Clinical trial NCT02964507
Conditions: Neoplasms
Keywords: GSK525762 HR+/HER2- advanced or metastatic breast cancer mTPI
Sponsor: GlaxoSmithKline
Start date: 2019-09-26; Completion date: 2021-07-19
Enrollment: 124 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a combination Phase I and Phase II study, with an aim to evaluate the combination of GSK525762 and fulvestrant in women with HR+/HER2- advanced or metastatic breast cancer, who have disease that has progressed after prior treatment with at least one line of endocrine therapy. The objectives of the study are to first identify, in open-label single-arm Phase I, a recommended Phase II dose of GSK525762 that may be combined safely with fulvestrant. Phase I will follow a modified toxicity probability interval (mTPI) design, and a sentinel group will be evaluated first for dose-limiting toxicity and further expanded to collect additional safety data. This will be followed by a double-blind, randomized controlled Phase II, to identify the clinical activity of the two study treatments when given in combination. The composition of Phase II will be selected at the end of Phase I.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: GSK525762 intervention 2: Placebo intervention 3: Fulvestrant
Intervention descriptions: intervention 1: GSK525762 will be administered. intervention 2: Placebo will be administered. intervention 3: Fulvestrant will be administered.

Protocol documents:
Prot_000.pdf: 
2015N238773_06
CONFIDENTIAL
The GlaxoSmithKline group of companies
201973
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase I/II dose escalation and expansion study to investigate 
the safety, pharmacokinetics, pharmacodynamics and clinical
activity of GSK525762 in combination with fulvestrant in 
subjects with hormone receptor-positive/HER2-negative
(HR+/HER2-) advanced or metastatic breast cancer
Compound Number:
GSK525762
Development Phase:
I/II
Effective Date:
06-MAY-2020
Protocol Amendment Number:  6
Author (s):
 
 
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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CONFIDENTIAL
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201973
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2015N238773_00
2016-AUG-11
Original
2015N238773_01
2016-OCT-21
Amendment No. 1
Amendment 1 applies to all global study sites.
Based upon review and comment on the protocol by the FDA, the following changes are 
being implemented: Clarification of the permitted prophylactic anticoagulation therapies 
in Exclusion Criteria #4; Correction of the spelling of goserelin throughout the protocol; 
Clarification of how to read the liver algorithms in Section 5.4.1; Changes to the toxicity 
management guidelines in Appendix 2, Table 12 for the following: Update to the dose 
interruption/ reduction/discontinuation guidelines for Grade 4 thrombocytopenia; Dose 
reduction for subjects if QTcF 60 msec change from baseline occurs OR QTcF 500; 
Permanent discontinuation of study medication for subjects with troponin levels 
approaching the threshold for MI; Clarification on length of follow-up for subjects with 
LVEF increase; Monitoring of blood sugar and dose reduction guidelines for subjects 
with moderate to severe hypoglycemia; Dose reduction and event management for 
subjects with Grade 3-4 diarrhea; Dose interruption and reduction for subjects with Grade 
3-4 mucositis; Dose interruption/reduction/discontinuation and event management for all 
Grades of pneumonitis; Dose interruption and/or reduction for subjects with Grade 3-4 
other non-hematologic events.
In addition to these requested changes from the FDA, other administrative changes to the 
protocol include: Clarification of timing for sites to report pregnancies to GSK (24 hours 
versus 2 weeks, based on reproductive toxicity seen in pre-clinical GSK525762 studies); 
Correction of spelling errors; Correction to the Medical Monitor contact information; 
Correction of a typo in the Phase 1 Time and Events table; Addition of clarifying 
language around survival follow up after the EoT visit; Addition of clarifying language 
around fresh biopsies; Addition of clarifying language around the timing of CBC draws 
in Week 1; Addition of clarifying language to inclusion criteria #6 and exclusion criterion 
#1-3 around prior treatment history; Clarified wording around disease assessment 
schedule after Week 52; Removal of Section 5.4.3.2 Valvular Toxicity Stopping Criteria, 
this section is part of the GSK template guidance and not mandatory for inclusion, and 
there are no pre-clinical/clinical valvular toxicity findings for GSK525762. Removal of 
this information will also reduce the number of assessments required for subjects; Update 
to the option of scan (now ECHO or MUGA) performed to monitor cardiac safety; 
Removal of Section 7.3.5.6 Disease Related Events, this section is only to be included if 
there are pre-defined disease related events, and this protocol has no pre-defined events; 
Update to the Grade 3 and Grade 4 thrombocytopenia management guidelines to make 
them more stringent, based upon emerging data that will be provided in an INDSR 
(October 2016); Removal of the fever management guidelines in Appendix 2, Table 12, 
as part of the ongoing safety review for GSK525762, there is no apparent clinical 
correlation to the preclinical in vitro findings suggesting a potential for fever.


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2015N238773_02
2017-JAN-31
Amendment No. 2
Amendment 02 applies to all sites in the United Kingdom.
Based upon review and comment on the protocol by the MHRA, the following changes 
are being implemented as a standalone amendment for the UK: Clarification of the length 
of time, post treatment completion, that the approved list of contraceptives must be used 
by female subjects of childbearing potential; clarification in Section 5.4 that pregnancy is 
a reason for subject discontinuation from the study.  A forthcoming amendment (03) will 
include these revisions as part of a global protocol amendment.
2015N238773_03
2017-MAR-07
Amendment No. 3
Amendment 03 applies to all global study sites.
Changes to the protocol include: Clarification to the prior treatment subjects may have 
received; update to the timelines of the study, based upon new enrollment projections; 
clarification of inclusion criteria #6 regarding prior treatment subjects may have received; 
clarification of exclusion criteria #1 and #3 regarding number of prior lines of therapy; 
addition of two new exclusion criteria regarding use of NSAIDS and history of bleeding 
events; clarification in Section 5.4 that pregnancy for subjects of childbearing potential is 
a cause for study discontinuation; clarification regarding the liquid that subjects are 
permitted to use when taking GSK525762; clarification around the dosing window for 
fulvestrant; addition of Table 3 which clarifies dose reductions; clarification around use 
of Aspirin; update to the prohibited meds table in Section 6.11.2.1 and the cautionary 
meds table in Section 6.11.2.3; clarification around use of medication containing 
acetaminophen; update to the schedule of assessments in the Time and Events tables for 
both Phase I and II of the study; update to the schedule of laboratory assessments in both 
Phase I and II of the study; update to the ± visit windows for Weeks 2, 3, 4, 5, and 9; 
added logistical and medical guidance around when on treatment fresh biopsies and 
planned surgical procedure can take place; updated the thrombocytopenia management 
guidelines in Table 13 to be in line with regulatory feedback; clarification of baseline 
imaging windows; clarification of approved contraception and length of time said 
contraception needs to be used post study treatment.
2015N238773_04
2017-OCT-18
Amendment No. 4
Amendment 04 applies to all global study sites.
Based upon review and comment on the protocol by the Agence Nationale de Sécurité du 
Médicament et des Produits de Santé (ANSM), the following changes are being 
implemented: language added to Section 6.11.2.3 around concomitant medications that 
are substrates of CYP3A4; update to the toxicity management guidelines for QTcF 
monitoring in Appendix 2, Table 13; Times and Events tables in Section 7.1, updated to 
clarify the schedule of assessments post week 49.
Additional changes to the protocol include: update to protocol authors; update to the
primary GSK medical monitor, update to Sponsor signatory; ERS1 mutational status in 
the objectives and endpoints has been updated to exploratory, and Section 7.7 has been 
updated to reflect the translational analysis changes; removal of the time to progression 
(TTP) endpoints; update to description of Ph I enrolment during the dose escalation phase 
and the definition of study completion in Ph II; update to statistical analysis descriptions 
throughout the protocol; addition of information around the dose escalation meetings; 


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Section 6.6 on the handling of GSK525762; clarification in Section 5.1, Table 2, 
regarding acceptability of both Troponin I or T; Times and Events tables in Section 7.1, 
updated to clarify ECHO/MUGA scan requirements for screening and W1D1, timing of 
on treatment biopsy collection in Ph I, lab assessment requirements, and length of 
screening window (also updated throughout the document); update to the toxicity 
management guidelines for QTcF re-challenge in Appendix 2, Table 13; removal of pre-
defined events of interest.
2015N238773_05
2018-SEP-11
Amendment No. 5
Amendment 05 applies to all global study sites. These changes are based upon revisions 
noted by the study team, and include: 
Updating the protocol title to hormone receptor positive (HR+/HER2- BC) to 
align with the inclusion criteria which requires both ER+ and PR+ BC subjects.
Corrections made throughout to align HR+/HER2- BC with the inclusion criteria 
and title. 
Update to clarify that dose level (DL) 2 (80 mg) has been discontinued.
Update to the author list and sponsor signatory. 
In introduction and Section 5.4 include requirement that the Medical Monitor (MM) 
should be consulted before a subject can discontinue one agent and continue on the other.
Study Design in Synopsis and Section 4: Original language describing Phase I and Phase 
II remains. New sections added to address the updates to Phase I which include DL2 
(80 mg) discontinuation, update the DL1 (60 mg) cohort 2 population to include subjects 
must have received greater than or equal to 12 months of prior Cyclin-Dependent Kinase 
(CDK)4/6+ Aromatase Inhibitor (AI) for metastatic disease and progressed while on 
treatment and allow bone only disease.
Revision in sub-sections of Section 4.7 to be in line with wording in the most recent 
Investigator’s Brochure. Inclusion/exclusion criteria: 

Provision of a fresh tumor biopsy sample at screening;  

letrozole has been expanded to include all AI agents;  

prior treatment allowed in the CDK4/6 patient population;

subjects must have received greater than or equal to 12 months of prior CDK4/6+ 
AI for metastatic disease and progressed while on treatment; 

bone only disease is allowed (screening biopsy not required after discussion with 
MM);  

update to criteria for severe or uncontrolled systemic diseases; update to criteria 
for baseline QTcF). 
Section 5.4.2 update to QTc stopping criteria; removal of former Section 6.3.1 Guidelines 
for Events of Special Interest;  in Section 6.11.1 include granulocyte colony-stimulating 
factors as a permitted medications; update to wording in Section 6.11.2.1 Prohibited 
Medication and removal of  former Table 4; update to wording in Section 6.11.2.3 
Cautionary Medication and removal of former Table 5; Clarification in Section 6.11.2.2 
regarding both prescription and non-prescription herbal preparations/medications;  
Time and Events Table 5 and Table 8: Updates regarding electrocardiograms (ECGs), 


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requirement of fresh biopsies at screening and collection window, clarification of 
requirements around fresh tumor biopsies sample and other general clarifications; 
Pregnancy Test- X has been removed from the Column for Q12wks (Wk49 and after). 
This was an error and Q4wks is correct. In Section 7.2.2 clarification regarding PK 
sample collection for subjects with interrupted dosing; Section 7.3.3.1 update to 
guidelines for electrocardiograms assessments; update to Table 9 Clinical Labs regarding 
collection of troponin and adding a list of acronyms in the footnotes; update to guidance 
regarding screening and on treatment biopsies in Section 7.5.1 and Section 7.7.2; update 
to toxicity management for QTcF events in Appendix 2 and explanation for reconsent; 
Collection of pregnancy information regarding elective termination is clarified that only 
those performed due to medical reasons are required to be reported.
2015N238773_06
2020-MAY-06
Amendment No. 6
Amendment 06 applies to all global study sites. These changes are based on the decision 
to close out the study and stop all new enrolment based on interim data failing to 
demonstrate meaningful clinical benefit in the proposed patient population.
The totality of Phase I data assessed at the interim analysis does not support continuing
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of hormone receptor-positive/HER2-negative (HR+/HER2-) advanced or 
metastatic breast cancer patients. Enrolment into the study is now closed. 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)

Updates to contraceptive measures required for study participants, based upon 
January 2020 updates to the fulvestrant Summary of Product Characteristics 

Update to the GSK signatory and GSK medical monitor

Provides updated guidance for subjects who have discontinued combination 
treatment and are on fulvestrant monotherapy

Provides clarification on clinical supply dosages available for the study

Administrative changes including minor clarifications, formatting and 
typographical errors


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number 
After-hours 
Phone/Cell/
Pager Number
Site Address and email address
Primary 
Medical 
Monitor 
 
MD
GlaxoSmithKline
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) # 
IND131933, EudraCT number 2016-003074-40
PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201973
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 201973......................................................14
2.
INTRODUCTION....................................................................................................25
2.1.
Study Rationale ..........................................................................................25
2.2.
Brief Background ........................................................................................25
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................28
4.
STUDY DESIGN ....................................................................................................30
4.1.
Overall Design ............................................................................................30
4.1.1.
Original Overall Design (Protocols 01-04)....................................30
4.1.2.
Revised Overall Design (Protocol Amendment 05) ......................34
4.1.2.1.
Change to DL1 Cohort 2:............................................34
4.1.3.
Type and Number of Subjects......................................................34
4.2.
Phase I .......................................................................................................35
4.2.1.
Type and Number of Subjects in Phase I.....................................36
4.2.2.
Treatment Arms and Duration......................................................36
4.2.3.
Dose Selection ............................................................................36
4.2.3.1.
Planned Dose Levels..................................................36
4.2.3.2.
Dose Level & Cohort Selection...................................36
4.2.3.3.
Dose Escalation & Cohort Safety Decisions ...............37
4.2.3.4.
Dose-Limiting Toxicity Definition.................................38
4.2.3.5.
Non-Limiting Toxicities ...............................................39
4.2.3.6.
Maximum Dose Increment..........................................40
4.2.3.7.
Alternative Dosing Schedules.....................................40
4.2.3.8.
Intra-Subject Dose Escalation ....................................40
4.2.4.
Data Review ................................................................................40
4.2.5.
Statistical Analysis.......................................................................41
4.2.5.1.
Safety Analysis...........................................................41
4.2.5.2.
Futility Analysis...........................................................41
4.3.
Decision to Proceed to Phase II..................................................................42
4.3.1.
Phase II Dose Selection...............................................................42
4.3.2.
Phase II Cohort Selection ............................................................42
4.4.
Phase II Prior Treatment History Specific Cohorts ......................................43
4.4.1.
Type and Number of Subjects......................................................43
4.4.2.
Treatment Arms and Duration......................................................43
4.4.3.
Dose Selection ............................................................................43
4.4.4.
Group Assignments .....................................................................43
4.4.5.
Statistical Design .........................................................................43
4.4.6.
Data Review ................................................................................44
4.5.
Design Justification.....................................................................................44
4.5.1.
Phase I ........................................................................................44
4.5.2.
Phase II .......................................................................................44
4.6.
Dose Justification........................................................................................45
4.6.1.
Starting Doses .............................................................................45
4.6.2.
Drug-Drug Interactions.................................................................46
4.6.3.
Overlapping Toxicities..................................................................46
4.7.
Benefit: Risk Assessment ...........................................................................47


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4.7.1.
Risk Assessment .........................................................................47
4.7.1.1.
Predicted Overlapping Toxicities ................................47
4.7.1.1.1.
Gastrointestinal Safety Findings .............47
4.7.1.1.2.
Hepatic Safety Findings..........................47
4.7.1.1.3.
Hematopoietic Safety Findings ...............48
4.7.1.1.4.
Reproductive Safety Findings.................49
4.7.1.1.5.
General Toxicity Findings .......................50
4.7.1.2.
Predicted Single-Agent Toxicities ...............................50
4.7.1.2.1.
Cardiovascular Safety Findings ..............50
4.7.2.
Benefit Assessment.....................................................................51
4.7.3.
Overall Benefit: Risk Conclusion..................................................51
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............51
5.1.
Inclusion Criteria.........................................................................................51
5.2.
Exclusion Criteria........................................................................................54
5.3.
Screening/Baseline/Run-in Failures............................................................56
5.4.
Withdrawal/Stopping Criteria.......................................................................56
5.4.1.
Liver Chemistry Stopping Criteria ................................................58
5.4.1.1.
Study Treatment Restart or Rechallenge....................60
5.4.2.
QTc Stopping Criteria ..................................................................60
5.4.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria..........61
5.4.4.
Other Stopping Criteria ................................................................61
5.5.
Subject and Study Completion....................................................................61
6.
STUDY TREATMENT ............................................................................................62
6.1.
Investigational Product and Other Study Treatment....................................62
6.2.
Treatment Assignment................................................................................63
6.2.1.
Phase I ........................................................................................63
6.2.2.
Phase II .......................................................................................64
6.3.
Planned Dose Adjustments.........................................................................64
6.4.
Blinding.......................................................................................................64
6.5.
Packaging and Labeling..............................................................................66
6.6.
Preparation/Handling/Storage/Accountability..............................................66
6.7.
Compliance with Study Treatment Administration.......................................66
6.8.
Treatment of Study Treatment Overdose....................................................67
6.9.
Treatment after the End of the Study ..........................................................67
6.10.
Dietary and Lifestyle Restrictions................................................................67
6.10.1.
Dietary Restrictions......................................................................67
6.10.2.
Female Subjects..........................................................................68
6.10.2.1.
Menopause Definition & Female Subjects of 
Non-Childbearing Potential.........................................68
6.10.2.2.
Female Subjects of Childbearing Potential .................68
6.11.
Concomitant Medications and Non-Drug Therapies....................................68
6.11.1.
Permitted Medications and Non-Drug Therapies..........................69
6.11.2.
Prohibited and Cautionary Medications and Non-Drug 
Therapies.....................................................................................69
6.11.2.1.
Prohibited Medications ...............................................69
6.11.2.2.
Prohibited Non-Drug Therapies ..................................69
6.11.2.3.
Cautionary Medications ..............................................70
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................71
7.1.
Time and Events Table...............................................................................72


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7.2.
Screening and Critical Baseline Assessments ............................................76
7.2.1.
Critical Baseline Assessments.....................................................76
7.2.2.
Visit Windows ..............................................................................77
7.3.
Safety .........................................................................................................78
7.3.1.
Physical Exams ...........................................................................78
7.3.2.
ECOG Performance Status..........................................................79
7.3.3.
Cardiac Safety .............................................................................79
7.3.3.1.
Electrocardiograms.....................................................79
7.3.3.2.
Echocardiogram or Multigated Acquisition 
Scan...........................................................................79
7.3.4.
Clinical Safety Laboratory Assessments ......................................80
7.3.5.
Adverse Events (AEs) and Serious Adverse Events 
(SAEs).........................................................................................81
7.3.5.1.
Time period and Frequency for collecting AE 
and SAE information...................................................82
7.3.5.2.
Method of Detecting AEs and SAEs ...........................82
7.3.5.3.
Follow-up of AEs and SAEs........................................82
7.3.5.4.
Cardiovascular and Death Events ..............................83
7.3.5.5.
Other sentinel events..................................................83
7.3.5.6.
Regulatory Reporting Requirements for SAEs............83
7.3.6.
Pregnancy ...................................................................................84
7.4.
Pharmacokinetics .......................................................................................84
7.5.
Pharmacodynamics ....................................................................................84
7.5.1.
Tumor Biopsy Collection/Surgical Procedures .............................85
7.6.
Evaluation of Anti-Cancer Activity ...............................................................85
7.6.1.
Phase I ........................................................................................86
7.6.2.
Phase II .......................................................................................86
7.7.
Translational Research...............................................................................86
7.7.1.
Tumor Biomarker Analysis...........................................................87
7.7.2.
Tumor Tissue...............................................................................87
7.7.3.
Circulating cell free DNA/RNA Analysis .......................................87
7.8.
Genetics .....................................................................................................88
7.9.
Value Evidence and Outcomes...................................................................88
7.9.1.
PRO-CTCAE ...............................................................................88
7.9.2.
EORTC-QLQ-C30 & EORTC-QLQ-BR23 ....................................88
8.
DATA MANAGEMENT ...........................................................................................89
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................89
9.1.
Hypotheses.................................................................................................89
9.1.1.
Phase I Safety .............................................................................89
9.1.2.
Phase I Efficacy...........................................................................89
9.1.3.
Phase II .......................................................................................90
9.2.
Sample Size Considerations.......................................................................91
9.2.1.
Sample Size Assumptions ...........................................................91
9.2.1.1.
Phase I.......................................................................91
9.2.1.2.
Phase II......................................................................92
9.2.2.
Sample Size Sensitivity................................................................92
9.2.3.
Sample Size Re-estimation or Adjustment...................................92
9.3.
Data Analysis Considerations .....................................................................92
9.3.1.
Analysis Populations....................................................................92
9.3.2.
Interim Analyses ..........................................................................93


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9.3.2.1.
Phase I.......................................................................93
9.3.2.1.1.
Dose Escalation and Safety 
Analyses.................................................93
9.3.2.1.2.
Efficacy Analyses ...................................93
9.3.2.2.
Phase II......................................................................96
9.3.3.
Final Analysis ..............................................................................97
9.4.
Key Elements of Analysis Plan ...................................................................97
9.4.1.
Safety Analyses...........................................................................97
9.4.2.
Extent of Exposure ......................................................................97
9.4.3.
Adverse Events............................................................................98
9.4.4.
Clinical Laboratory Evaluations....................................................98
9.4.4.1.
Other Safety Measures...............................................98
9.4.5.
Pharmacokinetic Analyses...........................................................98
9.4.5.1.
Pharmacokinetic Parameters......................................98
9.4.5.2.
Statistical Analysis of Pharmacokinetic Data ..............99
9.4.6.
Pharmacokinetic/Pharmacodynamic Analyses.............................99
9.4.7.
Tumor Kinetics Analysis...............................................................99
9.4.8.
Efficacy Analyses.......................................................................100
9.4.8.1.
Phase I.....................................................................100
9.4.8.2.
Phase II....................................................................101
9.4.9.
Other Analyses ..........................................................................102
9.4.9.1.
Translational Research Analyses .............................102
9.4.9.2.
Novel Biomarker(s) Analyses ...................................102
9.4.9.3.
Pharmacogenetic Analyses ......................................103
9.4.10.
Simulations and Design Operating Characteristics ....................103
9.4.10.1.
Simulation Description..............................................103
9.4.10.2.
Software Details .......................................................103
9.4.10.3.
Trial Sample Size and Simulation Scenarios ............103
9.4.10.4.
Operation Characteristics .........................................104
9.4.10.5.
Stopping Early..........................................................105
9.4.10.6.
Mean Proportion of advancing to Phase 2................105
10. STUDY GOVERNANCE CONSIDERATIONS......................................................105
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........105
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................105
10.3.
Quality Control (Study Monitoring) ............................................................106
10.4.
Quality Assurance.....................................................................................106
10.5.
Study and Site Closure .............................................................................107
10.6.
Records Retention....................................................................................107
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................108
11. REFERENCES.....................................................................................................109
12. APPENDICES......................................................................................................111
12.1.
Appendix 1: Abbreviations and Trademarks..............................................111
12.2.
Appendix 2: Management of Suspected Toxicity.......................................117
12.3.
Appendix 3: Rationale for Response Assumptions....................................125
12.3.1.
Phase 1 .....................................................................................125
12.3.2.
Phase 2 .....................................................................................126
12.3.3.
References ................................................................................127


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12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.....................128
12.4.1.
Contraception Guidance: ...........................................................128
12.4.2.
Collection of Pregnancy Information ..........................................128
12.4.3.
References ................................................................................129
12.5.
Appendix 5: ECOG Performance Status ...................................................131
12.6.
Appendix 6: Cockcroft and Gault Method for Calculated Creatinine 
Clearance .................................................................................................132
12.7.
Appendix 7: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 1.1 
[Eisenhauer, 2009]....................................................................................133
12.7.1.
Baseline Documentation of Target and Non-Target 
Lesions ......................................................................................133
12.8.
Appendix 8: Liver Safety Required Actions and Follow up 
Assessments ............................................................................................139
12.9.
Appendix 9: Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines.................................................................................................143
12.10. Appendix 10: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ..........................146
12.10.1. Definition of Adverse Events......................................................146
12.10.2. Definition of Serious Adverse Events.........................................147
12.10.3. Definition of Cardiovascular Events ...........................................149
12.10.4. Recording of AEs and SAEs ......................................................149
12.10.5. Evaluating AEs and SAEs..........................................................150
12.10.6. Reporting of SAEs to GSK.........................................................151
12.11. Appendix 11: Genetic Research ...............................................................152
12.12. Appendix 12: Country Specific Requirements...........................................155
12.13. Appendix 13: Child-Pugh score.................................................................156
12.14. Appendix 14: Protocol Amendment Changes............................................157
12.14.1. Amendment 01 ..........................................................................157
12.14.2. Amendment 02 ..........................................................................184
12.14.3. Amendment 03 ..........................................................................186
12.14.4. Amendment 04 ..........................................................................226
12.14.5. Amendment 05 ..........................................................................274
12.14.6. Amendment 06 ..........................................................................311


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1.
PROTOCOL SYNOPSIS FOR STUDY 201973
Rationale
In the United States, breast cancer is the most common malignancy in women, affecting 
an estimated one out of every eight females during her lifetime.  Breast cancer is 
subdivided into multiple clinical subtypes, based on the expression of steroid hormone 
receptors (estrogen receptor [ER] and progesterone receptor [PR]) and the receptor 
tyrosine kinase erb-b2 receptor tyrosine kinase 2 (ERBB2, known clinically as HER2).  
ER is a transcription factor that translocates to the nucleus upon binding to estradiol and 
other, related sex hormones.  Once inside the nucleus, it binds to deoxyribonucleic acid 
(DNA) at sites of open chromatin in order to drive the expression of ER-dependent genes.  
For the 70% of women whose tumors express ER (i.e., ER-positive breast cancer 
(ER+BC), endocrine therapy remains the cornerstone of therapy for most of these 
women, followed by cytotoxic chemotherapy once tumors no longer respond to hormonal 
agents.  Currently, approved endocrine therapies include the ER antagonist tamoxifen; 
the aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole; and fulvestrant, a 
selective ER antogonist.  Recently, improved progression-free survival (PFS) has been 
demonstrated by combining endocrine therapy with either the Mammalian Target of 
Rapamycin (mTOR) inhibitor everolimus or with the cyclin-dependent kinase (CDK) 4/6 
inhibitors (e.g. palbociclib).  Despite these advances, however, the disease remains 
incurable, and relapse (and thus need for novel therapeutic agents) is inevitable. 
Treatment-resistant ER+BC tumors continue to express ER, which in turn continues to 
bind to DNA and express ER-dependent genes.  Recently, the importance of epigenetic 
markers in the regulation of ER-dependent gene expression has been identified.  One set 
of proteins that is important for regulating epigenetic markers is the Bromodomain and 
Extraterminal (BET) family.  These proteins recognize acetyl groups on the tails of 
histones and are critical for recruiting transcriptional machinery necessary for gene 
expression.  BET proteins regulate a host of other downstream effectors that are critical 
for proliferation, differentiation, and cell survival.  BET inhibitors, including 
GSK525762, are currently being evaluated in the therapy of both solid tumors and 
hematologic malignancies.  
This study (201973) proposes to evaluate the combination of GSK525762, a potent 
inhibitor of the BET family of proteins, with fulvestrant, in women with HR+/HER2-
BC.  Both agents are inhibitors of distinct but convergent molecular mechanisms that are 
critical for growth and proliferation of breast cancer tumor cells.  This is a combination 
Phase I and Phase II study; the objectives are to first identify a dose of GSK525762 that 
may be combined safely with fulvestrant, followed by a Phase II study to identify clinical 
activity of the drugs when given in combination.


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Objective(s)/Endpoint(s)
Phase I
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Objectives
Endpoints
Primary

To determine a recommended Phase 2 dose 
(RP2D) of GSK525762, when given in 
combination with fulvestrant, in women with 
advanced or metastatic hormone receptor 
positive breast cancer (HR+/HER2- BC)

Safety profile (e.g., adverse events [AEs], 
serious adverse events [SAEs], dose-limiting 
toxicities [DLTs], dose reductions or delays), 
Overall Response Rate (ORR), defined as 
complete response [CR] rate plus partial 
response [PR] rate, pharmacokinetic [PK] data
Secondary

To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of GSK525762, 
when given in combination with fulvestrant in 
women with advanced or metastatic 
HR+/HER2- BC

AEs, 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 evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination in 
women with advanced or metastatic HR/HER2-
BC

Disease control rate (DCR; defined as CR plus 
PR plus stable disease [SD] rate), duration of 
response, and progression-free survival (PFS)

To characterize the exposure to GSK525762 
and fulvestrant, when given in combination.

Concentrations of GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination
Exploratory

To evaluate additional measures of clinical 
activity of GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic HR+/HER2- BC

Overall survival (OS)

To characterize the pharmacodynamics of 
GSK525762 and fulvestrant, when given in 
combination 

Transcriptomic and/or protein changes in 
molecular markers of BET inhibition and ER 
signaling in tumor tissue 

To identify potential indicators of sensitivity or 
response to GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic ER+BC.

Mutational analysis of tumor tissue; correlation 
of baseline somatic and tumor-specific genetic 
and genomic profiles with response.

To describe the kinetics of tumor growth in the 
presence of GSK525762 and fulvestrant for 
each treatment and investigate the relationship 
between tumor growth kinetics and clinical 
activity.

Tumor size over time, tumor growth rate 
constants, and time to tumor growth (TTG) 
predicted with the model parameters and 
relationship with clinical activity parameters. 

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant 

Relationship between GSK525762 and/or 
fulvestrant exposure markers (e.g. dose, Cmin, 


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Objectives
Endpoints
exposure and safety and efficacy parameters.
Cmax), and safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on 
symptoms and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes 
from baseline in select items from the PRO-
CTCAE

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Phase II
With the implementation of amendment 06, Phase II of the study is terminated.
Objectives
Endpoints
Primary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination, on progression-free survival in 
women with advanced or metastatic 
HR+/HER2- BC

Progression free survival (PFS), defined as the 
median time from the first dose of study 
treatment until objective tumor progression or 
death from any cause, whichever comes first
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC, on additional 
metrics of subject survival

Overall survival (OS)

To evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination

ORR, DCR

To characterize the exposure to GSK525762, 
when given in combination with fulvestrant.

GSK525762 and metabolites concentrations 
following administration in combination with 
fulvestrant

To characterize the exposure to fulvestrant 
when given alone or with GSK525762

Fulvestrant concentrations following 
administration alone or in combination with 
GSK525762
Exploratory

To identify potential indicators of sensitivity or 
response to GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic HR+/HER2- BC

Mutational analysis of tumor tissue; correlation 
of baseline somatic and tumor-specific genetic 
and genomic profiles with response

To describe the kinetics of tumor growth in the 
presence or absence of GSK525762 for each 

Tumor size over time, tumor growth rate 
constants, and time to tumor growth (TTG) 


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Objectives
Endpoints
treatment and investigate the relationship 
between tumor growth kinetics and clinical 
activity
predicted with the model parameters and 
relationship with clinical activity parameters

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant 
exposure and safety and efficacy parameters

Relationship between GSK525762 and/or 
fulvestrant exposure markers (e.g. dose, Cmin, 
Cmax), and safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on 
symptoms and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Overall Design
This study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control 
(Phase II) study with oral administration of GSK525762 in combination with fulvestrant 
in advanced or metastatic HR+/HER2- BC subjects, who have disease that has progressed 
after prior treatment with at least one line of endocrine therapy.
Original Overall Design (Protocols 01-04)
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of HR+/HER2- breast cancer to 
determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. [Changes have been made to this Phase]
Phase II of the study is designed as a randomized, double-blind, placebo-controlled 
cohort, the composition of which will be selected at the end of Phase I, based upon the 
totality of Phase I data.  This cohort will compare the efficacy of GSK525762 in 
combination with fulvestrant versus fulvestrant with GSK525762-matched placebo in 
subjects with disease that progressed on anti-estrogen and/or one or more AIs, or failure 
of a combination treatment with CDK4/6 inhibitor plus AI or a combination of both of 
these groups/patient populations.


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Study Schematic
Phase I:
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Phase I will study the safety, tolerability, PK, and efficacy of GSK525762 plus 
fulvestrant when administered in combination in up to two escalating dose levels (DLs).  
Eligible subjects must have advanced or metastatic HR+/HER2- BC that has been 
refractory to, or progressed despite, prior systemic therapy.  The combination of 
GSK525762 plus fulvestrant will be evaluated in an open-label fashion in two separate 
cohorts.  These cohorts will be evaluated at both DLs:
Subjects who have disease that has relapsed during treatment or within 12 months 
of completion of adjuvant therapy with an AI, OR disease that progressed during 
treatment with an AI for advanced/metastatic disease.  Prior ovarian suppression 
and/or tamoxifen are allowed as long as the other criteria are met. 
Subjects who have disease that has progressed during treatment with the 
combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole for advanced 
or metastatic disease.  Prior ovarian suppression and/or tamoxifen are allowed as 
long as the other criteria are met. 
Documented progression on the last line of systemic anti-cancer therapy is required.


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Phase I will follow a modified toxicity probability interval (mTPI) design. The design 
assumes (i) approximately 30 subjects will complete the dose-limiting toxicity (DLT) 
evaluation period and (ii) the true underlying toxicity rate for GSK525762 in combination 
with fulvestrant falls within the range from 25% to 35% and centered at 30%.
Subjects in DL1 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at one dose level lower than the single-agent RP2D.  Subjects will be 
enrolled into one of two possible cohorts, based on their prior treatment history, as 
defined above.  A sentinel group (comprising subjects enrolled in both cohorts) of at least 
3 and up to 10 subjects will be evaluated for safety.  If the DLT rate of the DL1 sentinel 
group does not exceed the maximum permitted toxicity rate, the following will occur in 
parallel:

At DL1, up to 35 subjects will be enrolled into each cohort

Evaluation of DL2 will begin
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at the single agent RP2D.   Subjects will be enrolled into one of two possible 
cohorts, based on their prior treatment history, as defined above.  A sentinel group 
(comprising subjects enrolled in both cohorts) of at least 3 and up to 10 subjects will be 
evaluated for safety.  During enrolment of the DL2 sentinel group, the enrolment for DL1 
will be temporarily closed. After completing the enrolment for the sentinel group of DL2, 
the enrolment for DL1 will be re-opened and the enrolment for DL2 will be temporarily 
closed while waiting for the 28 days DLT observation period to be completed for all 
subjects.
If the DLT rate of the DL2 sentinel group does not exceed the maximum permitted 
toxicity rate, enrolment for DL2 will be re-opened and the enrolment for DL1 will be 
temporarily closed until DL2 enrols the same number of subjects as DL1. After that, 
both DL1 and DL2 will be open to enrolment, and subjects will be assigned 1:1 to either 
DL1 or DL2 until one or the other dose level is filled or terminated.  All subjects would 
then be enrolled at the remaining dose level.
Each prior treatment history cohort (two per DL) may enroll up to 35 subjects (including 
subjects from the sentinel cohorts), for a total of approximately 70 subjects enrolled at 
each DL.  The number of subjects enrolled into each cohort may vary, as interim analyses 
for safety and efficacy may terminate any cohort if the DLT rate exceeds the maximum 
permitted toxicity rate, or if the efficacy rate does not exceed the historical overall 
response rate (ORR).
If the DLT rate of the sentinel group in DL1 exceeds the maximum permitted toxicity 
rate, then a lower dose level (DL-1) will be evaluated.  If the DLT rate of the sentinel 
group in DL2 exceeds the maximum permitted toxicity rate, then additional subjects will 
not be enrolled at DL2, and all subjects will be enrolled at DL1.
Subjects must have measurable disease per RECIST 1.1 criteria.  The primary endpoints 
of Phase I of the study are safety, tolerability, and clinical response, based on ORR. 
Additional efficacy data, including PFS and OS, will be collected from all subjects 
treated in Phase I.  The totality of data, including safety/tolerability, PK, and efficacy, 


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will be used to determine whether to proceed to Phase II, and which cohort and dose to be 
carried forward into Phase II.
Phase II: 
With the implementation of amendment 06, Phase II of the study is terminated.
Phase II is a randomized, double-blind, placebo-controlled study that will explore the 
clinical activity of GSK525762 and fulvestrant when given in combination, to subjects 
with advanced or metastatic HR+/HER2- BC.  The primary endpoint of Phase II is PFS.
The design for Phase II will be finalized based on the results from Phase I.
Phase II will be composed of one cohort, the composition and the dose of which will be 
decided based on the totality of the data at the end of Phase I.  If any of the prior 
treatment history-specific cohorts in Phase I are terminated early for toxicity or lack of 
efficacy at any dose, enrolment of subjects with those prior therapies at that dose will not 
be carried forward into Phase II.  
Phase II may enrol subjects who have disease that has progressed after prior therapy with:

AIs alone (either in the setting of primary metastatic disease or on-
treatment/within 12 months of discontinuing adjuvant endocrine therapy), OR

CDK4/6 inhibitor plus AI, OR

either AI therapy OR CDK4/6 inhibitor plus AI.  If both cohorts are permitted to 
enroll in Phase II, randomization will be stratified by prior CDK4/6 inhibitor-
based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-exposed) 
and corresponding stratified analysis will be provided at interim and final 
analyses.
Eligible subjects will be randomized 1:1 to receive GSK525762 plus fulvestrant (Arm A), 
or fulvestrant plus GSK525762-matched placebo (Arm B), in a double-blinded fashion.  
Note that subjects may have received up to one line of cytotoxic chemotherapy in the 
advanced/metastatic setting.  In addition, subjects enrolled in the CDK4/6 inhibitor plus 
AI cohort may have failed therapy with any number of lines of anti-estrogens and/or AIs.  
Subjects will be treated until progression, toxicity, or withdrawal of consent.  The 
primary endpoint of this Phase of the study will be progression free survival (PFS); 
comparison of primary and secondary endpoints will be performed between the 
investigational and control arms.
Revised Overall Design (Protocol Amendment 05)
While the overall study goals and design remain the same, changes have been made to 
Phase I of the study to address to emerging data and intended to better define the patient 
population most likely to benefit from combination treatment of molibresib plus 
fulvestrant. The following are to be noted:
1. DL1 Cohort 1 (60 mg, AI-failures) will complete enrolment to 35 subjects as 
under amendment 4 


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2. DL1 Cohort 2 (60 mg, CDK4/6 inhibitor plus AI failure) – change in inclusion 
criteria and to the number of subjects to be enrolled is detailed below.
3. DL2 (80 mg) both cohorts (Cohort 1 and Cohort 2) – enrolment is closed based on 
decreased tolerability and lack of efficacy as per protocol guidance.
4. Phase II design remains unchanged – as originally stated, this Phase of the study 
will be redesigned based after analysis of Phase I data.
Change to DL1 Cohort 2:
Enrolment into DL1 (60 mg) Cohort 2 is modified. Subjects previously treated 
with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole AI 
for advanced or metastatic disease will be enrolled as follows;  
o
Up to 32 subjects with measurable disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI. 
o
Up to 16 subjects with bone only disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI.
o
The total number of subjects enrolled into this cohort will be approximately 
75.
o
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met.
This requirement is based on emerging data and intended to better define the patient 
population most likely to benefit from combination treatment.
Treatment Arms and Duration
In Phase I, all subjects will receive GSK525762 in combination with fulvestrant.  
Subjects will begin combination therapy immediately, and will continue until 
unacceptable toxicity, progression of disease, withdrawal of consent, or death.  The total 
duration of Phase I will depend on recruitment rates, withdrawals due to toxicity or 
progression or death, with an approximate duration of 15 months.
Initial administration will consist of daily GSK525762 and the approved dose/regimen of 
fulvestrant.  Additional doses and schedules may be explored based on emerging safety, 
tolerability, and PK data.  No doses will be explored beyond 100 mg GSK525762 or 
500 mg (IM) fulvestrant, as 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.
Dose interruptions and/or reductions of GSK525762 and/or fulvestrant are permitted, as 
necessary, in response to toxicity or other events.  There will not be any pre-planned dose 
reductions.  The decision to interrupt/reduce dosing will take into account likely 
attribution of toxicity, and reduction/interruption of one agent or the other will be 


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permitted. Subjects who require dose reduction and/or discontinuation of one 
investigational agent may continue on the other agent until progression, withdrawal of 
consent, or unacceptable toxicity after discussion with the Medical Monitor.
Initial dosing in Phase I will maintain a fixed dose of fulvestrant (500 mg intramuscularly 
(IM) on days 1, 15, and 29 of cycle 1 and then monthly thereafter).  GSK525762 will 
initiate dosing at 60 mg once daily, which is one dose level lower than the single-agent 
RP2D.  Doses beyond the single-agent RP2D may be explored if the drug is tolerated and 
PK analysis demonstrates reduced GSK525762 exposure (AUC and/or Cmax) when 
administered in combination with fulvestrant.  In Phase I, a completed subject is one who 
is followed to death.
Phase II is a randomized, double-blind, placebo-controlled study in subjects with 
advanced or metastatic HR+/HER2- BC.  Subjects who have disease that has progressed 
on prior treatment with either AIs, or a combination of a CDK4/6 inhibitor and AI will be 
randomized to receive the approved dose of fulvestrant (500 mg intramuscularly (IM) on 
Days 1, 15, and 29 of cycle 1, and monthly thereafter) in combination with GSK525762, 
or fulvestrant with GSK525762 matched placebo.  The treatment cohort and dose taken 
into Phase II will be based upon the totality of data from Phase I.  
In Phase II, subjects will begin therapy immediately and will continue until unacceptable 
toxicity, progression of disease, or withdrawal of consent.  Dose adjustments of 
GSK525762 or fulvestrant are permitted as necessary based on toxicity or other events as 
noted above.  The total duration of Phase II will depend on recruitment rates, withdrawals 
due to toxicity or progression, and the timing of subjects’ duration on study, with an 
approximate duration of 16 months.
In Phase II, a completed subject is one who is followed until death.  Any subject who 
progresses while receiving study treatment or discontinues treatment due to a treatment-
emergent (i.e. unrelated or related to treatment) adverse event will be followed until 
death.  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 294 subjects worldwide with relapsed/refractory advanced or metastatic 
HR+/HER2- BC will be enrolled in the study as a whole.  Subjects may have disease 
which progressed during or within 12 months of stopping adjuvant therapy, or disease 
which was initially diagnosed as advanced or metastatic. Cohort 2 is modified to include 
a minimum of 48 subjects who have progressed after greater than or equal to 12 months 
of a CDK4/6 inhibitor (e.g., palbociclib) plus AI for advanced or metastatic disease with 
either measurable disease (32 subjects) or bone only disease (16 subjects).  In Phase I, up 
to 140 subjects will be treated.  The total number of subjects required will depend upon 
the safety profile of the combinations and the number of responses, as described in the 
full protocol.  In Phase II, approximately 154 subjects will be treated.


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Analysis
For evaluation of safety, Phase I will follow a mTPI design to identify the MTD of 
GSK525762 when administered in combination with fulvestrant.  Subject safety will be 
monitored continuously using a mTPI method, and individual cohort(s) may be 
terminated early if the toxicity exceeds pre-specified parameters.  No formal statistical 
hypotheses will be tested.  Analysis will be descriptive and exploratory.  All data will be 
pooled, and descriptive analyses will be summarized and listed by dosing cohort at study 
conclusion.  Dose escalation decision(s) will be based on the totality of clinical safety 
assessment based on a combination of reported safety events, as well as pharmacokinetic 
data.
For evaluation of efficacy in Cohort 1 (AI Failure) in Phase I, the primary goal is to 
demonstrate a clinically meaningful response rate, defined as an objective response rate 
(CR + PR) of 25% 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 
>0.25, assuming the maximum response rate for an ineffective drug is 10% and the 
minimum response rate for an effective drug is 25%.  For evaluation of efficacy in Cohort 
2 (CDK4/6+AI Failure) in Phase I, the primary goal is to demonstrate a clinically 
meaningful response rate in the measurable disease subjects only, defined as an objective
response rate (CR + PR) of 20% relative to a 5% response rate suggesting no activity.  
This will be conducted by testing the null hypothesis that P0<=0.05 versus the alternative 
that P1 >0.20, assuming the maximum response rate for an ineffective drug is 5% and the 
minimum response rate for an effective drug is 20%.  This portion of the study will 
employ Bayesian methods that allow the study to be frequently monitored with the 
constraint of both Type I and Type II error rates.  The first interim analysis in each cohort 
will be performed when at least 10 evaluable subjects have enrolled in that cohort.  
Enrolment to an individual cohort may be stopped early for toxicity or lack of efficacy, 
but cohorts will not be stopped early if the ORR meets or exceeds the alternate 
hypothesis at the interim analyses.
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population. 
With the implementation of Amendment 06, 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. There will be no Phase II.
In Phase II, the primary goal is to demonstrate a clinically meaningful improvement in 
PFS when GSK525762 is added to fulvestrant therapy.  For this study, “clinically 
meaningful” is defined as a hazard ratio (HR) of 0.5, indicating that the combination 
therapy doubles the PFS relative to the comparator arm.  The study will have 90% power 
to detect a hazard ratio (HR) of 0.5 with a one-sided 0.025 level test. A planned interim 


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analysis will be performed when 45 subjects have progressed or died; the study may be 
stopped at the time of interim analysis for safety as well as for futility or efficacy.


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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.  Fulvestrant 
induces selective degradation of the estrogen receptor (ER).  Together, they demonstrate 
synergistic effects against tumor cell growth in treatment-resistant breast cancer cell lines 
in vitro and in vivo.  The current protocol (study 201973) aims to test the safety, 
tolerability, PK, PD, and efficacy of this combination when administered concomitantly 
to women with advanced or metastatic Hormone Receptor-positive/HER2-negative
(HR+/HER2-) breast cancer (HR+/HER2- BC).
2.1.
Study Rationale
Advanced or metastatic HR+/HER2- BC is an incurable illness that will prove fatal for 
the majority of afflicted women.  Current standards of care (SoC) include endocrine 
therapy, targeted therapy, and chemotherapy.  Recent preclinical data suggest that 
altering the expression of the HR as well as other HR-responsive genes may provide 
therapeutic benefit for women for whom endocrine therapy alone has proven inadequate.  
One potential novel target for therapy is the BET family of proteins.  These proteins bind 
to chromatin and regulate gene expression, and data suggest that combination with 
endocrine therapy may provide therapeutic benefit and even restore sensitivity to HR-
targeted agents.  The current protocol (201973) proposes to evaluate the combination of 
the BET inhibitor GSK525762 with the ER-degrading agent fulvestrant in women with 
metastatic or advanced HR+/HER2- BC who have progressed on at least one line of prior 
endocrine therapy.
2.2.
Brief Background
In the United States, breast cancer is the most common malignancy in women, affecting 
an estimated one out of every eight females during her lifetime [Siegel, 2016].  While 
many cases of hormone receptor positive breast cancer can be treated definitively with a 
multi-modal approach of surgery, radiation, and/or hormonal manipulation, metastatic 
breast cancer remains an incurable disease for which current approaches are palliative.  
Given the prevalence of this disease, breast cancer remains an active area of clinical 
development.
Breast cancer is subdivided into multiple clinical subtypes, based on the expression of 
steroid hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and 
the receptor tyrosine kinase erb-b2 receptor tyrosine kinase 2 (ERBB2, known clinically 
as HER2).  The expression of these factors contributes to assessing the overall prognosis 
of the disease and drives therapeutic decision-making.  ER is a transcription factor that 
translocates to the nucleus upon binding to estradiol and other, related sex hormones.  
Once inside the nucleus, it binds to deoxyribonucleic acid (DNA) at sites of open 
chromatin in order to drive the expression of ER-dependent genes [Ross-Innes, 2012; 
Feng, 2014].  For the 70% of women [McNeil, 2006] whose tumors express the ER (i.e., 
ER-positive breast cancer (ER+BC), endocrine therapy remains the cornerstone of 
therapy for most of these women, followed by cytotoxic chemotherapy once tumors no 
longer respond to hormonal agents.  Currently, approved endocrine therapies include the 


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ER antagonist tamoxifen; the aromatase inhibitors (AIs) anastrozole, exemestane, and 
letrozole; and fulvestrant, a selective ER antagonist.  Recently, improved progression-
free survival (PFS) has been demonstrated by combining endocrine therapy with either 
the Mammalian Target of Rapamycin (mTOR) inhibitor everolimus [Baselga, 2012] or 
with the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib [Finn, 2015].  Despite 
these advances, however, the disease remains incurable, and relapse (and thus need for 
novel therapeutic agents) is inevitable. While patients proceed from one therapy to the 
next, they ultimately exhaust their options, ER HR+/HER2- BC an area of unmet need, as 
a result of this inexorable progression.
The mechanisms by which ER+BC tumors become resistant to endocrine therapy have 
been extensively investigated in recent years.  These include upregulation of growth 
factor receptor signalling pathways, mutations in the ER, and modulation of pathways 
that render BC cells more sensitive to estrogen [McNeil, 2006].  Upregulation of v-myc 
avian myelocytomatosis viral oncogene homolog (c-myc) and B-cell CLL/lymphoma 2 
(BCL2) gene products have been demonstrated to be critical for growth of ER+BC cells 
and tumors both in vitro and in vivo [Chrzan, 2001; Miller, 2011; Planas-Silva, 2007; 
McNeil, 2006].  These alterations lead to broad changes in gene expression that drive 
proliferative and anti-apoptotic effects within the tumor cells, and ultimately to tumor 
growth despite treatment with anti-estrogen therapy [Miller, 2011].
Treatment-resistant ER+BC tumors continue to express ER, which in turn continues to 
bind to chromatin and express ER-dependent genes [Ross-Innes, 2012].  This suggests 
that agents that directly downregulate ER expression and/or modulate ER binding to 
chromatin may lead to biologic and/or clinical responses.  Recently, the importance of 
epigenetic markers in the regulation of gene expression has been identified.  Cells possess 
machinery for post-translational modification (such as acetylation, methylation, or 
phosphorylation) of specific residues on histone tails.  These modifications “mark” those 
regions of chromatin for enhancement or silencing of gene expression.  The mechanism 
and importance of this “histone code” is only now being unravelled, and cells express 
enzymes for “writing” (i.e., transferring molecular moieties onto histone tails), “erasing” 
(i.e., removing those moieties when they are no longer required), and “reading” (i.e., 
identifying those marks and recruiting necessary machinery to have an effect on gene 
expression).
One subset of these “readers” is the Bromodomain and Extraterminal (BET) family.  
These proteins recognize acetyl groups on the tails of histones and are critical for 
recruiting transcriptional machinery necessary for gene expression.  BET proteins 
regulate a host of other downstream effectors that are critical for proliferation, 
differentiation, and cell survival.  BET inhibitors are currently being evaluated in the 
therapy of both solid tumors and hematologic malignancies.  GSK525762, is currently 
being studied in two separate trials: BET115521 and BET116183.  Both are Phase I/II 
studies, with the primary endpoint to evaluate safety and tolerability of GSK525762 and 
identify the single-agent maximally-tolerated dose (MTD).  In the BET115521 
monotherapy trial, ER+ breast cancer subjects with disease that progressed after multiple 
prior lines of therapy were enrolled.  A planned interim futility analysis in this population 
was performed, and GSK stopped enrolment in this single agent cohort, based upon 
limited benefit.  


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BET inhibition and ER-targeted therapy have been demonstrated to target ER expression 
and change ER-dependent gene expression in preclinical models.  A recent study 
demonstrated that BET inhibition leads to ER downregulation [Feng, 2014].  
Furthermore, BET inhibition leads to effects independent of ER expression, such as 
downregulation of c-myc and BCL2, in a variety of preclinical models [Wyce, 2013; 
Mertz, 2011; Delmore, 2011].  These pathways have been demonstrated to be critical for 
endocrine resistance [McNeil, 2006; Miller, 2011; Planas-Silva, 2007; Chrzan, 2001].  In 
tamoxifen-resistant cells (a model of progressive ER+BC), a combination of BET 
inhibitor plus fulvestrant (which selectively targets the ER for proteasomal degradation) 
suppressed cell growth in vitro and induced tumor shrinkage in vivo [Feng, 2014].  
Moreover, mouse xenograft models of ER+ disease demonstrated improved survival 
when animals were treated with the combination of GSK525762 and fulvestrant, versus 
vehicle or either agent alone (Figure 1).
Taken together, these preclinical data suggest a mechanism by which BET inhibitors and 
endocrine-targeted therapy may combine to provide synergistic benefit in HR+/HER2-
BC. 
Figure 1
In vivo study of MCF-7 cell mouse xenograft model; overall survival 
is improved when GSK525762 is combined with fulvestrant (purple 
line), compared to either agent alone
This study (201973) proposes to evaluate the combination of GSK525762, a potent 
inhibitor of the BET family of proteins, with fulvestrant, in women with HR+/HER2-
BC.  Both agents are inhibitors of distinct but convergent molecular mechanisms that are 
critical for growth and proliferation of breast cancer tumor cells.  This is a combination 
Phase I and Phase II study; the objectives are to first identify a dose of GSK525762 that 


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may be combined safely with fulvestrant, followed by a Phase II study to identify clinical 
activity of the drugs when given in combination.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Phase I
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Objectives
Endpoints
Primary

To determine a recommended Phase 2 dose 
(RP2D) of GSK525762, when given in 
combination with fulvestrant, in women with 
advanced or metastatic estrogen receptor 
positive breast cancer (HR+/HER2- BC)

Safety profile (e.g., adverse events [AEs], 
serious adverse events [SAEs], dose-limiting 
toxicities [DLTs], dose reductions or delays), 
Overall Response Rate (ORR), defined as 
complete response [CR] rate plus partial 
response [PR] rate, pharmacokinetic [PK] data
Secondary

To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of GSK525762, 
when given in combination with fulvestrant in 
women with advanced or metastatic 
HR+/HER2- BC

AEs, 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 evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination in 
women with advanced or metastatic 
HR+/HER2-BC

Disease control rate (DCR; defined as CR plus 
PR plus stable disease [SD] rate), duration of 
response, and progression-free survival (PFS)

To characterize the exposure to GSK525762 
and fulvestrant, when given in combination.

Concentrations of GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination
Exploratory

To evaluate additional measures of clinical 
activity of GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic HR+/HER2- BC

Overall survival (OS)

To characterize the pharmacodynamics of 
GSK525762 and fulvestrant, when given in 
combination 

Transcriptomic and/or protein changes in 
molecular markers of BET inhibition and HR
signaling in tumor tissue 

To identify potential indicators of sensitivity or 
response to GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic HR+/HER2- BC.

Mutational analysis of tumor tissue; correlation 
of baseline somatic and tumor-specific genetic 
and genomic profiles with response.


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Objectives
Endpoints

To describe the kinetics of tumor growth in the 
presence of GSK525762 and fulvestrant for 
each treatment and investigate the relationship 
between tumor growth kinetics and clinical 
activity.

Tumor size over time, tumor growth rate 
constants, and time to tumor growth (TTG) 
predicted with the model parameters and 
relationship with clinical activity parameters. 

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant 
exposure and safety and efficacy parameters.

Relationship between GSK525762 and/or 
fulvestrant exposure markers (e.g. dose, Cmin, 
Cmax), and safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on 
symptoms and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes 
from baseline in select items from the PRO-
CTCAE

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Phase II
With the implementation of amendment 06, Phase II of the study is terminated.
Objectives
Endpoints
Primary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination, on progression-free survival in 
women with advanced or metastatic 
HR+/HER2- BC

Progression free survival (PFS), defined as the 
median time from the first dose of study 
treatment until objective tumor progression or 
death from any cause, whichever comes first
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC, on additional 
metrics of subject survival

Overall survival (OS)

To evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination

ORR, DCR

To characterize the exposure to GSK525762, 
when given in combination with fulvestrant.

GSK525762 and metabolites concentrations 
following administration in combination with 
fulvestrant

To characterize the exposure to fulvestrant 
when given alone or with GSK525762

Fulvestrant concentrations following 
administration alone or in combination with 
GSK525762


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Objectives
Endpoints
Exploratory

To identify potential indicators of sensitivity or 
response to GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic HR+/HER2- BC

Mutational analysis of tumor tissue; correlation 
of baseline somatic and tumor-specific genetic 
and genomic profiles with response

To describe the kinetics of tumor growth in the 
presence or absence of GSK525762 for each 
treatment and investigate the relationship 
between tumor growth kinetics and clinical 
activity

Tumor size over time, tumor growth rate 
constants, and time to tumor growth (TTG) 
predicted with the model parameters and 
relationship with clinical activity parameters

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant 
exposure and safety and efficacy parameters

Relationship between GSK525762 and/or 
fulvestrant exposure markers (e.g. dose, Cmin, 
Cmax), and safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on 
symptoms and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- BC

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
4.
STUDY DESIGN
4.1.
Overall Design
This study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control 
study (Phase II) study with oral administration of GSK525762 in combination with 
fulvestrant in advanced or metastatic HR+HER2-BC subjects, who have disease that has 
progressed on prior treatment with at least one line of endocrine therapy.
4.1.1.
Original Overall Design (Protocols 01-04)
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of HR+/HER2- breast cancer to 
determine a recommended Phase 2 dose RP2D based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. [Changes have been made to this Phase, see 
changes below in Section 4.1.2]
Phase II of the study is designed as a randomized, double-blind, placebo-controlled 
cohort, the composition of which will be selected at the end of Phase I, based upon the 
totality of Phase I data.  This cohort will compare the efficacy of GSK525762 in 
combination with fulvestrant versus fulvestrant with GSK525762-matched placebo in 
subjects with disease that progressed on anti-estrogen and/or one or more AIs, or failure 


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of a combination treatment with CDK4/6 inhibitor plus letrozole or a combination of both 
of these groups/patient populations (Figure 2).
Figure 2
Study Schematic
Phase I:
Phase I will study the safety, tolerability, PK, and efficacy of GSK525762 plus 
fulvestrant when administered in combination in up to two escalating dose levels (DLs).  
Eligible subjects must have advanced or metastatic HR+/HER2- BC that has been 
refractory to, or progressed despite, prior systemic therapy.  The combination of 
GSK525762 plus fulvestrant will be evaluated in an open-label fashion in two separate 
populations of subjects (i.e., two cohorts).  These cohorts will be evaluated at both DLs 
(see Inclusion and Exclusion criteria in Section 5.1 and Section 5.2 for full details):
Subjects who have disease that has relapsed during treatment or within 12 months 
of completion of adjuvant therapy with an AI, OR disease that progressed during 
treatment with an AI for advanced/metastatic disease.  Prior ovarian suppression 
and/or tamoxifen are allowed as long as the other criteria are met.
Subjects who have disease that has progressed during treatment with the
combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole for advanced 


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or metastatic disease.  Prior ovarian suppression and/or tamoxifen are allowed as 
long as the other criteria are met.
Documented progression on the last line of systemic anti-cancer therapy is required.
Phase I will follow a modified toxicity probability interval (mTPI) design. The design 
assumes (i) approximately 30 subjects will complete the dose-limiting toxicity (DLT) 
evaluation period and (ii) the true underlying toxicity rate for GSK525762 in combination 
with fulvestrant falls within the range from 25% to 35% and centered at 30%.
Subjects in DL1 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at one dose level lower than the single-agent RP2D.  Subjects will be 
enrolled into one of two possible cohorts, based on their prior treatment history, as 
defined above.  A sentinel group (comprising subjects enrolled in both cohorts) of at least 
3 and up to 10 subjects will be evaluated for safety.  If the DLT rate of the DL1 sentinel 
group does not exceed the maximum permitted toxicity rate as defined by the mTPI, the 
following will occur in parallel:

At DL1, up to 35 subjects will be enrolled into each cohort

Evaluation of DL2
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at the single agent RP2D.   Subjects will be enrolled into one of two possible 
cohorts, based on their prior treatment history, as defined above.  A sentinel group 
(comprising subjects enrolled in both cohorts) of at least 3 and up to 10 subjects will be 
evaluated for safety.  During enrolment of the DL2 sentinel group, the enrolment for DL1 
will be temporarily closed. After completing the enrolment for the sentinel group of DL2, 
the enrolment for DL1 will be re-opened and the enrolment for DL2 will be temporarily 
closed while waiting for the 28 days DLT observation period to be completed for all 
subjects.
If the DLT rate of the DL2 sentinel group does not exceed the maximum permitted 
toxicity rate, enrolment for DL2 will be re-opened and the enrolment for DL1 will be 
temporarily closed until DL2 enrols the same number of subjects as DL1. After that, 
both DL1 and DL2 will be open to enrolment, and subjects will be assigned 1:1 to either 
DL1 or DL2 until one or the other dose level is filled or terminated.  All subjects would 
then be enrolled at the remaining dose level.  Refer to Section 4.2.3.2 for details of dose 
level and cohort selection.
Each cohort (two at each DL) may enroll up to 35 subjects, for a total of approximately 
70 subjects enrolled at each DL.  The total number of subjects enrolled into each cohort 
may vary, as interim analyses for safety and efficacy may terminate any cohort if the 
DLT rate exceeds the maximum permitted toxicity rate per the mTPI, or if the efficacy 
rate does not exceed the historical overall response rate (ORR).
If the DLT rate of the sentinel group in DL1 exceeds the maximum permitted toxicity 
rate as defined by the mTPI, then a lower dose level (DL-1) will be evaluated.  If the 
DLT rate of the sentinel group in DL2 exceeds the maximum permitted toxicity rate as 


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defined by the mTPI, then additional subjects will not be enrolled at DL2, and all subjects 
will be enrolled at DL1.
Subjects must have disease that is evaluable for response.  The primary endpoints of 
Phase I of the study are safety and clinical response, based on ORR. Additional efficacy 
data, including PFS and OS, will be collected from all subjects treated in Phase I.  The 
totality of data, including safety/tolerability, PK, and efficacy, will be used to determine 
whether to proceed to Phase II, and which cohort and dose to be carried forward into 
Phase II.
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population. 
With the implementation of Amendment 06, specific assessments and collection of 
survival follow-up data will no longer be required. Please see Section 7.1for further 
details. The study will conclude when the last subject has completed/discontinued study 
treatment and completed the end of treatment visit. There will be no Phase II.
Phase II:
Phase II is a randomized, double-blind, placebo-controlled study that will explore the 
clinical activity of GSK525762 and fulvestrant when given in combination, to subjects 
with advanced or metastatic HR+/HER2- BC.  The primary endpoint of Phase II is PFS.
Phase II will be composed of one cohort, the composition and the dose of which will be 
decided based on the totality of the data at the end of Phase I.  If any of the prior 
treatment history-specific cohorts in Phase I are terminated early for toxicity or lack of 
efficacy at any dose, enrolment of subjects with those prior therapies at that dose will not 
be carried forward into Phase II.  Phase II will enrol subjects who have disease that has 
progressed after prior therapy with:

AIs alone (either in the setting of primary metastatic disease or on-
treatment/within 12 months of discontinuing adjuvant endocrine therapy), OR

CDK4/6 inhibitor plus letrozole, OR

Either AI therapy OR CDK4/6 inhibitor plus letrozole.  If both cohorts are 
permitted to enroll in Phase II, randomization will be stratified by prior CDK4/6 
inhibitor-based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-
exposed) and corresponding stratified analysis will be provided at interim and 
final analyses.
Eligible subjects will be randomized 1:1 to receive GSK525762 plus fulvestrant (Arm A), 
or fulvestrant plus GSK525762-matched placebo (Arm B), in a double-blinded fashion.  
Note that subjects may have received up to one line of cytotoxic chemotherapy in the 
advanced/metastatic setting.  In addition, subjects enrolled in the CDK4/6 inhibitor plus 
letrozole cohort may have failed therapy with any number of lines of anti-estrogens 
and/or AIs.  Subjects will be treated until progression, toxicity, or withdrawal of consent.  


