing unequivocal progression 
in non-target lesions, or (iii) Date of last radiological assessment of measured lesions (if progression is based on increase in sum of measured lesions) 
2 An adequate assessment is defined as an assessment where the Investigator determined response is CR, PR, or SD. Note it can be scheduled or unscheduled. 
3 If PD and New anti-cancer therapy occur on the same day assume the progression was documented first e.g., outcome is progression and the date is the date of the assessment of 
progression)
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7.2.3. 
Population of Interest  
The secondary efficacy analyses will be based on the Modified All Treated population, 
unless otherwise specified. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints/variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (if appropriate), and listed. 
Secondary Statistical Analyses 
Endpoint(s) 
DCR 
ORR 
CTC 
CRR 
PSA Week 4 RR 
Method of Analysis 
Exact two-sided 95% CI  
Endpoint(s) 
Duration of PSA Response 
Time to Disease Progression 
rPFS 
Method of Analysis 
Kaplan-Meier method (if data warrant) with first, second and third quartiles 95% CI based on a g-
transformed confidence interval for S(t) where g is linear (Klein and Moeschberger method). 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the All Treated population, unless otherwise specified. 
All analyses will be presented by dose level for each arm separately. A subgroup analysis 
by number of lines of prior therapy (L2 vs. Lx) may also be provided. 
8.1. 
Adverse Events (AE) Analyses 
AE analyses including the analysis of adverse events, SAEs and other significant AEs will 
be based on GSK Core Data Standards. The details of the planned displays are provided in 
Appendix 10: List of Data Displays. 
All AEs will be graded according to National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.0. Adverse events will be coded by 
the Medical Dictionary for Regulatory Activities (MedDRA) to System Organ Class (SOC) 
and Preferred Term (PT). 
An overview summary will be presented for AEs, including counts and percentages of 
subjects for the following  
• Any AE,  
• Non-serious AEs, 
• AEs related to any study treatment,  
• AEs related to GSK525762,  
• AEs of Grade 3-4,  
• Grade 3-4 AEs related to any treatment,  
• Grade 3-4 AEs related to GSK525762,  
• AEs leading to permanent discontinuation of any study treatment,  
• AEs leading to permanent discontinuation of GSK525762,  
• AEs leading to dose reductions of any study treatment,  
• AEs leading to dose reductions of GSK525762,  
• AEs leading to dose interruptions/delays of any study treatment,  
• AEs leading to dose interruptions/delays of GSK525762,  
• SAEs,  
• SAEs related to any study treatment,  
• SAEs related to GSK525762,  
• Dose Limiting Toxicities.  
A summary of non-serious AEs that occurred in strictly 5% of the subjects or above will 
be provided (no rounding for the percentage will be used in terms of 5% threshold, e.g. 
events with 4.9% incidence rate should not be included in this table). This summary will 
contain the number and percentage of subjects and the number of occurrences of common 
non-serious adverse events. The summary tables will be displayed by SOC and PT. 
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. At the subject level a conservative approach will be used in 
computing the maximum grade when grades are missing, for instance when a grade will be 
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missing for at least one AE this subject maximum grade will be counted as unknown. AEs 
will be sorted by PT in descending order of total incidence. The summary will use the 
following algorithms for counting the subject: 
• PT row: Subjects experiencing the same AE preferred term several times with 
different grades will only be counted once with the maximum grade. 
• Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
In addition, the frequency and percentage of Adverse Events (AEs) (all grades) will be 
summarised and displayed in two ways: 1) in descending order of total incidence by PT 
only and 2) in descending order of total incidence by SOC and PT. In the SOC row, the 
number of subjects with multiple events under the same system organ class will be counted 
once.  
Separate summaries will be provided for study treatment-related AEs, one for any 
treatment-related and one for GSK525762-related. A study treatment related AE is defined 
as an AE for which the investigator classifies the relationship to study treatment as “Yes”. 
A worst-case scenario approach will be taken to handle missing relatedness data, i.e. the 
summary table will include events with the relationship to study treatment as ‘Yes’ or 
missing. The summary table will be displayed in descending order of total incidence by PT 
only. Summary of study treatment related AEs by maximum grade will also be provided. 
All AEs will be listed. Additionally, a listing of subject IDs for each individual Treatment 
Emergent Adverse Events will be produced. Lastly a summary of the number of patients 
experiencing DLT’s in each dose level will be provided. 
8.2. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of AE of special interest (AESI). These AESI are not defined in the protocol but 
are noted in the IB. Changes to the MedDRA dictionary may occur between the start of the 
study and the time of reporting and/or emerging data from on-going studies may highlight 
additional AESIs, therefore the list of terms to be used for each event of interest and the 
specific events of interest will be based on the safety review team (SRT) agreements in 
place at the time of the database lock. The details of the planned displays are provided in 
Appendix 10: List of Data Displays. 
The events of special interest include but are not limited to the following categories:  
• Haematopoietic thrombocytopenia Standardized MedDRA Query (SMQ) 
• Haemorrhages [excl laboratory terms] [NARROW] SMQ  
• Anaemias nonhaemolytic and marrow depression High Level Group Term (HLGT) 
• Torsade de pointes/QT prolongation [NARROW] SMQ 
• Drug related hepatic disorders - comprehensive search [NARROW] SMQ 
• Renal Prefered terms 
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Preferred terms for the events of special interest will be provided by the molibresib Pharma 
Safety representative before DBR based on the most up to date MedDRA version. 
The number and percentage of subjects with these events will be summarised by categories 
of AESI, PT, and maximum toxicity grade in one table. The summary and listing of event 
characteristics for each category of AESI will also be provided, including number of 
subjects with any event, number of events, number of subjects with any event that is 
serious, number of subjects with any event that is related to study treatment, the outcome 
of the event, maximum grade and the action taken for the event. The percentage for the 
number of subjects with an event will be calculated with total number of subjects as the 
denominator. The percentage for the event characteristics will be calculated with number 
of subjects with event as the denominator. The worst-case approach will be applied at 
subject level for the event outcome and maximum grade (i.e., a subject will only be counted 
once as the worst-case from all the events experienced by the subject). For action taken to 
an event, subjects will be counted once per action (e.g., if a subject has an event leading to 
both study treatment discontinuation and dose reduction, the subject will be counted once 
under both actions). 
For each category of AESI, a summary of onset and duration will be provided (Time to 
onset (days) and duration of first occurrence (days)). In addition to descriptive statistics 
(mean, median, minimum, maximum), time to onset will be summarised in categories of 1 
to 14 days, 15 to 28 days, and >28 days, and duration of first occurrence will be summarised 
in categories of 1 to 5 days, 6 to 10 days, and >10 days.  
8.3. 
Deaths and Serious Adverse Events  
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date from this subject including death is supposed to appear in the database, which should 
be part of the data cleaning process. All deaths will be summarised based on the number 
and percentage of subjects. This summary will classify subjects by time of death relative 
to the last dose of medication (>30 days or <=30 days) and the primary cause of death 
(disease under study, SAE related to study treatment, or other). A supportive listing will be 
generated to provide subject-specific details on subjects who died. 
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. Separate summaries will also be provided for study treatment-
related SAEs. The frequency and percentage of SAEs will be summarised in descending 
order of total incidence by PT only.  
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”. A worst-case scenario approach will be taken 
to handle missing data, i.e. the summary table will include events with the relationship to 
study treatment as ‘Yes’ or missing.   
SAEs are included in the listing of all AEs and separate supportive listings with subject-
level details will be generated for both fatal and non-fatal SAEs. 
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8.4. 
Adverse Events Leading to Discontinuation of Study 
Treatment and Other Significant Adverse Events 
The following categories of AEs will be summarised separately in descending order of total 
incidence by PT only and separate supportive listings will be generated with subject level 
details for those subjects: 
• AEs Leading to Permanent Discontinuation of GSK525762 
• AEs Leading to Dose Interruptions/Delays of GSK525762 
• AEs Leading to Dose Reductions of GSK525762 
• AEs Leading to Permanent Discontinuation of Any Study Treatment 
• AEs Leading to Dose Interruptions/Delays of Any Study Treatment 
• AEs Leading to Dose Reductions of Any Study Treatment 
8.5. 
Extent of Exposure 
Extent of exposure to GSK525762, abiraterone, and enzalutamide will be summarised 
separately. 
The duration of exposure to study treatment in months (from first day to last day of 
treatment) will be summarised. Descriptive statistics including mean, median, standard 
deviation, minimum, and maximum will be calculated for time on study treatment. The 
duration of treatment will also be summarised based on the following categories: <3 
months, 3-<6 month, 6-<12 months, >=12 months. 
The subject’s average daily dose, defined as the cumulative dose divided by the duration 
of exposure for each subject, will be summarised.  
Dose reductions will be summarised by number of reductions and reasons for reductions. 
Dose interruptions/delays will be summarised by number of interruptions, reasons for 
interruptions and duration of interruption (days). The mean, standard deviation, median, 
minimum and maximum will be computed for the duration of interruptions as well as the 
number and percentage of the interruptions for <7, 7-14, >14 days. Summary of dose 
escalation will also be provided, if applicable. All the dose reductions, dose escalations and 
dose interruptions/delays will be listed separately. 
Lastly, several summaries of study treatment exposure and dose modifications (e.g., 
summaries of total exposure, dose reductions, dose interruptions/delays, dose escalations, 
missed doses, and dose-limiting toxicities experienced) will be provided for GSK525762, 
abiraterone and enzalutamide. Corresponding listings will also be provided, including 
planned versus actual treatments received, drug accountability, total exposure, missed 
doses, and the various dose modifications (reductions, interruptions, delays, and 
escalations). 
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8.6. 
Clinical Laboratory Analyses 
Laboratory evaluations including clinical chemistry, haematology, urinalysis, and liver 
function tests will be based on GSK Core Data Standards. The details of the planned 
displays are in Appendix 10: List of Data Displays. 
The assessment of laboratory toxicities will examine the following laboratory tests:  
Clinical Chemistry 
Sodium  
Fasting Glucose 
Potassium 
Magnesium 
Chloride 
Calcium (total and ionized) 
Total Carbon Dioxide 
Total Protein 
Blood Urea Nitrogen 
Albumin 
Creatinine  
Lactate dehydrogenase 
Haematology 
White Blood cell count 
Haemoglobin 
Platelet count 
Automated White Blood Cell Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Liver Function 
Bilirubin (Total and Direct) 
Aspartate Aminotransferase 
Alanine Aminotransferase 
Alkaline Phosphatase 
Urinalysis 
Specific gravity 
pH 
Glucose 
Protein 
Blood 
Ketones 
Microscopic examination (if urinalysis is abnormal) 
Cardiac 
Troponin  
NT-proBNP (N-terminal pro b-type natriuretic peptide) 
Fasting Lipid Panel (Total Cholesterol, LDL, HDL, Triglycerides) 
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Other 
Coagulation: 
Prothrombin Time/INR 
Partial Thromboplastin Time 
Fibrinogen 
Factor VII Assay 
Endocrine: 
Thyroid Stimulating Hormone (TSH) 
Free Thyroxine 3 (Free T3) 
Free Thyroxine 4 (Free T4) 
Haemoglobin A1c 
PSA 
Testosterone 
Safety Screening: 
HIV  
HbSag 
HCV antibody 
Pancreatic Markers: 
Amylase 
Lipase 
 
A summary of laboratory values and change from baseline in lab values by scheduled 
visits using mean, median, standard deviation, minimum and maximum will be provided. 
Summaries of lab data will also be provided by maximum toxicity grade, using reported 
grades based on NCI-CTCAE v4.0. 
Summaries of worst-case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by NCI-CTCAE v4.0. These summaries will display the 
number and percentage of subjects with a maximum post-baseline grade increasing from 
their baseline grade. Any increase in grade from baseline will be summarised along with 
any increase to a maximum grade of 3 and any increase to a maximum grade of 4.   
Missing baseline grade will be assumed as grade 0. In addition, the summary will include 
grade increase from baseline by scheduled visits. For laboratory tests that are graded for 
both low and high values, summaries will be done separately and labeled by direction, 
e.g., sodium will be summarised as hyponatremia and hypernatremia. 
For lab tests that are not gradable by NCI-CTCAE v4.0, summaries of worst-case 
changes from baseline with respect to normal range will be generated. Decreases to low, 
changes to normal or no changes from baseline, and increases to high will be summarised 
at each scheduled visit as well as for the worst-case post-baseline results. If a subject has 
a decrease to low and an increase to high during the same time interval, then the subject 
is counted in both the “Decrease to Low” categories and the “Increase to High” 
categories. In addition, the summary will include worst-case changes from baseline with 
respect to normal range by scheduled visits. 
Separate summary tables for haematology, chemistry, liver function, urinalysis, cardiac 
function, coagulation, endocrine, and pancreatic laboratory tests will be produced. 
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A supporting listing of laboratory data for subjects with abnormalities of potential clinical 
concern will be provided, as will a separate listing of laboratory data with character 
values. 
Detailed derivation of baseline assessment is specified in Section 5.3. 
Unless otherwise specified, the denominator used for computing percentages will be 
based on the number of subjects with non-missing values for the given scheduled visit. 
Dipstick test results will be summarised at each scheduled visit. A supporting listing with 
subject level details will be provided. 
Summaries by visit 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 ‘worse case post baseline’ 
summaries which will capture a worst-case across all scheduled and unscheduled visits 
after the first dose of study treatment. 
8.6.1. 
Analyses of Liver Function Tests 
Summaries and listing of hepatobiliary laboratory events including possible Hy’s law cases 
will be provided in addition to bilirubin (total and direct), AST, ALT, and alkaline 
phosphatase (ALP) as described above.  
Possible Hy’s law cases are defined as any elevated (ALT≥3×ULN and total 
bilirubin≥2×ULN (> 35% direct bilirubin)) or (ALT≥3xULN and INR>1.5, if INR 
measured). Total bilirubin≥2×ULN can be within 28 days following the ALT elevation and 
if direct bilirubin is available on the same day, it must be ≥ 35% of total bilirubin. 
8.7. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs, ECHO/MUGA, 
performance status and vital signs will be based on GSK Core Data Standards, unless 
otherwise specified. The details of the planned displays are presented in Appendix 10: List 
of Data Displays. 
8.7.1. 
Vital Signs 
Values of vital signs as well as the change from baseline will be summarised by scheduled 
visit using mean, median, standard deviation, minimum and maximum.  
In addition, vital sign values will be categorized as follows: 
• Systolic Blood Pressure (BP, mmHg): Grade 0 (≤120), Grade 1 (>120-<140), Grade 
2 (≥140-<160) and Grade 3 (≥160) 
• Diastolic BP (mmHg): Grade 0 (≤80), Grade 1 (>80-<90), Grade 2 (≥90-<100), and 
Grade 3 (≥100) 
• Heart rate (beats/min): <60, ≥60-≤100, and >100 
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• Respiratory rate (breaths/min): <12, >12-≤18, >18-≤25, and >25 
• Temperature (°C): ≤35, >35-<38, ≥38 
Summaries of increase in vital signs from the baseline with respect to the categories defined 
above will be performed.  
8.7.2. 
Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status will be summarised at 
baseline and each post-baseline scheduled visit. Summaries will use frequency and 
percentage of subjects at each planned assessment time. A summary of change from 
baseline by scheduled visits will be performed, as well as the worst-case post-baseline and 
the best-case post-baseline changes during the study (improved, no change, deteriorated).  
8.7.3. 
ECG 
Per protocol, triplicate 12-lead ECGs will be obtained, prior to dosing, during the study 
using a standard 12-lead ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT and QTcF intervals. Baseline QTcF value is determined by the 
mean of the triplicate Week1 Day1 pre-dose QTcF results (see Section 5.3). If these results 
are not available, then the mean QTcF of the screening triplicate ECG results will be used.A 
summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst-case post-baseline. 
Change from baseline in ECG values will be summarized at each scheduled assessment 
time and for the worst-case post-baseline. Only the post-baseline assessments that used the 
same source (i.e. local or central cardiologist read) as the baseline assessments will be used 
to derive the change from baseline, data from the two sources will not be combined. 
QTcF prolongation will be monitored throughout the study. The QTc values based on 
Fridericia formula will be rounded to the integer and the values will be categorized into the 
following ranges: Grade 0 (<450 msec), Grade 1 (≥450-≤480 msec), Grade 2 (≥481-≤500 
msec), and Grade 3 (≥501 msec).  
Summaries of grade increase will be provided. These summaries will display the number 
and percentage of subjects with any grade increase, increase to grade 2 and increase to 
grade 3 at each scheduled assessment time and in the worst-case post-baseline. Missing 
baseline grade will be assumed as grade 0. 
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: ≥31-≤60 and >60 msec. A summary of change in QTc value 
will display the number and percentage of subjects with a change within each range at each 
scheduled assessment time and in the worst-case post-baseline. Subjects with missing 
baseline values will be excluded from this summary. 
Listings of abnormal ECG findings and a listing of ECG values will be provided. 
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8.7.4. 
LVEF 
Absolute change from baseline in LVEF will be summarised at each scheduled assessment 
time and in the worst-case post-baseline. Only the post-baseline assessments that used the 
same method (i.e. Electrocardiogram ECHO or Multiple Grated Acquisition MUGA) or 
source (i.e. local or central read)as the baseline assessments will be used to derive the 
change from baseline, data from different methods and sources should not be combined. 
The change from baseline will be categorized as follows: 
• No change or any Increase (i.e. increase of - <10%, 10 - <20%, ≥20%) 
• Any decrease (i.e. decrease of >0 - <10%, 10 - <20%, ≥20%) 
• ≥10% decrease and ≥ LLN 
• ≥10% decrease and < LLN 
• ≥20% decrease and ≥ LLN 
• ≥20% decrease and < LLN 
LVEF results will also be listed with subject level details including absolute change from 
baseline. 
8.7.5. 
Liver Events  
For any liver events that occur during the study, the liver event information for RUCAM 
(Roussel Uclaf Causality Assessment Method) score will be summarised, including 
whether the subject was age 55 or over, liver imaging normal or not, a biopsy was taken or 
not, whether there was fasting or significant dietary change, whether the subject took any 
unconventional medications, timing when the event occurs (while on treatment or after 
stopping treatment) and summary statistics for time from first dose to start of liver event 
and time from last dose to start of liver event. If the number of events does not support a 
summary, then only listings will be produced. 
For subjects with multiple events, the first event will be used for the summary tables. All 
events with subject level details will be displayed in a supporting listing. 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
9.1.1.1. 
Drug Concentration Measures 
Two major metabolites of GSK525762, GSK3529246 and GSK3536835, have been 
observed in humans. GSK3536835 was found to be unstable under bioanalytical 
conditions. Therefore, the two major active metabolites were measured together 
following full conversion of GSK3536835 to GSK3529246 prior to analysis and the 
active metabolites (GSK3529246 + GSK3536835) are reported as one entity, 
GSK3529246. 
Concentration of GSK525762, active metabolites (GSK3529246) and GSK525762 total 
active moiety (i.e. GSK525762 + GSK3529246 after conversion to nM concentrations) as 
well as abiraterone and enzalutamide will be listed for each subject.  
Summaries of plasma concentration will be produced separately for GSK525762 in both 
ng/mL and nM, active metabolites (GSK3529246) in both ng/mL and nM and the total 
active moiety of GSK525762 (GSK525762 + GSK3529246 after conversion to nM 
concentrations) in nM. Plasma concentration-time data will be summarized using 
descriptive statistics (n, mean, SD, median, minimum and maximum) by planned relative 
assessment time.  
One plot of concentration over time will be provided using actual elapsed time for Week 
1, Week 3 and overall duration of study for GSK525762 (in nM), GSK3529246 (in nM), 
Total active moiety (in nM) and abiraterone. 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic) for details of displays. 
9.1.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
Phoenix. This will be the responsibility of the PK group at PAREXEL under the direction 
of Clinical Pharmacology Modeling and Simulation (CPMS) Department, GSK. All 
calculations of non-compartmental parameters will be based on actual sampling times. 
Pharmacokinetic parameters listed below will be determined from the concentration-time 
data for GSK525762, active metabolites (GSK3529246)), the total active moiety (i.e. 
GSK525762 
+ 
GSK3529246 
after 
conversion 
to 
nM 
concentrations) 
and 
abiraterone/enzalutamide, as data permits. 
The molecular weight of GSK525762 is 424 g/mol and the molecular weight of 
GSK3529246 is 396 g/mol. 
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The total active moiety concentration in nmol/L will be computed as (GSK525762 
concentration in ng/mL / molecular weight of 424 * 1000) + (GSK3529246 concentration 
in ng/mL / molecular weight of 396 * 1000). 
Pharmacokinetic parameters described in Table 3 will be determined from the plasma 
concentration-time data, as data permits. 
Table 3 
Derived Pharmacokinetic Parameters 
Parameter 
Parameter Description 
AUC (0-τ) 
Area under the concentration-time curve over a dosing interval will be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
Cmax 
Maximum observed concentration, determined directly from the concentration-time 
data. 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Trough 
concentration (Cτ) 
Pre-dose (trough) concentration at the end of a dosing interval. 
NOTES: Additional parameters may be included as required. 
9.1.2. 
Summary Measure 
Summaries of plasma concentration and pharmacokinetic parameters will be produced 
separately for GSK525762, active metabolites (GSK3529246) , the total active moiety of 
GSK525762, abiraterone and enzalutamide. 
Plasma concentration-time data will be summarised using descriptive statistics (n, mean, 
SD, median, minimum and maximum) by planned relative assessment time. Mean and/ or 
median values will be plotted over time using nominal visit.  
Concentration-time profiles for GSK525762, GSK3529246 and total active moiety will be 
overlaid on the same plot after conversion to nM concentrations.  
 
The PK parameters described in Section 9.1.1.2 will also be summarised descriptively for 
plasma pharmacokinetic parameters (mean, standard deviation, median, minimum, 
maximum, geometric mean, and the standard deviation, (Coefficient of Variation) CV% 
and 95% CI of log-transformed parameters (if applicable) will be reported. 
9.1.3. 
Population of Interest  
The pharmacokinetic analyses will be based on the Pharmacokinetic population, unless 
otherwise specified. 
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10. 
PHARMACODYNAMIC ANALYSIS 
Tumour samples will be collected pre-dose and on-treatment in order to evaluate changes 
in molecular markers of BET inhibition (e.g., expression of RNA/proteins regulated by 
BET) and AR signalling.  
The pharmacodynamic analyses will be detailed in a Pharmacodynamic RAP supplement 
and will not be discussed as part of this RAP. 
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11. 
OTHER STATISTICAL ANALYSES 
11.1. 
Value Evidence and Outcomes 
The value evidence and outcomes analyses will be based on the Modified All Treated 
Subjects population, unless otherwise specified. All summaries and data listings will use 
treatment labels as specified in Section 5.1. Scoring details for EORTC-QLQ-C30, 
EORTC-QLQ-PR25, BPI-SF and PRO-CTCAE can be found in Appendix 6 Section 
13.6.6. Details of data displays are presented in Appendix 10: List of Data Displays. 
Summaries of absolute values and change from baseline of the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC-QLQ-
C30) and European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Prostate (EORTC-QLQ-PR25) scales will be provided in tables. Summaries 
of absolute values and change from baseline of the Brief Pain Inventory (BPI-SF) scores 
will be provided in tables. Summaries of absolute values and change from baseline of the 
PRO-CTCAE will be provided in tables. Single items EORTC-QLQ-C30, EORTC-QLQ-
PR25, BPI-SF and PRO-CTCAE will be provided in listings. 
Baseline will be defined as the visit prior to start of Week 1 Day 1 dosing. 
11.1.1. 
 EORTC-QLQ-C30 
The EORTC-QLQ-C30 is composed of both multi-item scales and single-item measures. 
These include five functional scales, three symptom scales, a global health status / Quality 
of Life (QoL) scale, and six single items. Each of the multi-item scales includes a different 
set of items - no item occurs in more than one scale. All of the scales and single-item 
measures range in score from 0 to 100. A high scale score represents a higher response 
level. Thus, a high score for a functional scale represents a high / healthy level of 
functioning, a high score for the global health status / QoL represents a high QoL, but a 
high score for a symptom scale / item represents a high level of symptomatology / 
problems. 
11.1.2. 
EORTC-QLQ-PR25 
While the EORTC-QLQ-C30 is an important tool for assessing the generic aspects of QoL, 
it has limitations and therefore a modular approach was adopted for disease-specific 
treatment measurements. An essential aspect of the “modular” approach to QoL assessment 
adopted by the EORTC Quality of Life Group is the development of modules specific to 
tumour site, treatment modality, or a QoL dimension, to be administered in addition to the 
core questionnaire (EORTC-QLQ-C30). The modules, like the core questionnaire, are 
designed for use in cancer clinical trials. The EORTC-QLQ-PR25 is a 25-item prostate 
cancer-specific scale intended to supplement, the EORTC-QLQ-30. It includes subscales 
assessing urinary symptoms (9 items), bowel symptoms (4 items), treatment-related 
symptoms (6 items) and sexual functioning (6 items). There are six prostate-specific 
domains: Urinary, Bowel, Use of Incontinence Aids, Treatment-Related Symptoms, 
Sexual Active and Sexual Function. Item scores are summed and transformed to a 0-100 
scale; higher scores represent higher functioning for the two sexual domains but, 
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conversely, higher scores represent more symptoms (i.e. worse Health Related Quality of 
Life (HRQoL) for the symptom scales.  
11.1.3. 
BPI-SF 
The BPI-SF is a 9-item self-administered questionnaire. It uses simple numeric rating 
scales from 0 to 10 and gives two main scores: a pain intensity score and a pain interference 
score. The two scores are calculated Pain intensity score and Pain interference score: is 
calculated from items 
to
and is used to rate the degree that pain interferes with 
 
and 
. The seven sub-items are rated from 0 
, to 10 
. The average of BPI-SF pain interference will be calculated at each 
routine visit as the mean of the scores for the 7 sub-items of pain interference. 
BPI-SF item “pain at its worst in 24 hours” will be used to categorize patients into severity 
categories of 1-4 (mild), 5-6 (moderate) and 7-10 (severe). Proportions over time will be 
presented in stacked bar charts over time. 
11.1.4. 
PRO-CTCAE 
The PRO-CTCAE is a patient-reported outcome (PRO) measurement system developed to 
evaluate symptomatic toxicity in patients on cancer clinical trials. It was designed to be 
used as a companion to the Common Terminology Criteria for Adverse Events (CTCAE) 
The PRO-CTCAE Item Library includes 124 items representing 78 symptomatic toxicities 
drawn from the CTCAE. PRO-CTCAE items evaluate the symptom attributes of 
frequency, severity, interference, amount, presence/absence. Each symptomatic AE is 
assessed by 1-3 attributes. PRO-CTCAE responses are scored from 0 to 4 (or 
 