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The primary endpoint of this Phase of the study will be progression free survival (PFS); 
comparison of primary and secondary endpoints will be performed between the 
investigational and control arms.
4.1.2.
Revised Overall Design (Protocol Amendment 05)
While the overall study goals and design remain same, changes have been made to 
Phase I of the study to address to emerging data and intended to better define the patient 
population most likely to benefit from combination treatment of molibresib plus 
fulvestrant. The following are to be noted:
1. DL1 Cohort 1 (60 mg, AI-failures) will complete enrolment to 35 subjects as 
under amendment 4
2. DL1 Cohort 2 (60 mg, CDK4/6 inhibitor plus AI failure) – change in inclusion 
criteria and to the number of subjects to be enrolled is detailed below in Section 
4.1.2.1.
3. DL2 (80 mg) both cohorts (Cohort 1 and Cohort 2) – enrolment is closed based on 
decreased tolerability and lack of efficacy as per protocol guidance.
4. Phase II design remains unchanged – as originally stated, this Phase of the study 
will be redesigned based after analysis of Phase I data.
4.1.2.1.
Change to DL1 Cohort 2:

Enrolment into DL1 (60mg) Cohort 2 is modified. Subjects previously treated 
with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus AI for 
advanced or metastatic disease will be enrolled as follows;  
o
Up to 32 subjects with measurable disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI. 
o
Up to 16 subjects with bone only disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI.
o
The total number of subjects enrolled into this cohort will be approximately
75.
o
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met.
This requirement is based on emerging data and intended to better define the patient 
population most likely to benefit from combination treatment. The required number of 
subjects is described in Section 9.2.
4.1.3.
Type and Number of Subjects
All subjects enrolled in this study will have a diagnosis of advanced or metastatic 
HR+/HER2- BC, that has progressed on prior treatment with at least one line of therapy, 


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or which has progressed while on or within 12 months of discontinuing adjuvant 
endocrine therapy. Cohort 2 is modified to include a minimum of 48 subjects who have 
progressed after greater than or equal to 12 months of a CDK4/6 inhibitor (e.g., 
palbociclib) plus AI for advanced or metastatic disease with either measurable disease 
(32 subjects) or bone only disease (16 subjects).
Approximately 140 subjects will be enrolled in Phase I, and approximately 154 subjects 
total will be enrolled in Phase II.  Further details of the type and number of subjects are 
described in Section 4.2.1 and Section 4.4.1.
4.2.
Phase I
The primary objective of Phase I is to determine a RP2D based on safety, tolerability, 
PK, and efficacy profiles observed after oral administration of GSK525762 in 
combination with fulvestrant in advanced or metastatic HR+HER2- BC subjects.  
As described in Section 4.6 and shown in Figure 2, dosing will begin at DL1.  Subjects in 
DL1 will begin dosing with fulvestrant at the approved dose, plus GSK525762 at one 
dose level lower than the single-agent RP2D (i.e., 60 mg of GSK525762 orally once daily 
and 500 mg of fulvestrant intramuscularly (IM) on Days 1, 15, and 29 of cycle 1, and 
monthly thereafter).  Subjects will be enrolled into one of two possible cohorts, based on 
their prior treatment history as described in Section 4.2.1.  Dose escalation decisions will 
be made based upon data from a small sentinel group pooled from across both cohorts.  
Once three subjects (irrespective of cohort) are enrolled at DL1, a modified toxicity 
probability interval table (Figure 3) will be used to determine whether to dose-escalate, 
dose-deescalate, or enroll additional subjects at DL1.  If additional subjects are required 
to make a dose escalation decision, then subjects will be enrolled in groups of 
approximately three to collect additional safety data.  Up to 10 subjects may be used for 
dose escalation decision making.  If the DLT rate of the DL1 sentinel group does not 
exceed the maximum permitted toxicity rate as defined by the mTPI, then two events will 
occur in parallel:

At DL1, additional subjects will be enrolled into each cohort, up to 35 subjects in 
each cohort as described below

Evaluation of DL2 will begin
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at 80 mg.   Subjects will be enrolled into one of two possible cohorts, based 
on their prior treatment history as described in Section 4.2.1.  As in DL1, a sentinel group 
of at least 3 and up to 10 subjects will be evaluated for safety.  If the DLT rate of the DL2 
sentinel group does not exceed the maximum permitted toxicity rate as defined by the 
mTPI, then up to 35 subjects will be enrolled into each cohort.
Each cohort (two at each DL) may enroll up to 35 subjects, for a total of approximately 
70 subjects enrolled at each dose level.  The total number of subjects enrolled into each 
cohort may vary, as interim analyses for safety and efficacy may terminate any cohort if 
the DLT rate exceeds the maximum permitted toxicity rate per the mTPI, or if the 
efficacy rate does not exceed the historical overall response rate (ORR).  Each dose level 


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may be over-enrolled in order to ensure that an adequate number of subjects complete the 
cohort in a timely manner.
4.2.1.
Type and Number of Subjects in Phase I
In Phase I, subjects must have a diagnosis of relapsed or refractory, advanced or 
metastatic, histologically or cytologically confirmed HR+/HER2- BC.  Full details of 
inclusion and exclusion criteria may be found in Section 5.1 and Section 5.2. See 
Protocol Section 4.1.2 for details on the type and number of subjects in Phase I. 
4.2.2.
Treatment Arms and Duration
In Phase I, all subjects will receive GSK525762 in combination with fulvestrant.  
Subjects will begin combination therapy and will continue until unacceptable toxicity, 
progression of disease, or withdrawal of consent. Enrolment into DL2 has been 
discontinued. See Protocol Section 4.1.2 for the current design. The total duration of 
study will depend on recruitment rates, withdrawals due to toxicity or progression, and 
the timing of subjects’ duration on study, with an estimate of 15 months for Phase I, and 
16 months for Phase II.
In Phase I, subjects in the sentinel groups will be replaced if they are unable to receive at 
least 75% of the scheduled doses (of both agents, at the intended strength) during the 28-
day DLT observation period for reasons other than toxicity.  Once the sentinel groups 
have cleared, all further subjects will not be replaced if they discontinue prematurely.
4.2.3.
Dose Selection
4.2.3.1.
Planned Dose Levels
The projected DLs of GSK525762 are 60 mg and 80 mg administered orally once daily.  
DL2 (80 mg) has been discontinued. If unacceptable toxicity is observed at the 60 mg 
DL, then 40 mg once daily may be explored (DL-1).  The projected DL of fulvestrant is 
the approved dose regimen of 500 mg intramuscularly (IM) on Days 1, 15, and 29 of 
cycle 1, and monthly thereafter.
Additional doses and schedules may be explored based on emerging safety, PK, and PD 
data. No doses will be explored beyond 100 mg GSK525762 or 500 mg (IM) fulvestrant, 
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.
4.2.3.2.
Dose Level & Cohort Selection
In Phase I, subjects will be enrolled into one of two cohorts based on their most recent 
prior treatment history, as described in Section 4.2.1.  Once three evaluable subjects 
(total, irrespective of cohort) have cleared the DLT evaluation period (refer to Section 
4.2.3.4 for definitions of ‘evaluable’ and for DLT details), then an mTPI method (Section 
4.2.3.3) will be used to determine whether to dose escalate to DL2 (if there is no DLT), 
reduce dose to DL-1 (if there are two or three DLTs), or continue enrolling subjects at 


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DL1 (if there is one DLT).  Additional subjects, up to 10 total evaluable, may be enrolled 
in groups of approximately three at DL1 prior to a final dose escalation/de-escalation 
decision.  If DL-1 is tested and found to be safe, then re-evaluation of DL1 may be 
attempted if guided by the model.  If both DL-1 and DL1 are being evaluated, then 
subjects will be randomized 1:1 to either DL-1 or DL1.
If DL1 is found to exceed the pre-specified toxicity, then DL-1 will be evaluated.  If DL2 
is found to exceed the pre-specified toxicity, then additional enrolment in DL2 will cease 
and all subjects will be enrolled to cohorts at DL1.
DL2 (80 mg) is discontinued. 
4.2.3.3.
Dose Escalation & Cohort Safety Decisions
A data review team, consisting (at a minimum) of the investigator(s), Medical Monitors, 
safety physician, pharmacokineticist, clinical representatives, and statistician will be 
responsible for determining whether dose escalation and expansion during Phase I should 
continue as planned according to the mTPI design rules together with the predicted DLT 
rates at all DLs.  Prior to the dose escalation decision, the data review team will review 
available relevant data on all AEs including non-DLT toxicities, laboratory assessments 
and other safety evaluations, as well as any available PK data as described in the Dose 
Escalation Plan.  Quality control of critical safety data will also be described in the Dose 
Escalation Plan, which includes ongoing study monitoring visits, Sponsor review of the 
clinical database, and confirmation by site investigators and/or delegate that the data is 
accurate and complete. The dose-escalation decision and rationale for each cohort will be 
discussed with investigators during teleconference(s). 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).
A modified Toxicity Probability Interval (mTPI) design will be implemented (Figure 3) 
[Ji, 2010].  The mTPI decision rule will be followed for monitoring safety until 35 
subjects have been assigned at the same dose 
The design assumes (i) Approximately 30 subjects will complete the DLT evaluation 
period and (ii) the true underlying toxicity rate for GSK525762 in combination with 
fulvestrant falls within the range from 25% to 35% and centered at 30%.  The monitoring 
rules guiding dose escalation are provided in Figure 3.  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 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 


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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 3
Dose-finding spreadsheet of the modified toxicity probability interval 
(mTPI) method
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
0
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D
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E
E
E
E
E
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E
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E
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E
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2
DU D
S
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E
E
E
E
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E
E
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E
E
E
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3
DU DU D
S
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4
DU DU DU D
D
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DU DU DU DU DU D
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DU DU DU DU DU DU D
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DU DU DU DU DU DU DU D
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DU DU DU DU DU DU DU DU DU D
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DU DU DU DU DU DU DU DU DU DU DU S
S
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DU DU DU DU DU DU DU DU DU DU DU DU D
S
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DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
S
S
S
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S
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DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
S
S
13
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU S
14
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
15
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
16
DU DU DU DU DU DU DU DU DU DU DU DU DU DU DU
17
DU DU DU DU DU DU DU DU DU DU DU DU DU DU
18
DU DU DU DU DU DU DU DU DU DU DU DU DU
19
DU DU DU DU DU DU DU DU DU DU DU DU
20
DU DU DU DU DU DU DU DU DU DU DU
21
DU DU DU DU DU DU DU DU DU DU
22
DU DU DU DU DU DU DU DU DU
23
DU DU DU DU DU DU DU DU
24
DU DU DU DU DU DU DU
25
DU DU DU DU DU DU
26
DU DU DU DU DU
27
DU DU DU DU
28
DU DU DU
29
DU DU
30
DU
Number of patients treated at current dose
Number of dose limiting toxicities (DLT's)
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
U = The current dose is unacceptably toxic
MTD = 30%
Sample Size = 30
Epsilon1 = 0.05
Epsilon2 = 0.05
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.
4.2.3.4.
Dose-Limiting Toxicity Definition
The mTPI decision rules are based on the number of DLTs; an event will be considered a 
DLT if it occurs within the first 28 days of treatment and meets at least one of the criteria 
listed in 
Table 1, unless it can be clearly established that the event is unrelated to treatment.


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Table 1
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

Alanine aminotransferase (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 72 h 
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

Other 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 4.2.3.5.

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
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 (of both agents, at the intended strength) for 
reasons other than toxicity (e.g., acute illness, disease progression) will not be evaluable for DLT purposes.
Refer to Appendix 2 for management of selected toxicities.
4.2.3.5.
Non-Limiting Toxicities
The following toxicities have been deemed to be non-limiting 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 
24 h with medical management (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 24 h
4.2.3.6.
Maximum Dose Increment
The pre-planned dose levels are described in Section 4.2.3.1. Only GSK525762 will be 
dose-escalated at each dose escalation step.
4.2.3.7.
Alternative Dosing Schedules
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging safety, tolerability, PK, and efficacy data.  
Schedules that incorporate a recovery period for GSK525762 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 for GSK525762 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 4.2.3.2.
The dosing schedule may also be adjusted to expand a prior dose cohort to further 
evaluate safety, tolerability, and/or PK 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.  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.
4.2.3.8.
Intra-Subject Dose Escalation
During Phase I, intra-subject dose escalation will not be permitted.  Upon completion of 
Phase I, any subject treated below the RP2D may be dose-escalated to a higher cleared 
dose level (not to exceed the RP2D) after discussion with the medical monitor.  Refer to 
Section 4.3 for more details. After discontinuation of DL2 subjects will not automatically 
be reduced to DL1 if they have a favourable risk/benefit profile. 
4.2.4.
Data Review
An independent data monitoring committee (IDMC) will not be implemented in Phase I 
of the study, as GSK has in place a comprehensive and robust review process of all data.  
During the dose expansion cohorts, all safety, efficacy, and PK data emerging from the 


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study will be reviewed by a Joint Team comprised of participating investigators and 
study coordinators, together with staff involved in the conduct of the study (i.e. Medical 
Monitor, Program Lead Physician, Safety (Pharmacovigilance) Physician, Clinical 
Pharmacokineticist, Statistician, and Clinical Scientist). 
Furthermore, multiple review points and mechanisms will be implemented to safeguard 
subject safety during the conduct of Phase I. The key elements of such safety reviews will 
include regularly scheduled data reviews and investigator meetings, specific safety 
review meetings, and a comprehensive dose selection meeting to be held at the end of 
Phase I (as described in Section 4.3).
4.2.5.
Statistical Analysis
In Phase I, Bayesian methods will be used to investigate clinical activity (defined as 
ORR).  This design also allows the study to be frequently monitored with the constraint 
of both Type I and Type II error rates and also allows the enrollment to be halted due to 
futility for a given cohort. For details of the design and decision rules, refer to 
Section 9.4.
Inference stemming from the Bayesian models of efficacy in subjects harboring 
HR+/HER2- BC is intended to inform decision making.  Actual decisions will depend on 
the totality of the efficacy and safety data.  The decision to terminate any 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, and PK data.  In some cases, 
additional subjects in a cohort may be enrolled even if the model suggests a low 
likelihood of activity.
The safety and efficacy of GSK525762 in combination with fulvestrant will be monitored 
by frequent interim analyses.  After at least 10 evaluable subjects are available in a 
cohort, the first interim data review on efficacy may take place. The data review on safety 
using mTPI method can be conducted at any time. Please see details in Section 9.4. 
Cohorts may be discontinued for toxicity or lack of efficacy as described below:
4.2.5.1.
Safety Analysis
At each safety interim analysis, the number of DLTs, number of evaluable subjects, and 
the observed DLT rate will be reported for each cohort.  The mTPI decision rule will be 
used for monitoring safety until 30 subjects have been assigned at the same dose, at 
which time further enrolment will halt. According to mTPI decision rules (Figure 3), 
once D or DU decision is met or observed DLT rate ≥0.33 for any cohort, the enrolment 
for that cohort will be stopped.
4.2.5.2.
Futility Analysis
When at least 10 evaluable subjects are available in a cohort, the first interim data review 
on efficacy may take place for that expansion cohort.  After that, interim analysis may be 
conducted after every 5 evaluable subjects become available. For each cohort, the 
enrolment for that cohort may be stopped due to futility if the Bayesian posterior 


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probability that the confirmed response rate ≥25% in Cohort 1 (AI Failure) or ≥20% in 
Cohort 2 (CDK4/6+AI Failure) (target) is small (e.g., less than a 10% chance). For 
details, please see Section 9.4.
Refer to Appendix 3 for a discussion of the response assumptions used in the statistical 
model.
4.3.
Decision to Proceed to Phase II
With the implementation of amendment 06, Phase II of the study is terminated.
The decision to proceed to Phase II will be based on totality of data including safety, 
efficacy, PK and PD data.
After RP2D is established, any subjects still receiving therapy with GSK525762 and 
fulvestrant may continue receiving drug(s) until progression, death, withdrawal of 
consent, or unacceptable toxicity, as described in Section 5.4.  Any subject treated below 
the RP2D may be dose-escalated to a higher dose level (not to exceed the RP2D).  Clinic 
visits and efficacy analysis should continue as described in the Time and Events Table.  
Refer to Section 9.1.2 for statistical consideration of dose/cohort selection.
4.3.1.
Phase II Dose Selection
Upon completion of Phase I, all available data (including data from subjects who 
prematurely discontinue therapy) will be compiled and summarized.  The dose(s) taken 
into Phase II will be based upon the totality of data from Phase I, including safety, 
tolerability, efficacy, and PK data.  
4.3.2.
Phase II Cohort Selection
The choice of cohort to be further studied in Phase II will depend on the safety and 
efficacy data from Phase I.  If any of the prior treatment history-specific cohorts in Phase 
I are terminated early for toxicity or lack of efficacy (as described in Section 4.2.3.3), 
enrolment of subjects with those prior therapies will not be carried forward into Phase II.  
Based on results from Phase I, Phase II will enrol subjects who have disease that has 
progressed after prior therapy with:

AIs alone (either in the setting of primary metastatic disease or on-
treatment/within 12 months of discontinuing adjuvant endocrine therapy), OR

CDK4/6 inhibitor plus AI, OR

either AI therapy OR CDK4/6 inhibitor plus AI.  If both cohorts are permitted to 
enroll in Phase II, randomization will be stratified by prior CDK4/6 inhibitor-
based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-exposed) 
and corresponding stratified analysis will be provided at interim and final 
analyses.


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4.4.
Phase II Prior Treatment History Specific Cohorts
Phase II is a randomized, placebo-controlled study of GSK525762 plus fulvestrant 
compared to fulvestrant with GSK525762-matched placebo for subjects with 
HR+/HER2- BC who have failed prior treatment with at least one line of endocrine-based 
therapy.  The primary endpoint is PFS for both groups, with a goal of doubling PFS (i.e., 
a hazard ratio of 0.5). Phase II will be redesigned based on the results for Phase I and the 
emerging data from literature.
4.4.1.
Type and Number of Subjects
Phase II will be comprised of one cohort; the specific composition of this cohort will 
depend on the totality of data from Phase I of the study as described in Section 4.3.  
Subjects must have a disease that did not respond to, or that progressed after, at least one 
line of prior therapy.  Refer to Section 4.3 for details of prior therapy and composition of 
the cohorts.
Refer to Section 9.2.1.2 for the statistical rationale for the number of subjects to be 
enrolled.
In Phase II, subjects will not be replaced if they prematurely discontinue therapy.
4.4.2.
Treatment Arms and Duration
Approximately 154 subjects will be enrolled in Phase II of the study.  The total duration 
of study will depend on recruitment rates, withdrawals due to toxicity or progression, and 
the timing of subjects’ duration on study, with an estimate of 16 months for Phase II.
4.4.3.
Dose Selection
Subjects will start dosing on Day 1 with the dose and schedule identified as the RP2D in 
Phase I of the study.  The final dose and regimen for Phase II will be decided upon 
completion of Phase I as described in Section 4.3.
4.4.4.
Group Assignments
Refer to Section 4.3.2 for details of the cohort that may enrol in Phase II.  The eligible 
cohort will be selected at the end of Phase I, and the rationale for selection will be 
communicated to sites in writing.
4.4.5.
Statistical Design
In Phase II, the primary goal is to demonstrate a clinically meaningful improvement in 
PFS when GSK525762 versus placebo is added to fulvestrant therapy.  For this study, 
“clinically meaningful” is defined as a hazard ratio (HR) of 0.5, indicating that the 
combination therapy doubles the PFS relative to the comparator arm.  A planned interim 
analysis will be performed when 45 subjects enrolled in Phase II have progressed or died; 
the study may be stopped at the time of interim analysis for safety as well as for futility or 
efficacy.  Refer to Section 9.4.8.2 for details of the statistical analysis and to Section 
9.4.10 for the explanation of the simulation.


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4.4.6.
Data Review
An IDMC will be utilized in Phase II of this study to ensure external objective medical 
and/or statistical review of safety and/or efficacy issues in order to protect the ethical and 
safety interests of subjects and to protect the scientific validity of the study. The schedule 
of any planned interim analysis and the analysis plan for IDMC review will be described 
in the charter.
4.5.
Design Justification
Given the unmet medical need of relapsed/refractory advanced HR+/HER2- BC, a Phase 
I/II study (201973) is proposed.  The study comprises an open-label, single arm Phase I, 
followed by a randomized, double-blind, placebo-controlled Phase II.
4.5.1.
Phase I
Phase I is a dose escalation/expansion study to determine the R2PD, whether to proceed 
to Phase II, and which cohort (defined by different lines of prior therapy) should be 
further studied in the randomized, blinded, controlled Phase II.  Decisions will be based 
on both efficacy as well as safety.
Efficacy will be monitored via frequent interim analyses.  Bayesian designs that allow the 
trial to be frequently monitored with the constraint of both Type I and Type II error rates 
will be used. Clinical response will be defined as confirmed ORR, per standard 
evaluation criteria (see Appendix 7 for definitions of response assessments and criteria). 
Bayesian predictive adaptive design [Lee, 2008] will be used to investigate the clinical 
activity in each cohort. The criteria will be based on a clinically ineffective response rate 
of 10% and 5% in Cohort 1 (AI Failure) and Cohort 2 (CDK4/6+AI Failure), respectively 
versus a clinically meaningful response rate 25% and 20% in Cohort 1 (AI Failure) and 
Cohort 2 (CDK4/6+AI Failure), respectively; the rationales for these response 
assumptions are described in Appendix 3.  
Dose escalation/de-escalation decisions will be based primarily on the mTPI design [Ji,
2010], a well-validated method for identifying the MTD of oncology therapeutics.
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed.
With the implementation of Amendment 06, 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.
4.5.2.
Phase II
Phase II is a randomized, double-blind, placebo-controlled study that will explore the 
clinical activity of GSK525762 and fulvestrant when given in combination to subjects 


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with advanced or metastatic HR+/HER2- BC, compared to control.  One interim analysis 
will be performed once 45 events have occurred.  Refer to Section 9.4.10 for details of 
statistical modeling and to Appendix 3 for rationale for clinical response assumptions.
4.6.
Dose Justification
GSK525762 and fulvestrant have not been previously administered in combination in 
subjects with cancer.  Both have been administered as single agents to women with 
HR+/HER2- BC, and fulvestrant is currently approved as a single agent and in 
combination with other agents to treat HR+/HER2- BC.
4.6.1.
Starting Doses
GSK525762: 
A Phase I/II study (BET115521) with GSK525762 (as a single agent) is currently 
underway in subjects with advanced solid tumors, including ER+BC. Doses of 2 to 
100 mg QD and doses of 20 mg and 30 mg BID have been evaluated. The RP2D was 
determined to be 80 mg QD with GSK525762 free base amorphous tablet, or 75 mg with 
the besylate salt tablet  based on available tablet strengths.  Section 5.3 of the 
GSK525762 Investigator’s Brochure [GlaxoSmithKline Document Number 
2011N113741_07] details the clinical experience to date with GSK525762 including 
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 administered in Phase I of this study will be reduced to 
60 mg of the besylate salt tablet, which represents a 20% dose reduction from the single-
agent RP2D. There were no dose limiting toxicities (DLT) observed at the 60 mg dose 
administered to subjects with solid tumors in the first time in human (FTIH) study 
BET115521 [GlaxoSmithKline Document Number 2011N113741_07].
Fulvestrant:
For fulvestrant, doses ranging from 125 to 500 mg have been administered to subjects 
with ER+BC. Doses of 250 mg and 500 mg have been studied extensively in Phase 3 
studies, and 500 mg was chosen based on superior clinical activity (fulvestrant package 
insert, Section 14). The currently approved dose of fulvestrant is 500 mg intramuscularly 
(IM) on days 1, 15, and 29 of cycle 1, and then monthly thereafter.  This is the approved 
dose for fulvestrant administered as a single agent, as well as in combination with 
palbociclib.  Dose reductions (to 250 mg administered on the same schedule) are 
stipulated for subjects with underlying hepatic impairment.  While the 
inclusion/exclusion criteria (Section 5.1 and Section 5.2) exclude subjects with 
significant liver dysfunction at baseline, emerging toxicity may warrant a dose reduction 
as described in Appendix 2.
For Phase I and Phase II of this study, fulvestrant will be administered at the 500 mg dose 
strength as detailed in the package insert.  Refer to Section 6.1 of this protocol or Section 
2.3 of the package insert for details of administration.


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4.6.2.
Drug-Drug Interactions
The risk of a pharmacokinetic drug-drug interaction between GSK525762 and fulvestrant 
is low. 
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.  
Metabolism of fulvestrant appears to involve combinations of a number of possible 
biotranformation pathways analogous to those of endogenous steroids, including 
oxidation, conjugation with glucuronic acid and/or sulphate, and aromatic hydroxylation.  
In vitro studies suggest that CYP3A4 is the only CYP isoenzyme involved in the 
oxidation of fulvestrant; however, the relative contribution of CYP enzymes in vivo is not 
known.  Drug-drug interaction studies using inducers and inhibitors of CYP3A4 
(rifampin and ketoconazole, respectively) did not alter fulvestrant pharmacokinetics.
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. GSK525762 did not 
activate the human Pregnane X receptor (hPXR) in an in vitro assay (EC50 >50 M); 
although based on in vitro hepatocyte and repeat dose clinical pharmacokinetic data, 
GSK525762 has the potential to induce CYP3A4.
Based on in vitro studies, fulvestrant is not an inhibitor of CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, or CYP3A4.  Co-administration of fulvestrant with midazolam, a sensitive 
substrate of CYP3A4, did not demonstrate any effect of fulvestrant administration on 
CYP3A4 activity.  
GSK525762 is a substrate for both breast cancer resistance protein (BCRP) and p-
glycoprotein (Pgp), whilst fulvestrant is not a substrate for either transporter.  Neither 
agent appears to inhibit BCRP nor Pgp at doses achieved in clinical studies.  
4.6.3.
Overlapping Toxicities
As monotherapy, GSK525762 and fulvestrant 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. 
In summary, the likelihood that GSK525762 or fulvestrant will have an effect on the PK 
of the other is low.  The AE profiles of both agents, however, contain some common 
toxicities.  Therefore, 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 QD in 
combination with the approved dose of fulvestrant.  Lower exposures (either via lower 
dose or intermittent dosing) may be evaluated if 60 mg QD proves to yield unacceptable 
toxicity in Phase I.


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4.7.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK525762 can be found in the Investigator’s Brochure (IB).  Summaries of findings 
from both clinical and non-clinical studies conducted with fulvestrant can be found in the 
package insert.  The following section outlines the risk assessment and mitigation 
strategy for this protocol.  
4.7.1.
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 GlaxoSmithKline Document Number 2011N113741_07 and 
the fulvestrant package insert.
4.7.1.1.
Predicted Overlapping Toxicities
4.7.1.1.1.
Gastrointestinal Safety Findings
Fulvestrant: As described in the fulvestrant package insert (Section 6.1), in a study 
comparing fulvestrant at 500 mg and 250 mg, some of the most commonly reported 
adverse effects per treatment arm were gastrointestinal, including nausea (9.7%, 13.6%) 
vomiting (6.1%, 5.6%), constipation (5%, 3.5%), and anorexia (6.1%, 3.7%).
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 (Appendix 2).  In the event of clinically significant 
toxicity, treatment will be withheld, and supportive therapy provided according to 
standard medical practice.
4.7.1.1.2.
Hepatic Safety Findings
Fulvestrant: As described in the fulvestrant package insert (Section 6.1), fulvestrant may 
cause liver enzyme abnormalities in a non-dose-dependent fashion.  In the pooled safety 
population of 1127 subjects from clinical trials comparing fulvestrant 250 mg versus 
fulvestrant 500 mg, increases in either aspartate aminotransferase (AST), ALT, or 
alkaline phosphatise were observed in >15% of subjects.  Grade 3-4 increases were rarer, 


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occurring in 1-2% of subjects.  Hyperbilirubinemia was not reported as a common 
adverse event in clinical trials of fulvestrant.
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 
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. Drug related elevated blood 
bilirubin was reported in 24%, AST elevation was reported in 11%, and 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.  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.
4.7.1.1.3.
Hematopoietic Safety Findings
Fulvestrant: As described in the fulvestrant package insert (Section 6.1), fulvestrant was 
associated with anemia in 4-5% of subjects; approximately 14% of subjects experienced 
some adverse reaction related to the heme or lymphatic system.  In addition, subjects with 
thrombocytopenia or other coagulopathies are at increased risk of adverse events, as 
fulvestrant is administered via IM injection, which could lead to intramuscular hematoma 
in subjects with impaired thrombosis and/or coagulation.
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 was observed, primarily at higher 
dose levels. Thrombocytopenia was only noted after more than a week of continuous 
dosing, and platelet counts recovered after cessation of the drug.  Refer to the 
GSK525762 IB for full details.  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% 


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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 the GSK525762 IB for full details.  
Monitoring and Management: Inclusion/exclusion criteria will require appropriate 
baseline hematologic and coagulation values prior to enrolment.  Subjects will undergo 
frequent complete blood count (CBC) measurements, and management guidelines 
(Appendix 2) are included in the protocol to guide dose interruption/reduction decisions.
4.7.1.1.4.
Reproductive Safety Findings
Fulvestrant:  As described in the fulvestrant package insert (Section 5.3 and Section 
8.1), fulvestrant can cause fetal harm when administered to a pregnant woman.  
Fulvestrant caused fetal loss or abnormalities in animals when administered during the 
period of organogenesis at doses significantly smaller than the maximum recommended 
human dose based on the body surface area. There are no adequate and well-controlled 
studies in pregnant women using fulvestrant.  
GSK525762: As described in the GSK525762 IB Section 4.4.4 [GlaxoSmithKline 
Document Number 2011N113741_07], female fertility was affected in rats given 30 
mg/kg/day GSK525762 for 15 days prior to mating and 15 days prior to mating through 
to Day 6 post coitus (pc). No fertility effects were observed when 30 mg/kg/day was 
given for 6 weeks followed by 6 weeks off-dose prior to mating.  Reproductive and 
developmental toxicity occurred in rats given GSK525762 ≥1mg/kg/day from conception 
through gestation day 17 (of 21 days) and when dosed at ≥10 mg/kg/day for 14 days and 
dosing stopped prior to mating or continued until Day 6 pc. 
In the BET115521 and BET116183 clinical trials, no pregnancies have been reported and 
all females of childbearing potential have been required to use non-hormonal forms of 
birth control with a failure rate of less than one percent.  Similarly, there have been no 
reports of pregnancy resulting from males on study with female partners of childbearing 
potential.  Refer to the GSK525762 IB for full details.
Monitoring and Management: Based on the findings in these reproductive and 
developmental toxicity studies in animals with both fulvestrant and GSK525762, there is 
a substantiated risk for adverse effects on embryo-fetal development and impacts on 
female fertility. Consequently, the proposed study will include strict contraceptive 
requirements for females of child-bearing potential (Section 6.10.2), described in 
Appendix 4.  Pregnancy tests will be required at screening and periodically during the 
study for all women of child-bearing potential, as indicated in the Time and Events table 
(Section 7.1). Women who become pregnant while on study will be required to 
discontinue therapy and will be followed as described in Appendix 4.


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4.7.1.1.5.
General Toxicity Findings
Fulvestrant: As described in the fulvestrant package insert (Section 12.2), fulvestrant 
was associated with fatigue in 8% of subjects receiving the approved dose of 500 mg IM. 
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, 
and the severity. These effects are generally managed by rest and withholding treatment 
if fatigue is intolerable. 
4.7.1.2.
Predicted Single-Agent Toxicities
4.7.1.2.1.
Cardiovascular Safety Findings
Fulvestrant: No significant cardiovascular safety findings have been described.
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 
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 or multigated acquisition (MUGA) 
scan 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.  Please refer to the study reference manual 
(SRM) for further detail.


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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.
4.7.2.
Benefit Assessment
Study 201973 is a Phase I/II dose-escalation and expansion study, and the first study of a 
BET inhibitor with the ER-degrading agent fulvestrant in women with metastatic or 
advanced ER+BC who have progressed on at least one line of prior endocrine therapy.  
Both GSK525762 and fulvestrant have been administered as single agents to women with 
HR+BC, and fulvestrant is currently approved as a single agent and in combination with 
other agents to treat ER+BC. Data obtained in study 201973 may provide a novel 
mechanism to overcome resistance in subjects with advanced or metastatic ER+BC.  In 
addition, this study will advance the molecular understanding of advanced malignancies 
and their treatment, and potentially help identify individuals more likely to benefit or 
have side effects from GSK525762 and/or fulvestrant.
4.7.3.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimise the risk to subjects participating in 
Phase I/II clinical trials, and potentially enriching for HR+/HER2- BC subjects who may 
respond to the combination of a BET inhibitor and an estrogen receptor antagonist, the 
potential risks identified in association with GSK525762 and fulvestrant are justified by 
the anticipated benefits that may be afforded to subjects with advanced or metastatic 
HR+/HER2- BC, who have failed prior therapies.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s) for 
GSK525762 and the fulvestrant 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:


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1. Written informed consent provided
2. Females 18 years old and greater (at the time of written consent)
3. Histologically or cytologically confirmed diagnosis of advanced or metastatic 
adenocarcinoma of the breast.
4. Documentation of ER-positive and/or PR-positive tumor (≥1% positive stained tumor 
cell nuclei) based on local testing of the most recent tumor biopsy, using an assay 
consistent with local standards.
5. Documentation of HER2-negative tumor based on local testing of the most recent 
tumor biopsy, as per most recent American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) guidelines [Wolff, 2013].  At the 
time of writing, HER2-negative tumor is defined as immunohistochemistry (IHC) 
score of 0 or 1+, or negative by in situ hybridization defined as a HER2/CEP17 ratio 
<2 or for single probe assessment of an average HER2 copy number <4.
6. Provision of mandatory screening fresh tumor biopsy sample during the screening 
period.
a.
Screening biopsy can be waived if a biopsy was collected within 3 months 
prior to first dose of study drug and was collected after the last anti-cancer 
treatment before coming into this study.
b. Subjects with inaccessible site of biopsy or who have a significant medical 
risk of obtaining the biopsy should be discussed with the Medical Monitor 
if they can qualify.
c.
Bone biopsies are not acceptable. Biopsies should be obtained from bone 
with metastatic soft-tissue component. Subjects with bone only disease 
may be enrolled upon review by Medical Monitor. 
7. History of prior therapy that satisfies one of the following criteria:
a.
AI failures: Disease that relapsed during treatment or within 12 months of 
completion of adjuvant therapy with an AI, OR disease that progressed 
during treatment with an AI for advanced/metastatic disease.  Prior 
ovarian suppression and/or tamoxifen are allowed as long as other criteria 
are met.
b. CDK4/6 inhibitor plus AI failures: Disease that progressed on a CDK4/6 
inhibitor plus AI, for advanced/metastatic disease with a minimum 
duration of treatment of 12 months (≥12 mo) with CDK4/6 inhibitor plus 
AI. Subjects with either measurable disease or bone only disease are 
allowed. Prior ovarian suppression and/or tamoxifen are allowed as long 
as other criteria are met.
8.
Documented progression on last line of systemic anti-cancer therapy with CDK4/6 
inhibitor + AI is required.
9. Any menopausal status
NOTE: If pre- or peri-menopausal at time of enrollment (refer to Section 6.10.2.1 for 
menopause definition), subject must be willing to initiate therapy or continue ongoing 
therapy with goserelin for at least 28 days prior to the first dose of fulvestrant.  


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Subjects on an alternative Luteinizing hormone-releasing hormone (LHRH) agent do 
not have to start goserelin prior to the first dose of fulvestrant, but they must agree to 
change to goserelin at the next scheduled dose and remain on goserelin for the 
remainder of the trial
10. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
criteria is required except for subjects with bone only disease.
11. All prior treatment- related toxicities must be NCI-CTCAE v4 ≤ Grade 1 (except 
alopecia (permitted at any grade) and peripheral neuropathy (permitted at ≤ Grade 2) 
at the time of treatment allocation. 
12. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1 
(See Appendix 5 for definitions). 
13. Adequate organ function as defined in Table 2.
Table 2
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
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
PT/INR and PTT
≤1.5 X upper limit of normal (ULN)
Hepatic
Albumin
2.5 g/dL
Total bilirubin
≤1.5 x ULNa
ALT 
2.5 ULN 
OR
<5 x 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
≥ 50 mL/min
Cardiac
Ejection fraction
≥ LLN by echocardiogram or MUGA scan
Troponin (I or T)
ULN 
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 6 for Cockcroft-Gault formula
14. Able to swallow and retain orally administered medication.
15. A female subject is eligible to participate if she is of:

Non-childbearing potential defined in Section 6.10.2.1

Child-bearing potential as defined in Section 6.10.2.2, and agrees to use one 
of the contraception methods as described in Appendix 4.


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
Negative serum pregnancy test ≤7 days prior to first study drug dose.

Female subjects who are lactating must discontinue nursing prior to the first 
dose of study treatment and must refrain from nursing throughout the 
treatment period and for at least 28 days following the last dose of study 
treatment.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Prior therapy with any BET inhibitor, any selective estrogen receptor degrader 
(SERD) including fulvestrant, or inhibitors of the PI3K/AKT/mTOR pathway.
2. Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis 
of advanced/metastatic disease.
3. ≥3 lines of systemic anti-cancer therapy in the advanced or metastatic setting.
NOTE:
a. Prior systemic anti-cancer therapy (cytotoxic chemotherapy, hormonal, CD4/6K 
inhibitor therapies) in the neoadjuvant/adjuvant setting does not count toward the 
lines of therapy.
4. Recent prior therapy, defined as:
a.
Any investigational or approved non-biologic anti-cancer drug within 14 days or 
five half-life (whichever is greater) prior to the first dose of GSK525762 and 
fulvestrant.
b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of 
GSK525762 and fulvestrant
c.
Any anti-cancer biologic agents within 42 days prior to the first dose of 
GSK525762 and fulvestrant
d. Any radiotherapy within 14 days prior to the first dose of GSK525762 and
fulvestrant.  If the subject received radiotherapy <90 days prior to study treatment, 
the irradiated lesion cannot be the only lesion used for evaluating response.
e.
Any major surgery within 28 days prior to the first dose of GSK525762 and 
fulvestrant
5. Concomitant active malignancy other than HR+/HER2- BC
NOTE: Subjects who have been disease-free and off therapy for 2 years, or subjects with 
a history of treated early stage cancers such as completely resected non-melanoma skin 
cancer or successfully treated in situ carcinoma of the cervix are eligible.  Subjects with 
second malignancies that are indolent or definitively treated may be enrolled even if less 
than 2 years have elapsed since treatment. Consult Medical Monitor if unsure whether 
second malignancies meet requirements specified above
6. 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 fulvestrant.  


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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.  
7. Current use of a prohibited medication or planned use of any forbidden medications 
during treatment with GSK525762 and fulvestrant.  This includes medications with 
significant risk of Torsades de pointes as well as those that are potent inducers or 
inhibitors of CYP3A4 enzymes (see Section 6.11.2.1 for the list of prohibited 
medications).
8. 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. 
b. Uncontrolled diabetes mellitus (despite therapeutic; compliance to 
intervention) as defined by a haemoglobin A1c (HbA1c) level more than 8% 
and/or occurrence of more than two episodes of ketoacidosis in the 12 months 
prior to the first dose of study drug.
9. Subjects with advanced/metastatic, symptomatic, visceral spread, that are at risk of 
life-threatening complications in the short-term including subjects with massive 
uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and 
over 50% of liver involvement in metastases.
10. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for Central nervous system (CNS) metastases that 
have had stable CNS disease (verified with consecutive imaging studies) for at least 1 
month, are asymptomatic and off corticosteroids, or are on stable dose of 
corticosteroids for at least 4 weeks prior to study Day 1 are permitted.  Subjects 
currently taking enzyme-inducing anticonvulsant (EIAC) must be transitioned to non-
enzyme inducing anticonvulsants prior to enrollment.
11. Cardiac abnormalities as evidenced by any of the following:

Baseline QTcF interval ≥480 msec 

Clinically significant conduction abnormalities or arrhythmias

NOTE:  Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.

Presence of cardiac pacemaker or defibrillator with a paced ventricular rhythm 
limiting ECG analysis. 

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).


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
History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects 
with a history of stent placement requiring ongoing antithrombotic therapy (e.g., 
clopidogrel, prasugrel) will not be permitted to enroll.

Clinically significant cardiomegaly, ventricular hypertrophy, or cardiomyopathy
12. 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).
13. 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.
14. History of known HIV infection.
15. Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 
or fulvestrant, or idiosyncrasy to drugs chemically related to the investigational drugs.
16. Hemoptysis >1 teaspoon in 24 hours within the last 28 days. 
17. Concurrent use of NSAIDs (except for cases where NSAIDs provide benefit over 
other analgesics and in these cases, consideration should be given to the prophylactic 
administration of a proton pump inhibitor) and high dose aspirin (allowed up to 
≤100 mg PO daily). Details are available in 6.11.2.1.
18. Subjects with history of known bleeding disorder(s) including clinically significant 
hemorrhage (e.g., GI, neurologic), within the past 6 months.
19. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption, such as malabsorption syndrome, chronic gastrointestinal disease, or 
major resection of the stomach and/or bowels that could preclude adequate absorption 
of the study medication.
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, and meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Appendix 10).
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 5.4.4.  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 


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progression, or equivocal radiographic imaging as described in Appendix 7) 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

pregnancy

discontinuation from combination treatment, or of GSK525762 with continuation 
on fulvestrant monotherapy for >6 months
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 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”. 
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic CRF. 


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If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event 
(AE)’ will be recorded as the primary reason for permanently discontinuation on the 
electronic CRF.   
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 or for futility.  These regimen(s) 
will not be carried forward into Phase II. 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.
In Phase II, individual prior treatment history-specific cohorts may be terminated if they 
meet criteria for toxicity or lack of efficacy as described in Section 9.1.2.  Any subject 
already enrolled in a terminated cohort may continue to receive therapy per protocol.
In Phase II, unless a disease cohort is closed early, survival follow-up will continue in 
each cohort until approximately 70% of the total number of subjects have died.  At such 
time, the study will be considered completed and any further follow-up on subjects 
enrolled will cease.
Subjects who require permanent discontinuation of one of the study treatments in a given 
combination may continue on the other treatment until disease progression, withdrawal of 
consent, or unacceptable toxicity after discussion with Medical Monitor. With the 
implementation of amendment 06, subjects who have permanently discontinued treatment 
with the combination, or of GSK525762 but have remained on fulvestrant monotherapy 
for >6 months should be discontinued from study.
At the time of study completion, subjects with radiologically confirmed lack of disease 
progression (from Phase I and Phase II) who are still receiving GSK525762 and/or 
fulvestrant may continue treatment through a separate mechanism (e.g., roll-over 
protocol) to be determined at that time.
Enrolment into the study is now closed. The study will conclude when the last subject has 
completed/discontinued study treatment and completed the end of treatment visit.
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 4 and Figure 5 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 4
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 8.


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Figure 5
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 8.
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
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 IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 9 for full guidance. 
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 


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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 fulvestrant 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).
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 Section 7.1.  Please refer to the LVEF 
management guidelines in Appendix 2 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 for review.  Instructions for submitting 
qualifying scans are provided in the Study Reference Manual (SRM).
5.4.4.
Other Stopping Criteria
To monitor for hematologic toxicity, CBCs will be drawn three times during the first 
week (includes screening), twice weekly for the next two weeks of study, once during the 
fourth week, 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, Medical Monitors, GSK Global Safety 
representative, clinical study representatives (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.
5.5.
Subject and Study Completion
In Phase I and II, a subject will be considered to have completed the study if they are 
followed until death.


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Subjects who have not died and are no longer being followed for survival are considered 
to have discontinued the study.  The End of Study electronic Case Record Form (eCRF) 
should only be completed when a subject is no longer being followed.  The study will be 
considered completed for purposes of final analysis when approximately 70% of the 
subjects enrolled in Phase II have died. However, the study could be stopped due to 
toxicity or futility before that when there is enough evidence to conclude as such.
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed.
With the implementation of Amendment 06, 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 (Phase 1)
Product 
name:
GSK525762C Tablets
Fulvestrant
Unit dose 
strength(s)/Do
sage level(s):
5mg
20mg
25mg
250 mg
Dosage form
Tablet
Tablet
Tablet
IM Injection
Manufacturer
GSK
GSK
GSK
AstraZeneca
Physical 
description:
White to slightly colored, round, biconvex 
tablet.
5-mL prefilled syringe containing 
250 mg/5 mL fulvestrant.
The solution for injection is a clear, 
colorless to yellow, viscous liquid.
Route/
Administratio
n/ Duration:
Oral; see Time and Event Tables for 
schedule and administration timings
IM
Dosing 
instructions:
Dose with 240 mL liquid* 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.)
Administer 500 mg intramuscularly into the 
buttocks slowly (1-2 minutes per injection) 
as two 5 mL injections, one in each buttock, 
on days 1, 15, 29, and once monthly 
thereafter.  There is a ±3-day dosing 
window for the fulvestrant.
NOTE: The Phase 1 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.  Phase 2 
formulation details will be provided in an amendment.
*Subjects may take BET with 240 mL of liquid (other than orange, grapefruit, pomelo, or exotic citrus fruit 
juice).  On serial PK days (W1D1 and W3D1), subjects must take BET with water only.
6.2.
Treatment Assignment
6.2.1.
Phase I
Subjects will be assigned to receive GSK525762 and fulvestrant in an open-label fashion.  
Placebo will not be administered in Phase I.  Subjects will be identified by a unique 
subject number that will remain consistent for the duration of the study.
During the initial evaluation of DL1, subjects will be enrolled into their prior therapy-
specific cohort.  Data from the first 3-10 subjects (irrespective of cohort) will be used to 
determine if DL1 exceeds the MTD.
Once DL1 has been cleared in dose escalation, subjects will be enrolled into their prior 
therapy-specific cohort at DL2.  Data from the first 3-10 subjects (irrespective of cohort) 
will be used to determine if DL2 exceeds the MTD.  Any additional subjects (prior to 


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DL2 clearing) will be enrolled in one of two prior treatment history-specific cohorts at 
DL1.
Once DL2 has been cleared in dose escalation, enrolment will be prioritized to DL2 until 
it enrols the same number of subjects as DL1. After that subjects will be enrolled into the 
prior treatment-specific cohorts at either DL1 or DL2 provided that:

There are remaining slots in the cohort

Either cohort has not closed due to unacceptable toxicity or lack of efficacy
If either cohort is filled or terminated, then all subjects will be enrolled in the remaining 
prior treatment-specific cohort until it is filled or terminated.
6.2.2.
Phase II
With implementation of amendment 06, Phase II of the study is terminated.
Subjects who have disease that has progressed after prior treatment with either AIs or 
CDK4/6 inhibitor plus AI will be randomized 1:1 to receive either fulvestrant plus 
GSK525762 or fulvestrant plus GSK525762-matched placebo.  Subjects will be assigned 
to their cohort in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
6.3.
Planned Dose Adjustments
There are no pre-planned dose adjustments per protocol.  
Subjects who experience toxicity may require dose delay and/or reduction of dose; for 
dose adjustment recommendations in response to toxicity, please refer to Appendix 2.  
Table 3 clarifies the dose reductions for GSK525762 at any planned dose level.
As described in Section 4.2.3.8, subjects receiving a dose below the RP2D at the end of 
Phase I may be dose escalated to a dose not to exceed the RP2D upon completion of 
Phase I.
Table 3
GSK525762 Dose Reductions
Current GSK525762 Dose: 
If subject requires dose level reduction: 
40 mg (DL-1)
No further dose reduction allowed
60 mg (DL1)
40 mg
80 mg (DL2)
60 mg
During any dose interruptions of GSK525762, fulvestrant may be continued at the 
protocol dose unless dose interruption of both products is required.
6.4.
Blinding
Phase I of the study will be open-label.  No blinding will be performed.  Investigators 
will have direct access to the subject’s individual study treatment.


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Phase II of the study will double-blind.  Based on results from Phase I, Phase II will enrol 
subjects who have disease that has progressed after prior therapy with:

AIs alone (either in the setting of primary metastatic disease or on-
treatment/within 12 months of discontinuing adjuvant endocrine therapy), OR

CDK4/6 inhibitor plus AI, OR

either AI therapy OR CDK4/6 inhibitor plus AI.  If both cohorts are permitted to 
enroll in Phase II, randomization will be stratified by prior CDK4/6 inhibitor-
based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-exposed) 
and corresponding stratified analysis will be provided at interim and final 
analyses
In Phase II, eligible subjects will be randomized 1:1 to receive GSK525762 plus 
fulvestrant (Arm A), or fulvestrant plus GSK525762-matched placebo (Arm B), in a 
double-blinded fashion.
The following guidelines will apply to Phase II:

The investigator or treating physician may unblind a subject’s treatment 
assignment only in the case of an emergency OR in the event of a serious 
medical condition when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject as judged by the 
investigator.  In this case, the treatment allocation shall only be shared if 
necessary, and if feasible, with personnel involved in the clinical management of 
the subject. Personnel exclusively involved in the clinical trial conduct, e.g., study 
coordinators, study nurses, and representatives from Contract Research 
Organization (CRO)/GSK, shall remain blinded to the treatment allocation.

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the 
treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 

The date and reason for the unblinding must be fully documented in the CRF 
A subject may continue in the study if that subject’s treatment assignment is unblinded. If 
a subject is discontinued, the primary reason for discontinuation (the event or condition 
which led to the unblinding) will be recorded in the CRF.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to investigators in accordance 
with local regulations and/or GSK policy.


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6.5.
Packaging and Labeling
GSK525762 and fulvestrant will be provided to the sites 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.

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 (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK525762 tablets.  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 study treatment dispensing visits, an evaluation of subject compliance with taken 
medication will be performed by reviewing the subject diary and reconciliation of tablet 
count for GSK525762.  However, on W3D1 in both Phase I and Phase II, only review of 
the subject diary will occur.  The investigator will make every effort to bring non-
compliant subjects into compliance. 
When subjects are dosed with GSK525762 or fulvestrant 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 and documented in the source documents and CRF. 


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A record of the number of GSK525762 tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
6.8.
Treatment of Study Treatment Overdose
For this study, any dose of GSK525762 or fulvestrant 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:

Contact the Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK525762 and/or fulvestrant 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 CRF.
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 therapy should be documented on the CRF. 
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.
Dietary and Lifestyle Restrictions
6.10.1.
Dietary Restrictions
GSK525762 can be taken under fasting or fed conditions, except on serial PK sampling 
days (Week [W] 1 Day [D] 1 and W3D1) in Phase I, as described below.


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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 of Phase I only), 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.  
6.10.2.
Female Subjects
6.10.2.1.
Menopause Definition & Female Subjects of Non-Childbearing Potential
For the purpose of this study (including eligibility), post-menopausal is defined as a 
subject who satisfies at least one of the following: 

Age ≥60 years old

Age under 60 years old with 12 months of spontaneous amenorrhea (in the 
absence of alternative physiological, pharmacological, or pathological cause), and 
serum estradiol and follicule stimulating hormone (FSH) level within the local 
laboratory’s reference range for postmenopausal females

Medically confirmed ovarian failure

Documented bilateral oophorectomy
Pre- and peri-menopausal women may be considered to be of non-childbearing potential 
provided they have undergone a documented hysterectomy, bilateral tubal ligation, or 
bilateral tubal occlusion procedure.  Note, however, that these subjects must still be 
administered goserelin as described in Section 5.1.
6.10.2.2.
Female Subjects of Childbearing Potential
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of ≤1% 
[Hatcher, 2011].  LHRH agonists/antagonists alone are insufficient for contraception for 
this study.  Please refer to Section 12.4.1 for a full list of permitted methods of 
contraception.
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 electronic case 
report form (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 CRF.


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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, granulocyte colony-stimulating factors (GCSF) 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.
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 fulvestrant.
6.11.2.
Prohibited and Cautionary 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 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 greater than 100 mg per day are not 
allowed.  The use of non-steroidal anti-inflammatory drugs (NSAIDS) will be excluded, 
except for when NSAIDS will provide benefit over other analgesics, and then 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.
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.
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.  


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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 prescription/non-prescription 
preparations/medications throughout the study until the final study visit due to the limited 
data on potential CYP-mediated interactions produced by those products.  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 that contain acetaminophen.  If a subject 
requires medication for hyperemesis, due to the potential of serotonin 5-HT3 receptor 
antagonists to increase QT duration corrected for heart rate by Fridericia’s formula 
(QTcF), palonosetron (administered per the prescribing information) and ondansetron (up 
to a maximum dose of 8 mg three times daily [TID]) are the only allowed drugs in this 
class. Intravenous administration is not allowed.  Drugs with a low risk of causing QTc 
prolongation (e.g., aprepitant) may be used without restriction.
Co-administration of GSK525762 and medicines 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 the current list of 
medications at www.crediblemeds.org 
After starting cautionary medications 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 in Appendix 
2.
GSK525762 is a substrate for BCRP and Pgp transporters.  Therefore, potent inhibitors of 
these transporters, such as cyclosporine, tacrolimus, or ketoconazole, should be used with 
caution, and additional monitoring for adverse effects should be utilized.
GSK525762 is an inhibitor of organic anion transporter 1A1 (OAT1) and organic anion 
transporter 3 (OAT3) in vitro.  Substrates of these transporters include agents such as 
methotrexate, penicillin G, and indomethacin. While co-administration of these agents 
with GSK525762 is not prohibited, they should be used with caution, and additional 
monitoring for adverse effects should be utilized.
GSK525762 is 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.
Questions regarding concomitant medications should be directed to the Medical Monitor 
for clarification.


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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 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. With the implementation of Amendment 06, specific assessments 
and collection of survival follow-up data will no longer be required. Please see 
Section 7.1 for further details.

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/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 4
Time and Events, Phase I
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
X
ECOG PS5
X
X
X
X
X
X
X
X
X
12-lead ECGs6
X
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
Week 13, 
25, 37, 
49
X
X
PRO-CTCAE9
X
Study Treatment
Administer GSK52576210
Daily
Administer Fulvestrant10
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication 
review
Continuous from signing of informed consent


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples11
Tumor biopsy12
X
Whole blood for exploratory 
analyses13
X
PGx blood sample14
X
Efficacy
CT chest/abdomen/pelvis15
X
EORTC-QLQ-C30 & 
EORTC-QLQ-BR2316
X
1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. With the implementation of amendment 06, following the EOT 
visit, subjects will be no longer be contacted approximately every 3 months (± 14 days) to collect survival data.
2.
Screening procedures should be performed as rapidly as possible within 28 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements.  Clinical lab 
assessments should be completed within 14 days prior to dosing, and in case of abnormal test values, retesting may be performed if medically indicated and within 14 days prior 
to Day 1. 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 within 28 days prior to Day 1 (first dose of 
study medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1). 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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. Post Week 49, assessments will be completed every 12 weeks.
5.
Post Week 49, ECOG assessments will be completed every 12 weeks.
6.
Triplicate ECGs should be performed at screening. All other timepoints can be single ECGs prior to dosing and evaluated for abnormality prior to administration of dose. Post 
Week 49, assessments will be completed every 12 weeks. Triplicate ECGs to be performed as clinically indicated, based upon abnormal findings.
7.
Refer to Table 5  for details of clinical safety labs and timing of collection
8.
Whatever scanning modality is used at screening should be maintained for all subsequent scans. An assessment is not performed at W9. Beginning at W13, scans will be 
performed once every 12 weeks.
9.
With the implementation of amendment 06, the PRO-CTCAE will no longer be collected.
10. Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for 
fulvestrant dosing.  On PK collection days in Week 1 and Week 3, subjects should abstain from food from 8 h prior until 2 h after dose as described in Section 6.10.1.  Post Week 
49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.
11. With the implementation of amendment 06, PK samples will no longer be collected.
12. With the implementation of amendment 06, tumor biopsies will no longer be collected, and the EOT tumor biopsy will no longer be collected.


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13. With the implementation of amendment 06, whole blood for exploratory analyses will no longer be collected.
14. With the implementation of amendment 06, if a PGx sample has not yet been collected, collection will no longer be required.
15. With the implementation of amendment 06, contrast-enhanced computed tomography (CT) scan data will no longer be required for disease assessment.
16. With the implementation of amendment 06, EORTC questionnaires will no longer be collected.


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Table 5
Time and Events, Phase I Laboratory Assessments
SCR
1
Week 1
Week 2
Week 3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
11
q4w
q12w
EOT
D
1
D
4
D
1
D
4
D1
D4
D1
D1
D1
D1
D1
D1
D1
W13 and 
after
W49 and 
after
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay2
X
X
X
Fasting blood glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Thyroid (Thyroid 
stimulating hormone
(TSH), free 
triiodothyronine (T3), 
free thyroxine (T4))3
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B 
surface antigen
(HBsAg), Hepatitis C 
Virus (HCV) Antibody
X
FSH/Estradiol4
X
Pregnancy test5
X
X
X
X
X
X
X
X
X
1.
Although strongly preferred, lab results for HBA1c, fasting lipids, TSH/T3/T4, and pancreatic enzymes are not required prior to dosing.
2.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
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).
4.
Only required at screening for pre- and peri-menopausal subjects
5.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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7.2.
Screening and Critical Baseline Assessments
Screening procedures should be performed as rapidly as possible within 28 days prior to 
Day 1 (first dose of study medication) to facilitate subject entry requirements. Clinical lab 
assessments should be completed within 14 days prior to dosing, and in case of abnormal 
test values, retesting may be performed if medically indicated and within 14 days prior to 
Day 1.
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Measurement(s) of target 
lesion(s) should be provided for at least two prior disease evaluations, if available.  
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.
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 28 days prior to Day 1 (first dose of study 
medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and 
ECHO/MUGA (within 35 days prior to Day 1).
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
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 imaging should be completed within 30 
days prior to the first dose of study drug.  Baseline characterization of target- and 
non-target lesions should be performed as described in Appendix 7. 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 magnetic resonance imaging (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.


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A baseline tumor biopsy sample is required for all subjects, as follows:

Phase I:
o
All subjects must provide a biopsy sample at screening.  A fresh biopsy 
specimen must be provided within 28 days prior to first study dose. A 
sample collected within 3 months of first dose is also acceptable only if it 
was collected after the last anticancer treatment.
o Subjects with bone only disease without any visceral tumor tissue 
amenable to biopsy may be enrolled without a biopsy sample only upon 
review by medical monitor
o Paired on treatment fresh biopsies are optional but encouraged. All
subjects enrolled in the study will be asked to provide paired fresh 
biopsies pre- and post-dose at the time points indicated in Section 7.1, as 
described in Section 7.5.1.  Fresh biopsies should be paired with plasma 
samples for PK, collected as close as possible to the biopsy (ideally within 
1 h).  Subjects should have at least four consecutive doses of GSK525762 
prior to collection of tumor biopsy, whether they have had a dose 
interruption or not.  Subjects will be informed at the time of informed 
consent whether paired fresh biopsies will be required. If a potential 
subject does not have a disease amenable to biopsy, participation may 
occur only upon discussion and approval of the medical monitor. Further 
details regarding sample type and processing will be provided in the SRM.

Phase II:
o All subjects must provide a fresh tissue specimen at screening. If an 
archival specimen is not available, then a fresh pre-treatment biopsy 
specimen must be provided.  On-study biopsies are not required
7.2.2.
Visit Windows
With the implementation of amendment 06, 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 the first dose of study drugs.  Baseline imaging should 
be completed within 30 days prior to the first dose of study drug.  Clinical lab 
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.  All other assessments should be completed with 28 days prior to first 
dose of study drug.
Week 1: Visits for Week 1 Day 1 must be performed on the day indicated.  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 ± 3 days.  
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days.  Assessments on 
Week 3 Day 4 may be scheduled ± 3 days.


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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 (due to toxicity), then serial PK collection 
should be rescheduled for a later timepoint 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 fulvestrant 
trough concentration.  
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 3 days.  The first disease assessment 
(at Week 9) may be scheduled ± 7 days.
Weeks 6, 7, 8, and 11: Lab visits 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 who have interrupted dosing, the 
collection should be postponed until the subject has received at least 7 consecutive doses 
of GSK525762.
Every 4-week, 8-week, and 12-week visits after Week 49: Every 4-week visits (and 
their associated laboratory studies) are no longer required, based on clinical judgment.  
Every 8-week and 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 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 Phase I and Phase II).
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 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.
Vital signs should be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.  


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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 should 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
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 7.
7.3.2.
ECOG Performance Status
The performance status will be assessed using the ECOG scale (Appendix 5) as specified 
in Section 7.1.
7.3.3.
Cardiac Safety
7.3.3.1.
Electrocardiograms
Triplicate 12-lead ECGs will be obtained at screening.  On treatment single ECGs will be 
completed, prior to dosing, on days specified in Section 7.1 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 may 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 06, transfer of ECG data to a central facility is no longer 
required.
7.3.3.2.
Echocardiogram or Multigated Acquisition Scan
For all subjects, ECHOs 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. 
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 06, transfer of scan data for independent cardiologist review is no longer 
required.


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Refer to Section 5.4.3 for LVEF stopping criteria.  For management of other changes 
identified by ECHO or MUGA, see Appendix 2.
7.3.4.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 6, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events tables.
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 CRF.
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 fulvestrant 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 6
Clinical Laboratory Tests
Clinical Chemistry
Sodium
Fasting Glucose
Potassium
Magnesium 
Chloride
Calcium (total and ionized)
Total Carbon Dioxide
Total Protein
Blood Urea Nitrogen*
Albumin
Creatinine
Hematology
White blood cell count
Automated White Blood Cell Differential: 
Hemoglobin
Neutrophils
Platelet count
Lymphocytes
Monocytes
Eosinophils
Basophils
Liver Function
Bilirubin (Total and Direct)**
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)
Urine hCG pregnancy test (only for women of child bearing potential.  Note that initial screening test must be serum 
hCG and subsequent tests may be serum or urine hCG)
Cardiac Studies
Troponin (I or T), 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
Thyroid-stimulating hormone (TSH)
Partial Thromboplastin Time or 
Activated Partial Thromboplastin 
Time (aPTT)
Free Thyroxine 3 (Free T3)
HIV, HbSag, HCV antibody
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Factor VII Assay
Hemoglobin A1c
Amylase
FSH and estradiol (for pre- and peri-
menopausal subjects only)
Lipase
*Direct and/or calculated BUN values are acceptable.
**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; 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 5 for timing of required studies
7.3.5.
Adverse Events (AEs) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 10.  The severity of adverse 
events will be graded utilizing the NCI-CTCAE v4.  Additional details regarding 
management of specific AEs or SAEs are described in Section 5.4, Appendix 2, and 
Appendix 10.