). There are as yet no standardized scoring rules for how to combine 
attributes into a single score or how best to analyze PRO-CTCAE data longitudinally. 
Scores for each attribute (frequency, severity and/or interference) will be presented 
descriptively (e.g. summary statistics or graphical presentations). 
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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
Klein, J. P., and Moeschberger, M. L. (1997). Survival Analysis: Techniques for 
Censored and Truncated Data. New York: Springer-Verlag. 
Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., 
Takeda, F. (1993). The European Organization for Research and Treatment of Cancer 
QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in 
Oncology. JNCI: Journal of the National Cancer Institute, 85(5), 365-376. 
van Andel G, et al. An international field study of the EORTC QLQ-PR25: a 
questionnaire for assessing the health-related quality of life of patients with prostate 
cancer. European journal of cancer. 2008 Nov;44(16):2418-24. 
George van Andel, Andrew Bottomley, Sophie D. Fosså, Fabio Efficace, Corneel Coens, 
Stephane Guerif, Howard Kynaston, Paolo Gontero, George Thalmann, Atif Akdas, Sven 
D’Haese, Neil K. Aaronson, An international field study of the EORTC QLQ-PR25: A 
questionnaire for assessing the health-related quality of life of patients with prostate 
cancer, European Journal of Cancer, Volume 44, Issue 16, 2008,Pages 2418-2424 
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13. 
APPENDICES 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Specification document. 
13.1.1. 
Exclusions from Per Protocol Population 
No per protocol population is defined and used for this study. 
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13.2. 
Appendix 2: Schedule of Activities 
13.2.1. 
Protocol Defined Schedule of Events 
Refer to protocol Section 7.1 Time and Events Table. 
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13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
For PSA response at 12 weeks and PSA response confirmation at 4 weeks, 5 days 
assessment window will be applied. 
 
Analysis Set 
/ Domain 
Parameter (if 
applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Efficacy 
PSA Response 
W12 
-5 days 
+5 days 
Week 12 
 
PSA Response 
Confirmation 
W12 + 4 weeks 
-5 days 
+5 days 
Week 16 
 
PSA Response 
W4 
-7 days 
+7 days 
Week 4 
 
DCR 
24 weeks 
163 days 
 
Week 24 
NOTES: DCR is defined as the percentage of subjects with confirmed PR or CR or a SD at 24 weeks 
(minimum 163 days to account for visit window). Subjects with unknown or missing response will be 
treated as non-responders (i.e. these subjects will be included in the denominator when calculating 
the percentage 
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13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events 
13.4.1. 
Study Phases 
Disease assessments and AEs, SAEs, death, laboratory data, vital signs. ECGs, 
echocardiograms, performance status results and other safety domains will be assigned to 
the treatment phases defined below. Partial dates will be imputed into full dates, if 
applicable, for slotting data to the appropriate categories below. Flag variables (time in 
relation to study treatment) indicating the study time periods will be added to these datasets. 
Assessments and events will be classified according to the time of occurrence relative to 
Study Treatment Start Date. 
Treatment 
Phase 
Definition 
Pre-Treatment  
Date < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date 
abiraterone Run-
In Period 
Day -7 to Day 0 
enzalutamide 
Run-in Period 
Day –28 to Day 0 or Day -14 to Day 0 
Onset Time Since 
1st Dose (Days) 
• 
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date 
• 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date 
+1 
• 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date + 1 
13.4.2. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment. 
13.4.2.1. 
Treatment States for Disease Response Data 
Treatment State 
Definition 
Time to 
Progression 
Date of Progression or Date of Last Disease Assessment - Study Treatment Start 
Date + 1 
Time to 
Response 
Date of First Partial or Complete Response of a Confirmed Partial or Complete 
Response – Study Treatment Start Date + 1 
Duration of 
Response 
Date of Progression – Date of First Partial or Complete Response of a Confirmed 
Partial or Complete Response + 1 
 
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13.4.3. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
If AE onset date is on or after treatment start date and on or before 30 days after 
treatment end date. 
• 
Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment End Date + 30 
days.  
If AE onset date is prior to treatment start date and toxicity grade changes to 
worsening on or after treatment start date and on or before treatment end date + 30 
days. 
• 
AE onset Date < Study Treatment Start date and Study Treatment Start Date ≤ 
AE Worsening Date ≤ Study Treatment End Date + 30 day. 
Drug-related 
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing]. 
NOTES:  
• 
If the study treatment stop date is missing, then the AE will be considered to be On-Treatment as long 
as it started after treatment. 
• 
Time of study treatment dosing and start/stop time of AEs should be considered, if collected. 
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13.5. 
Appendix 5: Data Display Standards & Handling Conventions 
13.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: US1SALX00259 
HARP Compound 
: GSK525762\mid204697 
Analysis Datasets  
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG Version 
1.1).  
Generation of RTF Files 
RTF files will be generated for SAC and IA upon request. 
13.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location:  
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for reporting 
of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DPs.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
o Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
o The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
o Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
o Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables, except in cases where worst-case post-
baseline is calculated. 
• 
Unscheduled visits will not be included in figures, unless otherwise specified. 
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• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
13.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
PC WNL file (CSV format) for the non-compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
SOP_00000314000: Non-compartmental Analysis of Clinical Pharmacokinetic 
Data. 
Note: Concentration values will be imputed as per GUI_51487 
Descriptive 
Summary Statistics, 
Graphical 
Displays 
and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarised graphical displays only. Assign zero 
to NQ values. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived 
by 
PK 
analyst 
The following PK parameters will be derived by the PK Analyst: AUC0-τ, Cmax, 
Tmax and Cτ 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters 
Rule 
Being Followed 
Yes, refer to Standards for Handling NQ Impacted PK Parameters. 
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13.6. 
Appendix 6: Derived and Transformed Data 
13.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
If multiple assessments on different days are reported for the same scheduled assessment, then the 
worst-case assessment for that scheduled assessment will be analysed. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day 
• 
Calculated as the number of days from Study Treatment Start Date: 
o Ref Date = Missing → Study Day = Missing  
o Ref Date < Study Treatment Start Date → Study Day = Ref Date – Study Treatment Start Date 
o Ref Data ≥ Study Treatment Start Date → Study Day = Ref Date – (Study Treatment Start Date) 
+ 1 
Change from Baseline 
• 
Change from Baseline = Post-Baseline Visit Value – Baseline  
• 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change from 
Baseline is set to missing 
Date of Response 
For post-baseline disease assessments, the date of response (PR or better) is assigned to the earliest date 
of disease assessments; for other response categories (SD [or Non-CR/Non-PD], NE (Not Evaluable), PD), 
the date of response is assigned to the earliest date of disease assessments. 
Date of New Anti-Cancer Therapy 
Derived as the earliest date of new anti-cancer therapy, radiotherapy (where applicable) or cancer-related 
surgical procedure (where applicable).  
Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules specified 
in Section 13.7.2.1 
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13.6.2. 
Study Population 
Demographics 
Age 
• 
GSK standard Integrated Data Standards Library (IDSL) algorithms will be used for calculating age 
where birth date will be imputed as follows:  
o Any subject with a missing day will have this imputed as day ‘15’. 
o Any subject with a missing date and month will have this imputed as ‘30th June’.  
o Birth date will be presented in listings as ‘YYYY’. 
Body Mass Index (BMI) 
Calculated as Weight (kg) / [Height (m)]2 
Change from Baseline 
Change from Baseline = Post-Baseline Visit Value – Baseline 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change from 
Baseline is set to missing 
Date of Response 
For post-baseline disease assessments, the date of response (PR or better) is assigned to the earliest date 
of disease assessments; for other response categories (SD [or Non-CR/Non-PD], NE, PD), the date of 
response is assigned to the earliest date of disease assessments. 
Date of New Anti-Cancer Therapy 
Derived as the earliest date of new anti-cancer therapy, radiotherapy (where applicable) or cancer-related 
surgical procedure (where applicable).  
Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules specified 
in Section 13.7.2.1. 
13.6.3. 
Efficacy 
Primary Endpoint 
PSA Response Rate (RR) 
• 
Defined as proportion of subjects with a decrease of ≥ 50% in the PSA concentration from the 
baseline PSA value determined at least 12 weeks (±5 days) after start of treatment and confirmed 
≥ 4 weeks later by an additional PSA evaluation. 
Disease Control Rate (DCR) 
• 
DCR is defined as the percentage of subjects with confirmed PR or CR or a SD at 24 weeks 
(minimum 163 days to account for visit window). Subjects with unknown or missing response will 
be treated as non-responders (i.e. these subjects will be included in the denominator when 
calculating the percentage). 
Duration of PSA 
• 
Duration of PSA response is calculated from the time the PSA value first declines by at least 50% 
from the Week 1 Day 1 (baseline) value (must be confirmed by a second value) until the time 
there is an increase of 25% of PSA nadir, provided the absolute increase is at least 2ng/mL from 
the nadir . The increase must be confirmed by a second consecutive measurement that is at least 
25% above the nadir. If the PSA never shows a 25% increase over the nadir value, then the 
patient will be censored at the last PSA measurement 
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Primary Endpoint 
Time to disease progression 
• 
Time to disease progression is defined as the time from first dose date of study treatment to 
disease progression defined as one or more of the following criteria: 
o Radiographic progression by PCWG3-modified RECIST 1.1 for subjects with 
measurable disease 
o Bone progression on bone scan according to the PCGW3 criteria 
o PSA progression according to the PCWG3 criteria accompanied by any one of the 
following: investigator-defined clinical progression or either of the above RECIST 1.1 or 
bone progression 
o Investigator-defined clinical progression 
o Death due to any cause. 
Objective Response Rate 
• 
The ORR rate is defined as the percentage of subjects with a confirmed CR or a PR at any time 
as per PCWG3-modified RECIST 1.1. 
CTC Response Rate 
• 
CTC response rate is defined as the proportion of subjects with a CTC conversion to <5/7.5 mL 
blood at nadir (confirmed by a second consecutive value obtained four or more weeks later) for 
subjects with unfavourable CTC at baseline. 
Composite Response Rate (CRR) 
• 
CRR is a composite endpoint based on the following – 
o Response based on PCWG3 modified RECIST 1.1 
o PSA decrease of ≥50% from baseline at Week 12 or thereafter  
o Or CTC count conversion from unfavourable (>=5/7.5mL) at baseline to favourable 
(<5/7.5mL) confirmed by a second assessment at least 4 weeks later. 
PSA Week 4 Response Rate (Week 4 RR) 
• 
PSA Week 4 response rate (Week 4 RR) is defined as the response rate that a PSA reduction 
from baseline ≥ 30% is observed at 4 weeks. 
Progression Free Survival 
• 
rPFS will be defined as the time from study treatment start until the first date of either disease 
progression or death due to any cause. The date of disease progression will be defined as the 
earliest date of disease progression as assessed by the investigator using PCWG3-modified 
RECIST 1.1 or progression on bone scan. 
13.6.4. 
Safety 
Treatment Compliance 
• 
Treatment compliance for GSK525762 will be calculated based on the formula:  
Treatment Compliance = Total Cumulative Actual Dose/ (Planned Treatment Duration in Days * 
Frequency) 
Extent of Exposure 
• 
Number of days of exposure to GSK525762/Abi/Enza will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• 
Participants who were not screen failures but did not report a treatment start date will be categorised 
as having zero days of exposure.  
• 
The cumulative dose for GSK525762 will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
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• 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
Adverse Events 
AE’S OF Special Interest 
• 
Haematopoietic thrombocytopenia SMQ  
• 
Haemorrhages [excl laboratory terms] [NARROW] SMQ  
• 
Anaemias nonhaemolytic and marrow depression HLGT 
• 
Torsade de pointes/QT prolongation [NARROW] SMQ   
• 
Drug related hepatic disorders - comprehensive search [NARROW] SMQ    
• 
Renal Prefered Terms 
 
13.6.5. 
Pharmacokinetic 
PK Parameters 
GSK525762, GSK525762 relevant metabolites (i.e. GSK3529246) and GSK525762 total active moiety (i.e. 
GSK525762 + GSK3529246 after conversion to nM concentrations) as well as abiraterone and 
enzalutamide  
• 
If the concentrations are presented in ng/mL, then the conversion factor to nM is to multiply the 
concentration by (1000/MW). 
• 
PK parameters to be derived: Cmax, AUC0-τ, Tmax and Cτ 
 
13.6.6. 
Value Evidence and Outcomes 
EORTC QLQ-C30 
• 
The EORTC-QLQ-C30 is composed of both multi-item scales and single-item measures. These 
include five functional scales, three symptom scales, a global health status / QoL scale, and six 
single items. Each of the multi-item scales includes a different set of items - no item occurs in 
more than one scale. 
• 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
➢ Thus, a high score for a functional scale represents a high / healthy level of 
functioning,  
➢ a high score for the global health status / QoL represents a high QoL,  
➢ but a high score for a symptom scale / item represents a high level of symptomatology 
/ problems. 
• 
The principle for scoring these scales is the same in all cases: 
➢ Estimate the average of the items that contribute to the scale; this is the raw score. 
➢ Use a linear transformation to standardise the raw score, so that scores range from 0 to 
100; a higher score represents a higher ("better") level of functioning, or a higher 
("worse") level of symptoms.  
Technical Summary 
 
In practical terms, if items I1, I2, ... In are included in a scale, the procedure is as follows: 
 
Raw score 
Calculate the raw score 
 
RawScore = 
 
 
Linear transformation 
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EORTC QLQ-C30 
Apply the linear transformation to 0-100 to obtain the score S, 
 
• 
Functional scales:
• 
Symptom scales / items:and Global health status / QoL: 
 
 
Range is defined as the difference between the maximum possible value of RS and the minimum possible 
value. The QLQ-C30 has been designed so that all items in any scale take the same range of values. 
Therefore, the range of RS equals the range of the item values. Most items are scored 1 to 4, giving range 
= 3. The exceptions are the items contributing to the global health status / QoL, which are 7-point questions 
with range = 6, and the initial yes/no items on the earlier versions of the QLQ-C30 which have range = 1. 
 
EORTC QLQ-C30 
 
Scale 
Number of 
Items 
Item Range 
Item 
Numbers 
Functional 
Scales 
“Item range” is the difference between the possible maximum and the minimum response to individual 
items; most items take values from 1 to 4, giving range= 3. 
 
*Items for the scales marked * are scored positively (i.e. “
” is best) and therefore use the same 
algebraic equation as for symptom scales; however, the Body Image scale uses the algebraic equation for 
functioning scales.  
 
EORTC-QLQ-PR25 
• 
While the EORTC-QLQ-C30 is an important tool for assessing the generic aspects of QOL, it has 
limitations and therefore a modular approach was adopted for disease-specific treatment 
measurements. An essential aspect of the “modular” approach to QoL assessment adopted by 
the EORTC Quality of Life Group is the development of modules specific to tumour site, treatment 
modality, or a QoL dimension, to be administered in addition to the core questionnaire (EORTC-
QLQ-C30). The modules, like the core questionnaire, are designed for use in cancer clinical trials. 
• 
The EORTC-QLQ-PR25 is a 25-item prostate cancer-specific scale intended to supplement, the 
EORTC QLQ-30. It includes subscales assessing urinary symptoms (9 items), bowel symptoms 
(4 items), treatment-related symptoms (6 items) and sexual functioning (6 items). There are six 
prostate-specific domains: Urinary, Bowel, Use of Incontinence Aids, Treatment-Related 
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EORTC-QLQ-PR25 
Symptoms, Sexual Active and Sexual Function. Item scores are summed and transformed to a 0-
100 scale; higher scores represent higher functioning for the two sexual domains but, conversely, 
higher scores represent more symptoms (i.e. worse HRQoL) for the symptom scales. Items are 
4-point Likert response options of 1 
 to 4 
 
• 
The principle for scoring these scales is the same in all cases: 
➢ Estimate the average of the items that contribute to the scale; this is the raw score. 
➢ Use a linear transformation to standardise the raw score, so that scores range from 0 to 
100; a higher score represents a higher ("better") level of functioning, or a higher 
("worse") level of symptoms.  
Technical Summary 
 
In practical terms, if items I1, I2, ... In are included in a scale, the procedure is as follows: 
 
Raw score 
Calculate the raw score 
 
RawScore = 
 
 
Linear transformation 
Apply the linear transformation to 0-100 to obtain the score S, 
 
• 
Functional scales:
• 
Symptom scales / items: 
 
 
Range is the difference between the maximum possible value of RS and the minimum possible value. The 
EORTC-QLQ-PR25 has been designed so that all items in any scale take the same range of values. 
Therefore, the range of RS equals the range of the item values. Items are scored 1 to 4, giving range = 3. 
 
EORTC QLQ-PR25 
 
Scale 
Number of 
Items 
Item Range 
Item 
Numbers 
Functional 
Scales 
“Item range” is the difference between the possible maximum and the minimum response to individual 
items. 
 
*Items for the scales marked * are scored positively (i.e. “
” is best) and therefore use the same 
algebraic equation as for symptom scales; however, the Body Image scale uses the algebraic equation for 
functioning scales. 
 
Core questionnaire: The EORTC-QLQ-C30 is a "core questionnaire" which incorporates a 
range of physical, emotional and social health issues relevant to a broad spectrum of cancer 
patients; the core questionnaire should be used, unmodified, in all QLQ assessments. 
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Items: The individual questions on the EORTC- QLQ-C30 are called items, and are 
described as Q1, Q2, Q3, etc., where the suffix corresponds to the question-number on the 
QLQ questionnaire. 
Module: The core questionnaire may be supplemented by diagnosis-specific and/or 
treatment- specific questionnaire modules. Modules should be used unmodified and in 
conjunction with the core questionnaire. 
Raw score: The score formed by averaging the items that are included in a particular 
function or symptom scale. 
Scales: The QLQ comprises distinct scales, each of which represents a different aspect of 
QoL. 
Scale score: The raw score transformed to a standardised 0 - 100 final "scale score". 
Brief Pain Inventory Short Form (BPI-SF) 
• 
The BPI-SF is a 9-item self-administered questionnaire. It uses simple numeric rating scales from 
0 to 10 and gives two main scores: a pain intensity score and a pain interference score. The two 
scores are calculated as follows:  
➢ Pain intensity score is calculated from the four items (items
 and
 for
, 
 and 
. Each item is rated from 0 
 to 10 
 
. The average of BPI-SF pain intensity will be calculated at 
each routine visit as the mean of the 4 scores for the 4 items of pain intensity. 
➢  Pain interference score is calculated from items
 to
and is used to rate the degree 
that pain interferes with 
, and 
. The seven sub-items are rated from 0 
, to 10 
 The average of BPI-SF pain 
interference will be calculated at each routine visit as the mean of the scores for the 7 
sub-items of pain interference. 
Technical Summary 
 
In practical terms, if items I1, I2, ... In are included in a scale, the procedure is as follows: 
 
Score 
Calculate the score as: 
 
Score = 
 
 
BPI-SF 
 
Scale 
Number of 
Items 
Item Range 
Item 
Numbers 
Functional 
Scales 
 
 
 
 
 
 
 
 
 
 
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Brief Pain Inventory Short Form (BPI-SF) 
 
 
 
 
 
 
“Range” is the difference between the possible maximum and the minimum response to individual items. 
 
Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events  (PRO-CTCAE) 
• 
The response frequency distribution and proportion of subjects for each PRO-CTCAE item by visit 
will be presented and grouped first by visit, then by related term. 
• 
For subjects who do not have a response due to skipping patterns, they should be reported as 
“Not applicable”. Other subjects who do not provide a response or have dropped out would be 
treated as missing data. The number of subjects who provide a response should be reflected in 
the number of observations for the sample. 
• 
In addition to reporting the number and percent of subjects who have selected each response 
category, assign a value (See coding table below: 
 for 
; 
 for 
) and calculate the Mean (SD) and Median values for all 
subjects who have a valid response for a given visit. Subjects with missing or incomplete data 
(either due to drop outs, or subjects who have not provided a response – either due to missing 
data or skip patterns) should be excluded from calculating the Mean and Median. 
 
Levels and related code values 
• 
PRO-CTCAE responses should also be summarized by changes in health state. For each subject 
compare their current response with the response from their prior assessment and determine 
whether their symptoms improved, worsened or were stable: 
➢ Improved = current response level < prior response level 
➢ Worsened = current response level > prior response level 
➢ Stable = current response level = prior response level 
• 
Due to conditional branching and skip patterns it is possible that a response option may be 
missing, in these cases, the lowest level would be imputed in order to calculate the state change.  
Subjects who have data missing for other reasons (missing data, drop out) will be excluded for 
any item/visit where they have missing data. 
• 
In addition to reporting the response frequencies by visit, as suggested by FDA, report the results 
of PRO-CTCAE alongside the corresponding clinician-graded CTCAE results. 
• 
Categorize the highest level reported as either “Any Level” (subjects who had either a CTCAE or 
PRO-CTCAE response >0) or “High Level” (subjects who experienced ≥3 grade CTCAE or PRO-
CTCAE response). 
• 
Listings should include responses values (0-4, null for missing) for all PRO-CTCAE Items by 
subject by visit. 
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13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
All available data from subjects who were withdrawn from the study will be listed and 
all available planned data will be included in summary tables and figures, unless 
otherwise specified. 
13.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Responder 
Analysis  
For endpoints which determine the percentage of responders, subjects with unknown or 
missing response will be treated as non-responders and will be included in the denominator 
when calculating the percentages. 
13.7.2.1. 
Handling of Missing and Partial Dates 
Imputed partial dates can be used to derive study day, duration, or elapsed time variables 
unless otherwise specified. Imputed dates will not be used for deriving the last contact 
date in the overall survival analysis dataset. 
With the exception of new anti-cancer start date on the Oncology time to event analysis 
dataset and exposure end date on the Exposure analysis dataset, imputed dates will also 
not be stored on datasets.  
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition, partial dates may be imputed for ‘slotting’ data to study time periods or 
for specific analysis purposes as outlined below.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
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Example of date variables:  
XYZD_ - character date variable 
XYZDT - numeric date variable 
XYZDTFL - flag variable 
Details on imputing partial dates for specific datasets are outlined below. 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in subject listing displays. 
Adverse Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) 
to be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the 
start date of study treatment; in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
4: Study Phases and Treatment Emergent Adverse Events 
o Missing Stop Day: Last day of the month will be used, unless this is after 
the stop date of study treatment; in this case the study treatment stop date 
will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing. If completely missing start dates, TEAE flag is Yes. 
• 
Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied. 
Anti-Cancer 
Therapy 
and 
Radiotherapy 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. 
• 
Partial start dates will be imputed using the following convention:  
o If both month and day are missing, no imputation will be applied  
o If only day is missing:  
▪ 
If the month of partial date is the same as the month of last dosing 
date, minimum of (last dosing date + 1, last day of the month) will 
be used for the day.  
▪ 
If the month of partial date is the same as the month of last 
disease assessment and the last disease assessment is PD, 
minimum of (last date of disease assessment + 1, last day of the 
month) will be used for the day.  
▪ 
If both conditions above are met, the later date will be used for 
the day.  
▪ 
Otherwise, a ‘01’ will be used for the day. 
• 
No imputation for partial end dates will be performed. 
Surgical Procedures • 
Completely missing start or end dates will remain missing, with no imputation 
applied. 
• 
Partial start dates will be imputed using the following convention:  
o If both month and day are missing, no imputation will be applied  
o If only day is missing:  
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▪ 
If the month of partial date is the same as the month of last dosing 
date, minimum of (last dosing date + 1, last day of the month) will 
be used for the day.  
▪ 
If the month of partial date is the same as the month of last 
disease assessment and the last disease assessment is PD, 
minimum of (last date of disease assessment + 1, last day of the 
month) will be used for the day.  
▪ 
If both conditions above are met, the later date will be used for 
the day.  
▪ 
Otherwise, a ‘01’ will be used for the day. 
• 
No imputation for partial end dates will be performed. 
Concomitant 
Medications/Medical 
History/Blood 
Products 
• 
Partial dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
• 
No Imputation for completely missing start or end dates 
Time to Event and 
Response for Anti-
Cancer Therapy 
Where applicable: 
Radiotherapy, 
Surgical Procedures 
 
• 
Start dates for subsequent anti-cancer therapy, radiotherapy (where 
applicable), and surgical procedures (where applicable) will be temporarily 
imputed in order to define event and censoring rules for progression-free 
survival, response rate, or duration of response (i.e. start date for new anti-
cancer therapy). Dates will only be imputed when a month and year are 
available, but the day is missing. The imputed dates will not be stored on the 
anti-cancer therapy, radiotherapy, or surgical procedure datasets. The 
following rules will be used to impute the date when partial start dates are 
present on anti-cancer therapy radiotherapy, and/or surgical procedures 
datasets. 
• 
No Imputation for completely missing start dates 
• 
No imputation for missing start day and month (note: the eCRF should only 
allow for missing day) 
• 
If partial start date falls in the same month as the last dose of study treatment, 
then assign to earlier of (date of last dose of study treatment+1, last day of 
month).  
• 
If partial start date falls in the same month as the subject’s last assessment 
and the subject’s last assessment is progressive disease (PD), then assign to 
earlier of (date of PD+1, last day of month).  
• 
If both rules above apply, then assign to latest of the 2 dates  
• 
Otherwise, impute missing day to the first of the month. 
• 
No imputation for partial end dates will be performed 
GSK525762/ 
abiraterone / 
enzalutamide 
Exposure End 
Dates for Subjects 
Who Are Still on 
Study at the Time of 
Analysis 
• 
If treatment discontinuation date is missing, then assign exposure end date as 
the earliest of:  
o the date of the data cut-off,  
o the date of withdrawal from the study, or  
o the date of death. 
• 
The imputed exposure end date will be used to calculate cumulative dose and 
exposure duration. 
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• 
The imputed exposure end date will be stored in the exposure analysis dataset 
and an exposure end date imputation flag variable will be derived indicating 
which exposure end date records are imputed.  
• 
Imputed exposure end dates will also be stored on the study treatment end 
date variable. 
• 
For subjects who are still on study treatment, the on-therapy indicator variables 
(time in relation to study treatment) are assigned to on-therapy for all records 
where the 'dataset' 'date' is after or on the study treatment start date 
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13.8. 
Appendix 8: Values of Potential Clinical Importance 
13.8.1. 
Laboratory Values 
Reference ranges for all laboratory parameters collected throughout the study are provided 
by the laboratory. A laboratory value that is outside the reference range is considered either 
high abnormal (value above the upper limit of the reference range) or low abnormal (value 
below the lower limit of the reference range). Note: a high abnormal or low abnormal 
laboratory value is not necessarily of clinical concern. The laboratory reference ranges will 
be provided on the listings of laboratory data. Clinical laboratory test results outside of the 
reference range will be flagged in the listings. 
To identify laboratory values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign grades to the relevant laboratory parameters. NCI-CTCAE v4.0 can be found 
at http://ctep.cancer.gov/reporting/ctc.html.  
For laboratory data which are not listed in the NCI CTCAE v4.0, a summary of values 
outside the normal range will be provided. 
13.8.2. 
ECG 
Following table show the potential clinical importance criteria of 12-Lead ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
≥ 450 
< 481  
≥ 481  
< 501 
≥ 501  
 