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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-CTCTAE) 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. 
7.3.5.1.
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 (Section 7.3.5.3), at the timepoints specified in the Time and 
Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

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 10.

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 10.
7.3.5.2.
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?”
7.3.5.3.
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 (as defined in 
Appendix 10) will be followed until resolution, until the condition stabilizes, until the 


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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 10.
7.3.5.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 10 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 CRF 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.
7.3.5.5.
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.
7.3.5.6.
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 review and 
file it with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
7.3.6.
Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
treatment and until at least 90 days 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 Appendix 4.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
7.4.
Pharmacokinetics
With the implementation of amendment 06, PK samples will no longer be collected.
Blood samples for pharmacokinetic (PK) analysis of fulvestrant and GSK525762 
(including relevant metabolite[s]) will be collected at the time points indicated in Table 4.  
While GSK525762 PK samples will be collected at all time points starting on Week 1 
Day 1, only the pre-dose samples will be analyzed for fulvestrant. 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 
fulvestrant, 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 fulvestrant 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 06, tumor samples will no longer be collected.
Tumor samples will be collected pre-dose and on-treatment from a limited number of 
subjects in order to evaluate for changes in molecular markers of BET inhibition (e.g., 
expression of proteins regulated by BET proteins) and HR signalling.


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7.5.1.
Tumor Biopsy Collection/Surgical Procedures
A mandatory fresh tumor biopsy sample is required for all subjects during the screening 
period within 28 days of the first dose of study treatment. A sample collected within 
3 months of first dose is also acceptable only if it was collected after the last anti-cancer 
treatment. Bone biopsy sample is not acceptable. Biopsy requirement for subjects with 
bone only disease with no visceral tumor may be waived only upon review by GSK. 
a.
Screening biopsy can be waived if a biopsy was collected within 3 months 
prior to first dose of study drug and was collected after the last anti-cancer 
treatment before coming into this study.
b. Subjects with inaccessible site of biopsy or who have a significant medical 
risk of obtaining the biopsy should be discussed with the Medical Monitor 
if they can qualify.
c.
Bone biopsies are not acceptable. Biopsies should be obtained from bone 
with metastatic soft-tissue component. Subjects with bone only disease 
may be enrolled upon review by Medical Monitor. 
On treatment fresh biopsies are optional but encouraged. Subjects providing an on-
treatment fresh tumor biopsy must have received at least 4 consecutive doses of 
GSK525762 prior to the collection of the tissue.  A limited number of additional subjects 
may be requested to provide pre and on-treatment biopsies based on emerging data.  
Biopsy requirement(s) will be discussed with the subject prior to signing informed 
consent.  Any fresh on-treatment biopsy should be accompanied by a plasma sample 
collected as close as possible to the time of biopsy (preferably within 1 h).
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.
7.6.
Evaluation of Anti-Cancer Activity
With the implementation of amendment 06, CT scan data will no longer be required 
for disease assessment. See the Time and Events Table (Section 7.1) for the updated 
schedule of assessments. 
Tumor response will be assessed as outlined in the Time and Event Tables by the 
investigator using RECIST 1.1 (Appendix 7) guidelines and documented in the eCRF as: 
progressive disease (PD), stable disease (SD), partial response (PR), and complete 
response (CR).  See the SRM for additional instructions.
Lesion assessment method and timing, evaluation of disease, disease progression and 
response will be conducted according to Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) [Eisenhauer, 2009] as outlined below and in Appendix 7 of this protocol.  
Disease assessment modalities may include imaging (CT scan, MRI, bone scan, plain 
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assessment timepoint is the preferred imaging modality.  However, subjects with 
contraindication to CT may have other modalities performed as clinically indicated.
The baseline disease assessment will be completed within 30 days prior to the first dose 
of GSK525762 and fulvestrant, then approximately every 8 weeks thereafter and at the 
final study visit.

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 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 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.
Phase I
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. GSK may request an independent review of scans. See the SRM 
for additional details.  
7.6.2.
Phase II
GSK requires sites to provide electronic copies (upload digital images or images on CD) 
of scans for all subjects for central storage which will be transferred to a central 
independent imaging center.  Evaluation of response and PFS will be made by the 
Investigator/site radiologist as well as by an independent reviewer who is blinded to the 
subject’s therapy assignment.  See the SRM for additional details.
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 other measures of response to treatment with GSK525762 and 
fulvestrant in combination or with tumor progression status. The results gained may also 
be applied to medically related conditions.
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to GSK525762 and fulvestrant in combination is observed.


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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 fulvestrant 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 
fulvestrant 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 fulvestrant in combination may be identified by application of:

DNA/gene, RNA and protein analysis of tumor tissue.

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 
fulvestrant in combination utilizing baseline tissue (archival tissue or a recent biopsy) and 
tissue obtained at disease progression (if sample is available). Further details on sample 
requirements and collection will be provided in the SRM.
7.7.2.
Tumor Tissue
With the implementation of amendment 06, tumor samples will no longer be collected.
All enrolled subjects in the study will be required to submit a fresh tumor biopsy at
screening in order to conduct retrospective tests for the identification and/or validation of 
known and novel biomarkers. Further details on sample requirements and collection will 
be provided in the SRM.
Optional on-treatment tumor biopsy samples will be analyzed using appropriate 
technologies including, but not limited to, RNAseq, exome or targeted DNA sequencing, 
IHC, and/or qRT-PCR.
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 cell free DNA/RNA Analysis
With the implementation of amendment 06, blood samples will no longer be collected.


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Plasma isolated from blood collected at screening will be used to evaluate ESR1mutation 
status in circulating cell-free deoxyribonucleic (cfDNA) and/or RNA.
To further characterize the subject population, cfDNA and/or RNA measurements may be 
utilized to identify predictors of sensitivity or resistance to GSK525762 and fulvestrant in 
combination utilizing plasma isolated from blood at screening, on treatment and/or end of 
treatment.
7.8.
Genetics
With the implementation of amendment 06, 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 fulvestrant.
7.9.
Value Evidence and Outcomes
7.9.1.
PRO-CTCAE
With the implementation of amendment 06, 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-CTCTAE) Item Library (version 1.0) will be 
administered to select patients based on the availability of translated versions.
7.9.2.
EORTC-QLQ-C30 & EORTC-QLQ-BR23
With the implementation of amendment 06, the EORTC questionnaires will no longer be 
completed.
The effect of GSK525762 and fulvestrant, 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 questionnaires.  Both the EORTC-QLQ-
C30 (version 3) core questionnaire and the EORTC-QLQ-BR23 disease-specific modules 
will be administered.


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8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined CRFs, 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.  
CRFs (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
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population.
With the implementation of Amendment 06, 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. There will be no Phase II.
Any changes to planned analyses outlined below will be covered in the Reporting 
Analysis Plan (RAP).
9.1.
Hypotheses
9.1.1.
Phase I Safety
To evaluate for safety, Phase I will follow a mTPI design to identify the MTD of 
GSK525762 when administered in combination with fulvestrant. No formal statistical 
hypotheses will be tested.  Analysis will be descriptive and exploratory.  All data will be 
pooled, and descriptive analyses will be summarized and listed by dosing cohort at the 
end of Phase I.  Dose escalation decisions will be based on the totality of clinical safety 
assessment data, as well as PK data.
9.1.2.
Phase I Efficacy
For evaluation of efficacy in Cohort 1 (AI Failure) in Phase I, the primary goal is to 
demonstrate a clinically meaningful response rate, defined as an objective response rate 
(CR + PR) of 25% 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 


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>0.25, assuming the maximum response rate for an ineffective drug is 10% and the 
minimum response rate for an effective drug is 25%.  For evaluation of efficacy in Cohort 
2 (CDK4/6+AI Failure) in Phase I, the primary goal is to demonstrate a clinically 
meaningful response rate in the measurable disease subjects only, defined as an objective 
response rate (CR + PR) of 20% relative to a 5% response rate suggesting no activity.  
This will be conducted by testing the null hypothesis that P0<=0.05 versus the alternative 
that P1 >0.20, assuming the maximum response rate for an ineffective drug is 5% and the 
minimum response rate for an effective drug is 20%. Bayesian statistics will be employed 
to calculate the posterior probability that the ORR ≥25% and ≥10% for Cohort 1 (AI 
Failure) and ≥20% and ≥5% for Cohort 2 (CDK4/6+AI Failure) at interim assuming a 
Beta prior for the Binomial distributed data.  A weak prior Beta (0.0125, 0.0875) for 
Cohort 1 (AI Failure) and (0.005, 0.095) for Cohort 2 (CDK4/6+AI Failure) is used, 
which is equivalent to the information present in 0.1 subjects. 
9.1.3.
Phase II
In Phase II, the primary goal is to demonstrate a clinically meaningful improvement in 
PFS when GSK525762 is added to fulvestrant therapy.  For this study, “clinically 
meaningful” is defined as a hazard ratio (HR) of 0.5, indicating that the combination 
therapy doubles the PFS relative to the comparator arm.  A planned interim analysis will 
be performed when 45 subjects have progressed or died; the study may be stopped at that 
time for safety as well as for efficacy.
The primary objective of Phase II is to compare progression free survival (PFS) of the 
combinations of GSK525762 and fulvestrant therapy versus fulvestrant therapy alone in 
subjects with HR+/HER2- breast cancer.
Specifically, the study is designed to provide evidence with regard to PFS to support the 
null hypothesis: 
H0: λ = 1
or to reject it in favor of the alternative hypothesis: 
HA: λ < 1,
where λ is the hazard ratio: GSK525762 and fulvestrant / comparator. 
The study will have 90% power to detect a hazard ratio (HR) of 0.5 with a one-sided 
0.025 level test. Under the assumption of exponential PFS, this HR is equivalent to 100% 
increase in median progression-free survival for GSK525762 and fulvestrant versus 
comparator (11 months vs. 5.5 months).  Refer to Appendix 3 for a discussion of the 
response assumptions used in the study.


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9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
9.2.1.1.
Phase I
Up to 35 measurable disease subjects per DL in Cohort 1 and 32 measurable disease 
subjects per DL in Cohort 2 may be enrolled to collect safety/tolerability, PK, PD, and 
efficacy data. Sixteen additional bone only disease subjects will be enrolled into DL1 
cohort 2. 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 cohort, Bayesian predictive adaptive 
design will be used for testing hypotheses and sample size determination:
In Cohort 1 (AI Failure) the null and alternative hypotheses are:
H0: ORR≤10%
HA: ORR≥25%
When maximum sample size is 35, the design will have a Type I error () of 0.098 and 
80% power.  
In Cohort 2 (CDK4/6+AI Failure) the null and alternative hypotheses are:
H0: ORR≤5%
HA: ORR≥20%
When maximum sample size is 32, the design will have a Type I error () of 0.0535 and 
81% power.  
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 may be used 
for futility analysis.  
Simulation studies were conducted to evaluate the performance of the Bayesian design 
under various assumptions for the distribution of true ORRs across the cohorts. Operating 
characteristics including power, type I error, estimation of the ORR, 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 ≤0.09 on individual cohort. If both dose level are positive, the chance of 
advancing to phase 2 is as high as 94%.  For more details, please see Section 9.4.10


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9.2.1.2.
Phase II
Phase II will enrol approximately 154 subjects with advanced or metastatic HR+/HER2-
BC.  The decision composition and dose of this cohort will be decided at the end of Phase 
I, and will depend on the totality data from Phase I as described in Section 4.3. 
Based on available published data in treatment of metastatic ER+BC, the median PFS 
assumed for fulvestrant is approximately 5.5 months.  Refer to Appendix 3, which details 
the clinical experience to date.
The following assumptions were made in the estimation of sample size and the required 
number of events for PFS for each of the two primary comparisons:

Exponential distributions

Constant accrual rate of 6 subjects per month in the first 6 months and 15 subject 
per month after

10% loss-to-follow-up rate

A 1:1 randomization scheme

Power of 90% 
An overall of 2.5% one-sided risk of erroneously claiming benefit of the experimental 
arms over the control arm (comparator) in the case of no underlying difference between.
Seventy-seven (77) subjects per arm will be enrolled, leading to approximately 14 
months of accrual.  The first interim analysis for PFS will be performed when at least 45 
PFS events (per RECIST v1.1) have occurred across GSK525762 in combination with 
fulvestrant and comparator arm (around 12 months after the first subject enrolled).  The 
final analysis on PFS will be conducted when at least 90 PFS events (per RECIST 1.1) 
have been reported in GSK525762 combined with fulvestrant and comparator arm.
9.2.2.
Sample Size Sensitivity
Sample size sensitivity assessments are described in Section 9.4.10.
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 Intent-to-Treat (ITT) population will comprise all randomized subjects regardless 
of whether or not treatment was administered.  This population will be based on the 
treatment to which the subject was randomized and will be the primary population for the 
analysis of efficacy and VEO data in Phase II.


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The All Treated Population is defined as all subjects who receive at least one dose of 
GSK525762 plus fulvestrant. 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 progressed or died or permanently withdraw from the study 
treatment will be included in this population.  
The PK Population will consist of all subjects from the All Treated Population for whom 
a PK sample is obtained and analyzed.
Additional analysis populations may be defined in the RAP.
9.3.2.
Interim Analyses
9.3.2.1.
Phase I
9.3.2.1.1.
Dose Escalation and Safety Analyses
Once 3-10 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/expansion decisions in Phase I will be safety and 
tolerability of each dose cohort.
9.3.2.1.2.
Efficacy Analyses
Interim analyses during expansion cohorts
Interim data will be evaluated to monitor efficacy and safety, and a planned interim 
analysis will be performed when at least 10 evaluable subjects have been enrolled into 
each of the expansion cohorts at each 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 
Hierarchical model are described below. The decision will be made for each individual 
prior treatment history-specific cohort. 
For the separate interim looks in each cohort, the enrolment for that cohort may be 
stopped due to futility if the posterior probability that the confirmed ORR ≥25% or ORR 
≥20% in Cohort 1 and Cohort 2, respectively, is small (e.g., less than a 4% chance for a 
total sample size of 35 subjects).  Enrolment may also be stopped due to futility if the 
equivalent of no response is observed in the first 10 enrolled evaluable subjects in that 
cohort or less than 2 confirmed responses are observed in the first 14 and 19 evaluable 
subjects in Cohort 1 and Cohort 2, respectively.  The evaluable subject is defined as a 
subject, who has either progressed or died, withdrew from the study treatment, or is 
ongoing and has completed at least two post treatment disease assessments.  For example, 
when there are 14 evaluable subjects available at the time of interim analysis with only 
one response, then the cohort may be stop for futility.  Otherwise, the enrollment of the 
respective cohort will continue to the target sample size. 


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Futility interim analysis decision rules for the 10th to 34th evaluable subjects in Cohort 1 
(AI Failure) and 10th to 32nd evaluable subjects in Cohort 2 (CDK4/6+AI Failure), 
specifying the number of subjects with a confirmed response needed for continuing 
enrolment or stopping for futility when total sample size is up to 35 in Cohort 1 (AI 
Failure) and up to 32 in Cohort 2 (CDK4/6+AI Failure) is presented in Table 7 and Table 
9, respectively.  These rules are intended as a guideline.  Actual decisions will depend on 
the totality of the data.
Table 7
Decision Making Criteria for Futility in Cohort 1 (AI Failure)
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses to 
Stop Early for Futility
Probability of continuing 
enrolling when ORR=0.1
Probability of continuing 
enrolling when ORR=0.25 
10
0
0.6513
0.9437
11
0
0.6513
0.9437
12
0
0.6513
0.9437
13
0
0.6513
0.9437
14
1
0.3971
0.8843
15
1
0.3971
0.8843
16
1
0.3971
0.8843
17
1
0.3971
0.8843
18
1
0.3971
0.8843
19
1
0.3971
0.8843
20
1
0.3971
0.8843
21
2
0.2938
0.8674
22
2
0.2938
0.8674
23
2
0.2938
0.8674
24
2
0.2938
0.8674
25
2
0.2938
0.8674
26
2
0.2938
0.8674
27
3
0.2108
0.8511
28
3
0.2108
0.8511
29
3
0.2108
0.8511
30
3
0.2108
0.8511
31
3
0.2108
0.8511
32
4
0.1509
0.8369
33
4
0.1509
0.8369
34
4
0.1509
0.8369


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Table 8
Decision Making Criteria for Futility in Cohort 2 (CDK4/6+AI Failure)
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses to 
Stop Early for Futility
Probability of continuing 
enrolling when ORR=0.05
Probability of continuing 
enrolling when ORR=0.2 
10
0
0.4013
0.8926
11
0
0.4013
0.8926
12
0
0.4013
0.8926
13
0
0.4013
0.8926
14
0
0.4013
0.8926
15
0
0.4013
0.8926
16
0
0.4013
0.8926
17
0
0.4013
0.8926
18
0
0.4013
0.8926
19
1
0.2027
0.8566
20
1
0.2027
0.8566
21
1
0.2027
0.8566
22
1
0.2027
0.8566
23
1
0.2027
0.8566
24
1
0.2027
0.8566
25
1
0.2027
0.8566
26
1
0.2027
0.8566
27
2
0.1090
0.8362
28
2
0.1090
0.8362
29
2
0.1090
0.8362
30
2
0.1090
0.8362
31
2
0.1090
0.8362
Additionally, the ORR and safety endpoints will be jointly assessed using a utility 
function when both DL1 and DL2 are safe and effective. The dose with the best utility 
function may be picked as RP2D for Phase 2. The details of the utility function 
calculations will be discussed in Reporting and Analysis Plan (RAP).  This calculation is 
for guidance only, the final decision of RP2D will be based on totally of data.
The study population used for decision-making at the interim analyses on efficacy will be 
termed All Evaluable Subjects.  Since disease assessments are to be completed every 8 
weeks, subjects who have at least two post-baseline radiological disease assessments or 
have progressed or died or permanently withdraw from the study treatment will be 
included in this population.  Interim analysis on safety will be conducted on all treated 
subjects. 
Interim analyses at end of Phase I
Interim analyses of the data captured in Phase I may be undertaken for a given 
cohort/dose combination after each subject in the cohort/dose combination has had at 
least two post-baseline disease assessments or has progressed or died or withdrawn from 


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the study. Final analysis on Phase 1 PFS may be conducted when Phase 1 is completed. 
Data from the dose escalation and expansion cohort may be combined for some analyses, 
as appropriate.
9.3.2.2.
Phase II
An IDMC will be utilized in this study to ensure external objective medical and statistical 
review of efficacy and safety data in order to protect the ethical and safety interests of 
subjects and to protect the scientific validity of the study. The schedule of IDMC data 
reviews and the scope of the IDMC reviews are described in the IDMC charter, which is 
available upon request.
The interim analyses for PFS will be performed for the purpose of evaluating whether to 
stop the trial early for futility or benefit in PFS.
"Futility" would correspond to declaring the GSK525762 in combination with fulvestrant
arm be not better than the comparator arm in PFS.
Benefit: If a substantial prolongation in PFS is observed for the GSK525762 in 
combination with fulvestrant arm compared to the comparator arm, then consideration 
should be given to halting the trial due to observed benefit. Haybittle Peto method with a 
one-sided alpha of 0.0001 for PFS in favor of the experimental arm will serve as a 
guideline for potential benefit. Observation of substantial benefit as described above 
would signal further examination of available data by the IDMC, with consideration of 
altering the conduct, or terminating the study.
For the purpose of evaluating whether to stop the trial due to futility, a Gamma family 
beta spending function with a parameter of -0.5 will be utilized. The boundary does not 
represent a binding decision to stop the trial should this boundary be crossed. The 
boundaries are defined in EAST to preserve Type I error at 2.5% under the assumption of 
a non-binding futility rule. 
The EAST software package will be used to calculate the appropriate bounds at the time 
of the analyses, given the fraction of information available.  Assuming an accrual time of 
14 months and a follow-up time of 6 months and the accrual rate is 6 subjects per month 
in the first 6 months and 15 subjects per month after, the time point of interim analyses is 
around 13 months. An example of the nominal significance levels corresponding to the 
error spending functions as well as planned stopping boundaries and decision rules in 
terms of hazard ratios for the analysis time points of progression free survival, are as 
follows:

50% of expected events: stop for futility if HR>0.9247, stop for efficacy if 
HR<0.33

100% of expected events: α=0.025, claim superiority of the experimental arm if 
HR<0.66 


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At the interim analysis, if GSK525762 in combination with fulvestrant demonstrates no 
difference from the comparator arm, enrollment may be halted. The IDMC may also 
recommend halting the trial based on accruing safety information.
9.3.3.
Final Analysis
For Phase II, final analyses may be conducted when sufficient PFS events (90) have 
accrued for comparison of the combination arm with the comparator.  
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, patients 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 Phase I and Phase II will be presented in tabular and/or graphical format 
and summarized descriptively according to GSK’s Integrated Data Standards Library 
(IDSL) standards.
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.
9.4.2.
Extent of Exposure
Extent of exposure of GSK525762 and fulvestrant 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 fulvestrant will be summarized 
for each dose level administered.


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9.4.3.
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.
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 Phase I subjects and summarized by 
dose cohort according to International Data Standards Library (IDSL) standards.
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.
9.4.4.
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.
9.4.4.1.
Other Safety Measures
Data for vital signs, electrocardiograms (ECGs), and echocardiograms (ECHOs) or 
multigated acquisition scan (MUGA) will be summarized based on predetermined criteria 
identified to be of potential clinical concern.  Further details will be provided in the RAP.
9.4.5.
Pharmacokinetic Analyses
9.4.5.1.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) Department, GSK.
Pharmacokinetic (PK) analysis of GSK525762 (and its metabolite[s]) concentration-time 
data will be conducted by non-compartmental methods under the direction of Clinical 
Pharmacokinetics Modelling & Simulation (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:  


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
maximum observed plasma concentration (Cmax) 

time to Cmax (tmax)

trough concentration (Cτ)
Sparse plasma concentration-time data 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).
9.4.5.2.
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the pharmacokinetic (PK) parameters data will be the responsibility 
of Clinical Statistics, GSK.
GSK525762 and fulvestrant 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).  
9.4.6.
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 conventional RECIST 1.1 criteria (best confirmed 
response) 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.
9.4.7.
Tumor Kinetics Analysis
Data from Phase I and Phase II of the study may be combined to describe the kinetics of 
tumor growth based on the sum of longest diameters of target lesions. 
The kinetics of tumor growth may be described as a function of time using the Non Small 
cell lung cancer (NSCLC) model described by the FDA [Wang, 2009]. The tumor size 
(TS) is expressed as:


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TS(t) = BSL•e-SRt + PR•t
where TS(t) denotes the tumor size measured as the sum of longest distance (mm) of 
lesions or volume (mm3) at time t, BSL is the baseline tumor size, SR is the exponential 
tumor shrinkage rate constant and PR is the linear tumor progression rate.
The kinetics of tumor growth may also be described as a function of time using the model 
described by Claret [Claret, 2009]. The model is expressed as:
dTS(t)/dt = (KL-KD•e-t)•TS(t)
where TS(t) denotes the sum of longest distance (mm) of lesions or volume (mm3) at 
time t, with TS(0) being the baseline tumor size, KL represents the exponential tumor 
growth rate, KD represents the exponential rate of tumor shrinkage (i.e. drug effect on 
total tumor size), λ is the rate constant for drug resistance/disease progression.  A 
measure of exposure of one or more of the administered medications may be included in 
the models.
The equation proposed by Wang and/or Claret may be fit to the observed data using a 
mixed-effects model with NONMEM VII.  Other models of the kinetics of tumor growth, 
such as a 2-parameter model, may be used to analyze the data [Stein, 2011; Stein, 2012].
The time to tumor growth (TTG) may be estimated with parameters from the appropriate 
model. Subject characteristics such as baseline tumor size, performance status, lactate 
dehydrogenase (LDH), age, sex, race, prior therapies, or radiotherapy, may be evaluated 
to determine which covariates have a significant effect on the kinetics of tumor growth.
Relationship between tumor growth marker and clinical activity measured may be 
explored as well.
9.4.8.
Efficacy Analyses
9.4.8.1.
Phase I
For the Phase I final analysis, each dose and cohort will be analyzed separately.  In 
Cohort 2 (CDK4/6+AI Failure), measurable disease subjects and bone only disease 
subjects will be analyzed separately and combined within a dose.  However, bone only 
disease subjects will not be evaluated for ORR.  The focus of analyses that contain bone 
only disease subjects will be DCR, PFS and OS.
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 RECIST 1.1 
(Appendix 7). The disease control rate (DCR) is defined as the percentage of subjects 
with a confirmed CR, PR, or stable disease (SD) ≥6months as per disease-specific criteria 
(Appendix 7).  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 RECIST 1.1, will be listed 
and summarized separately, as appropriate.


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The observed confirmed and unconfirmed ORR will be reported at the interim and final 
analysis for each cohort specified in Phase 1 treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided. Bayesian inference 
based on summary statistics from the posterior distributions of each ORR will be reported 
at interim and final analyses. The posterior mean and posterior 2.5% and 97.5% 
percentiles of the ORR will be calculated for each cohort. In addition, the posterior 
probability that the ORR exceeds its corresponding historical control will be reported for 
each cohort.
The ORR differences of the same cohort between two doses will be provided along with 
corresponding 95% CI.  A chi-square test will be used to test for differences between 
doses if data warrant.
Duration of response is defined as the subset of subjects who show a confirmed CR or 
PR, the time from first documented evidence of CR or PR until the first documented sign 
of disease progression or death. Duration of response will be summarized descriptively 
for each cohort, if data warrant, using Kaplan-Meier medians and quartiles. Details on 
rules for censoring will be provided in the RAP.
Progression-free survival (PFS) 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 
objective disease progression will be defined as the earliest date of disease progression as 
assessed by the investigator using RECIST, version 1.1.  For subjects who have not 
progressed or died at the time of the PFS 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 PFS 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.  PFS 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 
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 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.
9.4.8.2.
Phase II
PFS along with 95% confidence interval for each treatment will be estimated using the 
Kaplan Meier method and treatment comparisons will be made using a log-rank test 
(defined in Section 9.1.3).  The median PFS for each treatment, the hazard ratio for each 
comparison along with 95% confidence intervals will be reported.
PFS will be defined as the time from randomization until the first date of either disease 
progression or death due to any cause and will be evaluated for the combination versus 


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the comparator.  The date of objective disease progression will be defined as the earliest 
date of disease progression as assessed by the investigator using RECIST 1.1.  For 
subjects who have not progressed or died at the time of the PFS 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 PFS 
event will be censored at the date of the last adequate disease assessment prior to the 
extended loss to follow-up or start of new anti-cancer therapy, respectively.  Further 
details on censoring rules will be outlined in the RAP.
Additional sensitivity and/or subgroup analyses for PFS may be pre-specified in the RAP, 
if appropriate.
The ORR will be tabulated based on number and percentage of subjects attaining either a 
confirmed or unconfirmed overall best response of CR or PR in the ITT population in 
Phase II.  The DCR will also be tabulated based on number and percentage of subjects 
attaining a confirmed CR, PR, or stable disease (SD) ≥ 6 months in the ITT population in 
Phase II.  Per RECIST 1.1., subjects with unknown or missing response data, including 
those who withdraw from the study without an assessment, will be treated as non-
responders (i.e., they will be included in the denominator when calculating the 
percentage).  No imputation will be performed for missing lesion assessment or tumour 
response data.  
OS along with 95% confidence interval for each treatment will be estimated using the 
Kaplan Meier method and treatment comparisons will be made using a log-rank test.  All 
cause mortality will be used and censoring will be performed using the date of last known 
contact for those who are alive or lost to follow-up at the time of analysis.  The hazard 
ratio along with 95% confidence intervals will be provided for each of the comparisons. 
Sensitivity analyses to ascertain the effect of baseline prognostic factors may be 
performed.  Details will be provided in the RAP.
Overall response rates (ORR) for each treatment group as well as for differences between 
the arms will be provided along with corresponding 95% CI.  A chi-square test will be 
used to test for differences between treatment arms.
9.4.9.
Other Analyses
9.4.9.1.
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.
9.4.9.2.
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 


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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.
9.4.9.3.
Pharmacogenetic Analyses
Further details on pharmacogenetic (PGx) analyses will be addressed in Appendix 11 and 
the PGx RAP.
9.4.10.
Simulations and Design Operating Characteristics
9.4.10.1.
Simulation Description
Extensive simulations have been conducted to develop and understand the performance 
of the seamless design, interim monitoring, and decision criteria.
9.4.10.2.
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.
9.4.10.3.
Trial Sample Size and Simulation Scenarios
Sample size requirements for halting enrollment 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 4 
subjects per month per cohort is assumed. The time from subject entry until the 
confirmed response assessment was performed is assumed to be 12 weeks. For each dose, 
a maximum 10 subjects will be assigned to the dose escalation stage and if that dose is 
safe to expand, a maximum of 35 subjects will be assigned to each cohort.  
Although actual enrollment may vary, the estimated enrollment rate of 4 subjects per 
month per cohort is incorporated into the simulations. 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 9 under 1000 simulations. The 
DLT rates and ORR listed are listed in the order of DL1 and DL2. 


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Table 9
Simulation Scenarios and Design Characteristics for One cohort
Scenarios     
(DL1 DL2)
<= MTD (%) 
Declare 
Efficacious 
if safe (%) 
Advance to phase 
2 (%) 
Average N 
Early 
termination 
due to 
futility (%) 
DLT rates/ 
ORRs 
DL1 
DL2 
DL1 
DL2 
DL1 DL2 Any 
dose 
DL1 
DL2 
DL1 
DL2 
0.1, 0.2 
/0.1,0.1 
Safe/Null 
98.2 
88.8
7.13
11.04
7.0
9.8
16.3
24.76
21.66
62.73
52.15
0.1, 0.2 
/0.1,0.25Safe/ 
one posi
97.8
0 
89.5 
9.1 
82.79 8.9
74.1
78.3
25.03
28.05 59.92 
5.47
0.1,0.2 
/0.25,0.25 
Safe/ Posi 
97.5 
87.5 
83.08 
81.14
81 
71
92.4
32.24
27.7 
7.49
7.77
0.2, 0.4 
/0.25,0.25 
One safe/ 
Posi 
90.1 
40.7 
80.47
83.78
72.5
34.1
79.3
27.69
10.36
5.77 
5.16 
0.2, 0.4 
/0.25,0.4 One 
safe/ Posi 
89.6
41.3
81.58
96.61
73.1
39.9
79.3
26.85
10.53
5.92
0.24
0.3, 0.4 
/0.25,0.25 
MTD, Toxi/ 
Posi 
71.3
25.1
79.38
79.88
56.6
19.8
60
19.54
6.09
5.47
6.77
9.4.10.4.
Operation Characteristics
The probability of declaring efficacy within an individual cohort if the dose is declared 
safe (power and type I error rate) per dose are examined across scenarios for the 
distribution of assumed true DLT rates and ORRs for each dose in one cohort. Similar 
results are expected for the other two cohorts. The power is the probability declaring 
efficacy when the true underlying ORR is larger than its corresponding historical control 
0.1. Type 1 error rate is the probability of declaring efficacy within an individual cohort 
when the true underlying response rate is equal to the historical control.
The power and type I error rate on individual dose level are calculated if the dose is 
determined to be safe. In the simulations that a particular dose is declared over MTD, it 
won’t be included in the calculation. When the dose is efficacious, the design maintains 
at least 80% power. The type I error rate is controlled to <0.11.  


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9.4.10.5.
Stopping Early
Table 9 also presents the proportion of trials that halt enrollment 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 50% and 63% of the time.
Responsive cohorts generally have lower than 9% chance stop early for futility.
9.4.10.6.
Mean Proportion of advancing to Phase 2
To evaluate the design performance in making the decision of advancing to Phase 2, 
Table 9 listed the probabilities of advancing any or both of the two doses to Phase 2 after 
Phase 1. In the scenario where both DLs are safe and positive, there is a 92.4% chance 
that at least one dose will be picked for Phase 2. When both dose levels are safe but not 
positive, there is 16% chance that at least one dose will be picked for Phase II. 
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.
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


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
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, 
monitors will contact the site prior to the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 


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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 multi-center studies, this can occur at one or more or at all sites.  
If GSK determines such action is needed, GSK will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, GSK will provide advance notification to the investigator or the head of 
the medical institution, where applicable, of the impending action.
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK will also promptly inform the relevant 
regulatory authorities of the suspension or premature discontinuation of the study and the 
reason(s) for the action.  
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the reason 
for the suspension or premature discontinuation.
10.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.
GSK will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements.  The minimum retention time will meet the 
strictest standard applicable to that site for the study, as dictated by any institutional 


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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.  GSK will provide the investigator with the randomization codes for their 
site only after completion of the full statistical analysis
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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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACLS
Advanced Cardiac Life Support
AE
Adverse Event
AI
Aromatase Inhibitor
ALP
Alkaline phosphatise
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
ANSM
Agence Nationale de Sécurité du Médicament et des Produits de Santé
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BAL
Bronchoalveolar lavage
BC
Breast Cancer
BCRP
Breast Cancer Resistance Protein
BET
Bromodomain and extra-terminal
BID
Bis in die - Twice daily
BLRM
Bayesian logistic regression model
BNP
B-type Natriuretic Peptide
CAP
College of American Pathologists
Cav
Average observed concentration
CBC
Complete blood count
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
CK
Creatine kinase
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacokinetics Modelling & Simulation
CR
Complete response
CRF
Case record form
CRO
Contract Research Organization
CT
Computerized Tomography
CV
Cardiovascular/ Coefficient of variance
CYP
Cytochrome P
Cτ
Pre-dose (trough) concentration at the end of a dosing interval
D
Day
DAP
Data Analysis Plan
DCR
Disease control rate
DHEA
Dehydroepiandrosterone


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dL
Deciliter
DL
Dose Level
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DLT
Dose limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DPM
Dirichlet Process Mixtures
DRE
Disease-related event
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of the treatment
ER
Estrogen Receptor
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FSH
Follicle Stimulating Hormone
FTIH
First time in human
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GCSF
Granulocyte Colony-Stimulating Factors 
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HbA1c
Hemoglobin A1c
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C Virus
HDL
High-density lipoprotein
HDL-C
High-density lipoprotein cholesterol
HepC
Hepatitis C
HIV
Human Immunodeficiency Virus
HPLC
High pressure liquid chromatography
hPXR
Human Pregnane X receptor
hr
Hour(s)
HR
Heart rate/Hazard Ratio
HR+HER2-
Hormone Receptor-positive, HER2-negative
HRT
Hormone replacement therapy
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IDMC
Independent data monitoring committee
IDSL
Integrated Data Standards Library
IEC 
Independent Ethics Committee


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Ig
Immunoglobulin
IHC
Immunohistochemistry
IL
Interleukin
IM
Intramuscularly
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent-to-Treat
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous
IVD
In vitro companion diagnostic device
Kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
LDL
Low-density lipoprotein
LDL-C
Low-density lipoprotein cholesterol
LHRH
Luteinizing hormone-releasing hormone
LLN
Lower limit of normal
LMWH
Low molecular weight heparin
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MFD
Maximum feasible dose
mg
Milligrams
Mins
Minute(s)
mL
Milliliter
MM
Medical Monitor
mmHg
Millimeter of Mercury
mmol
Millimole
MR
Minimal Response
MRI
Magnetic resonance imaging
mRNA
Messenger Ribonucleic acid
MSDS
Material Safety Data Sheet
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximally-tolerated dose
mTOR
Mammalian Target of Rapamycin
mTPI
Modified toxicity probability interval
MUGA
Multigated Acquisition Scan
NA
Not Applicable
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse 
Events
NE
Not Evaluable
NSCLC
Non Small cell lung cancer


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NT-proBNP
N-terminal pro–B-Type natriuretic peptide
NYHA
New York Heart Association
OAT1
Organic anion transporter 1A1
OAT3
Organic anion transporter 3
ORR
Overall response rate
OS
Overall survival 
P2D
Part 2 Dose
PCR
Polymerase chain reaction
PD
Pharmacodynamic/Progressive Disease
PET
Positron emission tomography
PFS
Progression free survival
Pgp
P-glycoprotein
PGx
Pharmacogenetics
PI
Principal Investigator
PK
Pharmacokinetic
PR
Partial response
PRO-CTCAE
Patient-Reported Outcomes Version of the Common Terminology 
Criteria for Adverse Events
PS
Performance status
PT
Prothrombin time/ Preferred (coded) term
PTT
Partial thromboplastin time
QD
quaque die - Once daily
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Part 2 Dose
RR
Time interval from the onset of one QRS complex to the onset of the 
next QRS complex/Response Ratio
SAE
Serious adverse event(s)
SCLC
Small cell lung cancer
SCR
Screening Visit
SD
Stable disease/ Standard deviation
SERD
Selective Estrogen Receptor Degrader
SoC
Standard of Care
SRM
Study Reference Manual
SRT
Safety Review Team
t1/2
Apparent terminal half-life
T3
Free triiodothyronine
T4
Free thyroxine
TID 
Three times daily
Tmax
Time of maximum concentration
TNF
Tumor Necrosis Factor
TS
Tumor size
TSH
Thyroid stimulating hormone
TTG
Time to tumor growth


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TTP
Time to progression
ULN
Upper limit of normal
USA
United States
W
Week
WBC
White blood cells


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


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12.2.
Appendix 2: Management of Suspected Toxicity
The following dose modification criteria in Table 10 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.


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Table 10
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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 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 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 abnormalties recur at the same dose level 
following a second rechallenge, GSK525762 should be 
permanently discontinued.
As per the fulvestrant package insert, because 
fulvestrant is administered intramuscularly, it should be 
used with caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use. 
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). 
As per the fulvestrant package insert, because 
fulvestrant is administered intramuscularly, it should be 
used with caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use.
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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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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 starting study treatment at a 
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 <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)
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
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).


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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 8 for reporting 
and follow-up of suspected liver events.
Elevated bilirubin, 
hypoalbuminemia, 
prolonged PT, ascites, 
and/or encephalopathy
Refer to Appendix 13 for definition of Child-Pugh score

Child-Pugh Class A: No change to fulvestrant dose 
required

Child-Pugh Class B: Reduce dose of fulvestrant to 
250 mg, administered as per the standard schedule.  
Fulvestrant dose may be re-escalated to 500 mg 
once liver function improves.

Child-Pugh Class C: Hold fulvestrant until liver 
function has improved
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 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use 
NCI-CTCAE v4.0 
[NCI, 2009] 
grading system) 
Fasting blood glucose 
>150 mg/dL to 250 mg/dL 
(Mild hyperglycemia)

Monitor fasting and preprandial glucose.

If persistant 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.
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 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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.
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 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
equivalent] IV once daily) if infectious origin is ruled 
out. Taper over 4-6 weeks.
Other non-
hematologic 
toxicity (except 
those listed in 
Section 4.2.3.5)
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.
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)
b.
These guidelines are for suspected drug associated fever; please perform any additional tests as clinically 
appropriate for other causes of fever such as infection.
c.
Fulvestrant should be restarted following the original schedule.
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: Rationale for Response Assumptions
The Bayesian statistical design utilized in the dose expansion cohort(s) in Phase I of the 
study will test the hypothesis that the combination of GSK525762 and fulvestrant will 
achieve a clinically meaningful response rate, versus the null hypothesis that the 
combination will achieve a response that is no better than historical controls.  The null 
and alternative hypotheses were determined based on historical response rates (including 
fulvestrant as a single agent).  
For Phase II of the study, the design will test the hypothesis that the combination of 
GSK525762 and fulvestrant will achieve a clinically meaningful improvement in 
progression-free survival when compared against either fulvestrant alone or to the 
currently approved standard of care.
When determining appropriate efficacy hurdles, the following factors were taken into 
account:

It is unlikely that the combination of GSK525762 and fulvestrant will be further 
combined with additional targeted therapy or chemotherapy. Therefore, the 
efficacy of the combination will need to outperform the current standard of care 
for this population.

The effect of the two drugs in combination must yield a higher response rate than 
fulvestrant alone in order to justify the potential additional toxicity and burden of 
a second medication.  Furthermore, since both drugs are likely to have some 
efficacy as single agents, the efficacy bar must be set significantly higher for the 
combination to mitigate the risk that any observed clinical activity is due 
primarily to only one component of the combination rather than both drugs given 
in combination.

The combination of GSK525762 and fulvestrant should perform at least as well 
as, if not better than, any combination of fulvestrant with other targeted therapy or 
with conventional chemotherapy in order to justify its use in combination.

The efficacy bar is set higher than any second or third-line drugs in order to 
evaluate whether GSK525762 plus fulvestrant represents a clinical benefit over 
the standard of care.
12.3.1.
Phase 1
The statistical design in the dose expansion portion of this study is based upon the 
hypothesis that the historical ORR of relapsed/refractory HR+/HER2- BC is 10%.  
Multiple large clinical trials have demonstrated an ORR of approximately 8-10% when 
fulvestrant alone is administered in the second line and later to patients previously treated 
with aromatase inhibitors [Chia, 2008, Di Leo, 2010, Cristofanilli, 2016].  Therefore, a 
historical value of 10% would suggest that GSK525762 plus fulvestrant was performing 
no better than fulvestrant alone in this population.  


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Furthermore, a null hypothesis of 0.1 would suggest that the combination would perform 
at least as well as other combinations currently used in clinical practice.  A comparable 
response rate (12.6%) was observed when everolimus was combined with exemestane in 
women who had previously failed AI therapy [Baselga, 2012].
Currently, the most robust ORR observed in line 2+ for ER+BC is from the combination 
of palbociclib plus fulvestrant.  In the pivotal PALOMA3 trial [Cristofanilli, 2016], an 
ORR of almost 25% was observed among women who had measurable disease at 
baseline.  This value, however, was not chosen as the historical response rate for the 
following reasons:  First, palbociclib has not been approved as a SoC worldwide at the 
time of this trial; as a consequence, palbociclib (and thus these potential results) are not 
available to all subjects who may enroll on this study.  Second, for women who have 
progressed on a combination of palbociclib and fulvestrant (who could be enrolled into 
the current study), there are no data to support a historical response rate of more than 
10%.
In order to detect a clinically meaningful response rate as described in Section 12.3, a 
target ORR of 25% was selected. This represents a more than doubling of the historical 
rate, and also matches the ORR observed in the palbociclib/fulvestrant combination 
[Cristofanilli, 2016].  Furthermore, it exceeds the ORR observed with any other single-
agent endocrine therapy in later lines [Robertson, 2003, Chia, 2008], as well as the other 
approved combination, everolimus plus exemestane [Baselga, 2012].
12.3.2.
Phase 2
The statistical design in Phase 2 of this study is based upon the hypothesis that the 
combination of fulvestrant plus GSK525762 will double the PFS (i.e., a hazard ratio of 
0.5) compared to fulvestrant alone (for subjects previously treated with AI and/or 
CDK4/6 inhibitor/AI) or compared to SoC (for subjects previously treated with CDK4/6 
inhibitor/fulvestrant).  This value is comparable to the PFS improvement identified in the 
palbociclib/fulvestrant study (HR=0.46; [Cristofanilli, 2016] as well as the 
everolimus/exemestane study (HR=0.43; [Baselga, 2012]).


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12.3.3.
References
Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. 
Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N 
Engl J Med. 2012 Feb 9;366(6):520-9.
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, 
randomized placebo controlled trial of fulvestrant compared with exemestane after prior 
nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone 
receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 
1;26(10):1664-70.
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al. Fulvestrant plus 
palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, 
HER2-negative metastatic breast cancer that progressed on previous endocrine therapy 
(PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised 
controlled trial. Lancet Oncol. 2016 Apr;17(4):425-39.
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, et al. 
Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 
500 mg in postmenopausal women with estrogen receptor-positive advanced breast 
cancer. J Clin Oncol. 2010 Oct 20;28(30):4594-600. 
Robertson JF, Osborne CK, Howell A, Jones SE, Mauriac L, Ellis M, et al. Fulvestrant 
versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal 
women: a prospective combined analysis of two multicenter trials. Cancer. 2003 Jul 
15;98(2):229-38.


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12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.4.1.
Contraception Guidance:
Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP)
The list does not apply to FRP with same-sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Non-hormonal intrauterine device (IUD) or intrauterine system (IUS) that meets the 
≤1% failure rate as stated in the product label
2.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
Note: Hormonal methods of contraception are not permitted since the efficacy of these 
methods in combination with GSK525762 has not been assessed. LHRH-acting agents 
alone are not considered an adequate form of contraception.  GSK525762 has been 
shown to effect female reproductive systems in animals, therefore women of childbearing 
potential should adhere to this contraceptive guidance whilst on study and for 7 months 
after cessation of treatment with GSK525762, to be in line with GSK525762 guidance.
Effective January 13, 2020, the EU fulvestrant Summary of Product Characteristics 
was updated to include effective contraceptive use for women of childbearing 
potential for 24 months post last dose. Please consult the local fulvestrant
prescribing information to ensure subjects are using effective forms of 
contraception for the appropriate length of time required after stopping treatment 
with fulvestrant.
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.    
12.4.2.
Collection of Pregnancy Information
Any female subject who becomes pregnant while participating will be withdrawn from 
the study.

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a subject's pregnancy.


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
Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

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.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 10.  While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
12.4.3.
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.
GlaxoSmithKline Document Number 2011N113741_05 Version 5. GSK525762 
Investigator's Brochure. Report Date 28-Mar-2016
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.


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International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
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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12.5.
Appendix 5: ECOG Performance Status
The performance status assessment is based on the ECOG scale [Oken 1982]
References
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.
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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12.6.
Appendix 6: 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]
References
Cockcroft DW, Gault MH.  Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron 1976; 16: 31-41.


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12.7.
Appendix 7: Guidelines for Assessment of Disease, Disease 
Progression and Response Criteria – adapted from RECIST 
1.1 [Eisenhauer, 2009]
12.7.1.
Baseline Documentation of Target and Non-Target Lesions

All baseline lesion assessments must be performed within 28 days of randomization. 

Lymph nodes that have a short axis of <10mm are considered non-pathological and 
should not be recorded or followed.

Pathological lymph nodes with <15mm and but 10mm short axis are considered 
non measurable.

Pathological lymph nodes with 15mm short axis are considered measurable and can 
be selected as target lesions, however lymph nodes should not be selected as target 
lesions when other suitable target lesions are available.  

Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
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). 
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. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable.   
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions.

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. 

The following are required at baseline: CT for Chest/Abdomen/Pelvis or MRI for 
Abdomen/Pelvis (in combination with a non-contrast enhanced CT of the Chest) as 
described in Section 7.2.1.  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).


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For subjects without CNS disease at baseline, subsequent brain scans should only be 
performed as clinically indicated (e.g. symptoms suggestive of CNS progression).
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 CRF.
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 
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].
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray [Eisenhauer, 2009].
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.


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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: The presence of at least one measurable lesion.  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. 
Response Criteria
Evaluation of target lesions
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).


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
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 5 mm.

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 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.
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.


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
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.
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 11 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 11
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


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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.  
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.
References
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).  
Euro J Cancer. 2009;45:228-247.


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12.8.
Appendix 8: 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 CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 9)

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 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 CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 


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measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
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 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
1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior to 
first dose of study treatment


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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 


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12.9.
Appendix 9: Liver Safety – Study Treatment Restart or 
Rechallenge Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
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 [Andrade, 2009] with initial liver injury (e.g. fever, rash, 
eosinophilia) 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009; Hunt, 2010]

evidence of drug-related preclinical liability (e.g. reactive metabolites;
mitochondrial 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:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available. 

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.   


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
If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

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 10.
2. Restart Following Transient Resolving Liver Stopping Events NOT Related to 
Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 


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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 to be notified of any adverse events, as per Appendix 10.
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, Hunt CM.  Drug-induced 
liver injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 


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12.10.
Appendix 10: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.10.1.
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 
condition.


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
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.
12.10.2.
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.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 


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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 8 for the required liver chemistry follow-up instructions


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12.10.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.10.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission 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 
the scale’s developer.


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
The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.10.5.
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 
information, amending the SAE data collection tool accordingly.


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
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 CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.10.6.
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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12.11.
Appendix 11: 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 fulvestrant, or any 
concomitant medicines;

Breast cancer 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. With the implementation of 
amendment 06, if a subject has consented for genetic research but the sample has yet to 
be collected, this will no longer be required.
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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12.12.
Appendix 12: Country Specific Requirements
The changes in amendment 02 apply to all sites in the United Kingdom.


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12.13.
Appendix 13: Child-Pugh score
Measure
1 point
2 points
3 points
Points
Class
Reference:
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the 
oesophagus for bleeding oesophageal varices. Br J Surg. 1973 Aug;60(8):646-9.
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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12.14.
Appendix 14: Protocol Amendment Changes
12.14.1.
Amendment 01
Protocol Amendment 1 applies to all global site(s) participating in the conduct of the 
study
Amendment 1 summary:
Amendment 1 applies to all global study sites.
Based upon review and comment on the protocol by the FDA, the following changes are 
being implemented: Clarification of the permitted prophylactic anticoagulation therapies 
in Exclusion Criteria #4; Correction of the spelling of goserelin throughout the protocol; 
Clarification of how to read the liver algorithms in Section 5.4.1; Changes to the toxicity 
management guidelines in Appendix 2, Table 12 for the following: Update to the dose 
interruption/ reduction/discontinuation guidelines for Grade 4 thrombocytopenia; Dose 
reduction for subjects if QTcF 60 msec change from baseline occurs OR QTcF 500; 
Permanent discontinuation of study medication for subjects with troponin levels 
approaching the threshold for MI; Clarification on length of follow-up for subjects with 
LVEF increase; Monitoring of blood sugar and dose reduction guidelines for subjects 
with moderate to severe hypoglycemia; Dose reduction and event management for 
subjects with Grade 3-4 diarrhea; Dose interruption and reduction for subjects with Grade 
3-4 mucositis; Dose interruption/reduction/discontinuation and event management for all 
Grades of pneumonitis; Dose interruption and/or reduction for subjects with Grade 3-4 
other non-hematologic events.
In addition to these requested changes from the FDA, other administrative changes to the 
protocol include: Clarification of timing for sites to report pregnancies to GSK (24 hours 
versus 2 weeks, based on reproductive toxicity seen in pre-clinical GSK525762 studies); 
Correction of spelling errors; Correction to the Medical Monitor contact information; 
Correction of a typo in the Phase 1 Time and Events table; Addition of clarifying 
language around survival follow up after the EoT visit; Addition of clarifying language 
around fresh biopsies; Addition of clarifying language around the timing of CBC draws 
in Week 1; Addition of clarifying language to inclusion criteria #6 and exclusion criterion 
#1-3 around prior treatment history; Clarified wording around disease assessment 
schedule after Week 52; Removal of Section 5.4.3.2 Valvular Toxicity Stopping Criteria, 
this section is part of the GSK template guidance and not mandatory for inclusion, and 
there are no pre-clinical/clinical valvular toxicity findings for GSK525762. Removal of 
this information will also reduce the number of assessments required for subjects; Update 
to the option of scan (now ECHO or MUGA) performed to monitor cardiac safety; 
Removal of Section 7.3.5.6 Disease Related Events, this section is only to be included if 
there are pre-defined disease related events, and this protocol has no pre-defined events; 
Update to the Grade 3 and Grade 4 thrombocytopenia management guidelines to make 
them more stringent, based upon emerging data that will be provided in an INDSR 
(October 2016); Removal of the fever management guidelines in Appendix 2, Table 12, 
as part of the ongoing safety review for GSK525762, there is no apparent clinical 
correlation to the preclinical in vitro findings suggesting a potential for fever.


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List of Specific Changes
Medical Monitor/Sponsor Information Page
Rationale Change 1:
Corrected the contact information for Dr. 
.
Previous text:
Role
Name
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/
Pager 
Number
Site Address and email address
Primary 
Medical 
Monitor 
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
Secondary 
Medical 
Monitor
 
 MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
Revised text:
Role
Name
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/
Pager 
Number
Site Address and email address
Primary 
Medical 
Monitor 
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
Secondary 
Medical 
Monitor
 
 MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Medical Monitor/Sponsor Information Page
Rationale Change 2:
A separate IND has been opened for this study, therefore a new IND# has been generated 
and added to the protocol.
Previous text:
Regulatory Agency Identifying Number(s): Investigational New Drug (IND) # 
IND112942, EudraCT number 2016-003074-40
Revised text:
Regulatory Agency Identifying Number(s): Investigational New Drug (IND) # 
IND112942131933, EudraCT number 2016-003074-40
Synopsis Rationale / Section 2.1 Brief Background
Rationale Change 3:
Clarified wording around fulvestrant’s mechanism of action.
Previous text:
Currently, approved endocrine therapies include the ER antagonist tamoxifen; the 
aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole; and a selective ER 
degrader fulvestrant.
Revised text:
Currently, approved endocrine therapies include the ER antagonist tamoxifen; the 
aromatase inhibitors (AIs) anastrozole, exemestane, and letrozole; and fulvestrant, a 
selective ER antogonist.  
Section 4.7.1.2.1 Risk Assessment, Predicted Single Agent Toxiticities, 
Cardiovascular Safety Findings, Management and Monitoring
Rationale for Change 4:
To accommodate local practice, both ECHO and MUGA scans can be used to monitor 
cardiac safety.
Previous text:
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.


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Revised text:
To monitor for cardiomyopathy and valvular toxicity, echocardiograms or multigated 
acquisition (MUGA) scan 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.  Please refer to the 
study reference manual (SRM) for further detail.
This change is also applied to Section 5.1 (pg 46), Section 5.4.3 (pg 53), Section 7.1 (pg 
66-69), Section 7.2.2 (pg71 ), Section 7.3.3.2 (pg73 ), Section 9.4.4.1 (pg 90), Appendix 
1 (pg105 )
Section 5.1 Inclusion Criteria – Inclusion #6
Rationale Change 5:
Clarification on prior treatment history for eligible subjects.
Previous text:
History of prior therapy that satisfies one of the following criteria:
d. Disease that progressed during treatment or within 12 months of completion of 
adjuvant therapy with tamoxifen and/or an AI
e. Disease that progressed during treatment or within 1 month after the end of treatment 
with prior tamoxifen, AI, or CDK4/6 inhibitor plus letrozole, for advanced/metastatic 
disease
Revised text: 
History of prior therapy that satisfies one of the following criteria:
a. AI failures: Disease that progressed during treatment or within 12 months of
    completion of adjuvant therapy with tamoxifen and/or an AI 
b. CDK4/6 inhibitor plus letrozole fairlures: Disease that progressed during treatment 
or within 1 month after the end of treatment with prior tamoxifen, AI, or the 
combination of a CDK4/6 inhibitor plus letrozole,for advanced/metastatic disease
Section 5.1 Inclusion Criteria – Inclusion #7
Rationale Change 6:
Correction of the spelling of goserelin.
Previous text:
16. Any menopausal status
NOTE: If pre- or peri-menopausal at time of enrollment (refer to Section 6.10.2.1 for 
menopause definition), subject must be willing to initiate therapy or continue ongoing 
therapy with gosrelin for at least 28 days prior to the first dose of fulvestrant.  
Subjects on an alternative Luteinizing hormone-releasing hormone (LHRH) agent do 


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not have to start gosrelin prior to the first dose of fulvestrant, but they must agree to 
change to gosrelin at the next scheduled dose and remain on gosrelin for the 
remainder of the trial
Revised text:
17. Any menopausal status
NOTE: If pre- or peri-menopausal at time of enrollment (refer to Section 6.10.2.1 for 
menopause definition), subject must be willing to initiate therapy or continue ongoing 
therapy with goserelin for at least 28 days prior to the first dose of fulvestrant.  
Subjects on an alternative Luteinizing hormone-releasing hormone (LHRH) agent do 
not have to start goserelin prior to the first dose of fulvestrant, but they must agree to 
change to goserelin at the next scheduled dose and remain on goserelin for the 
remainder of the trial
Section 5.2 Exclusion Criteria – Exclusion #1
Rationale Change 7:
Clarification of wording on prior treatment.
Previous text:
Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of 
advanced/metastatic disease, or disease which has progressed despite prior fulvestrant 
therapy.
Note: Prior cytotoxic therapy in the neoadjuvant/adjuvant setting does not count toward 
the one line limit
Revised text:
Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis of 
advanced/metastatic disease, or disease which has progressed despite prior fulvestrant 
therapy.
Note: Prior cytotoxic therapy in the neoadjuvant/adjuvant setting does not count toward 
the one line limit
Section 5.2 Exclusion Criteria – Exclusion #2
Rationale Change 8:
Clarification of wording on prior treatment.
Previous text:
This is a new exclusion criterion.


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Revised text:
Disease which has progressed despite prior fulvestrant therapy.
Section 5.2 Exclusion Criteria – Exclusion #3
Rationale Change 9:
Clarification of wording on prior treatment.
Previous text:
This is a new exclusion criterion.
Revised text:
≥3 lines of systemic anti-cancer therapy (including 1 line of chemotherapy).
Section 5.2 Exclusion Criteria – Exclusion # 6
Rationale Change 10:
Clarification of what specific prophylactic anticoagulation treatments are permitted.
Previous text:
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 fulvestrant. Low dose 
(prophylactic) LMWH or noval oral anticoagulant therapy is permitted. 
Revised text:
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 fulvestrant.  Low dose 
(prophylactic) LMWH or noval oral anticoagulant therapy is permitted. 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.
Section 5.4.1 Liver Chemistry Stopping Criteria
Rationale Change 11:
Provided clarification of how to read the liver algorithms (Figure 4 and Figure 5).


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Previous text:
See Figure 4 and Figure 5 for liver stopping criteria for subjects without and with liver 
metastases, respectively.
Revised text:
See Figure 4 and Figure 5 for liver stopping criteria for subjects without and with liver 
metastases, respectively.  The algorithms are best read from left to right.
Section 5.4.3.2 Valvular Toxicity Stopping Criteria
Rationale for change 12:
Language in this section is protocol template text, and not specific or relevant to 
GSK525762.
Previous text:
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by 
echocardiogram (ECHO) (Grade 2 mitral/tricuspid/aortic valvular toxicity per National 
Cancer Institute- Common Toxicity Criteria for Adverse Events [NCI-CTCAE], 
version 4) should temporarily discontinue GSK525762 and/or fulvestrant, and have a 
repeat evaluation by ECHO within 1 week.  ECHO should be repeated every 1 to 2 weeks 
for 4 weeks or until valve recovery to baseline.

If the valve recovers to baseline any time during the next 4 weeks after 
consultation and approval of the Medical Monitor, the subject may be restarted 
on GSK525762 and/or fulvestrant at a reduced dose(s).  For such subjects, 
monitoring of the valve via ECHO will then be performed 2 and 4 weeks after 
rechallenge, and every 4 weeks thereafter for 16 weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then 
the subject should permanently discontinue GSK525762 and/or fulvestrant.  The 
valve should continue to be monitored via ECHO every 4 weeks for 16 weeks or 
until resolution.
Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging with 
symptoms controlled by medical intervention) valvular toxicity must discontinue 
GSK525762 and/or fulvestrant.  Valvular toxicity should continue to be monitored every 
4 weeks for 16 weeks or until resolution.  If recovery occurs (return to baseline via 
imaging AND symptom resolution) within 4 weeks, the subject may restart GSK525762 
and/or fulvestrant at a reduced dose after consultation and approval of the Medical 
Monitor.
ECHO must be performed at baseline and at the final study visit.  Copies of all ECHO(s) 
and cardiology consultations performed on subjects who experience valvular toxicity will 
be required by GSK for review.  Instructions for submitting qualifying ECHOs are 
provided in the SRM.


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Revised text:
Section has been removed.
Section 5.4.4 Other Stopping Criteria
Rationale Change 13:
Clarification that CBCs drawn during Phase I, Week 1 will include screening.
Previous text:
To monitor for hematologic toxicity, CBCs will be drawn three times during the first 
week , twice weekly for the next two weeks of study, once during the fourth week, and 
then every four weeks, as described in the Time and Events table.  
Revised text:
To monitor for hematologic toxicity, CBCs will be drawn three times during the first 
week (includes screening), twice weekly for the next two weeks of study, once during 
the fourth week, and then every four weeks, as described in the Time and Events table.  
Section 7.1 Time and Events Tables – Table 5 and Table 7 Time and 
Events
Rationale Change 14:
A footnote has been added to the Time and Events tables for Phase I and Phase II to 
clarify survival follow-up post the EoT visit.
Previous text:
This is new text
Revised text:
Applies to subjects who withdraw for any reason prior to progression or who progress 
during study treatment. 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.
Section 7.1 Time and Events Tables – Table 6 Time and Events, Phase I 
Laboratory Assessments 
Rationale Change 15:
Correction of a typo in the visit schedule for Phase I, Week 3.


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Previous text:
SCR
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
EOT
D1
D4
D1
D4
D4
D1
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
X
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
Fasting blood 
glucose
X
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
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
Follicule 
stimulating 
hormone 
(FSH)/Estradiol1
X
Pregnancy test2
X
X
X
X
X
1.
Only required at screening for pre- and peri-menopausal subjects
2.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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Revised text:
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
X
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
Fasting blood 
glucose
X
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
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
Follicule 
stimulating 
hormone 
(FSH)/Estradiol1
X
Pregnancy test2
X
X
X
X
X
1.
Only required at screening for pre- and peri-menopausal subjects
2.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter
Section 7.1 Time and Events Tables – Table 5 Time and Events, Phase I 
Footnote 10
Rationale Change 16:
Addition of clarifying language around the fresh biopsies needed for the study.


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Previous text:
Screening (archival) tumor biopsy specimen required for all subjects; if archival sample 
is not available then fresh specimen must be provided as described in Section 7.7.2. 
Paired fresh biopsies must be provided pre- and on-treatment at the time points indicated 
for at least 6 subjects at each dose level.  A limited number of additional subjects may be 
requested to provide pre and on-treatment biopsies based on emerging data. Fresh 
biopsies should be paired with plasma samples for PK, collected as close as possible to 
biopsy (ideally within 1 h).  Refer to the SRM for further details.  
Revised text:
Screening (archival) tumor biopsy specimen required for all subjects; if archival sample 
is not available then fresh specimen must be provided as described in Section 7.7.2. 
Paired fresh biopsies must be provided pre- and on-treatment at the time points indicated 
for at least 6 subjects (out of 35 planned for enrollment) at each dose level.  A limited 
number of additional subjects may be requested to provide pre and on-treatment biopsies 
based on emerging data. Fresh biopsies should be paired with plasma samples for PK, 
collected as close as possible to biopsy (ideally within 1 h).  Refer to the SRM for further 
details.  
Section 7.2.2 Visit Windows
Rationale for change 17:
Clarification on wording for the disease assessment schedule after Week 52.
Previous text:
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 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.
Section 7.3.5.6 Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs
Rationale Change 18:
There are no pre-defined disease related events identified for this study, so the section has 
been removed.