Absolute PR Interval 
msec 
< 110  
> 220  
Absolute QRS Interval 
msec 
< 75  
> 110  
Change from Baseline 
Decrease from baseline QTcF 
Interval 
msec 
> 30 
≤ 60  
> 60  
 
Increase from Baseline QTcF 
msec 
 
>30 
≤ 60   
> 60  
 
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13.8.3. 
Vital Signs 
13.8.4. 
Left Ventricular Ejection Fraction 
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used 
to assign categories that align with the grades for ‘Ejection fraction decreased’. 
LVEF 
Units 
Clinical Concern Range 
Absolute Change from Baseline 
% 
0= < Increase < 10 
 
% 
10 ≤ Increase < 20 
 
% 
Increase ≥ 20 
 
% 
0 < Decrease < 10 
 
% 
10 ≤ Decrease < 20 
 
% 
Decrease ≥ 20 
 
% 
Decrease ≥ 0 and ≥ LLN 
 
% 
Decrease ≥ 10 and < LLN 
Relative Percent Change from Baseline 
% 
Decrease ≥ 20 and ≥ LLN 
 
% 
Decrease ≥ 20 and < LLN 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
>120   
<140 (Grade 1) 
mmHg 
≥140   
<160 (Grade 2) 
mmHg 
 
≥160 (Grade 3) 
Diastolic Blood Pressure 
mmHg 
> 80   
< 90 (Grade 1) 
mmHg 
≥ 90  
< 100 (Grade 2) 
mmHg 
 
≥ 100 (Grade 3) 
Heart Rate 
bpm 
< 60  
> 100 
Temperature 
Degrees C 
≤ 35 
≥ 38 
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13.9. 
Appendix 9: Abbreviations & Trade Marks 
13.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
AUC(0-τ)  
Area under the curve over a dosing interval 
BID 
Bis in die - Twice daily 
BP 
Blood Pressure 
BPI 
Brief Pain Inventory 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
Cmax  
Maximum observed concentration 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CRPC 
Castrate-resistant prostate cancer 
CRR 
Composite response rate 
CR 
Complete response 
CNV 
Copy number variation 
CSMU 
Clinically significant minimum utility 
CSR 
Clinical Study Report 
Cτ 
Pre-dose (trough) concentration at the end of a dosing 
interval 
CTC 
Circulating tumor cells 
DBF 
Database freeze 
DBR 
Database Release 
DCR 
Disease Control Rate 
DDI 
Drug-drug interactions 
DL80 
80 mg Dose Level 
DL120 
120 mg Dose Level 
DLT 
Dose-limiting toxicity 
DP 
Decimal Places 
DS 
Disposition dataset  
dU  
Utility of a given dose 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Record Form 
EC50 
50% of the maximum effect 
Emax 
Maximum effect 
EORTC – QLQ-
C30 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core-30 
EORTC – QLQ-
PR25 
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Core-25 
GSK 
GlaxoSmithKline 
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IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
LLN 
Lower limit of normal 
LVEF 
Left Ventricular Ejection Fraction 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
Maximum feasible dose 
mTPI 
Modified toxicity probability interval 
MTD 
Maximum tolerated dose 
NE 
Not evaluable 
NCI-CTCAE  
National Cancer Institute-Common Terminology Criteria 
NGS 
Next‐generation sequencing 
ORR 
Overall response rate 
OS 
Overall survival 
PCWG3  
Prostate cancer working group 3 
PD 
Progressive Disease 
PK 
Pharmacokinetic 
PR 
Partial response 
PRO-CTCAE 
Patient-Reported Outcomes Version of the Common 
Terminology Criteria for Adverse Events 
PSA 
Prostate-specific antigen 
PSA50 
Prostate-specific antigen from baseline ≥50% 
PSMA 
Prostate-specific membrane antigen 
PT 
Preferred term 
QoL 
Quality of life 
QTcF 
Friderica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RECIST 
Response Evaluation Criteria In Solid Tumours 
RP2D 
Recommended Phase II dose 
rPFS 
Radiological progression free survival 
RR 
Response rate 
RNA 
Ribonucleic acid 
RS 
Response dataset  
SAE 
Serious adverse event 
SAC 
Statistical Analysis Complete 
SD 
Stable disease 
SDTM 
Study Data Tabulation Model 
SNV 
Single-nucleotide variants 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
SRT 
Safety review team 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
Tmax 
Time to maximum concentration 
TTG 
Time to tumour growth 
ULN 
Upper limit of normal 
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13.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group 
of Companies 
 
Trademarks 
not 
owned 
by 
the 
GlaxoSmithKline Group of Companies 
NONE 
 
Phoenix  
 
 
SAS 
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13.10. 
Appendix 10: List of Data Displays 
13.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
13.10.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays. 
13.10.3. 
Deliverables 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.23 
 
Efficacy 
2.1 to 2.19 
2.1 to 2.10 
Safety 
3.1 to 3.65 
 
Pharmacokinetic 
4.1 to 4.13 
4.1 to 4.4 
Section 
Listings 
ICH Listings 
1 to 58 
Other Listings 
59 to 80 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES: Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column 
as ‘[Non-Standard] + Reference.’ 
Delivery  
Description 
DE 
Dose Escalation 
IA 
Interim Analysis 
SAC 
Primary Statistical Analysis Complete 
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13.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1.  
All Treated 
ES1 
Summary of Subject Status and Reason for Study Withdrawal 
By Dose Level for each Arm 
Order Reasons for Study 
Withdrawal as displayed in the 
eCRF. 
IA, SAC 
1.2.  
All Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
By Dose Level for each Arm 
SAC 
1.3.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of GSK525762 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
IA, SAC 
1.4.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of enzalutamide 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
IA, SAC 
1.5.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of abiraterone 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
SAC 
Populations Analysed 
1.6.  
All Screened 
SP1 
Summary of Study Population 
By Dose Level for each Arm  
Add footnote with populations 
definition/criteria. 
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Protocol Deviations 
1.7.  
All Treated 
DV1 
Summary of Major Protocol Deviations 
By Dose Level for each Arm 
SAC 
Demographic and Baseline Characteristics 
1.8.  
All Treated 
DM1 
Summary of Demographic Characteristics 
By Dose Level for each Arm 
DE, IA, SAC 
1.9.  
All Treated 
DM8 
Summary of Race and Racial Combinations 
By Dose Level for each Arm 
SAC 
1.10. 
All Treated 
DM11 
Summary of Age Ranges 
By Dose Level for each Arm 
SAC 
1.11. 
All Treated 
PS1A 
Summary of Performance Status at Baseline 
By Dose Level for each Arm  
Only include Baseline visit 
from Standard 
SAC 
1.12. 
All Treated 
LA1 
Summary of Disease Burden at Baseline 
By Dose Level for each Arm 
SAC 
1.13. 
All Treated 
DC1 
Summary of Disease Characteristics at Initial Diagnosis 
By Dose Level for each Arm 
Include in summary: stage at 
initial diagnosis, time since 
latest disease progression (in 
weeks), method by which 
progression was determined 
(radiological vs PSA rise) on 
prior disease progression 
IA, SAC 
1.14. 
All Treated 
DC2 
Summary of Disease Characteristics at Screening 
By Dose Level for each Arm 
IA, SAC 
Prior and Concomitant Medications 
1.15. 
All Treated 
MH1 
Summary of Prior Medical Conditions 
By Dose Level for each Arm 
SAC 
1.16. 
All Treated 
MH1 
Summary of On Treatment Medical Conditions 
By Dose Level for each Arm 
SAC 
1.17. 
All Treated 
OSP1 
Summary of Prior Cancer-Related Surgical Procedures 
By Dose Level for each Arm 
SAC 
1.18. 
All Treated 
OSP1 
Summary of On Treatment Cancer Related Surgical 
Procedure 
By Dose Level for each Arm 
SAC 
1.19. 
All Treated 
CM8 
Summary of Concomitant Medication by Ingredient 
By Dose Level for each Arm 
SAC 
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Medications to be sorted in 
descending order of overall 
incidence.  
Anti-Cancer Therapies 
1.20. 
All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
By Dose Level for each Arm 
IA, SAC 
1.21. 
All Treated 
CM1 
Summary of Prior Dictionary Coded Anti-Cancer Therapy  
By Dose Level for each Arm 
SAC 
1.22. 
All Treated 
AC3 
Summary of Number of Prior Anti-Cancer Therapy Regimens 
By Dose Level for each Arm 
SAC 
1.23. 
All Treated 
AC4 
Summary of Best Response to the Most Recent Prior Anti-
Cancer Therapy 
By Dose Level for each Arm 
IA, SAC 
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Study Population Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1.  
All Treated 
ES1 
Summary of Subject Status and Reason for Study Withdrawal 
By Dose Level for each Arm 
Order Reasons for Study 
Withdrawal as displayed in the 
eCRF. 
IA, SAC 
1.2.  
All Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
By Dose Level for each Arm 
SAC 
1.3.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of GSK525762 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
IA, SAC 
1.4.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of enzalutamide 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
IA, SAC 
1.5.  
All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of abiraterone 
By Dose Level for each Arm  
Order Reasons for 
Discontinuation as displayed in 
the eCRF 
SAC 
Populations Analysed 
1.6.  
All Screened 
SP1 
Summary of Study Population 
By Dose Level for each Arm  
Add footnote with populations 
definition/criteria. 
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Protocol Deviations 
1.7.  
All Treated 
DV1 
Summary of Major Protocol Deviations 
By Dose Level for each Arm 
SAC 
Demographic and Baseline Characteristics 
1.8.  
All Treated 
DM1 
Summary of Demographic Characteristics 
By Dose Level for each Arm 
DE, IA, SAC 
1.9.  
All Treated 
DM8 
Summary of Race and Racial Combinations 
By Dose Level for each Arm 
SAC 
1.10. 
All Treated 
DM11 
Summary of Age Ranges 
By Dose Level for each Arm 
SAC 
1.11. 
All Treated 
PS1A 
Summary of Performance Status at Baseline 
By Dose Level for each Arm  
Only include Baseline visit 
from Standard 
SAC 
1.12. 
All Treated 
LA1 
Summary of Disease Burden at Baseline 
By Dose Level for each Arm 
SAC 
1.13. 
All Treated 
DC1 
Summary of Disease Characteristics at Initial Diagnosis 
By Dose Level for each Arm 
Include in summary: stage at 
initial diagnosis, time since 
latest disease progression (in 
weeks), method by which 
progression was determined 
(radiological vs PSA rise) on 
prior disease progression 
IA, SAC 
1.14. 
All Treated 
DC2 
Summary of Disease Characteristics at Screening 
By Dose Level for each Arm 
IA, SAC 
Prior and Concomitant Medications 
1.15. 
All Treated 
MH1 
Summary of Prior Medical Conditions 
By Dose Level for each Arm 
SAC 
1.16. 
All Treated 
MH1 
Summary of On Treatment Medical Conditions 
By Dose Level for each Arm 
SAC 
1.17. 
All Treated 
OSP1 
Summary of Prior Cancer-Related Surgical Procedures 
By Dose Level for each Arm 
SAC 
1.18. 
All Treated 
OSP1 
Summary of On Treatment Cancer Related Surgical 
Procedure 
By Dose Level for each Arm 
SAC 
1.19. 
All Treated 
CM8 
Summary of Concomitant Medication by Ingredient 
By Dose Level for each Arm 
SAC 
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13.10.5. 
Efficacy Tables 
Medications to be sorted in 
descending order of overall 
incidence.  
Anti-Cancer Therapies 
1.20. 
All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
By Dose Level for each Arm 
IA, SAC 
1.21. 
All Treated 
CM1 
Summary of Prior Dictionary Coded Anti-Cancer Therapy  
By Dose Level for each Arm 
SAC 
1.22. 
All Treated 
AC3 
Summary of Number of Prior Anti-Cancer Therapy Regimens 
By Dose Level for each Arm 
SAC 
1.23. 
All Treated 
AC4 
Summary of Best Response to the Most Recent Prior Anti-
Cancer Therapy 
By Dose Level for each Arm 
IA, SAC 
Efficacy: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PSA Response Rate 
2.1.  
Modified All 
Treated 
PSA_NS1 
Summary of PSA Response determined >= 12 Weeks after 
Treatment (With Confirmation) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total  
Add baseline PSA value. 
IA, SAC 
2.2.  
Modified All 
Treated 
PSA_NS1 
Summary of PSA Response determined >= 12 Weeks after 
Treatment (With Confirmation) by Prior Treatment (Lx or L2) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Add baseline PSA value. 
IA, SAC 
2.3.  
Modified All 
Treated 
PSA_NS1 
Summary of PSA Response determined >= 12 Weeks after 
Treatment (With and Without Confirmation) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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Add baseline PSA value. 
2.4.  
Modified All 
Treated 
PSA_NS1 
Summary of PSA Response determined >= 12 Weeks after 
Treatment (With and Without Confirmation) by Prior Treatment 
(Lx or L2) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add baseline PSA value. 
IA, SAC 
Secondary Endpoints 
2.5.  
Modified All 
Treated 
RE1c 
Summary of Investigator-Assessed Disease Control Rate with 
Confirmation (RECIST 1.1 Criteria) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.6.  
Modified All 
Treated 
TTE6 
Summary of Kaplan-Meier Estimates of Time to Progression 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.7.  
Modified All 
Treated 
RE1a 
Summary of Best Overall Response (With Confirmation) 
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC  
2.8.  
Modified All 
Treated 
RE1a 
Summary of Best Overall Response (With and Without 
Confirmation)  
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC  
2.9.  
Modified All 
Treated 
RE1a 
Summary of Best Overall Response (With Confirmation) by 
prior treatment (Lx or L2) 
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC  
2.10. 
 Modified All 
Treated 
RE1a 
Summary of Best Overall Response (With and Without 
Confirmation) by prior treatment (Lx or L2) 
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC  
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2.11. 
 Modified All 
Treated 
RE1a 
Summary of Investigator Assessed Best Response (With 
Confirmation)  
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.12. 
 Modified All 
Treated 
RE1a 
Summary of Investigator Assessed Best Response ( Without 
Confirmation)  
Include DCR. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.13. 
 Modified All 
Treated 
RE1a 
Summary of CTC Response (Confirmed) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Subjects with 
CTC<5/7.5 mL at baseline will 
be excluded from this analysis” 
SAC 
2.14. 
 Modified All 
Treated 
LB1 
Summary of Percent Change from Baseline in CTC Actual 
Count by Visit 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.15. 
 Modified All 
Treated 
RE1a 
Summary of Composite Response Rate (CRR) (Confirmed) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
 SAC 
2.16. 
 Modified All 
Treated 
RE1a 
Summary of Week 4 PSA Response Rate 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.17. 
 Modified All 
Treated 
PSA_NS1 
Summary of Week 4 PSA Response Rate – Confirmed 
Include percentage of subjects 
having PSA ≥ 25% increase 
from baseline at 4 weeks.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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13.10.6. 
Efficacy Figures 
2.18. 
 Modified All 
Treated 
TTE6 
Summary of Kaplan-Meier Estimates of Radiographic 
Progression-Free Survival (rPFS) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.19. 
 Modified All 
Treated 
PPUF_NS6 
Summary of Posterior Probabilities for Utility Function. 
By Arm. By L2 vs. Lx 
subgroups and total 
IA 
Efficacy: Figures 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.1.  
Modified All 
Treated 
RE8A 
Waterfall Plot of Maximum Reduction from Baseline in PSA  
The plot will be color-coded for 
best overall response with 
confirmation. Indication of the 
subject number and dose level 
will be provided below the plot. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.2.  
Modified All 
Treated 
SP_NS7 
Spider Plot with Percent Change at Maximum Reduction from 
Baseline in PSA  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.3.  
Modified All 
Treated 
SP_NS7 
Spider Plot of Percent Change from Baseline in PSA 
Indication of the subject number 
and dose level will be provided 
below the plot. 
By Dose Level for each Arm. 
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2.4.  
Modified All 
Treated 
SP_NS7 
Spider Plot of Percent Change from Baseline in PSA by Prior 
Treatment (Lx or L2) 
Indication of the subject number 
and dose level will be provided 
below the plot. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
2.5.  
Modified All 
Treated 
RE8A 
Waterfall Plot of Investigator Assessed Maximum Percent 
Reduction from Baseline in Tumour Measurement in Target 
Lesions 
The plot will be color-coded for 
best response with confirmation. 
Indication of the subject number 
and dose level will be provided 
below the plot. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.6.  
Modified All 
Treated 
SP_NS7 
Spider Plot of Percent Change from Baseline in Target Tumour 
Size 
Indication of the subject number 
and dose level will be provided 
below the plot. 
By Dose Level for each Arm. 
IA, SAC 
2.7.  
Modified All 
Treated 
SP_NS7 
Spider Plot of Percent Change from Baseline in Target Tumour 
Size by Prior Treatment (Lx or L2) 
Indication of the subject number 
and dose level will be provided 
below the plot. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
2.8.  
Modified All 
Treated 
RE8A 
Waterfall Plot of Percent Change at Maximum Reduction from 
Baseline in CTC Counts  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
2.9.  
Modified All 
Treated 
SP_NS7 
Spider Plot of CTC Counts Percent Change from Baseline Over 
Time 
For subjects with unfavourable 
CTC at baseline. 
By Dose Level for each Arm.  
SAC 
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13.10.7. 
Safety Tables 
By L2 vs. Lx subgroups and 
total. 
2.10. 
Modified All 
Treated 
TTE10 
Kaplan Meier Plot of Radiographic Progression-Free Survival 
(rPFS) 
The plot will be color-coded for 
dose level for each arm. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1.  
All Treated 
OEX1 
Summary of Exposure to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary.  
Duration of exposure=Last dose 
date – first dose date +1; will be 
categorized into <3d, 3d-<6d, 
6d-<12d, >=12d.  
Avg. daily dose=cumulative 
dose / duration of exposure. 
DE, IA, SAC 
3.2.  
All Treated 
OEX1 
Summary of Exposure to abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
DE, SAC 
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In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
3.3.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
DE, IA, SAC 
3.4.  
All Treated 
OEX1 
Summary of Exposure to abiraterone – Lead in Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.5.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide – Lead in Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.6.  
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
 SAC 
3.7.  
All Treated 
ODMOD1 
Summary of Dose Reductions of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
3.8.  
All Treated 
ODMOD1 
Summary of Dose Reductions of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
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3.9.  
All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Categories <7, 7-14, >14 days 
for duration of interruption  
SAC 
3.10. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.11. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.12. All Treated 
ODMOD8 
Summary of Dose Escalations of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.13. All Treated 
AE19 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Adverse Events 
3.14. All Treated 
AE13 
Summary of Adverse Event Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.15. All Treated 
AE3 
Summary of Adverse Event Related to Any Study Treatment 
By Dose Level for each Arm.  
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By L2 vs. Lx subgroups and 
total. 
3.16. All Treated 
AE3 
Summary of Adverse Event Related to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.17. All Treated 
AE13 
Summary of Adverse Event of Grade 3-4 Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.18. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 Related to Any Study 
Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.19. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 related to 
GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.20. All Treated 
AE16 
Summary of Adverse Events by System Organ Class and 
Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.21. All Treated 
AE15 
Summary of Common 5% Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences) 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.22. All Treated 
AE5B 
Summary of All Adverse Events by Maximum Toxicity Grade by 
System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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3.23. All Treated 
AE5B 
Summary of Any Drug-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.24. All Treated 
AE5B 
Summary of All Adverse Events Related to GSK525762- by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.25. All Treated 
AE5B 
Summary of enzalutamide-Related Adverse Events by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.26. All Treated 
AE5B 
Summary of abiraterone-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
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3.27. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.28. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.29. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.30. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.31. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.32. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.33. All Treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, IA, SAC 
3.34. All Treated 
AE20 
Summary of Any Drug-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.35. All Treated 
AE20 
Summary of GSK525762-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
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3.36. All Treated 
AE3 
Summary of Adverse Events Classified as Dose-Limiting 
Toxicities (DLTs) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.37. All Treated 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by Preferred Term Regardless of Relatedness 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.38. All Treated 
AE5B 
Summary of Adverse Events of Special Interest Regardless of 
Relatedness 
By Event category, PT.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.39. All Treated 
ESI1 
Summary of Characteristics of Adverse Events of Special 
Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.40. All Treated 
ESI2b 
Summary of Onset and Duration of the First Occurrence (Days) 
of Treatment Emergent Adverse Events of Special Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
SAC 
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By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
3.41. All Treated 
DD1 
Summary of Deaths 
Include number of patients for 
which an SAE resulted in death. 
SAC 
Laboratory: Chemistry 
3.42. All Treated 
LB1 
Summary of Chemistry Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.43. All Treated 
LB18 
Summary of Chemistry Grade Changes from Baseline 
For lab tests that are not graded 
include worst case grade 
change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.44. All Treated 
LB3 
Summary of Chemistry Changes from Baseline with Respect to 
the Normal Range  
For lab tests that are not graded 
include worst case grade 
change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Haematology 
3.45. All Treated 
LB1 
Summary of Haematology Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.46. All Treated 
LB18 
Summary of Haematology Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
SAC 
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95 
 
By L2 vs. Lx subgroups and 
total. 
3.47. All Treated 
LB3 
Summary of Haematology Changes from Baseline with 
Respect to the Normal Range  
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Liver Events 
3.48. All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.49. All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Urinalysis 
3.50. All Treated 
UR1 
Summary of Worst-case Urinalysis Result Increases from 
Baseline 
Include tests done by Dipstick – 
Specific gravity, pH, Glucose, 
Protein, Blood, Ketones.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.51. All Treated 
LB18 
Summary of Urinalysis Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
 SAC 
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Coagulation 
3.52. All Treated 
LB3 
Summary of Coagulation Changes from Baseline with Respect 
to Normal Range 
Include worst case grade 
change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Vital Signs 
3.53. All Treated 
VS1 
Summary of Vital Signs 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.54. All Treated 
VS1 
Summary of Vital Sign Changes from Baseline 
Include all Vital Signs. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
ECG 
3.55. All Treated 
EG1 
Summary of ECG Findings 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.56. All Treated 
EG2 
Summary of ECG Findings Change from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
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3.57. All Treated 
EG10A 
Summary of Maximum QTcF Value Post-Baseline Relative to 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
3.58. All Treated 
EG11A 
Summary of Maximum Increase in QTcF Values Post-Baseline 
Relative to Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
Performance Status  
3.59. All Treated 
PS1A 
Summary of Performance Status 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.60. All Treated 
PS3A 
Summary of Change in Performance Status from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
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Left Ventricular Ejection Fraction 
3.61. 
All Treated 
OLVEF1A 
Summary of Left Ventricular Ejection Fraction Change from 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used  
the same method (i.e. 
Electrocardiogram ECHO or 
Multiple Grated Acquisition 
MUGA) and the same source 
(i.e. local or central cardiologist 
read) as the baseline 
assessments  are used to 
derive the change from 
baseline.” 
SAC 
Value Evidence and Outcomes 
3.62. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-C30 and Change from Baseline in 
EORTC-QLQ-C30 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.63. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-PR25 and Change from Baseline in 
EORTC-QLQ-PR25 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
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3.64. 
Modified All 
Treated 
SF4_NS2 
Summary of BPI-SF and Change from Baseline in BPI-SF 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.65. 
Modified All 
Treated 
SF4_NS2 
Summary of PRO-CTCAE  and Change from Baseline in PRO-
CTCAE 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1.  
All Treated 
OEX1 
Summary of Exposure to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary.  
Duration of exposure=Last dose 
date – first dose date +1; will be 
categorized into <3d, 3d-<6d, 
6d-<12d, >=12d.  
Avg. daily dose=cumulative 
dose / duration of exposure. 
DE, IA, SAC 
3.2.  
All Treated 
OEX1 
Summary of Exposure to abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
DE, SAC 
3.3.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
DE, IA, SAC 
3.4.  
All Treated 
OEX1 
Summary of Exposure to abiraterone – Lead in Period 
By Dose Level for each Arm.  
SAC 
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By L2 vs. Lx subgroups and 
total. 
3.5.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide – Lead in Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.6.  
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
 SAC 
3.7.  
All Treated 
ODMOD1 
Summary of Dose Reductions of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
3.8.  
All Treated 
ODMOD1 
Summary of Dose Reductions of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
3.9.  
All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Categories <7, 7-14, >14 days 
for duration of interruption  
SAC 
3.10. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
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3.11. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.12. All Treated 
ODMOD8 
Summary of Dose Escalations of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.13. All Treated 
AE19 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Adverse Events 
3.14. All Treated 
AE13 
Summary of Adverse Event Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.15. All Treated 
AE3 
Summary of Adverse Event Related to Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.16. All Treated 
AE3 
Summary of Adverse Event Related to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.17. All Treated 
AE13 
Summary of Adverse Event of Grade 3-4 Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.18. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 Related to Any Study 
Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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3.19. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 related to 
GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.20. All Treated 
AE16 
Summary of Adverse Events by System Organ Class and 
Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.21. All Treated 
AE15 
Summary of Common 5% Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences) 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.22. All Treated 
AE5B 
Summary of All Adverse Events by Maximum Toxicity Grade by 
System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.23. All Treated 
AE5B 
Summary of Any Drug-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.24. All Treated 
AE5B 
Summary of All Adverse Events Related to GSK525762- by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
SAC 
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By L2 vs. Lx subgroups and 
total. 
3.25. All Treated 
AE5B 
Summary of enzalutamide-Related Adverse Events by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.26. All Treated 
AE5B 
Summary of abiraterone-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.27. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.28. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.29. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.30. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
any Study Treatment 
By Dose Level for each Arm.  
SAC 
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By L2 vs. Lx subgroups and 
total. 
3.31. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.32. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.33. All Treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, IA, SAC 
3.34. All Treated 
AE20 
Summary of Any Drug-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.35. All Treated 
AE20 
Summary of GSK525762-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.36. All Treated 
AE3 
Summary of Adverse Events Classified as Dose-Limiting 
Toxicities (DLTs) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.37. All Treated 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by Preferred Term Regardless of Relatedness 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.38. All Treated 
AE5B 
Summary of Adverse Events of Special Interest Regardless of 
Relatedness 
By Event category, PT.  
By Dose Level for each Arm.  
IA, SAC 
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106 
 