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Previous text:
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the 
subject’s condition, are not to be reported as AEs or SAEs.
NOTE: If either of the following conditions applies, then the event is not a disease-
related event (DRE) and must be recorded and reported as an SAE: 

The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual subject, or

The investigator considers that there is a reasonable possibility that the event 
was related to treatment with the investigational product
Revised text:
Section has been removed.
Section 7.3.6 Pregnancy
Rationale Change 19:
Due to the pre-clinical reproductive toxicity findings with GSK525762, the timeframe for 
reporting of pregnancies by sites to GSK has been changed from 2 weeks to 24 hours.
Previous text:
Details of all pregnancies in female participants will be collected after the start of study
treatment and until at least 90 days post-last dose.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined Appendix 4.
Revised text:
Details of all pregnancies in female participants will be collected after the start of study
treatment and until at least 90 days 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 Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.


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Section 7.5.1 Tumor Biopsy Collection
Rationale Change 20:
Addition of clarifying language around the fresh biopsies needed for the study.
Previous text:
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of the first dose) 
and on-treatment at the time points indicated for at least 6 subjects at each dose level.  A 
limited number of additional subjects may be requested to provide pre and on-treatment 
biopsies based on emerging data.  Biopsy requirement(s) will be discussed with the 
subject prior to signing informed consent.  Any fresh on-treatment biopsy should be 
accompanied by a plasma sample collected as close as possible to the time of biopsy 
(preferably within 1 h).  Further details regarding sample type and processing will be
provided in the SRM.
Revised Text:
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of the first dose) 
and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned 
for enrollment) at each dose level.  A limited number of additional subjects may be 
requested to provide pre and on-treatment biopsies based on emerging data.  Biopsy 
requirement(s) will be discussed with the subject prior to signing informed consent.  Any 
fresh on-treatment biopsy should be accompanied by a plasma sample collected as close 
as possible to the time of biopsy (preferably within 1 h).  Further details regarding sample 
type and processing will be provided in the SRM.
Section 12.2 Appendix 2: Management of Suspected Toxicity
Rationale Change 21:
Based upon newly available data (provided in a recent INDSR), the Grade 3 
thrombocytopenia management guidelines have been updated to be more stringent.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 3 (platelets 
<50,000, 
≥25,000/mm3)
After discussion with medical monitor and using sound 
clinical judgement, continue GSK525762 at same dose or 
dose reduce to previously cleared dose level. Monitor CBC 
at least twice a week, or more frequently if clinically 
indicated.  
Investigators should delay fulvestrant injections until 
platelet count recovers to ≤ Grade 2 (>50,000/mm3).


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Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 3 (platelets
<50,000, 
≥25,000/mm3)
Withhold GSK525762 and check 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 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.
As per the fulvestrant package insert, because 
fulvestrant is administered intramuscularly, it should be 
used with caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Grade 4 
Thrombocytopenia
Rationale Change 22:
Based upon feedback from the FDA, and newly available data (provided in a recent 
INDSR), the management guidelines for Grade 4 thrombocytopenia have been updated to 
be more stringent.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
Grade 4 (platelets  
<25,000/mm3),and/or 
any grade accompanied 
by severe bleeding 
related to 
thrombocytopenia
Temporarily interrupt GSK525762 and monitor CBC every 
2-3 days. If platelet counts recover to Grade 3 and is 
steady for at least 2 CBC reads at least 3days apart, or 
rising, discuss with medical monitor resuming treatment at 
the same or adjusted dose (see Grade 3) based on sound 
clinical judgment.
Investigators should delay fulvestrant injections until 
platelet count recovers to ≤ Grade 2 (>50,000/mm3).


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Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Thrombocytopenia
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 (≥50,000u/l). 
As per the fulvestrant package insert, because fulvestrant 
is administered intramuscularly, it should be used with 
caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/ul (Grade 2) 
within 14 days, GSK525762 should be permanently 
discontinued.
If platelet count recovers to ≥50,000/ul (Grade 2) within 14 
days, GSK525762 may be continued at the 
current/reduced dose after discussion with the medical 
monitor . 
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria QTcF
Rationale Change 23:
Based upon feedback from the FDA, the management guidelines for QTcF restart if 60 
msec change from baseline occurs OR QTcF 500 have been updated to incorporate a 
dose reduction.


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Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
QTcF
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:
c. Maintain serum potassium > 4mol/L
d. 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 a 
previously cleared dose level 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)
(6)
QTcF reduced to <450 msec,
(7)
Potassium and magnesium levels are within 
institutional normal range,
(8)
A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the Medical 
Monitor),
(9)
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
(10) Institutional IRB (or equivalent) approval, and
(11) 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:
(4)
Evaluation by cardiologist.
(5)
Weekly assessments for QTcF should be 
performed for two weeks, and then next 
assessment at 4 weeks post-dose.

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 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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Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Troponin Level Increase
Rationale Change 24:
Based upon feedback from the FDA, the management guidelines for elevated troponin 
levels have been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
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 withdrawn and 
the subject will be referred immediately to a cardiologist for 
appropriate medical care.
May consider restarting study treatment at a reduced dose 
based on discussion with Medical Monitor.
Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
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 withdrawn


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
permanently discontinued and the subject will be 
referred immediately to a cardiologist for appropriate 
medical care.
May consider restarting study treatment at a reduced dose 
based on discussion with Medical Monitor.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria elevated LVEF
Ration Rationale Change 25:
Based upon feedback from the FDA, the management guidelines on length of follow up 
for elevated LVEF have been updated.
Previous text:
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.

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.


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Revised text:
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.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Moderate to Severe 
Hypoglycemia
Rationale Change 26:
Based upon feedback from the FDA, the management guidelines for moderate to severe 
hypoglycemia have been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe
intensity criteria; 
however for CRF 
reporting use 
NCI-CTCAE v4.0 
[NCI] grading 
system) 

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 

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
Medical Monitor


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Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use 
NCI-CTCAE v4.0 
[NCI] grading 
system) 

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 

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
Medical Monitor

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.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Grade 3-4 Diarrhea
Rationale Change 27:
Based upon feedback from the FDA, the management guidelines for Grade 3-4 diarrhea 
have been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Diarrhea

Grade 3 or 4

Above plus consider IV hydration, hospital admission 
and prophylactic antibiotics as appropriate.  Consider 
temporary discontinuation of study medications and 
discuss with Medical Monitor.

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with Medical 
Monitor.


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Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Diarrhea

Grade 3 or 4

Above plus consider IV hydration, hospital admission 
and prophylactic antibiotics as appropriate.  Consider 
temporary discontinuation of study medications and 
discuss with Medical Monitor. Withhold study drug 
until diarrhea has resolved to ≤Grade 1, continue 
diarrheal prophylaxis

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with Medical 
Monitor.

Restart  study treatment one dose level lower
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Grade 3-4 Mucositis
Rationale Change 28:
Based upon feedback from the FDA, the management guidelines for Grade 3-4 mucositis 
have been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Mucositis

Grade 3 or 4

(Above plus systemic opiate administration as 
needed.)  Consider IV hydration and hospital 
admission as appropriate.

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with Medical 
Monitor.


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Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Mucositis

Grade 3 or 4

(Above plus systemic opiate administration as 
needed.)  Consider IV hydration and hospital 
admission as appropriate.

May restart study treatment at a reduced dose or dose 
level pre-event based on discussion with Medical 
Monitor.

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.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Pneumonitis
Rationale Change 29:
Based upon feedback from the FDA, the management guidelines for pneumonitis have 
been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Pneumonitis
Grade 1

(For all Grades) Obtain high resolution chest CT.

Consider evaluation by pulmonologist.  Consider 
room air O2 saturation at rest via pulse oximetry 
reading (X 2, 5 mins apart).  Repeat evaluations every 
8-12 weeks until return to within normal limits (wnl).

Continue investigational drug(s) at current dose(s).
Grade 2

Hold investigational drug(s) until recovery to ≤ 
Grade 1, then reduce dose by at least 25%.  
Discontinue investigational drug(s) if no recovery to ≤ 
Grade 1 within 4 weeks.  May consider escalation to 
pre-event dose after discussion with Medical Monitor.

Consider evaluation by pulmonologist.  Consider 
pulmonary function tests including: spirometry, 
Diffusing Capacity of the Lung for Carbon Monoxide 
(DLCO), and room air O2 saturation at rest via pulse 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
oximetry reading (X 2, 5 mins apart).  Repeat 
evaluations every 8-12 weeks until return to wnl.  
Consider a bronchoscopy with biopsy and/or 
bronchoalveolar lavage.  (BAL).

Treat only if symptomatic.  Consider corticosteroids 
if symptoms are troublesome and infectious origin is 
ruled out.  Taper as medically indicated.
Grade 3 and 4

(Grade 3) Hold investigational drug(s) until recovery to 
≤ Grade 1; may consider restarting investigational 
drug(s) at a reduced dose(s) after discussion with 
Medical Monitor. Discontinue investigational drug(s) if 
no recovery to ≤ Grade 1 within 4 weeks.  (Grade 4) 
Discontinue investigational drug(s)

Evaluation by pulmonologist required.  

Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at rest 
via pulse oximetry reading (X 2, 5 mins apart).  Repeat 
evaluations at least every 8 weeks until return to 
normal.  Bronchoscopy with biopsy and/or BAL is 
recommended.

Consider treatment with corticosteroids (1-2 mg/kg of 
prednisone [or equivalent] IV once daily) if infectious 
origin is ruled out. Taper over 4-6 weeks.
Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Pneumonitis
Grade 1

(For all Grades) Obtain high resolution chest CT.

Consider evaluation by pulmonologist.  Consider 
room air O2 saturation at rest via pulse oximetry
reading (X 2, 5 mins apart).  Repeat evaluations every 
8-12 weeks until return to within normal limits (wnl).

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.

Continue investigational drug(s) at current dose(s).
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.  May consider escalation to 
pre-event dose after discussion with Medical Monitor.

Consider evaluation Must be evaluated by a 
pulmonologist.  Consider Perform pulmonary function 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
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. 8-12 weeks until return 
to wnl.  Consider a bronchoscopy with biopsy and/or 
bronchoalveolar lavage.  (BAL).

Treat only if symptomatic.  Consider corticosteroids 
if symptoms are troublesome and infectious origin is 
ruled out.  Taper as medically indicated.
Grade 3 and 4

(Grade 3) Hold investigational drug(s) until recovery to 
≤ Grade 1; may consider restarting investigational 
drug(s) at a reduced dose(s) after discussion with 
Medical Monitor. Discontinue investigational drug(s) if 
no recovery to ≤ Grade 1 within 4 weeks.  (Grade 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.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Fever Management
Rationale Change 30:
Fever management guidelines have been removed due to lack of fever events seen in the 
ongoing BET115521 and BET116183 studies.


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Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Fever b

Grade 1

Continue current dose(s) of study treatment(s) and 
monitor for change in severity.

Grade 2

Consider temporary discontinuation of study 
medication and monitor for change in severity.

Assess or inquire if the subject is experiencing in 
combination with fever: swelling, redness, extreme 
fatigue or nausea. Assess vital signs.

Collect “Cytokine blood samples” (which include blood 
sample for tumor Necrosis Factor (TNF)-alpha, 
Interleukin (IL)-1,IL-6, IL-10).  Collect blood culture and 
investigate viral infections as applicable.

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
Medical Monitor

Grade 3-4

Temporary discontinuation of study medication and 
monitor for change in severity

Assess or inquire if the subject is experiencing in 
combination with fever: swelling, redness, extreme 
fatigue or nausea.

Collect “Cytokine blood samples” (which include blood 
sample for TNF-alpha, IL-1,IL-6, IL-10).  Collect blood 
culture and investigate viral infections as applicable.

May consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussion with 
Medical Monitor.
Revised text:
Section has been removed.
Section 12.2 Appendix 2: Management of Suspected Toxicity – Table 
12: Dose Adjustment/Stopping Safety Criteria Grade 3-4 Other Non-
Hematologic Events
Rationale Change 31:
Based upon feedback from the FDA, the management guidelines for Grade 3-4 other non-
hematologic events have been updated.
Previous text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Other non-
hematologic 

Grade 3

Hold dose for one week intervals until ≤ drug-related 
Grade 2 then restart with no change for 1st episode. 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
toxicity (except 
those listed in 
Section 4.2.3.5)
Utilize an alternative, less frequent schedule or 
reduce by one dose level with 2nd episode. If no 
recovery to ≤Grade 1 after a 21 day delay, subject 
should go off protocol therapy.

Grade 4

Off protocol therapy

In rare situations, based on discussion and written 
agreement between Medical Monitor and investigator, 
if the subject is receiving benefit then the following 
criteria should be implemented: hold dose for one 
week intervals until < drug-related Grade 2 then 
restart with no change for 1st episode. Utilize an 
alternative, less frequent schedule or reduce by one 
dose level with 2nd episode. If no recovery to ≤Grade 
1* after a 21 day delay, subject should go off protocol 
therapy
Revised text:
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Other non-
hematologic 
toxicity (except 
those listed in 
Section 4.2.3.5)

Grade 3

Hold dose for one week intervals until ≤ drug-related 
Grade 2 until toxicity is ≤Grade 1, then restart with no 
change for 1st episode. Utilize an alternative, less 
frequent schedule or 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 go off protocol therapy.

Grade 4

Off protocol therapy

In rare situations, based on discussion and written 
agreement between Medical Monitor and investigator, 
if the subject is receiving benefit then the following 
criteria should be implemented: hold dose for one 
week intervals until < drug-related Grade 2 then 
restart with no change for 1st episode. Utilize an 
alternative, less frequent schedule or reduce by one 
dose level with 2nd episode. If no recovery to ≤Grade 
1* after a 21 day delay, subject should go off protocol 
therapy

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.


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12.14.2.
Amendment 02
Protocol changes for Amendment 02, from protocol changes to amendment 01 (21-
OCT-2016)
Amendment 02 summary:
Amendment 02 applies to all sites in the United Kingdom.
Based upon review and comment on the protocol by the MHRA, the following changes 
are being implemented as a standalone amendment for the UK: Clarification of the length 
of time, post treatment completion, that the approved list of contraceptives must be used 
by female subjects of childbearing potential; clarification in Section 5.4 that pregnancy is 
a reason for subject discontinuation from the study.  A forthcoming amendment (03) will 
include these revisions as part of a global protocol amendment.
List of Specific Changes
Section 5.4 Withdrawal/Stopping Criteria
Rationale Change 1:
Clarification in this section that pregnancy of a subject taking part in the study is reason 
for discontinuation from study.
Previous text:
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
Revised text:
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


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
a dose delay of >14 days unless the investigator and Medical Monitor agree that 
further treatment may benefit the subject

pregnancy
Section 12.4 Appendix 4, Section 12.4.1 - Modified List of 
HighlyEffective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP)
Rationale Change 2:
Clarification of the length of time, post treatment completion, that the approved list of 
contraceptives must be used by female subjects of childbearing potential.
Previous text:
The list does not apply to FRP with same-sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Intrauterine device (IUD) or intrauterine system
2.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
Note: Hormonal methods of contraception 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.  
Revised text:
The list does not apply to FRP with same-sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Intrauterine device (IUD) or intrauterine system
2.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.


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Note: Hormonal methods of contraception 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.  GSK525762 has been shown to effect 
female reproductive systems in animals, therefore women of childbearing potential 
should adhere to this contraceptive guidance whilst on study and for 7 months after 
cessation of treatment with GSK525762.
12.14.3.
Amendment 03
Protocol changes for Amendment 03, from protocol changes to amendment 02 (31-
JAN-2017
Amendment 03 summary:
Amendment 03 applies to all global study sites.
Changes to the protocol include: Clarification to the prior treatment subjects may have 
received; update to the timelines of the study, based upon new enrollment projections; 
clarification of inclusion criteria #6 regarding prior treatment subjects may have received; 
clarification of exclusion criteria #1 and #3 regarding number of prior lines of therapy; 
addition of two new exclusion criteria regarding use of NSAIDS and history of bleeding 
events; clarification in Section 5.4 that pregnancy for subjects of childbearing potential is 
a cause for study discontinuation; clarification regarding the liquid that subjects are 
permitted to use when taking GSK525762; clarification around the dosing window for 
fulvestrant; addition of Table 3 which clarifies dose reductions; clarification around use 
of Aspirin; update to the prohibited meds table in Section 6.11.2.1 and the cautionary 
meds table in Section 6.11.2.3; clarification around use of medication containing 
acetaminophen; update to the schedule of assessments in the Time and Events tables for 
both Phase I and II of the study; update to the schedule of laboratory assessments in both 
Phase I and II of the study; update to the ± visit windows for Weeks 2, 3, 4, 5, and 9; 
added logistical and medical guidance around when on treatment fresh biopsies and 
planned surgical procedure can take place; updated the thrombocytopenia management 
guidelines in Table 13 to be in line with regulatory feedback; clarification of baseline 
imaging windows; clarification of approved contraception and length of time said 
contraception needs to be used post study treatment.
List of Specific Changes
Title Page
Update to protocol author list


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Previous text:
 
 
Revised text:
 
Section 1 Protocol Synopsis for Study 201973:  Overall Design
Clarification of the design of Ph I
Previous text:
Phase I of the study is designed as single arm treatment with GSK525762 in combination 
with fulvestrant in two distinct populations of ER+ breast cancer to determine a 
recommended Phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetic, and 
efficacy profiles. 
Revised text:
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of ER+ breast cancer to 
determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. 
Section 1 Protocol Synopsis for Study 201973:  Overall Design
Clarification of the wording around the target subject population and prior therapy.
Previous text:
Subjects who have disease that has progressed with an anti-estrogen and/or AI 
(e.g., tamoxifen, anastrozole, exemestane, and/or letrozole) plus up to one line of 
cytotoxic chemotherapy administered in the advanced/metastatic setting.  
Subjects receiving adjuvant tamoxifen or AI at the time of metastatic diagnosis, 
or subjects whose disease progressed within 12 months of discontinuing adjuvant 
tamoxifen or AI, will be eligible to enroll in this cohort.
Subjects who have disease that has progressed during with a CDK4/6 inhibitor 
(e.g., palbociclib) plus letrozole (plus up to one line of cytotoxic chemotherapy 
administered in the advanced/metastatic setting and any number of lines of prior 
anti-estrogen and/or AI therapy)
PPD
PPD


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Revised text:
Subjects who have disease that has relapsed during treatment or within 12 
months of completion of adjuvant therapy with an AI, OR disease that 
progressed during treatment with an AI for advanced/metastatic disease.  
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met. progressed with an anti-estrogen and/or AI (e.g., tamoxifen, 
anastrozole, exemestane, and/or letrozole) plus up to one line of cytotoxic 
chemotherapy administered in the advanced/metastatic setting.  Subjects 
receiving adjuvant tamoxifen or AI at the time of metastatic diagnosis, or 
subjects whose disease progressed within 12 months of discontinuing adjuvant 
tamoxifen or AI, will be eligible to enroll in this cohort.
Subjects who have disease that has progressed during treatment with the 
combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole for 
advanced or metastatic disease.  Prior ovarian suppression and/or tamoxifen 
are allowed as long as the other criteria are met. (plus up to one line of 
cytotoxic chemotherapy administered in the advanced/metastatic setting and any 
number of lines of prior anti-estrogen and/or AI therapy)
Documented progression on the last line of systemic anti-cancer therapy is required.
Section 2.2 Brief Background
To provide an update on the ER+BC cohort in the ongoing BET115521 monotherapy 
trial.
Previous text:
One inhibitor, GSK525762, is currently being studied in two separate trials: BET115521 
and BET116183.  Both are Phase I/II studies, with the primary endpoint to evaluate 
safety and tolerability of GSK525762 and identify the single-agent maximally-tolerated 
dose (MTD).
Revised text:
One inhibitor, GSK525762, is currently being studied in two separate trials: BET115521 
and BET116183.  Both are Phase I/II studies, with the primary endpoint to evaluate 
safety and tolerability of GSK525762 and identify the single-agent maximally-tolerated 
dose (MTD).  In the ongoing BET115521 monotherapy trial, ER+ breast cancer 
subjects with disease that progressed after multiple prior lines of therapy were 
enrolled.  A planned interim futility analysis in this population was performed, and 
GSK has stopped enrollment in this single agent cohort, based upon limited benefit.
Section 4.1 Overall Design
Clarification of the design of Ph I


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Previous text:
Phase I of the study is designed as single arm treatment with GSK525762 in combination 
with fulvestrant in two distinct populations of ER+ breast cancer to determine a 
recommended Phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetic, and 
efficacy profiles. 
Revised text:
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of ER+ breast cancer to 
determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. 
Section 4.1 Overall Design: Phase I
Clarification of the wording around the target subject population and prior therapy.
Previous text:
Phase I will study the safety, tolerability, PK, and efficacy of GSK525762 plus 
fulvestrant when administered in combination in up to two escalating dose levels (DLs). 
Eligible subjects must have advanced or metastatic ER+BC that has been refractory to, or 
progressed despite, prior systemic therapy. The combination of GSK525762 plus 
fulvestrant will be evaluated in an open-label fashion in two separate populations of 
subjects (i.e., two cohorts). The same cohorts will be evaluated at multiple DLs:
Subjects who have disease that has progressed on prior treatment with an anti-
estrogen and/or AI (e.g., tamoxifen, anastrozole, exemestane, and/or letrozole) 
plus up to one line of cytotoxic chemotherapy administered in the 
advanced/metastatic setting
Subjects who have disease that has progressed on prior treatment with a CDK4/6 
inhibitor (e.g., palbociclib) plus letrozole (plus up to one line of cytotoxic 
chemotherapy administered in the advanced/metastatic setting and any number of 
lines of prior anti-estrogen and/or AI therapy)
Revised text:
Phase I will study the safety, tolerability, PK, and efficacy of GSK525762 plus 
fulvestrant when administered in combination in up to two escalating dose levels (DLs). 
Eligible subjects must have advanced or metastatic ER+BC that has been refractory to, or 
progressed despite, prior systemic therapy. The combination of GSK525762 plus 
fulvestrant will be evaluated in an open-label fashion in two separate populations of 
subjects (i.e., two cohorts). These The same cohorts will be evaluated at multiple both
DLs (see Inclusion and Exclusion criteria in Section 5.1 and Section 5.2 for full 
details):


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Subjects who have disease that has relapsed during treatment or within 12 
months of completion of adjuvant therapy with an AI, OR disease that 
progressed during treatment with an AI for advanced/metastatic disease.  
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met. progressed on prior treatment with an anti-estrogen and/or AI 
(e.g., tamoxifen, anastrozole, exemestane, and/or letrozole) plus up to one line of 
cytotoxic chemotherapy administered in the advanced/metastatic setting
Subjects who have disease that has progressed during treatment with the 
combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole for 
advanced or metastatic disease.  Prior ovarian suppression and/or tamoxifen 
are allowed as long as the other criteria are met. (plus up to one line of 
cytotoxic chemotherapy administered in the advanced/metastatic setting and any 
number of lines of prior anti-estrogen and/or AI therapy)
Documented progression on the last line of systemic anti-cancer therapy is required.
Section 4.3.2 Phase II Cohort Selection
Clarification of the wording around the target subject population and prior therapy.
Previous text:

either AI therapy OR CDK4/6 inhibitor plus letrozole.  If both cohorts are 
permitted to enroll in Phase II, randomization will be stratified by prior CDK4/6 
inhibitor-based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-
exposed) and corresponding stratified analysis will be provided at interim and 
final analyses
Note that in all cohorts, subjects may have received up to one line of cytotoxic 
chemotherapy in the advanced/metastatic setting.  In addition, subjects enrolled in the 
CDK4/6 inhibitor plus letrozole and the CDK4/6 inhibitor plus fulvestrant cohorts may 
have failed therapy with any number of lines of anti-estrogens and/or AIs.
Revised text:

either AI therapy OR CDK4/6 inhibitor plus letrozole.  If both cohorts are 
permitted to enroll in Phase II, randomization will be stratified by prior CDK4/6 
inhibitor-based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-
exposed) and corresponding stratified analysis will be provided at interim and 
final analyses
Note that in all cohorts, subjects may have received up to one line of cytotoxic 
chemotherapy in the advanced/metastatic setting.  In addition, subjects enrolled in the 
CDK4/6 inhibitor plus letrozole and the CDK4/6 inhibitor plus fulvestrant cohorts may 
have failed therapy with any number of lines of anti-estrogens and/or AIs.


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Section 4.6.2 Drug-Drug Interactions
Update wording around CYP3A4 induction of GSK525762.
Previous text:
Drugs as perpetrator: GSK525762 did not activate the human Pregnane X receptor 
(hPXR) in an in vitro assay (EC50 >50 M). Based on in vitro studies, fulvestrant is not 
an inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.  Co-administration 
of fulvestrant with midazolam, a sensitive substrate of CYP3A4, did not demonstrate any 
effect of fulvestrant administration on CYP3A4 activity.
Revised text:
GSK525762 did not activate the human Pregnane X receptor (hPXR) in an in vitro assay 
(EC50 >50 M); although based on in vitro hepatocyte and repeat dose clinical 
pharmacokinetic data, GSK525762 has the potential to induce CYP3A4.
Based on in vitro studies, fulvestrant is not an inhibitor of CYP1A2, CYP2C9, CYP2C19, 
CYP2D6, or CYP3A4.  Co-administration of fulvestrant with midazolam, a sensitive 
substrate of CYP3A4, did not demonstrate any effect of fulvestrant administration on 
CYP3A4 activity.
Section 4.7.1.1.1
Gastrointestinal Safety Findings
Referral to the full IB
Previous text:
GSK525762: No Grade 4 gastrointestinal effects were observed.
Revised text:
No Grade 4 gastrointestinal effects were observed.  Refer to the GSK525762 IB for full 
details.
Section 4.7.1.1.3. Hematopoietic Safety Findings
Referral to the full IB
Previous text:
GSK525762: Thrombocytopenia was only noted after more than a week of continuous 
dosing, and platelet counts recovered after cessation of the drug.


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Revised text:
Thrombocytopenia was only noted after more than a week of continuous dosing, and 
platelet counts recovered after cessation of the drug.  Refer to the GSK525762 IB for 
full details.
Section 4.7.1.1.4. Reproductive Safety Findings
Referral to the full IB
Previous text:
GSK525762: Similarly, there have been no reports of pregnancy resulting from males on 
study with female partners of childbearing potential.
Revised text:
Similarly, there have been no reports of pregnancy resulting from males on study with 
female partners of childbearing potential.  Refer to the GSK525762 IB for full details.
Section 4.7.1.2.1. Cardiovascular Safety Findings
Referral to the full IB
Previous text:
GSK525762: Full analysis of cardiac safety data will be performed at the end of dose 
escalation in the BET115521 study.
Revised text:
Full analysis of cardiac safety data will be performed at the end of dose escalation in the 
BET115521 study.  Refer to the GSK525762 IB for full details.
Section 4.7.1.2.1. Cardiovascular Safety Findings
Removal of valvular toxicity wording that was erroneously left in post amendment 02.
Previous text:
Monitoring and Management: To monitor for cardiomyopathy and valvular toxicity, 
echocardiograms or multigated acquisition (MUGA) scan will be performed at the time 
points specified in the Time and Events tables (Section 7.1).
Revised text:
Monitoring and Management: To monitor for cardiomyopathy and valvular toxicity, 
echocardiograms or multigated acquisition (MUGA) scan will be performed at the time 
points specified in the Time and Events tables (Section 7.1).


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Section 5.1. Inclusion Criteria
Clarification of the wording around the target subject population and prior therapy.
Previous text:
6. History of prior therapy that satisfies one of the following criteria:
a.
AI failures: Disease that progressed during treatment or within 12 months 
of completion of adjuvant therapy with tamoxifen and/or an AI  
b. CDK4/6 inhibitor plus letrozole failures: Disease that progressed during 
treatment or within 1 month after the end of treatment with prior 
tamoxifen, AI, or the combination of a CDK4/6 inhibitor plus letrozole, 
for advanced/metastatic disease
7. Any menopausal status
Revised text:
6. History of prior therapy that satisfies one of the following criteria:
a. AI failures: Disease that progressed relapsed during treatment or within 
12 months of completion of adjuvant therapy with tamoxifen and/or an AI, 
OR disease that progressed during treatment with an AI for 
advanced/metastatic disease.  Prior ovarian suppression and/or 
tamoxifen are allowed as long as other criteria are met.
b. CDK4/6 inhibitor plus letrozole failures: Disease that progressed during 
treatment or within 1 month after the end of treatment with prior 
tamoxifen, AI, orwith the combination of a CDK4/6 inhibitor plus 
letrozole, for advanced/metastatic disease.  Prior ovarian suppression 
and/or tamoxifen are allowed as long as other criteria are met.
7. Documented progression on last line of systemic anti-cancer therapy is 
required.
8. Any menopausal status
Section 5.1. Inclusion Criteria
Clarification of the length of time approved methods of contraception need to be used.
Previous text:
13. A female subject is eligible to participate if she is of:

Non-childbearing potential defined in Section 6.10.2.1

Child-bearing potential as defined in Section 6.10.2.2, and agrees to use one 
of the contraception methods as described in Appendix 4


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Revised text:
14. A female subject is eligible to participate if she is of:

Non-childbearing potential defined in Section 6.10.2.1

Child-bearing potential as defined in Section 6.10.2.2, and agrees to use one 
of the contraception methods as described in Appendix 4, from the time of 
the screening pregnancy test until 7 months after the last dose of study 
medication.
Section 5.2. Exclusion Criteria
Clarification of the wording around the target subject population and prior therapy.
Previous text:
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis 
of advanced/metastatic disease.
Note: Prior cytotoxic therapy in the neoadjuvant/adjuvant setting does not count 
toward the one line limit
2. Disease which has progressed despite prior fulvestrant therapy.
3. ≥3 lines of systemic anti-cancer therapy (including 1 line of chemotherapy).
4. Recent prior therapy, defined as:
a.
Any investigational or approved non-biologic anti-cancer drug within 14 days
prior to the first dose of GSK525762 and fulvestrant.
b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of 
GSK525762 and fulvestrant
c.
Any anti-cancer biologic agents within 28 days prior to the first dose of 
GSK525762 and fulvestrant
d. Any radiotherapy within 30 days prior to the first dose of GSK525762 and 
fulvestrant.  If the subject received radiotherapy <90 days prior to study treatment, 
the irradiated lesion cannot be the only lesion used for evaluating response.
e.
Any major surgery within 28 days prior to the first dose of GSK525762 and 
fulvestrant
5. Concomitant active malignancy other than ER+BC
NOTE: Subjects who have been disease-free and off therapy for 2 years, or subjects with 
a history of completely resected non-melanoma skin cancer or successfully treated in situ
carcinoma are eligible.


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Revised text:
1. Prior therapy with any BET inhibitor, any selective estrogen receptor degrader 
(SERD) including fulvestrant, or inhibitors of the PI3K/AKT/mTOR pathway.
2. Prior therapy with more than one line of cytotoxic chemotherapy following diagnosis 
of advanced/metastatic disease.
Note: Prior cytotoxic therapy in the neoadjuvant/adjuvant setting does not count 
toward the one line limit
3. Disease which has progressed despite prior fulvestrant therapy.
4. ≥3 lines of systemic anti-cancer therapy (including 1 line of chemotherapy) in the 
advanced or metastatic setting.
NOTE:
a. Prior systemic anti cancer therapy (cytotoxic chemo, hormonal, CD4/6K 
inhibitor therapies) in the neoadjuvant/adjuvant setting does not count 
toward the lines of therapy.
5. Recent prior therapy, defined as:
a.
Any investigational or approved non-biologic anti-cancer drug within 14 days or 
five half-life (whichever is greater) prior to the first dose of GSK525762 and 
fulvestrant.
b. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of 
GSK525762 and fulvestrant
c.
Any anti-cancer biologic agents within 28 42 days prior to the first dose of 
GSK525762 and fulvestrant
d. Any radiotherapy within 30 days prior to the first dose of GSK525762 and 
fulvestrant.  If the subject received radiotherapy <90 days prior to study treatment, 
the irradiated lesion cannot be the only lesion used for evaluating response.
e.
Any major surgery within 28 days prior to the first dose of GSK525762 and 
fulvestrant
6. Concomitant active malignancy other than ER+BC
NOTE: Subjects who have been disease-free and off therapy for 2 years, or subjects with 
a history of treated early stage cancers such as completely resected non-melanoma skin 
cancer or successfully treated in situ carcinoma of the cervix are eligible.  Subjects with 
second malignancies that are indolent or definitively treated may be enrolled even if 
less than 25 years have elapsed since treatment. Consult Medical Monitor if unsure 
whether second malignancies meet requirements specified above
Section 5.2. Exclusion Criteria
Clarification around cardiac abnormality exclusion criteria. 
Previous text:
11. Cardiac abnormalities as evidenced by any of the following:


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
Baseline QTcF interval ≥450 msec

Clinically significant conduction abnormalities or arrhythmia

NOTE: Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.

Presence of cardiac pacemaker

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects 
with a history of stent placement requiring ongoing antithrombotic therapy (e.g., 
clopidogrel, prasugrel) will not be permitted to enroll.

Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or 
cardiomyopathy
Revised text:
11. Cardiac abnormalities as evidenced by any of the following:

Baseline QTcF interval ≥450 msec

Clinically significant conduction abnormalities or arrhythmia

NOTE: Any clinically significant ECG assessments should be reviewed by the 
site cardiologist prior to study entry.

Presence of cardiac pacemaker or defibrillator with a paced ventricular 
rhythm limiting ECG analysis.

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. Subjects 
with a history of stent placement requiring ongoing antithrombotic therapy (e.g., 
clopidogrel, prasugrel) will not be permitted to enroll.

Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or 
cardiomyopathy
Section 5.2. Exclusion Criteria
Addition of exclusion criteria around NSAID use and history of bleeding.
Previous text:
16. Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
17. History of major gastrointestinal bleeding within the last 6 months.
18. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption, such as malabsorption syndrome, chronic gastrointestinal disease, or major 
resection of the stomach and/or bowels that could preclude adequate absorption of the 
study medication.


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Revised text:
16. Hemoptysis >1 teaspoon in 24 hours within the last 28 days.
17. Concurrent use of NSAIDs (except for cases where NSAIDs provide benefit over 
other analgesics and in these cases, consideration should be given to the 
prophylactic administration of a proton pump inhibitor) and high dose aspirin 
(allowed up to 100 mg PO daily). Details are available in Section 6.11.2.1.
18. Subjects with history of known bleeding disorder(s) including clinically 
significant hemorrhage (e.g., GI, neurologic), within the past 6 months.History of 
major gastrointestinal bleeding within the last 6 months.
19. Any clinically significant gastrointestinal (GI) abnormalities that may alter 
absorption, such as malabsorption syndrome, chronic gastrointestinal disease, or 
major resection of the stomach and/or bowels that could preclude adequate absorption 
of the study medication.
Section 6.1. Investigational Product and Other Study Treatment
Clarification of what liquids GSK525762 may be taken with.
Previous text:
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.)
Administer 500 mg intramuscularly into the 
buttocks slowly (1-2 minutes per injection) 
as two 5 mL injections, one in each buttock, 
on days 1, 15, 29, and once monthly 
thereafter.
NOTE: The Phase 1 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.  Phase 2 
formulation details will be provided in an amendment.
Revised text:
Dosing 
instructions:
Dose with 240 mL water liquid* 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.)
Administer 500 mg intramuscularly into the 
buttocks slowly (1-2 minutes per injection) 
as two 5 mL injections, one in each buttock, 
on days 1, 15, 29, and once monthly 
thereafter.  There is a ±3 day dosing 
window for the fulvestrant.
NOTE: The Phase 1 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.  Phase 2 
formulation details will be provided in an amendment.
*Subjects may take BET with 240 mL of liquid (other than orange, grapefruit, pomelo, or exotic citrus 
fruit juice).  On serial PK days (W1D1 and W3D1), subjects must take BET with water only.


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Section 6.3. Planned Dose Adjustments
Addition of a dose reduction table to the Planned Dose Adjustments Section.
Previous text:
Subjects who experience toxicity may require dose delay and/or reduction of dose; for 
dose adjustment recommendations in response to toxicity, please refer to Appendix 2.
As described in Section 4.2.3.8, subjects receiving a dose below the RP2D at the end of 
Phase I may be dose escalated to a dose not to exceed the RP2D upon completion of 
Phase I.
Revised text:
Subjects who experience toxicity may require dose delay and/or reduction of dose; for 
dose adjustment recommendations in response to toxicity, please refer to Appendix 2.  
Table 3 clarifies the dose reductions for GSK525762 at any planned dose level.
As described in Section 4.2.3.8, subjects receiving a dose below the RP2D at the end of 
Phase I may be dose escalated to a dose not to exceed the RP2D upon completion of 
Phase I.
Table 3
GSK525762 Dose Reductions
Current GSK525762 Dose: 
If subject requires dose level reduction: 
40mg (DL-1)
No further dose reduction allowed
60mg (DL1)
40mg
80mg (DL2)
60mg
During any dose interruptions of GSK525762, fulvestrant may be continued at the 
protocol dose unless dose interruption of both products is required.
Section 6.10.2.2.
Female Subjects of Childbearing Potential
Clarification around the acceptable failure rate of contraception used during the study.
Previous text:
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of <1% 
[Hatcher, 2011].  
Revised text:
Female subjects of childbearing potential must not become pregnant and so must be 
sexually inactive by abstinence or use contraceptive methods with a failure rate of ≤<1% 
[Hatcher, 2011].


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Section 6.11.2.1.
Prohibited Medications
Clarification around NSAID and aspirin use during the study.
Previous text:
Subjects should not receive other anti-cancer therapy (including chemotherapy, 
immunotherapy, biologic therapy, investigational therapy, or hormonal therapy [other 
than 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 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.
Revised text:
Subjects should not receive other anti-cancer therapy (including chemotherapy, 
immunotherapy, biologic therapy, investigational therapy, or hormonal therapy [other 
than 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 greater than 100 mg per day are not 
allowed.  The use of non-steroidal anti-inflammatory drugs (NSAIDS) will be 
excluded, except for when NSAIDS will provide benefit over other analgesics, and 
then be used with caution, including concomitant use of protocol 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.
Section 6.11.2.1.
Prohibited Medications
Update to the Prohibited Meds Table.


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Previous text:
Table 3
Drugs with a Risk of Torsades de Pointes that are Prohibited
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. (Please refer to a database like crediblemeds.org for 
updates since these are dynamic lists that change based on new information which cannot be updated on a static 
table)
Revised text:
Table 34
Drugs with a Risk of Torsades de Pointes that are Prohibited
Amiodarone
Droperidol
Methadone
Anagrelide
Erythromycin
Moxifloxacin
Astemizole Azithromycin
Escitalopram
Papaverine
Chloroquine
Flecainide
Pentamidine
Bepridil Chlorpromazine
Fluconazole
Pimozide
Cilostazol
Gatifloxacin
Probucol Procainamide
Ciprofloxacin
Grepafloxacin
Propofol
Citalopram
Halofantrine
Quinidine
Cisapride Clarithromycin
Haloperidol
Roxithromycin
Cocaine
Ibogaine
Sevoflurane
Disopyramide
Ibutilide
Sotalol
Dofetilide
Levofloxacin
Sparfloxacin Sulpiride
Domperidone
Levomepromazine
Terfenadine Sultopride
Donepezil
Levomethadyl Levosulpride
Terlipressin
Dronedarone
Mesoridazine
Thioridazine
Data Source: crediblemeds.org revision date 09 Jan17 Dec 20175. (The above table is not exhaustive. Please refer 
to a database like crediblemeds.org for updates at the time of screening a subject, since these are dynamic lists that 
change based on new information which cannot be updated on a static table.)


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Section 6.11.2.3.
Cautionary Medications
Update to the Cautionary Meds Table.
Previous text:
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QT duration corrected for heart rate by Fridericia’s 
formula (QTcF), palonosetron (up to a maximum dose of 0.25 mg daily) and ondansetron 
(up to a maximum dose of 8 mg three times daily [TID]) are the only allowed drugs in 
this class. Intravenous administration is not allowed. 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):
Table 34
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution
Alfuzosin
Granisetron
Pipamperone
Apomorphine
Hydrocodone ER
Promethazine
Aripiprazole
Iloperidone
Ranolazine
Artenimole+piperaquine
Imipramine
Rilpivirine
Asenapine
Isradipine
Risperidone
Atazanavir
Lithium
Roxithromycin
Atomoxetine
Mifepristone
Saquinavir
Bedaquiline
Mirabegron
Sertindole
Clomipramine
Mirtazapine
Tacrolimus
Clozapine
Moexipril/ hydrochlorothiazide
(HCTZ)
Telavancin
Delamanid
Nicardipine
Telithromycin
Desipramine
Norfloxacin
Tetrabenazine
Dexmedetomidine
Nortriptyline
Tizanidine
Dolasetron
Ofloxacin
Tolterodine
Famotidine
Olanzapine
Toremifene
Felbamate
Oxytocin
Trimipramine
Fingolimod
Paliperidone
Tropisetron
Foscarnet
Pasireotide
Vardenafil
Gemifloxacin
Perflutren lipid microspheres
Venlafaxine
Data Source: crediblemeds.org revision date 17 Dec 2015. Please refer to a database like crediblemeds.org for 
updates since these are dynamic lists that change based on new information which cannot be updated on a static table


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Revised text:
Subjects should minimize the use of medications that 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 QT duration corrected for heart rate by Fridericia’s 
formula (QTcF), palonosetron (up to a maximum dose of 0.25 mg administered per the 
prescribing information) and ondansetron (up to a maximum dose of 8 mg three times 
daily [TID]) are the only allowed drugs in this class. Intravenous administration is not 
allowed.  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):
Table 155
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution
Alfuzosin
Granisetron Hydrocodone ER
Risperidone
Apomorphine
Iloperidone
Roxithromycin Saquinavir
Aripiprazole
Imipramine
Sertindole
Artenimole+piperaquine
Isradipine
Solifenacin
Asenapine
Leuprolide
Tacrolimus
Atazanavir Atomoxetine
Lithium
Telavancin
Bedaquiline
Melperone
Telithromycin
Buprenorphine
Mifepristone
Tetrabenazine
Clomipramine
Mirabegron
Tiapride
Clozapine
Mirtazapine
Tizanidine
Cyamemazine
Moexipril/ hydrochlorothiazide
(HCTZ)
Tolterodine
Degareliz
Nicardipine
Toremifene Trimipramine
Delamanid
Norfloxacin
Tropisetron
Desipramine
Nortriptyline
Vardenafil
Dexmedetomidine
Ofloxacin
Venlafaxine
Dolasetron Efavirenz
Olanzapine Oxytocin
Zotepine
Ezogabine
Paliperidone
Famotidine
Pasireotide
Felbamate
Perflutren lipid microspheres
Fingolimod
Perphenazine
Flupentixol
Pipamperone
Foscarnet
Promethazine
Gemifloxacin
Ranolazine Rilpivirine
Data Source: crediblemeds.org revision date 09 Jan17 Dec 20175. The above table is not exhaustive. Please refer 
to a database like crediblemeds.org for updates at the time of screening a subject, since these are dynamic lists that 
change based on new information which cannot be updated on a static table.


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Section 7.2. Screening and Critical Baseline Assessments
Update to the time window for screening assessments.
Previous text:
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Measurement(s) of target 
lesion(s) should be provided for at least two prior disease evaluations, if available.  
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.
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.
Revised text:
Screening procedures should be performed as rapidly as possible within 14 days 
prior to Day 1 (first dose of study medication) to facilitate subject entry 
requirements. In case of abnormal test values, retesting may be performed if 
medically indicated and within 14 days prior to Day 1.
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  Medical, surgical, and treatment history including date of first 
diagnosis, best response to prior systemic therapy, histology, and current sites of disease 
will be taken as part of the medical history and disease status. Measurement(s) of target 
lesion(s) should be provided for at least two prior disease evaluations, if available.  
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.


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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 14 days prior to Day 1 (first dose of study 
medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) 
and ECHO/MUGA (within 35 days prior to Day 1) in the timeframe of the study.
Section 7.2.1.
Critical Baseline Assessments
Update to the time window for screening assessments.
Previous text:
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 7. 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 magnetic resonance imaging (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.
Revised text:
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 imaging should be completed within 
30 days prior to the first dose of study drug.  Baseline characterization of 
target- and non-target lesions should be performed as described in Appendix 7. 
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 magnetic resonance imaging (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.
Section 7.2.2.
Visit Windows
Update to the visit windows.


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Previous text:
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to the first dose of study drugs. All other assessments 
(including baseline imaging) 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 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.  Assessments on 
Week 3 Day 4 may be scheduled ± 2 days.
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 2 days.  The first disease assessment 
(at Week 9) may be scheduled ± 7 days.
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.
Revised text:
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to the first dose of study drugs.  Baseline imaging should 
be completed within 30 days prior to the first dose of study drug.  All other 
assessments (including baseline imaging) 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 2: Based on subject and clinic schedule, assessments can be ± 32 days.  
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days.  Assessments on 
Week 3 Day 4 may be scheduled ± 32 days.
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 32 days.  The first disease 
assessment (at Week 9) may be scheduled ± 7 days.
Every 4-week and 8-week visits after Week 9 until Week 5249: 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 5249: 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.
Section 7.3.4.
Clinical Safety Laboratory Assessments
Update to the Clinical Laboratory Tests Table.


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Previous text:
Table 9
Clinical Laboratory Tests
Coagulation Studies:
Endocrine Studies:
Safety Screening Studies:
Prothrombin Time/INR
Thyroid-stimulating hormone (TSH)
Pregnancy test (serum at screening,
Urine or serum post dose)
Partial Thromboplastin Time
Free Thyroxine 3 (Free T3)
HIV, HbSag, HCV antibody
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Hemoglobin A1c
Amylase
FSH and estradiol (for pre- and peri-
menopausal subjects only)
Lipase
Revised text:
Table 910
Clinical Laboratory Tests
Coagulation Studies:
Endocrine Studies:
Safety Screening Studies:
Prothrombin Time/INR
Thyroid-stimulating hormone (TSH)
Pregnancy test (serum at screening,
Urine or serum post dose)
Partial Thromboplastin Time
Free Thyroxine 3 (Free T3)
HIV, HbSag, HCV antibody
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Factor VII Assay
Hemoglobin A1c
Amylase
FSH and estradiol (for pre- and peri-
menopausal subjects only)
Lipase
Section 7.3.5.1.
Time period and Frequency for collecting AE and 
SAE information
Clarification of whom needs to be notified of AEs or SAEs
Previous text:

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 10.

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.
Revised text:

All SAEs will be recorded and reported to GSK or designee within 24 hours, as 
indicated in Appendix 10.

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.


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Section 7.5.1.
Tumor Biopsy Collection/Surgical Procedures
Updated title of the section and provided guidance added around amount of dosing 
needed prior to fresh biopsy collection, and required platelet counts for subjects prior to 
fresh biopsy collection.
Previous text:
Section 7.5.1.
Tumor Biopsy Collection
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of the first dose) 
and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for 
enrollment) at each dose level. A limited number of additional subjects may be requested 
to provide pre and on-treatment biopsies based on emerging data. Biopsy requirement(s) 
will be discussed with the subject prior to signing informed consent. Any fresh 
ontreatment biopsy should be accompanied by a plasma sample collected as close as 
possible to the time of biopsy (preferably within 1 h). Further details regarding sample 
type and processing will be provided in the SRM.
Revised text:
Section 7.5.1.
Tumor Biopsy Collection/Surgical Procedures
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of the first dose) 
and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for 
enrollment) at each dose level.  Subjects providing an on-treatment fresh tumor 
biopsy must have received at least 4 consecutive doses of GSK525762 prior to the 
collection of the tissue.  A limited number of additional subjects may be requested to 
provide pre and on-treatment biopsies based on emerging data.  Biopsy requirement(s) 
will be discussed with the subject prior to signing informed consent.  Any fresh on-
treatment biopsy should be accompanied by a plasma sample collected as close as 
possible to the time of biopsy (preferably within 1 h).  
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 7.6. Evaluation of Anti-Cancer Activity
Update to the time window for screening assessments.
Previous text:
The baseline disease assessment will be completed within 14 days prior to the first dose 
of GSK525762 and fulvestrant, then approximately every 8 weeks thereafter and at the 
final study visit.  See the Time and Events Table (Section 7.1) for the schedule of 
assessments of anti-cancer activity. 


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Revised text:
The baseline disease assessment will be completed within 14 30 days prior to the first 
dose of GSK525762 and fulvestrant, then approximately every 8 weeks thereafter and at 
the final study visit.  See the Time and Events Table (Section 7.1) for the schedule of 
assessments of anti-cancer activity. 
Appendix 2
Management of Suspected Toxicity 
Table 13
Dose Adjustment/Stopping Safety Criteria
Update to the Thrombocytopenia toxicity management guidelines.
Previous text:
Table 12
Dose Adjustment/Stopping Safety Criteria
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 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, 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.
As per the fulvestrant package insert, because fulvestrant 
is administered intramuscularly, it should be used with 
caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use. 
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 u/l). 
As per the fulvestrant package insert, because fulvestrant 
is administered intramuscularly, it should be used with 
caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use.
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/ u/l (Grade 2) 
within 14 days, GSK525762 should be permanently 


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discontinued.
If platelet count recovers to ≥50,000/ u/l (Grade 2) within 
14 days, GSK525762 may be continued at the current/ 
reduced dose after discussion with the medical monitor.
Revised text:
Table 1312
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 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 lower dose level, after discussion with medical 
monitor.  If safety lab abnormalties recur at the same 
dose level following a second rechallenge, GSK525762 
should be permanently discontinued.
As per the fulvestrant package insert, because fulvestrant 
is administered intramuscularly, it should be used with 
caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use. 
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 mm3u/l). 
As per the fulvestrant package insert, because fulvestrant 
is administered intramuscularly, it should be used with 
caution in patients with bleeding diatheses, 
thrombocytopenia, or anticoagulant use.
For subjects with moderate to severe bleeding requiring 
transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/ mm3u/l
(Grade 2) within 14 days, GSK525762 should be 
permanently discontinued.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
If platelet count recovers to ≥50,000/mm3u/l (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.
Section Appendix 4:
12.4.1.
Modified List of Highly Effective 
Methods for Avoiding Pregnancy in Females of Reproductive Potential 
(FRP)
Clarification around acceptable methods of contraception, and length of time they need to 
be used.
Previous text:
1.
Intrauterine device (IUD) or intrauterine system
2.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner. 
Note: Hormonal methods of contraception 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. GSK525762 has been shown to effect 
female reproductive systems in animals, therefore women of childbearing potential 
should adhere to this contraceptive guidance whilst on study and for 7 months after 
cessation of treatment with GSK525762.
Revised text:
1.
Non-hormonal iIntrauterine device (IUD) or intrauterine system (IUS) that meets 
the ≤1% failure rate as stated in the product label
2.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
Note: Hormonal methods of contraception 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.  GSK525762 has been shown to effect 
female reproductive systems in animals, therefore women of childbearing potential 


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should adhere to this contraceptive guidance whilst on study and for 7 months after 
cessation of treatment with GSK525762.
Section 12.7.1.
Baseline Documentation of Target and Non-Target 
Lesions
Removal of baseline brain scan wording that should have been removed in amendment 
02.
Previous text:
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).
Revised text:
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).
Other Protocol Changes
Addition of Table 3 in this section, which has resulted in the change of Table 
Numbers in the following sections.
Section 12.1.
Appendix 1: Abbreviations and Trademarks
Addition of new abbreviation 
Addition of SERD (Selective Estrogen Receptor Degrader) in the abbreviations list.


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Section 7.1 Time and Events Table
Update to the T&E tables to reflect assessment changes or additions.
Previous text
Table 5
Time and Events, Phase I
Procedure
SC
R
Week 1
Week 2
Week 3
Wee
k 4
Week 5
q4w
q8w
EOT
1
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D1
W9 
and 
there
after
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 Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments6
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram 
or MUGA7
X
X
X
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
Study Treatment
Administer 
GSK5257629
Daily
Administer 
Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood 
samples10
PK
PK
O
X
Tumor biopsy11
X
One sample, collected 
between W3D1 and 
W4D1, as close as 
possible to 3-6h post-
GSK525762 dose, 
X
12
Whole blood for 
exploratory
analyses
X
X
X
PGx blood sample
X
Efficacy


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Procedure
SC
R
Week 1
Week 2
Week 3
Wee
k 4
Week 5
q4w
q8w
EOT
1
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D1
W9 
and 
there
after
W9 and 
thereaft
er
CT 
chest/abdomen/pe
lvis13
X
X
X
EORTC-QLQ-C30 
& EORTC-QLQ-
BR2314
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. 
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.
2.
Screening echocardiograms should be completed within 35 days prior to the first dose of study drugs.  All other 
assessments (including baseline imaging) should be completed within 14 days prior to first dose of study drugs. 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.  
6.
Refer to Table 7 for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.
8.
Patient Reported Outcomes Version of the Common a Terminology Criteria for Adverse Events (PRO-CTCAE) 
Item Library (Version 1.0)
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be 
considered drug dispensing days.  On PK collection days in Week 1 and Week 3, subjects should abstain from 
food from 8 h prior until 2 h after dose as described in Section 6.10.1
10. “PK” = serial PK days.  Sample collections should be obtained at the following timepoints: Pre-dose, 30 m ± 5 m, 
1 h ± 10 m, 3 h ± 30 m.  “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional 
sample 4-8h 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). Pre-dose samples will be 
split to obtain a PK sample for fulvestrant analysis. Refer to the SRM for further details.
11. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then 
fresh specimen must be provided as described in Section 7.7.2. Paired fresh biopsies must be provided pre- and 
on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for enrollment) at each dose 
level.  A limited number of additional subjects may be requested to provide pre and on-treatment biopsies based 
on emerging data. Fresh biopsies should be paired with plasma samples for PK, collected as close as possible 
to biopsy (ideally within 1 h).  Refer to the SRM for further details.  
12. A tumor biopsy at the end of treatment is optional.
13. 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 7.  EOT disease assessment is not required if reason for 
discontinuing therapy was progressive disease and prior 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.
14. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) 
Core-30 and Breast 23 measures.


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Revised text
Table 56
Time and Events, Phase I
Procedure
S
C
R
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
q8w
q8w
EO
T1
D
1
D
4
D
1
D
4
D
1
D
4
D1
D1
W9 
and 
therea
fterto 
W49
W9 
and 
therea
fterto 
W49
W49 
and 
therea
fter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion 
Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments6
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA7
X
X
X
Week 
13, 25, 
37, 49
X
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
X
Study Treatment
Administer 
GSK5257629
Daily
Administer 
Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples10
P
K
P
K
O
X
Tumor biopsy11
X
One sample, 
collected between 
W3D1 and W4D1, 
as close as 
possible to 3-6h 
post-GSK525762 
dose 
X12
Whole blood for 
exploratory 
analyses
X
X
X
PGx blood sample
X


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Procedure
S
C
R
Week 1
Week 2
Week 3
Week 
4
Week 
5
q4w
q8w
q8w
EO
T1
D
1
D
4
D
1
D
4
D
1
D
4
D1
D1
W9 
and 
therea
fterto 
W49
W9 
and 
therea
fterto 
W49
W49 
and 
therea
fter
Efficacy
CT 
chest/abdomen/pel
vis13
X
X
X
X
EORTC-QLQ-C30 
& EORTC-QLQ-
BR2314
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. 
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.
2.
Screening echocardiograms should be completed within 35 days prior to the first dose of study drugs.  All other 
assessments (including baseline imaging) should be completed within 14 days prior to first dose of study 
drugs.Screening procedures should be performed as rapidly as possible within 14 days prior to Day 1 
(first dose of study medication) to facilitate subject entry requirements. In case of abnormal test values, 
retesting may be performed if medically indicated and within 14 days prior to Day 1. 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 within 14 days prior 
to Day 1 (first dose of study medication) unless otherwise indicated: CT scans (within 30 days prior to 
Day 1) and ECHO/MUGA (within 35 days prior to Day 1). 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.  
6.
Refer to Table 7 Table 7  for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at 
W13, scans will be performed once every 12 weeks.
8.
Patient Reported Outcomes Version of the Common a Terminology Criteria for Adverse Events (PRO-CTCAE) 
Item Library (Version 1.0).  Post Week 49, assessments will be completed every 8 weeks.
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be 
considered drug dispensing days.  There is a ±3 day window for fulvestrant dosing.  On PK collection days in 
Week 1 and Week 3, subjects should abstain from food from 8 h prior until 2 h after dose as described in Section 
6.10.1.  Post Week 49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for 
further details.
10. “PK” = serial PK days.  Sample collections should be obtained at the following timepoints: Pre-dose, 30 m ± 5 m, 
1 h ± 10 m, 3 h ± 30 m.  “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional 
sample 4-8h 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). Pre-dose samples will be 
split to obtain a PK sample for fulvestrant analysis. Refer to the SRM for further details.
11. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then 
fresh specimen must be provided as described in Section 7.7.2. Paired fresh biopsies must be provided pre- and 
on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for enrollment) at each dose 
level.  Subjects providing an on-treatment fresh tumor biopsy must have received at least 4 consecutive 
doses of GSK525762 prior to the collection of the tissue.  If the post-dose biopsy is not performed during 
this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon 
visit with the medical monitor after subject recovery.  A limited number of additional subjects may be 


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requested to provide pre and on-treatment biopsies based on emerging data. Fresh biopsies should be paired 
with plasma samples for PK, collected as close as possible to biopsy (ideally within 1 h).  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.Refer to the SRM for further details.
12. A tumor biopsy at the end of treatment is optional.
13. 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 7.  EOT disease assessment is not required if reason for 
discontinuing therapy was progressive disease and prior 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.
14. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) 
Core-30 and Breast 23 measures.  Post Week 49, assessments will be completed every 8 weeks.


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Previous Text:
Table 6
Time and Events, Phase I 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
X
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
Fasting blood 
glucose
X
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
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
Follicule 
stimulating 
hormone 
(FSH)/Estradiol1
X
Pregnancy test2
X
X
X
X
X
1.
Only required at screening for pre- and peri-menopausal subjects
2.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter
Revised text


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Table 76
Time and Events, Phase I Laboratory Assessments
S
C
R
Week 1
Week 2
Week 3
We
ek 
4
We
ek 
5
We
ek 
7
q4wWee
k 9
We
ek 
11
q4w
EO
T
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
D1
W19 and 
thereaft
erD1
D1
W13 
and 
therea
fter
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematolog
y
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Troponin, 
N-terminal 
pro–B-
Type 
natriuretic 
peptide 
(NT-
proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulatio
n
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII 
Assay1
X
X
X
Fasting 
blood 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting 
lipids
X
X
X
X
X
X
X
Thyroid 
(Thyroid 
stimulating 
hormone  
(TSH), 
free 
triiodothyr
onine (T3), 
free 
thyroxine 
(T4))
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HIV, 
Hepatitis B 
surface 
antigen
(HBsAg), 
Hepatitis 
C Virus
(HCV) 
Antibody
X


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S
C
R
Week 1
Week 2
Week 3
We
ek 
4
We
ek 
5
We
ek 
7
q4wWee
k 9
We
ek 
11
q4w
EO
T
D
1
D
4
D
1
D
4
D
1
D
4
D
1
D
1
D1
W19 and 
thereaft
erD1
D1
W13 
and 
therea
fter
FSH/Estra
diol2
X
Pregnancy 
test3
X
X
X
X
X
X
X
X
X
1.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
2.
Only required at screening for pre- and peri-menopausal subjects
3.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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Previous text
Table 7
Time and Events, Phase II
Procedure
SCR
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
q4w
q8w
EOT1
D1
D4
D1
D1
D1
D1
W9 and 
thereafter
W9 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion 
Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments6
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA7
X
X
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
Study Treatment
Administer 
GSK5257629
Daily
Administer Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
PK blood samples10
O
O
X
Tumor biopsy 
(archival)11
X
X12
Whole blood for 
exploratory analyses
X
X
X
PGx blood sample
X
Efficacy
CT 
chest/abdomen/pelvis13
X
X
X
EORTC-QLQ-C30 & 
EORTC-QLQ-BR2314
X
X
X
X
X
X
X
X


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1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 
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.
2.
Screening echocardiograms should be completed within 35 days prior to the first dose of study drugs.  All other 
assessments (including baseline imaging) should be completed within 14 days prior to first dose of study drugs. 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.
6.
Refer to Table 9  for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.
8.
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
Item Library (Version 1.0)
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be 
considered drug dispensing days.  
10. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample 
for fulvestrant analysis only for subjects who are receiving fulvestrant. Refer to the SRM for further details. 
11. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then 
fresh specimen must be provided.  Refer to Section 7.2.1 and to the SRM for further details.
12. Tumor biopsy at the end of treatment is optional.
13. CT should be performed with oral and intravenous (IV) contrast.  Any potential CR or PR should be confirmed as 
described in Appendix 7.  EOT disease assessment is not required if reason for discontinuing therapy was 
progressive disease and prior 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.
14. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) 
Core-30 and Breast 23 measures. 


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Revised text
Table 78
Time and Events, Phase II
Procedure
SC
R
Week 1
Week 
2
Week 
3
Week 
4
Week 
5
q4w
q8w
q8w
EOT1
D
1
D
4
D1
D1
D1
D1
W9 
and 
there
aftert
o W49
W9 
and 
there
aftert
o W49
W49 
and 
therea
fter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion 
Criteria
X
Disease 
Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments6
X
X
X
X
X
X
X
X
X
Echocardiogram or 
MUGA7
X
X
X
Week 
13, 
25, 
37, 49
X
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
X
Study Treatment
Administer 
GSK5257629
Daily
Administer 
Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant 
medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
PK blood samples10
O
O
X
Tumor biopsy 
(archival)11
X
X12
Whole blood for 
exploratory analyses
X
X
X
PGx blood sample
X
Efficacy
CT 
chest/abdomen/pelvi
s13
X
X
X
X
EORTC-QLQ-C30 & 
EORTC-QLQ-
BR2314
X
X
X
X
X
X
X
X
X


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1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 
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.
2.
Screening echocardiograms should be completed within 35 days prior to the first dose of study drugs.  All other 
assessments (including baseline imaging) should be completed within 14 days prior to first dose of study drugs. 
Screening procedures should be performed as rapidly as possible within 14 days prior to Day 1 (first 
dose of study medication) to facilitate subject entry requirements. In case of abnormal test values, 
retesting may be performed if medically indicated and within 14 days prior to Day 1. 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 within 14 days prior 
to Day 1 (first dose of study medication) unless otherwise indicated: CT scans (within 30 days prior to 
Day 1) and ECHO/MUGA (within 35 days prior to Day 1).
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of 
dose.
6.
Refer to Table 8Table 9  for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at 
W13, scans will be performed once every 12 weeks.
8.
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
Item Library (Version 1.0). Post Week 49, assessments will be completed every 8 weeks.
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be 
considered drug dispensing days.  There is a ±3 day window for the fulvestrant dosing.  Post Week 49, 
fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.      
10. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample 
for fulvestrant analysis only for subjects who are receiving fulvestrant. Refer to the SRM for further details. 
11. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then 
fresh specimen must be provided.  Refer to Section 7.2.1 and to the SRM for further details.  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.
12. Tumor biopsy at the end of treatment is optional.
13. CT should be performed with oral and intravenous (IV) contrast.  Any potential CR or PR should be confirmed as 
described in Appendix 7.  EOT disease assessment is not required if reason for discontinuing therapy was 
progressive disease and prior 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.
14. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) 
Core-30 and Breast 23 measures.  Post Week 49, assessments will be completed every 8 weeks.   