By L2 vs. Lx subgroups and 
total. 
3.39. All Treated 
ESI1 
Summary of Characteristics of Adverse Events of Special 
Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.40. All Treated 
ESI2b 
Summary of Onset and Duration of the First Occurrence (Days) 
of Treatment Emergent Adverse Events of Special Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.41. All Treated 
DD1 
Summary of Deaths 
Include number of patients for 
which an SAE resulted in death. 
SAC 
Laboratory: Chemistry 
3.42. All Treated 
LB1 
Summary of Chemistry Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.43. All Treated 
LB18 
Summary of Chemistry Grade Changes from Baseline 
For lab tests that are not graded 
include worst case grade 
change. 
SAC 
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By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
3.44. All Treated 
LB3 
Summary of Chemistry Changes from Baseline with Respect to 
the Normal Range  
For lab tests that are not graded 
include worst case grade 
change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Haematology 
3.45. All Treated 
LB1 
Summary of Haematology Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.46. All Treated 
LB18 
Summary of Haematology Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.47. All Treated 
LB3 
Summary of Haematology Changes from Baseline with 
Respect to the Normal Range  
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Liver Events 
3.48. All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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3.49. All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Urinalysis 
3.50. All Treated 
UR1 
Summary of Worst-case Urinalysis Result Increases from 
Baseline 
Include tests done by Dipstick – 
Specific gravity, pH, Glucose, 
Protein, Blood, Ketones.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.51. All Treated 
LB18 
Summary of Urinalysis Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
 SAC 
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Coagulation 
3.52. All Treated 
LB3 
Summary of Coagulation Changes from Baseline with Respect 
to Normal Range 
Include worst case grade 
change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Vital Signs 
3.53. All Treated 
VS1 
Summary of Vital Signs 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.54. All Treated 
VS1 
Summary of Vital Sign Changes from Baseline 
Include all Vital Signs. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
ECG 
3.55. All Treated 
EG1 
Summary of ECG Findings 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.56. All Treated 
EG2 
Summary of ECG Findings Change from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
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3.57. All Treated 
EG10A 
Summary of Maximum QTcF Value Post-Baseline Relative to 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
3.58. All Treated 
EG11A 
Summary of Maximum Increase in QTcF Values Post-Baseline 
Relative to Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
Performance Status  
3.59. All Treated 
PS1A 
Summary of Performance Status 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.60. All Treated 
PS3A 
Summary of Change in Performance Status from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
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Left Ventricular Ejection Fraction 
3.61. 
All Treated 
OLVEF1A 
Summary of Left Ventricular Ejection Fraction Change from 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used  
the same method (i.e. 
Electrocardiogram ECHO or 
Multiple Grated Acquisition 
MUGA) and the same source 
(i.e. local or central cardiologist 
read) as the baseline 
assessments  are used to 
derive the change from 
baseline.” 
SAC 
Value Evidence and Outcomes 
3.62. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-C30 and Change from Baseline in 
EORTC-QLQ-C30 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.63. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-PR25 and Change from Baseline in 
EORTC-QLQ-PR25 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
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3.64. 
Modified All 
Treated 
SF4_NS2 
Summary of BPI-SF and Change from Baseline in BPI-SF 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.65. 
Modified All 
Treated 
SF4_NS2 
Summary of PRO-CTCAE  and Change from Baseline in PRO-
CTCAE 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Exposure 
3.1.  
All Treated 
OEX1 
Summary of Exposure to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary.  
Duration of exposure=Last dose 
date – first dose date +1; will be 
categorized into <3d, 3d-<6d, 
6d-<12d, >=12d.  
Avg. daily dose=cumulative 
dose / duration of exposure. 
DE, IA, SAC 
3.2.  
All Treated 
OEX1 
Summary of Exposure to abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
DE, SAC 
3.3.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
DE, IA, SAC 
3.4.  
All Treated 
OEX1 
Summary of Exposure to abiraterone – Lead in Period 
By Dose Level for each Arm.  
SAC 
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By L2 vs. Lx subgroups and 
total. 
3.5.  
All Treated 
OEX1 
Summary of Exposure to enzalutamide – Lead in Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.6.  
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
 SAC 
3.7.  
All Treated 
ODMOD1 
Summary of Dose Reductions of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
3.8.  
All Treated 
ODMOD1 
Summary of Dose Reductions of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available 
 SAC 
3.9.  
All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Categories <7, 7-14, >14 days 
for duration of interruption  
SAC 
3.10. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of abiraterone 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
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3.11. All Treated 
ODMOD2 
Summary of Dose Interruptions/Delays of enzalutamide 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.12. All Treated 
ODMOD8 
Summary of Dose Escalations of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
May be replaced by a listing if 
minimal data available. 
SAC 
3.13. All Treated 
AE19 
Summary of Dose-Limiting Toxicities during the Determinative 
Period 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Adverse Events 
3.14. All Treated 
AE13 
Summary of Adverse Event Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.15. All Treated 
AE3 
Summary of Adverse Event Related to Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.16. All Treated 
AE3 
Summary of Adverse Event Related to GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.17. All Treated 
AE13 
Summary of Adverse Event of Grade 3-4 Overview 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.18. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 Related to Any Study 
Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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3.19. All Treated 
AE3 
Summary of Adverse Event of Grade 3-4 related to 
GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.20. All Treated 
AE16 
Summary of Adverse Events by System Organ Class and 
Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
IA, SAC 
3.21. All Treated 
AE15 
Summary of Common 5% Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of 
Participant and Occurrences) 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.22. All Treated 
AE5B 
Summary of All Adverse Events by Maximum Toxicity Grade by 
System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.23. All Treated 
AE5B 
Summary of Any Drug-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.24. All Treated 
AE5B 
Summary of All Adverse Events Related to GSK525762- by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
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By L2 vs. Lx subgroups and 
total. 
3.25. All Treated 
AE5B 
Summary of enzalutamide-Related Adverse Events by 
Maximum Toxicity Grade by System Organ Class and 
Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT.  
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.26. All Treated 
AE5B 
Summary of abiraterone-Related Adverse Events by Maximum 
Toxicity Grade by System Organ Class and Preferred Term 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
Subset for events related to 
GSk525762 only.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.27. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of GSK525762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.28. All Treated 
AE3 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.29. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.30. All Treated 
AE3 
Summary of Adverse Events Leading to Dose Reductions of 
any Study Treatment 
By Dose Level for each Arm.  
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By L2 vs. Lx subgroups and 
total. 
3.31. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of GSK52762 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, SAC 
3.32. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Interruptions/Delays of Any Study Treatment 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.33. All Treated 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term 
By Event category, PT, SOC.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
DE, IA, SAC 
3.34. All Treated 
AE20 
Summary of Any Drug-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.35. All Treated 
AE20 
Summary of GSK525762-Related Non-Fatal Serious Adverse 
Events 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.36. All Treated 
AE3 
Summary of Adverse Events Classified as Dose-Limiting 
Toxicities (DLTs) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.37. All Treated 
AE5B 
Summary of Adverse Events of Special Interest by Maximum 
Grade by Preferred Term Regardless of Relatedness 
Events in Descending Order of 
Total Incidence.  
By Event category, PT. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.38. All Treated 
AE5B 
Summary of Adverse Events of Special Interest Regardless of 
Relatedness 
By Event category, PT.  
By Dose Level for each Arm.  
IA, SAC 
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By L2 vs. Lx subgroups and 
total. 
3.39. All Treated 
ESI1 
Summary of Characteristics of Adverse Events of Special 
Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.40. All Treated 
ESI2b 
Summary of Onset and Duration of the First Occurrence (Days) 
of Treatment Emergent Adverse Events of Special Interest 
This table will be presented 
individually for each category of 
AESI: # subjects, # events, # 
subjects with SAE, # subjects 
with related SI events, outcome 
event, maximum grade, action 
taken. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.41. All Treated 
DD1 
Summary of Deaths 
Include number of patients for 
which an SAE resulted in death. 
SAC 
Laboratory: Chemistry 
3.42. All Treated 
LB1 
Summary of Chemistry Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.43. All Treated 
LB18 
Summary of Chemistry Grade Changes from Baseline 
For lab tests that are not graded 
include worst case grade 
change. 
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By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
3.44. All Treated 
LB3 
Summary of Chemistry Changes from Baseline with Respect to 
the Normal Range  
For lab tests that are not graded 
include worst case grade 
change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Haematology 
3.45. All Treated 
LB1 
Summary of Haematology Changes from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.46. All Treated 
LB18 
Summary of Haematology Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.47. All Treated 
LB3 
Summary of Haematology Changes from Baseline with 
Respect to the Normal Range  
For lab tests that are not 
graded; include worst case 
grade change. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Laboratory: Liver Events 
3.48. All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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3.49. All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Urinalysis 
3.50. All Treated 
UR1 
Summary of Worst-case Urinalysis Result Increases from 
Baseline 
Include tests done by Dipstick – 
Specific gravity, pH, Glucose, 
Protein, Blood, Ketones.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.51. All Treated 
LB18 
Summary of Urinalysis Grade Changes from Baseline 
For lab tests that are not 
graded; include worst case 
grade change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
 SAC 
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Coagulation 
3.52. All Treated 
LB3 
Summary of Coagulation Changes from Baseline with Respect 
to Normal Range 
Include worst case grade 
change.  
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
Vital Signs 
3.53. All Treated 
VS1 
Summary of Vital Signs 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.54. All Treated 
VS1 
Summary of Vital Sign Changes from Baseline 
Include all Vital Signs. 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
ECG 
3.55. All Treated 
EG1 
Summary of ECG Findings 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.56. All Treated 
EG2 
Summary of ECG Findings Change from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
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3.57. All Treated 
EG10A 
Summary of Maximum QTcF Value Post-Baseline Relative to 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
3.58. All Treated 
EG11A 
Summary of Maximum Increase in QTcF Values Post-Baseline 
Relative to Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total.  
Add footnote: “Only the post-
baseline assessments that used 
the same source (i.e. local or 
central cardiologist read) as the 
baseline assessments are used 
to derive the change from 
baseline.” 
SAC 
Performance Status  
3.59. All Treated 
PS1A 
Summary of Performance Status 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
SAC 
3.60. All Treated 
PS3A 
Summary of Change in Performance Status from Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
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Left Ventricular Ejection Fraction 
3.61. 
All Treated 
OLVEF1A 
Summary of Left Ventricular Ejection Fraction Change from 
Baseline 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Add footnote: “Only the post-
baseline assessments that used  
the same method (i.e. 
Electrocardiogram ECHO or 
Multiple Grated Acquisition 
MUGA) and the same source 
(i.e. local or central cardiologist 
read) as the baseline 
assessments  are used to 
derive the change from 
baseline.” 
SAC 
Value Evidence and Outcomes 
3.62. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-C30 and Change from Baseline in 
EORTC-QLQ-C30 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.63. 
Modified All 
Treated 
SF4_NS2 
Summary of  EORTC-QLQ-PR25 and Change from Baseline in 
EORTC-QLQ-PR25 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
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13.10.8. 
Pharmacokinetic Tables 
3.64. 
Modified All 
Treated 
SF4_NS2 
Summary of BPI-SF and Change from Baseline in BPI-SF 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
3.65. 
Modified All 
Treated 
SF4_NS2 
Summary of PRO-CTCAE  and Change from Baseline in PRO-
CTCAE 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and 
total. 
Summarize both Timepoints 
data and change from baseline 
at timepoints data in the same 
output. 
SAC 
Pharmacokinetic : Tables 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Drug Concentration Measure 
4.1.  
PK 
PK01 
Summary of GSK525762 Pharmacokinetic Concentration-Time 
Data 
By Arm. 
DE, SAC 
4.2.  
PK 
PK01 
Summary of GSK525762- active metabolite (GSK3529246) 
Pharmacokinetic Concentration-Time Data 
By Arm. 
DE, SAC 
4.3.  
PK 
PK01 
Summary of GSK525762 Total Active Moiety Pharmacokinetic 
Concentration-Time Data (in nM) 
GSK525762+GSK3529246.  
By Arm. 
DE, SAC 
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4.4.  
PK 
PK01 
Summary of abiraterone Pharmacokinetic Concentration-Time 
Data 
 
DE, SAC 
4.5.  
PK 
PK01 
Summary of enzalutamide Pharmacokinetic Concentration-Time 
Data 
Summary will be presented only 
for pre-dose as samples are 
collected only at Pre-dose. 
DE, SAC 
4.6.  
PK 
PK01 
Summary of Enzalutamide active metabolite Pharmacokinetic 
Concentration-Time Data 
Summary will be presented only 
for pre-dose as samples are 
collected only at Pre-dose. 
 