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Previous text
Table 8
Time and Events, Phase 2 Laboratory Assessments
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
EOT
D1
D4
D1
D1
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
Liver chemistry
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
Coagulation
X
X
X
X
X
X
X
X
X
Fasting blood 
glucose
X
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
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
FSH/Estradiol1
X
Pregnancy test2
X
X
X
X
X
1.
Only required at screening for pre- and peri-menopausal subjects
2. Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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Revised Text
Table 89
Time and Events, Phase 2 Laboratory Assessments
S
C
R
Week 1
Wee
k 2
Wee
k 3
Wee
k 4
Wee
k 5
Week 7
q4w
Wee
k 9
Wee
k 11
q4w
EO
T
D
1
D
4
D
1
D
1
D
1
D
1
D1
W9 
and 
there
after
D1
D1
W13 
and 
thereaft
er
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Liver 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
X
Factor VII 
Assay1
X
X
X
Fasting blood 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
Thyroid 
(Thyroid 
stimulating 
hormone  
(TSH), free 
triiodothyronin
e (T3), free 
thyroxine (T4))
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis 
B surface 
antigen
(HBsAg), 
Hepatitis C 
Virus (HCV) 
Antibody
X
FSH/Estradiol2
X
Pregnancy 
test3
X
X
X
X
X
X
X
X
X
1.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
2.
Only required at screening for pre- and peri-menopausal subjects
3.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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12.14.4.
Amendment 04
Protocol changes for Amendment 04, from protocol changes to amendment 03 (07-
MAR-2017)
Amendment 04 summary:
Amendment 04 applies to all global study sites.
Changes to the protocol include:
Based upon review and comment on the protocol by the Agence Nationale de Sécurité du 
Médicament et des Produits de Santé (ANSM), the following changes are being 
implemented: language added to Section 6.11.2.3 around concomitant medications that 
are substrates of CYP3A4; update to the toxicity management guidelines for QTcF 
monitoring in Appendix 2, Table 13; Times and Events tables in Section 7.1, updated to 
clarify the schedule of assessments post week 49.
Additional changes to the protocol include: update to protocol authors; update to the 
primary GSK medical monitor; update to Sponsor signatory; ERS1 mutational status in 
the objectives and endpoints has been updated to exploratory, and Section 7.7 has been 
updated to reflect the translational analysis changes; removal of the time to progression 
(TTP) endpoints; update to description of Ph I enrolment during the dose escalation phase 
and the definition of study completion in Ph II; update to statistical analysis descriptions 
throughout the protocol; addition of information around the dose escalation meetings; 
Section 6.6 on the handling of GSK525762; clarification in Section 5.1, Table 2, 
regarding acceptability of both Troponin I or T; Times and Events tables in Section 7.1, 
updated to clarify ECHO/MUGA scan requirements for screening and W1D1, timing of 
on treatment biopsy collection in Ph I, lab assessment requirements, and length of 
screening window (also updated throughout the document); update to the toxicity 
management guidelines for QTcF re-challenge in Appendix 2, Table 13; removal of pre-
defined events of interest.
List of Specific Changes
Title Page
Updated protocol author list
Previous text:
 
 
Revised text:
 
PPD
PPD


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Sponsor Signatory
Updated to:
Li Yan, MD, PhD
VP, Head Unit Physician
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information
Previous Text
Role
Name
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/
Pager 
Number
Site Address and email address
Primary 
Medical 
Monitor 
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
Revised Text
Role
Name
Day Time 
Phone 
Number 
After-hours 
Phone/Cell/
Pager 
Number
Site Address and email address
Primary 
Medical 
Monitor 
 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
 
Section 1 Protocol Synopsis for Study 201973:
Objective(s)/Endpoint(s)
Rationale: The objectives/endpoints section in synopsis was modified so that evaluation 
of ESR1 mutational status was captured as an exploratory endpoint and not a secondary 
endpoint.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Phase I
Previous text:
Objectives
Endpoints
Secondary

To evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination in women 
with advanced or metastatic ER+BC

Disease control rate (DCR; defined as CR plus PR 
plus stable disease [SD] rate), duration of response, 
and progression-free survival (PFS), Time to 
progression (TTP)

To characterize the exposure  to GSK525762 and 
fulvestrant, when given in combination.

Concentrations of  GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes from 
baseline in select items from the PRO-CTCAE
Revised text:
Objectives
Endpoints
Secondary

To evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination in women 
with advanced or metastatic ER+BC

Disease control rate (DCR; defined as CR plus PR 
plus stable disease [SD] rate), duration of response, 
and progression-free survival (PFS), Time to 
progression (TTP)

To characterize the exposure to GSK525762 and 
fulvestrant, when given in combination.

Concentrations of  GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes from 
baseline in select items from the PRO-CTCAE

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response


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Objectives
Endpoints
metastatic ER+BC
Phase II
Previous Text
Objectives
Endpoints
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic ER+BC, on additional metrics of 
subject survival

Overall survival (OS),  time to progression 
(TTP)

To evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination

ORR, DCR

To characterize the exposure  to GSK525762, when 
given in combination with fulvestrant.

GSK525762 and metabolites concentrations 
following administration in combination with 
fulvestrant

To characterize the exposure to fulvestrant when 
given alone or with GSK525762

Fulvestrant concentrations following administration 
alone or in combination with GSK525762

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant exposure 
and safety and efficacy parameters

Relationship between GSK525762 and/or fulvestrant 
exposure markers (e.g. dose, Cmin, Cmax), and 
safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires
Revised text:
Objectives
Endpoints
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic ER+BC, on additional metrics of 
subject survival

Overall survival (OS),  time to progression 
(TTP)

To evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination

ORR, DCR

To characterize the exposure  to GSK525762, when 

GSK525762 and metabolites concentrations 


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Objectives
Endpoints
given in combination with fulvestrant.
following administration in combination with 
fulvestrant

To characterize the exposure to fulvestrant when 
given alone or with GSK525762

Fulvestrant concentrations following administration 
alone or in combination with GSK525762

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant exposure 
and safety and efficacy parameters

Relationship between GSK525762 and/or fulvestrant 
exposure markers (e.g. dose, Cmin, Cmax), and 
safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic ER+BC

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Overall Design
Phase I, 3rd paragraph
Rationale: The enrolment management was clarified.
Previous Text
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at the single agent RP2D.   Subjects will be enrolled into one of two possible 
cohorts, based on their prior treatment history, as defined above.  A sentinel group 
(comprising subjects enrolled in both cohorts) of at least 3 and up to 10 subjects will be 
evaluated for safety.  If the DLT rate of the DL2 sentinel group does not exceed the 
maximum permitted toxicity rate, then up to 35 subjects will be enrolled into each cohort.  
If both DL1 and DL2 are open to enrollment, then subjects will be randomized 1:1 to 
either DL1 or DL2 until one or the other dose level is filled or terminated.  All subjects 
would then be enrolled at the remaining dose level.
Each prior treatment history cohort (two per DL) may enroll up to 35 evaluable subjects 
(including subjects from the sentinel cohorts), for a total of approximately 70 subjects 
enrolled at each DL.  


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Revised text:
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at the single agent RP2D.   Subjects will be enrolled into one of two possible 
cohorts, based on their prior treatment history, as defined above.  A sentinel group 
(comprising subjects enrolled in both cohorts) of at least 3 and up to 10 subjects will be 
evaluated for safety.  During enrolment of the DL2 sentinel group, the enrolment for 
DL1 will be temporarily closed. After completing the enrolment for the sentinel 
group of DL2, the enrolment for DL1 will be re-opened and the enrolment for DL2 
will be temporarily closed while waiting for the 28 days DLT observation period to 
be completed for all subjects.
If the DLT rate of the DL2 sentinel group does not exceed the maximum permitted 
toxicity rate, then up to 35 subjects will be enrolled into each cohort.  Ifenrolment for 
DL2 will be re-opened and the enrolment for DL1 will be temporarily closed until 
DL2 enrols the same number of subjects as DL1. After that, both DL1 and DL2 
arewill be open to enrollment, thenand subjects will be randomizedassigned 1:1 to either 
DL1 or DL2 until one or the other dose level is filled or terminated.  All subjects would 
then be enrolled at the remaining dose level.
Each prior treatment history cohort (two per DL) may enroll up to 35 evaluable subjects 
(including subjects from the sentinel cohorts), for a total of approximately 70 subjects 
enrolled at each DL.
Section 1 Protocol Synopsis for Study 201973:  Analysis (2nd paragraph)
Rationale: The synopsis was updated to clarify enrollment for interim analysis.
Previous Text
The first interim analysis in each cohort will be performed once 10 evaluable subjects 
have enrolled in that cohort.  Enrollment to an individual cohort may be stopped early for 
toxicity or lack of efficacy, but cohorts will not be stopped early if the ORR meets or 
exceeds the alternate hypothesis at the interim analyses.
Revised text
The first interim analysis in each cohort will be performed once when at least 10 
evaluable subjects have enrolled in that cohort.  Enrollment to an individual cohort may 
be stopped early for toxicity or lack of efficacy, but cohorts will not be stopped early if 
the ORR meets or exceeds the alternate hypothesis at the interim analyses.
Section 3 OBJECTIVE(S) AND ENDPOINT(S)
Rationale: The objectives/endpoints section was modified so that evaluation of ESR1 
mutational status was captured as an exploratory endpoint and not a secondary endpoint.


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Phase I
Previous text:
Objectives
Endpoints
Secondary

To evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination in women 
with advanced or metastatic ER+BC

Disease control rate (DCR; defined as CR plus PR 
plus stable disease [SD] rate), duration of response, 
and progression-free survival (PFS), Time to 
progression (TTP)

To characterize the exposure  to GSK525762 and 
fulvestrant, when given in combination.

Concentrations of  GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes from 
baseline in select items from the PRO-CTCAE
Revised text:
Objectives
Endpoints
Secondary

To evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination in women 
with advanced or metastatic ER+BC

Disease control rate (DCR; defined as CR plus PR 
plus stable disease [SD] rate), duration of response, 
and progression-free survival (PFS), Time to 
progression (TTP)

To characterize the exposure  to GSK525762 and 
fulvestrant, when given in combination.

Concentrations of  GSK525762, GSK525762 
relevant metabolites and fulvestrant following 
administration in combination

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires. Changes from 
baseline in select items from the PRO-CTCAE

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response


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Objectives
Endpoints
metastatic ER+BC
Phase II
Previous Text
Objectives
Endpoints
Secondary

To evaluate the effect of treatment with GSK525762 
and fulvestrant, when given in combination in 
women with advanced or metastatic ER+BC, on 
additional metrics of subject survival

Overall survival (OS),  time to progression (TTP)

To evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination

ORR, DCR

To characterize the exposure  to GSK525762, when 
given in combination with fulvestrant.

GSK525762 and metabolites concentrations 
following administration in combination with 
fulvestrant

To characterize the exposure to fulvestrant when 
given alone or with GSK525762

Fulvestrant concentrations following administration 
alone or in combination with GSK525762

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant exposure 
and safety and efficacy parameters

Relationship between GSK525762 and/or fulvestrant 
exposure markers (e.g. dose, Cmin, Cmax), and 
safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires
Revised text:
Objectives
Endpoints
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic ER+BC, on additional metrics of 
subject survival

Overall survival (OS),  time to progression 
(TTP)

To evaluate the clinical activity of GSK525762 
and fulvestrant, when given in combination

ORR, DCR

To characterize the exposure  to GSK525762, when 
given in combination with fulvestrant.

GSK525762 and metabolites concentrations 
following administration in combination with 


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Objectives
Endpoints
fulvestrant

To characterize the exposure to fulvestrant when 
given alone or with GSK525762

Fulvestrant concentrations following administration 
alone or in combination with GSK525762

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
ER+BC

Targeted sequencing of tumor tissue to determine 
correlation between ESR1 mutations and clinical 
response
Exploratory

To evaluate the exposure response relationship 
between GSK525762 and/or fulvestrant exposure 
and safety and efficacy parameters

Relationship between GSK525762 and/or fulvestrant 
exposure markers (e.g. dose, Cmin, Cmax), and 
safety/efficacy parameters.

To evaluate the effect of GSK525762 and 
fulvestrant, when given in combination, on symptoms 
and quality of life

To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or response 
to GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic ER+BC

Change from baseline in EORTC-QLQ-C30 and 
EORTC-QLQ-BR23 questionnaires

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Section 4.1 Overall Design: Phase I
Rationale: The enrolment management was clarified.
Previous Text
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at 80 mg once daily.   Subjects will be enrolled into one of two possible 
cohorts, based on their prior treatment history, as defined above.  A sentinel group of at 
least 3 and up to 10 subjects will be evaluated for safety.  If the DLT rate of the DL2 
sentinel group does not exceed the maximum permitted toxicity rate as defined by the 
mTPI, then up to 35 subjects will be enrolled into each cohort.  If both DL1 and DL2 are 
open to enrollment, then subjects will be randomized 1:1 to either DL1 or DL2 until one 
or the other dose level is filled or terminated.  All subjects would then be enrolled at the
remaining dose level.  Refer to Section 4.2.3.2 for details of dose level and cohort 
selection.
Each cohort (two at each DL) may enroll up to 35 evaluable subjects, for a total of 
approximately 70 subjects enrolled at each DL.
Revised Text
Subjects in DL2 will begin dosing with fulvestrant at the approved dose, plus 
GSK525762 at the single agent RP2Dat 80 mg once daily.   Subjects will be enrolled 


2015N238773_06
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into one of two possible cohorts, based on their prior treatment history, as defined above.  
A sentinel group (comprising subjects enrolled in both cohorts) of at least 3 and up to 
10 subjects will be evaluated for safety.  During enrolment of the DL2 sentinel group, 
the enrolment for DL1 will be temporarily closed. After completing the enrolment 
for the sentinel group of DL2, the enrolment for DL1 will be re-opened and the 
enrolment for DL2 will be temporarily closed while waiting for the 28 days DLT 
observation period to be completed for all subjects.
If the DLT rate of the DL2 sentinel group does not exceed the maximum permitted 
toxicity rate, enrolment for DL2 will be re-opened and the enrolment for DL1 will be 
temporarily closed until DL2 enrols the same number of subjects as DL1. After that, 
both DL1 and DL2 will be open to enrollment, and subjects will be assigned 1:1 to 
either DL1 or DL2 until one or the other dose level is filled or terminated.as defined 
by the mTPI, then up to 35 subjects will be enrolled into each cohort.  If both DL1 and 
DL2 are open to enrollment, then subjects will be randomized 1:1 to either DL1 or DL2 
until one or the other dose level is filled or terminated.  All subjects would then be 
enrolled at the remaining dose level.  Refer to Section 4.2.3.2 for details of dose level and 
cohort selection.
Each cohort (two at each DL) may enroll up to 35 evaluable subjects, for a total of 
approximately 70 subjects enrolled at each DL.  
Section 4.2 Phase I
Rationale: The term evaluable was removed for alignment with the statistical analysis 
plan.
Previous Text
Each cohort (two at each DL) may enroll up to 35 evaluable subjects, for a total of 
approximately 70 subjects enrolled at each dose level.
Revised Text
Each cohort (two at each DL) may enroll up to 35 evaluable subjects, for a total of 
approximately 70 subjects enrolled at each dose level.
Section 4.2.3.2 Dose Level & Cohort Selection
Rationale: The enrolment management was clarified
Previous Text.
If DL2 is found to be safe in this sentinel group, enrollment will continue simultaneously 
into both DL1 and DL2.  Any eligible subject will be randomized 1:1 to either DL1 or 
DL2 until the cohort at either dose level is full or closed early for toxicity or lack of 
efficacy.  Once the randomization starts, the toxicity (DLT rate) will be monitored using 
Bayesian logistic regression model (BLRM).


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Revised Text
If DL2 is found to be safe in this sentinel group, enrollment will be prioritized to DL2 
until it enrols the same numbers of subjects as DL1continue simultaneously into both 
DL1 and DL2.  After that, any eligible subject will be randomized assigned 1:1 to either 
DL1 or DL2 until the cohort at either dose level is full or closed early for toxicity or lack 
of efficacy.  Once the randomization starts, the toxicity (DLT rate) will be monitored 
using Bayesian logistic regression model (BLRM).
Section 4.2.3.3 Dose Escalation & Cohort Safety Decisions, 1st
paragraph
Rationale: The Dose Escalation Plan was added per an update to GSK written standards.
Previous Text.
A data review team, consisting (at a minimum) of the investigator(s), Medical Monitors, 
safety physician, pharmacokineticist, clinical representatives, and statistician will be 
responsible for determining whether dose escalation and expansion during Phase I should 
continue as planned according to the mTPI design rules together with the predicted DLT 
rates at all DLs.  Prior to the dose escalation decision, the data review team will review 
available relevant data on all AEs including non-DLT toxicities, laboratory assessments 
and other safety evaluations, as well as any available 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).
Revised Text
A data review team, consisting (at a minimum) of the investigator(s), Medical Monitors, 
safety physician, pharmacokineticist, clinical representatives, and statistician will be 
responsible for determining whether dose escalation and expansion during Phase I should 
continue as planned according to the mTPI design rules together with the predicted DLT 
rates at all DLs.  Prior to the dose escalation decision, the data review team will review 
available relevant data on all AEs including non-DLT toxicities, laboratory assessments 
and other safety evaluations, as well as any available PK data as described in the Dose 
Escalation Plan.  Quality control of critical safety data will also be described in the 
Dose Escalation Plan, which includes ongoing study monitoring visits, Sponsor 
review of the clinical database, and confirmation by site investigators and/or 
delegate that the data is accurate and complete. The dose-escalation decision and 
rationale for each cohort will be discussed with investigators during 
teleconference(s). 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).
Section 4.2.5.1 Safety Analysis
Rationale: The term evaluable was removed for alignment with the statistical analysis 
plan.


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Previous Text
At each safety interim analysis, the number of DLTs, number of evaluable subjects, and 
the observed DLT rate will be reported for each cohort.  The mTPI decision rule will be 
used for monitoring safety until 35 evaluable subjects have been assigned at the same 
dose, at which time further enrollment will halt.
Revised Text
At each safety interim analysis, the number of DLTs, number of evaluable subjects, and 
the observed DLT rate will be reported for each cohort.  The mTPI decision rule will be 
used for monitoring safety until 35 evaluable subjects have been assigned at the same 
dose, at which time further enrollment will halt.
Section 4.2.5.2 Futility Analysis
Rationale: The term posterior was removed for alignment with the statistical analysis 
plan.
Previous Text
When at least 10 evaluable subjects are available in a cohort, the first interim data review 
on efficacy may take place for that expansion cohort.  After that, interim analysis may be 
conducted after every 5 evaluable subjects become available. For each cohort, the 
enrollment for that cohort may be stopped due to futility if the Bayesian posterior 
probability that the confirmed response rate ≥25% (target) is small (e.g., less than a 10% 
chance). For details, please see Section 9.4.
Revised Text
When at least 10 evaluable subjects are available in a cohort, the first interim data review 
on efficacy may take place for that expansion cohort.  After that, interim analysis may be 
conducted after every 5 evaluable subjects become available. For each cohort, the 
enrollment for that cohort may be stopped due to futility if the Bayesian posterior
predictive probability that the confirmed response rate ≥25% (target) is small (e.g., less 
than a 10% chance). For details, please see Section 9.4.
Section 4.3 Decision to Proceed to Phase II
Rationale: These sections were updated to clarify the determination of RP2D and 
beginning of Part II.
Previous Text
Phase I will be considered complete when a RP2D has been established.  The decision to 
proceed to Phase II will be based on totally of data including safety, efficacy, PK and PD 
data.


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At the completion of Phase I, any subjects still receiving therapy with GSK525762 and 
fulvestrant may continue receiving drug(s) until progression, death, withdrawal of 
consent, or unacceptable toxicity, as described in Section 5.4.
Revised Text
Phase I will be considered complete when a RP2D has been established.  The decision to 
proceed to Phase II will be based on totally totality of data including safety, efficacy, PK 
and PD data.
At the completion of Phase IAfter RP2D is established, any subjects still receiving 
therapy with GSK525762 and fulvestrant may continue receiving drug(s) until 
progression, death, withdrawal of consent, or unacceptable toxicity, as described in 
Section 5.4.
Section 4.5.1 Phase I, 3rd paragraph
Rationale: These sections were updated for alignment with the statistical analysis plan.
Previous Text
Dose escalation/de-escalation decisions will be based primarily on the mTPI design [Ji, 
2010], a well-validated method for identifying the MTD of oncology therapeutics.  To 
facilitate dose escalation/de-escalation decisions, a Bayesian logistic regression model 
(BLRM) may be utilized to predict the probability of DLT at the DLs yet to be tested. 
Specifically, a 4 parameter BLRM for combination treatment will be fitted on the dose 
limiting toxicity data (i.e., absence or presence of DLT) accumulated throughout the 
dose-escalation to model the dose-toxicity relationship of GSK525762 and fulvestrant 
when given in combination [Gasparini, 2009]. This model will take into account all 
available data at all dose levels. Dose re-escalation after a de-escalation step may be 
permitted based on the results of the model and of the mTPI decision rules.
Revised Text
Dose escalation/de-escalation decisions will be based primarily on the mTPI design [Ji, 
2010], a well-validated method for identifying the MTD of oncology therapeutics.  To 
facilitate dose escalation/de-escalation decisions, a Bayesian logistic regression model 
(BLRM) may be utilized to predict the probability of DLT at the DLs yet to be tested. 
Specifically, a 4 parameter BLRM for combination treatment will be fitted on the dose 
limiting toxicity data (i.e., absence or presence of DLT) accumulated throughout the 
dose-escalation to model the dose-toxicity relationship of GSK525762 and fulvestrant 
when given in combination [Gasparini, 2009]. This model will take into account all 
available data at all dose levels. Dose re-escalation after a de-escalation step may be 
permitted based on the results of the model and of the mTPI decision rules.
Section 5.1 Inclusion Criteria
Table 2 Definitions for Adequate Organ Function


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Rationale: Either troponin I or T may be used for determination of troponin levels.
Previous Text
Cardiac
Ejection fraction
≥ LLN by echocardiogram or MUGA scan
Troponin (T)
ULN 
Revised Text
Cardiac
Ejection fraction
≥ LLN by echocardiogram or MUGA scan
Troponin (I or T)
ULN 
Section 5.4 Withdrawal/Stopping Criteria, 11th paragraph
Rationale: The study completion criteria were modified for clarity.
Previous Text
In Phase II, unless a disease cohort 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, the cohort will be closed and any further follow-up on subjects 
enrolled in that cohort will cease.  
Revised Text
In Phase II, unless a disease cohort 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, the study will be considered completed the cohort will be closed
and any further follow-up on subjects enrolled in that cohort will cease.  
Section 5.5 Subject and Study Completion, 2nd paragraph
Rationale: The study completion criteria were modified for clarity.
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 electronic Case Record Form (eCRF) 
should only be completed when a subject is no longer being followed.  Phase 1 of the 
study can be considered completed for purpose of a final Part 1 analysis if 70% of the 
subjects have progressed or died.  The study will be considered completed for purposes 
of a final analysis when approximately 70% of subjects enrolled in Phase II have 
progressed or died.


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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 electronic Case Record Form (eCRF) 
should only be completed when a subject is no longer being followed.  Phase 1 of the 
study can be considered completed for purpose of a final Part 1 analysis if 70% of the 
subjects have progressed or died.  The study will be considered completed for purposes 
of final analysis when approximately 70% of the subjects enrolled in Phase II have 
died. However, the study could be stopped due to toxicity or futility before that 
when there is enough evidence to conclude as such.for purposes of a final analysis 
when approximately 70% of subjects enrolled in Phase II have progressed or died.
Section 6.2.1 Phase I, 4th paragraph
Rationale: The enrolment management guidelines were modified for clarity.
Previous Text
Once DL2 has been cleared in dose escalation, subjects will be enrolled into the prior 
treatment-specific cohorts at either DL1 or DL2 provided that:

There are remaining slots in the cohort

Either cohort has not closed due to unacceptable toxicity or lack of efficacy
Revised Text
Once DL2 has been cleared in dose escalation, enrolment will be prioritized to DL2 
until it enrols the same number of subjects as DL1. After that subjects will be 
enrolled into the prior treatment-specific cohorts at either DL1 or DL2 provided that:

There are remaining slots in the cohort

Either cohort has not closed due to unacceptable toxicity or lack of efficacy
Section 6.6 Preparation/Handling/Storage/Accountability, 2nd
paragpraph
Rationale: The additional precautions for drug handling were included for safety.
Previous Text

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 
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.


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Revised Text

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 
Limited exposure and precautionary action (example: wearing gloves, washing 
hands post exposure, etc.) should be taken by site staff dispensing GSK525762 
tablets.
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 6.11.2.3 Cautionary Medications, 6th paragraph, new text added
Rationale: Information was added pertaining to concomitant medications that are 
substrates of CYP3A4.
Previous Text
GSK525762 in as 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.
Revised Text
GSK525762 in as inhibitor of organic anion transporter 1A1 (OAT1) and organic anion 
transporter 3 (OAT3) in vitro.  Substrates of these transporters include agents such as 
methotrexate, penicillin G, and indomethacin. While co-administration of these agents 
with GSK525762 is not prohibited, they should be used with caution, and additional 
monitoring for adverse effects should be utilized.
GSK525762 is 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.
Questions regarding concomitant medications should be directed to the Medical Monitor 
for clarification.
Section 7.2 Screening and Critical Baseline Assessments


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Rationale: Clinical baseline assessments were modified to better accommodate screening 
patients for eligibility criteria.
Previous Text
Screening procedures should be performed as rapidly as possible within 14 days prior to 
Day 1 (first dose of study medication) to facilitate subject entry requirements. In case of 
abnormal test values, retesting may be performed if medically indicated and within 14 
days prior to Day 1.
Revised Text
Screening procedures should be performed as rapidly as possible within 14 28 days prior 
to Day 1 (first dose of study medication) to facilitate subject entry requirements. Clinical 
lab assessments should be completed within 14 days prior to dosing and iIn case of 
abnormal test values, retesting may be performed if medically indicated and within 14 
days prior to Day 1.
Section 7.2 Screening and Critical Baseline Assessments
Rationale: Clinical baseline assessments were modified to better accommodate screening 
patients for eligibility criteria.
Previous Text
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 14 days prior to Day 1 (first dose of study 
medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and 
ECHO/MUGA (within 35 days prior to Day 1).
Revised Text
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 2814 days prior to Day 1 (first dose of study 
medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and 
ECHO/MUGA (within 35 days prior to Day 1).
Section 7.2.1 Critical Baseline Assessments
Rationale: Clinical baseline assessments were modified to better accommodate screening 
patients for eligibility criteria.
Previous Text

Phase I:


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o
All subjects must provide a biopsy sample at screening.  Archival tissue is 
permitted; however, if no archival tissue is available then a fresh biopsy 
specimen must be provided.
o At least 6 subjects at each dose level will be required to provide paired 
fresh biopsies pre- and post-dose at the time points indicated in 
Section 7.1, as described in Section 7.5.1.  Fresh biopsies should be paired
with plasma samples for PK, collected as close as possible to the biopsy 
(ideally within 1 h).  Subjects will be informed at the time of informed 
consent whether paired fresh biopsies will be required.  Further details 
regarding sample type and processing will be provided in the SRM.
Revised Text

Phase I:
o
All subjects must provide a biopsy sample at screening.  Archival tissue is 
permitted; however, if no archival tissue is available then a fresh biopsy 
specimen must be provided within 14 days prior to first study dose.
o At least 6 subjects at each dose level will be required to provide paired 
fresh biopsies pre- and post-dose at the time points indicated in 
Section 7.1, as described in Section 7.5.1.  Fresh biopsies should be paired 
with plasma samples for PK, collected as close as possible to the biopsy 
(ideally within 1 h).  Subjects should have at least four consecutive 
doses of GSK525762 prior to collection of tumor biopsy, whether they 
have had a dose interruption or not.  Subjects will be informed at the 
time of informed consent whether paired fresh biopsies will be required.  
Further details regarding sample type and processing will be provided in 
the SRM.
Section 7.2.2 Visit Windows
Rationale: The visit windows were updated to better accommodate visit assessments.
Previous Text
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to the first dose of study drugs.  Baseline imaging should 
be completed within 30 days prior to the first dose of study drug.  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.
Revised Text
Screening (baseline to pre-dose): Screening echocardiogram or MUGA scan should be 
completed within 35 days prior to the first dose of study drugs.  Baseline imaging should 
be completed within 30 days prior to the first dose of study drug.  Clinical lab 


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assessments should 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.  All other assessments should be 
completed with 28 days prior to first dose of study drug.
Section 7.2.2 Visit Windows
Rationale: The visit windows were updated to better accommodate visit assessments.
Previous Text
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 3 days.  The first disease assessment 
(at Week 9) 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 5 days.
Every 4-week and 8-week visits after Week 49: 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.
Revised Text
Weeks 4, 5, and 9: Clinic visits may be scheduled ± 3 days.  The first disease assessment 
(at Week 9) may be scheduled ± 7 days.
Weeks 6, 7, 8, and 11: Lab visits may be scheduled ± 3 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 5 days.
Every 4-week, and 8-week, and 12-week visits after Week 49: Every 4-week visits (and 
their associated laboratory studies) are no longer required, based on clinical judgment.  
Every 8-week and 12-week clinic visits can be scheduled 7 days.
Section 7.3.4 Clinical Safety Laboratory Assessments
Table 10 Clinical Laboratory Tests
Rationale: The laboratory assessments were clarified for BUN values and bilirubin 
assessments.


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Previous Text
Clinical Chemistry
Sodium
Fasting Glucose
Potassium
Magnesium 
Chloride
Calcium (total and ionized)
Total Carbon Dioxide
Total Protein
Blood Urea Nitrogen
Albumin
Creatinine
Liver Function
Bilirubin (Total and Direct)
Aspartate Aminotransferase
Alanine Aminotransferase
Alkaline Phosphatase
Cardiac Studies
Troponin (I or T at local laboratory)
NT-proBNP
Fasting Lipid panel (Total Cholesterol, LDL, HDL, triglycerides)
Note: Not all studies are performed at each visit; please refer to Section 7.1, Table 7 and Table 9 for timing of required 
studies
Revised Text
Clinical Chemistry
Sodium
Fasting Glucose
Potassium
Magnesium 
Chloride
Calcium (total and ionized)
Total Carbon Dioxide
Total Protein
Blood Urea Nitrogen*
Albumin
Creatinine
Liver Function
Bilirubin (Total and Direct)**
Aspartate Aminotransferase
Alanine Aminotransferase
Alkaline Phosphatase
Cardiac Studies
Troponin (I or T at local laboratory)
NT-proBNP
Fasting Lipid panel (Total Cholesterol, LDL, HDL, triglycerides)
*Direct and/or calculated BUN values are acceptable.
**Direct Bilirubin is only required if total bilirubin values are abnormal.
Note: Not all studies are performed at each visit; please refer to Section 7.1, Table 7 and Table 9 for timing of required 
studies
Section 7.3.5.3 Follow-up of AEs and SAEs
Rationale: All AEs are followed until resolution.
Previous Text
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 


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(as defined in Appendix 10) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 10.
Revised Text
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 10) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Appendix 10.
Section 7.5.1 Tumor Biopsy Collection/Surgical Procedures
Rationale: Clarification was added to the collection of biopsies
Previous Text
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of the first dose) 
and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for 
enrollment) at each dose level.
Revised Text
In Phase I, paired fresh biopsies must be provided pre- (within 14 days of prior to the 
first dose) and on-treatment at the time points indicated for at least 6 subjects (out of 35 
planned for enrollment) at each dose level.
Section 7.7.1 Tumor Biomarker Analysis
Rationale: The methods performed for exploratory analysis were updated and clarified.
Previous Text
Evaluation of ESR1 mutation status will be performed, using a pre-treatment biopsy 
sample (archival tissue or a recent biopsy) on all tumors. 
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 
fulvestrant in combination utilizing baseline tissue (archival tissue or a recent biopsy) and 
tissue obtained at disease progression (if sample is available).
Revised Text
Evaluation of ESR1 mutation status will be performed, using a pre-treatment biopsy 
sample (archival tissue or a recent biopsy) on all tumors. 


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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 
fulvestrant in combination utilizing baseline tissue (archival tissue or a recent biopsy) and 
tissue obtained at disease progression (if sample is available).
Section 7.7.3 Circulating cell free DNA/RNA Analysis (New subsection 
added)
Rationale: The methods performed for exploratory analysis were updated and clarified.
Revised Text
Plasma isolated from blood collected at screening will be used to evaluate 
ESR1mutation status in circulating cell-free deoxyribonucleic (cfDNA) and/or RNA.
To further characterize the subject population, cfDNA and/or RNA measurements 
may be utilized to identify predictors of sensitivity or resistance to GSK525762 and 
fulvestrant in combination utilizing plasma isolated from blood at screening, on 
treatment and/or end of treatment.
Section 9.1.2 Phase I Efficacy
Rationale: The statistical methodology and terminology for efficacy analysis was 
corrected and clarified.
Previous Text
Phase I portion of the study will employ a Bayesian predictive adaptive design [Lee, 
2008] that allows the trial to be monitored more frequently at multiple stages. The criteria 
will be based on a historically unimportant ORR of 10% versus an ORR of interest of 
25%.  Bayesian statistics will be employed to calculate the posterior probability that the 
RR ≥25% and ≥10% at interim assuming a Beta prior for the Binomial distributed data.  
Predictive probability calculates the probability that the RR ≥25% or ≥10% given the 
responses have already been observed.
Revised Text
Phase I portion of the study will employ a Bayesian predictive adaptive design [Lee, 
2008] that allows the trial to be monitored more frequently at multiple stages. The criteria 
will be based on a historically unimportant ORR of 10% versus an ORR of interest of 
25%.  Bayesian statistics will be employed to calculate the posterior predictive
probability that the RR ≥25% and ≥10% at interim assuming a Beta prior for the 
Binomial distributed data.  Predictive probability calculates the probability that the RR 
≥25% or ≥10% given the responses have already been observed.
Section 9.1.2 Phase I Efficacy
Rationale: The term posterior was removed for alignment with the statistical analysis 
plan and other corrections noted.


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Previous Text
For the separate interim looks in each cohort, the enrollment for that cohort may be 
stopped due to futility if the posterior probability that the confirmed RR ≥25% is small 
(e.g., less than a 4% chance for a total sample size of 35 subjects).  Enrollment may also 
be stopped due to futility if the equivalent of no response is observed in the first 10 
enrolled evaluable subjects in that cohort or less than 1 confirmed responses are observed 
in the first 14 evaluable subjects.  The evaluable subject is defined as a subject, who has 
either progressed, withdrew from the study, was lost to follow-up, or is ongoing and has 
completed at least one post treatment disease assessment.  For example, when there are 
14 evaluable subjects available at the time of interim analysis with only one response, 
then the cohort may be stop for futility.  Otherwise, the enrollment of the respective 
cohort will continue to the target sample size. 
Revised Text
For the separate interim looks in each cohort, the enrollment for that cohort may be 
stopped due to futility if the posterior predictive probability that the confirmed RR ≥25% 
is small (e.g., less than a 4% chance for a total sample size of 35 subjects).  Enrollment 
may also be stopped due to futility if the equivalent of no response is observed in the first 
10 enrolled evaluable subjects in that cohort or less than 1 confirmed responses are 
observed in the first 14 evaluable subjects.  The evaluable subject is defined as a subject, 
who has either progressed or died, withdrew from the study treatment, was lost to 
follow-up, or is ongoing and has completed at least one two post treatment disease 
assessments.  For example, when there are 14 evaluable subjects available at the time of 
interim analysis with only one response, then the cohort may be stop for futility.  
Otherwise, the enrollment of the respective cohort will continue to the target sample size. 
Section 9.3.1 Analysis Populations
Rationale: The definition of evaluable subjects was updated.
Previous Text
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 and have been on study for at least 49 days or have progressed or 
died or permanently withdraw from the study will be included in this population.  
Revised Text
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 and have been on study for at least 49 days or have progressed or 
died or permanently withdraw from the study treatment will be included in this 
population.  
Section 9.3.2.1.1 Dose Escalation and Safety Analyses


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Rationale: The statistical methodology for mTPI was described elsewhere in the 
protocol.
Previous Text
Once 3-10 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/expansion decisions in Phase I will be safety and 
tolerability of each dose cohort.
To facilitate dose escalation/de-escalation decisions, a Bayesian logistic regression model 
(BLRM) may be utilized to predict the probability of DLT at the dose levels yet to be 
tested.  Specifically, a 4-parameter BLRM for combination treatment will be fitted on the 
dose limiting toxicity data (i.e., absence or presence of DLT) accumulated throughout the 
dose-escalation to model the dose-toxicity relationship of GSK525762 and fulvestrant 
when given in combination. Prior distributions of two parameters for GSK525762 will be 
calculated based on the toxicity data observed in the FTIH study where GSK525762 is 
administered alone; similarly, prior distributions of two parameters for fulvestrant will be 
determined based on data observed in the FTIH study where fulvestrant is administered 
alone; a non-informative prior will be assumed for the parameter which accounts for the 
combination of two compounds. Further details regarding such analyses will be provided 
in the RAP.
Revised Text
Once 3-10 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/expansion decisions in Phase I will be safety and 
tolerability of each dose cohort.
To facilitate dose escalation/de-escalation decisions, a Bayesian logistic regression model 
(BLRM) may be utilized to predict the probability of DLT at the dose levels yet to be 
tested.  Specifically, a 4-parameter BLRM for combination treatment will be fitted on the 
dose limiting toxicity data (i.e., absence or presence of DLT) accumulated throughout the 
dose-escalation to model the dose-toxicity relationship of GSK525762 and fulvestrant 
when given in combination. Prior distributions of two parameters for GSK525762 will be 
calculated based on the toxicity data observed in the FTIH study where GSK525762 is 
administered alone; similarly, prior distributions of two parameters for fulvestrant will be 
determined based on data observed in the FTIH study where fulvestrant is administered 
alone; a non-informative prior will be assumed for the parameter which accounts for the 
combination of two compounds. Further details regarding such analyses will be provided 
in the RAP.
Section 9.3.2.1.2 Efficacy Analyses
Rationale: The statistical methodology and terminology for efficacy analyses was 
corrected and clarified.


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Previous Text
Interim analyses during expansion cohorts
Interim data will be evaluated to monitor efficacy and safety, and a planned interim 
analysis will be performed when 10 evaluable subjects have been enrolled into each of 
the expansion cohorts at each 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 
Hierarchical model are described below. The decision will be made for each individual 
prior treatment history-specific cohort. 
The study population used for decision-making at the interim analyses on efficacy will be 
termed All Evaluable Subjects.  This will be the population for Bayesian model and 
summaries of response if data warrant.  Because subjects enroll at different times, not all 
subjects will have been on the study long enough to have single or multiple disease 
assessments.  Since disease assessments are to be completed every 8 weeks, subjects who 
have at least two post-baseline radiological disease assessments and have been on study 
for at least 49 days or have progressed or died or permanently withdraw from the study 
will be included in this population.  Interim analysis on safety will be conducted on all 
treated subjects. 
Revised Text
Interim analyses during expansion cohorts
Interim data will be evaluated to monitor efficacy and safety, and a planned interim 
analysis will be performed when at least 10 evaluable subjects have been enrolled into 
each of the expansion cohorts at each 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 
Hierarchical model are described below. The decision will be made for each individual 
prior treatment history-specific cohort. 
The study population used for decision-making at the interim analyses on efficacy will be 
termed All Evaluable Subjects.  This will be the population for Bayesian model and 
summaries of response if data warrant.  Because subjects enroll at different times, not all 
subjects will have been on the study long enough to have single or multiple disease 
assessments.  Since disease assessments are to be completed every 8 weeks, subjects who 
have at least two post-baseline radiological disease assessments and have been on study 
for at least 49 days or have progressed or died or permanently withdraw from the study 
treatment will be included in this population.  Interim analysis on safety will be 
conducted on all treated subjects. 
Section 9.4.8.1 Phase I
Rationale: The term posterior was removed for alignment with the statistical analysis 
plan.


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Previous Text
The observed confirmed and unconfirmed ORR will be reported at the interim and final 
analysis for each cohort specified in Phase 1 treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided. Bayesian inference 
based on summary statistics from the posterior distributions of each ORR will be reported 
at interim and final analyses. The posterior mean and posterior 2.5% and 97.5% 
percentiles of the ORR will be calculated for each cohort. In addition, the posterior 
probability that the ORR exceeds its corresponding historical control will be reported for 
each cohort.
Revised Text
The observed confirmed and unconfirmed ORR will be reported at the interim and final 
analysis for each cohort specified in Phase 1 treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided. Bayesian inference 
based on summary statistics from the posterior distributions of each ORR will be reported 
at interim and final analyses. The posterior mean and posterior 2.5% and 97.5% 
percentiles of the ORR will be calculated for each cohort. In addition, the posterior 
predictive probability that the ORR exceeds its corresponding historical control will be 
reported for each cohort.
Section 9.4.10.6 Mean Proportion of advancing to Phase 2
Rationale: The statistical methodology and terminology for safety and efficacy analyses 
were corrected and/or clarified.
Previous Text
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 Phase 1. In the scenario where both DLs are safe and positive, there is a 92.4% 
chance that at least one dose will be picked for Phase 2. 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 for Phase 
II. 
Revised Text
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 Phase 1. In the scenario where both DLs are safe and positive, there is a 92.4% 
chance that at least one dose will be picked for Phase 2. 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 for Phase 
II. 


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Section 10.3 Quality Control (Study Monitoring)
Rationale: The text was clarified as PAREXEL monitors will perform the monitoring 
visits.
Previous Text

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  
Revised Text

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  
Section 12.2 Appendix 2: Management of Suspected Toxicity Table 13 
Dose Adjustment/Stopping Safety Criteria
Rationale: The cardiac management guidelines were updated in response to the Agence 
Nationale de Sécurité du Médicament et des Produits de Santé (ANSM).
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.
If 60 msec change 
from baseline occurs
OR
QTcF 500 
(average of three ECGs 
over at least 15 
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.


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
minutes)
This subject may consider restarting study treatment at a 
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

Elevated bilirubin, 
hypoalbuminemia, 
prolonged PT, 
ascites, and/or 
encephalopathy
Refer to Appendix 13 for definition of Child-Pugh score

Child-Pugh Class A: No change to fulvestrant dose 
required

Child-Pugh Class B: Reduce dose of fulvestrant to 
250 mg, administered as per the standard schedule.  
Fulvestrant dose may be re-escalated to 500 mg once 
liver function improves.

Child-Pugh Class C: Hold fulvestrant until liver 
function has improved
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 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use 
NCI-CTCAE v4.0 
[NCI, 2009] 
grading system) 

Fasting blood 
glucose >150 mg/dL 
to 250 mg/dL (Mild 
hyperglycemia)

Monitor fasting and preprandial glucose.

If persistant 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.
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.
Revised Text


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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:
c. Maintain serum potassium > 4mol/L
d. Maintain serum magnesium levels >0.85 mmol/L

Discontinue any concomitant medications with 
potential for QTcF prolongation.

Consider 24 hour or longer telemetry monitoring if 
clinically indicated.
If 60 msec change from 
baseline occurs
OR
QTcF 500 
(average of three ECGs over 
at least 15 minutes)
Discontinue GSK525762 and notify the Medical Monitor. 

Evaluation by cardiologist

Supplement electrolytes to recommended levels:
c. Maintain serum potassium > 4mol/L
d. 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 a 
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
(5)
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 


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Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelines
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
Section 12.7.1 Baseline Documentation of Target and Non-Target 
Lesions
Rationale: The baseline assessment was modified to accommodate patient visit 
schedules.
Previous Text

All baseline lesion assessments 
must be performed within 14 days of randomization.
Revised Text

All baseline lesion assessments 
must be performed within 14 28 days of randomization.
Section 12.10.2 Definition of Serious Adverse Events
Rationale: The terminology “events of special interest” was removed to clarify that all 
SAEs are followed until resolution.
Previous Text
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.
h.
Protocol-specific SAEs (events of special interest):
LVEF decreases (Section 5.4.3) meeting stopping criteria


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Liver chemistry abnormalities meeting stopping criteria (Section 5.4.1)
QTcF prolongation meeting stopping criteria (Section 5.4.2)
New primary cancers

Refer to Appendix 8 for the required liver chemistry follow-up instructions
Revised Text
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.
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

Refer to Appendix 8 for the required liver chemistry follow-up instructions


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Section 7
Rationale: The Times and Events tables in Section 7.1 was updated to clarify ECHO/MUGA scan requirements for screening and W1D1, 
timing of on treatment biopsy collection in Ph I, lab assessment requirements, and length of screening window (also updated throughout 
the document).
Table 16
Time and Events, Phase I
Previous Text
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
EOT1
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 Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs (Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments6
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA7
X
X
X
Week 13, 
25, 37, 49
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK5257629
Daily
Administer Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication review
Continuous from signing of informed consent


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Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples10
PK
PK
O
X
Tumor biopsy11
X
One sample, collected 
between W3D1 and W4D1, as 
close as possible to 3-6h post-
GSK525762 dose 
X12
Whole blood for exploratory 
analyses
X
X
X
PGx blood sample
X
Efficacy
CT chest/abdomen/pelvis13
X
X
X
X
EORTC-QLQ-C30 & EORTC-
QLQ-BR2314
X
X
X
X
X
X
X
X
X


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1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 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.
2.
Screening procedures should be performed as rapidly as possible within 14 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements. In case of abnormal test 
values, retesting may be performed if medically indicated and within 14 days prior to Day 1. 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 within 14 days prior to Day 1 (first dose of study medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1). 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of dose.  
6.
Refer to Table 7  for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at W13, scans will be performed once every 12 weeks.
8.
Patient Reported Outcomes Version of the Common a Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0).  Post Week 49, assessments will be completed every 8 
weeks.
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for fulvestrant dosing.  
On PK collection days in Week 1 and Week 3, subjects should abstain from food from 8 h prior until 2 h after dose as described in Section 6.10.1.  Post Week 49, fulvestrant will continue to be 
administered every 4 weeks.  Refer to the SRM for further details.
10.
“PK” = serial PK days.  Sample collections should be obtained at the following timepoints: Pre-dose, 30 m ± 5 m, 1 h ± 10 m, 3 h ± 30 m.  “O” = sample collections to be obtained pre-dose, 0.5-
1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample for fulvestrant analysis. Refer to the SRM for further details.
11.
Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then fresh specimen must be provided as described in Section 7.7.2. Paired fresh 
biopsies must be provided pre- and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for enrollment) at each dose level.  Subjects providing an on-treatment fresh 
tumor biopsy must have received at least 4 consecutive doses of GSK525762 prior to the collection of the tissue.  If the post-dose biopsy is not performed during this timeframe due to lab 
abnormalities or subject status, it should be performed at the next agreed upon visit with the medical monitor after subject recovery.  A limited number of additional subjects may be requested to 
provide pre and on-treatment biopsies based on emerging data. Fresh biopsies should be paired with plasma samples for PK, collected as close as possible to biopsy (ideally within 1 h).  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.Refer to the SRM for 
further details.
12.
A tumor biopsy at the end of treatment is optional.
13.
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 7.  EOT disease assessment 
is not required if reason for discontinuing therapy was progressive disease and prior 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.
14.
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures.  Post Week 49, assessments will be completed 
every 8 weeks.


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Revised Text
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
X
ECOG PS5
X
X
X
X
X
X
X
X
X
12-lead ECGs (Triplicate)65
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments76
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA87
X
X
X
Week 13, 
25, 37, 49
X
X
PRO-CTCAE98
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK525762109
Daily
Administer Fulvestrant109
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication 
review
Continuous from signing of informed consent


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples1110
PK
PK
O
X
Tumor biopsy1211
X
One sample, collected 
between W3D41 and 
W54D1, as close as possible 
to 3-6h post-GSK525762 
dose 
X1312
Whole blood for exploratory 
analyses
X
X
X
PGx blood sample
X
Efficacy
CT chest/abdomen/pelvis1413
X
X
X
X
EORTC-QLQ-C30 & 
EORTC-QLQ-BR231514
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. 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.
2.
Screening procedures should be performed as rapidly as possible within 28 days 14 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements. Clinical lab 
assessments should be completed within 14 days prior to dosing, and iIn case of abnormal test values, retesting may be performed if medically indicated and within 14 days prior to Day 1.
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 within 14 28 days prior to Day 1 (first dose of study medication) unless otherwise indicated: 
CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1). 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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. Post Week 49, assessments will be completed every 12 weeks.
5.
Post Week 49, ECOG assessments will be completed every 12 weeks.
6.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of dose. Post Week 49, assessments will be completed every 12 weeks.
7.
Refer to Table 7  for details of clinical safety labs and timing of collection
8.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at W13, scans will be performed once every 12 weeks.
9.
Patient Reported Outcomes Version of the Common a Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0).  Post Week 49, assessments will be completed every 8 
weeks.
10. Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for fulvestrant dosing.  On 
PK collection days in Week 1 and Week 3, subjects should abstain from food from 8 h prior until 2 h after dose as described in Section 6.10.1.  Post Week 49, fulvestrant will continue to be 
administered every 4 weeks.  Refer to the SRM for further details.


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11. “PK” = serial PK days.  Sample collections should be obtained at the following timepoints: Pre-dose, 30 m ± 5 m, 1 h ± 10 m, 3 h ± 30 m.  “O” = sample collections to be obtained pre-dose, 0.5-1h 
post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample for fulvestrant analysis. Refer to the SRM for further details.
12. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then fresh specimen must be provided within 14 days prior to first study dose as described 
in Section 7.7.2. Paired fresh biopsies must be provided pre- and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for enrollment) at each dose level.  Subjects 
providing an on-treatment fresh tumor biopsy, whether they have had a dose interruption of GSK525762 or not, must have received at least 4 consecutive doses of GSK525762 prior to the 
collection of the tissue.  If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the medical 
monitor after subject recovery.  A limited number of additional subjects may be requested to provide pre and on-treatment biopsies based on emerging data. Fresh biopsies should be paired with 
plasma samples for PK, collected as close as possible to biopsy (ideally within 1 h).  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.Refer to the SRM for further details.
13. A tumor biopsy at the end of treatment is optional, but strongly encouraged when clinically feasible.
14. 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 7.  EOT disease assessment is 
not required if reason for discontinuing therapy was progressive disease and prior assessment was within 14 days of EOT visit. Subjects with contraindication to contrast-enhanced computed 
tomography (CT) or MRI may have other imaging performed as described in Section 7.2.1.
15. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures.  Post Week 49, assessments will be completed 
every 8 weeks.
Section 7 Table 7
Time and Events, Phase I Laboratory Assessments
Previous Text


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SCR
Week 1
Week 2
Week 3
Week 4
Week 5
Week 7
Week 9
Week 11
q4w
EOT
D1
D4
D1
D4
D1
D4
D1
D1
D1
D1
D1
W13 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Troponin, N-terminal 
pro–B-Type natriuretic 
peptide (NT- proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay1
X
X
X
Fasting blood glucose
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
Thyroid (Thyroid 
stimulating hormone  
(TSH), free 
triiodothyronine (T3), 
free thyroxine (T4))
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B 
surface antigen 
(HBsAg), Hepatitis C 
Virus (HCV) Antibody
X
FSH/Estradiol2
X
Pregnancy test3
X
X
X
X
X
X
X
X
X
1.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
2.
Only required at screening for pre- and peri-menopausal subjects
3.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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Revised Text
SCR1
Week 1
Week 2
Week 3
Week 
4
Week 
5
Week 
6
Week 
7
Week 8
Week 9
Week 
11
q4w
Q12w
EOT
D1
D4
D1
D4
D1
D4
D1
D1
D1
D1
D1
D1
D1
W13 and 
thereafter
W49 and 
thereafter
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII 
Assay21
X
X
X
Fasting blood 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Thyroid 
(Thyroid 
stimulating 
hormone  
(TSH), free 
triiodothyronine 
(T3), free 
thyroxine (T4))3
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X


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SCR1
Week 1
Week 2
Week 3
Week 
4
Week 
5
Week 
6
Week 
7
Week 8
Week 9
Week 
11
q4w
Q12w
EOT
D1
D4
D1
D4
D1
D4
D1
D1
D1
D1
D1
D1
D1
W13 and 
thereafter
W49 and 
thereafter
HIV, Hepatitis 
B surface 
antigen
(HBsAg), 
Hepatitis C 
Virus (HCV) 
Antibody
X
FSH/Estradiol42
X
Pregnancy 
test53
X
X
X
X
X
X
X
X
X
X
1.
Although strongly preferred, lab results for HBA1c, fasting lipids, TSH/T3/T4, and pancreatic enzymes are not required prior to dosing.
2.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
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).
4.
Only required at screening for pre- and peri-menopausal subjects
5.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter
Section 7 Table 17
Time and Events, Phase II
Previous Text
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
EOT1
D1
D4
D1
D1
D1
D1
W9 to W49
W9 to W49
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X


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Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
12-lead ECGs (Triplicate)5
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments6
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA7
X
X
X
Week 13, 
25, 37, 49
X
PRO-CTCAE8
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK5257629
Daily
Administer Fulvestrant9
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
PK blood samples10
O
O
X
Tumor biopsy (archival)11
X
X12
Whole blood for exploratory 
analyses
X
X
X
PGx blood sample
X
Efficacy
CT chest/abdomen/pelvis13
X
X
X
X
EORTC-QLQ-C30 & EORTC-
QLQ-BR2314
X
X
X
X
X
X
X
X
X


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1.
Applies to subjects who withdraw for any reason prior to progression or who progress during study treatment. 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.
2.
Screening procedures should be performed as rapidly as possible within 14 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements. In case 
of abnormal test values, retesting may be performed if medically indicated and within 14 days prior to Day 1. 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 within 14 days prior to Day 1 (first dose of study medication) unless otherwise indicated: CT scans 
(within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1).
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.
5.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of dose.
6.
Refer to Table 9  for details of clinical safety labs and timing of collection
7.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at W13, scans will be performed once every 12 weeks. 
8.
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0). Post Week 49, assessments will be 
completed every 8 weeks.
9.
Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for 
the fulvestrant dosing.  Post Week 49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.      
10.
“O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample for 
fulvestrant analysis only for subjects who are receiving fulvestrant. Refer to the SRM for further details. 
11.
Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then fresh specimen must be provided.  Refer to Section 7.2.1 and 
to the SRM for further details.  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.
12.
Tumor biopsy at the end of treatment is optional.
13.
CT should be performed with oral and intravenous (IV) contrast.  Any potential CR or PR should be confirmed as described in Appendix 7.  EOT disease assessment is not 
required if reason for discontinuing therapy was progressive disease and prior 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.
14.
European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures.  Post Week 49, assessments 
will be completed every 8 weeks.  


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Revised Text
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D1
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
X
ECOG PS5
X
X
X
X
X
X
X
X
X
12-lead ECGs (Triplicate)65
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory 
Assessments76
X
X
X
X
X
X
X
X
X
Echocardiogram or MUGA87
X
X
X
Week 13, 
25, 37, 49
X
X
PRO-CTCAE98
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK525762109
Daily
Administer Fulvestrant109
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication review
Continuous from signing of informed consent
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
PK blood samples1110
O
O
X
Tumor biopsy (archival)1211
X
X1312
Whole blood for exploratory 
analyses
X
X
X
PGx blood sample
X
Efficacy


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CT chest/abdomen/pelvis1413
X
X
X
X
EORTC-QLQ-C30 & EORTC-
QLQ-BR231514
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. 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.
2.
Screening procedures should be performed as rapidly as possible within 1428 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements.  Clinical lab 
assessments should be completed within 14 days prior to dosing, and in In case of abnormal test values, retesting may be performed if medically indicated and within 14 days prior to 
Day 1. 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 within 1428 days prior to Day 1 (first dose of study medication) unless 
otherwise indicated: CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1).
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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.  Post Week 49, assessments will be completed every 12 weeks.
5.
Post Week 49, ECOG assessments will be completed every 12 weeks.
6.
Triplicate ECGs should be performed prior to dosing and evaluated for abnormality prior to administration of dose. Post Week 49, assessments will be completed every 12 weeks.
7.
Refer to Table 9  for details of clinical safety labs and timing of collection
8.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  Beginning at W13, scans will be performed once every 12 weeks. 
9.
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0). Post Week 49, assessments will be completed every 8 
weeks. 
10. Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for the fulvestrant 
dosing.  Post Week 49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.      
11. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample for fulvestrant analysis only for subjects 
who are receiving fulvestrant. Refer to the SRM for further details. 
12. Screening (archival) tumor biopsy specimen required for all subjects; if archival sample is not available then fresh specimen must be provided within 14 days prior to first study dose.  
Refer to Section 7.2.1 and to the SRM for further details.  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.
13. Tumor biopsy at the end of treatment is optional, but strongly encouraged when clinically feasible.
14. CT should be performed with oral and intravenous (IV) contrast.  Any potential CR or PR should be confirmed as described in Appendix 7.  EOT disease assessment is not required if reason 
for discontinuing therapy was progressive disease and prior assessment was within 14 days of EOT visit. Subjects with contraindication to contrast-enhanced computed tomography (CT) or 
MRI may have other imaging performed as described in Section 7.2.1.
15. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures.  Post Week 49, assessments will be 
completed every 8 weeks.  
Section 7 Table 18
Time and Events, Phase 2 Laboratory Assessments
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SCR
Week 1
Week 2
Week 3
Week 4
Week 5
Week 7
Week 9
Week 11
q4w
EOT
D1
D4
D1
D1
D1
D1
D1
D1
D1
W13 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
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
X
X
X
X
X
Factor VII Assay1
X
X
X
Fasting blood glucose
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
Thyroid (Thyroid 
stimulating hormone  
(TSH), free 
triiodothyronine (T3), free 
thyroxine (T4))
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B surface 
antigen (HBsAg), 
Hepatitis C Virus (HCV) 
Antibody
X
FSH/Estradiol2
X
Pregnancy test3
X
X
X
X
X
X
X
X
X
1.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
2.
Only required at screening for pre- and peri-menopausal subjects
3.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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Revised Text
SCR1
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 
11
q4w
q12w
EOT
D1
D4
D1
D1
D1
D1
D1
D1
D1
D1
D1
W13 and 
thereafter
W49 and 
thereafter
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Troponin, N-
terminal pro–B-
Type natriuretic 
peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay21
X
X
X
Fasting blood 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Thyroid (Thyroid 
stimulating 
hormone  (TSH), 
free 
triiodothyronine 
(T3), free 
thyroxine (T4))3
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B 
surface antigen
(HBsAg), Hepatitis 
C Virus (HCV) 
Antibody
X
FSH/Estradiol42
X
Pregnancy test53
X
X
X
X
X
X
X
X
X
X


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1.
Although strongly preferred, lab results for HBA1c, fasting lipids, TSH/T3/T4, and pancreatic enzymes are not required prior to dosing.
2.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
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).
4.
Only required at screening for pre- and peri-menopausal subjects
5.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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12.14.5.
Amendment 05
Protocol changes for Amendment 05 (11-SEP-2018), from protocol changes to 
amendment 04 (18-OCT-2017)
Amendment 05 summary:
Amendment 05 applies to all global study sites.
Changes to the protocol include:
These changes are based upon revisions noted by the study team, and include: 
Updating the protocol title to hormone receptor positive (HR+/HER2- BC) to align with 
the inclusion criteria which requires both ER+ and PR+ BC subjects.
Corrections made throughout to align HR+/HER2- BC with the inclusion criteria and 
title. 
Update to clarify that DL 2 (80 mg) has been discontinued.
Update to the author list and sponsor signatory. 
In introduction and Section 5.4 include requirement that the Medical Monitor (MM) 
should be consulted before a subject can discontinue one agent and continue on the other.
Study Design in Synopsis and Section 4: Original language describing Phase I and Phase 
II remains.  New sections added to address the updates to Phase I which include DL2 
(80mg) discontinuation, update the DL1 (60mg) cohort 2 population to include subjects 
must have received greater than or equal to 12 months of prior CDK4/6+ AI for 
metastatic disease and progressed while on treatment and allow bone only disease. 
Revision in sub-sections of Section 4.7 to be in line with wording in the most recent 
Investigator’s Brochure. Inclusion/exclusion criteria: 

Provision of a fresh tumor biopsy sample at screening;  

letrozole has been expanded to include all AI agents;  

prior treatment allowed in the CDK4/6 patient population;

subjects must have received greater than or equal to 12 months of prior CDK4/6+ 
AI for metastatic disease and progressed while on treatment; 

bone only disease is allowed (screening biopsy not required after discussion with 
MM);  

update to criteria for severe or uncontrolled systemic diseases; update to criteria 
for baseline QTcF). 
Section 5.4.2 update to QTc stopping criteria; removal of former Section 6.3.1 Guidelines 
for Events of Special Interest;  in Section 6.11.1 include granulocyte colony-stimulating 
factors as a permitted medications; update to wording in Section 6.11.2.1 Prohibited 
Medication and removal of  former Table 4; update to wording in Section 6.11.2.3 
Cautionary Medication and removal of former Table 5; Clarification in Section 6.11.2.2 
regarding both prescription and non-prescription herbal preparations/medications;  


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Time and Events Table 5 and Table 8: Updates regarding ECGs, requirement of fresh 
biopsies at screening and collection window, clarification of requirements around fresh 
tumor biopsies sample and other general clarifications; Pregnancy Test- X has been 
removed from the Column for Q12wks (Wk49 and after). This was an error and Q4wks is 
correct. In Section 7.2.2 clarification regarding PK sample collection for subjects with 
interrupted dosing; Section 7.3.3.1 update to guidelines for electrocardiograms 
assessments; update to Table 9 Clinical Labs regarding collection of troponin and adding 
a list of acronyms in the footnotes; update to guidance regarding screening and on 
treatment biopsies in Section 7.5.1 and Section 7.7.2; update to toxicity management for 
QTcF events in Appendix 2 and explanation for reconsent.
In Section 9.2.1.1, added the new cohort 2 based on prior experience, interim analysis 
and futility analysis is planned. In Section 9.4.8.1, subjects with bone only disease will be 
included in the final analysis 
Collection of pregnancy information regarding elective termination is clarified that only 
those performed due to medical reasons are required to be reported.
List of Specific Changes
Text which has been added to the protocol is indicated in Appendix 12 by underlined
text. Text which has been deleted from the protocol is indicated in Appendix 12 by strike 
through format.
Common amendment 1
Rationale for change: Updated to better reflect the target patient population.
REVISED TEXT
Throughout the protocol
ERHR+HER2
Common amendment 2
Rationale for change: IB version have been updated from 2011N113741_05 to 
2011N113741_07.
REVISED TEXT
2011N113741_05 2011N113741_07
Title page
Rationale for change: Updated title to better reflect the target patient population of the 
study.
REVISED TEXT
Title of the study
A phase I/II dose escalation and expansion study to investigate the safety, 
pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in 


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combination with fulvestrant in subjects with hormone receptor-positive, HER2-negative 
advanced or metastatic breast cancer (HR+/HER2-) ER+ breast cancer
Author (s)
 
Sponsor Signatory
Li Yan Michael Streit, MD , PhD
VP, Head Unit Physician Clinical Development Lead, Oncology
Section 1: protocol synopsis
Rationale for change: Clarification aligns with original inclusion criteria and does not 
reflect a change. Original language left intact and new revised section added for clarity. 
Closure of DL2 is based on review of interim safety and efficacy analysis and determined 
with agreement with investigators. DL1 cohort 1 subject enrolment is not impacted. 
Addition of requirement for subjects to have ≥12 months of prior treatment is to evaluate 
subjects who have experienced prolonged response with this combination. Subjects with 
bone only disease are added to reflect 30% of metastatic breast cancer population.
REVISED TEXT
Objective(s)/Endpoint(s)
Phase I
Objectives
Endpoints
Primary

To determine a recommended Phase 2 dose (RP2D) 
of GSK525762, when given in combination with 
fulvestrant, in women with advanced or metastatic 
hormone estrogen receptor positive breast cancer 
(EHR+/HER2- BC)

Safety profile (e.g., adverse events [AEs], serious 
adverse events [SAEs], dose-limiting toxicities 
[DLTs], dose reductions or delays), Overall 
Response Rate (ORR), defined as complete 
response [CR] rate plus partial response [PR] rate, 
pharmacokinetic [PK] data
Secondary

To determine the safety, tolerability, and 
maximum tolerated dose (MTD) of GSK525762, 
when given in combination with fulvestrant in 
women with advanced or metastatic 
ERHR+/HER2- BC

AEs, 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 evaluate the clinical activity of GSK525762 and 
fulvestrant, when given in combination in women 
with advanced or metastatic HR+/HER2-ER BC

Disease control rate (DCR; defined as CR plus PR 
plus stable disease [SD] rate), duration of response, 
and progression-free survival (PFS)
Exploratory

To evaluate additional measures of clinical activity of 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
HR+/HER2ER BC

Overall survival (OS)

To identify potential indicators of sensitivity or 

Transcriptomic Mutational analysisstudies of tumor 
PPD


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Objectives
Endpoints
response to GSK525762 and fulvestrant, when 
given in combination in women with advanced 
or metastatic ER+BC.
tissue; correlation of baseline somatic and tumor-
specific genetic and genomic profiles with response.