Pharmacokinetic Parameters 
4.7.  
PK 
PK06 
Summary of Derived GSK525762 Pharmacokinetic Parameters  
By Dose Level for each Arm.  
PK parameters:  AUC (0-τ) in 
ng.hr/mL, Cmax in ng/mL, Tmax 
in h, Ctrough in ng/mL 
DE, SAC 
4.8.  
PK 
PK06 
Summary of Derived GSK525762 Active Metabolite 
(GSK3529246) Pharmacokinetic Parameters  
By Dose Level for each Arm.  
PK parameters:  AUC (0-τ) in 
ng.h/mL, Cmax in ng/mL, Tmax 
in h, Ctrough in ng/mL 
DE, SAC 
4.9.  
PK 
PK06 
Summary of Derived GSK525762 Total Active Moiety 
Pharmacokinetic Parameters  
By Dose Level for each Arm.  
PK parameters:  AUC (0-τ) in 
mol.h/L, Cmax in nmol/L, Tmax in 
h, Ctrough in nmol/L 
DE, SAC 
4.10. 
PK 
PK06 
Summary of Derived abiraterone Pharmacokinetic Parameters  
Only Ctrough (ng/mL) 
SAC 
4.11. 
PK 
PK06 
Summary of Derived enzalutamide Pharmacokinetic Parameters  
Only Ctrough (ng/mL) 
SAC 
4.12. 
PK 
PK06 
Summary of Derived enzalutamide Active Metabolite 
Pharmacokinetic Parameters  
Only Ctrough (ng/mL) 
SAC 
4.13. 
PK 
PK06 
Summary of Derived enzalutamide Total Active Moiety 
Pharmacokinetic Parameters  
Only Ctrough (ng/mL) 
SAC 
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13.10.9. 
Pharmacokinetic Figures 
 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Drug Concentration Measure 
4.1.  
PK 
PK17 
Mean  GSK525762, GSK3529246, and the total active moiety  
Concentration-Time Plots (Linear and Semi-Log) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and total.  
GSK525762, GSK3529246, and 
the total active moiety 
concentration-time profiles will be 
overlaid on the same plot once 
concentrations have been 
converted to nM concentrations 
DE, SAC 
4.2.  
PK 
PK17 
Mean abiraterone Concentration-Time Plots (Linear and Semi-
Log) 
 
DE, AC 
4.3.  
PK 
PK18 
Median GSK525762, GSK3529246, and the total active moiety 
Concentration-Time Plots (Linear and Semi-Log) 
By Dose Level for each Arm.  
By L2 vs. Lx subgroups and total. 
GSK525762, GSK3529246, and 
the total active moiety 
concentration-time profiles will be 
overlaid on the same plot once 
concentrations have been 
converted to nM concentrations 
SAC 
4.4.  
PK 
PK18 
Median abiraterone Concentration-Time Plots (Linear and Semi-
Log) 
 
SAC 
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13.10.10. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
All Treated 
ES2 
Listing of Reasons for Subject Withdrawal 
 
DE, SAC 
2.  
All 
Screened 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
3.  
All Treated 
ES7 
Listing of Run-in Failure 
 
SAC 
4.  
All Treated 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
Include last dose date 
SAC 
Populations Analysed 
5.  
All Treated 
SP3 
Listing of Subjects Excluded from Any Population 
 
SAC 
Protocol Deviations 
6.  
All Treated 
DV2 
Listing of Protocol Deviations 
Include both major and non-
major PDs 
SAC 
7.  
All Treated 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Baseline and Disease Characteristics 
8.  
All Treated 
DM2 
Listing of Demographic Characteristics 
 
SAC 
9.  
All Treated 
DM9 
Listing of Race 
 
SAC 
Exposure 
10.  
All Treated 
TA1 
Listing of Planned and Actual Treatments 
 
SAC 
11.  
All Treated 
COMP3C 
Listing of GSK525762 Drug Accountability 
 
SAC 
12.  
All Treated 
OEX3a 
Listing of Exposure Data to GSK525762 
 
SAC 
13.  
All Treated 
OEX8B 
Listing of Exposure Data to abiraterone 
 
SAC 
14.  
All Treated 
OEX8B 
Listing of Exposure Data to enzalutamide 
 
SAC 
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15.  
All Treated 
ODMOD10A 
Listing of Dose Reductions for GSK525762 
 
SAC 
16.  
All Treated 
ODMOD10A 
Listing of Dose Reductions for abiraterone 
 
SAC 
17.  
All Treated 
ODMOD10A 
Listing of Dose Reductions for enzalutamide 
 
SAC 
18.  
All Treated 
ODMOD11A 
Listing of Dose Interruptions/Delays for GSK525762 
 
SAC 
19.  
All Treated 
ODMOD11A 
Listing of Dose Interruptions/Delays  for abiraterone 
 
SAC 
20.  
All Treated 
ODMOD11A 
Listing of Dose Interruptions/Delays  for enzalutamide 
 
SAC 
21.  
All Treated 
ODMOD15A 
Listing of Dose Escalations for GSK525762 
 
SAC 
Adverse Events 
22.  
All Treated 
OAE04 
Listing of All Adverse Events 
 
DE, SAC 
23.  
All Treated 
OAE04 
Listing of All AEs by Severity Grade 
 
SAC 
24.  
All Treated 
OAE03 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
25.  
All Treated 
OAE04 
Listing of Dose-Limiting Adverse Events 
 
DE, SAC 
26.  
All Treated 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Class, Preferred Term and Verbatim Text 
 
SAC 
Serious and Other Significant Adverse Events 
27.  
All Treated 
OAE04 
Listing of Fatal Serious Adverse Events 
 
DE, SAC 
28.  
All Treated 
OAE04 
Listing of Non-Fatal Serious Adverse Events 
 
SAC 
29.  
All Treated 
OAE04 
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment 
Based on Action taken question 
on AE/SAE 
DE, SAC 
30.  
All Treated 
OAE04 
Listing of Adverse Events Leading to Withdrawal from the Study 
 
SAC 
31.  
All Treated 
OAE04 
Listing of Adverse Events Leading to Dose Reductions for any 
Study Drug 
 
DE, SAC 
32.  
All Treated 
OAE04 
Listing of Adverse Events Leading to Dose Interruptions/Delays 
for any Study Drug 
 
DE, SAC 
33.  
All Treated 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
 
SAC 
34.  
All Treated 
OAE04 
Listing of Adverse Events of Special Interest 
 
SAC 
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Dose-Limiting Toxicity 
35.  
All Treated 
DL3 
Listing of Dose-Limiting Toxicities during the Determinative 
Period 
 
DE, SAC 
Laboratory 
36.  
All Treated 
OLB7 
Listing of Chemistry Laboratory Data for Subjects with Lab 
Values Outside of Normal Range 
 
SAC 
37.  
All Treated 
OLB7 
Listing of Haematology Laboratory Data for Subjects with Lab 
Values Outside of Normal Range 
 
SAC 
38.  
All Treated 
UR2A 
Listing of Urinalysis Data for Subjects with Any Value of Potential 
Clinical Importance 
 
SAC 
39.  
All Treated 
LB13 
Listing of Coagulation and Other Laboratory data  
 
SAC 
40.  
All Treated 
OLB7 
Listing of Coagulation and Other Laboratory Data for Subjects 
with Lab Values Outside of Normal Range 
 
SAC 
41.  
All Treated 
LB14 
Listing of Laboratory Data with Character Results 
 
SAC 
Pharmacokinetic  
42.  
PK 
PK07 
Listing of GSK525762 Pharmacokinetic Concentration-Time Data   
SAC 
43.  
PK 
PK07 
Listing of abiraterone Pharmacokinetic Concentration-Time Data  
 
SAC 
44.  
PK 
PK07 
Listing of enzalutamide Pharmacokinetic Concentration-Time 
Data  
 
SAC 
45.  
PK 
PK07 
Listing of GSK525762 Active Metabolite (GSK3529246) 
Pharmacokinetic Concentration-Time Data 
 
SAC 
46.  
PK 
PK07 
Listing of enzalutamide  Active Metabolite Pharmacokinetic 
Concentration-Time Data  
 
SAC 
47.  
PK 
PK07 
Listing of GSK525762 Total Active Moiety Pharmacokinetic 
Concentration-Time Data 
 
SAC 
48.  
PK 
PK13 
Listing of Derived GSK525762 Pharmacokinetic Parameters 
 
SAC 
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49.  
PK 
PK13 
Listing of Derived GSK525762 Total Active Moiety 
Pharmacokinetic Parameters 
 
SAC 
50.  
PK 
PK13 
Listing of Derived GSK525762 Active Metabolite (GSK3529246) 
Pharmacokinetic Parameters 
 
SAC 
Efficacy 
51.  
Modified All 
Treated 
RE2 
Listing of PSA Values by Visit 
Include change from baseline, % 
change from baseline 
SAC 
52.  
Modified All 
Treated 
RE12 
Listing of Subject Best Response for Interim Review by First 
Dose Date 
 
IA 
53.  
Modified All 
Treated 
LA2 
Listing of Investigator-Assessed Target Lesions (RECIST 1.1 
Criteria) 
 
SAC 
54.  
Modified All 
Treated 
LA3 
Listing of Investigator-Assessed Non-Target Lesions (RECIST 
1.1 Criteria) 
 
SAC 
55.  
Modified All 
Treated 
LA4 
Listing of Investigator-Assessed New Lesions (RECIST 1.1 
Criteria) 
 
SAC 
56.  
Modified All 
Treated 
RE5 
Listing of Investigator - Assessed Responses (With and Without 
Confirmation) (RECIST 1.1)  
Include an additional row at the 
end of each subject for Best 
Response without confirmation. 
SAC 
57.  
Modified All 
Treated 
RE2 
Listing of CTC Counts by Visit 
Include change from baseline, % 
change from baseline 
SAC 
58.  
Modified All 
Treated 
TTE9 
Listing of Time to Disease Progression 
 
SAC 
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13.10.11. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Demographic and Baseline Characteristics 
59.  
All Treated 
SU2 
Listing of Substance Use 
 
SAC 
60.  
All Treated 
DC3 
Listing of Disease Characteristics at Initial Diagnosis 
 
SAC 
61.  
All Treated 
DC4 
Listing of Disease Characteristics at Screening 
 
SAC 
62.  
All Treated 
MD2 
Listing of Metastatic Disease at Screening 
 
SAC 
Prior and Concomitant Medication 
63.  
All Treated 
MH2 
Listing of Medical Conditions 
Include Prior and Current. Status 
column will indicate the same 
SAC 
64.  
All Treated 
CM2 
Listing of Concomitant Medications 
 
DE, SAC 
65.  
All Treated 
BP4 
Listing of Blood Products or Blood Supportive Care Products 
Include Prior (BP4) and on 
treatment (BP5) 
SAC 
66.  
All Treated 
OSP3 
Listing of Surgical Procedures 
 
SAC 
67.  
All Treated 
AE2 
Listing of Relationship Between ATC Level1, Ingredient and 
Verbatim Text 
 
SAC 
Anti-Cancer Therapy 
68.  
All Treated 
AC6 
Listing of Anti-Cancer Therapy 
Including Prior and Subsequent 
IA, SAC 
69.  
All Treated 
AC7 
Listing of Anti-Cancer Radiotherapy 
Including Prior and Subsequent 
SAC 
70.  
All Treated 
AC7 
Listing of Surgical Procedures 
Including on treatment and 
follow-up 
SAC 
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ECG 
71.  
All Treated 
EG5 
Listing of All ECG Findings for Subjects with an Abnormal Finding  
SAC 
72.  
All Treated 
EG3 
Listing of ECG Values for Subjects with Abnormal Values 
 
SAC 
Vital Signs 
73.  
All Treated 
VS4 
Listing of Vital Signs 
 
DE, SAC 
74.  
All Treated 
OVT7A 
Listing of Vital Signs with Abnormal Values 
 
SAC 
LVEF 
75.  
All Treated 
OLVEF2A 
Listing of Left Ventricular Ejection Fraction Results 
 
SAC 
Laboratory 
76.  
All Treated 
OLB13 
Listing of Laboratory Data with Character Results 
 
SAC 
Value Evidence and Outcomes 
77.  
Modified All 
Treated 
SF6 
Listing of EORTC-QLQ-C30 
 
SAC 
78.  
Modified All 
Treated 
SF6 
Listing of EORTC-QLQ-PR25 
 
SAC 
79.  
Modified All 
Treated 
BPI4 
Listing of BPI-SF 
 
SAC 
80.  
Modified All 
Treated 
SF6 
Listing of PRO-CTCAE 
 
SAC 
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13.11. 
Appendix 11: Example Mock Shells for Data Displays 
Data Display Specification will be made available on Request. 
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