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
HR+/HER2- ER BC

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Phase II
Objectives
Endpoints
Primary

To evaluate the effect of treatment with GSK525762 
and fulvestrant, when given in combination, on 
progression-free survival in women with advanced or 
metastatic HR+/HER2- ER BC

Progression free survival (PFS), defined as the 
median time from the first dose of study treatment 
until objective tumor progression or death from any 
cause, whichever comes first
Secondary

To evaluate the effect of treatment with 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or 
metastatic HR+/HER2- ER BC, on additional 
metrics of subject survival

Overall survival (OS)
Exploratory

To identify potential indicators of sensitivity or 
response to GSK525762 and fulvestrant, when given 
in combination in women with advanced or 
metastatic HR+/HER2- ER BC

Transcriptomic studiesMutational analysis of tumor 
tissue; correlation of baseline somatic and tumor-
specific genetic and genomic profiles with response

To evaluate ESR1 mutational status as a potential 
indicator of sensitivity and/or response to 
GSK525762 and fulvestrant, when given in 
combination in women with advanced or metastatic 
HR+/HER2- ER+BC

Targeted sequencing to determine correlation 
between ESR1 mutations and clinical response
Overall Design
Original Overall Design (Protocols 01-04)
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of ERHR+/HER2- breast cancer 
to determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. [Changes have been made to this Phase]
This cohort will compare the efficacy of GSK525762 in combination with fulvestrant 
versus fulvestrant with GSK525762-matched placebo in subjects with disease that 
progressed on anti-estrogen and/or one or more AIs, or failure of a combination treatment 


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with CDK4/6 inhibitor plus letrozole AI or a combination of both of these groups/patient 
populations.
Study Schematic
Phase II-Paragraph 1
Phase II is a randomized, double-blind, placebo-controlled study that will explore the 
clinical activity of GSK525762 and fulvestrant when given in combination, to subjects 
with advanced or metastatic ERHR+/HER2- BC.  The primary endpoint of Phase II is 
PFS. The design for Phase II will be finalized based on the results from Phase I.
Phase II-Paragraph 2
Phase II maywill enroll subjects who have disease that has progressed after prior therapy 
with:

CDK4/6 inhibitor plus letrozoleAI, OR

either AI therapy OR CDK4/6 inhibitor plus letrozoleAI.  If both cohorts are 
permitted to enroll in Phase II, randomization will be stratified by prior CDK4/6 
inhibitor-based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-
exposed) and corresponding stratified analysis will be provided at interim and 
final analyses.
Phase II-Paragraph 3
In addition, subjects enrolled in the CDK4/6 inhibitor plus letrozole AI cohort may have 
failed therapy with any number of lines of anti-estrogens and/or AIs.
Text added
Revised Overall Design (Protocol Amendment 05)
While the overall study goals and design remain same, changes have been made to 
Phase I of the study to address to emerging data and intended to better define the patient 
population most likely to benefit from combination treatment of molibresib plus 
fulvestrant. The following are to be noted:
1. DL1 Cohort 1 (60 mg, AI-failures) will complete enrolment to 35 subjects as 
under amendment 4 
2. DL1 Cohort 2 (60 mg, CDK4/6i plus AI failure) – change in inclusion criteria and 
to the number of subjects to be enrolled is detailed below. 
3. DL2 (80 mg) both cohorts (Cohort 1 and Cohort 2) – enrolment is closed based on 
decreased tolerability and lack of efficacy as per protocol guidance.
4. Phase II design remains unchanged – as originally stated, this Phase of the study 
will be redesigned based after analysis of Phase I data.
Change to DL1 Cohort 2:


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Enrolment into DL1 (60 mg) Cohort 2 is modified. Subjects previously treated 
with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus letrozole AI 
for advanced or metastatic disease will be enrolled as follows;  
o
Up to 32 subjects with measurable disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI. 
o
Up to 16 subjects with bone only disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI.
o
The total number of subjects enrolled into this cohort will be approximately 
75.
o
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met.
This requirement is based on emerging data and intended to better define the patient 
population most likely to benefit from combination treatment.
Treatment and duration-Paragraph 3
Subjects who require dose reduction and/or discontinuation of one investigational agent 
may continue on the other agent until progression, withdrawal of consent, or 
unacceptable toxicity after discussion with the Medical Monitor.
Type and Number of Subjects-Paragraph 1
Approximately 294 subjects worldwide with relapsed/refractory advanced or metastatic 
ER HR+/HER2- BC will be enrolled in the study as a whole.  Subjects may have disease 
which progressed during or within 12 months of stopping adjuvant therapy, or disease 
which was initially diagnosed as advanced or metastatic. Cohort 2 is modified to include 
a minimum of 48 subjects who have progressed after greater than or equal to 12 months 
of a CDK4/6 inhibitor (e.g., palbociclib) plus AI for advanced or metastatic disease with 
either measurable disease (32 subjects) or bone only disease (16 subjects).
Analysis-Paragraph 2
For evaluation of efficacy in Cohort 1 (AI Failure) in Phase I, the primary goal is to 
demonstrate a clinically meaningful response rate,, defined as an overall objective 
response rate (CR + PR) of 25% 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 >0.25, assuming the maximum response rate for an ineffective drug is 10% and 
the minimum response rate for an effective drug is 25%.  For evaluation of efficacy in 
Cohort 2 (CDK4/6+AI Failure) in Phase I, the primary goal is to demonstrate a clinically 
meaningful response rate in the measurable disease subjects only, defined as an objective 
response rate (CR + PR) of 20% relative to a 5% response rate suggesting no activity.  
This will be conducted by testing the null hypothesis that P0<=0.05 versus the alternative 
that P1 >0.20, assuming the maximum response rate for an ineffective drug is 5% and the 
minimum response rate for an effective drug is 20%.
Section 2: Introduction


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Rationale for change: To align it with the population originally specified in the 
Inclusion and Exclusion criteria which requires both ER+ and PR+ breast cancer subjects.
Section 2.1: Study Rationale
REVISED TEXT
Advanced or metastatic ER HR+/HER2- +BC is an incurable illness that will prove fatal 
for the majority of afflicted women.  Current standards of care (SoC) include endocrine 
therapy, targeted therapy, and chemotherapy.  Recent preclinical data suggest that 
altering the expression of the ERHR as well as other ERHR-responsive genes may 
provide therapeutic benefit for women for whom endocrine therapy alone has proven 
inadequate.  One potential novel target for therapy is the BET family of proteins.  These 
proteins bind to chromatin and regulate gene expression, and data suggest that 
combination with endocrine therapy may provide therapeutic benefit and even restore 
sensitivity to HRER-targeted agents.  The current protocol (201973) proposes to evaluate 
the combination of the BET inhibitor GSK525762 with the ER-degrading agent 
fulvestrant in women with metastatic or advanced ER HR+/HER2- BC who have 
progressed on at least one line of prior endocrine therapy.
Section 2.2: Brief Background
Rationale for change: As noted above.
REVISED TEXT
Paragraph 2
While patients proceed from one therapy to the next, they ultimately exhaust their 
options, ER HR+/HER2-  BC an area of unmet need, as a result of this inexorable 
progression.
Paragraph 5
In the ongoing BET115521 monotherapy trial, ER+ breast cancer subjects with disease 
that progressed after multiple prior lines of therapy were enrolled.  A planned interim 
futility analysis in this population was performed, and GSK has stopped enrollment in 
this single agent cohort, based upon limited benefit.
Paragraph 7
Taken together, these preclinical data suggest a mechanism by which BET inhibitors and 
endocrine-targeted therapy may combine to provide synergistic benefit in HR+/HER2 
BC.
Section 3: Objective (s) and Endpoints
Rationale for change As noted above.
REVISED TEXT
Please refer to Section 1: Synopsis - Objective(s)/Endpoint(s). Same changes applies 
here.
Section 4.1.1: Original Overall Design (Protocols 01-04)
Rationale for change As noted above.
REVISED TEXT


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4.1.1
Original Overall Design (Protocols 01-04)
Paragraph 1
Phase I of the study is designed as parallel single arm treatment with GSK525762 in 
combination with fulvestrant in two distinct populations of ER+HR+/HER2- breast 
cancer to determine a recommended Phase 2 dose RP2D based on safety, tolerability, 
pharmacokinetic, and efficacy profiles. [Changes have been made to this Phase, see 
changes below in Section 4.1.2]
Section 4.1.2: Revised Overall Design (Protocol Amendment 05)
Rationale for change: Closure of DL2 was based on review of interim safety and 
efficacy analysis and determined with agreement with investigators. Addition of 
requirement for subjects to have ≥12 months of prior treatment is to evaluate subjects 
who have experienced prolonged response with this combination. Subjects with bone 
only disease are added to reflect 30% of metastatic breast cancer population.
REVISED TEXT
Section added
4.1.2
Revised Overall Design (Protocol Amendment 05)
While the overall study goals and design remain same, changes have been made to 
Phase I of the study to address to emerging data and intended to better define the patient 
population most likely to benefit from combination treatment of molibresib plus 
fulvestrant. The following are to be noted:
1. DL1 Cohort 1 (60 mg, AI-failures) will complete enrolment to 35 subjects as 
under amendment 4 
2. DL1 Cohort 2 (60 mg, CDK4/6i plus AI failure) – change in inclusion criteria and 
to the number of subjects to be enrolled is detailed below in Section 4.1.2.1. 
3. DL2 (80 mg) both cohorts (Cohort 1 and Cohort 2) – enrolment is closed based on 
decreased tolerability and lack of efficacy as per protocol guidance.
4. Phase II design remains unchanged – as originally stated, this Phase of the study 
will be redesigned based after analysis of Phase I data.
Section 4.1.2.1: Change to DL1 Cohort 2
Rationale for change: As noted above.
REVISED TEXT
4.1.2.1 Change to DL1 Cohort 2
Enrolment into DL1 (60mg) Cohort 2 is modified. Subjects previously treated 
with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus AI for 
advanced or metastatic disease will be enrolled as follows;  
o
Up to 32 subjects with measurable disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI. 


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o
Up to 16 subjects with bone only disease who have progressed after greater 
than or equal to 12 months of prior treatment with CDK4/6 inhibitor plus AI.
o
The total number of subjects enrolled into this cohort will be approximately 
75.
o
Prior ovarian suppression and/or tamoxifen are allowed as long as the other 
criteria are met.
This requirement is based on emerging data and intended to better define the patient 
population most likely to benefit from combination treatment. The required number of 
subjects is described in Section 9.2.
Section 4.1.3: Type and Number of Subjects
Rationale for change: Addition of DL1 (60mg) cohort 2 population to include subjects 
must have received greater than or equal to 12 months of prior CDK4/6+ AI for 
metastatic disease and progressed while on treatment and allow bone only disease.
REVISED TEXT
Paragraph 1
All subjects enrolled in this study will have a diagnosis of advanced or metastatic 
ERHR+/HER2- BC, that has progressed on prior treatment with at least one line of 
therapy, or which has progressed while on or within 12 months of discontinuing adjuvant 
endocrine therapy. Cohort 2 is modified to include a minimum of 48 subjects who have 
progressed after greater than or equal to 12 months of a CDK4/6 inhibitor (e.g., 
palbociclib) plus AI for advanced or metastatic disease with either measurable disease 
(32 subjects) or bone only disease (16 subjects).
Paragraph 2
Approximately 140 subjects will be enrolled in Phase I (35 subjects in each of two 
cohorts at two DLs), and approximately 154 subjects total will be enrolled in Phase II.
Section 4.2.1: Type and Number of Subjects in Phase I
Rationale for change: As noted above.
REVISED TEXT
See Protocol Section 4.1.2 for details on the type and number of subjects in Phase I.
Text deleted
Eligible subjects will be enrolled into one of two potential cohorts:
Subjects who have disease that has relapsed during treatment or within 12 months of 
completion of adjuvant therapy with an AI, OR disease that progressed during treatment 
with an AI for advanced/metastatic disease.  Prior ovarian suppression and/or tamoxifen 
are allowed as long as the other criteria are met. 


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Subjects who have disease that has progressed during treatment with the combination of a 
CDK4/6 inhibitor (e.g., palbociclib) plus letrozole for advanced or metastatic disease.  
Prior ovarian suppression and/or tamoxifen are allowed as long as the other criteria are 
met.
Documented progression on the last line of systemic anti-cancer therapy is required.
During Phase I, up to 140 subjects may be enrolled.  Two DLs will be studied; each DL 
will comprise two cohorts (each defined by most recent prior therapy) of up to 35 
subjects each.  The total number of subjects required will depend upon the totality of the 
data, including the safety and efficacy of each DL in each cohort.
Section 4.2.2: Treatment Arms and Duration
Rationale for change: The cohort DL 2 (80 mg) has been discontinued.
REVISED TEXT
Paragraph 1
Enrolment into DL2 has been discontinued. See Protocol Section 4.1.2 for the current 
design. If both DLs are enrolling concurrently, subjects will be prioritized to the more 
recent dose level (e.g. DL2) until the sentinel group is filled.  Subjects will then be 
enrolled into the first dose level (e.g. DL1) until the DL2 sentinel group has demonstrated 
that the second DL does not exceed the MTD.  All additional subjects will then be 
randomized 1:1 to receive one of the two dose combinations.
Section 4.2.3.1: Planned Dose Levels
Rationale for change: DL 2 (80 mg) has been discontinued.
REVISED TEXT
Paragraph 1
The projected DLs of GSK525762 are 60 mg and 80 mg administered orally once daily.  
DL2 (80 mg) has been discontinued.
Section 4.2.3.2: Dose Level and Cohort Selection
Rationale for change: DL 2 (80mg) has been discontinued.
REVISED TEXT
Text deleted
Once this sentinel group of 3-10 evaluable subjects has cleared the DLT window at DL1, 
two cohorts will open at DL2.  Subjects will be prioritized to treatment at DL2; any 
additional subjects enrolled prior to clearance of the DL2 sentinel group will be enrolled 
into one of the DL1 cohorts, based on their most recent prior treatment history.  The DL2 
DLT evaluation will occur as described for DL1, with a sentinel group of 3-10 evaluable 
subjects spread across the two cohorts.  
If DL2 is found to be safe in this sentinel group, enrollment will be prioritized to DL2 
until it enrols the same number of subject as DL1.  After that, any eligible subject will be 
assigned 1:1 to either DL1 or DL2 until the cohort at either dose level is full or closed 
early for toxicity or lack of efficacy.


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Paragraph 5
DL2 (80 mg) is discontinued.
Section 4.2.3.8: Intra-Subject Dose Escalation
Rationale for change: DL 2 (80 mg) has been discontinued
REVISED TEXT
Text added
After discontinuation of  DL2 subjects will not automatically be reduced to DL1 if they 
have a favourable risk/benefit profile.
Section 4.2.5.1: Safety Analysis
Rationale for change: Updated subject numbers to reflect modified cohort analysis.
REVISED TEXT
The mTPI decision rule will be used for monitoring safety until 3530 subjects have been 
assigned at the same dose, at which time further enrollment will halt.
Section 4.2.5.2: Futility Analysis
Rationale for change: The cohort DL 2 (80 mg) has been discontinued
REVISED TEXT
For each cohort, the enrollment for that cohort may be stopped due to futility if the 
Bayesian predictive posterior probability that the confirmed response rate ≥25% in 
Cohort 1 (AI Failure) or ≥20% in Cohort 2 (CDK4/6+AI Failure) (target) is small (e.g., 
less than a 10% chance). For details, please see Section 9.4.
Section 4.3.2: Phase II Cohort Selection
Rationale for change: Letrozole has been expanded to include all AI agents.
REVISED TEXT
Paragraph 2, sub points 2 and 3

CDK4/6 inhibitor plus letrozole AI, OR

either AI therapy OR CDK4/6 inhibitor plus letrozole AI.
Section 4.4: Phase II Prior Treatment History Specific Cohorts
Rationale for change: Revised to reflect intent to redesign Part II.
REVISED TEXT:
Phase II will be redesigned based on the results for Phase I and the emerging data from 
literature The treatment cohort and dose(s) taken into Phase II will be based upon the 
totality of data from Phase I.
Section 4.4.6: Data Review
Rationale for change: Minor update.
REVISED TEXT:


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The schedule of any planned interim analysis and the analysis plan for IDMC review will 
be is described in the charter, which is available upon request.
Section 4.5.1: Phase I
Rationale for change: Revised criteria for modified Cohort 2.
REVISED TEXT:
The criteria will be based on a clinically ineffective response rate of 10% and 5% in 
Cohort 1 (AI Failure) and Cohort 2 (CDK4/6+AI Failure), respectively versus a clinically 
meaningful response rate 25% and 20% in Cohort 1 (AI Failure) and Cohort 2 
(CDK4/6+AI Failure), respectively; the rationales for these response assumptions are 
described in Appendix 3.
Section 4.7.1: Risk Assessment
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure.
REVISED TEXT
For a full list of predicted and observed toxicities, refer to the GSK525762 Investigator’s 
Brochure (IB) GlaxoSmithKline Document Number 2011N11374_07 and the FDA 
package insert for fulvestrant.
Section 4.7.1.1.1: Risk Assessment
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure.
REVISED TEXT
Paragraph 2
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 
gastrointestinal 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.Nausea was reported 
in 29% of subjects, dysgeusia was reported in 19%, decreased appetite was described in 
17%, and diarrhea was reported in 16% 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 
gastrointestinal GI effects were observed.  Refer to the GSK525762 IB for full details.
Section 4.7.1.1.2: Hepatic Safety Findings
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure..
REVISED TEXT
Paragraph 2
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. 


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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 
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.  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.  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.  Approximately 
21% of subjects treated with GSK525762 experienced elevated blood bilirubin; 4% of 
subjects (all in the solid tumor study) experienced Grade 3 hyperbilirubinemia.  In 
addition, 8% of subjects experienced alanine aminotransferase (ALT) elevation (no 
Grade 3 or Grade 4 events were reported), and 6% of subjects experienced Aspartate 
aminotransferase (AST) elevation (one Grade 3 event was reported, in the solid tumor 
study).  All liver findings resolved after the cessation of study drug.  Refer to the 
GSK525762 IB for full details.
Section 4.7.1.1.3: Hematopoietic Safety Findings
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure.
REVISED TEXT
Paragraph 2, 3 and 4
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 was observed, primarily at higher 
dose levels. 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 


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cessation of the drug.  Refer to the GSK525762 IB for full details.  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 the GSK525762 IB for full details.
Section 4.7.1.1.5: General Toxicity Findings
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure..
REVISED TEXT
Section added
4.7.1.1.5: General Toxicity Findings
Fulvestrant: As described in the FDA package insert (Section 12.2), fulvestrant was 
associated with fatigue in 8% of subjects receiving the approved dose of 500 mg IM. 
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, 
and the severity. These effects are generally managed by rest and withholding treatment 
if fatigue is intolerable.
Section 4.7.1.2.1: Cardiovascular Safety Findings
Rationale for change: Based on updates to the Molibresib Investigator’s Brochure.
REVISED TEXT
Paragraph 2 and 3
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 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 


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measures PR, QRS, QT and QTcF intervals. As clinically indicated, tThe mean from 
triplicate ECGs will be evaluated at each time point.
Text deleted
In the BET115521 and BET116183 clinical trials, evaluation of cardiac safety data from 
subjects treated up to the 100 mg QD cohort by the cut-off date of May 15, 2015 
demonstrated no significant QTc prolongation after single and repeat dose administration.  
Full analysis of cardiac safety data will be performed at the end of dose escalation in the 
BET115521 study.  Refer to the GSK525762 IB for full details.
Section 5.1 Inclusion Criteria
Rationale for change: Updated to allow screening biopsy analysis and to develop 
predictive biomarkers of response to understand patient population that will significantly 
benefit from molibresib. The fulvestrant window of collection was added so that subjects 
do not need to repeat a biopsy as long as the most recent sample was after prior treatment. 
On therapy biopsy is not mandatory but is encouraged in order to evaluate for changes in 
molecular markers of molibresib inhibition and ER signaling. The pre and post dose 
biopsy samples was added to evaluate ER and ER target gene changes and/or other 
pathways altered by the combination treatment and provide a better understanding of 
molecular changes due to the combination treatment. The study does not need to be 
restricted to only letrozole because there are other treatments in this same class.
Requirement of greater than or equal to 12 months of treatment is to evaluate subjects 
who had prolonged response to the prior treatments.
REVISED TEXT
Added Inclusion Criteria No. 6
6. Provision of mandatory screening fresh tumor biopsy sample during the screening 
period.
a.
Screening biopsy can be waived if a biopsy was collected within 3 months 
prior to first dose of study drug and was collected after the last anti-cancer 
treatment before coming into this study.
b. Subjects with inaccessible site of biopsy or who have a significant medical 
risk of obtaining the biopsy should be discussed with the Medical Monitor 
if they can qualify.
c.
Bone biopsies are not acceptable. Biopsies should be obtained from bone 
with metastatic soft-tissue component. Subjects with bone only disease 
may be enrolled upon review by Medical Monitor. 
Inclusion Criteria No. 7, 8 and 10
7. History of prior therapy that satisfies one of the following criteria:
a. AI failures: Disease that relapsed during treatment or within 12 months 
of completion of adjuvant therapy with an AI, OR disease that progressed 
during treatment with an AI for advanced/metastatic disease.  Prior 


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ovarian suppression and/or tamoxifen are allowed as long as other criteria 
are met.
b. CDK4/6 inhibitor plus letrozole AI failures: Disease that progressed on 
during treatment with the combination of a CDK4/6 inhibitor plus
letrozole AI, for advanced/metastatic disease with a minimum duration of 
treatment of 12 months (≥12 mo) with CDK4/6 inhibitor plus AI. Subjects 
with either measurable disease or bone only disease are allowed. Prior 
ovarian suppression and/or tamoxifen are allowed as long as other criteria 
are met.
8. Documented progression on last line of systemic anti-cancer therapy with CDK4/6 
inhibitor + AI is required.
10. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
criteria is required except for subjects with bone only disease.
Section 5.2 Exclusion Criteria
Rationale for change: Updates to the criteria for severe or uncontrolled systemic 
diseases were made to provide greater clarity. Update to criteria for baseline QTcF was 
based on review of QTc data from clinical studies with GSK525762 as described in the 
Molibresib Investigator’s Brochure.
REVISED TEXT
Exclusion criteria no. 3, 8 and 11
3. ≥3 lines of systemic anti-cancer therapy in the advanced or metastatic setting.
NOTE:
a. Prior systemic anti-cancer therapy (cytotoxic chemotherapy, hormonal, CD4/6K 
inhibitor therapies) in the neoadjuvant/adjuvant setting does not count toward the 
lines of therapy.
8. 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. 
b. Uncontrolled diabetes mellitus (despite therapeutic; compliance to 
intervention) as defined by a haemoglobin A1c (HbA1c) level more than 8% 
and/or occurrence of more than two episodes of ketoacidosis in the 12 months 
prior to the first dose of study drug.


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11. Cardiac abnormalities as evidenced by any of the following:

Baseline QTcF interval ≥4850 msec 
Section 5.4 Withdrawal/Stopping Criteria
Rationale for change: To include requirement that the Medical Monitor (MM) should be 
consulted before a subject can discontinue one agent and continue on the other.
REVISED TEXT
Paragraph 12
Subjects who require permanent discontinuation of one of the study treatments in a given 
combination may continue on the other treatment until disease progression, withdrawal of 
consent, or unacceptable toxicity after discussion with Medical Monitor.
Section 5.4.2. QTc Stopping Criteria
Rationale for change: To update to QTc stopping criteria.
REVISED TEXT
Paragraph 2
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 n<60 msec change 
from baseline
Section 6.2.2 Phase II
Rationale for change: Letrozole has been expanded to include all AI agents.  
REVISED TEXT
Subjects who have disease that has progressed after prior treatment with either AIs or 
CDK4/6 inhibitor plus letrozole AI will be randomized 1:1 to receive either fulvestrant 
plus GSK525762 or fulvestrant plus GSK525762-matched placebo.  Subjects will be 
assigned to their cohort in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated internal software.
Section 6.3. Planned Dose Adjustments
Rationale for change: Removal of former Section for consistency with other 
modifications in the protocol and IB.


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REVISED TEXT
Section 6.3.1 deleted
6.3.1 Guidelines for Events of Special Interest
Events of special interest are defined in Appendix 10  The severity of adverse events 
(AEs) will be graded utilizing the National Cancer Institute- Common Toxicity Criteria 
for Adverse Events (NCI-CTCAE), version 4.  Guidelines for dose modifications and 
interruptions for management of common toxicities associated with the study treatment(s) 
are provided in Appendix 2.
Section 6.4.
Blinding
Rationale for change: Letrozole has been expanded to include all AI agents.
REVISED TEXT
Paragraph 2
Phase II of the study will double-blind.  Based on results from Phase I, Phase II will 
enroll subjects who have disease that has progressed after prior therapy with:

AIs alone (either in the setting of primary metastatic disease or on-
treatment/within 12 months of discontinuing adjuvant endocrine therapy), OR

CDK4/6 inhibitor plus letrozoleAI, OR

either AI therapy OR CDK4/6 inhibitor plus letrozoleAI.  If both cohorts are 
permitted to enroll in Phase II, randomization will be stratified by prior CDK4/6 
inhibitor-based therapy (i.e., CDK4/6 inhibitor-naïve versus CDK4/6 inhibitor-
exposed) and corresponding stratified analysis will be provided at interim and 
final analyses
Section 6.11.1 Permitted Medications and Non-Drug Therapies
Rationale for change: To include granulocyte colony-stimulating factors (GCSF) as 
permitted medication since GCSF is frequently used as supportive care in patients with 
breast cancer and should be included as an option for subjects when clinically indicated.
REVISED TEXT
Paragraph 1
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products,  granulocyte colony-stimulating factors (GCSF) 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.


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Section 6.11.2.1 Prohibited Medications
Rationale for change: Update to wording, removal of former Table 4 based on review of 
cardiac safety data from clinical studies with GSK525762 as reflected in the Molibresib 
Investigator’s Brochure.
REVISED TEXT
Paragraph 2
Subjects may continue to use Aspirin, but doses greater than 100 mg per day are not 
allowed.  The use of non-steroidal anti-inflammatory drugs (NSAIDS) will be excluded, 
except for when NSAIDS will provide benefit over other analgesics, and then be used 
with caution, including concomitant use of protoncol pump inhibitors.
Text deleted
Co-administration of the medications listed in Table 4 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 4
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
Levosulpride
Terlipressin
Donepezil
Methadone
Thioridazine
Data Source: crediblemeds.org revision date 09 Jan 2017. The above table is not exhaustive. Please refer to a 
database like crediblemeds.org for updates at the time of screening a subject, since these are dynamic lists that 
change based on new information which cannot be updated on a static table.
Section 6.11.2.2 Prohibited Non-Drug Therapies


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Rationale for change: Update to include cclarification regarding both prescription and 
non-prescription herbal preparations/medications. Herbal medication language further 
clarified to avoid unknown interactions.
REVISED TEXT
Paragraph 2
Subjects will abstain from using herbal prescription/non prescription 
preparations/medications throughout the study until the final study visit due to the limited 
data on potential CYP-mediated interactions produced by those products.  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.
Section 6.11.2.3 Cautionary Medications
Rationale for change: Update to wording, removal of former Table 5 based on review of 
cardiac safety data from clinical studies with GSK525762 as reflected in the Molibresib 
Investigator’s Brochure.
REVISED TEXT
Subjects should minimize the use of medications that 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 QT duration corrected for heart rate by Fridericia’s 
formula (QTcF), palonosetron (administered per the prescribing information) and 
ondansetron (up to a maximum dose of 8 mg three times daily [TID]) are the only 
allowed drugs in this class. Intravenous administration is not allowed.  Drugs with a low 
risk of causing QTc prolongation (e.g., aprepitant) may be used without restriction.
Co-administration of GSK525762 and medicines 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 the current list of medications at 
www.crediblemeds.org These medications include (but are not limited to):


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Table 5
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
Degareliz
Mirtazapine
Tetrabenazine
Delamanid
Moexipril/
hydrochlorothiazide (HCTZ)
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 Jan 2017.  The above table is not exhaustive.  
Please refer to a database like crediblemeds.org for updates at the time of screening a subject, 
since these are dynamic lists that change based on new information which cannot be updated 
on a static table.


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Section 7.1.
Time and Events Table
Rationale for change: Updates regarding ECGs, requirement of fresh biopsies at screening and collection window, clarification of 
requirements around fresh tumor biopsies sample and other general clarifications.
REVISED TEXT
Table 5: Time and Events, Phase I
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Safety
12-lead ECGs (Triplicate)6
X
X
X
X
X
X
X
X
X
X
Pregnancy test5
X
X
X
X
X
X
X
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
Tumor biopsy12
X
One sample, collected 
between W3D4 and W5D41, 
as close as possible to 3-6h 
post-GSK525762 dose
X13
6. Triplicate ECGs should be performed at screening. All other timepoints can be single ECGs prior to dosing and evaluated for abnormality prior to administration of dose. Post Week 
49, assessments will be completed every 12 weeks. Triplicate ECGs to be performed as clinically indicated, based upon abnormal findings.
8. Whatever scanning modality is used at screening should be maintained for all subsequent scans. An assessment is not performed at W9. Beginning at W13, scans will be performed 
once every 12 weeks.
12. Mandatory Screening (archival) tumor biopsy specimen is required for all subjects; if archival sample is not available then fresh specimen must be provided within 2814 days prior 
to first study dose as described in Section 7.5.1. Paired fresh biopsies must be provided pre- and on-treatment at the time points indicated for at least 6 subjects (out of 35 planned for 
enrollment) at each dose level.    Subjects providing an optional on-treatment fresh tumor biopsy, whether they have had a dose interruption of GSK525762 or not, must have received 
at least 4 consecutive doses of GSK525762 prior to the collection of the tissue.  If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject 
status, it should be performed at the next agreed upon visit with the medical monitor after subject recovery.  A limited number of additional subjects may be requested to provide pre-
and on-treatment biopsies based on emerging data. Fresh biopsies should be paired with plasma samples for PK, collected as close as possible to biopsy (ideally within 1 h).  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. Refer to the 
SRM for further details.


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Table 6: Time and Events, Phase I Laboratory Assessments
SCR
1
Week 1
Week 2
Week 3
Week 
4
Week 
5
Week 
6
Week 
7
Week 
8
Week 
9
Week 
11
q4w
q12w
EOT
D
1
D
4
D
1
D
4
D1
D4
D1
D1
D1
D1
D1
D1
D1
W13 and 
after
W49 and 
after
Pregnancy test5
X
X
X
X
X
X
X
X
X
X
Table 7: Time and Events, Phase II
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D1
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Safety
12-lead ECGs (Triplicate)6
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
Tumor biopsy (archival)12
X
X13
6. Triplicate ECGs should be performed at screening. All other timepoints can be single ECGs prior to dosing and evaluated for abnormality prior to administration of dose. Post Week 49, 
assessments will be completed every 12 weeks.  Triplicate ECGs to be performed as clinically indicated, based upon abnormal findings.
8. Whatever scanning modality is used at screening should be maintained for all subsequent scans.  An assessment is not performed at W9. Beginning at W13, scans will be performed 
once every 12 weeks. 
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0). Post Week 49, assessments will be completed every 
8 weeks. 
12. Screening (archival) tumor biopsy specimen is required for all subjects; if archival sample is not available thenthe fresh specimen must be provided within 14 28 days prior to first study 
dose. It is acceptable to collect tumor biopsy specimen within the screening period. A sample collected within 3 months of first dose is also acceptable only if it was collected after the last 
anticancer treatment.   Refer to Section 7.2.1 and to the SRM for further details.  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.
Table 8: Time and Events, Phase 2 Laboratory Assessments
SCR
1
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
q4w
q12w
EOT
D1
D
4
D1
D1
D1
D1
D1
D1
D1
D1
D1
W13 and 
after
W49 and 
after
Pregnancy test5
X
X
X
X
X
X
X
X
X
X


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Section 7.2.1. Critical Baseline Assessments
Rationale for change: Biopsy collection was updated to fulfil exploratory 
pharmacodynamic analysis of tumor tissue. Flexibility was included to allow subjects 
who are not able to undergo a biopsy a means of still enrolling in the trial. On treatment 
biopsy is clarified as optional and requirement of 6 paired samples is removed to avoid 
excluding subjects who are not able to undergo a biopsy.
REVISED TEXT
A baseline tumor biopsy sample is required for all subjects, as follows:

Phase I:
o
All subjects must provide a biopsy sample at screening.  Archival tissue is 
permitted; however, if no archival tissue is available then a A fresh biopsy 
specimen must be provided within 2814 days prior to first study dose. A 
sample collected within 3 months of first dose is also acceptable only if it 
was collected after the last anticancer treatment.
o
Subjects with bone only disease without any visceral tumor tissue 
amenable to biopsy may be enrolled without a biopsy sample only upon 
review by medical monitor
o Paired on treatment fresh biopsies are optional but encouraged. Allt east 6 
subjects enrolled in the study at each dose level will be askedrequired to 
provide paired fresh biopsies pre- and post-dose at the time points 
indicated in Section 7.1, as described in Section 7.5.1.  Fresh biopsies 
should be paired with plasma samples for PK, collected as close as 
possible to the biopsy (ideally within 1 h).  Subjects should have at least 
four consecutive doses of GSK525762 prior to collection of tumor biopsy, 
whether they have had a dose interruption or not.  Subjects will be 
informed at the time of informed consent whether paired fresh biopsies 
will be required. If a potential subject does not have a disease amenable to 
biopsy, participation may occur only upon discussion and approval of the 
medical monitor Further details regarding sample type and processing will 
be provided in the SRM.

Phase II:
o All subjects must provide an archivala fresh tissue specimen at screening. 
If an archival specimen is not available, then a fresh pre-treatment biopsy 
specimen must be provided.  On-study biopsies are not required
Section 7.2.2. Visit Windows
Rationale for change: Clarification regarding PK sample collection for subjects with 
interrupted dosing.
REVISED TEXT


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Paragraph 5 and 8
Week 3: Assessments on Week 3 Day 1 may be delayed up to 2 days.  Assessments on 
Week 3 Day 4 may be scheduled ± 3 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 be rescheduled for a later 
timepoint when the subject is again being dosed for at least 7 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 fulvestrant 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 who have interrupted dosing, the 
collection should be postponed until the subject has received at least 7 consecutive doses 
of GSK525762.   
Section 7.3.3.1 Electrocardiograms
Rationale for change: Update to guidelines for electrocardiograms assessments.
REVISED TEXT
Paragraph 1 and 2 
Triplicate 12-lead ECGs will be obtained at screening.  On treatment single ECGs will be 
completed, prior to dosing, on days specified in Section 7.1 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 >4850 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 W1D1 predose QTcF 
results. If these results are not available, then the mean QTcF of the screening triplicate 
ECG results should be used.
Section 7.3.4. Clinical Safety Laboratory Assessments
Rationale for change: Update to Table for Clinical Laboratory tests regarding collection 
of troponin and adding a list of acronyms in the footnotes.
REVISED TEXT
Table 9 Clinical Laboratory Tests


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Cardiac Studies
Troponin (I or T), 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
Thyroid-stimulating hormone (TSH)
Partial Thromboplastin Time or 
Activated Partial Thromboplastin 
Time (aPTT)
Free Thyroxine 3 (Free T3)
HIV, HbSag, HCV antibody
Fibrinogen
Free Thyroxine 4 (Free T4)
Pancreatic Markers:
Factor VII Assay
Hemoglobin A1c
Amylase
FSH and estradiol (for pre- and peri-
menopausal subjects only)
Lipase
*Direct and/or calculated BUN values are acceptable.
**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; HIV = Human immunodeficiency virus; HbSag = Hepatitis B surface antigen; HCV 
= Hepatitis C virus  
Section 7.5 Pharmacodynamics
Rationale for change: Biopsy collection was updated to fulfil exploratory 
pharmacodynamic analysis of tumor tissue.
REVISED TEXT
Tumor samples will be collected pre-dose and on-treatment from a limited number of 
subjects in order to evaluate for changes in molecular markers of BET inhibition (e.g., 
expression of proteins regulated by BET proteins) and ERHR signalling.
Section 7.5.1 Tumor Biopsy Collection/Surgical Procedures
Rationale for change: Update to guidance regarding screening and on treatment biopsies
as noted above.
REVISED TEXT
A mandatory fresh tumor biopsy sample is required for all subjects during the screening 
period within 28 days of the first dose of study treatment. A sample collected within 3 
months of first dose is also acceptable only if it was collected after the last anti-cancer 
treatment. Bone biopsy sample is not acceptable. Biopsy requirement for subjects with 
bone only disease with no visceral tumor may be waived only upon review by GSK. 
a.
Screening biopsy can be waived if a biopsy was collected within 3 months 
prior to first dose of study drug and was collected after the last anti-cancer 
treatment before coming into this study.
b. Subjects with inaccessible site of biopsy or who have a significant medical 
risk of obtaining the biopsy should be discussed with the Medical Monitor 
if they can qualify.


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c.
Bone biopsies are not acceptable. Biopsies should be obtained from bone 
with metastatic soft-tissue component. Subjects with bone only disease 
may be enrolled upon review by Medical Monitor. 
In Phase I, paired fresh biopsies must be provided pre- (within 14 days prior to the first 
dose) and on-treatment at the time points indicated for at least 6 subjects (out of 35 
planned for enrollment) at each dose level.  On treatment fresh biopsies are optional but 
encouraged. Subjects providing an on-treatment fresh tumor biopsy must have received at 
least 4 consecutive doses of GSK525762 prior to the collection of the tissue.  A limited 
number of additional subjects may be requested to provide pre and on-treatment biopsies 
based on emerging data.  Biopsy requirement(s) will be discussed with the subject prior 
to signing informed consent.  Any fresh on-treatment biopsy should be accompanied by a 
plasma sample collected as close as possible to the time of biopsy (preferably within 1 h).  
Section 7.7.1 Tumor Biomarker Analysis
Rationale for change: As noted above.
REVISED TEXT
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 
fulvestrant in combination utilizing baseline tissue (archival tissue or a recent biopsy) and 
tissue obtained at disease progression (if sample is available). Further details on sample 
requirements and collection will be provided in the SRM.
Section 7.7.2 Tumor Tissue
Rationale for change: Update to guidance regarding screening and on treatment biopsies
REVISED TEXT
All enrolled subjects in the study will be asked required to submit an archival fresh tumor 
biopsy at screening baseline in order to conduct retrospective tests for the identification 
and/or validation of known and novel biomarkers. If an archival specimen is not 
available, Aa fresh biopsy will be required. Further details on sample requirements and 
collection will be provided in the SRM.
A small number of subjects (at least 6 per dose level) enrolled in Phase I must submit 
fresh tumor biopsies collected pre- and post-dose as described in Section 7.5.1 and the 
SRM.
Optional on-treatment tumor biopsy Ssamples will be analyzed using appropriate 
technologies including, but not limited to, RNAseq, exome or targeted DNA sequencing, 
IHC, and/or qRT-PCR.  
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. 
Section 9.1.2 Phase I Efficacy


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Rationale for change: The statistical analysis plan was updated to provide details of 
analysis for Cohort 2.
REVISED TEXT
For evaluation of efficacy in Cohort 1 (AI Failure) in Phase I, the primary goal is to 
demonstrate a clinically meaningful response rate, defined as an objective response rate 
(CR + PR) of 25% 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 
>0.25, assuming the maximum response rate for an ineffective drug is 10% and the 
minimum response rate for an effective drug is 25%.  For evaluation of efficacy in Cohort 
2 (CDK4/6+AI Failure) in Phase I, the primary goal is to demonstrate a clinically 
meaningful response rate in the measurable disease subjects only, defined as an objective 
response rate (CR + PR) of 20% relative to a 5% response rate suggesting no activity.  
This will be conducted by testing the null hypothesis that P0<=0.05 versus the alternative 
that P1 >0.20, assuming the maximum response rate for an ineffective drug is 5% and the 
minimum response rate for an effective drug is 20%. Bayesian statistics will be employed 
to calculate the posterior probability that the ORR ≥25% and ≥10% for Cohort 1 (AI 
Failure) and ≥20% and ≥5% for Cohort 2 (CDK4/6+AI Failure) at interim assuming a 
Beta prior for the Binomial distributed data.  A weak prior Beta (0.0125, 0.0875) for 
Cohort 1 (AI Failure) and (0.005, 0.095) for Cohort 2 (CDK4/6+AI Failure) is used, 
which is equivalent to the information present in 0.1 subjects. A secondary endpoint for 
Phase I is to demonstrate a clinically meaningful response ratio (RR), defined as an ORR 
(confirmed CR + confirmed PR) of 25% relative to a 10% ORR suggesting no activity.  
This will be conducted by testing the null hypothesis that P0<=0.1 versus the alternative 
that P1 >= 0.25, assuming the maximum RR for an ineffective drug is 10% and the 
minimum RR for an effective drug is 25%.  This portion of the study will employ the 
Bayesian method that allows the trial to be frequently monitored with the constraint of 
controlling both Type I and Type II error rates.  Enrollment to an individual cohorts may 
be stopped early for toxicity or lack of efficacy, but will not be stopped early if the ORR 
meets or exceeds the alternate hypothesis at the interim analyses.  The rationale for 
selecting these response rates is detailed in Appendix 3.
The Phase I portion of the study will employ a Bayesian predictive adaptive design [Lee, 
2008] that allows the trial to be monitored more frequently at multiple stages. The criteria 
will be based on a historically unimportant ORR of 10% versus an ORR of interest of 
25%.  Bayesian statistics will be employed to calculate the predictive probability that the 
RR ≥25% and ≥10% at interim assuming a Beta prior for the Binomial distributed data.  
Predictive probability calculates the probability that the RR ≥25% or ≥10% given the
responses have already been observed.  A weak prior Beta (0.0125, 0.0875) is used, 
which is equivalent to the information present in 0.1 subjects. The first interim analysis 
may be conducted when at least 10 evaluable subjects are available for each cohort at a 
given dose. Futility interim analysis decision rules for the 10th to 34th evaluable subjects, 
specifying the number of subjects with a confirmed response needed for continuing 
enrollment or stopping for futility when total sample size is up to 35 in a particular cohort 
is presented in Table 10.  These rules are intended as a guideline.  Actual decisions will 
depend on the totality of the data.


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Table 10
Decision Making Criteria for Futility
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses to 
Stop Early for Futility
Probability of continuing 
enrolling when ORR=0.1
Probability of continuing 
enrolling when ORR=0.25 
10
0
0.6513
0.9437
11
0
0.6513
0.9437
12
0
0.6513
0.9437
13
0
0.6513
0.9437
14
1
0.3971
0.8843
15
1
0.3971
0.8843
16
1
0.3971
0.8843
17
1
0.3971
0.8843
18
1
0.3971
0.8843
19
1
0.3971
0.8843
20
1
0.3971
0.8843
21
2
0. 2938
0. 8674
22
2
0.2938
0.8674
23
2
0.2938
0.8674
24
2
0.2938
0.8674
25
2
0.2938
0.8674
26
2
0.2938
0.8674
27
3
0.2108
0.8511
28
3
0.2108
0.8511
29
3
0.2108
0.8511
30
3
0.2108
0.8511
31
3
0.2108
0.8511
32
4
0.1509
0.8369
33
4
0.1509
0.8369
34
4
0.1509
0.8369
For the separate interim looks in each cohort, the enrollment for that cohort may be 
stopped due to futility if the predictive probability that the confirmed RR ≥25% is small 
(e.g., less than a 4% chance for a total sample size of 35 subjects).  Enrollment may also 
be stopped due to futility if the equivalent of no response is observed in the first 10 
enrolled evaluable subjects in that cohort or less than 1 confirmed responses are observed 
in the first 14 evaluable subjects.  The evaluable subject is defined as a subject, who has 
either progressed or died, withdrew from the study treatment, or is ongoing and has 
completed at least two post treatment disease assessments.  For example, when there are 
14 evaluable subjects available at the time of interim analysis with only one response, 
then the cohort may be stop for futility.  Otherwise, the enrollment of the respective 
cohort will continue to the target sample size. 


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When the total sample size in a treatment arm is 35 and at least 6 responders out of 35 
subjects are observed, we can claim null hypothesis is rejected and the phase 2 part on 
that cohort and dose may follow.  
The ORR and safety endpoints will be jointly assessed using a utility function when both 
DL1 and DL2 are safe and effective. The dose with the best utility function may be 
picked as RP2D for Phase 2. The details of the utility function calculations will be 
discussed in Reporting and Analysis Plan (RAP).  This calculation is for guidance only, 
the final decision of RP2D will be based on totally of data.
Section 9.2.1.1 Phase I
Rationale for change: The requirement of subjects with ≥ 12 months of prior treatment 
was added to evaluate subjects who have experienced prolonged response. Subjects with 
bone only disease were added to reflect 30% of the metastatic breast cancer population.  
REVISED TEXT
Up to 70 35 measurable disease subjects per DL in Cohort 1 and 32 measurable disease 
subjects per DL in Cohort 2 will may be enrolled into two cohorts (based on prior 
therapy) at each DL (approximately 35 per cohort) to collect safety/tolerability, PK, PD, 
and efficacy data. Sixteen additional bone only disease subjects will be enrolled into DL1 
cohort 2. 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 cohort, Bayesian predictive adaptive 
design will be used for testing hypotheses and sample size determination:
In Cohort 1 (AI Failure) the null and alternative hypotheses are:
H0: ORR≤10%
HA: ORR≥25%
When maximum sample size is 35, the design will have a Type I error () of 0.098 and 
80% power.  
In Cohort 2 (CDK4/6+AI Failure) the null and alternative hypotheses are:
H0: ORR≤5%
HA: ORR≥20%
When maximum sample size is 32, the design will have a Type I error () of 0.0535 and 
81% power.  
Section 9.3.2.1.2 Efficacy Analyses
Rationale for change: The statistical plan was updated to reflect modification of Cohort 
2.


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REVISED TEXT
Interim analyses during expansion cohorts
Interim data will be evaluated to monitor efficacy and safety, and a planned interim 
analysis will be performed when at least 10 evaluable subjects have been enrolled into 
each of the expansion cohorts at each 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 
Hierarchical model are described below. The decision will be made for each individual 
prior treatment history-specific cohort. 
For the separate interim looks in each cohort, the enrollment for that cohort may be 
stopped due to futility if the posterior probability that the confirmed ORR ≥25% or ORR 
≥20% in Cohort 1 and Cohort 2, respectively, is small (e.g., less than a 4% chance for a 
total sample size of 35 subjects).  Enrollment may also be stopped due to futility if the 
equivalent of no response is observed in the first 10 enrolled evaluable subjects in that 
cohort or less than 2 confirmed responses are observed in the first 14 and 19 evaluable 
subjects in Cohort 1 and Cohort 2, respectively.  The evaluable subject is defined as a 
subject, who has either progressed or died, withdrew from the study treatment, or is 
ongoing and has completed at least two post treatment disease assessments.  For example, 
when there are 14 evaluable subjects available at the time of interim analysis with only 
one response, then the cohort may be stop for futility.  Otherwise, the enrollment of the 
respective cohort will continue to the target sample size. 
Futility interim analysis decision rules for the 10th to 34th evaluable subjects in Cohort 1 
(AI Failure) and 10th to 32nd evaluable subjects in Cohort 2 (CDK4/6+AI Failure), 
specifying the number of subjects with a confirmed response needed for continuing 
enrollment or stopping for futility when total sample size is up to 35 in Cohort 1 (AI 
Failure) and up to 32 in Cohort 2 (CDK4/6+AI Failure) is presented in Table 10and 11, 
respectively.  These rules are intended as a guideline.  Actual decisions will depend on 
the totality of the data.


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Table 10
Decision Making Criteria for Futility in Cohort 1 (AI Failure)
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses to 
Stop Early for Futility
Probability of continuing 
enrolling when ORR=0.1
Probability of continuing 
enrolling when ORR=0.25 
10
0
0.6513
0.9437
11
0
0.6513
0.9437
12
0
0.6513
0.9437
13
0
0.6513
0.9437
14
1
0.3971
0.8843
15
1
0.3971
0.8843
16
1
0.3971
0.8843
17
1
0.3971
0.8843
18
1
0.3971
0.8843
19
1
0.3971
0.8843
20
1
0.3971
0.8843
21
2
0.2938
0.8674
22
2
0.2938
0.8674
23
2
0.2938
0.8674
24
2
0.2938
0.8674
25
2
0.2938
0.8674
26
2
0.2938
0.8674
27
3
0.2108
0.8511
28
3
0.2108
0.8511
29
3
0.2108
0.8511
30
3
0.2108
0.8511
31
3
0.2108
0.8511
32
4
0.1509
0.8369
33
4
0.1509
0.8369
34
4
0.1509
0.8369


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Table 11
Decision Making Criteria for Futility in Cohort 2 (CDK4/6+AI Failure)
Number of Evaluable 
Subjects 
This Number of 
Confirmed Responses to 
Stop Early for Futility
Probability of continuing 
enrolling when ORR=0.05
Probability of continuing 
enrolling when ORR=0.2 
10
0
0.4013
0.8926
11
0
0.4013
0.8926
12
0
0.4013
0.8926
13
0
0.4013
0.8926
14
0
0.4013
0.8926
15
0
0.4013
0.8926
16
0
0.4013
0.8926
17
0
0.4013
0.8926
18
0
0.4013
0.8926
19
1
0.2027
0.8566
20
1
0.2027
0.8566
21
1
0.2027
0.8566
22
1
0.2027
0.8566
23
1
0.2027
0.8566
24
1
0.2027
0.8566
25
1
0.2027
0.8566
26
1
0.2027
0.8566
27
2
0.1090
0.8362
28
2
0.1090
0.8362
29
2
0.1090
0.8362
30
2
0.1090
0.8362
31
2
0.1090
0.8362
Additionally, the ORR and safety endpoints will be jointly assessed using a utility 
function when both DL1 and DL2 are safe and effective. The dose with the best utility 
function may be picked as RP2D for Phase 2. The details of the utility function 
calculations will be discussed in Reporting and Analysis Plan (RAP).  This calculation is 
for guidance only, the final decision of RP2D will be based on totally of data.
The study population used for decision-making at the interim analyses on efficacy will be 
termed All Evaluable Subjects.  This will be the population for Bayesian model and 
summaries of response if data warrant.  Because subjects enroll at different times, not all 
subjects will have been on the study long enough to have single or multiple disease 
assessments.  Since disease assessments are to be completed every 8 weeks, subjects who 
have at least two post-baseline radiological disease assessments or have progressed or 
died or permanently withdraw from the study treatment will be included in this 
population.  Interim analysis on safety will be conducted on all treated subjects. 
Section 9.4.8.1 Phase I


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Rationale for change: The statistical plan was updated to reflect modification of Cohort 
2.
REVISED TEXT
Paragraph 1 
For the Phase I final analysis, each dose and cohort will be analyzed separately.  In 
Cohort 2 (CDK4/6+AI Failure), measurable disease subjects and bone only disease 
subjects will be analyzed separately and combined within a dose.  However, bone only 
disease subjects will not be evaluated for ORR.  The focus of analyses that contain bone 
only disease subjects will be DCR, PFS and OS.
Paragraph 3
The observed confirmed and unconfirmed ORR will be reported at the interim and final 
analysis for each cohort specified in Phase 1 treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided. Bayesian inference 
based on summary statistics from the posterior distributions of each ORR will be reported 
at interim and final analyses. The posterior mean and posterior 2.5% and 97.5% 
percentiles of the ORR will be calculated for each cohort. In addition, the predictive 
posterior probability that the ORR exceeds its corresponding historical control will be 
reported for each cohort.
Section 11: References
Rationale for change: Information from updated IB was used
REVISED TEXT
GlaxoSmithKline Document Number 2011N113741_05.  Investigator Brochure for 
GSK525762.  Report Date 28-Mar-2016
GlaxoSmithKline Document Number 2011N113741_07.  Investigator Brochure for 
GSK525762.  Report Date 18-May-2018
Section 12.1 Appendix 1: Abbreviations and Trademarks
Rationale for change: Addition of abbreviation.
REVISED TEXT
Table of Abbreviation
GCSF
Granulocyte Colony-Stimulating Factors 
HR+HER2-
Hormone Receptor-positive, HER2-negative
Section 12.2 Appendix 2: Management of Suspected Toxicity
Rationale for change: Update to toxicity management for QTcF events in Appendix 2 
and explanation for reconsent.


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REVISED TEXT
Table 12: Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/
Stopping Criteria
Management Guidelinesc
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:
e. Maintain serum potassium > 4mol/L
f. 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
ORAND
QTcF 500 msec
ANDOR
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:
e. Maintain serum potassium > 4mol/L
f. 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 a 
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)
(7)
QTcF reduced to <4850 msec,
(8)
Potassium and magnesium levels are within 
institutional normal range,
(9)
A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the Medical 
Monitor),
(10) 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
(11) 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:
(4)
Evaluation by cardiologist.
(5)
Weekly assessments for QTcF until ≤30 msec 
change from baseline reached, and then next 
assessment at 4 weeks post-dose. 
(6)
If QTcF results have not resolved to baseline by 
4 weeks post-dose, then continue every 4-5 
weeks until resolution
Footnote added:
c. Fulvestrant should be restarted following the original schedule. 
Section 12.3.2 Phase 2
Rationale for change: Minor update to include all AI inhibitors consistent with Part 1. 


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REVISED TEXT
The statistical design in Phase 2 of this study is based upon the hypothesis that the 
combination of fulvestrant plus GSK525762 will double the PFS (i.e., a hazard ratio of 
0.5) compared to fulvestrant alone (for subjects previously treated with AI and/or 
CDK4/6 inhibitor/letrozoleAI) or compared to SoC (for subjects previously treated with 
CDK4/6 inhibitor/fulvestrant).  This value is comparable to the PFS improvement 
identified in the palbociclib/fulvestrant study (HR=0.46; [Cristofanilli, 2016] as well as 
the everolimus/exemestane study (HR=0.43; [Baselga, 2012]).
Section 12.4 Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information
Rationale for change: Updated to clarify that elective termination for non-medical 
reasons do not require additional collection of data.  
REVISED TEXT
Section number added
12.4.1. Contraception Guidance:
Section 12.4.2 Collection of Pregnancy Information
Rationale for change: Collection of pregnancy information regarding elective 
termination is clarified that only those performed due to medical reasons are required to 
be reported
REVISED TEXT

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.


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12.14.6.
Amendment 06
Protocol changes for Amendment 06 (06-MAY-2020), from protocol changes to 
amendment 05 (11-SEP-2018)
Protocol Amendment 06 applies to all global site(s) participating in the conduct of 
the study
Amendment 06 summary:
Amendment 06 applies to all global study sites. These changes are based on decision to 
close out the study and stop all new enrolment based on interim data failing to 
demonstrate meaningful clinical benefit in the proposed patient population.
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed. 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)

Updates to contraceptive measures required for study participants, based upon 
January 2020 updates to the fulvestrant Summary of Product Characteristics 

Update to the GSK signatory and GSK medical monitor

Provides updated guidance for subjects who have discontinued combination 
treatment and are on fulvestrant monotherapy

Provides clarification on clinical supply dosages available for the study

Administrative changes including minor clarifications, formatting and 
typographical errors


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List of Specific Changes
Text which has been added to the protocol is indicated in Appendix 12 by underlined
text. Text which has been deleted from the protocol is indicated in Appendix 12 by strike 
through format.
Title Page
Rationale for change: Update to protocol author list
REVISED TEXT
Author (s):
 
 
Section Title Page-Sponsor Signatory
Rationale for change: Update to sponsor signatory
REVISED TEXT
Michael Streit, MD
Clinical Development Lead, Oncology
Hesham A. Abdullah, MD, MSc, RAC
SVP, Head of Clinical Development, Oncology
Section Title Page-MEDICAL MONITOR/SPONSOR INFORMATION 
PAGE
Rationale for change: Update to Medical Monitor information
PPD


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REVISED TEXT
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number 
After-hours 
Phone/Cell/
Pager Number
Site Address and email address
Primary 
Medical 
Monitor 
MD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
GSK R&D, Gunnels Wood, Stevenage, 
Herts, SG1 2NY 
Secondary 
Medical 
Monitor
 
 MD, 
PhD
GlaxoSmithKline
1250 South Collegeville Road, 
UP4410
Collegeville, PA 19426, USA
  
Section 1: protocol synopsis
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population.
REVISED TEXT
Objective(s)/Endpoint(s)
Phase I
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Phase II
With the implementation of amendment 06, Phase II of the study is terminated.
Study Schematic
Phase I:
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Phase II:
With the implementation of amendment 06, Phase II of the study is terminated.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Number Of Subjects
Analysis
Third and fourth paragraph
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population. 
With the implementation of Amendment 06, 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. There will be no Phase II.
Section 3 OBJECTIVE(S) AND ENDPOINT(S)
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population.
REVISED TEXT
Phase I
With the implementation of amendment 06, Phase I of the study is closed to enrolment.
Phase II
With the implementation of amendment 06, Phase II of the study is terminated.
Section 4.1.1. Original Overall Design (Protocols 01-04)
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. Specific assessments that are no 
longer required, due to the status of the study, are being removed to minimize patient 
burden.
REVISED TEXT
Phase I tenth paragraph onwards
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population. 
With the implementation of Amendment 06, specific assessments and collection of 
survival follow-up data will no longer be required. Please see Section 7.1 for further 


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details. The study will conclude when the last subject has completed/discontinued study 
treatment and completed the end of treatment visit. There will be no Phase II.
Section 4.3. Decision to Proceed to Phase II
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population.
REVISED TEXT
With the implementation of amendment 06, Phase II of the study is terminated.
Section 4.5.1. Phase I
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. Specific assessments that are no 
longer required, due to the status of the study, are being removed to minimize patient 
burden.
REVISED TEXT
Fourth paragraph onwards
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed.
With the implementation of Amendment 06, 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 4.7.1.1.4.
Reproductive Safety Findings
Rationale for change: Updates to contraceptive measures required for study 
participants, based upon January 2020 updates to the fulvestrant Summary of Product 
Characteristics have been added to Appendix 4.
REVISED TEXT
Monitoring and Management: Based on the findings in these reproductive and 
developmental toxicity studies in animals with both fulvestrant and GSK525762, there is 
a substantiated risk for adverse effects on embryo-fetal development and impacts on 
female fertility. Consequently, the proposed study will include strict contraceptive 
requirements for females of child-bearing potential (Section 6.10.2), described in 
Appendix 4.  Pregnancy tests will be required at screening and periodically during the 
study for all women of child-bearing potential, as indicated in the Time and Events table 


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(Section 7.1). Women who become pregnant while on study will be required to 
discontinue therapy and will be followed as described in Appendix 4.
Section 5.1. Inclusion Criteria
Rationale for change: Updates to contraceptive measures required for study 
participants, based upon January 2020 updates to the fulvestrant Summary of Product 
Characteristics have been added to Appendix 4.
REVISED TEXT
Criteria 15
15. A female subject is eligible to participate if she is of:

Non-childbearing potential defined in Section 6.10.2.1

Child-bearing potential as defined in Section 6.10.2.2, and agrees to use one 
of the contraception methods as described in Appendix 4, from the time of 
the screening pregnancy test until 7 months after the last dose of study 
medication.
Section 5.4. Withdrawal/Stopping Criteria
Rationale for change: Provides updated guidance for subjects who have discontinued 
combination treatment and are on fulvestrant monotherapy.
REVISED TEXT
Second paragraph last bullet point

discontinuation from combination treatment, or of GSK525762 with continuation 
on fulvestrant monotherapy for >6 months
Twelfth paragraph onwards
Subjects who require permanent discontinuation of one of the study treatments in a given 
combination may continue on the other treatment until disease progression, withdrawal of 
consent, or unacceptable toxicity after discussion with Medical Monitor. With the 
implementation of amendment 06, subjects who have permanently discontinued treatment 
with the combination, or of GSK525762 but have remained on fulvestrant monotherapy 
for >6 months should be discontinued from study.
At the time of study completion, subjects with radiologically confirmed lack of disease 
progression (from Phase I and Phase II) who are still receiving GSK525762 and/or 
fulvestrant may continue treatment through a separate mechanism (e.g., roll-over 
protocol) to be determined at that time.
Enrolment into the study is now closed. The study will conclude when the last subject has 
completed/discontinued study treatment and completed the end of treatment visit.


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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 based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. Specific assessments that are no 
longer required, due to the status of the study, are being removed to minimize patient 
burden.
REVISED TEXT
Third paragraph onwards
The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed.
With the implementation of Amendment 06, 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 6.1. Investigational Product and Other Study Treatment
Rationale for change: Provides clarification on clinical supply dosages available for the 
study.
REVISED TEXT


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Investigational Product (Phase 1)
Product 
name:
GSK525762C Tablets
Fulvestrant
Unit dose 
strength(s)/Do
sage level(s):
5 mg
20 mg
25 mg
250 mg
Dosage form
Tablet
Tablet
Tablet
IM Injection
Manufacturer
GSK
GSK
GSK
AstraZeneca
Physical 
description:
White to slightly colored, round, biconvex 
tablet.
5-mL prefilled syringe containing 
250 mg/5 mL fulvestrant.
The solution for injection is a clear, 
colorless to yellow, viscous liquid.
Route/
Administratio
n/ Duration:
Oral; see Time and Event Tables for 
schedule and administration timings
IM
Dosing 
instructions:
Dose with 240 mL liquid* 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.)
Administer 500 mg intramuscularly into the 
buttocks slowly (1-2 minutes per injection) 
as two 5 mL injections, one in each buttock, 
on days 1, 15, 29, and once monthly 
thereafter.  There is a ±3-day dosing 
window for the fulvestrant.
NOTE: The Phase 1 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.  Phase 2 
formulation details will be provided in an amendment.
*Subjects may take BET with 240 mL of liquid (other than orange, grapefruit, pomelo, or exotic citrus fruit 
juice).  On serial PK days (W1D1 and W3D1), subjects must take BET with water only.
Section 6.2.2. Phase II
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population.
REVISED TEXT
With implementation of amendment 06, Phase II of the study is terminated.
Section 7. STUDY ASSESSMENTS AND PROCEDURES
Rationale for change: These changes are based on the decision to close out the study 
and stop all new enrolment based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. 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
Third paragraph third bullet

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. With the implementation of Amendment 06, specific assessments 
and collection of survival follow-up data will no longer be required. Please see 
Section 7.1 for further details.


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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 based on interim data 
failing to demonstrate meaningful clinical benefit in the proposed patient population. Specific assessments that are no longer required, due 
to the status of the study, are being removed to minimize patient burden.
REVISED TEXT
Table 4
Time and Events, Phase I
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
X
ECOG PS5
X
X
X
X
X
X
X
X
X
12-lead ECGs6
X
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
Week 13, 
25, 37, 
49
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK52576210
Daily


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Administer Fulvestrant10
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication 
review
Continuous from signing of informed consent


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D4
D1
D4
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Pharmacokinetics (PK), Pharmacodynamics (PD) & Pharmacogenomics (PGx)
PK blood samples11
PK
PK
O
X
Tumor biopsy12
X
One sample, collected 
between W3D4 and W5D4, as 
close as possible to 3-6h post-
GSK525762 dose
X13
Whole blood for exploratory 
analyses13
X
X
X
PGx blood sample14
X
Efficacy
CT 
chest/abdomen/pelvis14pelvis
15
X
X
X
X
EORTC-QLQ-C30 & 
EORTC-QLQ-BR2315BR2316
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 06, following the EOT 
visit, subjects will 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.
2.
Screening procedures should be performed as rapidly as possible within 28 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements. Clinical 
lab assessments should be completed within 14 days prior to dosing, and in case of abnormal test values, retesting may be performed if medically indicated and within 14 days 
prior to Day 1. 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 within 28 days prior to Day 1 
(first dose of study medication) unless otherwise indicated: CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1). 
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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. Post Week 49, assessments will be completed every 12 weeks.
5.
Post Week 49, ECOG assessments will be completed every 12 weeks.
6.
Triplicate ECGs should be performed at screening. All other timepoints can be single ECGs prior to dosing and evaluated for abnormality prior to administration of dose. Post 
Week 49, assessments will be completed every 12 weeks. Triplicate ECGs to be performed as clinically indicated, based upon abnormal findings.
7.
Refer to Table 5  for details of clinical safety labs and timing of collection
8.
Whatever scanning modality is used at screening should be maintained for all subsequent scans. An assessment is not performed at W9. Beginning at W13, scans will be 
performed once every 12 weeks.


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9.
With the implementation of amendment 06, the PRO-CTCAE will no longer be collected. Patient Reported Outcomes Version of the Common a Terminology Criteria for 
Adverse Events (PRO-CTCAE) Item Library (Version 1.0).  Post Week 49, assessments will be completed every 8 weeks.
10. Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for 
fulvestrant dosing.  On PK collection days in Week 1 and Week 3, subjects should abstain from food from 8 h prior until 2 h after dose as described in Section 6.10.1.  Post 
Week 49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.
11. With the implementation of amendment 06, PK samples will no longer be collected. “PK” = serial PK days.  Sample collections should be obtained at the following 
timepoints: Pre-dose, 30 m ± 5 m, 1 h ± 10 m, 3 h ± 30 m.  “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose 
samples will be split to obtain a PK sample for fulvestrant analysis. Refer to the SRM for further details.
12. With the implementation of amendment 06, tumor biopsies will no longer be collected, and the EOT tumor biopsy will no longer be collected. Mandatory Screening 
tumor biopsy specimen is required for all subjects; within 28 days prior to first study dose as described in Section 7.5.1. .    Subjects providing an optional on-treatment fresh 
tumor biopsy, whether they have had a dose interruption of GSK525762 or not, must have received at least 4 consecutive doses of GSK525762 prior to the collection of the 
tissue.  If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the 
medical monitor after subject recovery.  Fresh biopsies should be paired with plasma samples for PK, collected as close as possible to biopsy (ideally within 1 h).  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. Refer 
to the SRM for further details.
13. With the implementation of amendment 06, whole blood for exploratory analyses will no longer be collected. A tumor biopsy at the end of treatment is optional, but 
strongly encouraged when clinically feasible.
14. With the implementation of amendment 06, if a PGx sample has not yet been collected, collection will no longer be required. 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 7.  EOT disease assessment is not required if 
reason for discontinuing therapy was progressive disease and prior assessment was within 14 days of EOT visit. Subjects with contraindication to contrast-enhanced 
computed tomography (CT) or MRI may have imaging performed as described in Section 7.2.1.
15. With the implementation of amendment 06, contrast-enhanced computed tomography (CT) scan data will no longer be required for disease assessment. European 
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures. Post Week 49, assessments will be 
completed every 8 weeks.
16. With the implementation of amendment 06, EORTC questionnaires will no longer be collected.
Table 6
Time and Events, Phase II
Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D1
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Screening2
Informed Consent
X
Demography
X
Medical History
X


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D1
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
Inclusion/Exclusion Criteria
X
Disease Characteristics
X
Prior Therapy3
X
Register Subject
X
Safety
Physical Exam4
X
X
X
X
X
X
X
X
X
ECOG PS5
X
X
X
X
X
X
X
X
X
12-lead ECGs6
X
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
Week 13, 
25, 37, 49
X
X
PRO-CTCAE9
X
X
X
X
X
X
X
X
X
Study Treatment
Administer GSK52576210
Daily
Administer Fulvestrant10
X
X
X
X
AE/SAE review
Continuous from signing of informed consent
Concomitant medication 
review
Continuous from signing of informed consent
Pharmacokinetics (PK), Translational Studies & Pharmacogenomics (PGx)
PK blood samples11
O
O
X
Tumor biopsy12
X
X13
Whole blood for exploratory 
analyses
X
X
X
PGx blood sample
X
Efficacy
CT chest/abdomen/pelvis14
X
X
X
X
EORTC-QLQ-C30 & EORTC-
QLQ-BR2315
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. 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 


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Procedure
SCR
Week 1
Week 2
Week 3
Week 4
Week 5
q4w
q8w
q8w
q12w
EOT1
D1
D4
D1
D1
D1
D1
W9 to 
W49
W9 to 
W49
W49 and 
thereafter
W49 and 
thereafter
email.
2.
Screening procedures should be performed as rapidly as possible within 28 days prior to Day 1 (first dose of study medication) to facilitate subject entry requirements.  Clinical lab 
assessments should be completed within 14 days prior to dosing, and in case of abnormal test values, retesting may be performed if medically indicated and within 14 days prior to Day 
1. 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 within 28 days prior to Day 1 (first dose of study medication) 
unless otherwise indicated: CT scans (within 30 days prior to Day 1) and ECHO/MUGA (within 35 days prior to Day 1).
3.
Including dates of imaging and sizes of target lesion(s) used for RECIST 1.1 evaluation, if available.
4.
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. Post Week 49, assessments will be completed every 12 weeks.
5.
Post Week 49, ECOG assessments will be completed every 12 weeks.
6.
Triplicate ECGs should be performed at screening. All other timepoints can be single ECGs prior to dosing and evaluated for abnormality prior to administration of dose. Post Week 49, 
assessments will be completed every 12 weeks.  Triplicate ECGs to be performed as clinically indicated, based upon abnormal findings.
7.
Refer to Table 7  for details of clinical safety labs and timing of collection
8.
Whatever scanning modality is used at screening should be maintained for all subsequent scans.  An assessment is not performed at W9. Beginning at W13, scans will be performed 
once every 12 weeks. 
9.
Patient Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Item Library (Version 1.0). Post Week 49, assessments will be completed 
every 8 weeks. 
10. Drugs should be administered as described in Section 6.1.  Visits where fulvestrant is administered will be considered drug dispensing days.  There is a ±3 day window for the 
fulvestrant dosing.  Post Week 49, fulvestrant will continue to be administered every 4 weeks.  Refer to the SRM for further details.      
11. “O” = sample collections to be obtained pre-dose, 0.5-1h post-dose, and an optional sample 4-8h 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). Pre-dose samples will be split to obtain a PK sample for fulvestrant analysis only for 
subjects who are receiving fulvestrant. Refer to the SRM for further details. 
12. Screening tumor biopsy specimen is required for all subjects;the fresh specimen must be provided within 28 days prior to first study dose. It is acceptable to collect tumor biopsy 
specimen within the screening period. A sample collected within 3 months of first dose is also acceptable only if it was collected after the last anticancer treatment.    Refer to Section 
7.2.1 and to the SRM for further details.  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.
13. Tumor biopsy at the end of treatment is optional, but strongly encouraged when clinically feasible
14. CT should be performed with oral and intravenous (IV) contrast.  Any potential CR or PR should be confirmed as described in Appendix 7.  EOT disease assessment is not required if 
reason for discontinuing therapy was progressive disease and prior assessment was within 14 days of EOT visit. Subjects with contraindication to contrast-enhanced computed 
tomography (CT) or MRI may have imaging performed as described in Section 7.2.1.
15. European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core-30 and Breast 23 measures.  Post Week 49, assessments will be 
completed every 8 weeks.  


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Table 7
Time and Events, Phase 2 Laboratory Assessments
SCR
1
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Week 7
Week 8
Week 9
Week 11
q4w
q12w
EOT
D1
D
4
D1
D1
D1
D1
D1
D1
D1
D1
D1
W13 and 
after
W49 and 
after
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Troponin, N-
terminal pro–B-
Type natriuretic 
peptide (NT-
proBNP)
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay2
X
X
X
Fasting blood 
glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Thyroid (Thyroid 
stimulating 
hormone (TSH), 
free 
triiodothyronine 
(T3), free thyroxine 
(T4))3
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
HIV, Hepatitis B 
surface antigen
(HBsAg), Hepatitis 
C Virus (HCV) 
Antibody
X
FSH/Estradiol4
X
Pregnancy test5
X
X
X
X
X
X
X
X
X


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1.
Although strongly preferred, lab results for HBA1c, fasting lipids, TSH/T3/T4, and pancreatic enzymes are not required prior to dosing.
2.
Also perform if PT or INR are ≥1.5XULN, or in case of bleeding event
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).
4.
Only required at screening for pre- and peri-menopausal subjects
5.
Serum pregnancy test within 7 days prior to first dose; urine or serum test thereafter


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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 based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. Specific assessments that are no 
longer required, due to the status of the study, are being removed to minimize patient 
burden.
REVISED TEXT
First paragraph added
With the implementation of amendment 06, specific assessments and collection of 
survival follow-up data will no longer be required. Please see Section 7.1 for further 
details.
Section 7.3.3. Cardiac Safety
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
7.3.3.1. Electrocardiograms
Last paragraph
ECG data willmay 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 06, transfer of ECG data to a central facility is no longer 
required.
7.3.3.2. Echocardiogram or Multigated Acquisition Scan
Second paragraph
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 06, 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


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First paragraph and second paragraph first sentence
With the implementation of amendment 06, PK samples will no longer be collected.
Blood samples for pharmacokinetic (PK) analysis of fulvestrant and GSK525762 
(including relevant metabolite[s]) will be collected at the time points indicated in Table 4
and Table 6.
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
With the implementation of amendment 06, 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 06, CT scan data will no longer be required 
for disease assessment. See the Time and Events Table (Section 7.1) for the updated 
schedule of assessments. 
Fifth Paragraph
The baseline disease assessment will be completed within 30 days prior to the first dose 
of GSK525762 and fulvestrant, then approximately every 8 weeks thereafter and at the 
final study visit. See the Time and Events Table (Section 7.1) for the schedule of 
assessments of anti-cancer activity.
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
With the implementation of amendment 06, tumor samples will no longer be collected.
Section 7.7.3. Circulating cell free DNA/RNA Analysis
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
With the implementation of amendment 06, blood samples 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
With the implementation of amendment 06, 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. Value Evidence and Outcomes
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
7.9.1. PRO-CTCAE
With the implementation of amendment 06, 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-CTCTAE) Item Library (version 1.0) will be 
administered to select patients based on the availability of translated versions.
7.9.2. PRO-CTCAE EORTC-QLQ-C30 & EORTC-QLQ-BR23
With the implementation of amendment 06, the EORTC questionnaires will no longer be 
completed.
The effect of GSK525762 and fulvestrant, 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 questionnaires.  Both the EORTC-QLQ-
C30 (version 3) core questionnaire and the EORTC-QLQ-BR23 disease-specific modules 
will be administered.
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 based on interim data failing to demonstrate meaningful 
clinical benefit in the proposed patient population. 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


2015N238773_06
CONFIDENTIAL
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The totality of Phase I data assessed at the interim analysis does not support continuing 
investigation of GSK525762 (molibresib) in combination with fulvestrant for the 
treatment of HR+/HER2- advanced or metastatic breast cancer patients. Enrolment into 
the study is now closed as interim data failed to demonstrate meaningful clinical benefit 
in this patient population.
With the implementation of Amendment 06, 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. There will be no Phase II.
Any changes to planned analyses outlined below will be covered in the Reporting 
Analysis Plan (RAP).
Section 12.4.1. Contraception Guidance
Rationale for change: Updates to contraceptive measures required for study 
participants, based upon January 2020 updates to the fulvestrant Summary of Product 
Characteristics have been added to Appendix 4, Section 12.4.1.
REVISED TEXT
Note: Hormonal methods of contraception are not permitted since the efficacy of these 
methods in combination with GSK525762 has not been assessed. LHRH-acting agents 
alone are not considered an adequate form of contraception.  GSK525762 has been 
shown to effect female reproductive systems in animals, therefore women of childbearing 
potential should adhere to this contraceptive guidance whilst on study and for 7 months 
after cessation of treatment with GSK525762, to be in line with GSK525762 guidance. 
Effective January 13, 2020, the EU fulvestrant Summary of Product Characteristics 
was updated to include effective contraceptive use for women of childbearing 
potential for 24 months post last dose. Please consult the local fulvestrant 
prescribing information to ensure subjects are using effective forms of 
contraception for the appropriate length of time required after stopping treatment 
with fulvestrant.
Section 12.11.
Appendix 11: Genetic Research
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
Study Assessments and Procedures
Last paragraph
Subjects can request their sample to be destroyed at any time. With the implementation of 
amendment 06, if a subject has consented for genetic research but the sample has yet to 
be collected, this will no longer be required.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201973 
 
1 
 
Division 
: Worldwide Oncology Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a Phase I/II Dose Escalation 
and Expansion Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity of 
GSK525762 in Combination with Fulvestrant in Subjects with 
Hormone Receptor-Positive/HER2-Negative (HR+/HER2-) 
Advanced or Metastatic Breast Cancer. 
Compound Number  : GSK525762 
Effective Date  
: 11-AUG-2020 
 
Description: 
• The purpose of this RAP is to describe the planned analyses and output to be included 
in the Phase I Clinical Study Report for Protocol 201973. This includes the Primary 
Clinical Study Report (CSR) and any End-of-Study outputs that will be generated. 
• This RAP is intended to describe the planned efficacy, safety and pharmacokinetics 
analyses required for Phase I of the study.  
• This RAP will be provided to the study team members to convey the content of Phase 
I data review and interim analysis deliverables, as well as to provide details of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author: 
Author 
Date 
 
Senior Biostatistician, Biostatistics FSP, PAREXEL employee on 
behalf of GlaxoSmithKline 
30-JUL-2020 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201973 
 
2 
 
RAP Team Reviewers: 
Reviewer 
Date 
Approval Method 
 
Clinical Scientist, Oncology Clinical 
Development 
10-AUG-2020 
Email 
 
Director, Clinical Pharmacology Modelling 
and Simulation, GSK 
03-AUG-2020 
Email 
 
Medical Director, Oncology Clinical 
Development  
07-AUG-2020 
Email 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Approver 
Date 
Approval Method 
 
Senior Statistics Director, Biostatistics, GSK 
11-AUG-2020 
Email 
 
Programming Director, Biostatistics, GSK 
31-JUL-2020 
Email 
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TABLE OF CONTENTS 
PAGE 
RAP AUTHOR: ................................................................................................................ 1 
RAP TEAM REVIEWERS:............................................................................................... 2 
CLINICAL STATISTICS AND CLINICAL PROGRAMMING LINE APPROVALS: ............. 2 
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 ............................................... 11 
2.4.1. Dose Escalation Phase ............................................................................... 11 
2.4.2. Dose Expansion Phase ............................................................................... 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.1.1. Dose Escalation Phase ............................................................................... 12 
3.1.1.1. 
Displays to be Created for Dose Escalation Review .................... 13 
3.1.2. Dose Expansion Phase ............................................................................... 14 
3.1.2.1. 
Interim Futility Analysis ................................................................ 14 
3.1.2.2. 
Interim Efficacy Analyses ............................................................. 16 
3.1.2.3. 
Displays to be Created for Dose Expansion Review .................... 16 
3.2. 
Final Analysis ............................................................................................. 17 
4. 
ANALYSIS POPULATIONS ................................................................................... 18 
4.1. 
Protocol Deviations ..................................................................................... 18 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 20 
5.1. 
Study Treatment and Sub-group Display Descriptors ................................. 20 
5.2. 
Reporting Conventions ............................................................................... 21 
5.3. 
Baseline and Post-Baseline Definitions ....................................................... 22 
5.3.1. Change from baseline ................................................................................. 22 
5.3.2. Multiple Assessments ................................................................................. 22 
5.4. 
Multicentre Studies ..................................................................................... 23 
5.5. 
Examination of Covariates, Other Strata, and Subgroups ........................... 23 
5.5.1. Covariates and Other Strata ....................................................................... 23 
5.5.2. Examination of Subgroups .......................................................................... 23 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 23 
6. 
STUDY POPULATION ANALYSES ....................................................................... 24 
6.1. 
Overview of Planned Study Population Analyses ........................................ 24 
6.2. 
Disposition of Subjects ................................................................................ 24 
6.3. 
Protocol Deviations ..................................................................................... 24 
6.4. 
Demographic and Baseline Characteristics ................................................. 25 
6.5. 
Concomitant Medications ............................................................................ 25 
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7. 
EFFICACY ANALYSES .......................................................................................... 26 
7.1. 
Endpoints / Variables .................................................................................. 26 
7.2. 
Summary Measures .................................................................................... 28 
7.3. 
Population of Interest .................................................................................. 28 
7.4. 
Statistical Analyses / Methods .................................................................... 29 
8. 
SAFETY ANALYSES ............................................................................................. 29 
8.1. 
Adverse Events Analyses ........................................................................... 29 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 31 
8.3. 
Deaths and Serious Adverse Events ........................................................... 32 
8.4. 
Adverse Events Leading to Discontinuation of Study Treatment and 
Other Significant Adverse Events ............................................................... 32 
8.5. 
Extent of Exposure ..................................................................................... 32 
8.6. 
Pregnancies ................................................................................................ 33 
8.7. 
Clinical Laboratory Analyses ....................................................................... 33 
8.7.1. Analyses of Liver Function Tests ................................................................ 36 
8.8. 
Other Safety Analyses ................................................................................ 36 
8.8.1. Vital Signs ................................................................................................... 36 
8.8.2. Performance Status .................................................................................... 37 
8.8.3. ECG ............................................................................................................ 37 
8.8.4. LVEF .......................................................................................................... 38 
8.8.5. Liver Events ................................................................................................ 38 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 38 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 38 
9.1.1. Endpoint / Variables .................................................................................... 38 
9.1.1.1. 
Drug Concentration Measures ..................................................... 38 
9.1.1.2. 
Derived Pharmacokinetic Parameters .......................................... 39 
9.1.2. Summary Measure ..................................................................................... 40 
9.1.3. Population of Interest .................................................................................. 40 
10. PHARMACODYNAMIC ANALYSIS ........................................................................ 40 
11. OTHER STATISTICAL ANALYSES ....................................................................... 40 
11.1. 
Value Evidence and Outcomes ................................................................... 40 
12. REFERENCES ....................................................................................................... 41 
13. APPENDICES ........................................................................................................ 42 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 42 
13.1.1. Exclusions from Per Protocol Population .................................................... 42 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 43 
13.3. 
Appendix 3: Assessment Windows ............................................................. 44 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 45 
13.4.1. Study Phases ............................................................................................. 45 
13.4.2. Treatment States ........................................................................................ 45 
13.4.2.1. 
Treatment States for Disease Response Data ............................. 45 
13.4.3. Treatment Emergent Flag for Adverse Events ............................................ 46 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 47 
13.5.1. Reporting Process ...................................................................................... 47 
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13.5.2. Reporting Standards ................................................................................... 47 
13.5.3. Reporting Standards for Pharmacokinetic ................................................... 48 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 50 
13.6.1. General ....................................................................................................... 50 
13.6.2. Study Population ......................................................................................... 51 
13.6.3. Efficacy ....................................................................................................... 51 
13.6.4. Safety ......................................................................................................... 52 
13.6.5. Value Evidence and Outcomes ................................................................... 54 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 58 
13.7.1. Premature Withdrawals ............................................................................... 58 
13.7.2. Handling of Missing Data ............................................................................ 58 
13.7.3. Handling of Missing and Partial Dates ........................................................ 58 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 62 
13.8.1. Laboratory Values ....................................................................................... 62 
13.8.2. ECG ............................................................................................................ 62 
13.8.3. Vital Signs ................................................................................................... 62 
13.8.4. Left Ventricular Ejection Fraction ................................................................ 63 
13.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 64 
13.10. Appendix 10: Abbreviations & Trademarks ................................................. 65 
13.10.1. 
Abbreviations ............................................................................... 65 
13.10.2. 
Trademarks ................................................................................. 66 
13.11. Appendix 11: List of Data Displays.............................................................. 67 
13.11.1. 
Data Display Numbering .............................................................. 67 
13.11.2. 
Mock Example Shell Referencing ................................................ 67 
13.11.3. 
Deliverables ................................................................................. 67 
13.11.4. 
Study Population Tables .............................................................. 68 
13.11.5. 
Efficacy Tables ............................................................................ 70 
13.11.6. 
Efficacy Figures ........................................................................... 71 
13.11.7. 
Safety Tables ............................................................................... 72 
13.11.8. 
Pharmacokinetic Tables ............................................................... 81 
13.11.9. 
Pharmacokinetic figures ............................................................... 83 
13.11.10. 
ICH Listings ................................................................................. 84 
13.11.11. 
Non-ICH Listings .......................................................................... 90 
13.12. Appendix 12: Example Mock Shells for Data Displays ................................ 93 
 
 
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1. INTRODUCTION 
The purpose of this RAP is to describe the analyses to be performed in support of the 
Clinical Study Report for GSK Protocol 201973. 
Revision Chronology: 
Original 
11-AUG-2016 
2015N238773_00 
Amendment No. 1 
21-OCT-2016 
2015N238773_01 
Amendment No. 2 
31-JAN2017 
2015N238773_02 
Amendment No. 3 
07-MAR-2017 
2015N238773_03 
Amendment No. 4 
18-OCT-2017 
2015N238773_04 
Amendment No. 5 
11-SEP-2018 
2015N238773_05 
Amendment No. 6 
06-MAY-2020 
2015N238773_06 
 
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 
Primary Objectives 
Primary Endpoints 
• 
To determine a recommended Phase 2 
dose (RP2D) of GSK525752, when given 
in combination with fulvestrant, in 
women with advanced or metastatic 
hormone receptor-positive/HER2-
negative breast cancer (HR+/HER2− 
BC). 
• 
Safety profile (e.g., adverse events 
[AEs], serious adverse events [SAEs], 
dose-limiting toxicities [DLTs], dose 
reductions or delays), overall response 
rate (ORR; defined as complete response 
[CR] rate plus partial response [PR] 
rate), pharmacokinetic (PK) parameters. 
Secondary Objectives 
Secondary Endpoints 
• 
To determine the safety, tolerability and 
maximum tolerated dose (MTD) of 
GSK525762, when given in combination 
with fulvestrant in women with advanced 
or metastatic HR+/HER2− BC. 
• 
AEs, 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 evaluate clinical activity of 
GSK525762 and fulvestrant, when given 
in combination, in women with advanced 
or metastatic HR+/HER2− BC. 
• 
Disease control rate (DCR; defined as 
rate of CR plus PR plus stable disease 
[SD]), duration of response (DoR), and 
progression-free survival (PFS). 
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Objectives 
Endpoints 
• 
To characterize the exposure to 
GSK525762 and fulvestrant, when given 
in combination, in women with advanced 
or metastatic HR+/HER2− BC. 
• 
Concentrations of GSK525762, 
GSK525762 relevant metabolites, and 
fulvestrant following administration in 
combination. 
Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate additional measures of 
clinical activity of GSK525762 and 
fulvestrant, when given in combination, 
in women with advanced or metastatic 
HR+/HER2− BC. 
• 
Overall survival (OS). 
• 
To characterize the pharmacodynamics 
of GSK525762 and fulvestrant, when 
given in combination, in women with 
advanced or metastatic HR+/HER2− BC. 
• 
Transcriptomic and/or protein changes in 
molecular markers of BET inhibition and 
HR signalling in tumor tissue. (Analyses 
may not be conducted if insufficient 
sample size.) 
• 
To identify potential indicators of 
sensitivity or response to GSK525762 
and fulvestrant, when given in 
combination, in women with advanced or 
metastatic HR+/HER2− BC. 
• 
Mutational analysis of tumor tissue; 
correlation of baseline somatic and 
tumor-specific genetic and genomic 
profiles with response. (Analyses may 
not be conducted if insufficient sample 
size.) 
• 
To describe the kinetics of tumor growth 
in the presence of GSK525762 and 
fulvestrant for each treatment and 
investigate the relationship between 
tumor growth kinetics and clinical 
activity. 
• 
Tumor size over time, tumor growth rate 
constants, and time to tumor growth, 
predicted by the model parameters 
defining relationships with clinical 
activity parameters. 
• 
To evaluate the exposure-response 
relationship between GSK525762 and/or 
fulvestrant exposure and safety and 
efficacy parameters. 
• 
Relationship between GSK525762 
and/or fulvestrant exposure markers 
(e.g., dose, Cmin, Cmax), and safety and 
efficacy parameters. 
• 
To evaluate the effect of GSK525762 
and fulvestrant, when given in 
combination, on symptoms and quality of 
life. 
• 
Change from baseline in EORTC-QLQ-
C30 and EORTC-QLQ-BR23 
questionnaires. Changes from baseline in 
select items from the PRO-CTCAE. 
• 
To evaluate ESR1 mutational status as a 
potential indicator of sensitivity and/or 
response to GSK525762 and fulvestrant, 
when given in combination, in women 
with advanced or metastatic 
HR+/HER2− BC. 
• 
Targeted sequencing to determine 
correlation between ESR1 mutations and 
clinical response. 
 
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• 
Phase I of the study is designed as a parallel, single-arm, dose 
escalation/expansion phase to determine the RP2D based on safety, 
tolerability, PK and efficacy profiles observed after oral administration of 
GSK525762 in combination with fulvestrant, in advanced or metastatic 
HR+/HER2− BC subjects. The combination of GSK525762 plus 
fulvestrant will be evaluated in an open-label fashion in separate 
populations (i.e., cohorts) of subjects. Subjects will be enrolled into one of 
the following cohorts based on treatment history:  
1. Cohort 1 – Subjects with disease that relapsed during prior treatment 
or within 12 months after completing adjuvant therapy with an 
aromatase inhibitor (AI), or disease that progressed during prior 
treatment with an AI for advanced/metastatic disease. Prior ovarian 
suppression and/or tamoxifen are allowed, given all other criteria are 
met. 
2. Cohort 2 – Subjects with disease that progressed during prior treatment 
with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus 
letrozole for advanced/metastatic disease. Prior ovarian suppression 
and/or tamoxifen are allowed, given all other criteria are met. 
• 
Phase I will follow a modified toxicity probability interval (mTPI) design, 
assuming (a) approximately 30 subjects will complete the DLT evaluation 
period and (b) the true underlying toxicity rate for GSK525762 in 
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Overview of Study Design and Key Features 
combination with fulvestrant falls within the range of 25% to 35%, 
centered at 30%. 
• 
Cohort 1 may enrol up to 35 subjects, while Cohort 2 may enrol up to 32 
subjects. However, the total number of subjects enrolled into each cohort 
may vary, as interim analyses for safety and efficacy may terminate 
enrolment within a cohort if the observed DLT rate exceeds the maximum 
permitted toxicity rate per the mTPI, or if the efficacy rate does not exceed 
the historical ORR. 
• 
Dosing will begin at dose level 1 (DL1), with subjects administered 
GSK525762 at 60 mg orally once daily and fulvestrant at 500 mg 
intramuscularly (IM) on Days 1, 15 and 29 of Cycle 1 and then monthly 
thereafter. Subjects will be enrolled into cohorts based on their treatment 
history. Once three evaluable subjects (total, irrespective of cohort) have 
cleared the DLT evaluation period of 28 days, then an mTPI method will 
be used to determine whether to dose escalate to DL2 (if there is no DLT), 
reduce dose to DL-1 (if there are two or three DLTs), or continue enrolling 
subjects at DL1 (if there is one DLT). Up to 10 additional subjects may be 
enrolled in groups of approximately three at DL1 prior to a final dose 
escalation/de-escalation decision. If DL-1 is tested and found to be safe, 
then re-evaluation of DL1 may be attempted, if guided by the model. If 
both DL-1 and DL1 are being evaluated, then subjects will be randomized 
1:1 to either DL-1 or DL1. 
• 
Once a sentinel group of 3-10 evaluable subjects has cleared the DLT 
evaluation period of 28 days at DL1, the two cohorts will open at DL2. 
The DL2 DLT evaluation will occur as described for DL1, with a sentinel 
group of 3-10 evaluable subjects spread across the two cohorts. 
• 
For each cohort, enrolment within the cohort may be stopped due to futility 
if the Bayesian predictive probability of confirmed response rate ≥25% 
(target) is small. Guidelines for interim futility analysis decision rules for 
the 10th through 34th evaluable subject are presented in Section 3.1.2.1, 
Interim Futility Analysis. The guidelines specify the number of subjects 
with confirmed responses needed for continued enrolment versus stopping 
for futility when the total sample size is ≤34 subjects in the cohort. 
• 
The decision to proceed to Phase II will be based on the totality of data 
from Phase I, including safety, efficacy and PK data.  
• 
While the overall study goals and design remain the same, changes have 
been made to Phase I of the study in order to address the emerging data 
and better define the patient population most likely to benefit from the 
combination treatment of GSK525762 plus fulvestrant. The following are 
to be noted: 
1. DL1 Cohort 1 (60 mg, AI failures) will enrol up to 35 subjects, as per 
Protocol Amendment 5. 
2. DL1 Cohort 2 (60 mg, CDK4/6 + AI failure) – change in inclusion 
criteria and to the number of subjects to be enrolled is detailed below. 
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Overview of Study Design and Key Features 
3. DL2 (80 mg) both cohorts (Cohort 1 and Cohort 2) – enrolment is 
closed based on decreased tolerability and lack of efficacy, as per 
protocol guidance. 
• 
Enrolment into DL1 (60mg) Cohort 2 is modified. Subjects previously 
treated with the combination of a CDK4/6 inhibitor (e.g., palbociclib) plus 
AI for advanced or metastatic disease will be enrolled as follows: 
o Up to 32 subjects with measurable disease who have progressed after 
greater than or equal to 12 months of prior treatment with CDK4/6 
inhibitor plus AI. 
o Up to 16 subjects with bone only disease who have progressed after 
greater than or equal to 12 months of prior treatment with CDK4/6 
inhibitor plus AI. 
o Prior ovarian suppression and/or tamoxifen will be allowed, given all 
other criteria are met. 
 Dosing 
The projected dose levels of GSK525762 for Phase I dose escalation are 60 mg 
(DL1) and 80 mg (DL2), each administered orally once daily. If unacceptable 
toxicity is observed at 60 mg, then 40 mg once daily may be explored (referred 
to as DL-1). 
The projected dose level of fulvestrant is the approved dose regimen of 500 mg 
IM on Days 1, 15 and 29 of Cycle 1 and then monthly thereafter. 
Time and 
Events 
Refer to Tables 4 and 5 in Section 7.1 of the Protocol. 
Treatment 
Assignment 
Study Phase I is an open label, single-arm phase. If one dose level is open for 
enrolment, subjects will be assigned to the dose at that level. If more than one 
dose level is open for enrolment, subjects will be randomly assigned to one of 
the open dose levels with 1:1 allocation. 
Interim 
Analysis 
After at least 10 evaluable subjects become available in each expansion cohort, 
futility analyses will be performed. After that, interim analysis may be 
conducted after every 5 evaluable subjects become available. Phase I interim 
analyses may also be undertaken for each expansion cohort after the last 
subject enrolled in the cohort has been followed for 6 months or has 
progressed, died, or withdrawn from the study treatment.  
Enrolment to an individual cohort may be stopped due to futility if the 
Bayesian posterior probability that the confirmed ORR ≥25% in Cohort 1 (AI 
failure) or ≥20% in Cohort 2 (CDK4/6 + AI failure) is small (see Tables 1 and 
2). Enrolment may also be stopped due to futility if the equivalent of no 
response is observed in the first 10 enrolled evaluable subjects in that cohort or 
if fewer than 2 confirmed responses are observed in the first 14 and 19 
evaluable subjects in Cohort 1 and Cohort 2, respectively. 
Decision-making criteria for futility are presented in Table 9 for Cohort 1 (AI 
failure) and Table 10 for Cohort 2 (CDK4/6 + AI failure) in Section 9.3.2 of 
the Protocol. 
Final 
Analysis 
The study will be considered complete for purposes of a final analysis when 
approximately 70% of all enrolled subjects have died. 
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Overview of Study Design and Key Features 
Study 
Status 
The totality of Phase I data assessed at the interim analysis does not support 
continuing investigation of GSK525762 (molibresib) in combination with 
fulvestrant for the treatment of HR+/HER2- advanced or metastatic breast 
cancer patients. As interim data failed to demonstrate meaningful clinical 
benefit in this patient population, enrolment into the study is now closed and 
the study will not incorporate Phase II. 
With the implementation of Amendment 06, 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. 
 
2.4. 
Statistical Hypotheses / Statistical Analyses 
2.4.1. Dose Escalation Phase 
Dose escalation decisions will be based on the totality of clinical safety assessment data, 
as well as PK data. All analyses will be descriptive in nature. 
2.4.2. Dose Expansion Phase 
For evaluation of efficacy in Cohort 1 (AI Failure) in Phase I, the primary goal is to 
demonstrate a clinically meaningful response rate, defined as an ORR (equal to CR rate + 
PR rate) of 25% relative to a 10% response rate suggesting no activity. This will be 
achieved by testing the null hypothesis of P0 ≤ 0.1 versus the alternative of P1 > 0.25, 
assuming the maximum response rate for an ineffective drug is 10% and the minimum 
response rate for an effective drug is 25%.  
For evaluation of efficacy in Cohort 2 (CDK4/6 + AI Failure) in Phase I, the primary goal 
is to demonstrate a clinically meaningful response rate in subjects with measurable 
disease only. In this cohort, a meaningful response rate is defined as an ORR of 20% 
relative to a 5% response rate suggesting no activity. This will be achieved by testing the 
null hypothesis of P0 ≤ 0.05 versus the alternative of P1 > 0.20, assuming the maximum 
response rate for an ineffective drug is 5% and the minimum response rate for an 
effective drug is 20%.  
Bayesian statistics will be employed to calculate the posterior probability that the ORR 
≥25% and ≥10% for Cohort 1 (AI Failure) and ≥20% and ≥5% for Cohort 2 (CDK4/6+AI 
Failure) at interim assuming a Beta prior for the Binomial distributed data. A weak prior 
Beta (0.0125, 0.0875) for Cohort 1 and (0.005, 0.095) for Cohort 2 will be used, which is 
equivalent to the information present in 0.1 subjects. 
 
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3. PLANNED ANALYSES 
3.1. 
Interim Analyses 
3.1.1. Dose Escalation Phase 
No formal interim analysis will be performed for dose escalation decisions in Phase I. 
These decisions instead will be based primarily on ongoing data review using Spotfire 
visualization, with additional outputs created by Statistics and Programming if necessary. 
The assessments driving dose escalation decisions will focus on the safety and tolerability 
of GSK525762 combined with fulvestrant within each combination of dose level x 
cohort. Descriptive analyses will be based on the All Treated Population (defined in 
Section 4, Analysis Populations). 
The mTPI design rules, together with predicted dose-limiting toxicity rates at all dose 
levels, will support the determination of whether to move forward with dose escalation 
and expansion as planned for Phase I. The mTPI design rests on the assumptions that (a) 
approximately 30 subjects will complete the DLT evaluation period and (b) the true 
underlying toxicity rate for GSK525762 in combination with fulvestrant falls within the 
range of 25% to 35%, centred at 30%.  
The monitoring rules guiding dose escalation are provided in Figure 1, below. Columns 
provide the numbers of subjects treated at the current dose level, while rows provide the 
corresponding numbers of subjects experiencing toxicity. Entries within the table 
represent the dose-finding decisions of 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, then the highest dose level is below MTD and the next subject(s) will be 
treated at the same dose level. In addition, decision U indicates that the current dose level 
is of unacceptably high toxicity and should be subsequently excluded from the trial. For 
example, when one of three subject experiences toxicity, the decision is located at row 
1/column 3, which is to stay at current dose level (S). Consequently, the next cohort of 
subjects will be treated at the same dose level currently being used. If none of three 
subjects experience toxicity, the decision is shown at row 0/column 3, which is to 
escalate (E) to a higher dose (if available) or to otherwise stop dose escalation when 6 
evaluable subjects have been treated at the current dose. Thus, the next cohort of subjects 
may be treated at the next higher dose level. If three of three subjects experience toxicity, 
the decision is to de-escalate (DU) to the next lower dose level and subsequently 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 
 
 
3.1.1.1. Displays to be Created for Dose Escalation Review 
Review of preliminary data will be performed after 3-10 evaluable 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 will be able to view subject-level 
data. In addition to the review of Spotfire data visualisations, summary displays may be 
provided by Statistics and Programming, as necessary.  
GSK has in place a comprehensive and robust review process of all data. During the dose 
expansion cohorts, all safety, efficacy, and PK data emerging from the study will be 
reviewed by a Joint Team comprised of participating investigators and study 
coordinators, together with staff involved in the conduct of the study (i.e. Medical 
Monitor, Program Lead Physician, Safety (Pharmacovigilance) Physician, Clinical 
Pharmacokineticist, Statistician, and Clinical Scientist).  
Furthermore, multiple review points and mechanisms will be implemented to safeguard 
subject safety during the conduct of Phase I. The key elements of such safety reviews will 
include regularly scheduled data reviews and investigator meetings, specific safety 
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review meetings, and a comprehensive dose selection meeting to be held at the end of 
Phase I. 
Prior to determining a dose level for the next cohort, exploratory analyses may be 
conducted to assess the potential relationships between dose level and safety, PK, and 
pharmacodynamic parameters using all data from available cohorts.  
The GSK study team, in collaboration with study investigators, will review all relevant 
data (as well as the results of any exploratory analyses) to determine whether the current 
dose showed acceptable toxicity and to decide the next dose level to be administered 
based on the totality of the data. 
3.1.2. Dose Expansion Phase 
3.1.2.1. Interim Futility Analysis 
Interim data will be evaluated to monitor efficacy and safety, and a planned interim 
analysis will be performed when at least 10 evaluable subjects have been enrolled into 
each of the expansion cohorts at each DL. Enrolment may be stopped early in any of the 
expansion cohorts for toxicity or lack of efficacy. The decision criteria for early stopping 
for futility is based on the Bayesian Hierarchical model described below. The decision 
will be made for each individual prior treatment history-specific cohort. 
For the futility interim analyses in each cohort, the enrolment for that cohort may be 
stopped due to futility if the posterior probability that the confirmed ORR ≥25% or ORR 
≥20% in Cohort 1 and Cohort 2, respectively, is small (e.g., less than a 4% chance for a 
total sample size of 35 subjects). Enrolment may also be stopped due to futility if the 
equivalent of no objective response (i.e., no confirmed CR or PR) is observed in the first 
10 evaluable subjects in that cohort or if fewer than 2 objective responses are observed in 
the first 14 and 19 evaluable subjects in Cohort 1 and Cohort 2, respectively. An 
evaluable subject is defined as a subject who has progressed, died, or withdrawn from the 
study treatment, or is still undergoing treatment and has completed at least two post-
baseline disease assessments. For example, if 14 evaluable subjects show only one 
response at the time of interim analysis, then the cohort may be stopped for futility. 
Otherwise, enrolment within the respective cohort will continue to the target sample size. 
Futility interim analysis decision rules for the 10th through 34th evaluable subject in 
Cohort 1 (AI Failure) and 10th through 31st evaluable subject in Cohort 2 (CDK4/6 + AI 
Failure) are presented in Tables 1 and 2, respectively. These rules, which are intended to 
function as guidelines, specify the number of objective responses (i.e., confirmed CRs or 
PRs) required to continue enrolment (vs. stop for futility) when the total target sample 
sizes are up to 35 in Cohort 1 and 32 in Cohort 2. Importantly, actual decisions will 
depend on the totality of the data. 
 
 
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Table 1 – Decision Making Criteria for Assessing Futility in Cohort 1 (AI Failure) 
 
 
 
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Table 2 – Decision Making Criteria for Assessing Futility in Cohort 2 (CDK4/6 + AI 
Failure) 
 
 
3.1.2.2. Interim Efficacy Analyses  
Interim efficacy analyses may also be performed for each expansion cohort after the last 
subject enrolled in the cohort has been followed for 6 months or has progressed, died, or 
withdrawn from the study treatment. 
3.1.2.3. Displays to be Created for Dose Expansion Review 
The All Evaluable Population (see Section 4, Analysis Populations) will be used for 
futility analyses. As subjects enrol at different times, not all subjects may be on study 
long enough to undergo multiple or even single post-baseline disease assessment(s). An 
evaluable subject is a subject who has progressed, died, or withdrawn from the study 
treatment, or is still undergoing treatment and has completed at least two post-baseline 
disease assessments.  
The All Treated Population (see Section 4, Analysis Populations) will be used to produce 
study population, efficacy (other than futility), and safety summaries. 
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The ORR is defined as the percentage of subjects in the population who show a best 
overall response (BOR) of confirmed CR or PR per RECIST v1.1. The ORR will be 
provided with its exact 95% confidence interval (CI). 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).  
A listing of subject status and BOR will be provided. This listing will be sorted by date of 
the subject’s first dose and will show whether each subject is still undergoing study 
treatment, whether the subject has had at least two post-baseline radiological disease 
assessments, whether the subject is considered evaluable for the futility analysis, and the 
subject’s BOR (including confirmed and unconfirmed response). 
Summaries, as well as data listings, of AEs, drug related AEs, AEs leading to study 
treatment discontinuation and other dose modifications, SAEs, fatal SAEs, study 
treatment related SAEs, exposure to GSK525762 and fulvestrant, and GSK525762 and 
fulvestrant dose modification(s) will be provided. In addition, summaries of laboratory 
assessments, vital signs, ECGs, Eastern Cooperative Oncology Group (ECOG) scores, 
and left ventricular ejection fraction (LVEF) results will be provided. 
PK analysis will be performed using the PK Population (as defined in Section 4, Analysis 
Populations), with results presented by subgroups representing combinations of dose 
level x cohort, for GSK525762, its relevant metabolites, and fulvestrant (see Section 
5.5.2 for subgroup descriptions). For further evaluation of the PK of GSK525762, the 
results within this study may also be compared to the results of other studies, wherein 
higher dose level(s) were administered. 
Refer to Appendix 11: List of Data Displays for the full list of displays. 
3.2. 
Final Analysis 
The final analysis will be performed when approximately 70% of all enrolled subjects 
have died. Also, the final analysis will occur after all required database cleaning activities 
have been completed and both final database release (DBR) and database freeze (DBF) 
have been declared by Data Management. 
As the study and project have been terminated, the primary analysis will occur once the 
termination decision has been confirmed, and the final analysis will occur once all 
ongoing subjects have completed the study. 
As final analysis may be performed when some subjects are still in follow-up and 
additional data may be available by study closure, an amendement to this RAP may be 
performed, if needed for guiding a re-run of the analysis described below. 
 
 
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4. ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screened 
Population 
Subjects who consent to participate in the trial. 
• 
Screen failures 
• 
Enrolled subjects  
All Treated 
Population 
Subjects who receive at least one dose of study 
treatment (GSK525762 or fulvestrant).  
In addition to primary analyses of study 
population, safety, and efficacy, this population 
will be used for decision-making during dose 
escalation. 
• 
Study population 
• 
Anti-cancer 
activity 
• 
Safety 
Modified All 
Treated 
Population 
All subjects who receive at least one dose of 
GSK525762 and fulvestrant. 
• 
Efficacy 
• 
Safety (if 
different from the 
All Treated 
population) 
All Evaluable 
Population 
Subjects who have at least two post-baseline 
radiological disease assessments or have 
progressed or died or permanently withdrawn 
from the study treatment. 
This population will be used for decision-
making at the interim futility analysis. 
• 
Dose escalation 
phase 
• 
Interim futility 
analyses 
PK Population 
Subjects from the All Treated Population for 
whom a PK sample is obtained and analysed. 
• 
PK analysis 
NOTE: Please refer to List of Data Displays, which details the population to be used for each display 
being generated. 
4.1. 
Protocol Deviations 
Major protocol deviations (e.g., deviations related to study inclusion/exclusion criteria, 
conduct of the trial, subject management, or subject assessment) will be summarised and 
all protocol deviations will be listed. 
Protocol deviations will be tracked by the study team throughout the study in accordance 
with the Protocol Deviation Specifications developed by PAREXEL. To ensure that all 
important deviations are captured and categorised in the protocol deviations dataset, data 
will be reviewed prior to DBF at the end of Phase I. This dataset will be the basis for all 
summaries and listings of protocol deviations, including a separate summary and separate 
listing dedicated to all deviations related to inclusion/exclusion criteria. These latter data 
displays will be based on data recorded on the inclusion/exclusion electronic case report 
form (eCRF). 
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As no Per Protocol Population has been defined for this study, protocol deviations will 
not be used to determine membership in any particular analysis population. 
 
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5. CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Data will be summarised and listed according to GSK reporting standards, as applicable. 
Summaries and listings will be displayed by or will otherwise incorporate the subgroups 
described below and in Section 5.5.2, Examination of Subgroups. 
5.1. 
Study Treatment and Sub-group Display Descriptors 
Data will be summarised and listed according to GSK reporting standards, as applicable. 
All data displays (tables, figures, and 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 study treatment 
dose level. Actual dose levels will depend on outcomes of the dose escalation phase but 
will follow the same format. Subgroups described in Section 5.5.2, Examination of 
Subgroups, may also be used in summaries. 
Treatment Description 
Treatment Label / Column 
Header 
Order[1] 
GSK525762 60mg + fulvestrant 500 
mg 
GSK762 60 mg + FUL 500 mg 
1 
GSK525762 80mg + fulvestrant 500 
mg 
GSK762 80 mg + FUL 500 mg 
2 
Fulvestrant 500 mg 
Fulvestrant 500 mg [2] 
3 
GSK525762 60mg  
GSK762 60 mg [2] 
4 
GSK525762 80mg  
GSK762 80 mg [2] 
5 
NOTES: 
1. Order represents treatments being presented in TFL, as appropriate. 
2. Required only for tables that are displayed separately for individual treatment. 
Sub-Group Descriptions 
Interactive response technology (IRT)  
Data Displays for Reporting  
Code 
Description 
Description [1] 
Order [2] 
A 
DL1_COHORT1 
GSK762 60 mg + FUL 500mg 
(AI Failure) 
1 
A 
DL1_COHORT2 
GSK762 60 mg + FUL 500mg 
(CDK4/6 + AI Failure < 12M) 
2 
A 
DL1_COHORT2 
GSK762 60 mg + FUL 500mg 
(CDK4/6 + AI Failure >= 12M) 
3 
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Sub-Group Descriptions 
Interactive response technology (IRT)  
Data Displays for Reporting  
Code 
Description 
Description [1] 
Order [2] 
A 
DL1_COHORT2 
GSK762 60 mg + FUL 500mg 
(CDK4/6 + AI Failure >= 12M 
Bone Only Disease) 
4 
B 
DL2_COHORT1 
GSK762 80 mg + FUL 500mg 
(AI Failure) 
5 
B 
DL2_COHORT2 
GSK762 80 mg + FUL 500mg 
(CDK4/6 + AI Failure) 
6 
NOTES:  
1. The duration of 12 months equals, on average, 365.25 days. 
2. Order represents the order of treatments as presented in each TFL display. 
5.2. 
Reporting Conventions 
• Unless otherwise specified, the denominator used in the calculation of percentages 
will be based on the number of subjects with non-missing values for the given 
scheduled visit and assessment or parameter. 
• All data are reported according to the dose/regimen initially received by the subject.  
• At 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. 
• 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 mean/median plots. Listings of PK concentration-
time data will be displayed 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. 
• Programmers should refer to GSK IDSL standards (as applicable) for decimal place 
conventions and expand if necessary. Unless stated otherwise, descriptive summaries 
will include n, mean, standard deviation (SD), median, minimum, and maximum for 
continuous variables and n and percentage for categorical variables. Minimum and 
maximum values will be displayed with the same precision as original source data, 
mean and median values will be displayed with one additional decimal place, and SD 
values will be displayed with two additional decimal places.   
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• This is a multicentre study. Data from all study centres will be integrated into 
derivations and summaries without controlling for centre effects. 
• Analyses will be performed using SAS statistical software version 9.4 or later. 
Programs will be imported into HARP, and the final outputs will be produced by 
running drivers in HARP. Some graphics may be produced using Tibco Spotfire 
Clinical Graphics, comprising S-Plus (R) version 7.0.6 or later.   
• Deviations from any planned analyses in this RAP will be identified in the final CSR. 
5.3. 
Baseline and Post-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 do not receive the study treatment, baseline will be defined as 
the latest 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.  
Unless otherwise stated, if baseline data are missing, then no derivations (e.g., change 
from baseline) will be performed and baseline will be set to missing. 
5.3.1. Change from baseline 
Following the initiation of treatment, absolute change from baseline will be calculated as: 
post-baseline value – baseline value. 
Percent (i.e., relative) change from baseline will be calculated as: (absolute change from 
baseline value ÷ baseline value) x 100. 
If either the baseline value or post-baseline value is missing, then both the absolute and 
relative changes from baseline will be set to missing. 
5.3.2. Multiple Assessments 
All data will be reported as corresponding to a nominal visit, as no visit windows will be 
applied during dataset creation. Data from unscheduled visits will be included in 
summaries reporting worst-case post-baseline results only and in all relevant data listings.  
For summaries in which data are collapsed across multiple planned time intervals, the 
means of intervals will be summarised. 
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With the exceptions of ECG and echocardiogram (ECHO) or multiple gated acquisition 
(MUGA) assessments, if multiple assessments of the same type are performed on 
different days but reported for the same scheduled assessment, then only the worst-case 
assessment results for that scheduled assessment will be analysed. 
With the exceptions of laboratory, ECG, and ECHO/MUGA assessments, the reporting of 
multiple assessments of the same type on the same date for the same visit or timepoint 
will be addressed by using the mean of the multiple reported measurements within 
analyses.  
For laboratory assessments, data may be collected from both local and central 
laboratories for the same visit or timepoint, but, in such case, only data from the central 
laboratory will be analysed to maintain comparability across measurements and subjects.   
For ECG and ECHO/MUGA assessments, both local investigator and central cardiologist 
readings will be performed for each visit/timepoint. For these assessments, only post-
baseline data collected using the same method (i.e., ECG, ECHO vs. MUGA) and by the 
same source (i.e., local vs. central cardiologist read) as the baseline assessment will be 
used to derive change from baseline. 
Data from all assessments, regardless of whether scheduled or unscheduled and 
performed singly or in multiple, will be included in the data 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 Covariates, Other Strata, and 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 (a) the 
study phases (Phase I vs. Phase II), (b) the combinations of dose level (e.g., DL-1, DL1, 
DL2) and cohort (Cohort 1 [AI Failure] vs. Cohort 2 [CDK4/6 + AI Failure]), and (c) the 
combinations of dose level, prior treatment, timing of a progressive disease response to 
prior treatment, and evidence of bone-only disease (see Section 5.1, Study Treatment and 
Sub-group Display Descriptors, for descriptions). 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined across 
multiple appendices: 
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Section 
Component 
13.3 
Appendix 3: Assessment Windows 
13.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
13.5 
Appendix 5: Data Display Standards & Handling Conventions 
13.6 
Appendix 6: Derived and Transformed Data 
13.7 
Appendix 7: Reporting Standards for Missing Data 
13.8 
Appendix 8: Values of Potential Clinical Importance 
 
6. STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
Study population analyses will be based on the All Treated Population, unless otherwise 
specified. Analyses will include descriptive summaries and data listings of subject 
disposition, protocol deviations, demographic and baseline characteristics, prior and 
concomitant medications, and treatment exposure, based on GSK Core Data Standards. 
Details of all planned displays are presented in Appendix 11: List of Data Displays. 
6.2. 
 Disposition of Subjects 
Using the All Screened Population, the numbers and percentages of subjects in each 
analysis population (described in Section 4, Analysis Populations) will be summarised. A 
listing of subjects excluded from the analysis populations and both a summary and a 
listing of subject screening status and reasons for screen failure will 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 that they are displayed on the 
eCRF. A listing of study treatment discontinuation will be generated. The listing will 
include last dose date, reasons for study treatment discontinuation, and study phase of 
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 either are ongoing or 
withdrew from the study. Primary reasons for study withdrawal will also be summarised. 
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 categorization) will be included in a listing. A separate listing dedicated to 
deviations related to inclusion/exclusion criteria will also be provided. Protocol 
deviations will be classified as “major” and “minor”, based on Protocol Deviation 
Specifications. 
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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, and weight will be summarised as continuous variables, whereas sex, race, and 
ethnicity will be summarised as categorical variables. Age will be additionally 
summarised as a categorical variable using the EudraCT categories of 18-64, 65-84 and 
≥85 years and GSK IDSL categories of ≤18, 18-65, 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. 
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. 
Disease characteristics at initial diagnosis and study screening will be summarised 
separately and provided in separate listings. As appropriate per summary, characteristics 
may include primary tumor type, stage, lesion status, time since initial diagnosis, and 
time since latest disease progression. Sites of metastatic disease at screening will be both 
summarised and included in a listing, and, lastly, a summary describing disease burden at 
baseline will be provided.  
Anti-cancer therapy will be coded using the GSK drug coding dictionary. Separate 
summaries will be produced for prior anti-cancer therapy (dedicated to all therapies, 
including radiotherapies), prior dictionary-coded therapy, and number of therapy 
regimens. The details of prior and subsequent anti-cancer therapies will be disclosed in 
two listings, one for all therapies and one for radiotherapies. A summary of best response 
to the most recent prior anti-cancer therapy will also be provided. 
Prior and on-treatment cancer-related surgical procedures will be summarized separately 
but included in the same listing. 
6.5. 
Concomitant Medications 
Concomitant medications, coded using the GSK drug coding dictionary, will be both 
summarised and included in a listing. 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 will be counted once per 
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. 
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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. 
 
7. EFFICACY ANALYSES 
Efficacy analyses will be based on the Modified All Treated Population, unless otherwise 
specified. The results of all efficacy analyses will be presented by subject subgroup, 
defined by the combination of dose level, prior treatment, timing of a progressive disease 
response to prior treatment, and evidence of bone-only disease (see Section 5.5.2, 
Examination of Subgroups). 
7.1. 
Endpoints / Variables 
Best Overall Response (BOR) 
BOR is defined as the best confirmed or unconfirmed response observed following the 
initiation of treatment through first documentation of progressive disease (PD) or 
initiation of new anti-cancer therapy, whichever occurs earlier. Responses following the 
onset of treatment will be assessed by the investigator per RECIST v1.1 criteria and, 
listed from best to worst, may include: CR, PR, SD (or non-CR/non-PD), PD, and not 
evaluable (NE). 
Objective Response Rate (ORR) 
ORR is defined as the percentage of subjects in the population who demonstrate a BOR 
of confirmed CR or PR, as assessed by the investigator per RECIST v1.1 criteria. 
Disease Control Rate (DCR) 
DCR is defined as the percentage of subjects in the population with a confirmed CR, 
confirmed PR, or SD lasting ≥6 months, as assessed by the investigator per RECIST v1.1 
criteria.  
Duration of Response (DoR) 
DoR is defined as the time (in months) from date of first documented evidence of 
confirmed CR or PR to the date of first documented PD, as assessed by the investigator 
per RECIST v1.1 criteria, or to the date of death due to any cause among subjects with a 
BOR of confirmed CR or PR. Subjects who have not shown disease progression or died 
at the time of analysis will be considered censored as of the date of their last evaluable 
disease assessment. Censoring rules will follow those for PFS, specified in Table 3. 
Progression-Free Survival (PFS) 
PFS is defined as the time (in months) from the date of first dose until the date of first 
documented PD, as assessed by the investigator per RECIST v1.1 criteria, or date of 
death due to any cause, whichever occurs first. Subjects who have not shown disease 
progression or died at the time of analysis will be considered censored as of the date of 
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their last evaluable disease assessment. Rules for determining the dates of PFS events and 
censoring are described in Table 3. 
 
Table 3 – Assignments of Progression and Censoring Dates for PFS Analysis 
Scenario 
Date of Event (PD 
and/or Death) or 
Censored  
Event (PD 
and/or Death) 
or Censored 
No adequate baseline assessments1 and subject 
has not progressed or died (if the subject has 
progressed/died, follow the rules for death 
indicated at the bottom of the table). Note that 
PD may be documented in the RS (Response) 
or DS (Disposition) dataset. 
First dose 
Censored 
No post-baseline assessments and subject has 
not died (if the subject has died, follow the 
rules for death indicated at the bottom of the 
table) and subject has no documented PD in 
DS dataset. 
First dose 
Censored 
PD/death documented before any new anti-
cancer therapy is received. Note that this 
includes PD/death at baseline or without 
adequate assessments. 
Date of assessment of 
PD2 or date of death, 
whichever occurs first 
Event 
With post-baseline assessment(s) but no 
documented PD/death or new anti-cancer 
therapy. 
Date of last ‘adequate’ 
assessment of response1 
Censored 
No adequate post-baseline assessment before 
start of new anti-cancer therapy and no PD 
documented in DS dataset. 
First dose 
Censored 
With adequate post-baseline assessment(s) and 
new anti-cancer therapy started but without PD 
documented3 
Date of last ‘adequate’ 
assessment of response1 
(prior to starting new 
anti-cancer therapy)  
Censored 
Death or PD documented in RS or DS dataset 
(without prior or new anti-cancer therapy) after 
two or more missed consecutive scheduled 
assessments 
Date of last ‘adequate’ 
assessment of response1 
(prior to missed 
assessments) or date of 
first dose without 
‘adequate’ assessment1,4 
Censored  
1 An adequate assessment is defined as a scheduled or unscheduled assessment in which the Investigator 
determines a disease response of CR, PR, or SD. 
2 Equals the earliest of (a) date of radiological assessment showing new lesion (if progression is based on 
new lesion), or (b) date of radiological assessment showing unequivocal progression in non-target lesions, 
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or (c) date of last radiological assessment of measured lesions (if progression is based on increase in sum of 
measured lesions). 
3 If documentation of PD and start of new anti-cancer therapy occur on the same day, PD will be assumed 
to have occurred first (i.e., prior to new therapy), with PD reported as the outcome and the assessment date 
reported as the event date. 
4 Relevant if the previous assessment is (a) earlier than Day 274 and the difference between PD/death and 
last adequate assessment is >126 days, or (b) between Day 274 and Day 344 and the difference between 
PD/death and last adequate assessment is >154 days, or (c) after Day 344 and the difference between 
PD/death and last adequate assessment is >182 days. Note that scheduled disease assessment window is +/- 
7 days. 
7.2. 
Summary Measures 
Objective Response Rate (ORR) 
The number and percentage (representing ORR) of subjects in the population who show a 
BOR of confirmed CR or PR will be presented with exact 95% CI for ORR. Subjects 
with unknown or missing responses will be considered to be non-responders (i.e., 
subjects will be included in the denominator when calculating percentage). A spider plot 
of percent change from baseline in target lesions over time per subject and a waterfall 
plot of maximum percent reduction from baseline in tumour measurement per subject 
will be provided. 
Disease Control Rate (DCR)  
The number and percentage (representing DCR) of subjects in the population who show a 
BOR of confirmed CR, confirmed PR, or SD lasting ≥6 months will be presented with 
exact 95% CI for DCR. Subjects with unknown or missing responses will be treated as 
non-responders (i.e., subjects will be included in the denominator when calculating 
percentage). 
Duration of Response (DoR) 
Given a sufficient number of responses, DoR will be summarised using the Kaplan-Meier 
method. The median and 25th and 75th percentiles of DoR will also be estimated, with 
their corresponding 95% CIs estimated using the Brookmeyer-Crowley method (1982). 
Progression-Free Survival (PFS) 
PFS will be estimated using the Kaplan-Meier method. The median and 25th and 75th 
percentiles of PFS will also be estimated, with their corresponding 95% CIs estimated 
using the Brookmeyer-Crowley method (1982). A Kaplan Meier curve may also be 
produced, if the data warrant. 
7.3. 
Population of Interest  
Efficacy analyses will be based on the Modified All Treated Population, unless otherwise 
specified. 
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7.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 11: 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 will be 
summarised using descriptive statistics, graphically presented (if appropriate), and listed. 
Primary Statistical Analyses 
Endpoint(s) 
Method of Analysis 
ORR 
Percentage, Exact 95% CI 
Secondary Statistical Analyses 
Endpoint(s) 
Method of Analysis 
DCR 
Percentage, Exact 95% CI  
DoR 
Kaplan-Meier median and 25th and 75th percentiles, 
Brookmeyer-Crowley 95% CIs (if data warrant) 
PFS 
Kaplan-Meier median and 25th and 75th percentiles, 
Brookmeyer-Crowley 95% CIs (if data warrant) 
 
8. SAFETY ANALYSES 
Safety analyses will be based on the All Treated Population, unless otherwise specified. 
The results of all safety analyses will be presented by subject subgroup, defined by the 
combination of dose level, prior treatment, timing of a progressive disease response to 
prior treatment, and evidence of bone-only disease (see Section 5.5.2, Examination of 
Subgroups). 
8.1. 
Adverse Events Analyses 
Analyses of AEs, including summaries of all AEs, SAEs, and other significant AEs, will 
be based on GSK Core Data Standards. Moreover, all analyses will be performed on 
treatment-emergent AEs (TEAEs) only (see Section 15.4.3 for definition). The details of 
the planned displays are provided in Appendix 11: List of Data Displays. 
All AEs will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) 
System Organ Class (SOC) and Preferred Term (PT), as well as graded according to the 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 4.0.  
Several summaries of AEs will be produced, including counts and percentages of subjects 
with:  
• Any AE.  
• Non-serious AEs. 
• AEs related to study treatment (any, GSK525762, fulvestrant).  
• AEs of Grade 3-4.  
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• Grade 3-4 AEs related to study treatment (any, GSK525762, fulvestrant).  
• AEs leading to permanent discontinuation of study treatment (any, GSK525762, 
fulvestrant).  
• AE leading to dose reductions of study treatment (any, GSK525762, fulvestrant).  
• AEs leading to dose interruptions/delays of study treatment (any, GSK525762, 
fulvestrant).  
• SAEs.  
• SAEs related to study treatment (any, GSK525762, fulvestrant). 
• Non-fatal SAEs related to study treatment (any, GSK525762, fulvestrant).  
• Dose-limiting toxicities. 
 
A summary of common non-serious AEs (those that occur in ≥5% of subjects) will be 
provided (no rounding for the percentage will be used in terms of 5% threshold; e.g., 
events with 4.9% incidence rate will not be included in this table). This summary will 
contain the numbers and percentages of subjects per common non-serious adverse event. 
This summary table and those bulleted above will be displayed by SOC and PT. 
A summary of the numbers and percentages of subjects with any AEs by maximum grade 
will be produced. At the subject level, a conservative approach will be taken to compute 
the maximum grade of AEs. Specifically, when grade is missing for one or more AEs for 
a single subject, the subject’s maximum grade will be considered unknown. AEs will be 
sorted by MedDRA PT in descending order of total incidence. The summary will use the 
following algorithms for counting the subject: 
• PT row: Subjects who experience multiple AEs of the same PT but with different 
grades will only be counted once with the maximum grade. 
• Any event row: Each subject with at least one AE will be counted only once at the 
maximum grade no matter how many events they have. 
In addition, the frequency and percentage of AEs (all grades) will be summarised and 
displayed in two ways: (1) in descending order of total incidence by MedDRA PT only 
and (2) in descending order of total incidence by MedDRA SOC x PT. In the SOC row, 
the number of subjects with multiple events of the same SOC will be counted only once.  
Separate summaries will be provided for study treatment-related AEs, including 
GSK525762-related, fulvestrant-related, and any treatment-related (i.e., GSK525762 or 
fulvestrant-related) AEs. A study treatment-related AE is defined as an AE for which the 
investigator classifies the relationship to study treatment as “Yes”. A worst-case scenario 
approach will be taken to handle missing relatedness data. That is, 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. A summary of 
study treatment-related AEs by maximum grade will also be provided. 
A summary of the number of subjects who experience DLTs will be provided. Lastly, all 
AEs, including DLTs, will be described in subject-level data listings. 
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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 AESIs are not defined in the protocol 
but are noted in the Investigational Brochure. Changes to the MedDRA dictionary may 
occur between the start of the study and time of reporting, and emerging data from on-
going studies may highlight additional AESIs. Therefore, the specific AESIs to be studied 
and the list of terms to be used per AESI will be based on Safety Review Team 
agreements that are in place at the time of database lock. Details of the planned displays 
are provided in Appendix 11: List of Data Displays. 
AESIs will include, but may not be limited to, the following categories: 
• Haematopoietic thrombocytopenia, Standardised MedDRA Query (SMQ) 
• Haemorrhages [excluding 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 Preferred Terms 
The PTs for AESIs will be provided by the GSK525762 Pharma Safety representative 
before DBR, based on the most up-to-date MedDRA version. 
The number and percentage of subjects with AESIs will be summarised by AESI 
category, PT, and maximum toxicity grade in one table. A summary and a listing of event 
characteristics for each AESI category will also be provided, including number of 
subjects with any event, number of events, number of subjects with any serious event, 
number of subjects with any study treatment-related event, outcome of the event, 
maximum grade, and action taken for the event. The percentage of subjects with an AESI 
will be calculated using the total number of subjects as the denominator. The percentages 
of subjects associated with individual event characteristics will be calculated using the 
number of subjects with any AESI as the denominator. At a subject level, a worst-case 
approach will be applied for determining event outcome and maximum grade. That is, a 
subject with multiple AESIs will be counted only once based on the worst case from all 
AESIs experienced by the subject. For action taken to an event, subjects will be counted 
once per action. For example, if a subject has an event leading to both reduction of the 
study treatment dose and discontinuation of the study treatment, the subject will be 
counted once under both actions. 
For each category of AESI, a summary of time to onset (in days) and duration of first 
occurrence (in days) will be provided, with each analysed as both a continuous and a 
categorical variable. Time to onset will be summarised within categories of 1-14 days, 
15-28 days, and >28 days, and duration of first occurrence will be summarised within 
categories of 1-5 days, 6-10 days, and >10 days. 
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8.3. 
Deaths and Serious Adverse Events 
For any subject who withdraws consent, no data after the date of consent withdrawal 
from this subject, including death, should 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 in the 
population. Within this summary, subjects will be classified by time of death relative to 
last dose of medication (>30 days vs. 30 days) and primary cause of death (disease 
under study, SAE related to study treatment, or other). A subject-level data listing will be 
generated to disclose the details of all death events.  
All SAEs will be tabulated based on the number and percentage of subjects from the 
population who experience the specific SAE. Multiple summary tables will be generated, 
with statistics displayed in descending order of total incidence per 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 relatedness data. That is, summary tables will include events with 
the relationship to study treatment as “Yes” or missing.  
SAEs will be 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. 
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 subjects with: 
• AEs leading to permanent discontinuation of study treatment (any, GSK525762, or 
fulvestrant).  
• AEs leading to dose interruptions/delays of study treatment (any, GSK525762, or 
fulvestrant). 
• AEs leading to dose reductions of study treatment (any, GSK525762, or fulvestrant). 
8.5. 
Extent of Exposure 
Details of the extent of exposure to GSK525762 and fulvestrant will be both summarised 
and listed separately.  
GSK525762: 
The duration of exposure to study treatment in months (from first day of treatment to end 
of treatment in Phase I) will be summarised. Descriptive statistics, including mean, 
median, standard deviation, minimum, and maximum, will be computed for duration of 
study treatment. In addition, treatment duration will be summarised within the following 
categories: <3 months, 3 months to <6 months, 6 months to <12 months, and ≥12 months. 
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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 number and percentage 
within categories of reason for reduction. Dose interruptions/delays will be summarised 
by number of interruptions/delays, reasons for interruption/delay, and duration of 
interruption/delay (in days). Descriptive statistics, including mean, standard deviation, 
median, minimum, and maximum, will be computed for interruption/delay duration, and 
the number and percentage of subjects within the interruption/delay duration categories 
of <7, 7-14, and >14 days will also be computed. A summary of dose escalation will also 
be provided, if applicable. All dose modifications (reductions, interruptions/delays, and 
escalations) will be listed separately. 
Fulvestrant: 
Duration of exposure, as well as cumulative dose and dose intensity (defined in Section 
15.6.3), will be summarised for fulvestrant using descriptive statistics for a continuous 
variable. 
Dose reductions will be summarised by number of reductions and number and percentage 
within categories of reason for reduction. Dose delays will be summarised by number of 
delays, number and percentage within categories of reason for delay, and duration of 
delay (in days). Descriptive statistics, including mean, standard deviation, median, 
minimum, and maximum, will be computed for delay duration. Missed doses will be 
summarised by number of missed doses and number and percentage within categories of 
reason for missed dose.  
These summaries of dose modifications will be provided only if the data warrant. All 
dose reductions, interruptions/delays, and missed doses will be listed separately. 
8.6. 
Pregnancies  
Details of all pregnancies will be collected after the start of study treatment and until at 
least 90 days post-last dose of study drug. While pregnancy itself is not considered to be 
an AE or SAE, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be recorded as an AE or SAE. If a subject should become pregnant 
while on study, then information describing the pregnancy will be included in the 
narratives, and no separate table or listing will be produced. 
8.7. 
Clinical Laboratory Analyses 
Laboratory tests, including clinical chemistry, haematology, urinalysis, and liver function 
tests, will be based on GSK Core Data Standards. Details of the corresponding planned 
displays can be found in Appendix 11: List of Data Displays. Laboratory tests performed 
for the assessment of toxicity will include the following:  
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Figure 2 – Clinical Laboratory Tests 
Clinical Chemistry 
Sodium  
Fasting Glucose 
Potassium 
Magnesium 
Chloride 
Calcium (total and ionized) 
Total Carbon Dioxide 
Total Protein 
Blood Urea Nitrogen 
Albumin 
Creatinine  
Hematology 
White Blood cell count  
Hemoglobin 
Platelet count 
Automated White Blood Cell Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Liver Function 
Bilirubin (Total and, if Total is abnormal, then Direct needed) 
Aspartate Aminotransferase (AST) 
Alanine Aminotransferase (ALT) 
Alkaline Phosphatase 
Urinalysis 
Specific gravity 
pH 
Glucose  
Protein  
Blood  
Ketones  
Microscopic examination (if urinalysis is abnormal) 
Cardiac 
Troponin (I or T), may be collected at central laboratory if local draw is not possible 
N-terminal pro b-type natriuretic peptide (NT-proBNP) 
Fasting Lipid Panel (Total Cholesterol, LDL, HDL, Triglycerides) 
Other 
Coagulation: 
Prothrombin Time/Internal Normalized Ratio (INR) 
Partial Thromboplastin Time (or Activated Partial Thromboplastin Time [aPTT]) 
Fibrinogen 
Factor VII Assay 
Endocrine: 
Thyroid Stimulating Hormone (TSH) 
Free Thyroxine 3 (Free T3) 
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Free Thyroxine 4 (Free T4) 
Hemoglobin A1c 
FSH (for pre- and peri-menopausal subjects only) 
Estradiol (for pre- and peri-menopausal subjects only) 
Safety Screening: 
HIV  
HbSag 
HCV antibody 
Pancreatic Markers: 
Amylase 
Lipase 
 
A summary of laboratory values and derived change-from-baseline values by scheduled 
visit will be provided, using mean, median, standard deviation, minimum and maximum. 
Summaries of laboratory data will also be provided by maximum toxicity grade, using 
reported grades based on NCI-CTCAE v4.0. For any subject, a missing baseline grade 
will be assumed as grade 0. 
Summaries of worst-case grade increase from baseline grade will be provided for all 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.   
Summaries will also include grade increase from baseline by scheduled visit. For 
laboratory tests that are graded for both low and high values, summaries will be 
generated separately and labeled by direction (e.g., low and high sodium level will be 
summarised as hyponatremia and hypernatremia, respectively). 
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, and 
coagulation laboratory tests will be produced. 
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, Baseline and Post-
Baseline Definitions. 
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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. 
Although all data will be reported according to the nominal visit for which they were 
recorded (i.e., no visit windows will be applied), summaries by visit will include data 
from scheduled assessments only. Unscheduled assessment data will be incorporated into 
“worse-case post-baseline” summaries, which capture the worst case across all scheduled 
and unscheduled visits following first dose of study treatment. 
8.7.1. Analyses of Liver Function Tests 
In addition to chemistry laboratory summaries and listings incorporating bilirubin (total 
and direct), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
alkaline phosphatase results, a summary and a listing of liver monitoring/stopping events 
defined by liver chemistry will be provided.  
A summary and a listing of hepatobiliary laboratory abnormalities, including possible 
Hy’s Law cases, will also be provided. Possible Hy’s law cases will be defined as any 
event of either: (a) ALT ≥3 × the upper limit of normal (ULN) and bilirubin ≥2 × ULN 
(>35% direct bilirubin) or (b) ALT ≥3 × ULN and INR >1.5, if INR is 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. 
8.8. 
Other Safety Analyses 
The analyses of non-laboratory safety test results, including those from vital signs, 
performance status, ECG, and ECHO/MUGA assessments, will be based on GSK Core 
Data Standards, unless otherwise specified. The details of the planned displays are 
presented in Appendix 11: List of Data Displays. 
8.8.1. Vital Signs 
Raw vital sign values, as well as computed changes 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 
• Respiratory rate (breaths/min): <12, ≥12 - ≤18, >18 - ≤25, and >25 
• Temperature (°C): ≤35, >35 - <38, ≥38 
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Summaries of increase in vital signs from the baseline with respect to the categories 
defined above will be performed. These summaries will display the number and 
percentage of subjects in the population with any grade increase, an increase to grade 2, 
and an increase to grade 3 at each scheduled visit and at the visit showing the worst-case 
post-baseline results. 
8.8.2. Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status will be summarised at 
baseline and each post-baseline scheduled visit. Summaries will include the numbers and 
percentages of subjects in the population at each planned assessment time. A summary of 
change-from-baseline by scheduled visit will be generated, as will a summary of the 
worst-case and best-case post-baseline changes during the study (i.e., using categories of 
improved, no change, and deteriorated). A supporting listing will also be provided.  
8.8.3. 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 heart rate and 
measures PR, QRS, QT and QTcF intervals. The baseline QTcF value will be computed 
as the mean of the triplicate Week 1 Day 1 pre-dose QTcF results (see Section 5.3, 
Baseline and Post-Baseline Definitions). 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 with normal, abnormal clinically 
significant, and abnormal not clinically significant ECG findings will be displayed by 
scheduled visit, as well as for the worst-case post-baseline assessment.  
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 two sources will not be combined. 
QTcF prolongation will be monitored throughout the study. QTcF values will be rounded 
to the integer and 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 in the population with any grade increase, an increase to grade 
2, and an increase to grade 3 at each scheduled visit and at the visit showing the worst-
case post-baseline results. Missing baseline grade will be assumed as grade 0. 
Changes in QTc values will be categorized into ranges of clinical concern, namely 
differences of 31-60 msec and >60 msec from baseline. A summary of change in QTc 
value will display the number and percentage of subjects in each range of clinical concern 
per scheduled visit and at the visit showing the worst-case post-baseline results. Subjects 
with missing baseline values will be excluded from this summary. 
Listings of all ECG results and all abnormal ECG findings will be provided. 
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8.8.4. LVEF 
Both absolute and relative change from baseline in LVEF will be summarised at each 
scheduled visit and at the visit showing the worst-case post-baseline results. Only the 
post-baseline assessments that used the same method (ECHO or MUGA) and source 
(local or central) as the baseline assessments will be used to derive the change from 
baseline. Absolute change from baseline will be categorized as follows: 
• No change or any increase (i.e., increases of 0 to <10%, 10 to <20%, and ≥20%) 
• Any decrease (i.e., decreases of >0 to <10%, 10 to <20%, and ≥20%) 
• Decrease ≥10% and ≥ lower limit of normal (LLN) 
• Decrease ≥10% and < LLN 
• Decrease ≥20% and ≥ LLN 
• Decrease ≥20% and < LLN 
Relative change from baseline will be categorized as follows: 
• Decrease ≥20% and ≥ LLN 
• Decrease ≥20% and < LLN 
A listing of all LVEF results will be produced, including both absolute and relative 
changes from baseline. 
8.8.5. Liver Events  
For any liver events that occur during the study, the Roussel Uclaf Causality Assessment 
Method (RUCAM) score will be derived and incorporated into a listing of data describing 
liver monitoring/stopping events. The score incorporates whether the subject was age 55 
years or older, the subject became pregnant, liver imaging was normal or not, a biopsy 
was taken or not, fasting or significant dietary change occurred, and the subject took any 
unconventional medications, as well as the relative timing of the event (i.e., while on 
treatment vs. after stopping treatment) and computed durations from first dose to start of 
the liver event and from last dose to start of the liver event.  
9. PHARMACOKINETIC ANALYSES 
9.1. 
Primary 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. 
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Concentrations of GSK525762, active metabolites (GSK3529246), and GSK525762 total 
active moiety (i.e. GSK525762 + GSK3529246 after conversion from ng/mL to nM 
concentrations) and fulvestrant 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. 
Mean/median plots of concentration (GSK525762 in nM, GSK3529246 in nM, and total 
active moiety in nM on the same plot) over time will be provided for each analyte using 
actual elapsed time for Week 1 and Week 3 for GSK525762, GSK3529246, and Total 
active moiety and using overall duration of the study for fulvestrant. 
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 
The PK parameters presented in the table below will be derived during programming. 
This will be the responsibility of the Statistics and Programming group at PAREXEL 
under the direction of the Clinical Pharmacology Modeling and Simulation (CPMS) 
Department at GSK.  
The parameters will be determined from the concentration-time data for GSK525762 (in 
ng/mL), active metabolites (GSK3529246 in ng/mL), and total active moiety (i.e. 
GSK525762 + GSK3529246 in nM), as data permits.  
The molecular weight of GSK525762 is 424 g/mol, and the molecular weight of 
GSK3529246 is 396 g/mol. The total active moiety concentration in nmol/L will be 
computed as (GSK525762 concentration in ng/mL / molecular weight of 424 x 1000) + 
(GSK3529246 concentration in ng/mL / molecular weight of 396 x 1000). 
 
Parameter Parameter Description 
Cmax 
Maximum observed concentration; determined directly from the concentration-
time curve. 
Tmax 
Time from first administration to occurrence of Cmax; determined directly from 
the concentration-time curve. 
Cτ 
Also referred to as “Ctrough”; observed concentration at the end of a dosing 
interval, immediately before the next administration; determined directly from 
the concentration-time curve. 
NOTE: Additional parameters may be included as required 
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9.1.2. Summary Measure 
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, and fulvestrant.  
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/scheduled visit.  
Concentration-time profiles for GSK525762, GSK3529246, and the total active moiety of 
GSK525762 will be overlaid on the same plot conversion to nM concentrations. 
The PK parameters described in Section 9.1.1.2 will also be summarised descriptively 
(using mean, SD, median, minimum, maximum, geometric mean with SD, coefficient of 
variation [CV], and 95% CI of log-transformed parameters, if applicable), separately for 
GSK525762, active metabolites (GSK3529246), and the total active moiety of 
GSK525762. 
9.1.3. Population of Interest  
The primary PK analyses will be based on the PK Population, unless otherwise specified. 
10. 
PHARMACODYNAMIC ANALYSIS 
The pharmacodynamic analyses will be detailed in a Pharmacodynamic RAP supplement 
and will not be discussed as part of this RAP. 
 
11. 
OTHER STATISTICAL ANALYSES 
11.1. Value Evidence and Outcomes 
The value evidence and outcomes analyses will be based on the Modified All Treated 
Population, unless otherwise specified. All summaries and data listings will use treatment 
labels as specified in Section 5.1, Study Treatment and Sub-group Display Descriptors.  
Summaries of raw values and absolute change-from-baseline values from the European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-
30 (EORTC-QLQ-C30) and Breast-23 (EORTC-QLQ-BR23) scales will be provided in 
tables. Summaries of raw values and absolute change-from-baseline values from Patient 
Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) 
will be provided in tables. Single items from EORTC-QLQ-C30, EORTC-QLQ-BR23, 
and PRO-CTCAE will be provided in listings. 
Baseline will be defined as the visit prior to the start of Week 1 Day 1 dosing. Details of 
data displays are presented in Appendix 11: List of Data Displays. 
 
 
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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
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. 
 
 
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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 study in accordance 
with the Protocol Deviation Specification document. 
13.1.1. 
Exclusions from Per Protocol Population 
No Per Protocol Population will be defined or used for this study. 
 
 
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13.2. Appendix 2: Schedule of Activities 
Refer to Protocol Section 7, Study Assessments and Procedures. 
 
 
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13.3. Appendix 3: Assessment Windows 
No assessment windowing will be applied in this study. 
 
 
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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, 
ECHO/MUGA scans, ECOG 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. 
NOTES: If the study treatment stop date is missing, then the AE will be considered to be On-Treatment. 
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 or Date of Death) – (Date of First Partial or Complete 
Response of a Confirmed Partial or Complete Response) + 1 
Treatment 
Phase 
Definition 
Pre-Treatment  
Date  < Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date  ≤ Date ≤ Study Treatment Stop Date 
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 
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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 
days). 
Drug-Related 
If relationship is marked ‘YES’ on Inform/CRF (or if value is missing). 
NOTES:  
• 
If completely missing start dates, then the AE will be considered as TEAE. 
• 
If the study treatment stop date is missing, then the AE will be considered to be On-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\mid201973 
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: 
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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. 
• 
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. 
ADPC data file  
To create ADPC the SDTM PC domain dataset will be merged with the 
Subject-Level Analysis Dataset (to get demographic information) and with 
SDTM EX domain (to get reference timepoint date). 
Reference timepoint date will be populated for both study drug and active 
metabolite based on study treatment information from SDTM EX domain. 
To populate analysis values in ADPC (AVAL(C)) adjustments to the 
PCSTRESN will be done based on imputation rules from "Non-
Compartmental Analysis of Pharmacokinetic Data, CPMS Global" 
document. 
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Total Moiety parameter will be added, along with concentrations of study 
drug and active metabolite, and derived as the sum of study drug and active 
metabolite concentrations converted to nM units. 
The molecular weight of GSK525762 is 424 g/mol and the molecular 
weight of GSK3529246 is 396 g/mol. The total active moiety concentration 
in nmol/L will be computed as (GSK525762 concentration in ng/mL / 
molecular weight of 424 x 1000) + (GSK3529246 concentration in ng/mL / 
molecular weight of 396 x 1000). 
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 Parameters to 
be Derived by PK 
Programmer 
The following PK parameters will be derived by the PK Programmer: 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. 
• 
Subjects 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 to Reference Date: 
o 
If Ref Date = Missing, then Study Day = Missing. 
o 
If Ref Date < Study Treatment Start Date, then Study Day = Ref Date – Study 
Treatment Start Date. 
o 
If Ref Data ≥ Study Treatment Start Date, then Study Day = Ref Date – (Study 
Treatment Start Date) + 1.     
Change from Baseline 
• 
Absolute Change from Baseline = Post-Baseline Visit Value – Baseline Value. 
• 
Percent (i.e., Relative) Change from Baseline = ([Post-Baseline Visit Value – Baseline 
Value] ÷ Baseline Value) x 100. 
If either the Baseline or Post-Baseline Visit Value is missing, then both Absolute and Relative 
Change from Baseline are 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 showing the response (not to the date on which 
confirmation ultimately occurs); for other response categories not requiring confirmation (SD 
[or Non-CR/Non-PD], NE, PD), the date of response is also assigned to the earliest date of 
disease assessments showing the response.    
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 13.7.3.  
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13.6.2. 
Study Population 
13.6.3. 
Efficacy 
Primary Endpoint 
Objective Response Rate (ORR) 
• 
Defined as the percentage of subjects in the population who demonstrate a Best 
Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response 
(PR), as assessed by the investigator per RECIST v1.1 criteria.  
• 
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). 
Secondary Endpoints 
Disease Control Rate (DCR) 
• 
Defined as the percentage of subjects in the population with a confirmed CR, 
confirmed PR, or Stable Disease (SD) lasting ≥6 months, as assessed by the 
investigator per RECIST v1.1 criteria.  
• 
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 Response (DoR) 
• 
Defined as the time (in months) from date of first documented evidence of confirmed 
CR or PR to the date of first documented progressive disease (PD), as assessed by the 
investigator per RECIST v1.1 criteria, or to the date of death due to any cause 
(whichever occurs first) among subjects with a BOR of confirmed CR or PR.  
• 
Subjects who have not shown disease progression or died at the time of analysis will 
be considered censored as of the date of their last evaluable disease assessment, but 
censoring rules for other unique scenarios (e.g., receipt of new anti-cancer therapy) 
will adhere those rules defined for PFS. 
Progression Free Survival (PFS) 
• 
Defined as the time (in months) from the date of first dose until the date of first 
documented PD, as assessed by the investigator per RECIST v1.1 criteria, or date of 
death due to any cause, whichever occurs first.  
• 
Subjects who have not shown disease progression or died at the time of analysis will 
be considered censored as of the date of their last evaluable disease assessment. Rules 
for determining the dates of PFS events and censoring are described in Table 3. 
Demographics 
Age 
• 
GSK standard 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 
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13.6.4. 
Safety 
Adverse Events 
AEs of Special Interest 
• 
Haematopoietic thrombocytopenia Standardised MedDRA Query (SMQ) 
• 
Haemorrhages [excluding 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 Preferred Terms 
 
ECHO/MUGA 
Only the post-baseline assessments that use the same method (i.e., ECHO or MUGA) and 
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. 
 
 
 
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Extent of Exposure 
• 
Number of days of exposure to GSK525762 will be calculated based on the formula:   
o Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1. 
• 
Number of days of exposure to fulvestrant will be calculated based on the formulas:   
o 
Duration of Exposure in Days = ([Treatment Stop Date + 13] –Treatment Start Date) + 
1, if the last dose date is the first two doses.  
o 
Duration of Exposure in Days = ([Treatment Stop Date + 27] –Treatment Start Date) + 
1, if the last dose date is not the first two doses. 
• 
Subjects 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 calculated based on the formula: 
o Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
• 
The cumulative dose for fulvestrant will be calculated based on the formula: 
o Cumulative Dose = Sum of (Total Daily Dose) 
• 
The relative dose intensity for GSK525762 will be calculated based on the formula:  
o Relative Dose Intensity (%) = (Dose Intensity / Planned Dose Intensity) x 100. 
 
Laboratory Parameters 
If a laboratory value that is expected to have a numeric value for summary purposes has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used 
to determine how much to add or subtract in order to impute the corresponding numeric value.  
Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01 
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1 
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
 
 
 
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13.6.5. 
Value Evidence and Outcomes 
EORTC QLQ-C30 and EORTC QLQ-BR23 
• 
Both the QLQ-C30 and the QLQ-BR23 are composed of multi-item scales and single-item 
measures. The QLQ-C30 includes a global health status/QoL scale, five functional scales, 
and nine symptom scales/items. The QLQ-BR23 includes five functional scales and four 
symptom scales/items. 
• 
Each of the multi-item scales includes a different set of items; no item occurs in more than 
one scale. 
• 
All the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
o 
Thus, a high score for the global health status/QoL represents a high QoL, and 
o 
a high score for a functional scale represents a high/healthy level of functioning, but 
o 
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: 
o 
Estimate the average of the items that contribute to the scale to calculate the raw 
score. 
o 
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: 
(1) Calculate the raw score: 
RawScore =
(2) Apply the linear transformation to 0-100 to obtain the score S: 
• 
Global health status / QoL:
• 
Functional scales:
• 
Symptom scales / items: 
Range is the difference between the maximum possible value of RS and the minimum possible 
value. Both questionnaires have 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 QLQ-C30 items contributing to 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 
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EORTC QLQ-C30 and EORTC QLQ-BR23 
 
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. “very much” 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.  
 
, is not applicable if item 
is “
.” 
, is not applicable if item is “
.” 
 
EORTC QLQ-BR23 
 
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. 
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EORTC QLQ-C30 and EORTC QLQ-BR23 
 
*Items for the scales marked * are scored positively (i.e., “very much” 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.  
 
 is not applicable if item 
is “
.” 
, is not applicable if item
is “
.” 
 
PRO-CTCAE 
• 
The response frequency distribution and proportion of subjects for each PRO-CTCAE item 
will be presented by visit.  This should be grouped first by visit, then by related term. 
• 
Subjects who do not have a response due to skipping patterns should be reported as “Not 
applicable”.  Other subjects who do not provide a response or have withdrawn from the 
study should 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 dropouts, 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 summarised 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, based on the 
following criteria: 
o Improved = current response level < prior response level 
o Worsened = current response level > prior response level 
o 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 the FDA, report 
the results of PRO-CTCAE alongside the corresponding clinician-graded CTCAE results.   
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PRO-CTCAE 
• 
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 response values (0-4, null for missing) for all PRO-CTCAE Items 
by subject and visit. 
 
 
 
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13.7. Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
The study will be considered completed for purposes of final analysis 
when approximately 70% of enrolled subjects have died. However, as 
originally planned, the study can be stopped due to toxicity or futility 
before this time-point when there is enough evidence to conclude as such.  
• 
Given current study status, the totality of Phase I data assessed at the 
interim analysis does not support continuing investigation of GSK525762 
(molibresib) in combination with fulvestrant for the treatment of 
HR+/HER2- advanced or metastatic breast cancer patients. As interim data 
failed to demonstrate meaningful clinical benefit in this patient population, 
enrolment into the study is now closed and the study will not incorporate 
Phase II. 
• 
With the implementation of Amendment 06, 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. 
• 
All available data from subjects who have 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 occur when any requested data are not provided, leading to 
blank fields on the collection instrument: 
• 
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 are excluded from the table.  
• 
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. 
13.7.3. 
Handling of Missing and Partial Dates 
Imputed partial dates can be used to derive study day, duration (e.g. duration of adverse 
events), or elapsed time variables. Imputed dates will not be used for deriving the last 
contact date in the overall survival analysis dataset. 
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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 
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 
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Element 
Reporting Detail 
events will be missing. If completely missing start dates, TEAE flag is 
Yes. 
• 
Start or end dates of which are completely missing (i.e., no year 
specified) will remain missing, with no imputation applied. 
Anti-Cancer 
Therapy 
(including 
Radiotherapy) 
and Surgical 
Procedures  
• 
Completely missing start 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. 
• 
Completely or partially missing end dates will remain missing, with no 
imputation applied. 
Concomitant 
Medications, 
Medical 
History, and 
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, and, 
where 
applicable, 
Radiotherapy 
and 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. 
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Element 
Reporting Detail 
• 
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. 
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 
date of the data cutoff, 
o 
date of withdrawal from the study, or  
o 
death date. 
• 
The imputed exposure end date will be used to calculate cumulative 
dose and exposure duration. 
• 
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, National Cancer Institute 
Common Terminology Criteria for Adverse Events (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 
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 
msec 
 
> 30   
≤ 60   
> 60   
 
Increase from Baseline QTcF 
msec 
 
> 30   
≤ 60   
> 60   
 
13.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
> 120 
< 140 (Grade 1) 
≥ 140 
< 160 (Grade 2) 
 
≥ 160 (Grade 3) 
Diastolic Blood Pressure 
mmHg 
> 80 
< 90 (Grade 1) 
≥ 90 
< 100 (Grade 2) 
 
≥ 100 (Grade 3) 
Heart Rate 
bpm 
< 60  
> 100 
Temperature 
Degrees C 
≤ 35 
≥ 38 
 
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13.8.4. 
Left Ventricular Ejection Fraction 
LVEF 
Units 
Clinical Concern Range 
Absolute Change from Baseline 
% 
Increase ≥ 0 and < 10 
Increase ≥ 10 and < 20 
Increase ≥ 20 
Decrease > 0 and < 10 
Decrease ≥ 10 and < 20 
Decrease ≥ 20 
Decrease ≥ 10 and ≥ LLN 
Decrease ≥ 10 and < LLN 
Decrease ≥ 20 and ≥ LLN 
Decrease ≥ 20 and < LLN 
Relative Change from Baseline 
% 
Decrease ≥ 20 and ≥ LLN 
Decrease ≥ 20 and < LLN 
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’. 
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13.9. Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Not applicable. 
 
 
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13.10. Appendix 10: Abbreviations & Trademarks 
13.10.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AI 
Aromatase Inhibitor 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical-Therapeutic-Chemical 
BOR 
Best Overall Response 
BP 
Blood Pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CR 
Complete Response 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DBF 
Database Freeze 
DBR 
Database Release 
DCR 
Disease Control Rate 
DL 
Dose Level 
DLT 
Dose-Limiting Toxicity 
DoR 
Duration of Response 
DP 
Decimal Place 
DS 
Disposition Dataset 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Core-30 
EORTC-QLQ-BR23 European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire Breast-23 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
HLGT 
High Level Group Term 
HR+/HER2− BC 
Hormone Receptor-Positive/HER2-Negative Breast Cancer 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDSL 
Integrated Data Standards Library 
IM 
Intramuscular(ly) 
INR 
International Normalized Ratio 
LLN 
Lower Limit of Normal 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum Tolerated Dose 
mTPI 
Modified Toxicity Probability Interval 
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Abbreviation 
Description 
MUGA 
Multiple Gated Acquisition 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease  
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response or ECG parameter (context dependent) 
PRO 
Patient Reported Outcomes 
PT 
Preferred Term 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
RS 
Response Dataset 
RUCAM 
Roussel Uclaf Causality Assessment Method 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SD 
Standard Deviation or Stable Disease (context dependent) 
SDTM 
Study Data Tabulation Model 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard Operation Procedure 
TEAE 
Treatment-Emergent Adverse Event 
TFL 
Tables, Figures, and Listings  
ULN 
Upper Limit of Normal 
13.10.2. 
Trademarks 
 
 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
SAS 
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13.11. Appendix 11: List of Data Displays 
13.11.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.22 
N.A. 
Efficacy 
2.1 to 2.3 
2.1 to 2.3 
Safety 
3.1 to 3.51 
N.A. 
Pharmacokinetic 
4.1 to 4.8 
4.1 to 4.5 
Section 
Listings 
ICH Listings 
1 to 50 
Other Listings 
51 to 71 
13.11.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 12: Example Mock Shells for Data Displays. 
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.’ 
13.11.3. 
Deliverables 
Delivery  
Description 
IA 
Interim Analysis 
RP2D 
Recommended Phase 2 Dose Analysis 
SAC 
Final Statistical Analysis Complete for Phase I 
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13.11.4. 
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 
 
RP2D, SAC 
1.2. 
 All 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen 
Failure 
 
SAC 
1.3. 
 All Treated 
SD4 
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment 
Order the Reasons as 
displayed in the eCRF; present 
treatment status and reasons 
separately for GSK525762, 
fulvestrant, and overall within 
the same table. 
IA, RP2D, SAC 
Populations Analysed 
1.4. 
 All 
Screened 
SP1 
Summary of Study Population 
 
IA, RP2D, SAC 
Protocol Deviations 
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1.5. 
 All Treated 
DV1 
Summary of Major Protocol Deviations 
 
RP2D, SAC 
Demographic and Baseline Characteristics 
1.6. 
 All Treated 
DM1 
Summary of Demographic Characteristics 
 
IA, RP2D, SAC 
1.7. 
 All Treated 
DM6 
Summary of Race and Racial Combinations 
 
RP2D, SAC 
1.8. 
 All Treated 
DM11 
Summary of Age Ranges 
 
RP2D, SAC 
1.9. 
 All Treated 
PS1A 
Summary of ECOG Performance Status at Baseline 
Only include baseline visit 
from standard. 
RP2D, SAC 
1.10.  All Treated 
LA1 
Summary of Disease Burden at Baseline 
 
RP2D, SAC 
1.11.  All Treated 
DC1 
Summary of Disease Characteristics at Initial Diagnosis 
 
IA, RP2D, SAC 
1.12.  All Treated 
DC2 
Summary of Disease Characteristics at Screening 
 
IA, RP2D, SAC 
1.13.  All Treated 
MD1 
Summary of Metastatic Disease at Screening 
 
RP2D, SAC 
Prior and Concomitant Medications 
1.14.  All Treated 
MH1 
Summary of Past Medical Conditions 
 
RP2D, SAC 
1.15.  All Treated 
MH1 
Summary of Current Medical Conditions 
 
RP2D, SAC 
1.16.  All Treated 
OSP1 
Summary of Prior Cancer-Related Surgical Procedures 
 
RP2D, SAC 
1.17.  All Treated 
OSP1 
Summary of On-Treatment Cancer-Related Surgical 
Procedures 
 
RP2D, SAC 
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13.11.5. 
Efficacy Tables 
1.18.  All Treated 
CM8 
Summary of Concomitant Medication by Ingredient 
Medications to be sorted in 
descending order of overall 
incidence. 
RP2D, SAC 
Anti-Cancer Therapies 
1.19.  All Treated 
AC1 
Summary of Prior Anti-Cancer Therapy 
Present all therapies (including 
radiotherapies). 
IA, RP2D, SAC 
1.20.  All Treated 
CM1 
Summary of Prior Dictionary Coded Anti-Cancer 
Therapy 
 
RP2D, SAC 
1.21.  All Treated 
AC3 
Summary of Number of Anti-Cancer Therapy 
Regimens 
 
RP2D, SAC 
1.22.  All Treated  AC4 
Summary of Best Response to Prior Anti-Cancer 
Therapy 
 
RP2D, SAC 
Efficacy: Tables 
No. 
Population 
IDSL / TST ID 
/ Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Overall Response Rate 
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13.11.6. 
Efficacy Figures 
2.1. 
Modified All 
Treated 
RE1a 
Summary of Investigator Assessed Best 
Response (RECIST v1.1 Criteria) 
Show all categories of BOR, 
including CR and PR each split 
up into confirmed and 
unconfirmed. Categories would  
then include: CR confirmed, CR, 
unconfirmed, PR confirmed, PR 
unconfirmed, SD, PD, and NE. 
Also, include ORR and DCR (as 
defined in this RAP). 
IA, SAC 
Secondary Endpoints 
2.2. 
Modified All 
Treated 
TTE6 
Summary of Duration of Response 
 
RP2D, SAC 
2.3. 
Modified All 
Treated 
TTE6 
Summary of Progression-Free Survival 
Produce only if data warrant. 
RP2D, SAC 
Efficacy: Figures 
No. 
Population IDSL / TST ID 
/ Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.1. 
 Modified 
All Treated 
RE8A 
Waterfall Plot of Maximum Percent Reduction 
from Baseline in Tumour Measurement (Target 
Lesions) 
The plot will be color-coded for 
best overall response with 
confirmation. Indication of the 
subject number and dose and 
cohort will be provided below the 
IA, RP2D, 
SAC 
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13.11.7. 
Safety Tables 
plot. Max percent reduction will 
be based on target lesions. 
2.2. 
 Modified 
All Treated 
Non-Standard 1 
Spider Plot of Percent Change from Baseline in 
Target Lesion Diameter 
 
IA, RP2D, 
SAC 
2.3. 
 Modified 
All Treated 
TTE10 
Kaplan-Meier Plot of Progression-Free Survival  
 
RP2D, 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 
In OEX1, the time on study 
treatment categories can be 
modified if necessary. 
IA, RP2D, SAC 
3.2. 
All Treated 
OEX5 
Summary of Exposure to Fulvestrant 
In OEX5, the categories of number 
of subjects who received a given 
number of cycles can be modified if 
necessary. 
IA, RP2D, SAC 
3.3. 
All Treated 
ODMOD1 
Summary of Dose Delays/Interruptions of 
GSK525762 
This may be replaced by a listing if 
minimal data available. 
RP2D, SAC 
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3.4. 
All Treated 
ODMOD1 
Summary of Dose Reductions of GSK525762 
This may be replaced by a listing if 
minimal data available. 
RP2D, SAC 
3.5. 
All Treated 
ODMOD8 
Summary of Dose Escalations of GSK525762 
This may be replaced by a listing if 
minimal data available. 
RP2D, SAC 
3.6. 
All Treated 
ODMOD3 
Summary of Dose Delays/Interruptions of 
Fulvestrant 
 
RP2D, SAC 
3.7. 
All Treated 
ODMOD1 
Summary of Dose Reductions of Fulvestrant 
 
RP2D, SAC 
3.8. 
All Treated 
ODMOD4 
Summary of Missed Doses of Fulvestrant 
 
RP2D, SAC 
3.9. 
All Treated 
AE19 
Summary of Dose-Limiting Toxicities during 
the Determinative Period 
 
RP2D, SAC 
Adverse Events 
3.10. All Treated 
AE13 
Adverse Event Overview 
 
IA, SAC 
3.11. All Treated 
AE16 
Summary of All Adverse Events by System 
Organ Class and Preferred Term 
 
RP2D, SAC 
3.12. All Treated 
AE5B 
Summary of Adverse Events of Special Interest 
Regardless of Relatedness 
 
IA, RP2D, SAC 
3.13. All Treated 
AE5B 
Summary of Adverse Events of Special Interest 
by Maximum Grade Regardless of Relatedness 
 
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3.14. All Treated 
AE5B 
Summary of Drug-Related Adverse Events by 
System Organ Class and Preferred Term and 
Maximum Grade 
Include Any Treatment-Related, 
GSK525762-Related, and 
Fulvestrant-Related in the same 
table, with separate headers and 
starting on separate pages. 
RP2D, SAC 
3.15. All Treated 
AE5B 
Summary of All Adverse Events by System 
Organ Class and Preferred Term and 
Maximum Grade 
 
IA, RP2D, SAC 
3.16. All Treated 
AE13 
Summary of Grade 3-4 Adverse Events 
Overview 
 
RP2D, SAC 
3.17. All Treated 
AE3 
Summary of Drug-Related Adverse Events by 
Maximum Grade 3-4 
Include Total Column. 
Include Any Treatment-Related, 
GSK525762-Related, and 
Fulvestrant-Related in the same 
table, with separate headers and 
starting on separate pages. 
RP2D, SAC 
3.18. All Treated 
AE3 
Summary of Adverse Events Leading to 
Permanent Discontinuation of Study Treatment  
Include Any Treatment, 
GSK525762, and Fulvestrant in the 
same table, with separate headers 
and starting on separate pages. 
IA, RP2D, SAC 
3.19. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Reductions in Study Treatment 
Include Any Treatment, 
GSK525762, and Fulvestrant in the 
same table, with separate headers 
and starting on separate pages. 
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3.20. All Treated 
AE3 
Summary of Adverse Events Leading to Dose 
Delays or Interruptions in Study Treatment 
Include Any Treatment, 
GSK525762, and Fulvestrant in the 
same table, with separate headers 
and starting on separate pages. 
IA, RP2D, SAC 
3.21. All Treated 
AE15 
Summary of Common (>=5%) Non-serious 
Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and 
Occurrences) 
 
RP2D, SAC 
3.22. All Treated 
AE16 
Summary of Serious Adverse Events by 
System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
RP2D, SAC 
3.23. All Treated 
AE3 
Summary of Drug-Related Serious Adverse 
Events 
Include Any Treatment-Related, 
GSK525762-Related, and 
Fulvestrant-Related in the same 
table. Page by these categories with 
header description in top left-hand 
corner. 
IA, RP2D, SAC 
3.24. All Treated 
AE20 
Summary of Drug-Related Non-Fatal Serious 
Adverse Events 
Include Any Treatment-Related, 
GSK525762-Related, and 
Fulvestrant-Related in the same 
table. Page by these categories with 
header description in top left-hand 
corner. 
RP2D, SAC 
3.25. All Treated 
AE3 
Summary of Adverse Events Classified as 
Dose-Limiting Toxicities (DLTs) 
 
RP2D, SAC 
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3.26. All Treated 
ESI1 
Summary of Characteristics of Adverse Events 
of Special Interest 
This table will be presented 
individually for each category of 
AESI. 
SAC 
3.27. All Treated 
ESI2b 
Summary of Onset and Duration of the First 
Occurrence of Adverse Events of Special 
Interest 
This table will be presented 
individually for each category of 
AESI. 
SAC 
3.28. All Treated 
DD1 
Summary of Deaths 
 
RP2D, SAC 
Laboratory: Chemistry 
3.29. All Treated 
LB1 
Summary of Chemistry Changes from Baseline 
 
SAC 
3.30. All Treated 
LB18 
Summary of Chemistry Grade Changes from 
Baseline 
For lab tests that are graded, include 
worst-case changes. 
RP2D, SAC 
3.31. All Treated 
LB3 
Summary of Chemistry Changes from Baseline 
with Respect to the Normal Range 
For lab tests that are graded, include 
worst-case changes. 
RP2D, SAC 
Laboratory: Haematology 
3.32. All Treated 
LB1 
Summary of Haematology Changes from 
Baseline 
 
SAC 
3.33. All Treated 
LB18 
Summary of Haematology Grade Changes 
from Baseline 
For lab tests that are graded. 
RP2D, SAC 
3.34. All Treated 
LB3 
Summary of Haematology Changes from 
Baseline with Respect to the Normal Range 
For lab tests that are graded. 
RP2D, SAC 
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Laboratory: Liver Events 
3.35. All Treated 
LIVER1 
Summary of Liver Monitoring/Stopping Event 
Reporting 
 
SAC 
3.36. All Treated 
LIVER10 
Summary of Hepatobiliary Laboratory 
Abnormalities Including Possible Hy’s Law 
Cases 
Summarize by ascending dose level 
and total. 
Possible Hy’s law cases will be 
defined as any event of either: (a) 
ALT ≥3 × the upper limit of normal 
(ULN) and bilirubin ≥2 × ULN 
(>35% direct bilirubin) or (b) ALT 
≥3 × ULN and INR >1.5, if INR is 
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. 
SAC 
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Urinalysis 
3.37. All Treated 
UR1 
Summary of Worst-Case Urinalysis Result 
Increases from Baseline 
Include tests done by Dipstick – 
Specific gravity, pH, Glucose, 
Protein, Blood, Ketones. 
RP2D, SAC 
3.38. All Treated 
LB18 
Summary of Urinalysis Grade Changes from 
Baseline 
For lab tests that are graded. 
RP2D, SAC 
Coagulation 
3.39. All Treated 
LB3 
Summary of Coagulation Changes from 
Baseline with Respect to Normal Range 
 
SAC 
Vital Signs 
3.40. All Treated 
VS1 
Summary of Vital Signs 
Include all parameters (heart rate, 
diastolic blood pressure, systolic 
blood pressure, respiratory rate, and 
temperature). 
RP2D, SAC 
3.41. All Treated 
VS1 
Summary of Vital Sign Changes from Baseline 
Again, show changes from baseline 
for all parameters (heart rate, 
diastolic blood pressure, systolic 
blood pressure, respiratory rate, and 
temperature). 
RP2D, SAC 
ECG 
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3.42. All Treated 
EG1 
Summary of ECG Findings 
 
RP2D, SAC 
3.43. All Treated 
EG2 
Summary of Change from Baseline in ECG 
Values 
 
RP2D, SAC 
3.44. All Treated 
EG10A 
Summary of Maximum QTcF Value Post-
Baseline Relative to Baseline 
Include QTcF > 500 msec. 
Include footnote for baseline 
definition. 
Specify the data source in the title 
(i.e., local read vs. central read). 
Also, add footnote: “Only the post-
baseline assessments that used the 
same source as the baseline 
assessment (i.e., local or central 
cardiologist read) are used to derive 
change from baseline.” 
RP2D, SAC 
3.45. All Treated 
EG11A 
Summary of Maximum Increase in QTcF 
Values Post-Baseline Relative to Baseline 
Include QTcF > 500 msec. 
Include footnote for baseline 
definition. 
Specify the data source in the title 
(i.e., local read vs. central read). 
Also, add footnote: “Only the post-
baseline assessments that used the 
same source as the baseline 
assessment (i.e., local or central 
RP2D, SAC 
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cardiologist read) are used to derive 
change from baseline.” 
Performance Status 
3.46. All treated 
PS1A 
Summary of ECOG Performance Status 
 
RP2D, SAC 
3.47. All treated 
PS3A 
Summary of Change in ECOG Performance 
Status from Baseline 
 
RP2D, SAC 
Left Ventricular Ejection Fraction 
3.48. All Treated 
OLVEF1A 
Summary of Change from Baseline in Left 
Ventricular Ejection Fraction 
 
RP2D, SAC 
Value Evidence and Outcomes 
3.49. All Treated 
SF4_NS2 
Summary of and Change from Baseline in 
EORTC-QLQ-C30 
 
SAC 
3.50. All Treated 
SF4_NS2 
Summary of and Change from Baseline in 
QLQ-BR23 
 
SAC 
3.51. All Treated 
SF4_NS2 
Summary of and Change from Baseline in 
PRO-CTCAE 
 
SAC 
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13.11.8. 
Pharmacokinetic Tables 
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 Dose Level and 
Cohort 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL  
RP2D, SAC 
4.2. 
PK 
PK01 
Summary of GSK3529246 Pharmacokinetic 
Concentration-Time Data by Dose Level and 
Cohort 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
concentrations in ng/mL 
RP2D, SAC 
4.3. 
PK 
PK01 
Summary of Total Active Moiety of GSK525762 
Pharmacokinetic Concentration-Time Data by 
Dose Level and Cohort 
Use descriptive statistics (n, mean, 
SD, median, min and max) by 
planned relative assessment time; 
TAM concentration in nM 
RP2D, SAC 
4.4. 
PK 
PK01 
Summary of Fulvestrant Pharmacokinetic 
Concentration-Time Data by Dose Level and 
Cohort 
Summary presented only for pre-
dose as fulvestrant samples are 
collected only at pre-dose; use 
descriptive statistics (n, mean, SD, 
median, min and max) by planned 
relative assessment time; 
concentrations in ng/mL 
RP2D, SAC 
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Pharmacokinetic Parameters 
4.5. 
PK 
PK06 
Summary of Derived GSK525762 
Pharmacokinetic Parameters  
PK parameters: Cmax, Tmax, Ctrough 
determined from the concentration-
time data in ng/ml and in nM after 
conversion from ng/mL to nM; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable 
RP2D, SAC 
4.6. 
PK 
PK06 
Summary of Derived GSK3529246 
Pharmacokinetic Parameters  
PK parameters: Cmax, Tmax, Ctrough 
determined from the concentration-
time data in ng/ml and in nM after 
conversion from ng/mL to nM; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable 
RP2D, SAC 
4.7. 
PK 
PK06 
Summary of Derived Total Active Moiety of 
GSK525762 Pharmacokinetic Parameters  
PK parameters: Cmax, Tmax, Ctrough 
determined from the concentration-
time data after conversion from 
ng/mL to nM; descriptive 
summaries: mean, SD, median, min, 
max, geometric mean & SD, CV%, 
and 95%CI of log-transformed 
parameters, if applicable 
SAC 
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13.11.9. 
Pharmacokinetic figures 
4.8. 
PK 
PK06 
Summary of Derived Fulvestrant 
Pharmacokinetic Parameters  
PK parameters: Cmax, Tmax, Ctrough 
determined from the concentration-
time data in ng/ml and in nM after 
conversion from ng/mL to nM; 
descriptive summaries: mean, SD, 
median, min, max, geometric mean 
& SD, CV%, and 95%CI of log-
transformed parameters, if 
applicable 
RP2D, SAC 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / TST ID 
/ Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Drug Concentration Measure 
4.1. 
PK 
PK17 
Overlay of Mean GSK525762 (nM), Mean 
GSK3529246 (nM), and Mean Total Active Moiety of 
GSK525762 (nM) Concentration-Time Curves  
Include both Wk1 and Wk3 
(on separate plots within the 
panel) and, for each, show 
both linear and semi-log 
curves.  
SAC 
4.2. 
PK 
PK18 
Overlay of Median GSK525762 (nM), Median 
GSK3529246 (nM), and Median Total Active Moiety of 
GSK525762 (nM) Concentration-Time Curves 
Include both Wk1 and Wk3 
(on separate plots within the 
panel) and, for each, show 
both linear and semi-log 
curves.  
SAC 
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13.11.10. 
ICH Listings 
4.3. 
PK 
PK16 
GSK525762 (ng/mL) Concentration-Time Curves by 
Dose Level/Cohort and Week  
Overlay the curves for the 
different dose level/cohorts 
on the same plot but show 
separate plots within the 
panel for Wk 1 and Wk 3; 
concentration in ng/mL. 
SAC 
4.4. 
PK 
PK16 
GSK3529246 (ng/mL) Concentration-Time Curves by 
Dose Level/Cohort and Week  
Overlay the curves for the 
different dose level/cohorts 
on the same plot but show 
separate plots within the 
panel for Wk 1 and Wk 3; 
concentration in ng/mL. 
SAC 
4.5. 
PK 
PK16 
Total Active Moiety of GSK525762 (nM) 
Concentration-Time Curves by Dose Level/Cohort and 
Week  
Overlay the curves for the 
different dose level/cohorts 
on the same plot but show 
separate plots within the 
panel for Wk 1 and Wk 3; 
concentration in nM. 
SAC 
ICH: Listings 
No. 
Population 
IDSL / TST ID 
/ Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
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1. 
All Treated 
ES2 
Listing of Reasons for Subject Withdrawal 
 
RP2D, SAC 
2. 
All Screened 
ES7 
Listing of Reasons for Screen Failure 
 
SAC 
3. 
All Treated 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
 
RP2D, SAC 
Populations Analysed 
4. 
All Screened 
SP3 
Listing of Subjects Excluded from Any population 
 
RP2D, SAC 
Protocol Deviations 
5. 
All Treated 
DV2 
Listing of Protocol Deviations 
 
RP2D, SAC 
6. 
All Treated 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
 
SAC 
Baseline and Disease Characteristics 
7. 
All Treated 
DM2 
Listing of Demographic Characteristics 
 
RP2D, SAC 
8. 
All Treated 
DM9 
Listing of Race 
 
RP2D, SAC 
Treatment Exposure 
9. 
All Treated 
TA1 
Listing of Planned and Actual Treatments 
 
RP2D, SAC 
10. 
All Treated 
COMP3C 
Listing of GSK525762 Drug Accountability 
 
RP2D, SAC 
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11. 
All Treated 
OEX3a 
Listing of Exposure Data to GSK525762 
 
RP2D, SAC 
12. 
All Treated 
OEX8B 
Listing of Exposure Data to Fulvestrant 
 
RP2D, SAC 
13. 
All Treated 
ODMOD10A 
Listing of Dose Reductions for GSK525762 
 
RP2D, SAC 
14. 
All Treated 
ODMOD10A 
Listing of Dose Reductions for Fulvestrant 
 
SAC 
15. 
All Treated 
ODMOD11A 
Listing of Dose Interruptions/Delays for GSK525762 
 
RP2D, SAC 
16. 
All Treated 
ODMOD11A 
Listing of Dose Interruptions/Delays for Fulvestrant 
 
RP2D, SAC 
17. 
All Treated 
ODMOD11A 
Listing of Missed Doses for Fulvestrant 
 
RP2D, SAC 
18. 
All Treated 
ODMOD15A 
Listing of Dose Escalations for GSK525762 
 
RP2D, SAC 
Adverse Events 
19. 
All Treated 
OAE04 
Listing of All Adverse Events 
 
RP2D, SAC 
20. 
All Treated 
OAE03 
Listing of Subject Numbers for Individual Adverse 
Events 
 
RP2D, SAC 
21. 
All Treated 
OAE04 
Listing of Dose-Limiting Adverse Events 
 
RP2D, SAC 
22. 
All Treated 
AE2 
Listing of Relationship Between Adverse Event System 
Organ Class, Preferred Term and Verbatim Text 
 
SAC 
Serious and Other Significant Adverse Events 
23. 
All Treated 
OAE04 
Listing of Fatal Serious Adverse Events 
 
RP2D, SAC 
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24. 
All Treated 
OAE04 
Listing of Non-Fatal Serious Adverse Events 
 
RP2D, SAC 
25. 
All Treated 
OAE04 
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment 
Based on Action taken 
question on AE/SAE. 
RP2D, SAC 
26. 
All Treated 
OAE04 
Listing of Adverse Events Leading to Dose Reductions 
for any Study Drug 
 
RP2D, SAC 
27. 
All Treated 
OAE04 
Listing of Adverse Events Leading to Dose 
Interruptions/Delays for any Study Drug 
 
RP2D, SAC 
28. 
All Treated 
AE14 
Listing of Reasons for Considering as a Serious Adverse 
Event 
 
SAC 
29. 
All Treated 
OAE04 
Listing of Adverse Events of Special Interest 
 
SAC 
Dose-Limiting Toxicity 
30. 
All Treated 
DL3 
Listing of Dose-Limiting Toxicities during the 
Determinative Period 
 
RP2D, SAC 
Laboratory 
31. 
All Treated 
LB13 
Listing of Chemistry Laboratory Data for Subjects with 
Lab Values Outside of Normal Range 
 
SAC 
32. 
All Treated 
LB13 
Listing of Haematology Laboratory Data  for Subjects 
with Lab Values Outside of Normal Range 
 
SAC 
33. 
All Treated 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
 
SAC 
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34. 
All Treated 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline 
 
SAC 
35. 
All Treated 
UR2A 
Listing of Urinalysis Data for Subjects with Any Value 
of Potential Clinical Importance 
 
RP2D, SAC 
36. 
All Treated 
LB13 
Listing of Coagulation and Other Laboratory data  
 
SAC 
37. 
All Treated 
OLB7 
Listing of Coagulation and Other Laboratory Data for 
Subjects with Lab Values Outside of Normal Range 
 
SAC 
38. 
All Treated 
LB14 
Listing of Laboratory Data with Character Results 
 
SAC 
Pharmacokinetic  
39. 
PK 
PK07 
Listing of GSK525762 Pharmacokinetic Concentration-
Time Data by dose level and population 
In ng/mL and nM. 
RP2D, SAC 
40. 
PK 
PK07 
Listing of GSK3529246 Pharmacokinetic 
Concentration-Time Data by dose level and population  
In ng/mL and nM. 
SAC 
41. 
PK 
PK07 
Listing of Total Active Moiety of GSK525762 
Pharmacokinetic Concentration-Time Data by dose level 
and population 
In nM. 
SAC 
42. 
PK 
PK07 
Listing of Fulvestrant Pharmacokinetic Concentration-
Time Data by dose level and population 
In ng/mL. 
SAC 
43. 
PK 
PK13 
Listing of Derived GSK525762 (nM) Pharmacokinetic 
Parameters  
Cmax, Tmax, Ctrough, 
determined from 
RP2D, SAC 
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concentration (ng/mL) -
time data. 
44. 
PK 
PK13 
Listing of Derived GSK3529246 (nM) Pharmacokinetic 
Parameters 
Cmax, Tmax, Ctrough, 
determined from 
concentration (ng/mL) -
time data. 
SAC 
45. 
PK 
PK13 
Listing of Derived Total Active Moiety of GSK525762 
(nM) Pharmacokinetic Parameters 
Cmax, Tmax, Ctrough, 
determined from 
concentration (nM) - time 
data. 
SAC 
Efficacy 
46. 
All Evaluable 
RE12 
Listing of Subject Best Response for Interim Review by 
First Dose Date 
Sort by date of first dose. 
IA 
47. 
Modified All 
Treated 
LA2 
Listing of Investigator-Assessed Target Lesions 
(RECIST v1.1 Criteria) 
 
RP2D, SAC 
48. 
Modified All 
Treated 
LA3 
Listing of Investigator-Assessed Non-Target Lesions 
(RECIST v1.1 Criteria) 
 
RP2D, SAC 
49. 
Modified All 
Treated 
LA4 
Listing of Investigator-Assessed New Lesions (RECIST 
v1.1 Criteria) 
 
RP2D, SAC 
50. 
Modified All 
Treated 
RE5 
Listing of Investigator-Assessed Best Overall Responses 
(RECIST v1.1)  
 
RP2D, SAC 
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13.11.11. 
 Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Demographic and Baseline Characteristics 
51. 
All Treated 
SU2 
Listing of Substance Use 
 
SAC 
52. 
All Treated 
DC3 
Listing of Disease Characteristics at Initial Diagnosis 
 
RP2D, SAC 
53. 
All Treated 
DC4 
Listing of Disease Characteristics at Screening 
 
RP2D, SAC 
54. 
All Treated 
MD2 
Listing of Metastatic Disease at Screening 
 
RP2D, SAC 
Prior and Concomitant Medication 
55. 
All Treated 
MH2 
Listing of Medical Conditions 
Include Prior and Current, with 
Status column indicating same. 
RP2D, SAC 
56. 
All Treated 
CM2 
Listing of Concomitant Medications 
 
SAC 
57. 
All Treated 
BP4 
Listing of Blood Products or Blood Supportive Care 
Products 
Include Prior (BP4) and On-
Treatment (BP5). 
SAC 
58. 
All Treated 
OSP3 
Listing of Surgical Procedures 
Include Prior and On-
Treatment. 
SAC 
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59. 
All Treated 
AE2 
Listing of Relationship Between ATC Level1, 
Ingredient and Verbatim Text 
 
SAC 
Anti-Cancer Therapy 
60. 
All Treated 
AC6 
Listing of All Anti-Cancer Therapy 
Including Prior and Subsequent. 
RP2D, SAC 
61. 
All Treated 
AC7 
Listing of Anti-Cancer Radiotherapy 
Including Prior and Subsequent. 
RP2D, SAC 
ECG 
62. 
All Treated 
EG5 
Listing of All ECG Findings for Subjects with an 
Abnormal Finding 
 
RP2D, SAC 
63. 
All Treated 
EG3 
Listing of ECG Values for Subjects with Abnormal 
Values 
 
RP2D, SAC 
64. 
All Treated 
EG3 
Listing of QTcF Values of Potential Clinical 
Importance 
 
SAC 
Vital Signs 
65. 
All Treated 
VS4 
Listing of Vital Signs 
 
SAC 
66. 
All Treated 
OVT7A 
Listing of Vital Signs with Abnormal Values 
 
RP2D, SAC 
LVEF 
67. 
All Treated 
OLVEF2A 
Listing of Left Ventricular Ejection Fraction Results 
 
RP2D, SAC 
Laboratory 
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68. 
All Treated 
OLB13 
Listing of Laboratory Data with Character Results 
 
SAC 
Value Evidence and Outcomes 
69. 
Modified 
All Treated 
SF6 
Listing of EORTC-QLQ-C30 Results 
 
SAC 
70. 
Modified 
All Treated 
SF6 
Listing of EORTC-QLQ-BR23 Results 
 
SAC 
71. 
Modified 
All Treated 
SF6 
Listing of PRO-CTCAE Results 
 
SAC 
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13.12. Appendix 12: Example Mock Shells for Data Displays 
Example Non-Standard 1                                   
Protocol: 201973                                                                            Page 1 of 1 
Population: Modified All Treated                                                          (Data as of: 30MAY2013) 
 
Figure 1 
Spider Plot of Percent Change from Baseline In Target Lesion Diameter 
 
 
 
 
                                                 
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PPD
PPD
PPD
PPD
PPD
PPD